APRIL 2011 VOL 2 NO 2

Preparing for Future Trendsin Cancer Care Impact of survivorship, technology on care deliveryBy Daniel Denvir

Prominent Oncologist ApplaudsFirst Conference of AVBCC Stakeholder Integration Crucial for Personalized Medicine Interview with Al B. Benson, III, MD, FACPProfessor of Medicine and Associate Director for Clinical Investigations, RobertH. Lurie Comprehensive Cancer Center, Northwestern University; ImmediatePast President, ACCC; and Immediate Past Chair, Board of Directors, NCCN

NCCN Expert Panel ConsidersValue, Utilization of MolecularTesting in Clinical PracticeWill ultimately reduce costs, toxicities from inappropriatetreatments By Audrey Andrews

©2011 Engage Healthcare Communications, LLC

On March 29-30, 2011, approxi-mately 200 oncologists, pay-ers, managed care executives,

and drug manufacturers gathered inPhiladelphia for the First AnnualConference of the Association forValue-Based Cancer Care. VBCC askedDr Benson to share his thoughts on theconference and some of the issues itprovoked.

Q: From your vantage point at thetop of academic, clinical, and researchexpertise in oncology, did you find thisconference of benefit? Did the meetingprovide value to the variety of health-care stakeholders attending it, includ-ing community oncologists, payers,and manufacturers?

Dr Benson: Absolutely. There is ageneral concern in healthcare thatinstead of encouraging people to worktogether to discuss these very seriousissues in healthcare delivery, there areefforts to force people to distancethemselves, particularly from industry,and work in silos, which is not in thepublic’s interest. We need a very trans-parent process that allows people tounderstand these various associationsbut also to understand that solving somany complex healthcare issues willtake everybody working together. The fact that we are having a forum

with this conference, where cliniciansand third-party carriers are discussingissues together, where the pharmaceu-tical industry and the diagnostic indus-

www.ValueBasedCancerCare.com

Washington, DC—Oncologists mustplan for and invest in future trends andexpected growth using available evi-dence-based information, said RebeccaBooi, PhD, Director of Cancer Solutionsat Sg2, during the 2011 Associationof Community Cancer Centers 37thAnnual National Meeting.

The boom in cancer survivors,already near 12 million today, will be acrucial factor in reshaping the face ofcancer care. The survivorship popula-tion is expected to grow by 80% overthe next decade, as cancer treatmentsimprove and the baby boomers age

Hollywood, FL—The number of mole -cular tests to assess the potential effica-cy of cancer therapies for an individualpatient is rapidly increasing, but theirvalue and validity in cancer careremain controversial. An expert panelat the 2011 National ComprehensiveCancer Network (NCCN) AnnualConference discussed how to regulatethe tests done, the need for better datato determine their value and cost-effec-tiveness, as well as new approaches tooptimal uses. Lee Newcomer, MD, MHA, Senior

Vice President of Oncology Services atUnitedHealthcare, framed the discus-sion, noting that “evidence” for a goodassay comprises 3 points:

• Analytic validity:Do you get the sameresult 99 times out of 100?

• Clinical validity: Is what you’re meas-uring going to result in a validchange?

Continued on page 18

Continued on page 8


APRIL 2011 VOL 2 NO 2

VALUE PROPOSITIONS

Value of vitamin D in cancer prevention . . . . . . . . . . . . . . . . . . . . . . . . . . 3MEETING COVERAGE

NCCN annual conference . . . . . . . . . 8ACCC annual meeting . . . . . . . . . . . 17Genitourinary cancers symposium . . . . . . . . . . . . . . . . . . . . . . 25HOPA annual meeting . . . . . . . . . . . 38Gastrointestinal cancers symposium . . . . . . . . . . . . . . . . . . . . . . 48

VBCC PERSPECTIVE

The potential of personalized medicine for targeted therapies . 28HEALTH POLICY

Implications of CMS’s decision on Provenge . . . . . . . . . . . 28ODAC on the accelerated approvals process . . . . . . . . . . . . . . . 30BEST PRACTICES

The value of EHRs for leading oncology networks . . . . . . . . . . . . . . 36

I N S I D E

AVBCC Conference | March 29-30 | Philadelphia

Full Coverage of the First Annual Conference of the Association for Value-Based Cancer Care Coming in July

FDA UPDATES

3VOL. 2 NO. 2 www.ValueBasedCancerCare.com I

FDA Approved First GenericDocetaxelThe US Food and Drug Admin -

istration (FDA) approved docetaxelinjection (Hospira)—the first genericformulation of Taxotere (sanofi-aven-tis). Generic docetaxel is already avail-able in Europe and Australia.Docetaxel, an antineoplastic chemo -

therapy medication, is indicated for

the treatment of several cancers at dif-ferent stages, including metastatic andadjuvant breast cancer; metastaticandrogen-independent prostate cancer;advanced non–small-cell lung cancer;advanced gastric adenocarcinoma;and locally advanced squamous-cellcarcinoma of the head and neck.Unlike the original brand-name

drug, which requires a 2-step prepara-

tion method, the new generic formula-tion comes in a single-vial formula-tion. According to Thomas Moore,Hospira president, in addition to thepotential cost-savings, another valu-able feature of the generic formulationis its “differentiated delivery system,designed to enhance caregiver safety.”Docetaxel will be available in 20-mg,

80-mg, and 160-mg vials at the origi-

nal 10-mg/mL concentration. (March9, 2011)

Ipilimumab a Powerful NewTargeted Drug for AdvancedMelanomaApplying its priority review route,

the FDA approved the biologic med-ication ipilimumab (Yervoy; Bristol-Myers Squibb) as a second-line thera-py for the treatment of advancedmelanoma. Ipilimumab is the firstdrug that has shown improved overallsurvival (OS) in late-stage disease, andis the first drug approved for thispatient population in the past 13 years. This new targeted therapy repre-

sents a new class of drug, known as atargeted T-cell antibody. It works byblocking cytotoxic T-lymphocyte–asso-ciated antigen 4, which enhances anti-tumor T-cell response. In 2010, an estimated 68,130 new

cases of melanoma were diagnosed inthe United States, resulting in approx-imately 8700 deaths, according to theNational Cancer Institute. Late-stagemelanoma has very few treatmentoptions, and none has so far shownimproved OS. Ipilimumab “is the first therapy

approved by the FDA to clearly de m -onstrate that patients with metastaticmelanoma live longer by taking thistreatment,” said Richard Pazdur, MD,Director of the Office of OncologyDrug Products in the FDA’s Center forDrug Evaluation and Research. The pivotal study (study 020) was

conducted in previously treated unre-sectable patients with stage III or stageIV melanoma. Patients receiving thecombination of ipilimumab and a pep-tide vaccine had a median survival of10 months compared with 6.4 monthswith the vaccine alone. Ongoing follow-up of patients who

received ipilimumab shows that com-plete responses can continue for >6 yearsin some patients. However, only 10.9%of the patients receiving ipilimumab(N = 676) showed complete or partialresponse, as with other targeted thera-pies, which work on subsets of patients.A new study (study 024) has now

shown that ipilimumab is also effec-tive in previously untreated pa tientswith metastatic melanoma. In thisstudy, ipilimumab chemotherapy(dacarbazine) im proved OS comparedwith chemo therapy alone.Ipilimumab is associated with severe

adverse events, which may requireimmunosuppressive therapy withsteroids. Because of the potential forlife-threatening complications, patientsreceiving this drug may require a mul-tidisciplinary team to manage them. The common adverse effects associ-

ated with ipilimumab include fatigue,Continued on page 4

VALUE PROPOSITIONS

IOM Questions Value of Vitamin D inCancer Prevention Many reports have suggested the potential benefit of

vitamin D in cancer prevention. Now the Institute ofMedicine (IOM) has issued a statement (online, March23, 2011, N Engl J Med) questioning the causalitybetween vitamin D and cancer. Lead author JoAnn Manson, MD, DrPH, Brigham and

Women’s Hospital, Harvard Medical School, said, “Giventhat the potential role of vitamin D in cancer preventionhas been widely touted, many people were surprised thatcancer-related considerations didn’t figure prominently”in the recent IOM report on vitamin D and overall health.A careful review of the “evidence regarding vitamin D’srole in preventing cancer, however, revealed that theresearch is inconsistent and doesn't establish a cause–effect relationship,” according to the IOM. It is important to remember that no large-scale ran-

domized clinical trials have yet investigated this link,and therefore a negative conclusion regarding the poten-tial link between vitamin D and cancer prevention is justas premature as a positive conclusion. It has takenresearchers years to acknowledge the benefits of vitaminD for overall well-being. Large trials investigating theassociation between vitamin D and cancer are ongoing,but results will not be available for another 5 or 6 years.

New Assay for Tumor Stem CellsPotential Game ChangerA new editorial published in the Journal of Clinical

Oncology (Wicha MS, et al, March 21, 2011) highlightsthe potential benefits of a new assay for measuring cir-culating tumor cells (CTCs) in the bloodstream ofpatients with cancer. This assay uses genetic markers toidentify cancer cells, including stem-like cells. Cancerstem cells are the cells with the “greatest invasive andmetastatic capacity” within the tumor, according to theeditorialists. The most widely used assay in the United States for

identifying CTCs, CellSearch, has limited utilitybecause of “low sensitivity and poor specificity,” Wichaand colleagues write. A report of a new investigational assay published in

the same issue of the journal does “establish the highlyreproducible analytic validity of this assay in patientswith colorectal cancers,” say Wicha and colleagues. Thisassay, they add, “could have enormous utility for direct-ing adjuvant therapy for patients with this disease.”

Academic Institutions Join OncologyDrug Development A new spirit of collaboration between manufacturers

and academic centers suggests the high value seen byall in pursuing research and development (R&D) inoncology.

• Yale Medical School and Gilead Sciences. GileadSciences, which until now focused much of its efforts ondrugs for HIV/AIDS, has recently announced it hasjoined the search for the Holy Grail in cancer therapies.According to a report in the Wall Street Journal (April 1,2011), Gilead has contracted with Yale University Schoolof Medicine to focus on new cancer drugs. Gilead willpay Yale Medical School $40 million to apply itsresearch expertise in cancer and genomic medicinebased in its Cancer Biology Institute to develop newoncolytics over a 4-year period. If successful, this effortcould be extended to 10 years, to the tune of $100 mil-lion. The explosion in new targeted therapies for cancerthat are currently in development (see article on colorec-tal cancer therapies, page 49, this issue) is clearly driv-ing this new venture, which will make use of some ofthe best research and clinical expertise in the country toadvance the future cancer therapies.

• Nuclea Biotech and Boston Medical Center focuson diagnostics for prostate/breast cancer. A new prom-ising partnership between biomarker pioneer NucleaBiotechnologies and Boston Medical Center (BMC), oneof Boston’s leading teaching hospitals, is a new collabo-rative effort to advance personalized medicine forprostate cancer. According to Drug Discovery News(2011[7]; www.drugdiscoverynews.com/index.php?newsarticle=4679), Nuclea will pay BMC almost $1.5million in the next 3 years to support R&D for newgenetic diagnostics and radiologic modalities for early-stage tumors. The value in this collaboration is theready access each company brings to the tools andknowledge of each partner to enhance this researcheffort. “We would like to come up with our first diag-nostic test within a year,” said Patrick Muraca, Nuclea’spresident and CEO. “The new testing modality in geneprotein expression, combined with radiologic testingtools, will help confirm the presence of cancers.”

FROM THE LITERATURE

FDA UPDATES

4 I VALUE-BASED CANCER CARE I April 2011 VOL. 2 I NO. 2

diarrhea, skin rash, endocrine defi-ciencies (gland or hormone), andinflammation of the intestines (colitis).Severe-to-fatal autoimmune reactionswere seen in 12.9% of patients treatedwith ipilimumab. (March 25, 2011)

Peginterferon Alfa-2b forMetastatic Melanoma afterDefinitive Surgical ResectionThe FDA approved peginterferon

alfa-2b (Sylatron; Schering Corpora -tion) for the treatment of patients withmelanoma with microscopic or grossnodal involvement within 84 days ofdefinitive surgical resection, includingcomplete lymphadenectomy.The recommended dose and sched-

ule for Sylatron is 6 µg/kg/week, sub-cutaneously for 8 doses, followed by3 µg/kg/week subcutaneously. Themax i mum treatment period is 5 years.The approval was based on a single,

5-year trial, EORTC 18991, an open-label, multicenter trial with 1256patients. Patients who had been ade-quately surgically resected for theirprimary cutaneous mela noma andaffected regional lymph nodes wererandomized to peginterferon alfa-2bor to 5-year observation. The primary end point, relapse-free

survival (RFS), was defined as the timeto the earliest of local or regional recur-rence, distant metastases, or death.Based on 696 RFS events, an improve-ment in RFS for peginterferon alfa-2b–treated patients was observed. The esti -mated median RFS was 34.8 monthswith the active treatment and 25.5months in the observation arm. After525 deaths during the study, no differ-ence in OS was seen between the 2groups. The most common (>60%) grade 1-4

adverse reactions in the peginterferonalfa-2b group were fatigue, increasedalanine transaminase, increased aspar-tate aminotransferase, pyrexia, head -ache, anorexia, myalgia, nausea, chills,and injection site reactions.A total of 33% of patients receiving

therapy discontinued treatment be -cause of adverse events. (March 29,2011) �

National Projections: 27% Rise in

Cost of Cancer Care in 2020

The constant change in the inci-dence of cancer, the rate of survival,and treatment practices have ledinvestigators to estimate anew the costof cancer care in the United States(which is currently based on 2003 esti-mates). In this new analysis (MariottoAB, et al. J Natl Cancer Inst. 2011;103:1-12), investigators used projections

based on phase of cancer care andtumor sites for 13 cancer types in menand 16 types in women between 2010and 2020. The prevalence rate was based on

Surveillance, Epidemiology, and EndResults (SEER) program data. Netannual costs were estimated fromrecent Medicare-SEER claims through2006. All costs were adjusted to 2010dollars. Sensitivity analysis was used

to assess future trends of cancer ratesand costs.Cancer survivorship numbers are

13.8 million in 2010 compared with18.1 million in 2020; associated costsfor cancer are $124.57 billion in 2010,$157.77 billion in 2020—a 27% increasein costs. The largest increases involvethe continuing phase of care forprostate cancer (42%) and breast can-cer in women (32%). If the costs

increase by 2% in the first year of can-cer care and last year of life, overall2020 cancer costs will total $173 billion,a 39% increase from 2010.The costs for the top 5 cancer types

in 2010 were: • Female breast: $16.50 billion• Colorectal: $14.14 billion• Lymphoma: $12.14 billion• Lung: $12.12 billion• Prostate: $11.85 billion.

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikesPotential consequences of febrile neutropenia may be serious and can impact patient care

First- and every-cycle Neulasta® achieved:

94% reduction in febrile neutropenia

(17% placebo vs 1% Neulasta®; P < 0.001).1,2

93% reduction in febrile neutropenia–

related hospitalization (14% placebo

vs 1% Neulasta®; P < 0.001).1,2

80% reduction in febrile neutropenia–

related IV anti-infective use (10% placebo

vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety InformationDo not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS.

Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebo- treated patients.

Please see brief summary of Neulasta® Prescribing Information on the adjacent page.

* Regimens associated with ≥ 17% risk of febrile neutropenia.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.

© 2010 Amgen. All rights reserved. MC49047-A-1 04-10 www.neulasta.com

Ipilimumab...Continued from page 3


FROM THE LITERATURE

KRAS Mutation PredictsTreatment Outcomes of Anti-EGFR TherapiesMutation in the KRAS gene has been

shown to prevent the benefit of anti-epithelial growth factor receptor (EGFR)therapy in patients with colorectal can-cer (CRC) in previous studies. Ongoingrandomized clinical studies are nowinvestigating whether KRAS testing canhelp predict survival outcomes in

patients with advanced CRC who arereceiving cetuximab (Erbitux) or panitu-mumab (Vectibix) therapy.In a new meta-analysis (Dahabreh IJ,

et al. Ann Intern Med. 2011;154:37-49),45 publications were eligible for analy-sis, representing 24 nonoverlappingstudies. Of these, 4 were reanalyses ofrandomized controlled trials of anti-EGFR therapy compared with bestsupportive care or with chemo therapy

alone, from which no significant bene-fit was found in overall survival (OS)or progression-free survival (PFS) inpatients with KRAS mutations. The 22 studies with nonoverlapping

populations showed a specificity of0.49 (positive likelihood ratio, 7.35)and a sensitivity of 0.93 (negative like-lihood ratio, 0.55).This meta-analysis of patients with

CRC with or without the KRAS muta-

tion who were treated with anti-EGFRtherapy shows that OS is almost 80%longer in those with wild-type KRAS.Furthermore, median PFS or time toprogression was shorter in patientswith KRAS-positive tumors than withthe wild-type KRAS. This high positivity ratio suggests

that KRAS mutations are a strong pre-dictor of reduced survival, diseaseprogression, and treatment failure.This study corroborates the warningon the US Food and Drug Adminis -tration (FDA) labeling that restricts theuse of anti-EGFR antibody therapy topatients with CRC who test negativefor KRAS mutations.

Denosumab a New Option forPreventing Skeletal-RelatedEvents in Advanced Cancer In metastatic bone disease or myelo-

ma, bisphosphonates such as zoledron-ic acid (Zometa) are used to delay orprevent skeletal-related events (SREs).Although zoledronic acid is effective indelaying the onset of SREs, it is admin-istered intravenously and can lead totreatment-associated renal complica-tions and acute-phase reactions.Results of a phase 3 randomized,

double-blind, double-dummy studycomparing the use of denosumab(Xgeva) with zoledronic acid showedthat denosumab may be a more flexi-ble option (Henry DH, et al. J ClinOncol. 2011;29:1125-1132). A total of 1776 patients with solid

tumors and bone metastases or withosteolytic lesions from myeloma wererandomized to subcutaneous deno-sumab and an intravenous (IV) place-bo or to IV zoledronic acid and a sub-cutaneous placebo. The primary endpoint was a noninferiority comparisonof the 2 treatments based on the timeto a first SRE (ie, pathologic fracture,radiotherapy or surgery, or spinal cordcompression).At 34 months, denosumab was non-

inferior (trending toward significance)to zoledronic acid (hazard ratio, 0.84;P = .0007) in delaying the onset of a firstSRE in patients with advanced cancerand bone metastasis or myeloma. The overall survival and disease

progression rates were similar be -tween the 2 drugs, as were those ofmost adverse events. Hypocalcemiaoccurred more often with denosumab;acute-phase SREs after the first dose,and adverse renal events occurredmore often with zoledronic acid. The researchers concluded that in

the treatment of bone metastasis, deno-sumab offers the convenience of subcu-taneous administration, withoutmonitoring for renal or acute-phase re - actions. The FDA approved denosum-ab last year for the prevention of SREsin patients with metastatic cancer. �

BRIEF SUMMARY OF PRESCRIBING INFORMATIONNeulasta® (pegfi lgrastim) injection, for subcutaneous use

INDICATIONS AND USAGENeulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically signifi cant incidence of febrile neutropenia.Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

CONTRAINDICATIONSDo not administer Neulasta to patients with a history of serious allergic reactions to pegfi lgrastim or fi lgrastim.

WARNINGS AND PRECAUTIONSSplenic RuptureSplenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute Respiratory Distress SyndromeAcute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infi ltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS.

Serious Allergic ReactionsSerious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfi lgrastim or fi lgrastim.

Use in Patients With Sickle Cell DisordersSevere sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving fi lgrastim, the parent compound of pegfi lgrastim.

Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe granulocyte-colony stimulating factor (G-CSF) receptor through which pegfi lgrastim and fi lgrastim act has been found on tumor cell lines. The possibility that pegfi lgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfi lgrastim is not approved, cannot be excluded.

ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary:• Splenic Rupture [See Warnings and Precautions]• Acute Respiratory Distress Syndrome [See Warnings

and Precautions]• Serious Allergic Reactions [See Warnings and Precautions]• Use in Patients with Sickle Cell Disorders [See Warnings

and Precautions]• Potential for Tumor Growth Stimulatory Effects on Malignant

Cells [See Warnings and Precautions]The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfi lgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not refl ect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.The following adverse reaction data in Table 1 are from a

randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other.Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2

(N = 467)

Musculoskeletal and connective tissue disordersBone pain 26% 31%Pain in extremity 4% 9%

LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfi lgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfi lgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfi lgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.The detection of antibody formation is highly dependent on the sensitivity and specifi city of the assay, and the observed incidence of antibody positivity in an assay may be infl uenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.

Postmarketing ExperienceThe following adverse reactions have been identifi ed during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta.Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions]Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions]Hypersensitivity reactions: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and fl ushing [see Warnings and Precautions]Respiratory, thoracic, and mediastinal disorder: ARDS [see Warnings and Precautions]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Cutaneous vasculitis

DRUG INTERACTIONSNo formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these fi ndings when interpreting bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Pegfi lgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on

body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefi t to the mother justifi es the potential risk to the fetus.In animal reproduction studies, when pregnant rabbits received pegfi lgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfi lgrastim approximately 10 times the recommended human dose (based on body surface area).Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing MothersIt is not known whether pegfi lgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric UseSafety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profi le and pharmacokinetics of pegfi lgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfi lgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric UseOf the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal ImpairmentIn a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfi lgrastim.Therefore, pegfi lgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATIONThe recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.NOTE: The needle cover on the single-use prefi lled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfi lgrastim)

Manufactured by:Amgen Inc.One Amgen Center Drive Thousand Oaks, California 91320-1799

© 2011 Amgen Inc. All rights reserved.www.neulasta.com 1-800-77-AMGEN (1-800-772-6436)

v 12.0 MC45288-B


PublisherNicholas [email protected]

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Mission StatementValue-Based Cancer Care provides a forum for payers,providers, and the entire oncology team to considerthe cost-value issues particular to cancer treatments.This unique focus is achieved through news coveragefrom major hematology/oncology meetings and thecancer literature, supplemented with commentariesand perspectives from those involved in evaluatingtherapies, treating patients, and paying for care.

BPA Worldwide membership applied for August 2010.

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Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 6 times ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2011 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark ofEngage Health care Communi cations, LLC. No partof this publication may be reproduced or transmittedin any form or by any means now or hereafter known,electronic or mechanical, including photocopy,recording, or any informational storage and retrievalsystem, without written permission from the publish-er. Printed in the United States of America.

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IN THIS ISSUE

VBCC Editorial BoardAl B. Benson III, MD FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie ComprehensiveCancer Centerof Northwestern University, Chicago, ILImmediate Past President, ACCCPast Chair, NCCN Board of Director

Bruce A. Cutter, MD, MMMCutter HealthCare ConsultingSpokane, WA

Craig Deligdish, MDFlorida Comprehensive CancerNetworkMelbourne, FL

Peter G. Ellis, MDUniversity of Pittsburgh School ofMedicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDITA PartnersPhiladelphia, PA

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and American Enterprise InstituteNew York, NY

Section EditorDawn Holcombe, FACMPE, MBA,ACHEPresident, DGH ConsultingSouth Windsor, CT

David Hom, MBASoluciaFarmington, CT

Philip E. Johnson, MS, RPh, CPhH. Lee Moffitt Cancer CenterTampa, FL

Ira Klein, MD, MBAAetnaHartford, CT

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhRegence BlueCross BlueShield of OregonPortland, OR

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Ed Pezalla, MD, MPHAetna Pharmacy ManagementHartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM. D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHFoley HoagWashington, DC

Brian K. Solow, MD, FAAFPPrescription SolutionsIrvine, CA

Timothy Tyler, PharmD, FCSHPDirector of Pharmacy ServicesComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

G. Rhys Williams, ScD, MSAmgenThousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSBioPharma Partners, LLCNew York, NY

NCCN CONFERENCEValue, Utilization of Molecular TestingClinical Guidelines UpdatesMore...

ACCC MEETINGThe New HITECH Rules for Medical PracticesDebating the Role of Pathways, GuidelinesMore...

GENITOURINARY CANCERS SYMPOSIUM Abiraterone Acetate Improves Survival in Prostate Cancer

PSA Not Needed More than 10 Years afterProstatectomy

More...

HOPA ANNUAL MEETINGMaking Oncolytics Worth the CostStrategies to Cut Costs in Oncology Practice

GASTROINTESTINAL CANCERS SYMPOSIUMNovel Pathways for Colorectal CancerTherapies

Hypertension a Good Sign with SunitinibMore...

HEALTH POLICYImplications of CMS’s Coverage Decision on Provenge

ODAC to Tighten Accelerated Approvals for Cancer Drugs

More...

VBCC PERSPECTIVEThe Promise of Personalized Medicine for Targeted Therapies

CONTINUING EDUCATIONVTE Prevention Strategies for Patients with Cancer

EGFREGFREGFREGFR

RASRAS

MEKMEK

ERKERK

BRAFBRAF

The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4

Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2

The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2:

~50% of melanoma tumors4

~40% of papillary thyroid tumors4,5

~30% of serous ovarian tumors5

~10% of colorectal tumors6

~10% of prostate tumors6

In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this

biomarker are currently in development.2

Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel

therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic

BRAF inhibition, please visit www.ResearchBRAF.com

To contact your account manager for more information on BRAF visit: genentechmm.com

Oncogenic BRAF:A new potential therapeutic target1,2

References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.

Demonstrating the Value of Innovation©2011 Genentech, Inc., So. San Francisco, CA MCM0000269700 02/11

A Member of the Roche Group

NCCN ANNUAL CONFERENCE


• Clinical utility: Is there somethingyou can do with the information?

Regulatory Standards Lacking for

Test Validity

Panelists agreed that greater regula-tory standards are needed for molecu-lar tests. “One of the major problemswe’re facing is the heterogeneity andvariability of these tests,” notedAndrew C. von Eschenbach, MD,former Commissioner of the US Foodand Drug Administration (FDA) andDirector of the National Cancer In -stitute, and currently Senior Directorfor Strategic Initiatives at the Centerfor Health Transformation. “It’s goingto get even more complex as we devel-op other markers in the area of pro-teomics and metabolomics. So we’relaying a foundation here, and it’simportant that we get it right, becausewe’re going to have to build on it,” Drvon Eschenbach said.“Molecular tests are regulated by

how they are marketed, not by claimsfor what the test can do. If a test is mar-keted as a kit, it is regulated by theFDA. If it tests for certain things—anexample is the test that screens theblood supply—it is regulated by theFDA. The FDA would like to regulateon the basis of the claims being madearound the test, but they have notstepped in to do that,” said ScottGottlieb, MD, former FDA DeputyCommissioner and now a fellow at theAmerican Enterprise Institute.“What has concerned the FDA is

that regulation follows, not necessarilythe complexity of the test or the claimsbeing made around it, but how the testis being marketed,” Dr Gottlieb said.“So if a test is marketed as a kit, it hasto be FDA-approved. If it is being per-formed as a laboratory service inside aCLIA [Clinical Laboratory Improve -ment Amendments] laboratory, it isregulated by CLIA and could escapeFDA regulation.” Because of the variability in their per-

formance and minimal regulation, theaccuracy of current test results may bequestionable, said panel moderatorClifford Goodman, PhD, of the LewinGroup. Dr Newcomer added that 30%of the results from the originaltrastuzumab registration trial werefound to be inaccurate. “This meansthat 1 of 3 breast cancer patients in thecommunity may be getting the wrongresult.” That is, women with a false-positive HER2 test result “would begetting a year’s worth of therapy thatwould not be helpful,” Dr Newcomernoted. Those with false-negative results“would be missing a year of very valu-able therapy that could save her life.”

Nevertheless, the use of moleculartesting in breast cancer has becomeroutine. According to Dr Newcomer, incertain subsets of patients with breastcancer, 94% of the treatment decisionsare made based on the risk score of theOncotype DX molecular test.

Better regulatory oversight of theanalytic validity of molecular testingwould be expected to correct some ofthese failings and improve clinicalconfidence, the panel agreed. Dr vonEschenbach reiterated the need toensure the consistency of the tests’claims and results, regardless ofwhere they are performed, as well asallowing the FDA to develop the infra-structure necessary “to bring order outof chaos.” Dr von Eschenbach stressed the

“tremendous amount of resistance onthe part of developers, because of thebelief that if you placed these tests inthe hands of the FDA for regulation,that—by its very nature—would under -mine innovation, create significantbarriers to progress….I don’t say thatthose concerns are not well-founded,but I do say that those concerns caneasily or systematically be overcome.”

“We need to put it in the hands ofthe agency that has the scientific infra-structure to be able to make scientificdecisions about these tests, as well asbe able to judge their clinical utility,”Dr von Eschenbach argued. DrGottlieb also supports having theFDA, or CLIA, regulate analytic valid-ity of testing. According to Dr Gottlieb, there is

movement in this direction. Within thenext 12 to 24 months, a new regulatoryscheme will be applied to molecular

testing based on work being done at theFDA and on Capitol Hill at this time. Nevertheless, “The keystone of the

debate is whether or not a regulatoryauthority should be regulating theclinical validity and the clinical utili-ty,” Dr Gottlieb said. “Determininghow important the test result is to theclinical decision that needs to be madeis best left to the clinical community.”Mark G. Kris, MD, Chief of the

Thoracic Oncology Service, MemorialSloan-Kettering Cancer Center, agreedthat this is best left to the research com-munity. “It is our job as clinicalresearchers to provide the data thatregulators and payers need to makedecisions,” he said.

Toward Personalized Medicine

Dr Goodman asked, “How do weknow that these molecular testswork?” Dr Kris, who specializes intreating lung cancer, has been a ferventadvocate of molecular testing and hasspearheaded much research on its clin-ical application. He noted 2 instancesin which DNA-based testing is firmlydriving treatment decisions—testingfor the epidermal growth factor recep-tor (EGFR) in advanced lung cancerand for the KRAS gene in colorectalcancer. In these settings, genetic assayscan clearly predict whether a certaintargeted agent will be effective in agiven patient. Patients with the KRAS mutation

have virtually no chance of respond-ing to the EGFR inhibitors cetuximab(Erbitux) or panitumumab (Vectibix),whereas there is a “decent chance” oftumor shrinkage with these drugs inpatents lacking the mutation. Inpatients with lung cancer, there is a70% response to treatment with theEGFR inhibitor gefitinib (Iressa) forthose with EGFR mutations comparedwith just 1% in those without themutation. “Molecular testing is nowpart of standard guidelines and label-ing for these 2 drugs,” Dr Kris said.But Michael Kolodziej, MD, Chief of

Oncology, St. Peter’s Hospital, Albany,NY, said he sees obstacles to utilizingeven established molecular tests in hispractice. Some tests do not lead totreatments that make a clear differencein patient survival; he experiences dif-ficulties and delays in obtaining tissuespecimens needed to perform themolecular tests. “We are aspiring to anera of personalized medicine, but wearen’t there yet,” he said.At Memorial Sloan-Kettering Can -

cer Center and a handful of othermajor cancer centers, oncologists havean easier time with testing. At Sloan-Kettering, patients with non–small-

cell lung cancer (NSCLC) routinelyundergo a panel of genetic tests, DrKris reported, acknowledging thatjust 1 of the 8 tests in the multiplexassay is backed by phase 3 clinical trialevidence.

Insufficient Evidence, Patient

Education

The concern that data supportingmolecular and genetic testing areimmature was echoed by the panel.“There is evidence, evidence withpractical hurdle, and inadequate evi-dence. EGFR mutational analysis isevidence, but we will not order othertests without good evidence—NewEngland Journal of Medicine level of evi-dence,” said Dr Kolodziej. Louis B. Jacques, MD, Director of the

Coverage and Analysis Group, Centersfor Medicare & Medicaid Services,agreed that clinicians and payers can-not always be certain a given testworks. “What we mean by knowing atest works is the same thing that youmean when you look at your 13-year-old and you say, ‘You’re going to be asuccessful adult.’...The challenge for usis we are looking at this vast array of,say, 8000 adolescents and are beingasked to prepay a Harvard educationfor all of them. And what we don’tknow now, because they are adoles-cents and the evidence about them hasnot matured, is whether Harvard maybe the wrong place for many of them.”

Patient advocate ElizabethThompson, who is with the Susan G.Komen for the Cure organization,agreed. “Cancer treatment at NCCNinstitutions centers on a group ofpeople looking at a wide variety offactors, and these tests are one part ofthe decision-making module,” shesaid. “How ever, while the UnitedStates is leading the world in terms ofwhat molecular testing means forpatient care and outcomes, we stilldon’t have enough information.”

NCCN Expert Panel Considers Value, Utilization of... Continued from cover

Continued on page 9

“Determininghow importantthe test resultis to the clini -cal decision

that needs to be made is best left to the clinicalcommunity.”

—Scott Gottlieb, MD

“How ever,while theUnited States is leading theworld in terms

of what molecular testingmeans for patient care andoutcomes, we still don’t have enough information.”

—Elizabeth Thompson

“We are aspiring to an era of personalized medicine,but we aren’t there yet.”

—Michael Kolodziej, MD



Hollywood, FL—Chairpersons of thevarious National ComprehensiveCancer Network (NCCN) tumor pan-els presented clinical practice updatesat the recent 16th Annual Conferenceof the NCCN. Key updates, and rele-vant discussions, are highlighted.

Key Changes in Breast CancerRecommendationsPivotal research in 2010 led to

changes that are immediately applica-ble to clinical practice in breast cancer,said panel chair Robert W. Carlson,MD, Stanford Comprehensive CancerCenter, Palo Alto, CA.

Pharmacotherapy

Despite the recent controversyregarding the US Food and DrugAdministration (FDA) recommenda-tion to remove the metastatic breast

cancer indication for bevacizumab(Avastin), the NCCN affirmed thecombination of bevacizumab andpaclitaxel in its treatment guidelines.The panel members were not as con-fident in the use of bevacizumabwith other approved chemotherapyagents.The NCCN decision was based on

the argument that “if the data werecompelling 2 years ago, they are com-pelling enough today,” Dr Carlsonsaid. The panel, however, did add afootnote to the guidelines, acknowl-edging that the use of the drug doesnot improve overall survival (OS) andonly “modestly improves time to pro-gression and response rates.” Eribulin (Halaven), a cytotoxic

agent, is now a “preferred” agent forwomen with previously treatedmetastatic breast cancer, based on the

2010 EMBRACE (An InternationalStudy on MRI-Guided Brachytherapyin Locally Advanced Cervical Cancer)trial, in which 762 patients were ran-domized to treatment by physicians’choice or to eribulin. One-year OS was53.9% for the eribulin arm versus43.7% for the treatment by physicians’choice arm, and median OS was 13.12months versus 10.65 months, repre-senting a 19% risk reduction with thenew agent. The addition of denosumab (Xgeva)

in this patient population to help pre-vent skeletal-related events was basedon a study presented at the AmericanSociety of Clinical Oncology 2010meeting (abstract 1024) showing 23%fewer skeletal-related events, versuszoledronic acid (Zometa), although OSand disease-free survival were similarto the control group.

Other Changes

The panel also recommends that themetastatic breast cancer work-upinclude the determination of hormonaland HER2/neu status “if unknown,originally negative, or not overex-pressed.” This was based on grow -ing evidence showing discordancebetween primary and recurrent dis-ease. “This recommendation is likelyto get stronger as these data are for-mally published,” Dr Carlson added. Representing a significant departure

from current clinical practice, thepanel has given a thumbs-down tocomplete axillary lymph node dissec-tion in women with clinically node-negative T1-T2 tumors, and <3involved sentinel lymph nodes whoundergo surgery and radiation thera-py. This change is based on the land-

NCCN Expert Panel Considers Value, Utilization of... Continued from page 8

NCCN 2011 Clinical Guidelines Updates By Audrey Andrews

Ms Thompson added that for manypatients, these tests are “confusingand challenging.” Educated patientsare aware of these tests and frequent-ly request them, but still have troubleapplying them to their specific situa-tions. They often report that theirOncotype DX recurrence risk score islow, yet their oncologist still advo-cates chemotherapy. “Patients call us and say, ‘This is

what the test said, but this is what mydoctor is saying. What should I do?’Generally, we refer people to a majormedical center for a second opinion,”Ms Thompson said. Dr Newcomer, however, said his

data show that 94% of oncologistsfollow the recommendations for alow-risk score. “At the end of the day,” Dr Kolodziej

said, “I am a cautious optimist. Therewill prove to be value in some molecu-lar testing, and it will prove to be pre-dictive of response to a specific thera-py.” Dr Gottlieb agreed, “If there wereno value inherent in these tests, I don’tthink they would exist.”

Is There Value for the Dollar?

Is the value of the result obtainedwith molecular testing worth the highcost of the average assay? This may behard to determine. The price of testingvaries tremendously. For example,EGFR mutation testing costs approxi-mately $800 at Memorial Sloan-Kettering, and this cost also coverstesting for an additional 7 gene muta-

tions found in NSCLC, Dr Kris noted. Other genetic tests, however, are

considerably more expensive. “WhatDr Kris does not see is the 180-genom-ic panel that I also get billed for on aroutine lung cancer patient,” DrNewcomer said. “Those tests are 98%unproven.” Dr Newcomer stressedthat “a small set of genes can belongtogether; that makes perfect sense.But we have both ends of the spec-trum—people who are being reason-able, and those who are expandingthose panels dramatically with noevidence whatsoever. I worry thatdecisions will be made based on thoseother 180 tests and they won’t be evi-dence-based.”Moving forward, he said, “We need

to be led by the first precept in medi-cine: first, do no harm….We are alldesperately eager to make thesegenetic tests work, but we cannot getahead of ourselves, or we will hurtpatients in the interim. We need toorganize to get the data. We need to

find out what works and doesn’twork, and patiently collect that beforewe eagerly accept or embrace all ofthis new technology.”Attempting to put the issue of cost

into perspective, Dr Jacques remindedthe audience that “everything aboutcancer is expensive,” including chemo -therapy, hospitalization, and the treat-ment of serious adverse events. Other panelists suggested that the

benefit will become clear in the long-run. “There is no question that bothfrom a theoretic and an emerging prac-tical perspective, these tests are amethodology for saving money inhealthcare,” Dr von Eschenbach noted.The application of molecular testingwill reduce unnecessary spending forinsufficient or inappropriate therapy,he maintained.The actual cost of a genetic test,

however, is just part of the economicdiscussion, the discussion made clear.Dr Newcomer revealed some surpris-ing problems with regard to billing.

“The current system does not itemizethe tests, and the coding system is anti-quated,” he said. “It just says ‘genetictest,’ which doesn’t allow us to assesseither the upfront costs or the down-stream benefits that might result fromthis kind of testing.”Dr Newcomer and other third-party

payers do not always know wherethese reimbursement dollars aregoing. “I have no idea what I amspending, or what I am actually get-ting, when we reimburse for genetictesting,” Dr Newcomer said. DrJacques agreed, “Anything short ofclinical utility casts a giant pall ofuncertainty over, frankly, whether Iought to be paying for this.”Dr Gottlieb also noted that logistics

issues cited by the clinicians (gettingthe specimen from the pathologydepartment to the laboratory perform-ing the test) will also become moot, asmore integrated entities become thenorm. “Anatomical pathologists areconsolidating themselves and alsopurchasing these molecular diagnosticcompanies,” he pointed out. Thisshould smooth out the process. Dr von Eschenbach summarized

the views expressed by the panel,stating, “These tests are becomingmechanisms for saving money andimproving outcomes for our patients.We need to make sure we have themechanisms in place to make deci-sions about what is the right treat-ment, at the right dose, done for theright reason.” �

“These tests are becoming mechanisms forsaving money and improving outcomesfor our patients. We need to make surewe have the mechanisms in place to make decisions about what is the righttreatment, at the right dose, done for the right reason.”

—Andrew C. von Eschenbach, MD




mark American College of SurgeonsOn cology Group Z0011 study (GiulianoAE, et al. JAMA. 2011;305:569-575),which found no difference in locore-gional recurrences, disease-free sur-vival or OS between patients whounderwent complete dissection andthose who had a sentinel lymph nodedissection only.

“The panel decided to add the rec-ommendation to the main guidelinesbased on this single randomized trial,”Dr Carlson said. The recommendationis intended only for this well-definedsubset of the patient population.Finally, citing discrepancies between

major studies, the panel did not rec-ommend that patients be tested for theCYP2D6 polymorphism, which hasbeen implicated in resistance to tamox-ifen. “The current NCCN guidelinesare silent on this issue. Oncologistsshould interpret this as a recommen-dation not to perform CYP2D6 testingat this time,” he said.

Prostate Cancer UpdateThe question of active surveillance

or immediate treatment for a subset ofmen with prostate cancer was thefocus of the updated guidelines forprostate cancer. James L. Mohler, MD,Roswell Park Cancer Institute, dis-cussed the recommendation for morerigorous monitoring of men opting foractive surveillance (or watchful wait-ing) and new treatment options foradvanced prostate cancer.“The NCCN remains concerned

about overdiagnosis and overtreat-ment of prostate cancer, as growingevidence suggests that overtreatmentcommits too many men to side effectsthat outweigh a very small risk ofprostate cancer death,” Dr Mohler said. Active surveillance is a viable

option for many men with very lowrisk or even low risk of progression. In2010, the guidelines established the“very-low-risk” category, which incor-porated the strictest criteria for clini-cally insignificant prostate cancer. Thisrecommendation is for active surveil-lance as the sole initial treatment for

men meeting these criteria who have alife expectancy of >20 years. Men atlow risk for prostate cancer and a lifeexpectancy of <10 years should also berecommended for active surveillance,the guidelines state. The 2011 guidelines made active

surveillance monitoring more rigorousfor men in the very-low-risk category:with a life expectancy of <20 years,prostate-specific antigen (PSA) shouldbe measured at least every 6 months, aprostate examination must be done atleast every 12 months, and repeatbiopsies should be considered as oftenas every 12 months.Dr Mohler noted conundrums relat-

ed to active surveillance and PSA test-ing, including overtreatment rates,clinical risks associated with biopsies,and differing criteria for active surveil-lance and disease progression in largeclinical series. All need to be taken intoconsideration in treatment decisions. “Ultimately, this decision must be

based on careful individualizedweighting of a number of factors, andis an option that needs to be thorough-ly discussed,” Dr Mohler said.

Pharmacotherapy

A significant change was the addi-tion of sipuleucel-T (Provenge) as animmunotherapy option for a subset ofmen with recurrent metastatic prostatecancer, based on an observed OSadvantage. “The guidelines have beenmodified to include sipuleucel-T as acategory 1 recommendation. It isappropriate as salvage treatment forpatients with castration-recurrent can-cer who have minimally symptomaticdisease, a performance status of 0 or 1,and a life expectancy of at least 6months,” Dr Mohler noted.The panel also voted to include

cabazitaxel (Jevtana) as a new second-line option for men with castration-recurrent metastatic disease who faildocetaxel (Taxotere), also based onobserved OS advantage. Finally, denosumab was added as

an alternative to zoledronic acid(Zometa) for the prevention of skele-tal-related events. The choice of agentfor bone protection, however, de -pends on the presence of comorbidi-ties and whether the patient has beentreated with zoledronic acid previous-ly, he emphasized.

Non–Small-Cell Lung CancerThe use of epidermal growth fac-

tor receptor (EGFR) mutations andhistologic subtype to tailor therapyare pivotal updates to the non–small-cell lung cancer (NSCLC) guidelines,said David S. Ettinger, MD, Sidney

Kimmel Comprehensive Cancer Cen -ter, Johns Hopkins School of Medi -cine, Baltimore.

Molecular Diagnostic Testing

The 2011 NCCN guidelines havechanged the evaluation process forsystemic therapy for recurrent ormetastatic disease to first establish thehistologic subtype and then performEGFR testing based on that subtype.Treatment recommendations for ad -vanced NSCLC should be tailoredbased on these determinations. “Weare heading toward the era of muta-tion driving the therapy, and it’sextremely important for our patients,”said Dr Ettinger.Therefore, a major change is evident

in the molecular diagnostics section.Updated information on EGFR andKRAS gene status, as well as a newaddition on EML4-ALK is included.More than 60,000 new cases of NSCLCannually are estimated to be driven bythese gene mutations, Dr Ettinger said.EGFR testing is now a category 1

recommendation for adenocarcinoma,large cell, and NSCLC not-otherwise-specified (NOS), but this is not recom-mended for squamous-cell carcinoma.Dr Ettinger emphasized the need toacquire tissue for genetic testing inNSCLC: “Histology matters, and NOSis unacceptable.” All patients who have adenocarci-

noma should undergo studies formolecular mutations. Although thereis yet no standard method for detect-ing EML4-ALK in NSCLC, polymerasechain reaction, immunohistochem-istry, and fluorescence in situ hybrid -ization are being evaluated.

Pharmacotherapy

Bevacizumab plus a platinum dou-blet (for patients who received first-line erlotinib [Tarceva] and haveadenocarcinoma) was added as atreatment option. Bevacizumab pluspaclitaxel/carboplatin (Taxol/Para -platin) may be an effective option fornonsquamous-cell tumors but notsquamous-cell tumors. Bevacizumabis changing the landscape of treatmentof stage IV disease, Dr Ettinger said.Crizotinib, an agent targeting EML4-

ALK, may change the prognosis of the5% to 10% of patients with this muta-tion. A recent clinical trial of patientswith EML4-ALK+ adenocarcinomashowed robust responses to this novelagent (Kwak EL, et al. N Engl J Med.2010;363:1693-1703). Updated resultsof this study will be important.

Non-Hodgkin LymphomaA new guideline for posttransplant

lymphoproliferative disease (PTLD)and the promotion to a category 1 rec-ommendation for 2 therapies for follic-ular lymphoma took center stage innon-Hodgkin lymphoma. “PTLD hasemerged as a significant complicationof solid organ and allogeneic bonemar row transplantation,” said AndrewD. Zelenetz, MD, PhD, MemorialSloan-Kettering Cancer Center, NY.Understanding PTLD has helped to

identify high-risk patients. “The singlebiggest risk factor for PTLD is the pres-ence of an Epstein-Barr virus [EBV]mismatch between the recipient andthe donor,” Dr Zelenetz said. “Thetime from organ transplant is criticallyimportant, with most of these lesionsdeveloping within the first year.”

The NCCN guidelines for PTLDrecommend certain tests as either “es -sential” or “useful in selected cases.”Among the essential tests are histo -pathology, immunophenotyping, andthe EBV-ISH assay. EBV viral load maybe useful in selected cases. Dependingon the PTLD subtype, recommendedtreatment options include the reduc-tion of immunosuppression, which iseffective in 23% to 64% of patients, andsingle-agent rituximab (Rituxan), par-ticularly for early and polymorphiclesions, where responses may reach90%. “I would reserve chemoim-munotherapy for patients in whomother simpler maneuvers have failed,”Dr Zelenetz said.

Category 1 for 2 FollicularLymphoma TherapiesSignificant changes in follicular lym-

phoma are centered on the upgradingof 2 therapies from lower-level recom-mendations to category 1 (the highestranking). This includes the combina-tion of bendamustine (Treanda) andrituximab (B-R) for first-line treatment,and rituximab maintenance and radio -immunotherapy (90Y ibritumomabtiuxetan [Zevalin]) following first-remission treatment.In the 2009 pivotal trial comparing

B-R plus standard therapy with CHOP(cyclophosphamide [Cytoxan], dox-orubicin [Adriamycin], vincristine[Oncovin], and prednisone [Delta -

NCCN 2011 Clinical Guidelines Updates... Continued from page 9


“PTLD has emerged as a significant complicationof solid organ andallogeneic bone marrowtransplantation.”

—Andrew D. Zelenetz, MD, PhD

“Oncologistsshouldinterpret thisas a recom -mendation

not to perform CYP2D6testing at this time.”

—Robert W. Carlson, MD


11VOL. 2 NO. 2 www.ValueBasedCancer.com I

sone]) plus rituximab (CHOP-R), B-Rsignificantly improved progression-free survival (PFS) and complete re -sponse rates versus CHOP-R, al -though there was no difference in OS.Radioimmunotherapy after chemo -

the rapy and rituximab maintenance arenow more strongly recommended basedon an improvement in PFS followingfirst-remission therapy, al though noimprovement was seen in OS.Observation is still an appropriate

approach in the NCCN algorithm forthe initial treatment of follicular lym-phoma. “No maintenance strategy in[follicular lymphoma] has yet demon-strated a benefit in OS,” Dr Zelenetzsaid; therefore, delayed treatmentremains a viable option. He empha-sized the importance of individualizedtreatment for this patient population.

New First-Line Rx for ChronicMyelogenous LeukemiaSecond-generation tyrosine kinase

inhibitors, now approved for first-linetherapy for chronic myelogenousleukemia (CML), offer newly diag-nosed patients more options and arenow recommended by the NCCN,said Susan O’Brien, MD, University ofTexas M. D. Anderson Cancer Center. The addition of nilotinib (Tasigna)

and dasatinib (Sprycel) as first-lineoptions in addition to imatinib(Gleevec) is a key update to the CMLguidelines. In recent studies, dasatiniband nilotinib were associated with sig-nificantly improved response rates andreductions in accelerated or blast phaseat 12 months. In the EvaluatingNilotinib Efficacy and Safety in ClinicalTrials-Newly Diagnosed Patients(ENESTnd) study, major molecularresponses were achieved at 24 monthsby >60% of newly diagnosed patientstreated with nilotinib versus 37% ofpatients receiving imatinib, and <2% ofnilotinib-treated patients progressed toaccelerated phase or blast crisis versus4% to 6% with imatinib. “This is the most clinically relevant

data in the short-term, because trans-formation heralds a very poor progno-sis,” Dr O’Brien noted. Other studiesreported at ASH reached similar con-clusions. Dr O’Brien said the data show that

the 2 newer agents are “almost iden-tical” in improving short-term endpoints, although their impact on PFSand OS has not been established.With 3 approved front-line agents,oncologists can either start patientson a newer drug from the start orreserve the newer agents for salvagetherapy, for which they have provedvery effective. �

NCCN 2011 Clinical Guidelines... Continued from page 10

NCCN 2011 GuidelinesUpdateBreast Cancer

� The new cytotoxic agent eribulinwas added as an option formetastatic disease

� Denosumab was added as anoption for preventing skeletal-related events in patients with bone metastases

� Bevacizumab, in combination withpaclitaxel, was reaffirmed as an op tion for metastatic disease

� Determination of hormonal status and HER2/neu status isrecommended for patients withmetastatic disease

Chronic Myelogenous Leukemia

� Nilotinib and dasatinib wereadded as first-line treatmentoptions, but their impact on PFSand OS has not been established

Head and Neck Cancer

� Human papillomavirus is agrowing concern in head and neckcancers, and testing for the viruswas added as a recommendation in work-up

� New algorithm for mucosal mela -noma; treatment should follow theguidelines for malignant melanoma

Malignant Melanoma

� In defining clinical stage IBmelanoma, mitotic index hasreplaced Clark level; Clark level isoptional on the pathologist’s report

� The presence of any mitosis(mitotic rate ≥1 mm2) in a thinmelanoma (≤1 mm) upstages thepatient to stage IB and hasimplications for sentinel lymph nodebiopsy (SLNB)

� SLNB should be discussed andoffered to patients with stage IA orII melanomas; the threshold forconsidering SLNB is a risk ofrecurrence of approximately 7%

� For follow-up of patients withstage IIA or lower melanoma, theupdated guidelines place lessemphasis on routine blood workand cross-sectional imaging

Multiple Myeloma

� The regimen of bortezomib/cyclo -phosphamide/dexamethasone be came a category 2A option forinduction therapy in the transplantsetting, and lenalidomide/bortezomib/dexamethasone was listed aspromising category 2B alternative

� Lenalidomide maintenance, whichnearly doubles PFS, has beenadded as a new option afterautologous stem-cell transplant

� Melphalan/prednisone/lenalidomide and bortezomib/dexamethasone became category2A options in the nontransplantsetting

� Cyclophosphamide/bortezomib/dexamethasone and cyclophospha -mide/lenalidomide/dexamethasonewere added as category 2A salvagetreatment option

Non-Hodgkin’s Lymphoma

� A new guideline for PTLD

� Recommended treatment optionsfor PTLD include reduction of immu -no suppression, single-agent ritux -imab, and chemoimmunotherapy

� Category 1 recommendedtreatments for follicular lymphomanow include bendamustine/rituximab for first-line treatment and rituximab maintenance andradioimmunotherapy for after first-remission treatment

Non–Small-Cell Lung Cancer

� Testing for EGFR is now category1 recommendation for adenocarci -noma, large-cell, and NSCLC not-otherwise-specified, but is notrecommended for squamous-cellcarcinoma

� Mutational status—particularlyEGFR, KRAS, and EML4-ALK—affects the choice of treatmentoptions

� The use of surgery after inductiontherapy for patients with stage IIIA(N2) disease is debated; the benefitof surgery in this heterogeneicgroup remains unclear

� Patients with a single lymph node<3 cm can be considered for amultimodality approach thatincludes surgical resection

Ovarian Cancer

� Women with borderline epithelialovarian cancer of low malignantpotential should be primarilymanaged surgically

� For women wishing to maintainfertility, surgery should be limited tounilateral salpingo-oophorectomy,and standard debulking surgery is recommended for those notconcerned about fertilitypreservation

� Stage II, III, or IV epithelial ovariancancer should have intraperitonealchemotherapy first-line; updatedrecommendations include dose-

dense paclitaxel as a possibletreatment option, although this may be more toxic

� The NCCN has decided to delayrecommending the addition ofbevacizumab to carboplatin/paclitaxel up front; participation in clinical trials is encouraged

� Discussion of the pros and cons of monitoring CA-125 levels is recommended, based on data showing a lack of survival benefit when treatment for relapse was initiated on a rise in CA-125

� Recommendations were addedfor the management of infusiondrug reactions

Prostate Cancer

� A new “very-low-risk” categoryincorporates very strict criteria forclinically insignificant prostatecancer

� Active surveillance is recom -mended as the sole initial treat -ment for men meeting the criteriafor very-low-risk disease who havea life expectancy of >20 years

� More rigorous active surveillancemonitoring for men in the very-low-risk category

� Active surveillance should berecom mended for men with low-risk prostate cancer and a lifeexpectancy of <10 years

� Sipuleucel-T was added as an im -munotherapy option for asymptomaticor minimally symptomatic castration-recurrent metastatic disease inpatients with ≥6 months’ lifeexpectancy

� Cabazitaxel is a new second-line option for castration-recurrentmeta static disease after progressionwith docetaxel

� Denosumab is an alternative tozoledronic acid for the prevention of skeletal-related events

Sarcoma

� The recommended management of the desmoid tumor subtype ofsarcoma changed to reflect therecommendation to follow thesepatients carefully if their tumors aresmall and not located on the trunkand if surgery would lead toexcessive morbidity

� Several changes in staging include the reclassifying of lymph nodes as stage III rather than stage IV disease

at-a-glance

BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL

Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal

insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Patients should not begin a new cycle of treatment unless the ANC is 1500 cells/mm3, the platelet count is 100,000 cells/mm3, and creatinine

clearance is 45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

D

s

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Important Safety Information for ALIMTA (pemetrexed for injection)

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Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

See Warnings and Precautions for specific information regarding ibuprofen administration.

Use in Specific Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence): The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

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ALIMTA (pemetrexed for injection)

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AVBCC ANNUAL CONFERENCE


Prominent Oncologist Applauds First Conference... Continued from cover

try are talking with insurers, with cli-nicians—there is hope that this type ofcommunication has great potential foreach of these critical groups in health-care delivery to understand whereeach component is coming from, andunderstand each other’s issues, whichwe trust over the long-run will lead tocreative solutions. To try to put peoplein “good guy, bad guy” categories isnot productive for anyone. If we look at the drug development

side, the pharmaceutical industryclearly needs the expertise that comesfrom clinicians in terms of trial devel-opment, particularly regarding inte-gration of biological principles anddisease-specific expertise. We need theongoing scientific expertise from labo-ratory scientists, from imagingexperts, as well as from drug develop-ers—all working together to designthe very best trials. These include the trials done

through the public sector, that is, theNational Cancer Institute, includingthe cooperative groups. Such interac-tions are absolutely essential, becausethe drugs after all are coming fromindustry. But for the industry trialsalso, we want the very best trialsdeveloped across the board. We wanttrials that will bring forward impor-tant human biological data to help usbetter select patients who are morelikely to benefit from the various drugsunder development. And this is goingto take encouragement; an environ-ment where people are communicat-ing with each other.

Q: Does it also relate to payers orpolicymakers?

Dr Benson: Indeed. Insurance carri-ers, including our policymakers andgovernment agencies, clearly need tocomprehend what it takes to delivereffective oncologic care. There is theneed to understand how we can offerthis care to the greatest number of peo-ple—access is a critical issue—andhow can we make sure that we areusing the resources to the best advan-tage for the patient. They need tounderstand that we are makingprogress in our ability to selectpatients who will have the best oppor-tunity to benefit from these therapies,although we certainly have muchmore work ahead of us to accomplishthis goal across disease sites. At thesame time, we should make it clearwhen an agent is not going to providebenefit for the patient. In addition, to more effectively use

imaging, we need to look at risks andbenefits, to be able to decide when toorder particular scans, and so on. The

effective use of imaging requiresstrategic thinking for each patient todecide what is the intended goal, whatwe are going to learn from imaging,how is this imaging going to affect thecare delivered, and will it result inaltered decision-making. In otherwords we need to get people to thinkmore carefully what tests—diagnosticsand imaging alike—will truly addbenefit. Some tests of course are clearlyfor safety, and we have to considerwhat will help us make sure that an

intervention is being safely adminis-tered. Other issues are to look at theeffectiveness of the therapy, and tolook for recurrence, with the under-standing that if we find recurrence, weare going to intervene in an attempt toenhance outcome.

Q: This is directly relevant to a keyissue in oncology—personalized med-icine. Did the conference have any rel-evance to this?

Dr Benson: Yes, it goes hand inhand. To effectively achieve the goalof personalized medicine, you haveto have everyone in the healthcareenterprise engaged to understandand to help get us to our goal. Thatrequires an environment that encour-ages innovation on the one hand,even though innovation may come ata cost. On the other hand, if innovative

strategies help us with much betterpatient selection, in the long-run weare at the very minimum using dollarsmore effectively, but we could alsohave huge cost-savings. Perhaps thosecost-savings need to be invested inother components of healthcare, sothat our overall health expendituremay not actually decrease. Given ourexpanding and aging population and

the advances in providing care, wemay end up spending the sameamount but getting better outcomesfrom the dollars we spend. At least we would know that we

are getting value. We would projectthat value in healthcare deliverycould have other ramifications, suchas keeping more people gainfullyemployed, so that they are able tocare for themselves and their fami-lies, as well as contribute to the over-all economy.

Furthermore, expanded innovationshould lead to more jobs, more indus-try to enhance the economy, and moredevelopment of infrastructure. Thereare so many permutations that wecould foresee, but if we do not haveeverybody getting together and talk-ing about these issues, we are notgoing to have the optimal solutions.

Q: Where do you see personalizedmedicine today, and where will it bein, say, 5 years? Are we moving in theright direction?

Dr Benson: I think we are clearlymoving in the right direction, becauseif we look at the past 5 years, I don’tthink people could have predicted theadvancements that we see now. Wealready have more biologic factors weare able to use, at least in some circum-stances, for patient selection. Our tech-nology—the laboratory technology,the informatics technology—is alldeveloping at a very fast rate. Andthese kinds of developments enable usto do a lot of the work in terms ofunderstanding human biology. If we just look at the tumor assess-

ment technology, where in the pastpeople might have only been able todo experiments with fresh tissue, nowa huge amount of work can be done

from tumor bank material, for exam-ple. And because there is increasingunderstanding of human tumor biolo-gy, we hope that in the long-run thiswill drive drug development. I don’tthink we could have predicted the roleof KRAS in colon cancer, for example.The expectation is that this processwill accelerate. With the economic concerns, how-

ever, one question is whether we willcontinue to recognize that investing inhealthcare innovation is absolutelycritical, because not only will it lead tobetter understanding of human dis-ease, it should also lead to far betterways to deliver healthcare and todeliver appropriate treatments to peo-ple who will benefit from them.

Q: You mentioned value earlier,which is not an easy issue. How doyou understand value in cancer? Arewe talking about survival, reducedcosts? Some people say that a treat-ment that prolongs life for 1 or 2 weeksdoes not really provide value.

Dr Benson: That is part of the prob-lem when people are talking aboutoutcomes, and why we need differentparadigms for clinical trial design.Currently, when we evaluate a treat-ment, we have eligibility criteria, butthese are still for the most part verybroad. We know that cancers, even within a

given stage, are very heterogeneous.There are multiple biological path-ways that are engaged in the sametumor, and we know that within agiven group of patients, outcomesvary considerably. In such a situation,we know that an intervention is notgoing to benefit a certain percentage ofpatients. We are designing the trial sothat we project that a certain numberof patients will benefit, which willshow that the drug has activity for atleast some people in that group. So when we look at the statistics,

we are looking at this diverse popula-tion, and until we can truly separatethose who will not benefit, and thosewho have a high likelihood of benefit,we are not getting the full value of theintervention. When people make a comment such

as, “well, it only extends survival forthis limited period of time,” that is truein a broader collection of people whowere participating in the trial; but,clearly there are some individuals whogot great benefit—yet we are unable toadequately select those who wouldbenefit and those who would not.These trials that typically have rela-tively unselected populations of

To effectively achieve the goal of personalizedmedicine, we have to haveeveryone in the healthcareenterprise engaged tounderstand and to help get us to our goal. We hope to see much moreinteraction among themultiple stakeholders of the healthcare system, as has been evident at this conference.


See also VBCC Perspective, page 28

Washington, DC—The American Re -covery and Reinvestment Act (AARA)of 2009 provides up to $27 billion over10 years for the Centers for Medicare &Medicaid Services to offer cash incen-tives to encourage providers to makethe switch to electronic health records(EHRs), said Gena Cook, CEO, Navi -gating Cancer, a web-based companydedicated to oncology services.

Financial Implications

Speaking at the 2011 Association ofCommunity Cancer Centers annualmeeting, Ms Cook emphasized that thefocus should be on “meaningful”adoption of EHRs for improvingpatient care, according to the ARRA.Providers are encouraged to move

quickly to understand the comingchanges resulting from implementa-tion of the AARA and the HealthInformation Technology for Economicand Clinical Health (HITECH) Act,which falls under it. By 2015, providers who continue to

use paper records instead of EHRscould have their Medicare reimburse-ments reduced, she said.“What people aren’t thinking about

is what that really means. As you adopttechnology into your office, what doesthat mean for patients and their fami-lies?” she asked.

“This is a part of healthcare reform,where the train has already left the sta-tion. This has bipartisan support, andphysicians can start…receiving pay-ments this year.”Addressing providers’ concerns

about the cost of EHRs, she said it isbetter to reap the incentives now thanget hit with penalties later. To receivefederal funds, providers must demon-strate “meaningful use” of EHRs. The

objectives constituting meaningful usewill be implemented in 3 stages.

The 3 Implementation Stages

Stage 1, which has 20 objectives, has

been released; it includes providingpatients with a clinical summary andtimely electronic access to records. The objectives for stage 2 for 2013

ACCC ANNUAL MEETING


Contact your GSK representative for additional information or visit www.ARZERRA.com.

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Implementing the HITECH Rules in Oncology PracticesBy Daniel Denvir


“This is a part of healthcarereform, where the train has already left the station…and physicians can start…receiving payments this year.”

—Gena Cook

ACCC ANNUAL MEETING


and join Medicare (the populationmost susceptible to cancer).The settings where care is delivered

will also change, according to Dr Booi,with technological advances drivingtreatment from inpatient to outpatientsettings. “It will also expand the number

of treatments that are given,” shesays, “as we look at more multi-modality treatments and more com-plex interventions.”Epidemiologic trends in relation to

cancer are mixed—smoking is down,but obesity continues to rise, and bothtrends will have an impact on cancerrates and outcomes, considering thelink of these conditions to cancer.

Growth in Technologies

Two technologies have particulargrowth potential—interventional on -col ogy, which speeds recovery and low-ers the risk for complication, will be a“huge opportunity for growth and agreat source of program differentiationfor cancer centers.” Stereo tactic bodyradiation therapy, allowing for high-dose and high-accuracy treatment, isthe second anticipated growth area.

Screening. The recession hasdepressed the use of certain cancertreatments, most notably preventivescreening for colorectal cancer andmammography. However, the health-care reform has eliminated patientcost-sharing for many preventivescreenings, so utilization of these serv-ices can be expected to grow. Dr Booipredicts a 39% increase in mammogra-phy utilization over the next decade.

Surgical intervention. Increasedscreening and an aging populationwill, in turn, boost surgical interven-tion. “This is a big revenue opportuni-ty,” she says. “The performance strate-gy for colorectal cancer is to increaseyour screening rates, because this is

going to drive downstream utilizationof surgical resections, which we knowhave favorable margins.”

Chemotherapy. Chemotherapy isanother opportunity for growth. Evi -dence also suggests that chemo the -rapy will grow by 38%, thanks to more“complex and targeted” therapies.“What does this mean for planning?

I think on the inpatient side, it means becareful; don’t overplan for demand thatyou may not see. And on the outpatientside, it means also be careful, but interms of efficiency,” Dr Booi said.

Imaging. Positron-emission tomog-raphy (PET) will also likely see robustgrowth. After the National PETRegistry study determined that PETimproved treatment planning, theCenters for Medicare & MedicaidServices expanded coverage for PET. Dr Booi expressed skepticism over

the prospects for proton beam therapy.“Is adopting proton beam therapy aperformance strategy for cancer cen-ters?” she asked. Her reference to the$100-million to $150-million imagingmachines provoked a laugh from theaudience. “Well, maybe. Maybe not.”

Coordinated Care and Utilization

Dr Booi predicts that the increasingpressure to move toward coordinatedcare models such as accountable careorganizations and bundled paymentswill ultimately decrease utilization,because improved communicationwill result in fewer duplicate tests andbetter outpatient self-care.“If you’re communicating better, if

you’re improving hand-offs, then yourpatients are probably better manag-ing their diseases, they’re not beingexposed to duplicate or unnecessarytests, and they’re probably being bettereducated about managing their symp-toms in the outpatient setting. Sothey’re not being readmitted for com-plications like nausea or dehydrationas a result of their treatment.”Dr Booi endorses the utilization of

“time frames” to diminish wastefulbacklogs in the treatment process andreduce patient anxiety. This is some-thing that cancer centers can market to

patients; “we’ll get you in and outquickly.” She cited Gundersen Luth -eran Center in La Crosse, WI, whichreduced treatment to turnaround timeto 7 days, resulting in fewer negativebiopsies.In Memphis, TN, the Baptist Hos -

pital for Women decreased turn-around times without adding staff orequipment by establishing an onlinepreregistration portal and shiftingbusiness hours to better meet patientdemand. The Cleveland Clinic, which suf-

fered from long wait times for chemo -therapy, introduced targeted schedul-ing to address inefficiencies in infusionsuites. The patient satisfaction ratesoared to 98%.

Technology-Driven Oncology

Dr Booi anticipates strong growth inseeking treatment for prostate cancer,especially in the outpatient setting;much of this will be made up withreimbursable electronic visits, sheexpects. “I can imagine that this is kindof hard to grapple with. But thinkabout 2 years ago, could you haveimagined an iPad if you weren’t SteveJobs? And could you have imaginedthat today, iPads are being used forcheck-ins at cancer centers, for patienteducation, to keep patients entertainedduring treatment?”Dr Booi strongly believes that tech-

nology will revolutionize cancer care.“There are a lot of opportunities in thistechnology revolution that we canincorporate into the way we delivercare,” she said. �

Preparing for Future Trends... Continued from cover

Implementing the HITECH Rules... Continued from page 17

“The performance strategyfor colorectal cancer is toincrease your screening rates,because this is going to drivedownstream utilization ofsurgical resections….Thereare a lot of opportunities inthis technology revolutionthat we can incorporate intothe way we deliver care.”

—Rebecca Booi, PhD

may include implementing patientreminders, providing discharge in -structions, and secure online messag-ing. Providers may be compelled tohave 20% of their patients using webportals, Ms Cook said. Providers mustensure that a vendor is Health andHuman Services–certified.By 2015, stage 3 could require further

patient engagement, electronic self-management tools, EHR exchangingdata with personal health records,among other objectives. This process provides an opportuni-

ty to better engage patients in the treat-ment process. “Think about empower-ing your patient to be a part of care,”Ms Cook said. Patient portals have already been

implemented by some groups: 35% ofKaiser Permanente patients and 60%

of Group Health patients now usethe portals. “Not only do they givepatients electronic access to their healthinformation, but they give them toolsto manage a lot of transactions withinhealth,” Ms Cook said. “Their patientportals allow patients to requestappointments, request prescriptionrefills, and to do online consults forsimple things.”

Patient–Provider Communication

Responding to a question on pa -tients misinterpreting their raw med-ical data, Ms Cook noted that havingEHRs does not mean giving patientsaccess “to the entire chart” or theirentire information. Continuity-of-care documents and

continuity-of-care records are becom-ing the standard for communication

between provider and patient andbetween provider and provider. Ms Cook cited a recent Pew Internet

Research study (www.pewinternet.org/Press-Releases/2011/Health-Topics.aspx), which found that search-

ing for health information is the thirdmost popular activity online. In addition, a study published in the

Journal of Medical Internet Researchshowed that 75% of patients wantedonline access to medical records, labo-ratory results, and appointment sched-uling (Adler KG. Web portals in pri-mary care: an evaluation of patientreadiness and willingness to pay foronline services. J Med Internet Res.2006;8:e26).Patient privacy and security are

major concerns, and privacy advo-cates are pushing the government totake steps to strengthen data safe-guards. But the HITECH Act makesEHRs a certainty, and providersshould act proactively to implementa system that works best for theirpractice. �

“What people aren’tthinking about is what that really means. As youadopt technology into your office, what does that mean for patients and their families?”

—Gena Cook

See also article on page 36

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Washington, DC—Physicians aretugged in different directions bypatients, payers, and society at large(expressed via the legal system), withexpectations involving physicianautonomy, best practices, adherence tolocal standards of care, as well asnational guidelines. At the 2011 Association of Commun -

ity Cancer Centers Annual Meeting,oncologists debated the increasing roleof pathways and guidelines in clinicalpractice.

Variation in Treatment Not Always

a Bad Thing

Cary A. Presant, MD, FACP, anoncologist at the Wilshire OncologyMedical Group at the CaliforniaCancer Medical Center and Professorof Clinical Medicine at the Universityof Southern California Keck School ofMedicine, said that the 3 major trendsin medicine today—physician autono-my, guidelines or pathways, and per-sonalized medicine—often seem to bein conflict with one another.Physician autonomy goes to the

core of the profession, back to theHippocratic Oath of treating thepatient to the “best of my ability andjudgment,” Dr Presant said. “Physi -cian autonomy should not be let go of

in a setting where everyone seems tobe moving toward guidelines andpathways,” Dr Presant said. “Whatever is working seems to

change very quickly. Therefore, basingthe guideline on what has been work-ing may be basing the guideline onsomething that is really unsustain-able,” he reiterated.

A clinical oncologist is able to ac -count for factors such as the presence ofmultiple comorbidities that guidelinesmay not sufficiently take into account,or to analyze increasingly sophisticatedgenetic testing. In this sense, physicianautonomy and personalized medicinecan go hand in hand. “Society,” accord-

ing to Dr Presant, “grants doctors thatautonomy.”It is well established that guidelines

or pathways seek to diminish the vari-ation in treatment, which can lead topoor care and higher costs. This varia-tion, however, is not simply a result ofbad providers, Dr Presant claims;many physicians disagree about whatworks best. Imposing a single stan-dard can often be counterproductive. The narrowness of clinical trials fur-

ther makes it difficult to generalizesome standards to a broader patientpopulation, he said, noting that guide-line authors often have undisclosedconflicts of interest. “Decisions cannotbe made by one single guideline, or bya computer, or by one single laborato-ry evaluation.”

Pathways Allow for Patient

Variation

Presenting the other side of thisdebate, Roy A. Beveridge, MD,Executive Vice President and MedicalDirector at US Oncology, said he didnot perceive such tension betweenpathways and physician autonomy, orpersonal medicine. “In the pathways as they are now,

there are already provisions made forthose patients who have premeno paus -al or postmenopausal breast cancer;those patients who are PR [proges-terone receptor} positive or PR nega -

tive; those patients with colon cancerwho are KRAS positive and KRAS neg-ative; those patients with certain chro-mosomal abnormalities in terms ofleukemia or in terms of myeloma,” DrBeveridge said. US Oncology, a cancer healthcare

network with 460 community cancerpractices in 39 states, has developedLevel I Pathways known as InnoventOncology (www.innoventoncology.com). Innovent Oncology is continu-ously developed and maintained byUS Oncology member physicians,who access the system through a webportal and electronic health records.

“The development and use of evi-dence-based medicine by physiciansallows for physician autonomy andcontinues to apply the logic of Level Iunderstanding of treatments, whichallows for there to be even more per-sonalized care,” Dr Beveridge said.A study completed by Aetna

showed that providers using the LevelI Pathways lowered outpatient costsby 35% for patients treated for non–small-cell lung cancer, and thesepatients had the same 12-month over-all survival rate as patients not man-aged with this pathway. Dr Beveridge also countered con-

cerns that effective treatments arebeing put aside because of cost; thebest evidence-based treatment avail-able is always considered first line,and if 2 treatments have equal efficacy,toxicity will be taken into account todetermine use. If efficacy and toxicityare equal, the cost to patient and payerwill be considered as a pathway guide.Innovent Oncology also encourages

patient accrual to clinical trials; insuffi-cient patient participation in clinicaltrials continues to hinder drug re -search and development, according toDr Beveridge. �


ACCC ANNUAL MEETING

at a glance� Pathways and guidelines areincreasingly seen as the futureof oncology practice

� Some oncologists worry thatguidelines and pathways maybe compromising physicianautonomy to address patientvariability and best practices

� By contrast, other oncologistsbelieve that clinical guidelinesand pathways incorporate theprinciples of patient variabilityand differentiation in accord -ance with personal medicine

� The use of Level I Pathwayslowered outpatient costs by35% for patients treated fornon–small-cell lung cancer inone study, without compro -mising overall survival

“The development and useof evidence-based medicineby physicians allows forphysician autonomy andcontinues to apply the logicof Level I understanding oftreatments, which allows forthere to be even morepersonalized care.”

—Roy A. Beveridge, MD

Oncologists Debate the Place of Pathways and Guidelines in Clinical PracticeAre these tools compromising physicians’ autonomy and patient variability?By Daniel Denvir

“Physician autonomy shouldnot be let go of in a settingwhere everyone seems to bemoving toward guidelines and pathways. Whatever isworking seems to changevery quickly. Therefore,basing the guideline on whathas been working may bebasing the guideline onsomething that is reallyunsustainable.”

—Cary A. Presant, MD, FACP

Prominent Oncologist ApplaudsFirst Conference... Continued from page 16

patients can show the potential forthat drug for a much better selectedgroup of patients, and that shouldlead to more research to get to thepoint where we can identify the peo-ple who will benefit. With cancer medicine we are often

dealing with a continuum, and that iswhere the concept of incrementalbenefit comes in—if you have multi-ple regimens with incremental bene-fits for individuals, that can lead toprolongation of overall survival.Everyone would love to see a therapythat greatly improves the cure rateand greatly improves overall sur-vival. That clearly is possible if wecan better define populations of peo-ple where that may happen. But toget there, it is going to take muchmore profound understanding ofhuman biology. Continuing to invest

in drug development has to go handin hand with understanding tumorbiology. In summary, the design of clinical

trials will undergo a change in para-digm, where we are not just enteringhundreds or even thousands ofpatients on a given trial, but rather onstudies that are much more focusedwith selective populations, which willbe to everyone’s advantage in termsof risk versus benefit, efficacy, andresource utilization. People need to be speaking the

same language and understand theseprinciples. That takes all componentsof the healthcare enterprise to supportthese collaborative strategies. Wehope to see much more interactionamong the multiple stakeholders ofthe healthcare system, as has beenevident at this conference. �

ACCC ANNUAL MEETING


Accelerating Growth in REMS Programs a Challenge for Oncologists By Daniel Denvir

Addressing the 2011 Associ -ation of Community CancerCenters annual meeting atten-

dees, Timothy Tyler, PharmD, FCSHP,Director of Pharmacy Services at theDesert Regional Medical CenterComprehensive Cancer Center, PalmSprings, CA, outlined the considerabledemands and complications that havebeen added to oncology care with theintroduction of the Risk Evaluationand Mitigation Strategies (REMS) pro-gram for high-risk drugs. Many ofthese are cancer drugs, Dr Tyler said,and the US Food and Drug Admin -istration (FDA) has much work to doto calm provider fears and confusion. “REMS presents very significant

challenges for a lot of stakeholders,”said Dr Tyler. “Providers in communi-ty cancer centers have a fair number ofthese drugs.” He participated in aNational Comprehensive Cancer Net -work (NCCN) working group onREMS, which developed a white paperon increasing concerns in the oncologycommunity, including:• Increased and nonreimbursed work-load for physicians, pharmacists,and nurses

• A misleading focus on risks, not bal-anced against a discussion of benefits

• Lack of clarity and plain language inpatient communication

• Concern that onerous REMS pro-grams could make it potentiallyless likely for a provider to pre-scribe a drug and limit legitimateoff-label use.The NCCN group, however, also

recognized the potential for improvedpatient safety, citing examples inrecent years of major problems withprescription drugs (eg, Vioxx), whichis lending a sense of urgency to drugsafety. The FDA may now requiremanufacturers to develop REMS forboth existing and new drugs.

Risk a Familiar Face in Oncology

The oncology community is unique-ly well positioned to mitigate risk,despite the widespread use of oncologydrugs for off-label indications, he said.“The basic concern was that for

years we’ve had black box warnings,we’ve had contraindications,” said DrTyler. “In the oncology community,because we tend to go off label, theincorrect or correct assumption wasthat we’re not paying attention. Iwould say that because of the toxici-ties of the agents we’re dealing with,and the fragility of the patients, we

tend to be a little more in tune thanother populations.”Nurses and pharmacists, for exam-

ple, already use a double-check systemwhen administering chemotherapy. Thehigh toxicity of oncology drugs meansthat providers are already experiencedin discussing risks with patients.The most common REMS require-

ment is medication guides. Drugs thatpose a high-risk level can be required toinclude a communication plan for pro -viders. And oncology pharmacy direc-tors are now inundated with these. “Iget a stack of those a month,” he com-plained, but “how else do you commu-nicate with the prescribing communi-ty?” Dr Tyler asked. In the mosthigh-risk cases, an element to assuresafe use (ETASU) can be required,which can mandate prescriber training,certification, or credentials.

Manufacturers or Providers?

There is also concern that althoughthe FDA can only exercise control overmanufacturers, it is the providers whowill actually implement REMS in theclinical setting. “They don’t reallyhave any sticks or carrots. They’re justtrying to do what’s best by the prod-uct. Their biggest concern is havingtheir drug withdrawn from the mar-ket, which is the FDA’s ultimate trumpcard,” Dr Tyler noted.In 2010, an FDA panel decisively

rejected proposed REMS for opioids,insisting on a more exacting standardthat required training and not merelyeducation. The panel was respondingto growing concern about the wide-spread abuse of drugs such asOxycontin.

“The biggest drug category that’sbeen looked at is opioids,” Dr Tylerpointed out. “We use opioids likecandy in the oncology community.There are problems, but what’s thebest way to solve them?”

A Staggering Growth

The number of drugs subject toREMS is growing rapidly, from 136 inSeptember 2010 to 177 in March 2011,covering 113 unique entities (Table). All 177 drugs required a medication

guide, 43 required a communicationplan, and 21 required an ETASU. Of

those requiring an ETASU, 12 are usedin the cancer center setting; 11 are ofvital interest to oncology; and allexcept interferon are oral medications. All REMS were created or have been

modified over the past 18 months. Anadditional 46 drugs are related tohematology/oncology, 18 of whichhave a place in infusion centers, and 25include antibiotics.“If you’re involved in outpatient

care, you could see up to 82 of theseat the present moment. That’s kind ofa staggering number,” Dr Tyler point-ed out.Traditional chemotherapy has yet to

be subjected to REMS, but it is possiblethat it could. This would pose seriouschallenges to the oncology community.“It is an overwhelming force coming atyou. And in the physician office settingand the hospital setting, they don’thave a lot of slack,” he said. Dr Tyler cited a report saying that

33% of new molecular entities and bio-logic products approved by the FDA inthe first half of 2010 had REMSrequired.“All the paperwork we need to do is

not reimbursable. We might end updoing a lot to comply with the REMS,but there’s no added revenue. And Imay spend an extra 2 to 3 hours on apatient,” Dr Tyler noted.

Streamlining the Process

Electronic medical records and webtechnology could play an importantrole in streamlining REMS. “Efficien -cies become ever more important,” hesaid, so “electronic records, electronicinformation, is certainly one of thoseareas that is making it potentially easi-er for us to be compliant.”The NCCN working group recom-

mended streamlining the process andensuring that the burden does notbecome overwhelming, calling on theFDA and manufacturers to standard-ize risk categories and accompanyingREMS, and to deliver that informationthrough an online clearinghouse. Dr Tyler reports that the FDA

seemed to understand the problemsduring a 2010 meeting. He suggests,however, that Congress may ultimate-ly need to consider amending the FDAAmendments Act.“It is realistic to think that REMS can

help,” Dr Tyler said. “But as the num-ber and complexity of these thingsstart to skyrocket, challenges of bothprescribing and dispensing drugs aregoing to increase.” �

“It is realistic to think thatREMS can help. But as thenumber and complexity ofthese things start toskyrocket, challenges of bothpre scribing and dispensingdrugs are going to increase.”

—Timothy Tyler, PharmD, FCSHP

Table REMS Programs: September 2010 through March 2011

September 29, 2010 March 2, 2011

REMS programs: 136a REMS programs: 177a

Used in hematology/oncology: 6 Used in hematology/oncology: 11

Non-orals: 1 Non-orals: 6

Traditional drugs: 0 Traditional drugs: 0

Support hematology/oncology: 31 Support hematology/oncology: 46

Used in outpatient clinic: 11 (18 if adding antibiotics)

Used in outpatient clinic: 18 (25 if adding antibiotics)

Total REMS: 55 (~40%) Total REMS: 82 (~46%)

aExcluding deemed status and valid as of February 19, 2011.REMS indicates Risk Evaluation and Mitigation Strategy.Courtesy of Timothy Tyler, PharmD, FCSHP.

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If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

Please see Brief Summary for VELCADE on the next page of this advertisement.

UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP(36.7-month median follow-up)

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HR 0.65 (95% CI, 0.51-0.84); P=0.00084

In Previously Untreated Multiple MyelomaIMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT

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INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphomawho have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use ofantineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment withVELCADE.

Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while beingtreated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and adecreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients withpre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheralneuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment withVELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencingnew or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE.Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51%of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement inor resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. Thelong-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. Theseevents are observed throughout therapy. Caution should be used when treating patients with a history ofsyncope, patients receiving medications known to be associated with hypotension, and patients who aredehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensivemedications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset ofdecreased left ventricular ejection fraction have been reported, including reports in patients with no riskfactors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart diseaseshould be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure,cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causalityhas not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory DistressSyndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial,the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicinand VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therehave been reports of pulmonary hypertension associated with VELCADE administration in the absence ofleft heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonarysymptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patientsreceiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure,hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patientsdeveloping RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previouslyexperiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, andvomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid andelectrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia thatfollow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recoveringprior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases andrecovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence ofcumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In therelapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association withVELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, thecomplications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those withhigh tumor burden prior to treatment. These patients should be monitored closely and appropriateprecautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitantmedications and with serious underlying medical conditions. Other reported hepatic events includeincreases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upondiscontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure isincreased in patients with moderate or severe hepatic impairment. These patients should be treated withVELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma(N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) andpreviously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, thesafety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%),thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%),anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), coughand insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo);(each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension(each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia(each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) ofpatients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) andneutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%),and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination withmelphalan/prednisone is consistentwith the known safety profiles of bothVELCADE and melphalan/prednisone.The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vsmelphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea(48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%),constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%),pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%),asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%),rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%),dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain(14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%),hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension(12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%),arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposureof bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole,a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantlyreceiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closelymonitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS:

Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromVELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 andyounger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renalimpairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysisprocedure. For information concerning dosing of melphalan in patients with renal impairment, seemanufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate andsevere hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabeticpatients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADEtreatment may require close monitoring of their blood glucose levels and adjustment of the dose of theirantidiabetic medication.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139Copyright ©2009, Millennium Pharmaceuticals, Inc.

Brief Summary

All rights reserved. Printed in USA V1215 12/0910V-10-020410

Cambridge, MA 02139

GENITOURINARY CANCERS SYMPOSIUM


Orlando, FL—Abiraterone acetateholds promise of improving survivalin patients with metastatic castration-resistant prostate cancer across multi-ple patient subgroups, according toHoward I. Scher, MD, chief of theGenitourinary Oncology Service,Sidney Kimmel Center for Urologicand Prostate Cancers at MemorialSloan-Kettering Cancer Center, NewYork City, who reported results of atrial at the session “Prostate Cancer forthe Recurrent Disease” at the 2011Genitourinary Cancers Symposium. “Abiraterone acetate prolongs over-

all survival of men with metastatic cas-tration-resistant prostate cancer whohave progressed after docetaxel-basedchemotherapy, with a 35% reductionin mortality,” said Dr Scher. The drug is currently under review

by the US Food and Drug Admin -istration (FDA) and the manufacturersaid that an FDA decision is expectedlater this year. Early clinical studies suggested abi-

raterone acetate, a selective androgen

biosynthesis inhibitor blocking theaction of CYP17, restrains persistentandrogen synthesis from adrenal andintratumoral sources, thereby suppress-ing a growth stimulus for meta staticcastration-resistant prostate cancer.In a randomized, double-blind

study, Dr Scher and an internationalteam compared abiraterone acetate1000 mg daily and prednisone 5 mgtwice daily with placebo and pred-nisone in 1195 men with metastaticcastration-resistant prostate cancer,progressing after receiving docetaxel-based chemotherapy. Patients previ-ously treated with ketoconazole ormore than 2 previous chemotherapyregimens were excluded from thestudy. The 2 cohorts were well bal-anced in terms of age, race, perfor -mance status, pain, previous chemo -therapy regimens, type of progression,and extent of disease. In August 2010, after interim results

showed significant improved overallsurvival in the active cohort, the studywas unblinded, and men in the place-

bo group were offered abirateroneacetate. “The favorable effect on over-all survival was observed across multi-ple patient subgroups, including thosewith 1 prior chemotherapy, visceral dis -ease, as well as a pain intensity of 4 orgreater,” Dr Scher said.Nicholas J. Vogelzang, MD, head of

the Section of Genitourinary Cancer atthe Nevada Cancer Institute in LasVegas, said at the meeting that contin-uing the long trial was a waste of livesand money, because the researchers, ofwhich he was an investigator, saw theagent was active after 10 to 12 patients.Adverse events were similar in the 2

cohorts. Fluid retention and hypo ka -lemia were the 2 most common ad verse

reactions in the abiraterone group, butthey were typically low grade. Therewas a slight 2% increase in cardiac dis-orders, primarily tachycardia and atrialfibrillation, in the treatment group, butDr Scher said, the cardiac conditionswere easily managed. A. Oliver Sartor, MD, Professor of

Medicine at Tulane University in NewOrleans and co-chair of the session,commented that abiraterone acetatewill be a “game changer” in treatingmen with metastatic castration-resis-tant prostate cancer. “It will provide a new alternative for

patients with castration-resistant pros -tate disease postdiagnosis,” Dr Sartorsaid. “It will change practice.” �

Abiraterone Acetate Prolongs Survival in MetastaticProstate Cancer Potential game changer for men with this disease By Debra Wood, RN

“Abiraterone acetate prolongs overall survival of men with metastatic castration-resistant prostate cancer who have progressed after docetaxel-basedchemotherapy, with a 35% reduction in mortality.”

—Howard I. Scher, MD

Mutational Analysis Leads Search for New Treatments for Bladder CancerOrlando, FL—Novel therapies aredesperately needed for bladder can-cer, a common malignancy with apoor prognosis for advanced disease,said Matthew I. Milowsky, MD, medi -cal oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC),New York City, at the 2011 Genito -ur inary Cancers Symposium. “Bladder cancer is an absolutely

devastating disease, and the molecularcharacterization of these tumors isexciting,” Dr Milowsky said. Understanding of genetic muta-

tions associated with bladder cancerwill lead to targeted therapies, alreadyused in other cancer types. “If we areable to understand the molecularalterations that occur, then we can usemultiple therapies targeting thosealterations,” he said. “We are not thereyet, but we are getting close.”A number of genes associated with

bladder cancer are known to har -bor mutations, according to DrMilowsky. Low-grade, genomicallystable lesions are characterized byupfront alterations in fibroblastgrowth factor 3 (FGFR3) and the

HRAS gene, whereas high-grade,invasive tumors are characterizedupfront by alterations in tumor sup-pressors, such as p53, Rb, and PTENgenes, with a subgroup of tumorshaving mutations and overexpres-sion of FGFR3.

FGFR3 mutations are present inapproximately 15% of invasive bladdertumors, and overexpression occurs inapproximately 40% of invasive tumors.The MSKCC Bladder Cancer Onco -

genome Project uses mutational profil-ing, structural variation, and methyla-tion events to identify known driveralterations for guiding treatment ortrial selection and to identify geneticdrivers in patients in whom no knowndriver alteration has been identified. The team profiled select mutations

from 137 high-grade bladder cancerspecimens. They found FGFR3 muta-tions in 16 samples, BRAFmutations in2 of the tumors, PIK3CA mutations in17 specimens and Tp53mutations in 19samples. Dr Milowsky said it was pos-sible to identify morphologies usingmicroscopy and sort out patients withFGFR3mutations for clinical trials, and

he foresees a time when a physiciancan perform a core biopsy, subject it toa biomarker analysis, and use an agentto target the molecular alterations. Novel agents are being investigated

for genitourinary cancer targetingFGFR3, PIK3CA, and BRAF, and haveshown promising activity in other dis-eases. For example, TKI258 (dovitiniblactate) is a potent inhibitor of fibro -blast growth factor, vascular endothe-lial growth factor, and platelet-derivedgrowth factor receptor tyrosine kinas-es, which is now in clinical trials for

urothelial carcinoma. Other agents tar-geting the epidermal growth factorreceptor/HER2 pathway are ap provedfor other cancers.—DW �

“If we are able tounderstand the molecularalterations that occur,then we can use multipletherapies targeting thosealterations. We are notthere yet, but we aregetting close.”

—Matthew I. Milowsky, MD

CyberKnife Cost-Effective inthe Long-TermOrlando, FL—Although the cost ofCyberKnife to treat prostate cancer isinitially higher than surgery—anequally effective therapy—patientsexperience a better quality of life withCyberKnife than with other treatmentmodalities and have lower lifetimecosts compared with radiation andproton therapies.

CyberKnife uses image-guidedstereotactic radiosurgery to targettumors and requires fewer visits thanneeded with external beam radia-tion. Researchers at Innovus, SanFran cisco, used a Markov model tocompare payer and societal costsassociated with surgery, CyberKnife,


Orlando, FL—Most cases of prostatecancer biochemical recurrence afterradical prostatectomy occurs within 10years of surgery, and men whoprogress after that period are less like-ly to develop metastasis or die fromprostate cancer, according to results ofa large study conducted by a team ofexperts at Johns Hopkins MedicalSchool. The team concluded that clini-cians could counsel patients aboutrisks but stop prostate-specific antigen(PSA) testing 10 years postoperative.Stacy Loeb, MD, chief urology residentat Johns Hopkins, reported on theirfindings at the 2011 GenitourinaryCancers Symposium.“It’s reasonable to stop PSA testing

10 years after the radical prostatecto-my,” Dr Loeb said, adding that this is

the first large study with long-termfollow-up to evaluate the need forPSA, which can provoke great anxiety.“There are financial burdens and psy-chological complications of” repeatingthe test.

Large Study, Clear Results

Dr Loeb and colleagues studied10,609 men with clinically localizedprostate cancer who underwent radi-cal prostatectomy at Johns Hopkinsbetween 1978 and 2009, did notreceive hormonal therapy before sur-gery, and had accessible data aboutfollow-up care. At some point, 1648men (15.5%) developed biochemicalrecurrence. “The vast majority [of recurrences]

occurred within the first 5 years, and

then it dramatically dropped off,” DrLoeb pointed out. “Only 6.4% of therecurrences were after 10 years. Therewere very few of them.”Supporting the team’s conclusion

that PSA was not necessary after 10years were their data showing that:• Men with early recurrences weremore likely to develop metastasisthan men with late recurrences

• Men who progressed early on weremore likely to die from prostate can-cer than other men

• Among the men with a Gleasonscore of 6 with late recurrence, noone subsequently died.“Late recurrences are of a more

indolent fashion, most likely related tothe tumor biology,” Dr Loeb empha-sized. “It is so slow for the recurrence.It takes a long time to develop into aclinical event.”Dr Loeb said she hoped other

prostate cancer experts with long-termdata will analyze those cases and helpto develop a guideline for PSA testing,indicating that it is safe to stop PSAscreening if the cancer is undetectableafter 10 years.“We’re also interested in looking to

see if we can space it [the testing] outmore, perhaps every 2 or 5 years,which would decrease cost and anxi-ety,” Dr Loeb said. �

GENITOURINARY CANCERS SYMPOSIUM


Large Study Rules PSA Test Unnecessary >10 Years afterRadical ProstatectomyClinicians urged to counsel patients based on this evidence By Debra Wood, RN

“It’s reasonable to stop PSAtesting 10 years after theradical prostatectomy. There are financial burdens andpsychological complications of” repeating the test.

—Stacy Loeb, MD

CyberKnife Cost-Effective... Continued from page 25

intensity-modulated radiation thera-py (IMRT), and proton therapy andtheir related adverse events inpatients aged ≥65 years with prostatecancer. Societal costs include itemsassociated with a productive life andpaid for by the individual or family. “Surgery is cheaper, but is Cyber -

Knife better?” asked Anju Parthan,PhD, Senior Project Manager forHealth Economics & OutcomesResearch at Innovus. “It costs more,but you can have improved quality oflife,” she commented.All possible combinations of gas-

trointestinal, genitourinary, and sexualdysfunction long-term toxicities wereincluded. Toxicity probabilities wereobtained from the pooled results ofmultiple studies. Costs were assignedbased on published sources.The model projected lifetime costs

and quality-adjusted life-years (QALYs)for each treatment. Total lifetime costsfrom a payer perspective were:• $25,904 for CyberKnife• $22,295 for surgery• $38,915 for IMRT

• $58,100 for proton therapy. The incremental cost per QALY

gained with CyberKnife over surgerywas $9200 from a payer perspectiveand $4800 from a societal perspective. Dr Parthan said, “$9200 is a small

dollar value in the threshold of whatpayers are willing to pay for qualityof life.” That threshold “is in the$50,000 to $100,000 range in theUnited States.”At a threshold of $50,000 per QALY,

CyberKnife was cost-effective from apayer perspective 84% of the time. Dr Parthan added that a head-to-

head trial ideally would be used todetermine the most cost-effectivetreatment, but limitations associatedwith randomization do not make thatpos sible. Therefore, the research company

conducted a sensitivity analysis andconcluded that CyberKnife is a cost-effective strategy compared with sur-gery, and that its costs are less, withbetter quality of life, than externalbeam radiation therapy or protontherapy.—DW �

Orlando, FL—Very little is knownabout the underlying biology of neu-roendocrine prostate cancer, an ag -gressive form of the disease that canarise on its own or from an existingprostate adenocarcinoma. Patientstypically die within 1 year of diagno-sis, despite aggressive chemotherapy.New research suggests a clonal originof neuroendocrine prostate cancersfrom prostate adenocarcinoma andpossible treatment targets.At the 2011 Genitourinary Cancers

Symposium, Himisha Beltran, MD, afellow at Weill Cornell MedicalCollege, NY, reported about the use ofnext-generation RNA sequencing andoligonucleotide arrays to profile neu-roendocrine prostate cancer, prostateadenocarcinoma, and benign prostatesamples to assess for specific geneexpression. “We found Aurora kinaseA changes in neuroendocrine prostatecancers,” Dr Beltran said. She was pre-sented with the Merit Award forYoung Scientists at the meeting. Aurora kinase A, a cell-cycle kinase,

was overexpressed in the neuroen-docrine prostate cancer samples, andincluded a gene amplification ofAurora kinases and N-myc. “The functional distribution shows

they cooperate and can induce the

neuroendocrine phenotype in adeno-carcinoma cells involved in progres-sion,” Dr Beltran said. Only 5% of the prostate adenocarci-

noma samples had an Aurora kinaseor N-myc alteration, and it was notfound in any of the benign samples.

The researchers observed in vitroand in vivo sensitivity to the Aurorakinase inhibitor PHA-739358 in theneuroendocrine prostate cancer sam-ples but not in the adenocarcinomasamples. Neuroendocrine marker ex -pression was suppressed in the treatedxenografts. “Treatment with a kinase inhibitor

should prove effective for neuroen-docrine prostate cancer,” Dr Beltranconcluded.—DW �

“Treatmentwith a kinaseinhibitorshould proveeffective forneuroendo -

crine prostate cancer.” —Himisha Beltran, MD

Potential New Options for Neuroendocrine ProstateCancer

��

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On March 30, 2011, the Centersfor Medicare & MedicaidServices (CMS) announced its

highly anticipated proposed nationalcoverage decision concerning theprostate cancer immunotherapy sip-uleucel-T (Provenge; Dendreon). Thebiologic medication (which is oftenlabeled a “vaccine” because of itsimmunotherapeutic properties but israther a therapeutic, not a prophylac-tic, product) was approved by the USFood and Drug Administration (FDA)in April 2010 for the treatment of menwith asymptomatic or mildly symp -tomatic metastatic prostate cancer.According to the CMS proposed deci-sion, Medicare will reimburse payersfor the FDA-approved indication forthe drug and leave the coverage deci-

sion for off-label uses to its contractors. CMS “proposes that the evidence is

adequate to conclude that the use of[the] autologous cellular immunother-apy treatment—sipuleucel-T; Provengeimproves health outcomes for Medi -care beneficiaries with asymptomaticor minimally symptomatic metastaticcastrate-resistant (hormone refractory)prostate cancer, and thus is reasonableand necessary for that indication”(www.cms.gov). With the cost of this therapy estimat-

ed at $93,000 per patient, this product,like many recent cancer products, rais-es yet again the question of value fortherapies that extend life by weeks ormonths (the drug appears to extendlife on average by approximately 4months, although it is possible that in

a subset of patients this time could beextended considerably). On the FDA approval of the drug,

CMS instructed the Medicare Evi -dence Development and CoverageAdvisory Committee to review theevidence from clinical trials as part ofits coverage determination, an unusu-al step for CMS, considering the prox-imity of this process to FDA approval.

Off-Label Use

So far no evidence is available tosupport the use of Provenge for off-label uses in patients with prostatecancer. In what is considered an unex-pected move, CMS has left the cover-age decision for off-label use to payers’discretion. CMS says that this is in an effort to

allow access to the drug to patients inclinical trials that involve off-labeluses, with the hope “that unlabeleduses in the near future will take placeonly in the context of bona fide clinicalstudies,” discouraging providers fromprescribing it independent of clinicaltrials. “If this turns out to be an overlyoptimistic viewpoint,” however, CMSmay reconsider this strategy to makesure the Medicare coverage “is re -stricted to uses that are supported byrobust evidence.” Nevertheless, it is quite likely that

this decision also signals CMS’s hopethat payers will use the same evi-dence-based criteria to refuse to payfor off-label uses of the drug, again vis-à-vis its cost and the increasingly lim-

For all the talk about personalizedmedicine, in most cases the toolswe have in oncology are more

often disease site–focused than per-sonalized. Each tumor type has a list ofpotentially active agents. For example,in kidney cancer, I can talk to mypatients about sunitinib (Sutent),pazopanib (Votrient), bevacizumab(Avastin) and interferon, sorafenib(Nexavar), temsirolimus (Torisel), andeverolimus (Afinitor). However, I cannot tell an individual

patient which agent has the best prob-ability of working for him or her. Andwhen I see patients who have unex-pected outcomes, I am often left won-dering, what makes this person differ-ent? Why did he/she have such adramatic response? Or, why has thedisease progressed so quickly?In a perfect world, we would submit

a piece of tumor tissue or a blood sam-ple to the laboratory and receive areport that outlines the best treatmentfor that specific patient. Rather thanthinking of a patient’s tumor as lungcancer or breast cancer, we wouldthink about tumors in terms of theirmolecular markers and their potentialfor response to a particular targetedtherapy. This would allow us to improve the

value of the targeted therapy. Patients

would only be treated with medica-tions that were expected to help them,and clinicians would not waste valu-

able time treating them with agentsthat have no benefit and that can causetoxicity (both physical and financial).

Notable Examples

Two notable examples illustrate howwe can achieve our goal of practicingpersonalized medicine. The OncotypeDX assay measures the expression of21 genes to calculate a recurrence scorefor women with early-stage breast can-cer, allowing oncologists to identifywho is most likely to experience arecurrence and who is most likely tobenefit from chemotherapy, in an effortto reduce the risk of cancer recurrence.The assay is also a valuable tool inidentifying women who are destinedto do well without chemotherapy andcan be spared its toxicity. In patients with advanced colorectal

cancer, KRAS testing has helped toidentify patients with advanced col-orectal cancer who are unlikely torespond to agents targeting the epider-mal growth factor receptor, such aspanitumumab (Vectibix) or cetuximab(Erbitux).What the Oncotype DX assay and

KRAS testing have in common is thattheir clinical utility was establishedusing banked specimens from clinicaltrials. When used in the appropriatepatient population, we now know

how to interpret these test results, andhow to use the information to guideclinical practice, by identifying appro-priate candidates for therapy. Novel molecular tests have most

value when validated data demon-strate that they improve outcomesthrough better patient selection com-pared with established clinical criteria.

The Value of Clinical Trials

To optimize the potential value ofpersonalized medicine, physicians andpayers need to encourage patients toenroll in clinical trials. Currently only5% of American patients enroll in clin-ical trials; this slow pace delays thecompletion of studies and the transla-tion of new knowledge into practice. Providers should encourage eligible

patients to explore clinical trials earlyin their disease course, instead of as alast-resort option. Payers should elim-inate barriers to clinical trial coverage.Otherwise, countless patients willcontinue to be treated with standardtherapy. When treatment is given outside of

clinical trials, no primary data are col-lected or specimens banked. This infor-mation is critical to the development ofnew molecular tests to further person-alize medicine and improve the valueof treatment for future patients. �

VBCC PERSPECTIVE


CMS’s Coverage Decision on Provenge: Implications for Payers By Dalia Buffery, MA, ABD

The Potential for Personalized Medicine to Improvethe Value of Targeted TherapyBy Yu-Ning Wong, MD, MSCE, Medical Oncologist, Fox Chase Cancer Center, Philadelphia, PA, and Editorial Board Member of Value-Based Cancer Care


Novel molecular tests havemost value when validateddata demonstrate that theyimprove outcomes throughbetter patient selection.Currently only 5% ofAmerican patients enroll inclinical trials; this slow pacedelays the completion ofstudies and the translation of new knowledge intopractice.

HEALTH POLICY

See also article on page 49

HEALTH POLICY


ited resources for regional plans. Infact, it can also be argued that in itsstatement cited above, CMS is sendinga message to the company that off-label uses should be limited to clinicaltrials only at this point. It may also besending a message to other developersof oncology products that it would belooking at off-label uses more carefullyin the future. Time will tell.

VBCC Perspectives Revisited

Commenting on the question of off-label use after the approval of the druglast year in the October issue of VBCC,Lee Newcomer, MD, VBCC editorialboard member and Business Leader ofOncology Services for UnitedHealth -care, said, “Using the therapy forpatients who do not meet the preciseindications is simply conducting a$93,000 clinical trial with 1 subject.” A second VBCC editorial member,

Yu-Ning Wong, MD, MSCE, AssistantProfessor at Fox Chase Cancer Center,noted that “Oncologists are trained tocounsel patients about risks and bene-fits, including treatment-associatedsurvival improvement and toxicities.However…physicians are ill preparedto add the ‘cost and value’ dimensionto these discussions.”

Patient Registry to Provide

Additional Data

After its recent decision, CMS hasannounced it is “requesting publiccomments on this proposed determi-nation pursuant to section 1862 (l) ofthe Act. After considering the publiccomments, we will make a final deter-mination and issue a final decisionmemorandum.” CMS is expected toissue its final ruling by June 30, 2011.In its February 24, 2011, letter to

CMS, Dendreon noted it would ana-lyze its patient registry with the goal ofproviding long-term real-world infor-mation for various subgroups of

patients. The company expects thatmany patients in the registry are likelyto be Medicare patients, which willpresent the opportunity “to compareacross age-groups.” The company’s patient registry

will also support analysis of whetherblack men could benefit more thanother groups from Provenge. This isin response to comments by CMS ofan underrepresentation of black menin clinical trials of this drug (which is

not an uncommon situation in clini-cal trials conducted by many phar-maceutical companies), although theprostate cancer mortality rate amongblack men is double that of whitemen. �

With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology

offers health plans and oncology practices a comprehensive solution that enhances the quality and

consistency of patient care. With evidence-based medicine as the foundation of the program, we

further help patients by providing direct, personalized support and education between office visits

as well as advance care planning regarding future treatment and care preferences. Through this

patient-centric approach, we help health plans and oncology practices collaborate by aligning

incentives to drive better patient outcomes as well as encourage the efficient use of healthcare

resources. After all, isn’t cancer a disease we should manage together?

To learn more about how Innovent Oncology is transforming cancer care, visit us at innoventoncology.com or call 866-214-2194.

CMS’s Coverage Decision on Provenge... Continued from page 28

It can be argued that CMSis sending a message tothe company that off-label uses should belimited to clinical trialsonly at this point. It mayalso be sending a messageto other developers ofoncology products that itwould be looking at off-label uses more carefullyin the future.

On February 8, 2011, the USFood and Drug Admin is tra -tion (FDA) Oncologic Drugs

Advisory Committee (ODAC) voicedits support for tightening up theagency’s accelerated approval processfor new cancer drugs. The agency hasbeen criticized for failing to police theprogram, allowing drug companiesthat did not complete required post-marketing studies to keep the drugs onthe market for years. ODAC must strike a difficult bal-

ance, ensuring patients’ expeditedaccess to potentially life-saving med-ications, while keeping potentiallytoxic and untested treatments off themarket.Lee Newcomer, MD, UnitedHealth

Group Senior Vice President forOncology, supported the move. “TheFDA’s first responsibility is determin-ing safety and effectiveness,” he toldValue-Based Cancer Care (VBCC). “Theycompromised on the standards toallow access to potentially importantdrugs, but they still have the obliga-tion to ensure that the drugs did meetstandards.”

Postmarketing Issues

The committee quizzed 4 drug com-panies that had not yet completedpostmarketing trials on drugs ap -proved for 6 different indications,and discussed the following commonconcerns:• The prevalence of single-arm trialsover randomized clinical trials

• The timing of postmarketing trials• The number of trials that should berequired

• Holding pharmaceutical companiesaccountable when they depend oncooperative group trials conductedby others. “Water tends to seek its lowest

level,” said Richard Pazdur, MD, FDADirector of Oncology Drug Products.“And we frequently find sponsorscoming in and saying, ‘Dr Pazdur,what’s the fewest number of patientsand the lowest response rate that you’lltake?’ That’s problematic for us.”The accelerated approval program

has expedited the availability of drugsthat show early benefit on surrogateend points (eg, response rate and dura-tion). The approval is conditioned onresults of postmarketing trials meetinga definitive end point.In September 2009, a Government

Accountability Office report criticizedthe FDA for allowing pharmaceuticalcompanies to drag out postmarketingtrials. Failing to complete such trialsis now a federal violation subject to

financial penalties. Although the FDAhas yet to issue such a fine, the pres-sure is growing for heightened scruti-ny. The recent case of Avastin (beva-cizumab) is one such example. “While there’s no regulatory defini-

tion of due diligence related to thecompletion of postmarketing clinicaltrial requirements,” said Paul Kluetz,MD, Medical Officer at the FDADivision of Drug Oncology Products,“most would agree that over 7 years ofmarketing, an unproved drug, withat least some level of toxicity, is sub-optimal.” Barriers cited by drug com-panies include:

• Shifting standards of care • Difficulty of enrolling patients in arandomized trial of a drug that hasalready received the FDA’s impri-matur.According to Dr Kluetz, 49 new

indications for 37 oncology drug prod-ucts have been approved since theprogram was expanded to oncologydrugs in 1996. Of these drugs, 27 havecompleted required trials with a veri-fied clinical benefit; in addition, com-

panies have not been able to prove5 indications.

Pro and Con

Unlike the FDA’s accelerated ap -prov al process, the European “condi-tional approval” process must berenewed annually. By contrast, thisODAC meeting was its first since2005 to review postmarketing re -quirements.Silvana Martino, DO, Director, The

Angeles Clinic Breast Cancer Program,strongly criticized the FDA. “I’m verydisappointed that this process ofapproval has really become a screen-ing process,” she said. “Everyone’sinterested in ‘what is the least that wehave to offer.’ I think that this commit-tee and the FDA and others haveallowed that to become the mood ofscience within the field of oncol -ogy...where we are willing to acceptdrugs with the most minimal evi-dence….We’re dealing with drugs thathave barely any activity.” Acknowledging the need for

change, Dr Kluetz nevertheless insist-ed that, “While accelerated approvalallows for earlier marketing of promis-ing drugs, it does come at the expenseof increased uncertainty,” he said.“And while 10% of oncology indica-tions approved under acceleratedapproval were unable to prove a bene-fit, this should not be thought of as a

failure….The tradeoff is for earlieravailability of promising agents forsevere and life-threatening diseases.”Jeff Allen, PhD, Executive Director

of Friends of Cancer Research, sup-ports the program and cautionedagainst an overreaction. “The acceler-ated approval process has historical-ly shown to be an important tool toprovide patients with timely accessto highly beneficial treatments,” hetold VBCC.

“The FDA should have the appro-priate authority to ensure confirmato-ry trials are efficiently conducted. Butthere needs to remain a level of flexi-bility that allows the FDA and spon-sors to develop the desired evidence insuch trials. A blanket requirement forrandomized controlled trials may notbe the most appropriate approach inall cases,” said Dr Allen.

What Type of Postmarketing Trials?

Single-Arm Trials

Members of the panel agreed thatsingle-arm studies should be limited,acknowledging that those could beuseful in researching treatments forrare cancers. Of the cancer drugs ap -proved under the accelerated approvalprogram, 20 were based on random-ized clinical trials and 29 on single-arm studies. “There seems to be a real possibility

in a lot of these situations for runninga randomized trial,” said RalphD’Agostino, PhD, Boston UniversityProfessor and Chair of Mathematicsand Statistics. “And that should be thefirst item on the table.”With increased focus on molecular

therapies and subpopulations of pa -tients, randomization may not alwaysbe possible. “I don’t think anyonewould be interested in giving patientsa drug that doesn’t work, but if anexceptional case comes along withtruly outstanding results, there may bebetter approaches to sufficiently de m -on strate efficacy,” said Dr Allen.

Confirmatory Trials

The ODAC members unanimouslyagreed that the FDA should requirecompanies to complete 2 clinical trialsto prove benefit after receiving accel -erated approval. According to DrPazdur, oncology is alone in requiringonly 1 trial.

HEALTH POLICY


ODAC Supports Tightening Up Accelerated Approvals for New Cancer DrugsLax approach to postmarketing trials at issue By Daniel Denvir

“The FDA’s first responsibility isdetermining safety and effectiveness.They compromised on the standards toallow access to potentially importantdrugs, but they still have the obligationto ensure that the drugs did meet standards.” —Lee Newcomer, MD

“The accelerated approvalprocess has historicallyshown to be an importanttool to provide patients withtimely access to highlybeneficial treatments.”

—Jeff Allen, PhD

“While 10% of oncologyindications approved under accelerated approvalwere unable to prove a benefit, this should not be thought of as a failure.”

—Paul Kluetz, MD


Late last year, Frank R.Lichtenberg, PhD, Courtney C.Brown Professor of Business at

the Columbia University GraduateSchool of Business, NY, was awardedthe 2010 Garfield Economic ImpactAward, which is given annually to rec-ognize the work of economists whodemonstrate how medical and healthresearch impacts the economy. Theaward was given specifically for hisstudy, “The Effect of New CancerDrug Approvals on the Life Expec -tancy of American Cancer Patients,1978-2004.”1

Cancer Drug Costs Lower Than

Expected

This award-winning study showedthat cancer drugs that were introducedbetween 1978 and 2004 increased thelife expectancy of American patientswith cancer by almost 1 year, and thatthe cost of this additional year is<$7000 per patient, much lower thanprevious estimates of what Americansare willing to pay for an additionalyear of life.1

Given the recent, and increasinglyexpensive, developments in cancerdrug therapies, that annual costsounds low, but Dr Lichtenbergexplains that his is “a historical study.Most of the drugs taken by patientswith cancer are not brand new drugs.

In general, most drugs…are 20 yearsold, are off patent, and available ingeneric form. Therapy, then, becomesmuch less expensive.” However, “Most new therapies are

extremely expensive,” he acknowl-edged, “but the number of patientsusing them is relatively small com-pared with the overall population ofpatients with cancer.”

To back up this contention, DrLichtenberg cited ongoing work inwhich he has analyzed data on the top6 drugs used in 2008—4 of them werelaunched before 1984. And the 2 topdrugs were launched before 1996(unpublished data). “The point is thatthe most commonly used drugs arenot the brand new ones, and theydon’t account for a large fraction oftotal drug expenditure. If new drugswere widely used,” he acknowledged,

“they would indeed push coststhrough the roof.”Currently, cancer drugs account

for 5% of total drug expenditure,according to Dr Lichtenberg, anddrugs account for about one tenth oftotal healthcare expenditure. So can-cer drugs may account for half of 1%of total healthcare expenditure, hesuggested.

Innovation and Cancer Survival

The connection between innovationand patient longevity is a major aspectof Dr Lichtenberg’s work. His previ-ous research has shown that in someparts of the United States, new drugshave been adopted faster than in oth-ers, and in those states, there tended tobe faster growth in life expectancy.2

In another study looking at 5European countries, he found slowerdrug uptake in the United Kingdomrelative to other countries in Europe(including France, Spain, and Ger -many); perhaps not surprisingly there-fore, survival in the United Kingdomhas been worse.3 This slower druguptake in the United Kingdom maybe related to NICE (National Institutefor Health and Clinical Excellence),which carefully controls drug usebased on costs, but Dr Lichtenbergacknowledged that he has not studiedthis formally.Dr Lichtenberg is currently working

on a paper looking at innovation inpharmaceuticals and diagnostic imag-ing and the impact of innovation inthese 2 sectors on cancer mortality.4

Overall, imaging innovation and druginnovation jointly explain about 75%of the decline in cancer mortality. “Where there has been the most

rapid utilization of advanced imaging,we have also had the largest reductionsin cancer mortality,” Dr Lichtenbergelaborated. “In fact, the survival gainsfrom advanced imaging may be evenlarger than the survival gains fromchemotherapy innovation.”

The Value of Cancer Therapies

In terms of whether the economistand the oncologist might actually worktogether, Dr Lichtenberg acknowl-edged, “I’m not too closely connectedto the oncology community. I’ve occa-sionally interacted with ASCO [Ameri -can Society of Clinical Oncology] andother organizations, but my approachis more from 30,000 feet.” With regard to the physician–patient

discussions on the value of cancer ther-apies, he recognizes the differences inperspective between economists andpatients. “In principle, economists be -lieve that as a society we should consid-er benefits and costs. This is what com-parative effectiveness is about.” But interms of an individual patient, “aMedicare patient doesn’t care what thatorganization pays [for a treatment],only what he as an individual pays.” Cost discussions with patients are

relevant, Dr Lichtenberg noted, espe-cially for very expensive therapies.And if the government is paying forthese medications (as in the case ofMedicare Part D), there is no reasonwhy the government cannot exercise arole in terms of reimbursement, hesuggested.Clearly, insurance affects decision-

making; when people have insurance,they are not price-sensitive, and thiscan lead to excessive utilization oftherapies that are not necessarilyworthwhile. “We cannot expectpatients or physicians to be too con-cerned about costs if they are not bear-ing those costs,” Dr Lichtenberg con-cluded. �

References1. Lichtenberg FR. The effect of new cancer drugapprovals on the life expectancy of American cancerpatients, 1978-2004. Econ Innovation N Technol. 2009;18:407-428.2. Lichtenberg FR. The Quality of Medical Care,Behavioral Risk Factors, and Longevity Growth.NBER Working Paper No. 15068. Issued June 2009.www.nber.org/papers/w15068. Accessed December13, 2010.3. Lichtenberg FR. The effect of cancer drug vintage oncancer survival and mortality. Ann Oncol. 2007;18(suppl 3):iii67–iii77.4. Lichtenberg FR. Has medical innovation reducedcancer mortality? NBER Working Paper No. 15880.Issued April 2010. www.nber.org/papers/w15880.Accessed December 13, 2010.

CANCER DRUGS


Cancer Drugs and Life Expectancy Focus of Health Economist Based on an interview with Frank R. Lichtenberg, PhD

“We cannot expect patientsor physicians to be tooconcerned about costs if theyare not bearing those costs.”

—Frank R. Lichtenberg, PhD

“Where there has been the most rapid utilization of advanced imaging, we have also had the largestreductions in cancermortality.”

—Frank R. Lichtenberg, PhD

ODAC Supports Tightening...Continued from page 30

“It’s a basic principle of science,”noted Dr Newcomer. “Any observa-tion should be confirmed by an inde-pendent observer.”

Timing. Most ODAC members sup-ported requiring that postmarketingtrials be under way at the time of accel-erated approval.

Cooperative groups. ODAC membersvoiced support for making it necessaryfor only 1 of 2 confirmatory trials tobe conducted through cooperativegroups. Pharmaceutical companiescan not cede responsibility to coopera-tive groups, which carry out such stud-ies for their own purposes.There was concern over

GlaxoSmith-Kline’s failure to fulfillpostmarketing requirements in trialsfor Bexxar (tositumomab and iodine131I tositumomab) therapy to treat

relapsed and refractory low-grade fol-licular lymphoma. Two postmarketingcommitments were delayed and 1 isongoing. One of the trials set out tocompare Bexxar and rituximab(Rituxan) and had trouble accruingsufficient patients, seeking FDA per-mission to shift to a study that isalready being carried out by theSouthwest Oncol ogy Group. “We cannot be in a situation where a

regulatory requirement is transferredto a third party,” said Dr Pazdur.But some on the panel emphasized

that cooperative groups had been suc-cessful, particularly in pediatrics. DrNewcomer echoed the concern, cau-tioning against too much rigidity. “Thekey is doing a good study,” he said,“not the organizational structureunder which it is accomplished.” �

Progression-free survival (PFS) after progression on sunitinib or sorafenib1

100

80

60

40

20

Time (months)

Prob

abili

ty (%

)

Afinitor

4.9 months

1.9 months

Placebo

Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9)

Log rank P value=<0.0001

Hazard Ratio=0.3395% CI [0.25, 0.43]

0 2 4 86 10 12 14

4.9 months median PFS with Afinitor + BSC† (vs 1.9 months with placebo + BSC; P<0.0001)1

HR 0.33=67% reduction in risk of progression

Effective for patients with all prognostic scores1

Afinitor doubled median PFS after progression on sunitinib*1

In advanced RCC:

For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.comFor reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648).

*In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2

†BSC=best supportive care.

Important Safety InformationThere have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oralulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions ofhemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Please see Important Safety Information on right side of page.Please see Brief Summary of full Prescribing Information on the following pages.

Ins

References: 1. Afinitor [prescribing information]. East Hanover, NJ: NovartisPharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cellcarcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet.2008;372:449-456.

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2010 Novartis Printed in U.S.A. 10/10 AFI-1002330

22..55mmgg 55mmgg 1100mmgg

Afinitor is indicated for the treatment of patients withadvanced renal cell carcinoma after failure of treatmentwith sunitinib or sorafenib.Important Safety InformationAfinitor is contraindicated in patients with hypersensitivityto everolimus, to other rapamycin derivatives, or to any ofthe excipients.Non-infectious pneumonitis is a class effect of rapamycinderivatives, including Afinitor. Fatal outcomes have beenobserved. If symptoms are moderate or severe, patientsshould be managed with dose interruption until symptomsimprove or discontinuation, respectively. Corticosteroidsmay be indicated. Afinitor may be reintroduced at 5 mgdaily depending on the individual clinical circumstances.Afinitor has immunosuppressive properties and maypredispose patients to bacterial, fungal, viral or protozoaninfections, including infections with opportunisticpathogens. Localized and systemic infections, includingpneumonia, other bacterial infections, invasive fungalinfections, and viral infections including reactivation ofhepatitis B virus have occurred. Some of these infectionshave been severe (e.g. leading to respiratory or hepaticfailure) or fatal. Complete treatment of pre-existing invasivefungal infections prior to starting treatment. While takingAfinitor be vigilant for signs and symptoms of infection; ifa diagnosis of infection is made, institute appropriatetreatment promptly and consider interruption ordiscontinuation of Afinitor. If a diagnosis of invasivesystemic fungal infection is made, discontinue Afinitor andtreat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oralmucositis) have occurred in patients treated with Afinitor. Insuch cases, topical treatments are recommended, butalcohol- or peroxide-containing mouthwashes should beavoided. Antifungal agents should not be used unlessfungal infection has been diagnosed.Elevations of serum creatinine, glucose, lipids, andtriglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinicaltrials. Renal function, hematological parameters, bloodglucose, and lipids should be evaluated prior to treatmentand periodically thereafter. When possible, optimal glucoseand lipid control should be achieved before starting apatient on Afinitor.Avoid concomitant use with strong CYP3A4 or PgPinhibitors. If co-administration with moderate CYP3A4 orPgP inhibitors is required, use caution and reduce dose ofAfinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer.Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepaticimpairment.The use of live vaccines and close contact with those whohave received live vaccines should be avoided duringtreatment with Afinitor.Fetal harm can occur if Afinitor is administered to apregnant woman.The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia(33%), fatigue (31%), cough (30%), and diarrhea (30%).The most common grade 3/4 adverse reactions (incidence≥3%) were infections (9%), dyspnea (8%), fatigue (5%),stomatitis (4%), dehydration (4%), pneumonitis (4%),abdominal pain (3%), and asthenia (3%). The mostcommon laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%),hypertriglyceridemia (73%), hyperglycemia (57%),lymphopenia (51%), and increased creatinine (50%). Themost common grade 3/4 laboratory abnormalities(incidence ≥3%) were lymphopenia (18%), hyperglycemia(16%), anemia (13%), hypophosphatemia (6%), andhypercholesterolemia (4%). Deaths due to acute respiratoryfailure (0.7%), infection (0.7%), and acute renal failure(0.4%) were observed on the Afinitor arm.

AFINITOR (everolimus) tablets for oral administrationInitial U.S. Approval: 2009BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGEAFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure oftreatment with sunitinib or sorafenib.

4 CONTRAINDICATIONSHypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea,flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratoryimpairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS5.1 Non-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the ran-domized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. Theincidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%,respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, considerinterrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITORmay be reintroduced at 5 mg daily.For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy andthe use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR maybe re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.5.2 InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infec-tions, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virushave occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading torespiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk ofinfection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to startingtreatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if adiagnosis of an infection is made, institute appropriate treatment promptly and consider interruption ordiscontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinueAFINITOR and treat with appropriate antifungal therapy.5.3 Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the ran-domized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, ororal mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topi-cal treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoidedas they may exacerbate the condition. Antifungal agents should not be used unless fungal infection hasbeen diagnosed [see Drug Interactions (7.1)].5.4 Laboratory Tests and MonitoringRenal FunctionElevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions(6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum cre -atinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipidcontrol should be achieved before starting a patient on AFINITOR.Hematological ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of com plete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.5.5 Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong inhibitors ofCYP3A4 (e.g., ketoconazole, itraconazole, clarithro mycin, atazanavir, nefazodone, saquinavir, telithromycin,ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grape-fruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also beavoided during treatment [see Dosage and Administration (2.2) in the full prescribing information andDrug Interactions (7.1)].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) orPgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Inter -actions (7.1)].An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer(e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, car-bamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in thefull prescribing information and Drug Interactions (7.2)].5.6 Hepatic ImpairmentThe safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderatehepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure wasincreased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) andshould not be used in this population [see Dosage and Administration (2.2) in the full prescribing infor-mation and Use in Specific Populations (8.7)].5.7 VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps,rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.5.8 Use in PregnancyPregnancy Category DThere are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations(8.1)].

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].• Infections [see Warnings and Precautions (5.2)].6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observed inclinical practice.The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized,controlled trial in patients with meta static renal cell carcinoma who received prior treatment with sunitiniband/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78%were male. The median duration of blinded study treatment was 141 days (range 19-451) for patientsreceiving AFINITOR and 60 days (range 21-295) for those receiving placebo.The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue,cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections,dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most commonlaboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia,hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnor-malities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hyper -cholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure(0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergentadverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% forthe AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irre-spective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections,stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. Themost common medical interventions required during AFINITOR treatment were for infections, anemia, andstomatitis.Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organclass, the adverse reactions are presented in order of decreasing frequency.

Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate

in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day Placebo

N=274 N=137All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any Adverse Reaction 97 52 13 93 23 5Gastrointestinal Disorders

Stomatitisa 44 4 <1 8 0 0Diarrhea 30 1 0 7 0 0Nausea 26 1 0 19 0 0Vomiting 20 2 0 12 0 0

Infections and Infestationsb 37 7 3 18 1 0General Disorders and Administration Site Conditions

Asthenia 33 3 <1 23 4 0Fatigue 31 5 0 27 3 <1Edema peripheral 25 <1 0 8 <1 0Pyrexia 20 <1 0 9 0 0Mucosal inflammation 19 1 0 1 0 0

Respiratory, Thoracic and Mediastinal DisordersCough 30 <1 0 16 0 0Dyspnea 24 6 1 15 3 0Epistaxis 18 0 0 0 0 0Pneumonitisc 14 4 0 0 0 0

Skin and Subcutaneous Tissue DisordersRash 29 1 0 7 0 0Pruritus 14 <1 0 7 0 0Dry skin 13 <1 0 5 0 0

Metabolism and Nutrition DisordersAnorexia 25 1 0 14 <1 0

Nervous System DisordersHeadache 19 <1 <1 9 <1 0Dysgeusia 10 0 0 2 0 0

Musculoskeletal and Connective Tissue DisordersPain in extremity 10 1 0 7 0 0

Median Duration of Treatment (d) 141 60CTCAE Version 3.0aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.bIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most commonbeing nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis(3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).

cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonarytoxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with anincidence of <10% include:

Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills(4%), impaired wound healing (<1%)Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%),rhinorrhea (3%)Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythro -dysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion(4%), acneiform dermatitis (3%)Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset ofdiabetes mellitus (<1%)Psychiatric disorders: Insomnia (9%)Nervous system disorders: Dizziness (7%), paresthesia (5%)Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)Renal and urinary disorders: Renal failure (3%)Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)Musculoskeletal and connective tissue disorders: Jaw pain (3%)Hematologic disorders: Hemorrhage (3%)

Key treatment-emergent laboratory abnormalities are presented in Table 2.Table 2

Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Armthan the Placebo Arm

Laboratory Parameter AFINITOR 10 mg/day PlaceboN=274 N=137

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4% % % % % %

Hematologya

Hemoglobin decreased 92 12 1 79 5 <1Lymphocytes decreased 51 16 2 28 5 0Platelets decreased 23 1 0 2 0 <1Neutrophils decreased 14 0 <1 4 0 0

Clinical ChemistryCholesterol increased 77 4 0 35 0 0Triglycerides increased 73 <1 0 34 0 0Glucose increased 57 15 <1 25 1 0Creatinine increased 50 1 0 34 0 0Phosphate decreased 37 6 0 8 0 0Aspartate transaminase (AST)

increased 25 <1 <1 7 0 0Alanine transaminase (ALT)

increased 21 1 0 4 0 0Bilirubin increased 3 <1 <1 2 0 0

CTCAE Version 3.0aIncludes reports of anemia, leukopenia, lymphopenia, neutropenia, pancyto penia, thrombocytopenia.

Information from further clinical trialsIn clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, includingfatal outcomes.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.7.1 Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone therewere significant increases in everolimus exposure when AFINITOR was coadministered with:• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and

15.0-fold, respectively.• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and

4.4-fold, respectively.• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and

3.5-fold, respectively.Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions(5.5)].Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alterna-tive treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2)in the full prescribing information]7.2 Agents that may Decrease Everolimus Blood ConcentrationsCYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer ofCYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimustreatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers ofCYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP ifalternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpre-dictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].7.3 Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactionsbetween AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and prava -statin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)]There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraceptionwhile receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating andthrough organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantationand post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) andretarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetaltoxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommendeddose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oraldose approximately 1.6 times the recommended human dose on a body surface area basis. The effect inrabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lacta-tion. At approximately 10% of the recommended human dose based on body surface area, there were noadverse effects on delivery and lactation and there were no signs of maternal tox icity. However, therewas reduced body weight (up to 9% reduction from the control) and slight reduction in survival in off-spring (~5% died or missing). There were no drug-related effects on the developmental parameters(morphological development, motor activity, learning, or fertility assessment) in the offspring.Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).8.3 Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and effectiveness in pediatric patients have not been established.8.5 Geriatric UseIn the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percentwere 75 and over. No overall differences in safety or effectiveness were observed between these subjectsand younger subjects, and other reported clinical experience has not identified differences in responsesbetween the elderly and younger patients, but greater sensitivity of some older individuals cannot beruled out [see Clinical Pharmacology (12.3) in the full prescribing information].No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full pre-scribing information].8.6 Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renalimpairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recom -mended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].8.7 Hepatic ImpairmentFor patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mgdaily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions(5.6) and Clinical Pharmacology (12.3) in the full prescribing information].The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in thispatient population is not recommended [see Warnings and Precautions (5.6)].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved in either mice or rats given single oral doses of 2000 mg/kg (limit test).Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have beenadministered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGEStore AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).[See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture.Keep this and all drugs out of the reach of children.Procedures for proper handling and disposal of anticancer drugs should be considered. Several guide-lines on this subject have been published.AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

Revised: June 2010 T2010-56

Manufactured by:Novartis Pharma Stein AGStein, Switzerland

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936

©Novartis

ONCOLOGY BEST PRACTICES


Arecent survey by Kurt Salmonof best practices among lead-ing oncology networks in

the country (www.kurtsalmon.com/oncology) suggests that the use of elec-tronic health records (EHRs) in themost successful networks improvesthe flow of information betweenproviders by using fewer, more robustsystems with multiple access points,including EHRs, physician portals,and access through handheld devices. The study included more than 132

inpatient oncology sites within region-al oncology networks across theUnited States. It surveyed oncologyleaders about current and planned lev-els of oncology network development.The participants (who requested confi-dentiality as a condition for participa-tion) represent some of the largest andmost respected oncology centers in theUnited States today.The goal of the study was to provide

oncology networks information aboutthe level of EHRs and informationtechnology (IT) in oncology practices.Questions included:• What are the current “best practices”in EHR and IT systems?

• How do other oncology networksorganize their IT resources andsecure funding?

• In what ways will the systems devel-op over the next 3 to 5 years?

Characteristics of Best Practices

Characteristics of leading oncologynetworks with EHR best practicesinclude dedicated staff and increaseddedication to developing EHR andcommon IT systems across networksites; for example, it is rare that thesenetworks would have disparate reg-istry software. Most have also imple-mented common systems within spe-cific functional areas; for example, allradiation oncology is on one systemand inpatient care is on another sys-tem (Table). A key characteristic is their priority

for developing a common EHR acrossall elements of oncology care, with ITgoals and budgets that span multipleyears. Although multiple IT systemswill continue to exist, leading oncolo-gy networks bridge the gap with inter-faces, health information exchangesolutions, and physician portals. Given the specialized needs of oncol-

ogy, leading networks focus on anoncology-specific EHR that supportstight integration with clinical modali-

ties. They recognize the immenseopportunity of IT systems to link real-time clinical EHR with the longitudinaltumor registry to research clinical out-comes and protocol effectiveness.

To facilitate clinical informationflow today, leading networks comple-ment IT resources with a clinical coor-dinator who serves as the central pointto ensure information is gathered, cat-aloged, entered into IT systems, anddisseminated to members of the on -cology care team. Clinical records areoften received in various media. Theclinical coordinator incorporates allthese into the central EHR. Clinicalcoordinators also facilitate the sharingof updates and patient status withreferring physicians, who may nothave access to the central EHR.Leading oncology networks expect

the role of the clinical coordinator willcontinue to be essential well into thefuture, although their role will likelychange. They also have a stable funding

model and budget to support central-ized functions and network goals. Thisis accomplished in 1 of 2 ways: net-work sites contribute to a commonbudget or the system allocates funding

to the network. The regular planningand budgeting cycle encourages thedevelopment of multiyear EHR initia-tives, with some certainty that thegoals can be achieved.

Oncology EHR Development

Despite the widely held belief thatmost oncology networks have robustEHR capabilities, this is not the case.Very few have achieved the desiredlevel of IT sophistication; the vastmajority continue to operate in a large-ly paper-based care universe. Giventhe predominance of paper-basedmanual systems, it is no surprise thatoncology networks see expanding theirEHR capabilities as a high priority. For example, Paul Browne, Senior

Vice President and CIO, TrinityHealth, said, “Until there is a broad-based adoption of electronic healthrecords, our ability to understandissues of quality, equity, and cost willbe limited. Information technology isseen as critical to improving oncologypatient care.”Most oncology networks have a

common vision to move to a singleoncology EHR. One reason so fewhave adopted a single EHR to date isthe limitations of current systems. No

vendor has developed a comprehen-sive, mature oncology EHR platformthat is fully integrated with an enter-prise EHR, thus requiring networks topiece together different systems tosupport medical oncology, radiationoncology, inpatient care, and tumorregistry functions. In the rare cases where a single

oncology EHR exists, it is usuallyachieved through niche solutions tiedto treatment modalities and is onlypartially integrated with the hospital’senterprise EHR. Throughout the study,networks expressed the goal of devel-oping a unified oncology EHR amongthe sites, interfaced to the enterpriseEHRs, and leveraging health informa-tion exchange to connect externalproviders.Given the current and near-term

future capabilities of enterprise EHRsolutions, leading oncology networkswill likely live in an interfaced world,electronically exchanging clinical in -formation between general enterpriseEHR solutions and specialized oncolo-gy EHR solutions.

Greater Value in Oncology Care

The majority of oncology networkshave implemented some portion of thebest practices. All networks express adesire to move toward a more com-plete set of systems and resources andcommon EHR solutions; however,many lack the funding and organiza-tional cohesiveness to implementdesired staffing models or IT solutions. The main factors in the best prac-

tices for creating a common EHRinclude (1) a central guiding bodycomprised of network leadership andsite clinicians that set the EHR planand garner support from individualnetwork sites; and (2) financial re -sources dedicated to oncology EHR. Leading networks view implemen-

tation of an EHR as a requirement toadvance clinical care coordination fordemonstrating better outcomes, lower-ing cost, and increasing the value ofcare. As such, these networks createmultiyear plans and budgets to sup-port EHR development. We expectmany networks to adopt this view-point over the next few years andinvest in IT systems, interfaces, andhealth information exchange as a wayto create growth and value in thefuture. �

The Value of EHR Best Practices for Leading Oncology NetworksBy Gerard M. Nussbaum and Laura K. RehfeldMr Nussbaum is Director of Technology Services, and Ms Rehfeld is a manager in Kurt Salmon’s Healthcare Group

“Until there is a broad-based adoptionof electronic health records, our abilityto understand issues of quality, equity,and cost will be limited. Informationtechnology is seen as critical toimproving oncology patient care.”

—Paul Browne

Table Clinical and IT Components in Oncology Networks

Oncology Network has Oncology networks, %Leading oncology networks, %

A single EHR 25 100

A single system for imaging, laboratory,and testinga

33 100

A single tumor registry system 50 100

Common clinical protocolsb 17 100

aSystem may be integrated within a single EHR or separate.bNetwork has achieved common clinical protocols above adoption of standard guidelines,such as the National Cancer Institute Community Cancer Centers Program best practices.EHR indicates electronic health record; IT, information technology.Source: Kurt Salmon research of 132 inpatient oncology sites organized within regional networks across the US, 2010. www.kurtsalmon.com/oncology.

See also HITECH article, page 17

��

THANK YOU to the sponsors and to the nearly 200 oncologists, payers, and attendees

who made AVBCC’s First Annual Stakeholder Integration Conference in Philadelphia a great success

Complete conference coverage coming in the July 2011 issue��

HOPA ANNUAL MEETING


Salt Lake City, UT—When it comes tocancer, “how much is too much?” is acommon question. At the John G.Kuhn Keynote Lecture at the 2011Hematology/Oncology PharmacyAssociation annual meeting titled“The Cost of Cancer Therapy,” speak-er Tito Fojo, MD, PhD, with theNational Cancer Institute (NCI), saidcost is not the real issue. “If you framethe argument in terms of cost, you’regoing to lose it,” he said. Dr Fojo saidthe real issue is “about how effectivedrugs are and how toxic drugs are.”

Dr Fojo offered examples of drugsused in clinical situations that not onlyfail to improve survival but actuallyharm patients, such as cetuximab(Erbitux) for patients with metastaticcolorectal cancer (CRC) and beva-cizumab (Avastin) for patients withbreast cancer. He acknowledged thatcontroversy surrounds these examples

and not everyone shares his views,including Giuseppe Giaccone, MD,PhD, his supervisor at NCI and amember of the American Society ofClinical Oncology (ASCO) panelresponsible for adding the combina-tion of cetuximab and paclitaxel(Taxol) to the ASCO guidelines forfirst-line therapy of metastatic CRC.These therapies are also included inthe National Comprehensive CancerNetwork treatment guidelines.

The Unmet Promise of

Personalized Medicine

Dr Fojo’s review of the pivotal trialsused to support the US Food andDrug Administration (FDA) approvalof cetuximab in metastatic CRC andbevacizumab in breast cancer under-scores important considerations forvarious stakeholders when consider-ing drug development and use. “Ourdrug development, drug approval,and drug consumption strategiesneed better focus,” he said, lamentingthat despite the decade that haselapsed since imatinib (Gleevec) ush-ered in the “targeted therapy revolu-tion,” too many treatments are stillused indiscriminately in broad pa -tient populations. Dr Fojo sees room for improvement

at all levels—academia, the pharma-ceutical industry, government agenciessuch as the FDA, and clinicians treatingpatients with cancer. All are responsi-

ble for “our failure to deliver on thepromise of personalized medicine.” The example of cetuximab supports

Dr Fojo’s contention that drugs mustbe analyzed prospectively to identifypredictive markers before initiating tri-als. Four years after cetuximab’s 2004FDA approval, a study published inthe New England Journal of Medicineshowed it was ineffective in patientswith mutated KRAS. In 2009, ASCOissued its Provisional Clinical Opinionrecommending KRAS testing before

prescribing cetuximab, but left it as avoluntary option. Cetuximab inhibits epidermal

growth factor receptor (EGFR), and“as early as 1990, Bert Vogelstein atHopkins had reported that as many as50% of colorectal patients harboredKRAS,” Dr Fojo said. In 1998, KRASwas reported to be in the EGFR signal-ing pathway. “Despite this, we wentahead and conducted studies withoutlooking at this prospectively.” Continued investigation into the

causes of poor response to cetuximabamong some patients with wild-typeKRAS will likely reduce the viablepatient population even further.“Eventually, we’ll be able to identifythe 80% of patients that do not benefit,and give it only to the 20% who benefitsubstantially, and a drug that was mar-ginal to begin with will become highlyeffective,” said Dr Fojo.

What Constitutes an Acceptable

Improvement?

“Increasingly, therapies that demon-strate at best marginal improvementare being used in the treatment of can-cer,” he noted. With breast cancer, wemay even be going backward, withthe controversy over bevacizumab. Heemphasized that his views did not rep-resent those of the NCI. Dr Fojo faulted the decision to

approve bevacizumab based on datafrom the E2100 study, which suggestedthat adding it to paclitaxel significant-ly prolonged progression-free survival(PFS) but not overall survival (OS).

Although the study showed nonsignif-icant improvement in OS favoringbevacizumab, “Nonsignificant improve -ment is no improvement,” he said,adding that it was unusual for a studyto reflect major discordance betweenPFS and OS. Dr Fojo and colleague published a

review of major studies publishedsince 1996 with a significant improve-ment in PFS or OS and found “tightcorrelation between the two” (LancetOncol. 2010;11:1117-1119). He thereforebelieves E2100 is an outlier.Even if bevacizumab does improve

PFS, “delaying symptoms is a worth-while goal, but delaying PFS does notequal delaying symptoms,” he said.

Toxicities

Studies need to focus more onwhether regimens used are harmingpatients. In E2100, patients treated withbevacizumab had more than twice asmany adverse events as the controlgroup. Dr Fojo believes that toxicity isunacceptable when a treatment fails toimprove OS and is very expensive, buthe acknowledged that many breastcancer specialists disagree. The FLEXtrial, investigating cetuximab in meta -static CRC, also found high rates ofgrade 3 and 4 toxicities, particularlysevere skin reactions. With the growing use of oral thera-

pies for cancer, it is important thatstudies not overlook the grade 1 and 2toxicities, he said. “The scale wasdeveloped for chemotherapy, butwhen you are taking a drug every dayfor months on end, a grade 1 or 2 eventcan be very difficult.”Although cost is relevant for drugs

that cause serious adverse effects butdemonstrate minimal efficacy, Dr Fojosaid it comes down to the notion thatyou do not harm patients for littleimprovement in survival. Variousattempts to combine therapies havehurt patients, without helping them;he called for an end to this “incremen-tal approach” to treatment.Finding better treatments requires

determining the settings in which thedrugs work best, but also the ones inwhich they do not work. This wouldrequire major journals to give greaterweight to negative studies, he said,which are often relegated to second-and third-tier journals. It also requiresexpanding incentives for pharmaceu-tical companies to take a more person-alized approach to drug development,where rewards are likely to be lesslucrative. �

“If you frame the argumentin terms of cost, you’re going to lose it”; the realissue is “about how effectivedrugs are and how toxicdrugs are.”

—Tito Fojo, MD, PhD

“Our drug development, drug approval, and drugconsumption strategies need better focus.”

—Tito Fojo, MD, PhD

Making Cancer Drugs Worth the CostEfficacy and safety are the real “business” of medicineBy Christin Melton

Successful Strategies forDrug Cost-Containment inOncology PracticeSalt Lake City, UT—Before establish-ing measures your oncology practicecan implement to lower costs, reviewyour physicians’ prescribing habits,identify causes of drug waste, andlook for outlays that are not capturedin reimbursement channels, saidBhavesh Shah, RPh, BCOP, a clinicalpharmacy specialist with BostonMedical Center (BMC) at the 2011Hematology/Oncology PharmacistAssociation meeting. He outlined suc-cessful examples of cost-saving strate-gies that BMC has adopted.

The Benefit of Dose-Rounding

Rounding the dose of certain oncol-ogy biologics to within 10% of the

amount ordered is one successfulmeasure. The purpose is: • Ensure the drug is measured accu-rately

• Minimize drug waste• Maximize cost avoidance. The 10 drugs that are the most

amenable to dose-rounding are listedin the Table (page 40). “For any order that comes through

the pharmacy, the pharmacist canround the dose to the nearest vile sizefor the concentration,” said Mr Shah.The exceptions include when the dif-ference between the ordered dose andthe nearest vile size exceeds 10%.“That’s when we try to round it to the


nearest concentration size available.” Dose-rounding is only as effective as

the level of adherence by pharmacyclinicians. A retrospective study (JOncol Pharm Pract. 2010 Mar 23 [Epubahead of print]) showed that a 3-month pilot program to round dosesfor orders of 7 anticancer biologicswould have produced a 42% reductionin drug wastage and $24,434 in sav-ings (in 2005 dollars) had there been100% compliance with the program.Instead, because the dose-roundingprotocol was not used in 29 of the 126orders, savings amounted to only$15,922. It is important to includemeasures for monitoring adherence.

Chemotherapy Infusion

The following strategies implement-ed at BMC for chemotherapy infusionhave led to hundreds of thousands ofdollars in annual savings.

Shift Inpatient to Outpatient

Administration

Encourage your physicians to shiftfrom inpatient to outpatient chemo -therapy administration. “We devel-oped this because a lot of chemothera-py was being administered in thehospital, primarily due to conven-ience, where we got reimbursed byDRGs [diagnostic-related groups] butnot based on what the patient wasactually receiving,” Mr Shah said. Under Medicare, inpatient claims

can list only 1 DRG, whereas outpa-tient claims permit multiple ambulato-ry payment classifications (APCs).Chemotherapy drugs are also not bun-dled under APCs, allowing for greaterreimbursement. “Now, we always push our physi-

cians to do it on the day of, or the dayafter, hospital release, so we can cap-ture that cost,” he said, adding thatorders for inhospital chemotherapyadministration declined by 50%.

Test Rituximab before Infusion

Another new policy at BMC is to testthe dose of rituximab (Rituxan) beforestarting infusion. Mr Shah said that80% of patients receiving rituximab willhave a reaction to their first infusion,which leads to discontinuation anddrug waste. In 2009, infusion reactionsresulted in $50,000 in wasted rituximab.“We implemented a test dose for each

patient, and we saw a drastic decline inwaste of rituximab,” he said. The testdose is 100 mg and is administered to allpatients at BMC who are scheduled forrituximab infusion and have notreceived the drug for at least 6 months.In 2010, BMC saved approximately$2000 per patient using rituximab.

Follow Guidelines for Pegfilgrastim

When Mr Shah and his colleagueswere seeking ways to reduce costs,they observed that orders for pegfil-grastim (Neulasta) had increased.Based on published data, they thoughtit might be safe to delay administra-tion of white blood cell growth factorsupport for patients treated with pacli-taxel (Taxol). They tested this on 10 patients pre-

scribed 4 cycles of paclitaxel (175mg/m2 every 2 weeks), and adminis-tered a single dose of pegfilgrastimwith the first dose of the second cycleof paclitaxel. All patients completedtherapy without delay, with no neu-tropenic events or hospitalizations.Mr Shah speculated that delayingpefilgrastim led to less bone pain frompaclitaxel-induced arthralgia. It alsocut costs by $60,000.

He noted that pegfilgrastim wassometimes administered as primaryprophylaxis in situations inconsistentwith established practice guidelines.“There was a lot of inappropriate uti-lization, in metastatic prostate cancer,stage IV non–small-cell lung cancer[NSCLC], and metastatic colon can-cer,” said Mr Shah. They requestedthat physicians stop using growth fac-tor support when the intent was notcurative and use dose reductions ordelays instead. Physicians were also

told to stop giving it to patients receiv-ing chemotherapy with curative intentand an associated incidence of febrileneutropenia <20%. To adhere to evidence-based guide-

lines for pegfilgrastim, BMC requiredphysicians to administer it in the adju-vant setting for patients with colorectalcancer (CRC) and NSCLC, the neoad-juvant setting for patients with solidtumors whose operative procedurehad curative intent, and for patientswith a malignancy related to AIDS. Even with these measures, BMC

decreased expenditures by $250,000annually, which does not factor inpotential cost-savings from ensuringthat all appropriate patients receivedthe drug.

Rapid Infusion for Improved

Utilization

Mr Shah noted that no formal eco-nomic analysis has ever been done onthe cost-effectiveness of rapid infu-sion. Agents to consider for rapid infu-sion include rituximab, bevacizumab(Avastin), trastuzumab (Herceptin),cetuximab (Erbitux), as well as low-molecular-weight (LMW) iron dextran(INFeD). “This can increase yourresource utilization,” he said.One 2007 study tested a 90-minute

rituximab infusion in more than 1200patients, a 0% rate of grade 3/4 toxici-ty related to the faster infusion wasobserved. Other studies found 30-minute infusions of trastuzumab andbevacizumab and 60-minute infusionsof cetuximab and LMW iron dextranto be relatively safe. A higher rate of adverse events was

seen in patients allergic to >2 drugswho received LMW iron dextran. MrShah cautioned that Dexderm—anoth-er form of iron dextran—should not beused in a rapid fashion.

“I think rapid infusions are great. Ittotally increases the volume for yourclinic and decreases the absentees, andyou can get your patients out faster,”Mr Shah said; it also increases satisfac-tion among patients and nurses.

Cetuximab versus Panitumumab

BMC switched from cetuximab tothe lower-cost panitumumab (Vectibix)for CRC based on studies showing lit-tle difference in overall response rateor survival. Although the cost per 100mg is higher for panitumumab thanfor cetuximab ($618.81 vs $367.83,respectively), cetuximab requires an 8-vial loading dose. A BMC 4-week cost analysis of pan-

itumumab averaged $5953.70 com-pared with $8460.09 for cetuximab. Inaddition, reimbursement from theCenters for Medicare & MedicaidServices (CMS) was higher for pani-tumumab than for cetuximab($49.737/10 mg vs $87.326/10 mg).Other cost-savings with panitumumabincluded reduced chair time, becauseit can be administered every 2 weeks,and the reduction in febrile neutrope-nia treatment.

Handling Waste

BMC takes advantage of bio-oncolo-gy spoilage programs offered by phar-maceutical companies. “They’re notwell known, and you have to actuallycall, but...it’s pretty easy,” he said. “Wehad about $20,000 in waste that wesaved last year using these programs.Fill out a form and they send you acheck for the drug that’s been wasted.”Adopting such programs allows

you to request reimbursement fromCMS for “discarded drug/biologicalremaining in a single-use product afteradministering what is reasonable andnecessary for the patient’s condition”(per Pub. 100-04, Chapter 17, Section40 in the Medicare Claims ProcessingManual).Mr Shah said, “There’s a JW code

that mirrors the J code you’re billingfor.” CMS requires documenting thecause of waste in the patient’s medicalrecord, which BMC has implementedto recover those costs. When looking for ways to save

costs, patient safety is the most impor-tant consideration, he said.—CM �

HOPA ANNUAL MEETING


“We implemented a testdose for each patient and we saw a drastic decline inwaste of rituximab.”

—Bhavesh Shah, RPh, BCOP

“We had about $20,000 in waste that we saved lastyear using these programs.”

—Bhavesh Shah, RPh, BCOP

Successful Strategies for Drug Cost-Containment...Continued from page 38

Table 10 Anticancer Agents Amenable to Dose-Rounding

Drug Rounding amount

Infliximab Nearest 100 mg

Bevacizumab Nearest 100 mg

Rituximab Nearest 100 mg

Docetaxel Nearest 20 mg

Pemetrexed Nearest 100 mg

Cetuximab Nearest 100 mg

Oxaliplatin Nearest 5 mg or 50 mg

Gemcitabine Nearest 200 mg

Panitumumab Nearest 20 mg or 100 mg

Bendamustine Nearest 25 mg

Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With:� Treatment follow-up

— Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis

� Patient education materials

For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

INDICATIONS� DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease

has progressed or recurred after platinum-based chemotherapy� DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of

patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATIONBOXED WARNINGSCardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution � The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead

to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2

— Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose

— Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy

� Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate

— Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use

— The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions

� Severe myelosuppression may occur� DOXIL® dosage should be reduced in patients with impaired hepatic function� Accidental substitution has resulted in severe side effects. Do not substitute

for doxorubicin HCl on a mg per mg basis

CONTRAINDICATIONS� Patients with a history of hypersensitivity reactions to a conventional doxorubicin

formulation or the components of DOXIL®

� Nursing mothers

ADDITIONAL SAFETY INFORMATION� Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of

anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac

monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury

— In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a

5% decrease below institutional lower limit of normal)

� Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL®

— In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL®

— In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE

— Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage

— Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death

� DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow

� Hand-foot syndrome (HFS) may occur during therapy with DOXIL®

— Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required

— HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier• The reaction was mild in most patients, resolving in 1 to 2 weeks• The reaction can be severe and debilitating in some patients, resulting in

discontinuation of therapy� DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation� DOXIL® can cause fetal harm when used during pregnancy� Recall reaction has occurred with DOXIL® administration after radiotherapy� DOXIL® may interact with drugs known to interact with the conventional formulation

of doxorubicin HCl� In patients with recurrent ovarian cancer, the most common all-grade adverse reactions

(ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%)

— In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively)

were neutropenia (12% vs 76%) and anemia (6% vs 29%)� In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL®

plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)

— In addition, 19% vs <1% reported HFS

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

DOXIL® C.A.R.E.S. Provides Help and Support

12:56 PM

DOXIL®(doxorubicin HCl liposome injection) for intravenous infusionBRIEF SUMMARY. Please see Full Prescribing Information.

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for thetreatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-basedchemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’ssarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. MultipleMyeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myelomawho have not previously received bortezomib and have received at least one prior therapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have ahistory of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL[see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information].

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardialdamage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin,particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currentlyrecommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who havereceived radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agentssuch as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included incalculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered afterdiscontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should beadministered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should becarefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury isendomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have beenused to monitor cardiac function during anthracycline therapy. Any of these methods should be employed tomonitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiacinjury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the riskof myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL atstarting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, orbetween 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study,cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction(LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than theinstitutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity andcongestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast CancerDOXIL (n=250)

Patients who Developed Cardiotoxicity 10(LVEF Defined)

Cardiotoxicity (With Signs & Symptoms of CHF) 0Cardiotoxicity (no Signs & Symptoms of CHF) 10

Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiacfailure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema andpulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% ineach group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decreasebelow the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF.

Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in therandomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms:flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest andthroat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Inmost patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treatedwith DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because ofinfusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusionreactions have been reported. Medications to treat such reactions, as well as emergency equipment, should beavailable for immediate use. The majority of infusion-related events occurred during the first infusion. Similarreactions have not been reported with conventional doxorubicin and they presumably represent a reaction to theDOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimizethe risk of infusion reactions [see Full Prescribing Information].

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring isrequired during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With therecommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reductionor delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection,neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted indiscontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancertherapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination withother agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppressionwas generally moderate and reversible. In the three single-arm studies, anemia was the most commonhematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia(24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most commonhematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC<1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer,4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patientswith AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors astheir HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most commonadverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsisoccurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL.Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presentsdata on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [seeAdverse Reactions].

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling,pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of thepatients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skintoxicity. HFS toxicity grades are described in Dosage and Administration section [see Full PrescribingInformation]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% ofpatients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to twoweeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manageHFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and mayrequire discontinuation of treatment.

Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy,or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to thefetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of thedrug must be considered. Women of childbearing potential should be advised to avoid pregnancy duringtreatment with Doxil. [see Full Prescribing Information].

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-inducedtoxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration ofdoxorubicin HCl.

Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequentlyand at a minimum prior to each dose of DOXIL [see Warnings and Precautions].

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in moredetail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [seeWarnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [seeWarnings and Precautions]

The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis,vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia andanemia. The most common serious adverse reactions observed with DOXIL are described in Section AdverseReactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including:239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiplemyeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, theadverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflectthe rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXILin ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.

Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treatedwith DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in arandomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days(range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanicand other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian CancerDOXIL Topotecan

Patients Patients(n = 239) (n = 235)

Neutropenia500 - <1000/mm3 19 (7.9%) 33 (14.0%)<500/mm3 10 (4.2%) 146 (62.1%)

Anemia6.5 - <8 g/dL 13 (5.4%) 59 (25.1%)<6.5 g/dL 1 (0.4%) 10 (4.3%)

Thrombocytopenia10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%)<10,000/mm3 0 (0.0%) 40 (17.0%)

Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study ofDOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized StudyNon-Hematologic DOXIL (%) treated Topotecan (%) treatedAdverse Reaction 10% or Greater (n = 239) (n =235)

All Grades All Grades grades 3-4 grades 3-4

Body as a WholeAsthenia 40.2 7.1 51.5 8.1Fever 21.3 0.8 30.6 5.5Mucous Membrane 14.2 3.8 3.4 0DisorderBack Pain 11.7 1.7 10.2 0.9Infection 11.7 2.1 6.4 0.9Headache 10.5 0.8 14.9 0

DigestiveNausea 46.0 5.4 63.0 8.1Stomatitis 41.4 8.3 15.3 0.4Vomiting 32.6 7.9 43.8 9.8Diarrhea 20.9 2.5 34.9 4.2Anorexia 20.1 2.5 21.7 1.3Dyspepsia 12.1 0.8 14.0 0

Nervous Dizziness 4.2 0 10.2 0

RespiratoryPharyngitis 15.9 0 17.9 0.4Dyspnea 15.1 4.1 23.4 4.3Cough increased 9.6 0 11.5 0

Skin and AppendagesHand-foot syndrome 50.6 23.8 0.9 0Rash 28.5 4.2 12.3 0.4Alopecia 19.2 N/A 52.3 N/A

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTALSUBSTITUTION1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage maylead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a startingdose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclinesor anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may alsooccur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrentcyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, butnot limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in thechest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In mostpatients, these reactions resolve over the course of several hours to a day once the infusion is terminated. Insome patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treatsuch reactions, as well as emergency equipment, should be available for immediate use. DOXIL should beadministered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings andPrecautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should bereduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidentalsubstitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substitutedfor doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer withdoses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombo phlebitis, hypotension, cardiacarrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic andLymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia,hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia,sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash,exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. SpecialSenses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2%Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. Themedian time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2

and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immunesystem, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 countwas 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count atstudy entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs incombination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or moreantiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% onzalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) onsulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarilyfluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir,and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim)sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patientswith AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adversereactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis,progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s SarcomaPatients With Total Patients

Refractory or Intolerant WithAIDS-Related AIDS-Related

Kaposi’s Sarcoma Kaposi’s Sarcoma(n = 74) (n = 720)

Neutropenia<1000/mm3 34 (45.9%) 352 (48.9%)<500/mm3 8 (10.8%) 96 (13.3%)

Anemia<10 g/dL 43 (58.1%) 399 (55.4%)<8 g/dL 12 (16.2%) 131 (18.2%)

Thrombocytopenia<150,000/mm3 45 (60.8%) 439 (60.9%)<25,000/mm3 1 (1.4%) 30 (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in 5% of PatientsWith AIDS-Related Kaposi’s Sarcoma

Adverse Patients With Total PatientsReactions Refractory or Intolerant With

AIDS-Related AIDS-RelatedKaposi’s Sarcoma Kaposi’s Sarcoma

(n = 77) (n = 705)Nausea 14 (18.2%) 119 (16.9%)Asthenia 5 (6.5%) 70 (9.9%)Fever 6 (7.8%) 64 (9.1%)Alopecia 7 (9.1%) 63 (8.9%)Alkaline Phosphatase 1 (1.3%) 55 (7.8%)Increase Vomiting 6 (7.8%) 55 (7.8%)Diarrhea 4 (5.2%) 55 (7.8%)Stomatitis 4 (5.2%) 48 (6.8%)Oral Moniliasis 1 (1.3%) 39 (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’ssarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouthulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis,moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block,congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic andNutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages:maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every threeweeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combinationgroup were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age,58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reportedin 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple

myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology.

Adverse DOXIL + bortezomib BortezomibReaction (n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Blood and lymphatic system disordersNeutropenia 36 22 10 22 11 5Thrombocytopenia 33 11 13 28 9 8Anemia 25 7 2 21 8 2General disorders and administration site conditionsFatigue 36 6 1 28 3 0Pyrexia 31 1 0 22 1 0Asthenia 22 6 0 18 4 0Gastrointestinal disordersNausea 48 3 0 40 1 0Diarrhea 46 7 0 39 5 0Vomiting 32 4 0 22 1 0Constipation 31 1 0 31 1 0Mucositis/Stomatitis 20 2 0 5 <1 0Abdominal pain 11 1 0 8 1 0

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiplemyeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology. (continued)

Adverse DOXIL + bortezomib BortezomibReaction (n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Infections and infestationsHerpes zoster 11 2 0 9 2 0Herpes simplex 10 0 0 6 1 0InvestigationsWeight decreased 12 0 0 4 0 0Metabolism and Nutritional disordersAnorexia 19 2 0 14 <1 0Nervous system disordersPeripheral Neuropathy* 42 7 <1 45 10 1Neuralgia 17 3 0 20 4 1Paresthesia/dysesthesia 13 <1 0 10 0 0Respiratory, thoracic and mediastinal disordersCough 18 0 0 12 0 0Skin and subcutaneous tissue disordersRash** 22 1 0 18 1 0Hand-foot syndrome 19 6 0 <1 0 0*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathyperipheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.

**Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular,rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approvaluse of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic andMediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders:Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whosetreatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interactwith drugs known to interact with the conventional formulation of doxorubicin HCl.

USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients havenot been established.

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL incombination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years ofage or older. No overall differences in safety or efficacy were observed between these patients and youngerpatients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, andthrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patientwith hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5BManufactured by:Ben Venue Laboratories, Inc.Bedford, OH 44146Distributed by:Ortho Biotech Products, LPRaritan, NJ 08869-0670

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

TM

An ALZA STEALTH®

Technology Product

CONTINUING EDUCATION


The risk of venous thromboem-bolism (VTE) in the general pop-ulation is substantial, with an

approximate incidence of 1 VTE caseper 1000 individuals. This translates tomore than 200,000 new cases annuallyin the United States.1 More important,almost 30% of patients with VTE willdie within 30 days of the initial diag-nosis.1 Although not all those deathsare directly related to VTE or its seque-lae, approximately 20% of those dyingwithin this 30-day period will becaused by pulmonary embolism (PE).1

Despite significant advances in thediagnosis and management of VTE,its incidence has not substantiallychanged since the 1980s.1 The risk ofhaving VTE is elevated by a number offactors, including1:• Central venous catheter/transve-nous pacemaker

• Hospital or nursing home confine-ment

• Hormone replacement therapy • Increasing age• Male sex• Malignancy

• Neurologic disease with extremityparesis

• Oral contraceptives• Pregnancy• Previous superficial vein thrombosis

• Surgery• Trauma• Varicose veins.

Venous Thromboembolism and

Malignancy

VTE may be a presenting sign of anoccult malignancy. Of all new cases ofVTE, approximately 20% are associat-ed with active malignancy.2 It isremarkable to note that patients withcancer have a 4- to 6-fold higher riskfor VTE compared with patients with-out cancer.3 Therefore, otherwisehealthy adults presenting with VTEwithout an obvious cause may war-rant additional testing to rule outoccult malignancies.VTE is also a major concern for

patients with cancer, and it must beconsidered a serious complication ofan already-diagnosed cancer. For

patients with cancer, the incidence ofVTE approaches 1 in 200 patients.4

Approximately 20% of VTE casesoccur in patients with cancer,2 whichmeans that cancer-related cases of VTEaccount for more than 40,000 of the200,000 cases seen annually in theUnited States. Fifteen percent ofpatients with cancer will have sympto-matic, diagnosed VTE, and, astound-ingly, almost 50% of patients with can-cer are found to have VTE atpostmortem examination.5 The risk ofVTE in patients with cancer is com-pounded by the fact that many pa -tients in this population are older peo-ple, aged >55 years.VTE is the second leading cause of

death in hospitalized patients withcancer, and the risk of death from VTEin patients with cancer is 3- to 8-foldhigher than in comparable patientswithout cancer.6 Furthermore, patientswith cancer and symptomatic deep-vein thrombosis (DVT) exhibit a highrisk for recurrent DVT/PE that per-sists for many years after the initialepisode.7

Other Risk Factors

Other factors that increase the riskfor VTE in patients with cancerinclude the type of malignancy. Inmen, tumors of the prostate, colon,lung, and brain are among the cancertypes with the highest risk for VTE.In women, breast, ovarian, and lungcancers are associated with increasedVTE risk.4,8 Hematologic malignan-cies, such as lymphoma and multiplemyeloma, especially when the latterdisease is treated with immunomod-ulators, have a very high risk forVTE events.4

Finally, VTE increases the risk forcancer-related death in hospitalizedpatients.9 The Figure illustrates thatthe percentage of patients who suf-fer in-hospital death is higher witheither metastatic or nonmetasta ticdisease when VTE is a comorbidcondition.9

The risk for VTE is certainly in -creased in patients diagnosed with amalignancy. That risk can further becompounded by such factors as thetreatment of the disease by selected

Improving the Prevention and Treatment of VenousThromboembolism in Cancer: The Strategic Role of theHealth-System PharmacistPROGRAM P10076E

Initial Release Date: April 22, 2011 • Expiration Date: April 22, 2012.Estimated time to complete activity: 1 hour.

SPONSOR

This activity is sponsored by Medical Learning Institute, Inc., a nonprofit medical accredita-tion company, and Center of Excellence Media, LLC.

TARGET AUDIENCE

This activity was developed for health-system pharmacists and oncology pharmacists.

LEARNING OBJECTIVES

• Explain the epidemiology and risk factors of venous thromboembolism (VTE) in cancer• Summarize current evidence-based guidelines for prevention and treatment of VTE incancer, with special attention to the differences and similarities across guidelines

• Discuss key data from randomized clinical trials of low-molecular-weight heparins in prevention of recurrent VTE in cancer

• Describe emerging strategies in VTE prophylaxis and treatmentCOMMERCIAL SUPPORT ACKNOWLEDGMENT

This activity is supported by an educational grant from sanofi-aventis.

INSTRUCTIONS FOR CREDIT

There is no fee for this activity. To receive credit, participants must read this CE activity inits entirety and complete the posttest and evaluation. The posttest and evaluation can becompleted online at www.mlicme.org/p10076E.html.Upon completion of the evaluationand scoring 70% or better on the posttest, you will immediately receive your certificateonline. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.For questions regarding the accreditation of this activity, please contact Medical LearningInstitute, Inc., at 609-333-1693 or [email protected].

REGISTERED PHARMACY DESIGNATION

Medical Learning Institute, Inc., is accredited by the Accreditation Council for PharmacyEducation (ACPE) as a provider of continuing pharmacy education. Completion of thisactivity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The

universal activity number for this activity is 0468-9999-11-021-H01-P.

DISCLOSURES

Before the activity, all faculty and anyone that is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any finan-cial interest and/or relationship(s) they might have with any commercial interest producinghealthcare goods/services to be discussed during their presentation(s): honoraria, expens-es, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. Allidentified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. forfair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Paul Dobesh, PharmD, FCCP, BCPS, is a consultant to Ortho-McNeil and sanofi-aventis.

Gary M. Owens, MD, is a consultant to Auxilium, Biosense Webster, Centocor Ortho Biotech,Eli Lilly, Genentech, and Novartis.

Gary C. Yee, PharmD, FCCP, BCOP, is on the advisory board for Amgen.

Nancy Nesser, JD, PharmD, a reviewer for MLI, has nothing to disclose.

DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for the agent discussed in this program should be inferred.

Venous Thromboembolism a Major Concern in Patients with CancerBy Gary M. Owens, MD, President, Gary Owens Associates, Philadelphia, PA

Several international organiza-tions have developed clinicalpractice guidelines for the pre-

vention and treatment of venousthromboembolism (VTE) in patientswith cancer.1 In the United States, 3organizations have developed guide-lines for VTE—the American Collegeof Chest Physicians (ACCP), theAmerican Society of Clinical Oncology(ASCO), and the National Com pre -hensive Cancer Network (NCCN).2-4

The guidelines differ in their scopeand methods used to develop theguideline. The ACCP and ASCOguidelines are based on a systematicreview and formal evaluation of studyquality. The first NCCN guideline wasbased on a systematic review, butannual revisions are based on reviewof recently published research andresponses to questions asked by clini-cians at member institutions.1 TheASCO and NCCN guidelines are limit-ed to the prevention and treatment ofVTE in patients with cancer.

Prevention of Venous

Thromboembolism

The ACCP, ASCO, and NCCNguidelines agree that all hospitalizedpatients with cancer, including thoseundergoing surgery, should receiveprophylactic anticoagulation (in theabsence of contraindications).2-4 Re c -ommended agents include low-doseunfractionated heparin, low-molecu-lar-weight heparin (LMWH), or fonda-

parinux. Patients undergoing majorabdominal or pelvic surgery shouldreceive prolonged prophylaxis (ie, upto 4 weeks).For ambulatory cancer patients, the

ACCP, ASCO, and NCCN guidelinesagree that routine VTE prophylaxis isnot recommended. The ASCO andNCCN guidelines list certain high-riskpatient groups that are exceptions tothe recommendation (Table). Although the ASCO and NCCN

guidelines consider those who arereceiving thalidomide or lenalidomidewith chemotherapy or dexamethasoneas high-risk patients, the NCCN guide-line adds specific information on dex-amethasone dose and incorporates arisk assessment model and recommen-dations developed by an internationalgroup of experts.5 In contrast to otherVTE risk assessment models, that riskassessment model was developedspecifically for patients with multiplemyeloma who are treated with thalido-mide or lenalidomide. The recommended agents for VTE in

high-risk patients vary depending onthe guideline and risk category. TheASCO guideline does not list aspirin asa recommended prophylactic agent,probably because its literature searchonly included randomized controlledtrials published through the end of2006.3 The NCCN guideline recom-mends LMWH or full-dose warfarinfor most patients, but lists aspirin as anoption for selected patients (eg, low-

risk myeloma outpatients).4

This variability in the guidelinerecommendations reflects the lack ofrigorous evidence on the preventionof VTE in patients with multiplemyeloma. Guideline recommenda-tions are likely to change as theresults of randomized controlled tri-als are published. For example,Palumbo and colleagues recentlyreported the results of a randomizedcontrolled comparison of aspirin (100

mg/day), fixed low-dose warfarin(1.25 mg/day), or LMWH (enoxa-parin 40 mg/day) as VTE prophylax-is in 667 patients with multiplemyeloma treated with thalidomide-based regimens.6 Of 659 analyzedpatients, 43 (6.5%) developed anevent, a composite end point thatincluded serious thromboembolicevents, acute cardiovascular events,or sudden deaths during the first 6



chemotherapeutic agents, the place-ment of a centrally dwelling catheter,or even by surgical procedures target-ed at removing the lesion. It is therefore essential that oncolo-

gists and other providers caring forpatients with cancer are aware ofthese risks and take steps to preventand to aggressively manage cancer-related VTE. At a minimum, physi-cians must actively intervene to pre-vent VTE in patients with cancerwho are undergoing surgery or whoare hospitalized. In addition, strongconsideration should be given toconsider preventive therapies forhigh-risk ambulatory patients withcancer (eg, patients with myelomareceiving immunomodulatory thera-py) and to engage in long-term treat-ment (>6 months) for patients withcancer who have VTE to preventVTE recurrence. �

References1. Heit JA. Venous thromboembolism epidemiology:implications for prevention and management. SeminThromb Hemost. 2002;28(suppl 2):3-13.2. Heit JA, O’Fallon WM, Petterson TM, et al. Relativeimpact of risk factors for deep vein thrombosis andpulmonary embolism: a population-based study. ArchIntern Med. 2002;162:1245-1248.3.Heit JA, Silverstein MD, Mohr DN, et al. Risk factorsfor deep vein thrombosis and pulmonary embolism: apopulation-based case-control study. Arch Intern Med.2000;160:809-815.4. Lee AY, Levine MN. Venous thromboembolism andcancer: risks and outcomes. Circulation. 2003;107(23suppl 1):I-17-I-21.5. El-Shami K, Griffiths E, Streiff M. Nonbacterialthrombotic endocarditis in cancer patients: path -ogenesis, diagnosis, and treatment. Oncologist.2007;12:518-523.6. Heit JA, Silverstein MD, Mohr DN, et al. Predictorsof survival after deep vein thrombosis and pulmonaryembolism: a population-based case-control study.Arch Intern Med. 1999;159:445-453.7. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep vein thrombosis.Ann Intern Med. 1996;125:1-7.8. Heit JA. Cancer and venous thromboembolism:scope of the problem. Cancer Control. 2005;12(suppl1):5-10.9. Khorana AA, Francis CW, Culakova E, et al. Throm -boembolism in hospitalized neutropenic cancerpatients. J Clin Oncol. 2006;24:484-490.

Figure VTE and Inpatient Mortality

VTE indicates venous thromboembolism.Adapted with permission from Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

18

16

14

12

10

8

6

4

2

0All

(N = 66,016)Nonmetastatic

(N = 20,591)

No VTE VTE

Hospital deaths

Mo

rtality

, %

Metastatic(N = 17,360)

Guidelines for the Prevention and Treatment of VenousThromboembolism in CancerBy Gary C. Yee, PharmD, FCCP, BCOP, Professor of Pharmacy Practice and Associate Dean for Academic Affairs, College of Pharmacy, University of Nebraska MedicalCenter, Omaha, and a member of the utilization management committee and national pharmacy & therapeutics committee for a large pharmacy benefits manager


Table Comparison of Guidelines for the Prevention of VTE in Ambulatory Patients with Cancer

ASCO NCCN

Definition of high-risk patients

Patients receivingthalidomide orlenalidomide withchemotherapy ordexamethasone

Select patients receiving highly thrombotic antiangiogenic therapy (ie, multiple myeloma patients receiv-ing thalidomide/lenalidomide and high-dose dexamethasone [≥480mg/month]), doxorubicin, or multiagent chemotherapy)

Myeloma patients with ≥2 individualor myeloma risk factors

Recommendedagent(s)

LMWH or warfarin(INR ~1.5)

LMWH (eg, enoxaparin 40 mg sub -cutaneous every 24 hr) or warfarin (INR 2-3)

Low-risk myeloma outpatients: aspirin (81-325 mg/day)

ASCO indicates American Society of Clinical Oncology; INR, international normalized ratio;LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolism.

Patients with cancer undergoingsurgical procedures are at higherrisk for the development of

venous thromboembolism (VTE) com-pared with patients without cancerundergoing similar surgical proce-dures.1,2 Patients with cancer undergo-ing surgery are considered to be one ofthe highest risk groups for the develop-ment of VTE, with event rates similarto those in patients undergoing ortho-pedic surgery.3,4 This high risk for VTEis because patients undergoing cancersurgery end up with all 3 parts ofVirchow’s triad: venous stasis, vasculardamage, and a hypercoagulable state.Therefore, VTE prophylaxis in thesepatients is very recommended.3,4 Thedecision on what to use for prophylaxishas also been extensively studied.In the Enoxaparin in Cancer (ENOX-

ACAN) study, 631 patients undergoingelective abdominal or pelvic surgeryfor cancer were randomized to enoxa-parin 40 mg subcutaneously once dailyor to unfractionated heparin (UFH)5000 units subcutaneously 3 timesdaily.5 The first dose of anticoagulantwas given 2 hours before surgery and

continued for 10 days. The primaryend point of the ENOXACAN studywas the incidence of total VTE deter-mined by venography. Although theprimary end point was reduced byalmost 20% at 10 days with the use ofenoxaparin compared with UFH, thisdifference was not significant (14.7% vs18.2%). There was also no significantdifference in the incidence of totalbleeding or major bleeding (4.1% vs2.9%) between the groups. In the Canadian Colorectal DVT

Prophylaxis Trial, 1349 patients under-going colorectal surgery were random-ized to the same regimens of enoxa-parin and UFH6 as in the ENOXACANstudy. In this Canadian study, 35% ofthe patients (n = 475) were undergoingcolorectal surgery for cancer. In thissubgroup, the incidence of VTE was13.9% in the enoxaparin group com-pared with 16.9% in the UFH group.6

The efficacy and safety betweenusing a low-molecular-weight hepa rin(LMWH) or UFH for in-hospital VTEprophylaxis in patients undergoingsurgery for cancer has been evaluatedin a meta-analysis.7 This meta-analysisincluded 14 randomized trials thatcompared these regimens in surgicalcancer patients. Although patientsreceiving LMWH did not demonstrateany reduction in mortality (relative risk[RR], 0.89; 95% confidence interval[CI], 0.61-1.28), there was a significantreduction in deep-vein thrombosis(DVT) with the use of LMWH (RR,0.72; 95% CI, 0.55-0.94). Most of thisoverall benefit to the use of LMWHwas in the comparison to patientsreceiving UFH twice daily (RR, 0.66;95% CI, 0.44-0.99), with less differencedemonstrated in comparison to UFH

3 times daily (RR, 0.78; 95% CI, 0.53-1.15). There was also no significant dif-ference between the 2 regimens withregard to minor or major bleeding.7

Another important question thatarises with the use of VTE prophylaxisin patients having cancer surgery is theappropriate duration of prophylaxis.Although VTE prophylaxis for mostindications is usually given for theduration of hospitalization or until thepatient is mobile, data suggest that alonger duration is indicated in patientsundergoing surgery for cancer.

The ENOXACAN II study evaluatedpatients undergoing gastrointestinaltract, genitourinary tract, or femalereproductive organ cancer surgery.8 Allpatients received enoxaparin 40 mgsubcutaneously once daily for 6 to 10days. Patients (n = 332) were then ran-domized in a double-blind fashion tocontinue taking enoxaparin at thesame dose or placebo for an additional21 days. The primary end point wasthe incidence of venographic VTE at1 month, which was significantlyreduced by 60% with the use of enoxa-parin compared with placebo (4.8% vs12%; P = .02), as well as a 60% reduc-tion in proximal DVT (0.6% vs 1.8%).This significant 60% reduction in theprimary end point was still evident at

the 3-month follow-up (5.5% vs 13.8%;P = .01). The use of extended prophy-laxis with enoxaparin did not producea significant increase in any bleedingevent (5.1% vs 3.6%) or major bleeding(0% vs 0.4%) compared with placebo.8

These results have been confirmedby 2 additional studies.9,10 The Cancer,Bemiparin, and Surgery Evaluation(CANBESURE) study randomized 703patients undergoing abdominal orpelvic surgery for cancer to bemiparin3500 IU subcutaneously once daily orplacebo after completing 6 to 10 days ofbemiparin (same dose).9 At 3-monthfollow-up, major VTE was reduced bymore than 80% with the use of extend-ed bemiparin compared with placebo(0.8% vs 4.6%; P = .010). Major bleedingwas not significantly different betweenthe groups (0.6% vs 0.3%; P = .572).9

The Fragmin After Major AbdominalSurgery (FAME) trial was slightly dif-ferent in that it enrolled all patientsundergoing abdominal surgery andhad an open-label design.10 Patientswere randomized to dalteparin 5000 IUsubcutaneously once daily for 7 daysor 28 days. Overall, VTE events weresignificantly reduced with extended-duration dalteparin prophylaxis at the1-month follow-up (7.3% vs 16.3%; P =.012). Although 58% of the patients inthe FAME trial had abdominal surgeryfor cancer, the results for the subgroupof patients with cancer are not provid-ed. Minor and major bleeding were notsignificantly increased with the extend-ed duration of VTE prophylaxis. Basedon the results of these studies, extend-ed VTE prophylaxis is recommendedfor patients undergoing abdominal orpelvic surgery for cancer.3,4

Case Scenarios in the Prevention and Treatment of VTEin Patients with CancerBy Paul Dobesh, PharmD, FCCP, BCPS, Professor of Pharmacy Practice, University of Nebraska Medical Center College of Pharmacy, Omaha

Case Scenario 1J. B. is a 54-year-old obese manrecently diagnosed with stage IIIcolon cancer. He is admitted todayfor surgical resection of theinvolved bowel segment and willsubsequently receive FOLFOX (5-FU, leucovorin, and oxaliplatin) asadjuvant chemotherapy. He has nohistory of cancer or thromboem-bolic events. Is thromboembolisma concern in this patient?



months of treatment. The event ratefor the different thromboprophylaxisarms was not significantly different.Vali dated risk assessment models arealso needed to predict the risk of VTEin patients with multiple myeloma.

Treatment of Venous

Thromboembolism

The ACCP, ASCO, and NCCNguidelines agree that all patients withcancer and established VTE should betreated with anticoagulation.2-4 Re c -ommended agents include unfraction-ated heparin, LMWH, or fondaparin-

ux, and the recommended duration ofinitial therapy is a minimum of 5 days.Long-term therapy with LMWH is rec-ommended for up to 6 months.Each of the guidelines recommends

that anticoagulation be continued forlonger than 6 months in selectedpatients with cancer. The ACCP guide-line recommends “subsequent antico-agulation with LMWH or warfarinindefinitely or until the cancer isresolved” (grade 1C recommenda-tion).2 The ASCO guideline states that“indefinite anticoagulation should beconsidered for selected patients with

active cancer, such as those withmetastatic disease and those receivingchemotherapy” (panel consensus).3

The NCCN guideline recommendsindefinite anticoagulation if the pa -tient has active cancer or persistentrisk factors. �

References1. Khorana AA, Streiff MB, Farge D, et al. Venousthromboembolism prophylaxis and treatment in can-cer: a consensus statement of major guideline panelsand call to action. J Clin Oncol. 2009;27:4919-4926.2. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotictherapy for venous thromboembolic disease:American College of Chest Physicians Evidence-

Based Clinical Practice Guidelines (8th Edition). Chest.2008;133(6 suppl):454S-545S.3. Lyman GH, Khorana AA, Falanga A, et al. AmericanSociety of Clinical Oncology guideline: recommenda-tions for venous thromboembolism prophylaxis andtreatment in patients with cancer. J Clin Oncol.2007;25:5490-5505.4. National Comprehensive Cancer Network. Venousthromboembolic disease. Version 1. 2011. www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Ac -ces sed April 14, 2011. 5. Palumbo A, Rajkumar SV, Dimopoulos MA, et al.Prevention of thalidomide- and lenalidomide-asso-ciated thrombosis in myeloma. Leukemia. 2008;22:414-423.6. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, war-farin, or enoxaparin thromboprophylaxis in patientswith multiple myeloma treated with thalidomide: aphase III, open-label, randomized trial. J Clin Oncol.2011;29:986-993.

Guidelines for the Prevention and Treatment... Continued from page 45


Another important questionthat arises with the use ofVTE prophylaxis in patientshaving cancer surgery is theappropriate duration ofprophylaxis.



The treatment of VTE in patientswith cancer requires a differentapproach compared with that for

the patient without cancer. The typicalpatient without cancer who has VTEreceives an injectable anticoagulantand warfarin together for a minimumof 4 days and until the internationalnormalized ratio (INR) becomes thera-peutic in the range of 2 to 3. At thattime, the injectable anticoagulant(UFH, LMWH, or fondaparinux) isthen discontinued and the patient con-tinues taking warfarin for at least 3 to 6months, depending on the etiology ofthe VTE.4 In patients with cancer, themanagement should be an LMWH for3 to 6 months, without the typical initi-ation of warfarin. This different man-agement strategy is srongly recom-mended in clinical guidelines andsupported by well-conducted random-ized clinical trials. Although dalteparinis currently the only LMWH to beapproved by the US Food and DrugAdministration for treatment of VTE inpatients with cancer, all 3 LMWHsavailable in the United States have clin-ical evidence to support their use forVTE therapy.Tinzaparin was compared with a

standard vitamin K antagonist in thetreatment of VTE in the Trial of theEffect of Low-Molecular-Weight Hep -arin Versus Warfarin on Mortality inthe Long-Term Treatment of ProximalDeep Vein Thrombosis (LITE).11 In theLITE trial, 200 patients with cancerwith acute symptomatic proximal veinthrombosis were randomized in anopen-label fashion to tinzaparin 175IU/kg subcutaneously once daily for 3months or to UFH intravenous bolusand infusion overlapped with warfarinuntil day 6 and the INR was therapeu-tic (2-3), with warfarin continued for 3months. At 3 months, the incidence ofrecurrent VTE was reduced by 40% inthe tinzaparin group compared withthe usual-care group, but this did notachieve significance (6% vs 10%). Pa -tients receiving tinzaparin did have a

significant 56% reduction in recurrentVTE at the end of 12 months (7% vs16%; P = .04). The incidence of minorbleeding, major bleeding, and deathwere similar between the groups.11

In another study, enoxaparin 1.5mg/kg subcutaneously once daily for 3months was compared with the samedose of enoxaparin overlapped withwarfarin for at least 4 days, with war-farin continued at an INR of 2 to 3 for 3months.12 The 146 patients with cancerin this trial were diagnosed with pul-monary embolism (PE) and/or DVTand then randomized to 1 of the 2 treat-ment groups in an open-label fashion.The primary outcome of recurrent VTEand major bleeding at 3 monthsoccurred in 10.5% of enoxaparinpatients and 21.1% of warfarin patients(P = .09). While mortality was cut bymore than 50% with the use of enoxa-parin compared with warfarin (11.3%vs 22.7%; P = .07), this trial was notlarge enough to find a significant dif-ference in mortality. Fatal bleeding wassignificantly reduced with the use ofenoxaparin compared with warfarin(0% vs 8%; P = .03), whereas othermajor bleeding did not achieve statisti-cal significance (9% vs 17%; P = .07).12

Dalteparin was compared with war-farin therapy for treatment of PEand/or DVT in patients with cancer inthe Comparison of Low-Molecular-Weight Heparin versus Oral Anti -coagulant Therapy for Long-TermAnticoagulation in Cancer Patientswith Venous Thromboembolism(CLOT) trial.13 Patients in the CLOTtrial (n = 676) were randomized in anopen-label fashion for 6 months ofanticoagulant therapy. Patients ran-domized to dalteparin received 200IU/kg (maximum dose of 18,000 IU)subcutaneously once daily for 1month, and then approximately 150IU/kg subcutaneously once daily forthe remaining 5 months. The usual-care patients received dalteparin 200IU/kg (maximum dose of 18,000 IU)subcutaneously once daily overlappedwith a vitamin K antagonist for at least5 days, and the INR was therapeutic(2-3), with the vitamin K antagonistcontinued for the remaining 6 months.At 6 months, the primary end point ofrecurrent VTE was significantly re -duced by 50% with the use of dal-teparin compared with usual care (8%vs 16%; P = .002). Mortality was notreduced at 6 months with the use ofdalteparin compared with usual care(39% vs 41%; P = .53), and major bleed-ing was also not different between thegroups (6% vs 4%; P = .27).13

In a 12-month follow-up of theCLOT trial, mortality was 59% in both

groups (P = .62). In this trial, in 75% ofthe patients with metastases, the mor-tality rate with dalteparin was similarto that of usual care (72% vs 69%; P =.46).14 In the 25% of patients withoutmetastases, there was a 45% significantreduction in mortality with the use ofdalteparin compared with usual care(20% vs 36%; P = .03).14 Although thesedata are from a post hoc analysis of thedata, it clearly requires further study ina larger patient sample.One of the major questions that

remains unanswered from clinical tri-als is what to do after the initial 6-month treatment with LMWH? Thereare at least 4 options: 1. Give no further anticoagulationtherapy

2. Continue anticoagulation with war-farin (INR 2-3)

3. Continue anticoagulation with treat-ment doses of LMWH

4. Continue anticoagulation with pro-phylaxis doses of LMWH. Future research will need to focus on

answering the best approach for con-tinued therapy, if it is needed at all.

Current guidelines do not sup-port the use of primary VTEprophylaxis in patients with

cancer. Despite the current lack of arecommendation, clinical trials havebegun to demonstrate a benefit in pri-mary prophylaxis in certain patients athigh risk for cancer. A number of trials have evaluated

the ability of LMWH to prevent mor-tality in patients without a current VTEevent.15-19 One study evaluated theLMWH nadroparin for 6 weeks inpatients with metastasized or locallyadvanced solid tumors.15 Patients wererandomized to placebo or to therapeu-tic weight-adjusted nadroparin subcu-taneously twice daily for the first 2weeks and then once daily for another4 weeks. Median survival was 8.0months for patients receiving nadro -parin compared with 6.6 months forpatients receiving placebo (P = .021).Major bleeding was not significantlyincreased with the use of nadroparin(3% vs 1%; P = .021).15

Although these results with nadro -parin seem impressive, other trials ofLMWH for improvement in survival inpatients with cancer have not repeatedthese same findings. The Improvingwith Nadroparin the Prognosis inAdvanced Cancer Treatment (INPACT)trial evaluated 503 patients with hor-mone-refractory prostate cancer within6 months of diagnosis (41%), locallyadvanced pancreatic cancer within 3months of diagnosis (26%), or non–small-cell lung carcinoma (stage IIIB)within 3 months of diagnosis (33%).16

Patients in the INPACT trial were ran-domized to observation or subcuta-neous nadroparin. The nadro parin reg-imen consisted of full-dose treatmentfor 2 weeks, followed by half-dosetreatment for 4 weeks. Nadroparin wasthen given in up to 6 cycles of nonadroparin for 4 weeks followed by fulldose for 2 weeks. All-cause mortalitywas not different between thenadroparin and observation patients(57% vs 61%). These results were con-sistent across all types of cancer includ-ed in the trial. One limitation to the trialis the use of open-label nadroparin forthe treatment of VTE in 30% of theobservation patients.16

In the FAMOUS trial, subcutaneousdalteparin 5000 IU once daily or place-bo was given for 1 year to 385 patientswith advanced malignancy.17 Mortalityat 1, 2, and 3 years was not differentbetween the groups (P = .19).17

Trials evaluating LMWH for the pri-mary prevention of VTE have recentlybeen more consistent than the trialsevaluating mortality. In the Pro -phylaxis of Thromboembolism DuringChemotherapy (PROTECHT) trial,1150 patients with metastatic or locallyadvanced solid organ cancer were ran-domized in a double-blind fashion 2:1to a prophylaxis dose of nadroparin(3800 IU) subcutaneously once daily orplacebo for the duration of chemother-

apy (maximum of 4 months).18 The pri-mary end point of venous or arterialthromboembolic events was reducedby almost 50% with the use ofnadroparin compared with placebo(2% vs 3.9%; P = .02). The benefit was

Case Scenario 2A. K. is a 42-year-old woman diag-nosed with stage IIB breast cancer.She had a lumpectomy with surgi-cal axillary staging and has sincebeen receiving radiation andchemotherapy. Two months intotherapy, she presents to the hos -pital with right lower-leg pain,swelling, and tenderness. A du plexultrasound is positive for proximalDVT. What should be the approachto treatment in this patient?

Case Scenarios in the Prevention and Treatment... Continued from page 46

Case Scenario 3M. S. is a 65-year-old man withnewly diagnosed pancreatic can-cer. The oncology team has decid-ed to initiate treatment with gem -citabine and radiation. He has nohistory of thrombophilia or VTE,but the team wishes to discuss thepossible risks and benefits of pri-mary prevention in this patient.


Despite the current lack of a recommendation, clinicaltrials have begun todemonstrate a benefit inprimary prophylaxis incertain patients at high risk for cancer.



provided without a significant increasein major (0.7% vs 0%; P = .18) or minor(7.4% vs 7.9%) bleeding.18

In the CONKO-004 trial 312 chemo -therapy-naïve patients with advancedpancreatic cancer were randomized toobservation or enoxaparin 1 mg/kgsubcutaneously once daily for 12weeks followed by enoxaparin 40 mgsubcutaneously once daily.19 At the endof the initial 12 weeks of therapy, theprimary end point of symptomaticVTE was reduced by 87% with the useof enoxaparin (1.3% vs 9.9%; P <.01).This provides a number needed to treatof only 12 patients to prevent onesymptomatic VTE with the use ofenoxaparin in this patient population.The incidence of bleeding was not sig-nificantly increased during this 12-week period with the use of enoxa-parin (3.8% vs 2.6%; P = .6). After themedian follow-up period of 30 weeks,the lower dose of enoxaparin still pro-vided a significant reduction in symp-tomatic VTE (5% vs 14.5%; P <.05). Theincidence in bleeding was increased inboth groups compared with the 12-week assessment, but the differencewas still not statistically significant(6.3% vs 9.9%).19

Results of the Evaluation of AVE5026

in the Prevention of Venous Throm -boembolism in Cancer PatientsUndergoing Chemotherapy (SAVE-ONCO) trial should be available bymid-2011. This is the largest trial toevaluate the primary VTE prophylaxisin patients with cancer. The SAVE-ONCO trial is set to randomize 3200patients to semuloparin 20 mg subcu-taneously once daily or placebo for 3 to7 months. Semuloparin is an ultra-LMWH

with an anti-Xa to anti-IIa ratio ofmore than 30:1 compared with mostLMWHs that have a ratio of 3:1 or4:1.20 Semuloparin has a half-life of 16to 20 hours, which allows for once-daily administration. Semuloparin hasalready demonstrated efficacy andsafety in patients undergoing orthope-dic and abdominal surgery.20

If the results of the SAVE-ONCOtrial demonstrate a significant benefitof primary VTE prophylaxis, as seen inthe PROTECHT and CONKO-004 tri-als, a change in the guidelines support-ing primary VTE prophylaxis in appro-priate patients with cancer may bewarranted. �

References1. Gallus AS. Prevention of post-operative deep leg veinthrombosis in patients with cancer. Thromb Haemost.

1997;78:126-132.2. Rahr HB, Sørensen JV. Venous thromboembolism andcancer. Blood Coagul Fibrinolysis. 1992;3:451-460.3. Nicolaides A, Arcelus J, Belcaro G, et al. Pre vention ofvenous thromboembolism. European ConsensusStatement, 1-5 November 1991, developed at OakleyCourt Hotel, Windsor, UK. Int Angiol. 1992;11:151-159.4.Geerts WH, Bergqvist D, Pineo GF, et al. Prevention ofvenous thromboembolism American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines(8th Edition). Chest. 2008;133(6 suppl):381S-453S.5. Efficacy and safety of enoxaparin versus unfractionat-ed heparin for prevention of deep vein thrombosis inelective cancer surgery: a double-blind randomizedmulticenter trial with venographic assessment. ENOX-ACAN Study Group. Br J Surg. 1997;84:1099-1103.6. McLeod RS, Geerts WH, Sniderman KW, et al, for theCanadian Colorectal Surgery DVT Prophylaxis Trial.Subcutaneous heparin versus low-molecular-weightheparin as thromboprophylaxis in patients undergoingcolorectal surgery. Results of the Canadian ColorectalDVT Prophylaxis Trial: a randomized, double-blindtrial. Ann Surg. 2001;233:438-444.7. Akl EA, Terrenato I, Barba M, et al. Low-molecular-weight heparin vs unfractionated heparin for perioper-ative thromboprophylaxis in patients with cancer: a sys-tematic review and meta-analysis. Arch Intern Med.2008;168:1261-1269.8. Bergqvist D, Agnelli G, Cohen AT, et al. Duration ofprophylaxis against venous thromboembolism withenoxaparin after surgery for cancer. N Engl J Med.2002;346:975-980.9.Kakkar VV, Balibrea JL, Martínez-González J, et al, forthe CANBESURE Study Group. Extended prophylaxiswith bemiparin for the prevention of venous throm-boembolism after abdominal or pelvic surgery for can-cer: the CANBESURE randomized study. J ThrombHaemost. 2010;8:1223-1229.10. Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, etal, for the FAME Investigators. Prolonged prophylaxiswith dalteparin to prevent late thromboembolic compli-cations in patients undergoing major abdominal sur-gery: a multicenter randomized open-label study. JThromb Haemost. 2006;4:2384-2390.11. Hull RD, Pineo GF, Brant RF, et al, for the LITE Trial

Investigators. Long-term low-molecular-weight heparinversus usual care in proximal-vein thrombosis patientswith cancer. Am J Med. 2006;119:1062-1072.12. Meyer G, Marjanovic Z, Valcke J, et al. Comparisonof low-molecular-weight heparin and warfarin for thesecondary prevention of venous thromboembolism inpatients with cancer: a randomized controlled study.Arch Intern Med. 2002;162:1729-1735.13. Lee AYY, Levine MN, Baker RI, et al, for the CLOTInvestigators. Low-molecular-weight heparin versus acoumarin for the prevention of recurrent venous throm-boembolism in patients with cancer. N Engl J Med.2003;349:146-153.14. Lee AYY, Rickles FR, Julian JA, et al. Randomizedcomparison of low-molecular-weight heparin andcoumarin derivatives on the survival of patients withcancer and venous thromboembolism. J Clin Oncol.2005;23:2123-2129.15. Klerk CPW, Smorenburg SM, Otten H-M, et al. Theeffect of low-molecular-weight heparin on survival inpatients with advanced malignancy. J Clin Oncol.2005;23:2130-2135.16. Buller HR, Prins MH. The effect of the low-molecu-lar-weight heparin nadroparin on the survival inpatients with cancer: a randomized trial (for theINPACT Investigators). J Thromb Haemost. 2009;7(suppl2):1203. Abstract LB-MO-004.17. Kakkar AK, Levine MN, Kadziola Z, et al. Low-mol-ecular-weight heparin, therapy with dalteparin, andsurvival in advanced cancer: the Fragmin AdvancedMalignancy Outcome Study (FAMOUS). J Clin Oncol.2004;22:1944-1948.18.Agnelli G, Gussoni G, Bianchini C, et al, for the PRO-TECHT Investigators. Nadroparin for the prevention ofthromboembolic events in ambulatory patients withmetastatic or locally advanced solid cancer receivingchemotherapy: a randomised, placebo-controlled, dou-ble-blind study. Lancet Oncol. 2009;10:943-949.19. Riess HB, Pelzer U, Opitz B, et al. A prospective, ran-domized trial of chemotherapy with and without thelow molecular weight heparin (LMWH) enoxaparin inadvanced pancreatic cancer patients. J Thromb Haemost.2009;7(suppl 2):1203. Abstract LB-MO-003.20. Eikelboom JW, Weitz JI. New anticoagulants.Circulation. 2010;121:1523-1532.

Case Scenarios in the Prevention and Treatment... Continued from page 47

San Francisco, CA—The optimal treat-ment of early-stage colorectal cancer(CRC) is not well-established. At the2011 Gastrointestinal Cancers Sym -p osium, several studies presented in -volved molecular assays that stratifypatients according to a tumor’s geneticprofile.

18-Gene ColoPrint Assay

Outperforms Clinical Variables

One study reported validationresults from an 18-gene assay. “TheColoPrint facilitates the identificationof patients with stage II CRC with alow risk of recurrence and who there-fore don’t need chemotherapy,” saidRobert Rosenberg, MD, PhD, of Tech -nical University Munich. Of the 27% of patients who were

classified as high-risk by the ColoPrintassay, 80.5% were free of distantmetastases at 5 years compared with94.9% of those classified as low-risk. This test also outperformed the clin-

ical parameters recommended by theAmerican Society of Clinical Oncologyfor patients with stage II CRC. “Noother prognostic genetic profile in col-

orectal cancer has been subjected to asecond validation,” Dr Rosenbergsaid. Studies are under way in thiscountry and internationally. Commenting on this assay, Wells

Messersmith, MD, Director of theGastrointestinal Medical OncologyProgram at the University of Colo -rado, Denver, was concerned that thistest only tells us who not to treat. “Iwant a test that tells me who to treat,and the ColoPrint assay only tells mewho I probably should not be treat-ing—the good-risk patients. I alsowant to know the subset of ‘poor-risk’

patients who will benefit from adju-vant chemotherapy.”

5-Gene OncoDefender Validated,

Superior to NCCN Guidelines

A 5-gene assay claims to be doingthat. First validation results for theOncoDefender were announced at themeeting by Peter F. Lenehan, MD,PhD, Chief Medical Officer of EveristGenomics, Ann Arbor, MI, who evalu-ated this test at 3 Mayo Clinic sites. The study included 115 patients

with stage I and II CRC treated only bysurgery. The 5-gene test differentiatedthe risk of recurrence among early-stage patients more accurately thandid estimates using the NationalComprehensive Cancer Network

guidelines. The test correctly classified32 of 46 patients with recurrence, and38 patients of 69 without. High-risk patients had a significant-

ly greater probability of recurrencethan low-risk patients.Dr Lenehan said the OncoDefender

stands out among a growing list ofcompetitors in higher positive predic-tive value and better sensitivity. Mosttests have good negative predictivevalue, he said. “It is more clinically sig-nificant and cost-effective to definewho is at high risk for recurrence. Ourtest can say with more confidence thata patient has a tumor that is aggressiveand will recur.” He added, “Our test isthe first to also target stage I patients.”Approximately 15% of patients withstage I disease will turn out to haveaggressive disease.OncoDefender should become avail -

able soon, at a cost of $3400, with apatient assistance program. Geneassays used in breast cancer cost$3000 to $4000. The Oncotype DXRecurrence Score is already availablefor CRC, but it is not reimbursed byall payers. �

Competing Tests for Colorectal Cancer Risk RecurrenceBy Caroline Helwick

GASTROINTESTINAL CANCERS SYMPOSIUM

at a glance� Gene assays that identify aparticular tumor’s genetic profilecould help guide chemotherapy

� This represents an alternativeto evaluating each patient’sclinical criteria

� Whether these genetic testswill be reimbursed by all payersis still unclear

“It is more clinicallysignificant and cost-effectiveto define who is at highrisk for recurrence.”

—Peter F. Lenehan, MD, PhD



San Francisco, CA—Advances inmolecular profiling of colorectal can-cer (CRC) are leading to an explosionin novel agents that target pathwaysabove and beyond the epidermalgrowth factor receptor (EGFR). JosephTabernero, MD, Director of ClinicalResearch, Vall d’Hebron Institute ofOncology, Barcelona, discussed thefuture treatment of CRC at the 2011Gastrointestinal Cancers Symposium. “The good news is there are lots ofnew compounds. The challenge willbe to profile patients accurately, and toidentify the gene signatures of thosewho will benefit from the individualdrugs and combinations of agents,” DrTabernero said.

New Compounds for New

Mutations

The KRAS gene has an importantrole in CRC because constitutive muta-tions of KRAS predict resistance toanti-EGFR monoclonal antibodies,including cetuximab (Erbitux) andpanitumumab (Vectibix). The role of mutations of other signal

transducer proteins is now being eval-uated, including BRAF, NRAS,PIK3CA, AKT, PTEN, and TP53. Thesealso may prove to be useful “on/off”biomarkers for EGFR inhibitor efficacyin metastatic CRC, he said. “More effective monoclonal anti-

bodies are coming,” he reported.Promising results, including long-last-ing responses, have been observedwith the compounds GA201 andSYM004. “Objective response rateshave been achieved in very refractorypatients,” he noted.

Evolving HER-3 Target

HER-3 is also a new target, as it hasbeen implicated as a potential mecha-nism of resistance to EGFR inhibi -tors. Anti-HER3 compounds, there-fore, are in development, includingMEHD7945A—a dual anti-EGFR andHER-3 monoclonal antibody—MM121,and U3-1287-AMG888.

Monoclonal Antibodies Targeting

Additional Receptors

Monoclonal antibodies directedtoward other receptors are the thirdnovel concept. The insulin-like growthfactor-1 receptor (IGF-1R) protein isexpressed in 90% of colon cancers,whereas expression is nil in normalmucosa. Expression is associated withproliferation and tumor stage, andoverexpression, seen in approximately50% of patients, is an independentprognostic factor for worse survival. A recent randomized phase 2 study

of the IGF-1R monoclonal antibodyIMC-A12 in EGFR inhibitor-refractorypatients was negative, so research con-tinues to refine the gene signature andto find an effective agent for this target.

Other potential targets are the li -gand of the c-MET receptor and hepa-tocyte growth factor (HGF). Theseoncogenes are implicated in tumorinvasiveness, metastasis, and prolifer-ation; angiogenesis; and resistance totreatment. Promising efficacy wasshown by an HGF inhibitor whencombined with panitumumab inpatients with metastatic CRC in aninternational randomized phase 1/2trial, presented at the meeting by EricVan Cutsem, MD, University HospitalGasthuisberg, Belgium.

The study included 142 patients andevaluated the HGF inhibitor rilotu-mumab (AMG 102) and the IGF-1Rinhibitor ganitumumab (AMG 479).The rilotumumab/panitumumab com-bination proved promising, with 31%responses, compared with 22% re -sponses with panitumumab/ganitu-mumab, and 21% responses with pani-tumumab monotherapy; medianprogression-free survival was similarbetween the 2 combinations (5.2 and5.3 months, respectively) and signifi-cantly greater than with panitum u -mab alone (3.7 months), Dr VanCutsem said.Tumor necrosis factor–related apop-

tosis-inducing ligand (TRAIL) and itsreceptors constitute another avenue.TRAIL results in colon cancer cellgrowth inhibition, and TRAIL-R1expression correlates with improveddisease-free survival. Conatumumab(AMG 655) is directed to TRAIL-R2and has produced partial responses.Early-phase trials are studying thisagent in combination with standardchemotherapy regimens.

Inhibiting Activation Downstream

A fourth concept is to inhibit criti-cal downstream pathways, especiallythe mitogen-activated protein kinase(MAPK)/extracellular signal-regu-lated kinase (ERK) pathway, whichconsists of protein kinases thatrespond to external stimuli and regu-late proliferation, differentiation,and survival/apoptosis. There are atleast 2 drug-related targets, RAF andMEK, in this location, for whichmore than a dozen inhibitors are indevelopment.PI3K is also dysregulated in up to

50% of patients with advanced dis-ease, and its activation triggers a signaltransduction cascade promoting can-cer growth and survival. Its drug path-way includes PI3K, AKT, mTOR,TORC1-2, and PS6K. Nearly 20 rele-vant compounds are in development,some of which are dual inhibitors.

Potential Combinations and

Challenges

Many novel agents are thought tobe most effective in combination.Promising combinations are ERKpathway inhibitors (ie, an RAF in -hibitor plus MEK inhibitor); PI3Kpathway inhibitor combinations (ie,dual PI3K plus TORC1-2 inhibitors);ERK– and PI3K pathway inhibitorcombinations (ie, PI3K plus MEKinhibitors); AKT plus MEK inhibitors;and TORC1-2 plus MEK inhibitors.These may also be combined withchemotherapy.Despite these opportunities to stop

CRC cells in their tracks, Dr Tabernerocautioned that the challenges aheadare huge. Cancer cells behave differ-ently, depending on their molecularprofile, and operate under “plastic andevolutive phenomena” that extend toboth the gene level (eg, expression,mutation, amplification/deletion) andthe proteomic level (activation, phos-phorylation). “Cells change under thepressure of stress,” he said, “includingtreatment.” �

Future of Colorectal Cancer Therapy: Novel Targeted PathwaysPersonalized medicine key to explosion in drug development By Caroline Helwick

“The good news is there are lots of newcompounds. The challengewill be to profile patientsaccurately, and to identifythe gene signatures ofthose who will benefitfrom the individual drugsand combinations ofagents.”

—Joseph Tabernero, MD

at a glanceThe following novel concepts inCRC are leading to newtherapeutic modalities:

� More efficient anti-EGFRmonoclonal antibodies

� Monoclonal antibodiesdirected to other members ofthe EGFR/HER family

� Monoclonal antibodiesdirected to other receptors (c-MET, IGF-1R)

� Inhibitors of downstreameffectors (MAPK/ERK)

� Rationally based combinationtherapies

� Identification of populationswho will benefit from therapy(ie, personalized medicine)

IF YOU VALUE

YOU WILLALSOBENEFITFROM

Visit AHDBonline.com and subscribe to AHDB Today

See also VBCC Perspective, page 28



San Francisco, CA—For patients withgastrointestinal stromal tumors (GIST)being treated with sunitinib (Sutent),the development of hypertension dur-ing treatment was associated with asurvival benefit, said Suzanne George,MD, Dana-Farber Cancer Institute,Boston, at the 2011 GastrointestinalCancers Symposium.

Hypertension appears to be a classeffect of vascular endothelial growthfactor (VEGF) signaling pathwayinhibitors and has been proposed as abiomarker of clinical outcomes for

these agents. Sunitinib is a multitar-geted inhibitor of VEGF receptorsand the other receptor tyrosine kinaseapproved for the treatment of GISTafter failure with imatinib (Gleevec)treatment. In patients receiving sunitinib for

renal-cell carcinoma, the occurrence ofhypertension was a significant predic-tor of efficacy. “Sunitinib-associatedhypertension appeared to be correlat-ed with improved clinical outcomes,which support the hypothesis thathypertension may be a biomarker forantitumor efficacy,” Dr George said.

Safety, Efficacy of Hypertension

in GIST

The current study retrospectively ex -plored the association between hyper-tension and outcomes in 2 prospectiveclinical trials of sunitinib in GIST. Theefficacy analysis included 319 patients;the safety analysis included 1565patients. Hypertension was defined asa maximum systolic blood pressure(BP) ≥140 mm Hg and diastolic BP ≥90mm Hg. The development of hypertension at

any time during treatment was associ-ated with improved clinical outcomes,Dr George reported.

In the final multivariate analysis,investigators analyzed outcomes sepa-rately, according to maximum diastolicand systolic BP. Median progression-free survival and median overall sur-vival were significantly improved withelevated systolic or diastolic BP (Table). In all comparisons, the develop-

ment of hypertension was associatedwith a highly significant 50% reduc-tion in recurrence and death. Thesuperiority of these clinical outcomeswas not compromised by treatmentwith antihypertensive medications,Dr George said.Hypertension-associated adverse

events were rare, although patientswith hypertension had a slightlygreater frequency and severity of car-diovascular adverse events than thosewithout hypertension. Treating hyper-tension in this patient population isnecessary as in other populations.In addition to finding hypertension

as a marker for good outcomes in thispatient population in terms of cancer-related survival, Dr George said, “themessage is that physicians shouldmonitor for hypertension early intreatment, because its mean onset is 4to 6 weeks, and if they see it, they needto treat it.” �

Hypertension a Good Sign in Patients Receiving SunitinibBy Caroline Helwick

“In allcomparisons,the develop -ment ofhypertensionwas associ -ated with a highly

significant 50% reduction in recurrence and death.”

—Suzanne George, MD

Table Median PFS and OS Outcomes, by BP Status

BP status Median PFS Median OS P value

Systolic BP

Elevated 34 wks 89 wks <.001

Normotensive 16 wks 53 wks .001

Diastolic BP

Elevated 35 wks 93 wks <.001

Normotensive 17 wks 51 wks <.001

BP indicates blood pressure; OS, overall survival; PFS, progression-free survival.

San Francisco, CA—Two thirds ofpatients with advanced gastrointesti-nal stromal tumor (GIST) whose dis-ease progressed on available therapiesachieved disease control with sorafenib(Nexavar), according to Nicholas P.Campbell, MD, of the University ofChicago, who reported results of arecent study presented at the 2011Gastrointestinal Cancers Symposium. In this study, the average patient

with advanced-disease GIST survivedalmost 1 year after treatment with themultikinase inhibitor sorafenib, whichis currently indicated by the US Foodand Drug Administration (FDA) forthe treatment of hepatocellular andrenal-cell cancer. On average, patients with metastatic

GIST survive about 4 years after diag-nosis, thanks to treatment with ima-tinib (Gleevec) and sunitinib (Sutent),both FDA approved agents. Sorafenib was used in 38 patients

who had previously received imatinibalone or imatinib plus sunitinib. Of the38 patients, 5 had partial responsesand 21 achieved stable disease.

Median progression-free survival was5.2 months and overall survival was11.6 months. Some patients continuedusing the drug for as long as 3 years,said Dr Campbell.

Most patients had been previouslytreated with both available agents andwere receiving sorafenib as third-linetherapy. “The data demonstrate thatsorafenib has definitive clinical activi-ty in imatinib- and sunitinib-resistantGIST,” he said. “Prolonged diseasecontrol is possible in these patientswith refractory disease.”

Although sorafenib is not approvedfor GIST, the National ComprehensiveCancer Center guidelines recommendit as an option for patients with GISTrefractory to the 2 available agents.“After failure of imatinib and suni-tinib, the therapeutic options are limit-ed for patients with advanced GIST,”Dr Campbell noted. Rates of partial response were 17%

in patients treated with imatinib and13% in those receiving both agents;stable disease was noted in approxi-mately 50% of both groups. Al -together, 68% of all patients had dis-ease control with sorafenib as asecond- or third-line agent.The most common grade 3 adverse

events were hand–foot syndrome(45%) and hypertension (21%). Ap -proximately 60% of patients requireddose reductions.

Study Limitations

Commenting on the study, PeterEnzinger, MD, Director of the Gas -trointestinal Cancer TreatmentCenter at Dana-Farber, Boston, said

the response rate was indeed impres-sive, but “it is very difficult to inter-pret single-arm uncontrolled trialswith tyrosine kinase inhibitors.” Heproposed, however, that patientsmight have also responded to rechal-lenge with their initial drugs, and thiswas not tested. Dr Enzinger noted that grade 3

hand-foot syndrome in 45% of patientsis “substantial,” noting the toxicityprofile of sorafenib (including diarrheaand rash) “is not inconsequential.”“I agree with the investigators that

further studies of sorafenib (and thenewer multikinase inhibitor rego-rafenib) in GIST patients are warrant-ed,” he said. “Patients with GISTshould have access to new options, butthe clinical community should supportdefinitive phase 3 trials that allow cli-nicians and patients to differentiateavailable drugs so that best evidencecan support best practices.”The phase 3 Study of Regorafenib as

a 3rd-line or Greater Treatment forGIST (GRID) is currently enrollingworldwide, he added.—CH �

Sorafenib Active Third-Line in Refractory GISTBetter evidence is needed, side effects a concern

“The datademonstrate thatsorafenib hasdefinitive clinicalactivity in

imatinib- and sunitinib-resistant GIST.”

—Nicholas P. Campbell, MD

Photo © Todd Buchanan 2011

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