Chirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and...

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BREAST CANCERAccelerated Partial-Breast Irradiation: Outcomes and Future PerspectivesChirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACR

TREATMENT-RELATED DIARRHEAEffective Management and Prevention of Neratinib-Induced DiarrheaFederico Ustaris, MD, Cristina Saura, MD, Jack Di Palma, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD

DUCTAL CARCINOMADuctal Carcinoma In Situ: Review of the Role of Radiation Therapy and Current ControversiesFrank Vicini, MD, FACR, and Chirag Shah, MD

HEAD AND NECK CANCERMoving Forward in the Management of Squamous Cell Carcinoma of the Head and Neck: Promising Immuno-Oncology ApproachesBarbara Burtness, MD

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O n c o l o g y ®

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for Oncology Education

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Program DirectorsJ. Michael Dixon, MD Edinburgh Breast Unit Edinburgh, UK

Hyman B. Muss, MD University of North Carolina Lineberger Comprehensive Cancer Center Chapel Hill, NC

Debu Tripathy, MD The University of Texas MD Anderson Cancer Center Houston, TX

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Daniel P. Petrylak, MD Yale Cancer Center New Haven, CT

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Table of Contents

BREAST CANCER

Accelerated Partial-Breast Irradiation: Outcomes and Future PerspectivesChirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACRAccelerated partial-breast irradiation (APBI) is an adjuvant radiotherapy technique that, in some cases, can allow for the completion of radiation therapy (RT) in 1 week or less for women undergoing breast conservation. This review examines data supporting APBI utilization, while offering clinical guidelines and future directions to help clinicians select appropriate adjuvant RT techniques.

TREATMENT-RELATED DIARRHEA

Effective Management and Prevention of Neratinib-Induced DiarrheaFederico Ustaris, MD, Cristina Saura, MD, Jack Di Palma, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD Diarrhea, a common side effect of many cancer treatments, is the most common adverse event of nera-tinib, an irreversible pan-HER tyrosine kinase inhibitor. The authors review the effectiveness of lopera-mide prophylaxis in managing this toxicity in clinical trials of neratinib.

DUCTAL CARCINOMA

Ductal Carcinoma In Situ: Review of the Role of Radiation Therapy and Current ControversiesFrank Vicini, MD, FACR, and Chirag Shah, MDOver the past several decades, the incidence of ductal carcinoma in situ (DCIS) has increased. This review evaluates the role of adjuvant radiotherapy (RT) in women with DCIS, while discussing current controversies over omitting adjuvant RT and using APBI.

HEAD AND NECK CANCER

Moving Forward in the Management of Squamous Cell Carcinoma of the Head and Neck: Promising Immuno-Oncology Approaches Barbara Burtness, MDTesting of immune checkpoint inhibition in cancer types in which immune exhaustion may play a role has become a priority in oncology. A subset of squamous cell cancers of the head and neck display phenotypic changes that predict activity for immune checkpoint inhibitors. The author reviews a large number of ongoing or recently completed trials.

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Evolving Management Strategies for Triple-Negative Breast CancerTriple-negative breast cancers (TNBCs) are expected to comprise 10% to 20% of breast cancer diagnoses in 2015. In this interview, Tiffany A. Traina, MD, discusses the latest treatment advances and data in TNBC, including approved and investigational treatment strategies.

32

Patrick I. Borgen, MDChairman, Department of Surgery Maimonides Medical CenterDirector, Brooklyn Breast Cancer ProgramBrooklyn, NY

Julie R. Brahmer, MDAssociate Professor, Oncology Johns Hopkins University School of

MedicineSidney Kimmel Comprehensive Cancer

CenterBaltimore, MD

J. Michael Dixon, MD, OBEProfessor of Surgery and Consultant

SurgeonClinical Director, Breakthrough Research

UnitEdinburgh Breast UnitEdinburgh, UK

David R. Gandara, MDProfessor of MedicineDirector, Thoracic Oncology ProgramSenior Advisor to the DirectorDivision of Hematology/OncologyUC Davis Comprehensive Cancer CenterSacramento, CA

Andre Goy, MD, MSChairman and DirectorChief of LymphomaDirector, Clinical and Translational Cancer ResearchJohn Theurer Cancer Center at Hackensack University Medical CenterHackensack, NJ

Omid Hamid, MDChief, Translational Research and ImmunotherapyDirector, Melanoma TherapeuticsThe Angeles Clinic and Research InstituteLos Angeles, CA

Roy S. Herbst, MD, PhDEnsign Professor of Medicine (Medical

Oncology)Professor of PharmacologyChief of Medical OncologyAssociate Director for Translational ResearchYale Cancer CenterYale School of Medicine New Haven, CT

Thomas J. Lynch, Jr, MDDirector, Yale Cancer CenterPhysician-in-Chief, Smilow Cancer Hospital at Yale-New HavenRichard and Jonathan Sackler Professor of

Internal MedicineNew Haven, CT

Maurie Markman, MDPresident, Medicine and ScienceNational Director, Medical OncologyCancer Treatment Centers of AmericaPhiladelphia, PA

John L. Marshall, MDChief, Hematology and Oncology Director, Otto J. Ruesch Center for the

Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC

Hyman B. Muss, MDProfessor of OncologyUniversity of North CarolinaDirector of Geriatric OncologyLineberger Comprehensive Cancer CenterChapel Hill, NC

Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer

Center Texas Oncology The US Oncology NetworkDallas, TX

Daniel P. Petrylak, MDProfessor of Medicine (Medical Oncology) and of UrologyCo-Director, Signal Transduction Research

ProgramYale Cancer Center and Smilow Cancer

HospitalNew Haven, CT

Heather A. Wakelee, MDAssociate Professor, Medicine (Oncology)Stanford University Medical CenterStanford, CA

Jeffrey S. Weber, MD, PhDSenior Member and DirectorDonald A. Adam Comprehensive Melanoma Research CenterMoffitt Cancer CenterTampa, FL

PER® Executive Board/AJHO Editorial Board

4 www.ajho.com NOVEMBER 2015

It seems public awareness of breast cancer, the most common cancer among US women, is at an all-time high. Coming out of Breast Cancer Awareness month in October, we’ve recently seen the release of updated guidelines for mammogram screening from the American Cancer Society, the American College of Obstetricians and Gynecologists, and the US Preventive Services Task Force. Public figures and celebrities are speaking out about the disease in an effort to raise funds for research and grow public awareness even further.

The medical community is also honing its focus. This issue of The American Journal of Hema-tology/Oncology®, a peer-reviewed resource for oncology education and the official journal of Physicians’ Education Resource, LLC, features 4 articles relating to different aspects of breast cancer treatment.

In the first, Chirag Shah, MD; Vivek Verma, MD; Michael A. Weller, MD; Eric Westerbeck, BS; Kyle Reilly, BS; and Frank Vicini, MD, FACR, focus on the utilization and results of acceler-ated partial-breast irradiation, an adjuvant radiotherapy technique used in radiation therapy.

Federico Ustaris, MD; Cristina Saura, MD; Jack Di Palma, MD; Richard Bryce, MBChB, MRCGP, MFPM; Susan Moran, MD; Linda Neuman, MD; and Rolando Ruiz, MD, contributed the story “Effective Management and Prevention of Neratinib-Induced Diarrhea,” which reviews the effectiveness of loperamide prophylaxis in managing diarrhea resulting from the use of nerati-nib, a kinase inhibitor frequently used in treating breast cancer.

In our third breast cancer-related story, Frank Vicini, MD, FACR, and Chirag Shah, MD, take a look at the role of radiation therapy in treating women with ductal carcinoma in situ, which has been growing in incidence among breast cancer patients in recent decades.

Our fourth story this month concerns head and neck cancer—in this case, managing squamous cell carcinoma. Barbara Burtness, MD, comments on the results of some promising immuno- oncology approaches.

Our CME article for November also relates to breast cancer. Tiffany Traina, MD, discusses current and evolving strategies for treating triple-negative breast cancer. In this interview, she covers a variety of fascinating approaches including genetic testing, treatment options, emerging immunooncology agents and clinical trials.

Michael J. Hennessy, SrChairman and CEO

Chairman’s Note

The content of this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. American Journal of Hema-tology/Oncology makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. American Journal of Hematology/Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. American Journal of Hematology/Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of American Journal of Hematology/Oncology.

VOL. 11, NO. 11 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 5

EDITORIAL STAFF

Two articles in the November issue of AJHO highlight evolving management paradigms in low-risk cancers. There have even been challenges as to whether we should be diagnosing and treating very low-risk breast cancers, as the harms of therapy may outweigh the benefits in situations where survival from detection and therapy has not been demonstrated.

Of course, we are not yet ready to take that route, as our diagnostic assays are not yet able to fully discern the dangerous versus tame le-sions, even for T1N0 and non-invasive disease. However, we are dialing back on treatment intensity, as illustrated in our article on radiation therapy approaches for DCIS by Drs. Vicini and Shah. In particular, the use of a shorter course of radiation using hypofractionated therapy has been demonstrated for both in situ and invasive disease. This ther-apy is being increasingly adopted in this country, whereas it has been the standard in the UK and Canada for some time.

Accelerated partial breast irradiation (APBI), using a variety of techniques as described in the review by Drs. Shah and colleagues, is another example of “less is more.” This approach limits radiation fields and shortens treatments utilizing techniques that include interstitial brachytherapy, three-dimensional conformal or intensity-modulated external radiation, with the rationale that it could yield equivalent local control and better cosmesis.

As data from randomized trials are just beginning to be available, with many still pending, a conservative approach, using carefully selected patients, is generally recommended. However, the exact factors and cutpoints to be applied vary among the centers and organizations making recommendations. For now, intraoperative radiation therapy (IORT) needs to remain in a separate category, as higher local recur-rences have been seen compared to standard external beam radiothera-py; yet there may still be subsets to be defined, in the future, for which this approach could be suitable.

Long-term cosmesis, fibrosis, and patient-reported functional/symptom measures, as well as convenience, patient preference, and cost are all factors that will need to be weighed as this field evolves with the release of data and further refinements to radiation techniques. It is fortunate that the radiation oncology community has persevered in the organization of randomized trials testing APBI, so that as its use expands, so does the base of evidence that informs us on how to do so wisely.

CORPORATE OFFICERS Chairman and CEOMichael J. Hennessy, Sr

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Debu Tripathy, MD Editor-in-Chief

From the Editor Editor-in-ChiefDebu Tripathy, MD

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· BREAST CANCER ·


Accelerated Partial-Breast Irradiation: Outcomes and Future Perspectives

Chirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACR

IntroductionBreast-conserving therapy (BCT) represents one of the most sig-nificant advances in breast cancer treatment over the past sev-eral decades. With more than 20 years of follow-up, BCT has been shown to have equivalent rates of local control and overall survival (OS) compared with mastectomy, with improvements in patient quality of life.1-5 Randomized trials comparing BCT and mastectomy have consistently utilized whole-breast irradiation (WBI) with or without a tumor bed boost. Whole-breast irradia-tion typically requires 5 to 6 1/2 weeks of adjuvant radiotherapy (RT) for its completion. This lengthy duration of therapy is one factor responsible for many women failing to undergo adjuvant RT following breast-conserving surgery (BCS), despite the im-

provement in breast cancer mortality associated with RT.4,6

Over the past 2 decades, alternatives to standard WBI have emerged, including hypofractionated WBI (15–16 fractions) and accelerated partial-breast irradiation (APBI). Accelerated par-tial-breast irradiation is a technique that treats only the lumpec-tomy cavity plus a small area surrounding the surgical bed (mar-gin of tissue), rather than the whole breast. This concept is based upon patterns of failure data demonstrating that the majority of ipsilateral breast failures occur in close proximity to the lumpec-tomy cavity.7,8 The purpose of this review is to examine the data supporting the utilization of APBI, as well as clinical guidelines and future directions to help clinicians decide on appropriate adjuvant RT techniques for their patients with early stage breast cancer.

Results of Clinical TrialsClinical OutcomesThe earliest technique utilized to deliver APBI was interstitial brachytherapy (IB). This was initially used as either a boost fol-lowing WBI or as the sole radiation modality; consequently, it represents the technique with the most mature data. A random-ized study of 258 women from Hungary compared WBI with APBI delivered with either IB or electrons. At 10 years of fol-low-up, no difference in clinical outcomes, including local re-currence (5.1% vs 5.9%), was noted. Improvement in cosmetic outcomes compared with WBI was seen for those women treated with IB (81% vs 63%).9 These findings were consistent with a prospective study of 45 patients from the same institution: 12-year outcomes demonstrated a 9% rate of local recurrence, 78% excellent/good cosmesis, and low rates of toxicity, including a 2% rate of grade 3 fibrosis.10

A large, multi-institutional phase 3, noninferiority random-ized trial compared IB-based APBI to WBI, randomizing 1184 patients with low-risk, early stage breast cancer and was recent-ly published. With a median follow-up of 6.6 years, there was no difference in the 5-year rates of local recurrence (1.44% with APB–I vs 0.92% with WBI; P = 0.42) and no difference in the rates of regional recurrences, distant metastases, disease-free sur-vival, breast cancer mortality, or OS was noted. With respect to toxicity, WBI was associated with increased grade 2–3 breast

Abstract

Accelerated partial-breast irradiation (APBI) is an adjuvant

radiotherapy technique that allows for the completion of

radiation therapy (RT) in 1 week or less for women under-

going breast conservation. Traditionally delivered using

interstitial brachytherapy, APBI can also be performed

using newer techniques that include applicator-based

brachytherapy and external-beam techniques (3D-con-

formal RT, intensity-modulated RT). Long-term outcomes

with APBI encompass data from randomized trials, pro-

spective data, and single-institution series, which have

highlighted the efficacy as well as comparable recurrence

risks compared with whole-breast irradiation (WBI). Pro-

spective randomized comparisons of APBI with WBI have

demonstrated similar rates of tumor control, although

toxicity results vary based on the technique used with the

potential for improved toxicity with brachytherapy based

techniques. Moving forward, studies are under way to

evaluate shorter courses of APBI, with evidence-based

guidelines evolving to the increasing literature support-

ing the technique.

Key Words: breast cancer, radiation therapy, breast-con-

serving therapy, accelerated partial-breast irradiation,

brachytherapy

ACCELERATED PARTIAL BREAST IRRIDATION


pain (1.1% APBI vs 3.2% WBI; P = 0.04) and a trend for in-creased grade 2–3 late skin side effects (3.2% APBI vs 5.7% WBI, p = 0.08) with no difference in the rates of grade 2–3 sub-cutaneous late side effects (7.6% vs 6.3%) and grade 3 fibrosis (0% vs 0.2%).11

In the United States, the RTOG 95-17 phase II trial12 evalu-ated IB with either a high-dose rate (HDR; n = 66) or low-dose rate (LDR; n = 33) implant. Ninety-nine patients were enrolled, and at 5 years, low rates of local recurrence were noted (3% HDR/6% LDR). With longer follow-up (12 years), cosmetic outcomes remained stable, with 66% reporting excellent/good cosmesis and a 13% rate of grade 3 toxicity.13

Similar findings were noted in a prospective protocol pub-lished by Hattangadi et al,14 in which 50 patients received inter-stitial APBI via an LDR technique on a dose-escalation protocol. At 12 years, a 15% local recurrence rate was noted, with 67% of patients having excellent/good cosmesis. Toxicity outcomes demonstrated that 54% of patients had moderate/severe fibro-sis, 35% had fat necrosis, and 34% had telangiectasias.These studies demonstrating fair/poor cosmesis rates of 30% to 35% may be secondary to the rates of fibrosis and fat necrosis that can impact cosmesis.

A total of 199 patients treated with interstitial HDR APBI at William Beaumont Hospital were compared via a matched-pair analysis (age, tumor size, nodal status, receptor status, hormonal therapy) to patients treated with WBI; 12-year outcomes demon-strated no differences in rates of local recurrence, regional recur-rence, or survival.15 The Table presents key clinical studies by APBI technique.

Although IB provided a technique with excellent clinical out-comes and low rates of toxicity, the technical complexity and need for multiple catheters limited the scope and interest for its use. However, with the development of single-entry applica-tors, brachytherapy became a technique more readily available to patients and continues to evolve with the introduction of second-generation multilumen and strut devices. Initial studies with the single-lumen MammoSite applicator confirmed the feasibility of the technique, with 5-year outcomes from the ini-tial study demonstrating no recurrences and low toxicity rates; importantly, a correlation between cosmesis and skin distance was noted with the initial data, which served as a guideline for clinicians using the single-lumen devices.16

This initial success led to a prospective registry study of 1449 patients who were all treated with single-lumen devices, receiving 34 Gy over 5 days with twice-daily treatment. Five-year outcomes from this study demonstrated a 5-year local recurrence rate of 3.8%, with more than 90% of patients having excellent/good cosmesis.17 Over the past few years, multilumen and strut-based devices have been developed with improved dosimetric out-comes noted (improved target coverage with reduced skin, nor-mal breast tissue, and chest wall/rib doses).18-20 It is anticipated

that in light of these improvements, long-term outcomes with this new generation of devices will demonstrate lower rates of toxicity and the potential for improved cosmetic outcomes.

Recently, two observational studies were performed evaluating toxicity with brachytherapy-based APBI. Smith et al21 evaluated a cohort of Medicare beneficiaries and found higher rates of subsequent mastectomy and infectious and noninfectious com-plications with brachytherapy-based APBI; a recent analysis by the same group found higher rates of mastectomy in younger pa-tients with endocrine receptor–negative disease.22 Similarly, Pres-ley et al23 evaluated a cohort of Medicare beneficiaries and found higher rates of complications with brachytherapy-based APBI, in-cluding wound and skin complications. These studies both had significant limitations, including their use of billing codes rather than true clinical assessment, evaluation of brachytherapy prior to widespread clinical implementation with multilumen appli-cators, failure to evaluate clinical/pathologic features, and short follow-up, as well as the fact that the increase in mastectomy not-ed may not be clinically significant. It should be noted that fi-nal analysis of the American Society of Breast Surgeons Registry trial10 demonstrated low rates of toxicity and that cosmesis data from the randomized Hungarian trial has favored brachytherapy, as did recent toxicity data from the GEC-ESTRO trial.11,24 Multi-ple prospective and retrospective series of studies also have failed to confirm the findings of these observational studies, although smaller numbers of patients may limit the ability to detect small differences seen in large observational studies.13,16,18,20

Following surgery, some patients prefer to avoid an additional invasive procedure. External-beam RT (EBRT) APBI was devel-oped to allow for shorter-duration treatment without the need for an additional procedure; however, studies have shown that in order to account for patient motion, larger target volumes are needed, leading to higher doses to normal breast tissue.25 Ini-tial studies of the technique from William Beaumont Hospital demonstrated excellent clinical outcomes in 192 patients with no local recurrences at 5 years and an 80% rate of excellent/good cosmesis.26 These findings were supported by a report from the RTOG 0413/NSABP B-39 phase III trial that found no con-cerns regarding toxicity with the 3-dimensional conformal RT (3D-CRT) technique.27 However, studies from Tufts University and the University of Michigan (study utilized intensity modulat-ed radiation therapy) have raised concerns regarding toxicity and poor cosmesis, with increased rates of grade 3 or greater fibrosis (8%) and suboptimal cosmesis.28,29

These findings were confirmed by the RAPID randomized trial,29 a study that included 2135 patients over age 40 with inva-sive ductal carcinoma/ductal carcinoma in situ (DCIS), negative margins, pathologically node-negative, and tumors less than 3 cm. The study compared 3D-CRT APBI (38.5 Gy/10 fractions twice daily) with WBI (42.5 Gy/16 fractions (82%) or 50 Gy/25 fractions (18%), 21% boost) and found that APBI was associated

· BREAST CANCER ·


TABLE. Key Accelerated Partial-Breast Irradiation Studies

Study Type Patients (n)

Median Follow-Up (months)

Technique Local Recurrence

Toxicity

Interstitial

National Institute of Oncology, Hungary

Randomized 258 122 HDR (n=88)/ electrons (n=40)

10-year LR (5.1% WBI vs. 5.9% PBI, NS)

Improved excellent/good cosmesis with partial breast 81% vs 63%

GEC-ESTRO Randomized 1184 78 HDR/PDR 5 year LR (0.9% WBI vs. 1.4% APBI, NS)

Reduced breast pain and trend for reduced grade 2-3 late skin toxicity with APBI

RTOG 9517 Prospective 99 73 HDR (n=66)/ LDR (n=33)

5-year LR 3%/6% (HDR/LDR)

13% grade 3 skin toxicity, 37% skin dimpling, 45% fibrosis, 45% telangiectasias, 15% symptomatic fat necrosis, 66% excellent/good cosmesis

Harvard University Prospective 50 134 LDR (dose-escalation)

12-year LR 15% 67% excellent/good cosmesis, 35% fat necrosis, 34% telangiectasias, 22% grade 3/4 skin toxicity

William Beaumont Hospital

Matched-Pair Analysis

199 127 HDR 12-year LR (3.8% WBI vs 5% APBI, NS), no difference in RR, DFS, CSS, OS

Applicator

MammoSite Initial Trial

Prospective 70 (43 treated)

65 (n=36) Single-Lumen 5-year LR 0% 9.3% infection, 33% seroma, 12% symptomatic seroma, 4 patients with fat necrosis, 83% excellent/good cosmesis

MammoSite Registry

Prospective 1449 63 Single-Lumen 5-year LR 3.8% (3.7% invasive, 4.1% DCIS)

91% excellent/good cosmesis, 9.6% infection, symptomatic seroma 13%, 13% telangiectasias, 2.5% fat necrosis

External Beam

NSABP B-39/RTOG 0413; 2011

Randomized 1367 37 3D-CRT 3% Grade 3+ fibrosis

RAPID Randomized 2135 36 3D-CRT Increased adverse cosmesis with APBI, Grade 3 toxicity 1.4%, increased grade 1/2 toxicity with APBI

University of Florence

Randomized 520 60 IMRT 5-year IBTR 1.5%, no difference with WBI

Reduced acute and chronic toxicity with APBI, improved cosmetic outcome with APBI

RTOG 0319 Prospective 52 63 3D-CRT 4-year LR 6% 64% excellent/good cosmesis at 3 years, 5.8% grade 3 toxicity

William Beaumont Hospital

Retrospective 192 56 3D-CRT 5-year LR 0% 81% excellent/good cosmesis, 7.5% grade 3 fibrosis, 7.6% telangiectasias

Tufts University Retrospective 60 15 3D-CRT 8% grade 3/4 fibrosis, 82% excellent/good cosmesis

University of Michigan

Prospective 34 60 3D-CRT 5-yr LR 3% 73% excellent/good cosmesis, 0% grade 3 fibrosis

APBI=accelerated partial-breast irradiation; CRT= conformal radiotherapy; CSS=cancer-specific survival; DCIS=ductal carcinoma in situ; DFS=disease-free survival; HDR=high dose rate; IBTR= ipsilateral breast tumor recurrence; IMRT=intensity-modulated radiotherapy; LDR=low dose rate; LR=local recurrence; NS=nonsignificant; OS=overall survival; PBI=partial-breast irradiation; RR=regional recurrence; 3D-CRT=3-dimensional conformal radiotherapy; WBI=whole-breast irradiation.



with higher rates of grade 1 and 2 toxicity; cosmesis was evalu-ated by trained nurses and physicians reviewing photographs as well as patients, and APBI was associated with adverse cosmesis with each (29% vs 17%, 35% vs 17%, and 26% vs 18%, respec-tively).30 Similarly, RTOG 031931 evaluated the 3D-CRT APBI technique and found that although initial toxicity outcomes were low, cosmesis deteriorated with longer follow-up, with only 64% of patients having excellent/good cosmesis and a 5.8% rate of grade 3 or greater toxicity at 3 years.

In light of these concerns, new EBRT techniques are being developed that include intensity-modulated RT (IMRT), with initial results demonstrating lower rates of toxicity, although further follow-up is needed.32 A randomized study from the Uni-versity of Florence compared APBI (30 Gy/ 5 fractions daily) with WBI (50 Gy/25 fractions with 10 Gy boost); with a median follow-up of 5 years, no difference in local recurrence was not-ed, with improved acute and chronic toxicity and cosmesis using APBI.33 Whereas a previous IMRT study (University of Michigan) found higher rates of poor cosmesis, the improved cosmesis may be due to an alternative dose fractionation scheme in this trial. Evidence-Based GuidelinesMultiple evidence-based guidelines exist to assist clinicians in de-termining which patients are appropriate for APBI (off clinical trial) based on clinicopathologic criteria.34-37 The most recent set of guidelines were published by the American Brachytherapy So-ciety (ABS) and support APBI for patients aged 50 or older, with tumors 3 cm or less, all invasive cancers and DCIS histologies, negative margins, no lymphovascular space invasion (LVSI), and negative lymph nodes.34 Previously, Smith et al35 had published American Society for Therapeutic Radiology and Oncology (AS-TRO) consensus guidelines for APBI in 2009 that included age, BRCA status, tumor size, margins, LVSI, estrogen receptor status, multifocality/centricity, histology, nodal status, and receipt of neoadjuvant chemotherapy. However, several studies evaluating these guidelines failed to demonstrate a correlation between AS-TRO groupings and local recurrence; further, additions to the lit-erature have provided more clarity regarding certain cautionary factors (eg, DCIS).38-41 With the expected publication of mature data from several randomized trials in the years to come, it is anticipated that these guidelines will continue to evolve and may include tumor genetics, as well.

Future DirectionsAs APBI continues to advance as an adjuvant RT technique, fu-ture directions will focus on further shortening the duration of treatment and providing alternative methods to deliver RT. With regard to reducing the length of treatment, data have been pub-lished on schedules shorter than the traditional 5-day, twice-daily schedule. A prospective study from William Beaumont Hospital enrolled 45 patients to receive APBI via a single-lumen appli-

cator with a dose of 28 Gy delivered in 4 fractions over 2 days. With a median follow-up of 3.7 years, no ipsilateral breast tumor recurrences (IBTRs) were noted, with 4-year disease-free survival, cancer-specific survival, and OS of 96%, 100%, and 93%, respec-tively. Toxicity rates were low, with the only grade 1 or 2 toxicities being fat necrosis (18%) or asymptomatic seroma (42%). Three patients developed rib fractures.42 Further studies are under way to examine the long-term clinical efficacy and toxicity profiles with this fractionation scheme.43

One technique that is considered to be a form of PBI is intra-operative RT (IORT); however, significant differences exist com-pared with traditional APBI techniques, including differences in the physics, biology, and a lack of image guidance.44,45 Two randomized trials have been performed evaluating IORT. The ELIOT trial46 randomized 1305 patients to IORT (electrons) or WBI and found that with a median follow-up of 5.8 years, IORT was associated with higher rates of IBTR (4.4% vs 0.4%), with no difference in survival noted. WBI was associated with higher rates of skin toxicity, although events remained low, while IORT was associated with higher rates of fat necrosis.

Similarly, the TARGIT trial47 randomized 3451 patients to IORT (delivered with a low-energy x-ray source; 15.2%-21.6% received supplementary WBI) or WBI . The 5-year risk of local recurrence (although follow-up was only 29 months) was signifi-cantly higher with IORT (3.3% vs 1.3%), with no difference in survival noted. Importantly, the difference in local recurrence in the post-pathology stratum (5.4% vs 1.7%) exceeded the 2.5% noninferiority threshold of the trial. Much controversy has been raised by these results, with significant concerns regarding the methodology raised by several authors.48,49 In light of the higher local recurrence rates, lack of long-term follow-up, and method-ological concerns regarding the TARGIT trial, IORT should not be considered to be equivalent to WBI or APBI techniques and should not be used off-protocol at this time.

Preoperative PBI also has been evaluated using an intraoper-ative technique in a phase II study from North Carolina. With a 69-month follow-up, the actuarial rate of IBTRs was 15% in 53 enrolled patients. The authors expressed concerns regarding the higher rates of local recurrence, particularly in the caution-ary-risk group.50

ConclusionsAt this time, APBI represents an appropriate treatment option for appropriately selected women with early stage breast cancer. Mature results from randomized trials and prospective series have consistently demonstrated comparable clinical and surviv-al outcomes with low rates of toxicity with brachytherapy-based APBI. Although observational studies have raised concerns re-garding increased toxicity with brachytherapy-based APBI, these findings are not supported by randomized and prospective data and are further limited by the deficiencies of observational stud-

· BREAST CANCER ·


ies. With the advent of multilumen devices, toxicity rates are expected to continue to decline with brachytherapy APBI. In light of recent data, EBRT APBI techniques continue to evolve with the aim of reducing toxicity and improving cosmesis. Evi-dence-based guidelines have been created to assist clinicians in determining appropriate candidates for APBI and continue to evolve with emerging data. Intraoperative RT, while particularly convenient for patients and highly publicized recently, should not be considered a standard treatment option off-protocol at this time, with data demonstrating higher local recurrence rates with relatively short follow-up. We await the published results of other large, randomized phase III trials that have completed accrual comparing APBI to WBI to determine efficacy of this treatment and its associated side-effect profile.

Affiliations: Chirag Shah, MD, and Michael A. Weller, MD, are from the Cleveland Clinic, Taussig Cancer Institute, Department of Radiation Oncology, Cleveland, OH; Chirag Shah, MD, Eric Westerbeck, BS, and Kevin Reilly, BS, are from Northeast Ohio Medical University, Rootstown, OH; Vivek Verma, MD, is from the Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE; and Frank Vicini, MD, is from Michigan HealthCare Professionals, Farmington Hills, MI.Disclosures: The authors report no relevant financial conflicts to disclose.Address correspondence to: Frank A. Vicini, MD, FACR, Mich-igan HealthCare Professionals/21st Century Oncology, 28595 Orchard Lake Rd, Farmington Hills, MI 48334. Phone: 248-994-0632; fax: 248-553-7674; e-mail: [email protected]

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es and quality of life in young breast cancer survivors: a short-term follow-up. Am J Surg. 2013;206(5):625-631.6. White A, Richardson LC, Krontiras H, Pisu M. Socioeconom-ic disparities in breast cancer treatment among older women. J Women Health (Larchmt). 2014;23(4):335-341.7. Gage I, Recht A, Gelman R, et al. Long-term outcome follow-ing breast-conserving surgery and radiation therapy. Int J Radiat Oncol Biol Phys. 1995;33(2):245-251.8. Swanson TA, Vicini FA. Overview of accelerated partial breast irradiation. Curr Oncol Rep. 2008;10(1):54-60.9. Polgar C, Fodor J, Major T, Sulyok Z, Kásler M. Breast-con-serving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol. 2013;108(2):197-202.10. Polgar C, Major T, Fodor J, et al. Accelerated partial breast irradiation using high-dose-rate interstitial brachytherapy: 12-year update of a prospective clinical study. Radiother Oncol. 2010;94(3):274-279.11. Strnad V, Ott OJ, Hildebrandt G, et al; Groupe Européen de Curiethérapie of European Society for Radiotherapy and On-cology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2015. pii: S0140-6736(15)00471-7. [Epub ahead of print].12. Rabinovitch R, Winter K, Kuske R, et al. RTOG 95-17, a phase II trial to evaluate brachytherapy as the sole method of ra-diation therapy for stage I and II breast carcinoma–year 5 toxicity and cosmesis. Brachytherapy. 2014;13(1):17-22.13. Arthur DW, Winter K, Kuske RR, et al. A phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and survival outcomes of RTOG 95-17. Int J Radi-at Oncol Biol Phys. 2008;72(2):467-473.14. Hattangadi JA, Powell SN, MacDonald SM, et al. Accelerated partial breast irradiation with low-dose-rate interstitial implant brachytherapy after wide local excision: 12-year outcomes from a prospective trial. Int J Radiat Oncol Biol Phys. 2012;83(3):791-800.15. Shah C, Antonucci JV, Wilkinson JB, et al. Twelve-year clin-ical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matched-pair analysis. Radiother Oncol. 2011;100(2):210-214.16. Benitez PR, Keisch ME, Vicini F, et al. Five-year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early stage breast cancer. Am J Surg. 2007;194(4):456-462.17. Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite breast brachytherapy trial. Ann Surg Oncol. 2013;20(10):3279-3285.18. Shah C, Ghilezan M, Arthur D, et al. Initial clinical expe-



rience with multilumen brachytherapy catheters for accelerated partial breast irradiation. Brachytherapy. 2012;11(5):369-373.19. Cuttino LW, Arthur DW, Vicini F, et al. Long-term results from the Contura Multi-Lumen balloon breast brachyther-apy catheter phase 4 registry trial. Int J Radiat Oncol. Biol Phys 2014;90(5):1025-1029.20. Yashar CM, Blair S, Wallace A, Scanderberg D. Initial clini-cal experience with strut-adjusted volume implant brachytherapy applicator for accelerated partial breast irradiation. Brachytherapy. 2009;8(4):367-372.21. Smith GL, Xu Y, Buchholz TA, et al. Association between treatment with brachytherapy vs whole-breast irradiation and subsequent mastectomy, complications, and survival among old-er women with invasive breast cancer. JAMA. 2012;307(17):1827-1837.22. Smith GL, Huo J, Giordano SH, Hunt KK, Buchholz TA, Smith BD. Utilization and outcomes of breast brachytherapy in younger women. Int J Radiat Oncol Biol Phys. 2015;93(1):91-101.23. Presley CJ, Soulos PR, Herrin J, et al. Patterns of use and short-term complications of breast brachytherapy in the na-tional Medicare population from 2008-2009. J Clin Oncol. 2012;30(35):4302-4307.24. Shah C, Khwaja S, Badiyan S, et al. Brachytherapy-based par-tial breast irradiation is associated with low rates of complica-tions and excellent cosmesis. Brachytherapy. 2013;12(4):278-284.25. Baglan KL, Sharpe MB, Jaffray D, et al. Accelerated par-tial breast irradiation using 3D conformal radiation therapy (3D-CRT). Int J Radiat Oncol Biol Phys. 2003;55(2):302-311.26. Shah C, Wilkinson JB, Lanni T, et al. Five-year outcomes and toxicities using 3-dimensional conformal external beam ra-diation therapy to deliver accelerated partial breast irradiation. Clin Breast Cancer. 2013;13(3):206-211.27. Julian TB, Constantino JP, Vicini FA, et al. Early toxicity re-sults with 3D conformal external beam (CEBT) from the NSABP B-39/RTOG 0413 accelerated partial breast irradiation (APBI) trial. J Clin Oncol. 2011;29:S1011.28. Leonard KL, Hepel JT, Hiatt JR, Dipetrillo TA, Price LL, Wazer DE. The effect of dose-volume parameters and interfrac-tion interval on cosmetic outcome and toxicity after 3-dimen-sional conformal accelerated partial breast irradiation. Int J Radi-at Oncol Biol Phys. 2013;85(3):623-6299.29. Liss A, Ben-David MA, Jagsi R, et al. Decline of cosmetic outcomes following accelerated partial breast irradiation using intensity modulated radiation therapy; results of a single-in-stitution prospective clinical trial. Int J Radiat Oncol Biol Phys. 2014;89(1):96-102.30. Olivotto I, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using 3D conformal external beam ra-diation therapy. J Clin Oncol. 2013;31(32):4038-4045.31. Chafe S, Moughan J, McCormick B, et al. Late toxicity and

self-assessment of breast appearance/satisfaction of RTOG 0319: a phase 2 trial of 3-dimensional conformal radiation ther-apy-accelerated partial breast irradiation following lumpecto-my for stage I and II breast cancer. Int J Radiat Oncol Biol Phys. 2013;86:854-859.32. Lei RY, Leonard CE, Howell KT, et al. Four-year clinical up-date from a prospective trial of accelerated partial breast intensi-ty-modulated radiotherapy (APBIMRT). Breast Cancer Res Treat. 2013;140(1):119-133.33. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 ran-domised controlled trial. Eur J Cancer. 2015;51(4):451-463.34. Shah C, Vicini F, Wazer DE, Arthur D, Patel RR. The Amer-ican Brachytherapy Society consensus statement for accelerated partial breast irradiation. Brachytherapy. 2013;12(4):267-277.35. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated par-tial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74(4):987-1001.36. The American Society of Breast Surgeons. Consensus State-ment for Accelerated Partial Breast Irradiation. American Soci-ety of Breast Surgeons website. https://www.breastsurgeons.org/statements/PDF_Statements/APBI.pdf. Updated August 15, 2012. Accessed August 3, 2015.37. Polgar C, Van Limbergen E, Potter R, et al; GEC-ESTRO Breast Cancer Working Group. Patient selection for accelerat-ed partial-breast irradiation (APBI) after breast conserving sur-gery: recommendations of the Groupe European de Curiether-apie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol. 2010;94(3):264-273.38. Vicini FA, Arthur D, Wazer D, et al. Limitations of the Amer-ican Society of Therapeutic Radiology and Oncology consensus guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011;79(4):977-984.39. Shaitelman SF, Vicini FA, Beitsch P, Haffty B, Keisch M, Lyden M. Five-year outcome of patients classified using Ameri-can Society for Radiation Oncology consensus statement guide-lines for the application of accelerated partial breast irradiation: an analysis of patients treated on the American Society of Breast Surgeons MammoSite Registry Trial. Cancer. 2010;116(20):4677-4685.40. Christoudias MK, Collett AE, Stull TS, Gracely EJ, Frazier TG, Barrio AV. Are the American Society for Radiation Oncol-ogy guidelines accurate predictors of recurrence in early stage breast cancer patients treated with balloon-based brachytherapy? Int J Surg Oncol. 2013;2013:829050.41. Wilkinson JB, Beitsch PD, Shah C, et al. Evaluation of cur-rent consensus recommendations for accelerated partial breast irradiation: a pooled analysis of William Beaumont Hospital

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and American Society of Breast Surgeon MammoSite Registry Trial data. Int J Radiat Oncol Biol Phys. 2013;85(5):1179-1185.42. Wilkinson JB, Martinez AA, Chen PY, et al. Four-year results using balloon-based brachytherapy to deliver accelerated par-tial breast irradiation with a 2-day dose fractionation schedule. Brachytherapy. 2012;11(2):97-104.43. Safety study for short-course accelerated, hypofractionated partial breast radiotherapy (APBI) in women with early stage breast cancer using the Contura MLB. ClinicalTrials website. https://clinicaltrials.gov/ct2/show/NCT01072838?term= contura+breast&rank = 3 Accessed August 3, 2015.44. Khan AJ, Arthur DW, Vicini FA. On the road to intraoper-ative radiotherapy: more ‘proceed with caution’ signs. Oncology. 2013;27(2):113-114.45. Shah C, Khan AJ, Arthur D, et al. Intraoperative radiation therapy in breast cancer: not ready for prime time. Ann Surg On-col. 2014;21:351-353.46. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet On-col. 2013;14(13):1269-1277.47. Vaidya JS, Wenz F, Bulsara M, et al; TARGIT Trialists’ Group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local con-trol and overall survival from the TARGIT-1A randomised trial. Lancet. 2014;383(9917):603-613.48. Hepel J, Wazer DE. A flawed study should not define a new standard of care. Int J Radiat Oncol Biol Phys. 2015;91(2):255-257.49. Cuzick J. Radiotherapy for breast cancer, the TARGIT-A tri-al. Lancet. 2014;383(9930):1716.50. Vanderwalde NA, Jones EL, Kimple RJ, et al. Phase 2 study of pre-excision single-dose intraoperative radiation therapy for breast cancer: six-year update with application of the ASTRO ac-celerated partial breast irradiation consensus statement criteria. Cancer. 2013;119(9):1735-1743.

· TREATMENT-RELATED DIARRHEA ·


Effective Management and Prevention of Neratinib-Induced Diarrhea

Federico Ustaris, MD, Cristina Saura, MD, Jack Di Palma, MD, Richard Bryce, MBChB, MRCGP, MFPM,

Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD

IntroductionNeratinib (PB-272; Puma Biotechnology Inc, Los Angeles, CA, USA) is a potent small-molecule kinase inhibitor of human epi-dermal growth factor receptors HER1 (or EGFR1), HER2, and HER4.1,2 It binds irreversibly to the intracellular ATP-binding pocket of the HER2 receptor and reduces receptor autophos-phorylation.2 In vitro studies show that neratinib blocks down-stream signal transduction and cell cycle regulatory pathways in cancer cell lines, ultimately leading to decreased cell prolifera-tion.2 In animal studies, neratinib inhibits the growth of EGFR– and HER2–dependent tumor xenograft models when given oral-ly on a once-daily schedule.2

Neratinib is currently in late-stage clinical development, with regulatory submission planned in 2016. It has been investigated extensively in the treatment of metastatic HER2–positive breast cancer both as a single agent3-5 and in combination with che-motherapeutic and targeted agents.6-11 Overall response rates in

phase II studies ranged from 29% to 40% with neratinib mono-therapy in women with metastatic HER2–positive breast cancer who had previously been treated with chemotherapy and tras-tuzumab.3-5 Considerably higher response rates were observed when neratinib was combined with chemotherapeutic agents, for example, 63% with capecitabine8 and 72% to 75% with ne-ratinib plus paclitaxel.6,10 Of note, neratinib showed clinical ac-tivity in women who had been previously treated with trastuzum-ab,4,8 suggesting that it may be able to circumvent trastuzumab resistance.

Neratinib is also being investigated in early-stage HER2–pos-itive breast cancer. In a phase III trial of neratinib (ExteNET), a 12-month course of treatment improved invasive disease-free survival after 2 years of follow-up compared with placebo in women with early-stage HER2–positive breast cancer after tras-tuzumab-containing adjuvant therapy (hazard ratio 0.67, 95% CI 0.50–0.91; 1-sided P = .0046).12 Diarrhea was the most common adverse event with neratinib (grade 3, 40%; grade 4, <0.1%).12

As previous efforts to improve outcomes with extended adjuvant therapy with trastuzumab have been unsuccessful,13 neratinib is the first agent to significantly prolong disease-free survival in women with trastuzumab-treated early-stage breast cancer. Lon-ger term follow-up and assessment of overall survival in the Ex-teNET trial is ongoing.

Neratinib is taken orally at a dosage of 240 mg once daily on a continuous schedule.4 At this dosage, neratinib is generally well tolerated with a low incidence of grade 3/4 adverse events.4 The most commonly reported adverse event and dose-limiting toxici-ty of neratinib is diarrhea,3,4 a known class effect of EGFR-direct-ed tyrosine kinase inhibitors.14

In this article, we will discuss the incidence, severity and pat-terns of occurrence of diarrhea with neratinib, and how this may be effectively managed with initiation of intensive loperamide prophylaxis at the beginning of treatment.

Cancer Treatment-Related Diarrhea GradingThe standard tool most commonly used for grading the severity of diarrhea is the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Adverse Events.15 According to version 4.0 of these criteria, grade 1 (mild) diarrhea is defined as an in-

Abstract

Diarrhea is a common complication of many cancer treat-

ments and a side effect well understood by most oncol-

ogists. It requires prompt and effective management to

prevent sequelae, preserve dose intensity, and maintain

patient quality of life. Neratinib (PB-272; Puma Biotech-

nology Inc, Los Angeles, CA, USA) is an irreversible pan-

HER tyrosine kinase inhibitor in late-phase clinical devel-

opment. Diarrhea, the most common toxicity associated

with neratinib, is generally observed during the first cycle

of treatment. Intensive loperamide prophylaxis (ie, 16 mg

on day 1, tapering to 12 mg/day then 6-8 mg/day over the

course of cycle 1) has been introduced in clinical trials of

neratinib to better manage this toxicity. Safety data from

these trials suggest that a prophylactic regimen reduc-

es both the severity and duration of neratinib-associat-

ed diarrhea. Intensive loperamide prophylaxis should be

used in all patients receiving neratinib for the first cycle

of treatment.

Key words: Neratinib, diarrhea; prophylaxis, loperamide,

clinical trials



crease of <4 stools per day from baseline (or mild increase in ostomy output), with asymptomatic or mild symptoms such that intervention is not indicated.15 Grade 2 (moderate) diarrhea is defined as an increase of four to six stools per day from baseline (or moderate increase in ostomy output), requiring minimal, lo-cal, or non-invasive interventions only.15 Grade 3 (severe or med-ically significant) diarrhea is defined as an increase of ≥7 stools per day from baseline (or severe increase in ostomy output), in-continence, hospitalization (or prolongation of hospitalization)

limiting self-care activities of daily living.15 Grade 4 events are deemed to be life-threatening requir-ing urgent intervention.15 In clinical practice, patient symptom diaries are also generally used as an additional assessment tool in conjunction with the NCI-CTC criteria.

OccurrenceDiarrhea is a common side effect of many cancer treatments, including chemotherapeutic agents, molecularly targeted agents and pelvic radiother-apy. EGFR-directed tyrosine kinase inhibitors are associated with high frequencies of clinically important diarrhea, and depending on the agent, up to 95% of patients may experience some grade of diarrhea, although the risk of grade 3/4 events tends to be lower (<15%) (Table 1). Diarrhea is also common with several multi-agent HER2–di-rected regimens used in the treatment of HER2–positive breast cancer (Table 1). Further, it is recognized that regimens used for the treatment of colorectal cancer, particularly those involving fluoropyrimidines and irinotecan, carry a high risk of diarrhea.50 Data from randomized trials suggest that up to 80% of patients treated with regimens involving these agents may experience diarrhea, and 20% will commonly experience grade 3 or 4 diarrhea (Table 1).

ManagementDiarrhea caused by cancer treatments requires early intervention to prevent complications such as dehydration, electrolyte imbalances, and renal insufficiency.51 If left unmanaged, persistent di-arrhea can require additional resources beyond oral antidiarrheal agents (fluid replacement, octreotide, antibiotics, unplanned clinic visits, hospitalization) and can be costly to manage.52,53 Severe diarrhea can also lead to changes in treat-ment, including dose reductions and treatment discontinuation.52-54 These alterations may have a negative effect on tumor control, although the consequences of diarrhea-driven treatment modi-

fications and discontinuations on clinical outcomes have never been formally investigated.

Effective management should involve a continuous process of assessment, reassessment, and appropriate dietetic and pharma-cological interventions, with an increase in aggressive stepwise management as needed. There are several sets of guidelines for the management of cancer treatment-related diarrhea,50,51,55-59 although there is little consensus between them on the details of care. Treatment is often empirical and the guidelines have

TABLE 1. Chemotherapy Regimens and Targeted Agents Commonly Associated With Diarrhea. Data From Randomized Controlled Trials.

Agent or Regimen Incidence of Diarrhea, % Reference

All grade Grade 3/4

Erlotinib 55 6 16

Gefitinib 34–47 <1–4 17,18

Afatinib 96 15 19

Lapatinib 48 7 20

Idelalisib 43 13 21

Lapatinib + capecitabine 65 14 22

Capecitabine + docetaxel – 14 23

Cyclophosphamide, methotrexate +

5-fluorouracil

– 6 24

Pertuzumab, trastuzumab + docetaxel 67 8 25

Pertuzumab, trastuzumab, docetaxel +

carboplatin

72 12 26

Panobinostat, bortezomib +

dexamethasone

68 25 27

Irinotecan 76–82 16–36 28-30

5-Fluorouracil/leucovorin

Bolus (Mayo Clinic) 58–64 12–21 31-34

Bolus (Roswell Park) 79 29–30 32,35

Infusional (LV5FU2) 44–48 4–7 34,36-38

FOLFOX4 46–61 5–12 37-41

FOLFIRI 59–63 10–14 41-46

FOLFOXIRI 78 20 46

Capecitabine 46–48 11–12 31,33

XELOX 60–65 19–20 39,47

Bevacizumab + FOLFIRI 57 11–14 44,48

Cetuximab + FOLFIRI 63 11–16 45,48

Cetuximab + irinotecan 81 21–28 29,49

Panitumumab + FOLFIRI – 14 43

FOLFIRI indicates infused 5-fluorouracil, leucovorin, plus irinotecan; FOLFOX, infused 5-fluorouracil, leucovorin, plus oxaliplatin; FOLFOXIRI, infused 5-fluoroura-cil, leucovorin, oxaliplatin, and irinotecan; XELOX, capecitabine plus oxaliplatin.

EFFECTIVE MANAGEMENT AND PREVENTION OF NERATINIB-INDUCED DIARRHEA


served to highlight that there are few clinically relevant studies on which to base decisions relating to the management of cancer treatment-related diarrhea.5

Pharmacological treatment of cancer treatment-related di-arrhea is based primarily on the empirical use of opioids. Lop-eramide, a synthetic opiate, is the standard first-line treatment for chemotherapy-induced diarrhea.50,59 It acts as an agonist on opioid receptors in the gastrointestinal tract to decrease gut mo-tility.51 Systemic absorption of loperamide and systemic adverse events are minimal, although high-dose therapy can lead to par-alytic ileus.55 Alternative opioids recommended for cancer treat-ment-related diarrhea include deodorized tincture of opium50,59 and diphenoxylate plus atropine (Lomotil®).59 Octreotide is the other main pharmacologic intervention for cancer treatment-re-lated diarrhea. It is generally reserved for use in complicated cases or as a second-line treatment for persistent diarrhea after loperamide.50 Octreotide is a somatostatin analogue that decreas-es hormone secretion to prolong intestinal transit time, promote intestinal absorption of electrolytes, and decrease mesenteric blood flow.51 It is well tolerated, with the most common adverse events being mild abdominal pain and injection site pain.60

Other than the use of atropine for early cholinergic diarrhea associated with irinotecan infusion,61 prophylactic anti-diarrheal therapy is not standard for any cancer treatment. Several small studies have investigated the utility of different prophylactic anti-diarrheal regimens to reduce the frequency and severity of cancer treatment-related diarrhea. Activated charcoal62 and oral alkalinization63 may be beneficial for irinotecan-associated diar-rhea, and probiotics may have a role in preventing 5-fluorouracil (5-FU)-related diarrhea.64 However, studies of prophylactic oct-reotide65-67 and an intestinal adsorbent68 did not show benefit.

Many studies have investigated potential risk factors for the development of cancer treatment-related diarrhea (ie, genotype, clinical characteristics), although prospective studies are lacking and no predictors are used in clinical practice. Readers are referred to Andreyev et al55 for a more detailed discussion of this subject.

Occurrence of Diarrhea with NeratinibStudies with No or Suboptimal Antidiarrheal ProphylaxisDiarrhea management in initial trials of neratinib involved treat-ment with antidiarrheal agents and/or dose modifications only after diarrheal symptoms became apparent. A few studies includ-ed antidiarrheal prophylaxis, but the doses of loperamide used were proven to be suboptimal (ie, 2 or 4 mg/day).7,69,70 For ex-ample, in the Translational Breast Cancer Research Consortium 022 phase II study, the incidence of grade 3 diarrhea was 33% before the introduction of prophylaxis compared with 21% with low-dose loperamide prophylaxis (2 mg/day).69

From the studies with no or suboptimal prophylaxis, it was evident that most diarrhea events with neratinib occurred in the first month of treatment. For example, in the ExteNET trial, the overall incidence of grade 3 or higher diarrhea was 40%; howev-

er, 73% of these patients experienced grade 3 events during the first month of treatment. After the third month of treatment, grade 3 diarrhea was relatively infrequent with approximately 6% of patients on treatment or fewer experiencing grade 3 diarrhea after month 3. The rate of grade 2 diarrhea also declined from about 30% in the first month to 18% to 19% in months 2 and 3, and to 12% in month 12 (data on file, Puma Biotechnology Inc.).

In studies with no or suboptimal prophylaxis, treatment-emer-gent diarrhea with neratinib was generally of mild-to-moderate severity; grade 1/2 events occurred in 56% to 67% of patients (Table 2).4,12,61 The incidence of grade 3 diarrhea ranged from 30% to 53% (Table 2),4,9,12,70 with an incidence of 40% in the largest study performed to date (ExteNET).12 Where details of grade 4 events were available, these events were rare (0% to 3% of patients).3,4,6,7,9,10,12,69 The median duration of all grade events was 7 to 14 days per episode as reported in two studies (Table 2).

Diarrhea resolved in most patients either spontaneously or with standard management involving antidiarrheal medications and/or dose modifications.5 Neratinib dose reductions because of diarrhea were documented in 10% to 15% of patients.5,8,10 Most patients continued treatment despite the occurrence of di-arrhea, and treatment discontinuation as a result of diarrhea was uncommon (0% to 14% of patients).3-6,8,10,12,71

Studies with Intensive Loperamide ProphylaxisThe mainstay of management for neratinib-associated diarrhea is intensive prophylaxis with loperamide. An intensive prophylactic regimen was first instigated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) FB-8 study after the investi-gators noted a high occurrence of diarrhea in the first week of neratinib therapy despite early treatment with loperamide.9 Pro-phylaxis was initiated with the first dose of neratinib and given for the first cycle of treatment. Although the patient numbers in the NSABP FB-8 study were small, the introduction of intensive loperamide prophylaxis reduced the occurrence of grade 3 diar-rhea from 53% (8 of 15 patients) before its introduction to 0% (0 of 6 patients).9

Based on the early success of this regimen, intensive antidiar-rheal prophylaxis with loperamide for the first cycle of treatment has been introduced as a mandatory measure in new and on-

Practical Application

• Diarrhea is a common side effect of many cancer treatments and can lead to severe complications and treatment modifications if left unmanaged. Diarrhea is the most common adverse event of neratinib, a novel irreversible pan-HER tyrosine kinase inhibitor.

• Most higher-grade diarrhea with neratinib occurs during the first cycle of treatment.

• For effective management, neratinib should be used in conjunction with an intensive regimen of loperamide prophylaxis for the first cycle of treatment.



going trials of neratinib. The precise loperamide regimen used in these studies has evolved over the past 2 years to improve pa-tient compliance. However, the initial dose of loperamide has remained constant (ie, 4 mg with the first dose of neratinib), and all regimens have tapered to a lower dose of loperamide over the course of the first cycle. The recommended loperamide prophy-lactic regimen for use with neratinib is shown in Figure 1.

Safety data from trials that included intensive loperamide pro-phylaxis show a marked reduction in the incidence of grade 3 diarrhea to 0% to 17%, even though many of the patients who experienced grade 3 diarrhea did not receive the full prophylac-tic regimen due to compliance issues (Table 2).9,70,72 This com-pares with rates of 30% to 53% in studies with no or suboptimal prophylaxis (Table 2). The median duration of all-grade treat-ment-emergent diarrheal events was also reduced from 7 to 14 days to 2 days with loperamide prophylaxis (Table 2).

A detailed management algorithm for treatment-emergent diarrhea during neratinib therapy is shown in Figure 2. Any

FIGURE 1. Intensive Loperamide Prophylactic Regimen for Use With Neratinib

qid, 4-times daily; tid, 3-times daily.

FIGURE 2. Management Plan for Neratinib-Related Diarrhea

* Grade 1 diarrhea, grade 2 diarrhea lasting <5 days, or grade 3 diarrhea lasting <2 days.** Grade 2 diarrhea lasting >5 days or grade 3 diarrhea lasting >2 days despite optimal treatment or associated with fever, dehydration, or grade 3-4 neutropenia, or any grade 4 diarrhea.bid indicates twice daily; tid, 3-times daily.

Treatment-emerged diarrhea

DIETETIC MEASURES• Stop all lactose-containing products.• Drink 8 to 10 large glasses of clear liquids per day.• Eat frequent small meals.• Recommend low-fat diet enriched with bananas, rice, apple sauce and toast, ie, BRAT diet.

PHARMACOLOGIC INTERVENTIONSFIRST-LINE THERAPY - LOPERAMIDE• If receiving prophylaxis, increase loperamide dose to a maximum of 16 mg/day.• If new-onset diarrhea, take loperamide 4 mg with first bout of diarrhea followed by 2 mg every 4 hours or after every unformed stool (maximum 16 mg/day). Continue until diarrhea-free for 12 hours.• With recovery to ≤ grade 1, take loperamide 4 mg with each subsequent neratinib administration.SECOND-LINE THERAPYGrade 1• If persistent diarrhea on loperamide, add diphenoxylate hydrochloride plus atropine sulfate (Lomotil®) 2.5 mg every 6 to 8 hours.Grade 2• If persistent diarrhea on loperamide, add octreotide (short-acting) 150 μg subcutaneously tid, or after initial dose of short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg intramuscularly.Grade 3/4• After intensive loperamide therapy, titrate loperamide to keep diarrhea controlled (<4 stools/day).• Octreotide (100 to 150 μg subcutaneously bid or 25 to 50 μg/hour intravenously if dehydration is severe, with dose escalation up to 500 μg subcutaneously tid).• Intravenous fluids as appropriate.• Consider prophylactic antibiotics, especially if diarrhea is persistent beyond 24 hours or if there is fever or grade 3/4 neutropenia.• Stool cultures to exclude infectious causes.

NERATINIB• Continue at full dose (neratinib 240 mg)

NERATINIB• First occurrence: hold neratinib until ≤ grade 1.If recovery occurs:• ≤1 week, resume same dose neratinib.• 1 to 4 weeks, reduce neratinib dose.Second occurrence: reduce neratinib dose.Subsequent occurrences: reduce neratinib dose.

Neratinib dose reduction levels: 160 and 120 mg.

FLUID INTAKE• Fluid intake (~2L) should be maintained.

Uncomplicated cases* Persistent orcomplicated cases**

Die

teti

cPh

arm

acol

ogic

al t

reat

men

tD

ose

mod

ifica

tion

s

Neratinib

Loperamideprophylaxis

Day 1 Day 2-3

Cycle 1 Cycle 2 onwards

Day 4-End of cycle

16 mg(4 mgstartingdose +4 mg tid) As needed12 mg/day

(4mg tid)6-8 mg/day

(2 mg tid or qid)

240 mg once daily continuously



new-onset diarrhea may be managed with the maximum dose of loperamide (ie, 16 mg/day), with the addition of diphenoxylate plus atropine (Lomotil®) or octreotide according to severity. Di-etetic changes, such as the BRAT diet (ie, low-fat diet enriched with bananas, rice, applesauce, and toast), increased fluid intake, stopping all lactose-containing products, and frequent small meals, should also be encouraged. Treatment interruptions or dose reductions are recommended only if patients have signifi-

cant persistent diarrhea and are unresponsive to the above-men-tioned interventions.

Future Research With NeratinibA comprehensive clinical development program of neratinib is currently ongoing (Table 3). In a recently reported phase III trial (ExteNET), treatment with neratinib demonstrated a statistically significant improvement in invasive disease-free survival com-

TABLE 2. Occurrence of Diarrhea With Neratinib in Selected Studies With No or Suboptimal Prophylaxis and Studies That Included Intensive Loperamide Prophylaxis.

Study No or Suboptimal Loperamide Prophylaxis Loperamide Prophylaxisa

NSABP FB-8

10-005 3144A1-201 ExteNET NSABP FB-8

10-005 PUMA-NER-4201 PUMA-NER 5201

Population HER2+ MBC

HER2+ MBC HER2+ MBC HER2+ EBC HER2+ MBC HER2+ MBC HER2-mutated NSCLC

HER family mutated

solid tumors

Study treatment

Neratinib + trastu-zumab + paclitaxel

Neratinib + temsiroli-

mus

Neratinib Neratinib Neratinib + trastuzumab + paclitaxel

Neratinib + temsiroli-

mus

Nera-tinib + temsi-rolimus

Nerati-nib

Neratinib

Total patients, n 15 37b 66f 1408 6 41 14 13 81

Grade 1/2 –c 21 (57) 44 (67)f 781 (56) 5 (83) 24 (59) 12 (86) 9 (69) 37 (46)

Grade 3 8 (53) 12 (32) 20 (30)d,f 562 (40)d 0 7 (17) 2 (14) 1 (8) 10 (12)

Patients with grade 3 diar-rhea who were noncompliante with lopera-mide, n (%)

– – – –

0 4/7 (57) 1/2 (50)

1/1 (100)

–

Median duration of all-grade treat-ment-emergent diarrhea per episode, days.

– 14 7f – – 2 2 2 2

Trial registration

NCT01423123 NCT01111825 NCT00300781 NCT00878709 NCT01423123 NCT01111825 NCT01827267 NCT01953926

References 9 70; data on file, Puma

Biotechnolo-gy Inc

4; data on file, Puma

Biotechnol-ogy Inc


Biotechnol-ogy Inc


Biotechnolo-gy Inc


Biotechnol-ogy Inc

72; data on file, Puma Biotechnol-

ogy Inc

Data on file, Puma

Biotechnol-ogy Inc

aLoperamide 4 mg administered with the first dose of neratinib, followed by 2 mg every 4 hours for 3 days, then 2 mg every 6 to 8 hours for the remainder of cycle 1.bPatients received low-dose loperamide prophylaxis (4 mg/day). cGrade 1 and 2 diarrhea rate was 52% (11 out of 21 patients); however, patient numbers by cohort were not provided.dIncludes 1 grade 4 event.eDefined as less than 10 mg/day on day 1, 8 mg/day on days 2 or 3, or 6 mg/day until the end of cycle 1.fPatients with prior trastuzumab therapy.EBC indicates early-stage breast cancer; MBC, metastatic breast cancer; NSABP, National Surgical Adjuvant Breast and Bowel Project; NSCLC, non-small cell lung cancer



pared with placebo in patients with early-stage HER2–positive breast cancer who had previously received adjuvant trastuzumab. However, because no antidiarrheal prophylaxis was given in Ex-teNET, the rate of grade 3 (or higher) diarrhea was high (40%).12 To better understand the ability of high-dose loperamide pro-phylaxis to reduce neratinib-related diarrhea, a phase II study (PUMA-NER 6201) has been initiated to formally investigate the effectiveness of this loperamide prophylaxis regimen. Similar to ExteNET, the study is enrolling women with early-stage HER2–positive breast cancer following trastuzumab-based adjuvant therapy. All patients are receiving neratinib 240 mg/day plus intensive loperamide prophylaxis (ie, 4 mg with the first dose of neratinib, 4 mg 3-times daily for 2 weeks, then 4 mg twice daily).

The primary outcome of the study is the incidence and severity of diarrhea, and secondary outcomes include the incidence and severity of diarrhea by loperamide exposure.

In addition, there are several other phase II and III trials of ne-ratinib with loperamide prophylaxis in patients with early-stage and metastatic HER2–positive breast cancer (Table 3). NALA (PUMA-NER-1301) is a randomized phase III trial that is com-paring neratinib plus capecitabine with lapatinib plus capecit-abine as third-line therapy in patients with HER2–positive met-astatic breast cancer. The study was prompted by the findings of an earlier phase II study that reported notable activity with neratinib plus capecitabine.8 NALA will enroll approximately 600 patients from centers in Europe, Asia-Pacific, and North

TABLE 3. Ongoing Clinical Trials With Neratinib.

Protocol (Name)

Registration Identifier

Phase Cancer Setting Treatment

HER

2-ov

erex

pres

sing

or

-am

plifi

ed b

reas

t ca

ncer

3144A2-3004-WW (ExteNET)

NCT00878709 III Early-stage breast cancer

Adjuvant (post-trastu-zumab)

Neratinib vs placebo

PUMA- NER-6201

NCT02400476 II Early-stage breast cancer

Adjuvant (post-trastu-zumab)

Neratinib

NSABP FB-7 NCT01008150 II Early-stage breast cancer

Neoadjuvant Neratinib + paclitaxel vs trastuzumab + pacli-taxel vs neratinib + trastuzumab + paclitaxel

PUMA- NER-1301 (NALA)

NCT01808573 III Metastatic breast cancer

Third-line Neratinib + capecitabine vs lapatinib + capecitabine

10-005 NCT01111825 I/II Metastatic breast cancer

Trastuzum-ab-refractory

Neratinib + temsirolimus

TBCRC 022 NCT01494662 II Metastatic breast cancer

CNS metas-tases

Neratinib ± capecitabine

NSABP FB-10 NCT02236000 I/II Metastatic breast cancer

Second-line Neratinib + trastuzumab emtansine

ERBB

-mut

ated

ca

ncer

s

201209135 NCT01670877 II ERBB2-mutated meta-static breast cancer

First and later lines

Neratinib ± fulvestrant

PUMA- NER-4201

NCT01827267 II ERBB2-mutated advanced/metastatic NSCLC

First and later lines

Neratinib ± temsirolimus

PUMA- NER-5201 (BASKET)

NCT01953926 II Solid tumors (ERBB-mutated or EGFR amplified)

Incurable Neratinib

Oth

er

canc

ers NSABP FC-7 NCT01960023 I/II Wild-type KRAS,

NRAS, BRAF, PIK3CA metastatic colorectal cancer

Second and later lines

Neratinib + cetuximab

CNS indicates central nervous system; EGFR, epithelial growth factor receptor; NSABP, National Surgical Adjuvant Breast and Bowel Project; NSCLC, non-small cell lung cancer; TBCRC, Translational Breast Cancer Research Consortium.



and South America. The coprimary study endpoints are progres-sion-free survival and overall survival. Further phase II studies are testing neratinib alone or as part of a combination in tumors with HER2 or HER3 mutations, or EGFR-amplified tumors.

The precise molecular mechanism of neratinib-induced diar-rhea is unknown, but is postulated to be due to EGFR inhibition and resultant secretory diarrhea.55 Preclinical studies are ongo-ing to better characterize the histopathology, clinical symptoms, and blood biochemistry of neratinib-induced diarrhea, and to understand the on-target effects of neratinib on the gastrointesti-nal system and the specific mechanisms of the neratinib-related diarrhea.

ConclusionsDiarrhea is a recognized adverse event of many cancer treatments and a side effect well understood by most oncologists. Once diar-rhea occurs, it should be managed promptly and aggressively to prevent an escalation in severity and patient morbidity, and to maintain full-dose therapy. Diarrhea is a class effect of EGFR-di-rected tyrosine kinase inhibitors, and the most common toxicity of neratinib, a novel irreversible pan-HER tyrosine kinase inhib-itor. For patients receiving neratinib, preventive management with intensive loperamide prophylaxis is required to reduce the severity and duration of diarrhea. Loperamide prophylaxis should be started with the first dose of treatment and continued until the end of the first cycle, regardless of the presence or ab-sence of diarrhea. Any treatment-emergent diarrhea should be managed according to standard guidelines.

Initial trials with neratinib were all performed without the support of effective antidiarrheal prophylaxis. Intensive lopera-mide prophylaxis has been implemented and refined in ongoing and new trials of the drug. Preliminary safety data from these trials suggest that active management with intensive loperamide prophylaxis reduces the incidence, severity, and duration of ne-ratinib-associated diarrhea. The frequency of grade 3 diarrhea when neratinib is given with intensive loperamide prophylaxis (0% to 17%) is similar to rates observed with other EGFR-direct-ed tyrosine kinase inhibitors (1% to 14%), and considerably low-er than rates observed with many chemotherapy regimens used in routine oncology practice (Table 1).

Intensive loperamide prophylaxis provides an effective means of reducing the incidence, severity and duration of nerati-nib-associated diarrhea. It should be given for the first cycle of treatment in all patients receiving neratinib. Current diarrhea prophylaxis recommendations are 4 mg with the first dose of neratinib, then 4 mg 3 times on day 1 (for a total of 16 mg on day 1), 4 mg 3-times daily (for a total of 12 mg/day) on days 2 and 3, reducing to 2 mg 3- or 4-times daily (for a total of 6-8 mg/day) for the remainder of the first cycle. Nonpharmacologic interven-tions, including dietetic changes and increased fluid intake, are recommended for new-onset uncomplicated diarrhea.

Affiliations: Federico Ustaris, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD, are from Puma Biotechnology Inc, Los Angeles, CA, USA. Cristina Saura, MD, Medical Oncology De-partment, Vall d’Hebron University Hospital, Vall d’Hebron In-stitute of Oncology (VHIO), Barcelona, Spain. Jack Di Palma, MD, Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, Alabama, USA.Disclosures: Dr Saura declares consultancy work and involve-ment in paid advisory boards. Dr Di Palma is involved in an independent data management committee. Drs Bryce, Moran, Neuman, Ruiz, and Ustaris are employees of Puma Biotechnolo-gy Inc, and Drs Bryce and Neuman also declare stock ownership in the company.Source of Funding: Puma Biotechnology Inc was involved in the collection, analysis, and interpretation of safety data, and provid-ed funding for editorial assistance. Drs Bryce, Moran, Neuman, Ruiz, and Ustaris are employees of Puma Biotechnology Inc. All authors revised the manuscript for intellectual content and ap-proved the final version.Address Correspondence to: Dr Federico Ustaris; Phone: 424-248-6500; fax: 424-248-6501; email: [email protected]

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trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol. 2005;23(22):4866-4875.42. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal can-cer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237. 43. Peeters M, Price TJ, Cervantes A, et al. Randomized phase 3 study of panitumumab with fluorouracil, leucovorin, and irino-tecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin On-col. 2010;28(31):4706-4701.44. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, con-trolled trial of irinotecan plus infusional, bolus, or oral fluoropy-rimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786.45. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal can-cer. N Engl J Med. 2009;360(14):1408-1417.46. Falcone A, Ricci S, Brunetti I, et al. Phase 3 trial of infusion-al fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLF-OXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic col-orectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670-1676.47. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase 3 trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25(1):102-109.48. Heinemann V, von Weikersthal LF, Decker T, et al. FOLF-IRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065-1075. 49. Cunningham D, Humblet Y, Siena S, et al. Cetuximab mono-therapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345.50. Benson AB 3rd, Ajani JA, Catalano RB, et al. Recommend-ed guidelines for the treatment of cancer treatment-induced diar-rhea. J Clin Oncol. 2004;22(14):2918-2926.51. Kornblau S, Benson AB, Catalano R, et al. Management of cancer treatment-related diarrhea. Issues and therapeutic strate-gies. J Pain Symptom Manage. 2000;19(2):118-129.52. Arbuckle RB, Huber SL, Zacker C. The consequences of di-arrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist. 2000;5(3):250-259.53. Dranitsaris G, Maroun J, Shah A. Estimating the cost of illness in colorectal cancer patients who were hospitalized for severe chemotherapy-induced diarrhea. Can J Gastroenterol. 2005;19(2):83-87.



54. Arnold RJ, Gabrail N, Raut M, et al. Clinical implications of chemotherapy-induced diarrhea in patients with cancer. J Support Oncol. 2005;3(3):227-232.55. Andreyev J, Ross P, Donnellan C, et al. Guidance on the man-agement of diarrhoea during cancer chemotherapy. Lancet Oncol. 2014;15:e447-460.56. Andreyev HJ, Davidson SE, Gillespie C, et al. Practice guidance on the management of acute and chronic gastrointes-tinal problems arising as a result of treatment for cancer. Gut. 2012;61(2):179-192.57. Maroun JA, Anthony LB, Blais N, et al. Prevention and man-agement of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Work-ing Group on Chemotherapy-Induced Diarrhea. Curr Oncol. 2007;14(1):13-20.58. Wadler S, Benson AB 3rd, Engelking C, et al. Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol. 1998;16(9):3169-3178. 59. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Palliative Care, version 2 2015. http://www.nccn.org/professionals/physician_gls/pdf/pallia-tive.pdf. Accessed August 27, 2015.60. Gebbia V, Carreca I, Testa A, et al. Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following che-motherapy. Anticancer Drugs. 1993;4(4):443-445.61. CAMPTOSAR irinotecan hydrochloride injection, solution. Pfizer injectables, Revised 12/2014. Available from: http://label-ing.pfizer.com/ShowLabeling.aspx?id=533. Accessed October 30, 2015.62. Michael M, Brittain M, Nagai J, et al. Phase II study of activat-ed charcoal to prevent irinotecan-induced diarrhea. J Clin Oncol. 2004; 22(21):4410-4417.63. Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irino-tecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. Int J Cancer. 2001; 92(2):269-75.64. Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of col-orectal cancer: a randomised study. Br J Cancer. 2007; 97(8):1028-34.65. Meropol NJ, Blumenson LE, Creaven PJ. Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin. Am J Clin Oncol. 1998; 21(2):135-8.66. Rosenoff SH, Gabrail NY, Conklin R, et al. A multicenter, randomized trial of long-acting octreotide for the optimum pre-vention of chemotherapy-induced diarrhea: results of the STOP trial. J Support Oncol. 2006; 4(6):289-94.67. Hoff PM, Saragiotto DF, Barrios CH, et al. Randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in pa-tients with colorectal cancer: the LARCID trial. J Clin Oncol.

2014;32(10):1006-1011.68. Kee BK, Morris JS, Slack RS, et al. A phase II, randomized, double blind trial of calcium aluminosilicate clay versus placebo for the prevention of diarrhea in patients with metastatic col-orectal cancer treated with irinotecan. Support Care Cancer. 2015; 23(3):661-70.69. Freedman RA, Gelman RS, Wefel JS, et al. TBCRC 022: Phase II trial of neratinib for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer and brain metas-tases (BCBM). J Clin Oncol. 2014;32:5s (suppl; abstract 528).70. Gajria D, Modi S, Saura C, et al. A phase I/II study of nerati-nib plus temsirolimus in HER2+ metastatic breast cancer reveals ongoing HER2 pathway dependence in many patients despite sev-eral lines of HER2 targeted therapy. http://cancerres.aacrjour-nals.org/content/75/9_Supplement/P5-19-04.short?rss=1. Ac-cessed August 20, 2015.71. Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of nera-tinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol. 2014;32(2):68-75.72. Besse B, Soria J, Yao B, et al. Neratinib with or without tem-sirolimus in patients with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: An international randomized phase II study. Ann Oncol. 2014;25:1-41 (abstract A39).

· DUCTAL CARCINOMA ·


Ductal Carcinoma In Situ: Review of the Role of Radiation Therapy and Current Controversies

Frank Vicini, MD, FACR, and Chirag Shah, MD

IntroductionOver the past several decades, the incidence of ductal carcinoma in situ (DCIS) has increased, coinciding with the increased uti-lization of screening mammography.1 While no randomized tri-als comparing mastectomy and breast-conserving therapy (BCT) have been performed in patients with DCIS, BCT represents a standard of care in the treatment of DCIS, with long-term clin-ical outcomes and evidence-based guidelines supporting its uti-lization.2,3 Initial randomized studies evaluating BCT in women with DCIS included breast-conserving surgery (BCS) followed by whole-breast irradiation (WBI), and this became the standard as the studies demonstrated a 50% reduction in local recurrence with adjuvant radiotherapy (RT).4-7

However, published studies demonstrate that women under-going BCS do not always receive adjuvant RT due to factors in-cluding socioeconomic concerns, duration of treatment, and dis-

tance to treatment facilities.8,9 In light of this, clinicians continue to study women with DCIS in order to identify cohorts based on patient, clinical, and pathologic criteria that may not require ad-juvant RT, or those who may be treated with alternative RT tech-niques that can shorten the duration of treatment. The purpose of this review is to evaluate the role of RT in women with DCIS, as well as to evaluate current controversies that include omitting adjuvant RT and hypofractionation/accelerated partial-breast ir-radiation (APBI).

Results of Randomized TrialsRole of RadiotherapyThe role of RT in patients with DCIS was established with the publication of four randomized trials, which compared BCS with or without adjuvant RT, and consistently found a reduc-tion in local recurrence with RT. NSABP B-17 randomized 813 women to adjuvant RT (50 Gy to the whole breast) or no further treatment following lumpectomy. Wapnir et al4 have updated the results, and at 15 years, RT reduced the risk of all local recurrenc-es (35% vs 19.8%), with a 52% reduction in invasive ipsilateral breast tumor recurrence (IBTR; 19.6% vs 10.7%; P <.001) and a 47% reduction in DCIS IBTR (15.4% vs 9.0%; P <.001).

Similarly, an update of the European Organisation for Re-search and Treatment of Cancer (EORTC) 10853 trial5 con-firmed the benefit of adjuvant RT. This randomized trial in-cluded 1010 women with the same randomization as NSABP B-17 (observation vs standard fractionation WBI). At 15 years, adjuvant RT was associated with a reduction in local recurrence (31% vs 18%; P <.001), with similar findings noted for invasive recurrences (16% vs 10%; P =.007) and DCIS recurrences (16% vs 8%; P =.003), with all subgroups benefiting from RT.5

Similar findings were also noted from the SweDCIS trial,6 which randomized 1046 individuals following BCS with negative margins, and found an increase in the rate of local recurrenc-es when omitting RT (27% vs 12%), with similar reductions in invasive and DCIS recurrences noted, and no group based on stratification variables that had a low risk with excision alone.In order to address the role of RT in conjunction with endocrine therapy, randomized trials were performed evaluating the impact

Abstract

Despite a lack of randomized trials comparing breast-con-

serving therapy (BCT) and mastectomy, BCT represents

a standard of care in the management of ductal carci-

noma in situ (DCIS). Traditionally, BCT has consisted of

breast-conserving surgery (BCS) followed by adjuvant ra-

diotherapy (RT), with multiple randomized trials demon-

strating an approximately 50% reduction in rates of local

recurrence with adjuvant RT. However, over the past 2

decades, several trials have been performed to identify

a low-risk cohort of patients for whom BCS alone would

provide an acceptably low risk of local recurrence. Cur-

rently, patients who can forgo adjuvant RT without sig-

nificantly increasing their chance of local recurrence have

not been consistently identified. While future studies will

look at tumor genetics to help identify low-risk cohorts,

modern RT also allows for shortened courses of treat-

ment to reduce the duration of adjuvant RT.

Key words: Breast cancer, radiation therapy, DCIS, breast

-conserving therapy



of tamoxifen/endocrine therapy. The United Kingdom Coordi-nating Committee on Cancer Research (UKCCCR) study7 was a 4-arm trial that randomized 1701 women with DCIS following BCS to observation, adjuvant RT, tamoxifen, or both RT and tamoxifen. With a median follow-up of 12.7 years, adjuvant RT reduced the incidence of invasive IBTRs (P <.0001) and DCIS IB-TRs (P <.0001) as well as all new breast events (P<.0001). Tamox-ifen was found to reduce all breast events (P =.002) and DCIS IBTRs (P =.03), but did not significantly reduce invasive IBTRs (P =.8), and no synergy between RT and tamoxifen was noted.

NSABP B-24 was a randomized trial of 1799 patients with DCIS who were randomized to receive tamoxifen or placebo as a part of BCS (all underwent lumpectomy and adjuvant RT). The addition of tamoxifen was found to reduce invasive IBTRs by 32% (P =.025), with a nonsignificant reduction in DCIS IBTRs.4

Recently, the role of aromatase inhibitors (AIs) as compared with tamoxifen was evaluated in NSABP B-35,10 with results demonstrating an improvement in breast cancer–free interval at 10 years (93.5% vs 89.2%) when utilizing an AI in a randomized study of 3104 postmenopausal women with DCIS. The benefit of anastrozole was primarily noted in women less than age 60 years. Limited data are available at this time on the potential for synergism between AIs and RT.

A meta-analysis of the four randomized trials (NSABP B17,

EORTC 10853, SweDCIS, UKCCCR) was per-formed, and found a significant reduction in IBTR with adjuvant RT at 10 years (28% vs 13%), with a benefit noted for young and older patients.11 Howev-er, no survival benefit was noted. Importantly, even in women with small, low-grade tumors with negative margins, adjuvant RT reduced local recurrences. Re-cent series examining outcomes in women with DCIS treated with BCS and adjuvant RT with modern radiological, surgical, systemic, and RT techniques have confirmed excellent outcomes with surgery followed by adjuvant RT with endocrine therapy.12-14

Omitting Radiation TherapyMultiple prospective studies have been performed evaluating the omission of RT for low-risk patients as defined by clinical and pathologic criteria. The ECOG 5194 trial15 enrolled patients with low-/intermediate-grade DCIS (n=565) less than 2.5 cm or high-grade DCIS (n=105) less than 1 cm, with all patients having surgical margins greater than 3 mm following excision. Enrollment began in 1997 and was amended to allow for tamoxifen in 2000 (30% of patients). Initial data at 5 years demonstrated a 6.1% local recurrence rate in the low-/intermediate-grade cohort and a 15.3% recurrence rate in the high-grade cohort. However, with longer follow-up, the 12-year

rates of recurrence were 14.4% for the low-/intermediate-grade group and 24.6% for the high-grade cohort, with 7.5% and 13.4% respectively, being invasive.16

Similarly, a prospective study from the Dana-Farber Cancer Institute (DFCI) evaluated 158 patients with low-/intermedi-ate-grade DCIS with margins greater than 1 cm and less than 2.5 cm of extent on mammogram.17 Patients were treated with excision alone and did not receive endocrine therapy. With a median follow-up of 11 years, the 10-year local recurrence rate was 15.6% (75% in the original quadrant), with an annual rate of local recurrence of 1.9%, demonstrating a continuing risk of local recurrence with excision alone.

RTOG 980418 was a randomized trial evaluating the role of ad-juvant RT; patients with low-risk disease (nonpalpable, size <2.5 cm, margins >3mm, grade I/II or III with necrosis in <1/3 ducts, clinically node-negative) were randomized to excision alone or adjuvant RT (standard or hypofractionated WBI), with tamoxi-fen utilized at physician discretion (62% of patients). At 5 years, RT reduced the risk of local recurrence 3.2% versus 0.4%, and at 7 years the rates were 6.7% versus 0.9%, with acute grade 3 or greater toxicity rates of 4% in both arms. Late radiation toxicity was minimal, with 4.6% of patients having grade 2 and 0.7% grade 3 toxicity.

It should be noted that these studies relied on clinical and

TABLE. Treatment Options Following Breast-Conserving Surgery

Patients Age <50 Years

Standard Fractionation Whole-Breast Irradiation: Limited data on the omission of radiation (18.8%-20.5% of RTOG 9804, 20%-23.8% of ECOG 5194, 48% of DFCI) and current clinical guidelines do not support hypofractionated therapy (American Society for Radiology and Therapeutic Oncology [ASTRO]) or acceler-ated partial-breast irradiation (ASTRO/ABS). Standard fractionation treatment was utilized in multiple randomized phase III trials.

Patients Age >50 Years, Estrogen Receptor–Positive

Standard Fractionation Whole-Breast Irradiation

Hypofractionated Whole-Breast Irradiation: Clinical guidelines support the utili-zation of hypofractionated therapy in women over age 50 years. Retrospective data support the utilization of hypofractionated radiation in DCIS, with random-ized data supporting its utilization in early-stage invasive disease.

Accelerated Partial-Breast Irradiation: Clinical guidelines support the utilization of APBI in this cohort of patients, with prospective and retrospective data sup-porting low rates of failure. Must meet other clinical characteristics as well as be eligible.

Endocrine Therapy: Randomized and prospective trials have demonstrated high-er rates of local recurrence, with no difference in survival.

Patients Age >50 Years, Estrogen Receptor–Negative

Standard Fractionation Whole-Breast Irradiation

Hypofractionated Whole-Breast Irradiation

Accelerated Partial-Breast Irradiation

RADIATION THERAPY IN DUCTAL CARCINOMA


pathologic characteristics to de-fine low-risk cohorts of patients. Similarly, the Van Nuys Prognos-tic Index (VNPI) was developed and has been updated to include size, margin, age, and histology, with recommendations ranging from excision alone for low scores (4-6) to mastectomy for higher scores (10-12).19,20 However, exter-nal studies have failed to validate these findings, and further confir-matory studies are needed.21 More recently, data have emerged on the role of multigene assays iden-tifying low-risk cohorts of patients who may not require adjuvant RT following BCS. Solin et al15 evaluated a subset of patients from the ECOG 5194 trial (n = 327). They found that a prospectively defined scoring system using 12 genes (7 cancer-related, 5 refer-ence) was associated with the risk of developing IBTR; however, in the low-score group, the 10-year rate of IBTR was 10.6%, with rates of 26.7% and 25.9% for the intermediate- and high-score groups. A similar study from Rakovitch et al22 retrospectively eval-uated 718 patients from a population-based cohort treated with excision alone. With a median follow-up of 9.6 years, the risk score was independently associated with any local recurrence, in-cluding invasive and DCIS recurrences. While these studies are promising, further data are required comparing outcomes with and without adjuvant RT based on risk score grouping to define the difference in local recurrence with and without adjuvant RT, while accounting for endocrine therapy by risk group. In the in-terim, guidelines do exist for the omission of RT based on data from the ECOG trial. However, the failure for recurrences to pla-teau in the ECOG study does raise concern about omitting RT, particularly for the high-grade cohort, which had a 24.6% IBTR rate at 12 years. It should be noted that no difference in surviv-al has been found with this local recurrence increase; however, local recurrences are associated with potential for an invasive recurrence (50% of recurrences), a psychological impact, and ad-ditional cost associated with treatment of the recurrence. At this time, there is no standard as to what defines acceptable local re-currence rates, and some patients may accept a 10-year recurrence rate of 10%, as seen in the low-score DCIS groups presented by Solin et al. Informed discussion with patients is key to deciding whether to pursue adjuvant RT and which technique to employ.

Alternative OptionsSeveral alternatives to standard WBI exist to reduce the dura-tion of adjuvant RT and improve compliance with BCT. One such alternative is hypofractionation, which delivers treatment to

the whole breast while reducing treatment duration to 3 weeks. Whelan et al23 evaluated the role of hypofractionation in a ran-domized study of 1234 women with T1-2N0 (no DCIS), with patients receiving either standard fractionated (50 Gy/25 frac-tions) or hypofractionated (42.5 Gy/16 fractions) WBI following BCS. At 10 years, no difference in outcomes or toxicity profiles was noted, and cosmesis was comparable. Similar results have been noted in trials from the UK, where the START A and B trials demonstrated equivalent local control and the potential for improved cosmetic outcomes with hypofractionation.24

While there are limited prospective data on hypofractionation in a pure DCIS cohort, Lalani et al25 published a report of 1609 women with DCIS, with 40% (638) receiving hypofractionation and 60% (971) receiving standard fractionation; with a median follow-up of 9 years, local recurrence rates were similar between techniques. Similar results have been noted in several other stud-ies, and have led to increased utilization of hypofractionation for DCIS in the United States.26,27 Another alternative to standard fractionation WBI is APBI, which delivers treatment solely to the area surrounding the lumpectomy cavity in 1 week or less. Randomized trials comparing APBI with standard or hypofrac-tionated WBI have been completed, with randomized data from Hungary demonstrating equivalent clinical outcomes using the interstitial/electron technique, although this was not a study of patients with DCIS.28

Increasing data are available on patients with DCIS treated with APBI. Vicini et al29 published a series of 300 patients with DCIS treated with APBI. At 5 years, the rate of IBTR was 2.6% with comparable rates of IBTR as compared with invasive tu-mors. Similar findings have been noted from several institution-al series as well as multi-institutional series, with The American Brachytherapy Society (ABS) APBI consensus statement includ-ing DCIS in the acceptable treatment category.30-34

FIGURE. Treatment Options Following Breast-Conserving Surgery

Breast-Conserving Surgery

Standard Fractionation Radiation +/- Endocrine Therapy•Multiple Randomized Phase III trials

Endocrine Therapy•Receptor Positive•Higher rates of local recurrence in prospective studies•Not category 1 recommendation•Not well-defined criteria

Hypofractionated Radiation Therapy +/- Endocrine Therapy•DCIS not included in randomized trials•Included in RTOG 9804 •Retrospective Data

Accelerated PartialBreast Irradiation +/- Endocrine Therapy•Not included in initial randomized trials•Prospective Data •Randomized trials completed



Future DirectionsRecently, an observational Surveillance Epidemiology and End Results (SEER) study evaluated 10- and 20-year mortality in 108,196 patients following a diagnosis of DCIS. At 20-year follow-up, breast cancer mortality was 3.3%, with higher rates noted for women under age 35 years and African Americans. However, the risk of dying of breast cancer increased significantly with invasive IBTR (HR, 18.1; P <.001). Radiotherapy following BCS reduced local recurrence with no difference in mortality. While provocative, these data are observational and face the lim-itations of such analyses. Future studies are required before the concept of surveillance represents an appropriate standard for women with DCIS; at this time, the standard of care remains surgery (mastectomy or BCS) with or without RT.2

DiscussionCurrently, RT remains a key component of BCT in women with DCIS. Even with improvements in surgical techniques and ad-vancements in endocrine therapy, modern studies evaluating the role of RT have demonstrated a consistent reduction in local recurrence with RT that is reflected in current evidence-based guidelines.2 Randomized and prospective studies have attempted to identify cohorts of low-risk patients who demonstrate min-imal or no increase in local recurrence with the omission of RT, but traditional clinical and pathologic factors have failed to consistently identify such a group. Preliminary studies have been published, with further studies under way, evaluating the role of tumor genetics and multigene assays in identifying low-risk patients, and represent a potential tool for clinicians to utilize in the future. In the interim, alternative strategies include hypof-ractionated WBI and APBI to reduce the duration of adjuvant RT, allowing women to complete breast conservation and offer-ing the ability to improve compliance following BCS. Figure 1 provides a summary of treatment options for clinicians following BCS, with a synopsis of the data available for each treatment paradigm.

Clinical recommendations and treatment options are based on the available literature and evidence-based guidelines.

Affiliations: Frank Vicini, MD, FACR, is from Michigan Health-care Professionals, Farmington Hills, MI; and Chirag Shah, MD is from the Cleveland Clinic, Taussig Cancer Institute, Depart-ment of Radiation Oncology, Cleveland, OH.Disclosures: Dr. Shah is a speaker for Cianna Medical, Inc., a woman’s health company dedicated to the treatment of ear-ly-stage breast cáncer.Address correspondence to: Frank A. Vicini, MD, FACR, Mich-igan HealthCare Professionals/21st Century Oncology, 28595 Orchard Lake Rd, Farmington Hills, MI 48334. Phone: 248-994-0632; fax: 248-553-7674; email: [email protected].

REFERENCES1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):5-29.2. National Comprehensive Cancer Network. Survivorship (Ver-sion 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed July 25, 2015.3. Solin LJ, Fourquet A, Vicini FA, et al. Long-term outcome after breast-conservation treatment with radiation for mam-mographically detected ductal carcinoma in situ of the breast. Cancer. 2005;103(6):1137-1146.4. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488.5. Donker M, Litier S, Werutsky G, et al. Breast-conserving treat-ment with or without radiotherapy in ductal carcinoma in-situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol. 2013;31(32):4054-4059. 6. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reduction for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast. J Clin Oncol. 2008;26(8):1247-1252.7. Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet On-col. 2011;12(1):21-29.8. Greenberg CC, Lipsitz SR, Hughes ME, et al. Institutional variation in the surgical treatment of breast cancer: a study of the NCCN. Ann Surg. 2011;254(2):339-345.9. Shroen AT, Brenin DR, Kelly MD, et al. Impact of patient distance to radiation therapy on mastectomy use in early-stage breast cancer. J Clin Oncol. 2005;23(28):7074-7080.10. Margolese RG, Cecchini RS, Julian TB, et al. Primary results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole vs tamoxifen in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. J Clin Oncol. 2015;(suppl; abstr LBA500). 11. Early Breast Cancer Trialists Collaborative Group (EBCTCG), Correa C, McGale P, Taylor C, et al. Overview of the randomized trials in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr. 2010;2010(41):162-177.12. Akashi-Tanaka S, Fukutomi T, Nanasawa T, et al. Treatment of noninvasive carcinoma: fifteen-year results at the National Cancer Center Hospital in Tokyo. Breast Cancer. 2000;7(4):341-344.13. Shaitelman SF, Wilkinson JB, Kestin LL, et al. Long-term out-come in patients with ductal carcinoma treated with breast-con-serving therapy: implications for optimal follow-up strategies. Int J Radiat Oncol Biol Phys. 2012;83(3):e305-e312.

RADIATION THERAPY IN DUCTAL CARCINOMA


14. Wilkinson JB, Vicini FA, Shah C, et al. Twenty-year out-comes after breast-conserving surgery and definitive radiothera-py for mammographically detected ductal carcinoma in situ. Ann Surg Oncol. 2012;19(12):3785-3791.15. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013;105(10):701-710.16. Solin LJ, Gray R, Hughes LL, et al. Surgical excision with-out radiation for ductal carcinoma in situ of the breast: 12-year results from the ECOG-ACRIN E5194 study [published online September 14, 2015]. J Clin Oncol. 2015.17. Wong JS, Chen YH, Gadd MA, et al. Eight year update of a prospective study of wide excision alone for small low- or in-termediate-grade ductal carcinoma in situ of the breast. Breast Cancer Res Treat. 2014;143(2):343-350.18. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715.19. Silverstein MJ, Lagios MD, Craig PH, et al.A prognos-tic index for ductal carcinoma in situ of the breast, Cancer. 1996;77(11):2267-2274.20. Silverstein MJ, Lagios MD. Choosing treatment for patients with ductal carcinoma in situ: fine tuning the University of Southern California/Van Nuys Prognostic Index. J Natl Cancer Inst Monogr. 2010(41):193-196.21. McAusland SG, Hepel JT, Chong FK, et al. An attempt to in-dependently verify the utility of the Van Nuys Prognostic Index for ductal carcinoma in situ. Cancer. 2007;110(12):2648-2653.22. Rakovitch E, Nofech-Mozes S, Hanna W, et al. A popula-tion-based validation study of the DCIS score predicting recur-rence risk in individuals treated by breast-conserving surgery alone. Breast Cancer Res Treat. 2015;152(2):389-398.23. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362(6):513-520.24. Haviland JS, Owen JR, Dewar JA, et al. The UK Standard-isation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomized controlled trials. Lancet On-col. 2013;14(11):1086-1094.25. Lalani N, Paszat L, Sutradhar R, et al. Long-term outcomes of hypofractionation versus conventional radiation therapy af-ter breast-conserving surgery for ductal carcinoma in situ of the breast. Int J Radiat Oncol Biol Phys. 2014;90(5):1017-1024.26. Cante D, Franco P, Sciacero P, et al. Hypofractionation and concomitant boost to deliver adjuvant whole- breast radiation in ductal carcinoma in situ (DCIS): a subgroup analysis of a pro-spective case series. Med Oncol. 2014;31(2):838.27. Jagsi R, Falchook AD, Hendrix LH, et al. Adoption of hypof-ractionated radiation therapy for breast cancer after publication

of randomized trials. Int J Radiat Oncol Biol Phys. 2014;90(5):1001-1009.28. Polgar C, Fodor J, Major T, et al. Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol. 2013;108(2):197-202.29. Vicini F. Should ductal carcinoma-in-situ (DCIS) be removed from the ASTRO consensus panel cautionary group for off-pro-tocol use of accelerated partial breast irradiation (APBI)? A pooled analysis of outcomes for 300 patients with DCIS treated with APBI. Ann Surg Oncol. 2013;20(4):1275-1281.30. Benitez PR, Streeter O, Vicini F, et al. Preliminary results and evaluation of MammoSite balloon brachytherapy for partial breast irradiation in pure ductal carcinoma in situ: a phase II clinical study. Am J Surg. 2006;192:427-433. (4)31. Stull TS, Goodwin M, Gracely EJ, et al. A single-institution review of accelerated partial breast irradiation in patients consid-ered “cautionary” by the American Society for Radiation Oncol-ogy. Ann Surg Oncol. 2012;19(2):553-559.32. Israel PZ, Vicini F, Robbins AB, et al. Ductal carcinoma in situ of the breast treated with accelerated partial breast ir-radiation using balloon-based brachytherapy. Ann Surg Oncol. 2010;17(11):2940-2944.33. Kamrava M1, Kuske RR, Anderson B, Chen P, Hayes J, Quiet C, Wang PC, Veruttipong D, Snyder M, Jeffrey Demanes D. Out-comes of Breast Cancer Patients Treated with Accelerated Partial Breast Irradiation Via Multicatheter Interstitial Brachytherapy: The Pooled Registry of Multicatheter Interstitial Sites (PROMIS) Experience. Ann Surg Oncol. 2015 Apr 28. [Epub ahead of print]34. Shah C, Vicini F, Wazer DE, et al. The American Brachyther-apy Society consensus statement for accelerated partial breast ir-radiation. Brachytherapy. 2013;12(4):267-277.35. Narod SA, Iqbal J, Giannakeas V, et al. Breast cancer mortal-ity after a diagnosis of ductal carcinoma in situ [published online August 20, 2015]. JAMA Oncol. 2015 Oct 1;1(7):888-96.

· HEAD AND NECK CANCER ·


Moving Forward in the Management of Squamous Cell Carcinoma of the Head and Neck:

Promising Immuno-Oncology Approaches

Barbara Burtness, MD

IntroductionThe recent revolution in our understanding of the importance of the immune response to cancer has led to remarkable new

therapies for melanoma, renal cell cancer, and non–small cell lung cancer. Responses to immune checkpoint inhibitors are seen in cancers that are quite varied, and the responses can be of long duration. For this reason, rapidly moving to study im-mune checkpoint inhibition in additional cancer types in which immune exhaustion may play a role has become a priority in oncology.

Substantial evidence exists that a subset of squamous cell can-cers of the head and neck (SCCHN) display phenotypic chang-es that predict activity for immune checkpoint inhibitors.1 The endogenous T-cell compartment recognizes peptide epitopes displayed on major histocompatibility complexes on surfaces of malignant cells; thus, both antigen expression within tumors and immune cell infiltration of the tumor and its environment are important to characterize. CD8+ tumor-infiltrating lympho-cytes (TILs) are associated with improved survival after chemo-radiation for both human papillomavirus (HPV)-associated and HPV-negative SCCHN.2 Nonmutated proteins to which T-cell tolerance is incomplete because of a restricted tissue expression pattern may act as cancer rejection antigens. An additional class of antigens, referred to as neoantigens, are formed by peptides not coded by the normal human genome, but rather created by tumor-specific DNA alterations.

Linnemann and colleagues used a cancer exome–based ap-proach to identify neoantigens that can be recognized by T cells.3,4 Mutations that generate a novel protein sequence were identified and potential MHC-binding peptides were predicted for each. T-cell reactivity against the predicted neoantigens was then determined, revealing that only a minority of novel pep-tides resulting from mutation in cancers are immunogenic; how-ever, higher mutational burden is predicted to result in greater expression of immunogenic antigens, perhaps explaining the high activity of immune checkpoint inhibition in such hypermu-

Abstract

Testing of immune checkpoint inhibition in cancer types

in which immune exhaustion may play a role has be-

come a priority in oncology. Substantial evidence exists

that a subset of squamous cell cancers of the head and

neck display phenotypic changes that predict activity

for immune checkpoint inhibitors, treatments that inter-

fere with PD-1 or CTLA-4-dependent immune tolerance.

CD8+ tumor-infiltrating lymphocytes are associated with

improved survival after chemoradiation for both human

papillomavirus (HPV)-associated and HPV-negative head

and neck cancer. Cancer antigens may be present in the

head and neck either because of mutations that lead to

unique protein structures (neoantigens) or from the ex-

pression of viral antigens in HPV-associated cancers. The

PD-1 inhibitor pembrolizumab was tested in patients with

PD-L1–expressing head and neck cancer. The overall re-

sponse rate (ORR) to pembrolizumab was 19.6% (95% CI,

10.2%-32.4%), with the median duration of response not

reached at 8+ to 41+ weeks. Data supporting the activity

of immune checkpoint inhibition in squamous cancer of

the head and neck have also been obtained with the an-

ti-PD-1 antibody MEDI4736. The ORR for this agent in a

multitumor-type study was 11%; among PD-L1–positive

patients, 4 of 17 (24%) responded compared with 1 of 33

(3%) PD-L1–negative patients. A large number of ongoing

or recently completed trials are reviewed.

Key words: head and neck cancer; immunotherapy;

radiation

IMMUNO-ONCOLOGY MANAGEMENT OF SCCHN


table states as microsatellite instable colon cancer.5

Given the frequency of loss of tumor suppressor functions and the resulting known high mutational burden of HPV-negative SCCHN, the expression of mutationally associated neoantigens is predicted to be high in these cancers. APOBEC3B cytosine deaminase activity is induced in virally infected cells, and anal-ysis of The Cancer Genome Atlas SCCHN samples reveals a mutagenesis pattern consistent with APOBEC-mediated effects, raising the possibility that neoantigens are increased in HPV-as-sociated cancers as well.6

An additional pool of cancer rejection antigens of great rel-evance to SCCHN are viral antigens from viral open reading frames in virally associated cancers such as HPV-positive oro-pharynx cancer and Epstein-Barr virus–positive nasopharynx cancer. Lastly, viral infection has been associated with increased PD-L1 expression and expression of interferon response genes, also potentially setting the stage for effective use of immune checkpoint inhibition in the setting of virally associated cancers.

Clinical DataThe PD-1 inhibitor pembrolizumab was tested in a disease-spe-cific expansion cohort of patients with SCCHN in the phase Ib KEYOTE-012 study.7 Patients were eligible who had expression of the PD-1 ligand PD-L1, defined as at least 1% of tumor cell or stromal PD-L1 staining with a proprietary antibody. Archival tis-sue was acceptable for PD-L1 staining. Among the 104 patients screened, 81 (78%) were PD-L1–expressing, with the majority of PD-L1–positive cases displaying less than 20% PD-L1 staining. Human papillomavirus association for SCCHN was determined by local p16 immunohistochemical staining, and strong and diffuse staining of at least 70% of cells was required to deem a tumor p16-positive (HPV-associated). Of 61 eligible patients, 36 were p16-negative and 23 were p16-positive, with the status not known for two patients.

The overall response rate (ORR) to pembrolizumab per Re-sponse Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), by investigator assessment was 19.6% (95% CI, 10.2%-32.4%), with the median duration of response not reached at 8+ to 41+ weeks. The response rate was higher for patients with higher-level PD-L1 staining or expression of a 6-gene interferon response signature. PD-L2 expression may also be associated with improved response.8 Patients included in the analysis were those with measurable disease at baseline who received ≥1 dose of pembrolizumab and had ≥1 post-baseline tumor measurement or who discontinued the study due to progressive disease or an adverse event.

Data supporting the activity of immune checkpoint inhibition

in SCCHN also have been obtained with the anti-PD-1 antibody MEDI4736. The ORR for this agent in a multitumor-type study was 11%; among PD-L1–positive patients, 4 of 17 (24%) re-sponded compared with 1 of 33 (3%) PD-L1–negative patients.9

Ongoing TrialsNumerous current trials are attempting to ascertain the signif-icance of these responses for the future treatment of patients with SCCHN, including several phase 3 trials (Table). The Tri-al of Nivolumab vs Therapy of Investigator’s Choice in Recur-rent or Metastatic Head and Neck Carcinoma (CheckMate 141; NCT02105636) is open to patients with tumor progression or recurrence within 6 months of the last dose of platinum therapy in the adjuvant, primary, recurrent, or metastatic setting, and has an accrual target of 360 patients. The primary endpoint of the study is overall survival. A similar design is used in a phase 3 trial of pembrolizumab (MK-3475-040/KEYNOTE-040; NCT02252042) for patients with a history of failure of prior platinum therapy. This study has co-primary endpoints in the general population and in the population of PD-L1 strong-ex-pressing cancer, with a sample size of 600.

The possibility of durable response with less toxicity than usually seen with cisplatin-based approaches has also led to the question of whether immune checkpoint inhibition has a role in the first-line treatment of metastatic/recurrent SCCHN and if so, how it would best be integrated with current therapies. The implications of standard therapy for responsiveness to immuno-therapy are not fully understood. Standard treatments may lead to tolerogenic or immunogenic cell death; phenotypic changes in surviving cells that may be immunomodulatory have been de-scribed in several tumor types, and preclinical models support combination therapy. KEYNOTE-048 (NCT02358031) is a tri-al of pembrolizumab versus pembrolizumab plus platinum and 5-fluorouracil (5-FU) versus cetuximab plus platinum and 5-FU in the first-line treatment of metastatic or recurrent SCCHN. The primary endpoint of the trial is progression-free survival and the sample size is 750.

TABLE. Immune Checkpoint Inhibitors in Trials in Head and Neck Cancer

Agent Target Current Phase of Study

Pembrolizumab7 PD-1 III

Nivolumab (NCT02105636) PD-1 III

MEDI 3476 (NCT02369874) PD-L1 III

Ipilimumab CTLA-4 Ib

· HEAD AND NECK CANCER ·


Radiation and ImmunotherapyThe difficult question of how best to integrate immune check-point inhibitors with the standard radiation approaches that are the backbone of management of locally advanced SCCHN also is being addressed. Radiation is immunomodulatory, again supporting combination or sequential approaches. Radiation-in-duced hypoxia and direct vascular damage are hypothesized to release chemotactic signals, fostering dendritic cell maturation and antigen presentation, while DNA damage may result in the release of inflammatory cytokines.10-12 Investigators at the Univer-sity of Pittsburgh are conducting a phase 1 trial of ipilimumab, cetuximab, and radiation in patients with previously untreated stage III-IVB SCCHN (NCT01935921). The primary outcome measure for this study is the proportion of dose-limiting toxicities at each dosage level. Investigators at Yale University are activating a trial of pembrolizumab post radiation in patients with persistent disease, based on data that radiation upregulates expression of PD-L1 and the presence of TILs. Biopsy to document persistent disease will also be analyzed for PD-L1 and lymphocyte subsets and patients will receive pembrolizumab monotherapy for up to 3 months, followed by salvage resection if indicated.

Combinations With Novel AgentsADXS11-001 is a live attenuated bacterium engineered to secrete a fusion protein (tLLO-HPV-E7) consisting of a truncated frag-ment of the listeriolysin O (LLO) fused to full-length E7 peptide of HPV-16. A phase I/II trial investigates the combination of ADXS11-01 and the anti-PD-L1 antibody MEDI4736 in patients with metastatic or recurrent HPV-associated cervical cancer or SCCHN (NCT02291055). Evidence that cetuximab upregu-lates co-stimulatory (CD137) and co-inhibitory (PD-1) receptors on TILs and circulating lymphocytes forms the basis for pro-posed early-phase trials exploring the addition of nivolumab to cetuximab.13

ConclusionEarly clinical trial data have established that agents that inhibit the programmed death pathway by targeting either PD-1 or PD-L1 are active in both HPV-associated and HPV-negative SCCHN. PD-L1 high expression may be an enrichment biomarker, and current trials are designed with planned subset analyses by PD-L1 expression. Pseudoprogression has not been commonly ob-served in the trials reported to date, and the toxicity profile of pembrolizumab has appeared comparable in SCCHN to that in other cancers in which the drug has been studied. Conventional therapies for SCCHN (chemotherapy, cetuximab, and radiation) may play an important role in priming for immune checkpoint

inhibitors, and ongoing trials are examining the best schedules for integrating immunotherapy with standard regimens.

Affiliation: Barbara Burtness, MD, is from the Yale School of Medicine and Yale Cancer Center–Smilow Cancer Hospital at Yale-New Haven, New Haven, CT.Disclosure: Dr. Burtness has received honoraria from Merck and Amgen for consulting and from VentiRx and MediImmune for data safety and monitoring activities, and has received research funding to her institution from Merck and Advaxis.Address correspondence to: Barbara Burtness, MD, Yale School of Medicine, 333 Cedar St, New Haven, CT 06520-8028.Email: [email protected]

REFERENCES1. Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014. 50(7):627-632.2. Balermpas P, Rödel F, Rödel C, et al. CD8+ tumour-infiltrat-ing lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemo-radiotherapy: a multicentre study of the German Cancer Con-sortium Radiation Oncology Group (DKTK-ROG) [published online July 30, 2015]. Int J Cancer. 2016. doi: 10.1002/ijc.29683.3. Linnemann C, van Buuren MM, Bies L, et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med. 2015;21(1):81-85. 4. Schumacher TN, Schreiber RD. Neoantigens in cancer immu-notherapy. Science. 2015;348(6230):69-74.5. Le DT, Uram JT, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;33(suppl; abstr LBA100).6. Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton TR. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor devel-opment. Cell Rep. 2014;7(6):1833-1841. 7. Seiwert, TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associat-ed and non-HPV-associated head and neck (H/N) cancer. J Clin Oncol. 2014;32(suppl; abstr 6011).8. Yearly J, Gibson C, Yu N et al. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Presented at: the 2015 European Cancer Congress; 2015.9. Fury M, Ou SI, Balmanoukian AS, et al. 988PD - Clinical activity and safety of MEDI4736, an anti-PD-L1 antibody, in patients with head and neck cancer. Ann Oncol. 2014;25(sup-

IMMUNO-ONCOLOGY MANAGEMENT OF SCCHN


pl_4):iv340-iv356. 10. Deng, L., Liang H, Burnette B, et al. Irradiation and anti- PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687-695.11. Burnette B, Weichselbaum RR. Radiation as an immune modulator. Semin Radiat Oncol. 2013;23(4):273-280.12. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and ste-reotactic radiation produce long-term survival in mice with intra-cranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343-349.13. Kohrt HE, Colevas AD, Houot R, et al. Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest. 2014;124:2668-2682.

CME


Dates of certification: November 23, 2015, to November 23, 2016Medium: Print with online posttest, evaluation, and request for credit

Medical WriterKelly McCoy Hayden, PhDDisclosure: No relevant financial relationships with commercial inter-ests to disclose.

The American Journal of Hematology/Oncology® Editorial BoardDebu Tripathy, MDProfessor and ChairDepartment of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHouston, TX Disclosure: Grant/research support from Genentech/Roche, Pfizer, Puma Inc, and Novartis (clinical trial support contracted to the Univer-sity of Southern California and MD Anderson Cancer Center); consul-tant for Eisai, Oncoplex Diagnostics, Merck, and Novartis.

FacultyTiffany A. Traina, MDAssistant Attending Physician Breast Medicine ServiceDepartment of MedicineMemorial Sloan Kettering Cancer CenterAssistant Professor of MedicineWeill Cornell Medical CollegeNew York, NYDisclosure: consultant: Genentech/Roche, Eisai, Halozyme, Mundip-harma, Medivation, Pfizer, AstraZeneca, Bayer, and Immunomedics; grant/research support: Medivation, Eisai, Pfizer, Novartis, and Myriad Genetics.

Staff/Planner Disclosures and Conflict of Interest ResolutionThe staff of Physicians’ Education Resource®, LLC, (PER®) and the editorial staff of The American Journal of Hematology/Oncology® have no relevant financial relationships with commercial interests to disclose.

In accordance with Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial SupportSM, PER® resolved all conflicts of interest prior to the release of this CME activity using a multistep process.

OverviewThis activity is designed to inform physicians about the latest treat-ment advances and data in the management of triple-negative breast cancer (TNBC), including approved and investigational treatment strategies.

Target AudienceThis activity is directed toward medical oncologists, nurses, and nurse practitioners who manage and treat patients with TNBC. Breast surgeons, surgical oncologists, radiation oncologists, pathologists, fellows, physician assistants, and other healthcare providers interested in the treatment of TNBC are also invited to participate.

Learning ObjectivesAfter participating in this CME activity, learners should be better prepared to:• Discuss how biomarkers are being used to select treatment reg-

imens that may be particularly effective in certain subgroups of patients with advanced TNBC

• Summarize phase I clinical trial outcomes reported with immuno-therapy agents that are under investigation in advanced TNBC

• Describe recent research efforts that have sought to optimize neoad-juvant treatment of patients with early-stage TNBC

Accreditation/Credit DesignationPER®, LLC, is accredited by the Accreditation Council for CME to provide continuing medical education for physicians.PER®, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded by PER®.

Instructions for Participation/How to Receive AMA PRA Category 1 CreditTM

1. Read the article in its entirety.2. Use the QR Code or type http://www.ajho.com/go/Nov15CME into your Web browser to access the posttest.3. Complete and pass the posttest with a score of 70% or higher.4. Complete the evaluation and request for credit. Participants may immediately download a CME certificate upon successful completion of these steps.

Off-Label Disclosure and DisclaimerThis CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for CME purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

DisclaimerThe opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.

Contact information for questions about the activity:Physicians’ Education Resource, LLC666 Plainsboro Road, Suite 356Plainsboro, NJ 08536Phone: (888) 949-0045E-mail: [email protected]

Evolving Management Strategies for Triple-Negative Breast Cancer

EVOLVING MANAGEMENT STRATEGIES FOR TRIPLE-NEGATIVE BREAST CANCER


Moderator: Do you test all of your TNBC patients for BRCA muta-tions? Are there other genomic or molecular methods that can help clinicians to personalize therapy for patients with TNBC?Dr. Traina: In terms of clinical genetic testing for germline hered-itary BRCA mutations, the NCCN (National Comprehensive Can-cer Network ) Guidelines actually have a lower threshold for genetic testing when a patient has TNBC. So they recommend genetic test-

ing for patients 60 years and younger with TNBC. Therefore, I send any woman under the age of 60 who is diagnosed with TNBC for a clinical genetic consultation and BRCA testing, regardless of family history. That point is important because it has implications for the patient, as well as her family members, for identifying a heredity pre-disposition to breast cancer. But we’ll also talk in a bit about how testing for germline hereditary BRCA1/2 mutations has implications

Breast cancer is the most common cancer among women in the United States.1 Of the approximately 232,000 cases expected in 2015, triple-negative breast cancers (TNBCs) will comprise 10% to 20% (23,000 to 46,000) of diagnoses.1,2 Unfortunately, this subtype of breast cancer, which is negative for estrogen, progesterone, and HER2 receptors, is more aggressive and carries a worse prognosis than other subtypes. A main reason for its poor prognosis is that un-like ER/PR-positive and HER2–positive breast cancer, TNBC has no biological target for therapy that has been clinically validated, leaving chemotherapy as the only approved treatment option.2-3

In light of the poor prognosis of TNBCs, recent research has fo-cused on identifying biomarkers to help select patients for optimal treatment regimens. For example, many clinical trials are comparing outcomes of chemotherapy in subgroups of patients with BRCA1/2 wild-type and BRCA1/2–mutated metastatic TNBCs. As one exam-ple, the Triple Negative Breast Cancer trial (TNT trial) identified significant differences in objective response rates (ORRs) with first-line carboplatin or docetaxel among women with a known BRCA1/2 mutation compared to the all-comer population.4 Whereas first-line docetaxel and carboplatin elicited similar response rates in the to-tal patient population, more than twice the number of women with BRCA1/2–mutated TNBC responded to carboplatin than docetaxel (68% vs 33%, respectively; P = 0.03) presumably reflecting greater sensitivity to DNA-damaging platinum due to loss of BRCA-mediat-ed double strand DNA repair function.4

First-line taxanes still have a place in unselected patients with TNBC, however. This point is evidenced by outcomes from the phase III CALGB 40502 trial, which enrolled 799 patients with chemother-apy-naïve advanced breast cancer, including a subset of patients with TNBC. In the total population, which was concurrently treated with bevacizumab, paclitaxel achieved a similar progression-free survival (PFS) to nab-paclitaxel (11 vs 9.3 months, respectively [hazard ratio (HR) 1.20; P = 0.054]). By comparison, ixabepilone was inferior to weekly paclitaxel (7.4 vs 11 months, respectively [HR 1.59; P <.001]) with all taxoids given weekly.5

Early clinical trials of novel immunotherapy approaches are inves-tigating checkpoint inhibitors pembrolizumab (PD-1 antibody) and atezolizumab (PD-L1 antibody) in patients with metastatic TNBCs that express tumor or stromal PD-L1. In a phase Ib trial of 32 women with heavily pretreated TNBC, pembrolizumab elicited partial re-sponses in 16.1% of patients and stable disease in 9.7% of patients.6 Five patients experienced drug-related serious adverse events, includ-

ing grade 3 anemia, headache, aseptic meningitis, or pyrexia, and disseminated intravascular coagulation with thrombocytopenia and decreased blood fibrinogen.6 The encouraging activity associated with targeting the PD-L1/PD-1 pathway was confirmed in a phase I trial of atezolizumab (N = 27), which elicited a 24% unconfirmed ORR.7 Grade 3 to 5 drug-related AEs occurred in 11% of patients and included grade 3 adrenal insufficiency, neutropenia, nausea, vomiting, and decreased white blood cell levels, as well as grade 5 fatal pulmonary hypertension.7 These preliminary findings have led to the initiation of larger clinical trials, which will help define the potential role of immunotherapy in advanced TNBC.

Another potentially predictive biomarker for advanced TNBCs is the androgen receptor (AR). In the largest study of an AR antago-nist in TNBC (N = 75 evaluable patients), first- or second-line en-zalutamide, in combination with an endocrine therapy, achieved a median PFS of 32 weeks.8 In addition, an unexpected outcome of this phase II trial was that 47% of participants had an androgen-asso-ciated gene signature that was associated therapeutic response. This finding suggests that the AR may have a larger role in TNBC patho-physiology than previously thought and may be worth investigating in this setting.8

In early-stage TNBC, several clinical trials have also sought to identify optimal treatment regimens in the neoadjuvant setting. In particular, two large randomized phase II studies, Gepar-Sixto (N = 595) and CALGB 40603 (N = 454), found that compared with an anthracycline- and taxane-containing regimen alone, adding carbo-platin to these regimens improved the pathologic complete response (pCR) rate.9,10 As expected, however, these gains in efficacy came at the expense of additional toxicities, including neutropenia, throm-bocytopenia, anemia, and diarrhea and resulted in less delivered pa-clitaxel.9,10 Therefore, additional studies are warranted to determine whether these findings will translate to an overall survival and im-proved risk-to-benefit ratio for women with early TNBCs.

Also in early-stage TNBC, ongoing clinical trials are evaluating whether to administer adjuvant therapy to patients with TNBC who have residual disease after neoadjuvant therapy, and prior to surgery or to add platinum agents to standard anthracycline/taxane adjuvant therapy. Although the standard of care is to not typically administer post-operative chemotherapy, one drug that is being evaluated in this setting is olaparib in patients with BRCA mutations.11 Thus, clinical trial participation may be a viable option for some of these patients in whom adjuvant therapy may be warranted.

CME


for making treatment choices about conventional cytotoxic chemo-therapy and/or participation in clinical trials investigating agents that might work better in folks who have BRCA-associated TNBC.

Moderator: What is your preferred frontline approach for patients with BRCA-mutated triple-negative metastatic breast cancer and is there specific data that support that approach or approaches? Dr. Traina: There have been a couple of trials reported over the past year or two that help to guide the decision for the first-line treat-ment of women with metastatic TNBC. For someone who carries a BRCA mutation, the TNT trial that Andy Tutt (Andrew Tutt, MB, ChB, PhD, MRCP, FRCR, of Kings College and Institute of Cancer Research, London) reported about a year ago gives us the most guidance from a prospective randomized trial. That study had almost 400 women with either TNBC or known BRCA mutations, but only about 10% of participants had a known BRCA mutation. Women were randomized to either first-line carboplatin or first-line docetaxel, and what they found was for all-comer TNBC, response rates and PFS were comparable whether patients received docetaxel or carboplatin. But when they looked at the subset of women with BRCA-associated TNBC, granted a small subset, response rates with carboplatin were significantly higher than docetaxel. The difference was 68% versus 33% and the same held for median PFS. If you were BRCA-positive and you got carboplatin, median progression-free sur-vival was over 6 months, but if you were BRCA mutation positive and you had docetaxel, it was closer to 4 months, a 4-to-5 month range. Therefore, we finally have randomized prospective data that tells us that for patients with BRCA-associated TNBC, first-line platinum chemotherapy appeared to be a bit better than a first-line taxane.

Now, outside of having a BRCA-associated TNBC, a first-line tax-ane such as weekly paclitaxel still appears to be a preferred regimen. And we have data from the CALGB trial that Hope Rugo published where weekly paclitaxel was compared to ixabepilone or nab-pacli-taxel and, really, the weekly paclitaxel regimen came out on top. Nab-paclitaxel is not inferior. Ixabepilone actually appeared to be a bit worse, and weekly paclitaxel was very well tolerated. And that lack of difference held true in the subset of women that had TNBC. So, I think in short, the TNT trial told us that a first-line platinum che-motherapy appeared a bit better than docetaxel in BRCA-associated TNBC, but in all-comer TNBC, first-line treatment with a taxane is still very appropriate therapy.

Moderator: How about emerging immuno-oncology agents and clin-ical trials? Specifically, which of these agents are being evaluated in triple negative breast cancer and in what settings? Dr. Traina: Good question. The idea of immuno-oncology is really a hot topic right now, and the idea is that disrupting the interaction between PD-1 and PD-L1 between tumor and T cell helps to unleash the body’s own immune system in recognizing the tumor as foreign and attacking it. And so there are two agents in the past year that I think are furthest along in development in breast cancer to note. One is pembrolizumab and the other is atezolizumab. Both of these

compounds have been studied in stage I clinical trials. Rita Nanda presented the pembrolizumab data at the San Antonio Breast Cancer Symposium last year, and what was remarkable was that in a phase 1 trial, an anti-PD-1 antibody elicited response rates as high as 20% and prolonged stable disease in as many as 25% of patients with TNBC who were PD-L1-positive in either tumor or stroma. This was a tiny phase 1 trial, with a total of 30-something patients who were heavily pretreated. And to see a well-tolerated regimen with a response rate of about 20% is encouraging. These findings were somewhat confirmed in at AACR earlier this year with the other immuno-oncology agent, atezolizumab. A phase 1 trial reported in Breast showed that atezoli-zumab elicited response rates of about 20% in a heavily pretreated population.

Given the encouraging findings in phase 1 trials of pembrolizum-ab and atezolizumab, these two compounds are both moving forward in larger phase 2 studies that are accruing right now, some of which are focused solely on women with TNBC. The thought is that tri-ple-negative tumors, which have high turnover and a higher muta-tional load, may be more easily identifiable by the immune system because of their high mutation rates. For example, several trials are looking at pembrolizumab with or without chemotherapy. Essential-ly, that’s one of the big research questions: Should immuno-oncology agents be given as monotherapy or will giving them with a partner chemotherapy, like eribulin, kill more cells and release more antigen and help rev up the immune system a bit more? There is currently a large randomized trial that’s comparing pembrolizumab to treatment of physician’s choice, including either eribulin, capecitabine, or gem-citabine. There are also some trials looking at pembrolizumab in combination with other targeted therapies that will inhibit molecules that suppress the immune response. Similar trials are underway with atezolizumab. For example, there’s a study in TNBC of nab-paclitaxel with or without atezolizumab. So immuno-oncology is a rich area of investigation and a lot of answers are still remaining about whether these agents should be used as monotherapy or in combination with chemotherapy. There are even some trials examining radiation thera-py with pembrolizumab or with other checkpoint inhibitors. So a lot going on in this field.

Moderator: How about earlier stage or locally advanced triple-neg-ative breast cancer? What are the current treatment standards here? Dr. Traina: Starting with the adjuvant setting of early-stage TNBC, I think one important point to raise is that NCCN Guidelines rec-ognize that even small triple-negative tumors have a higher risk of recurrence. So they lowered the bar on even considering adjuvant chemotherapy for tumors that are as small as 5 mm node-negative cancers. So that’s one important point for the readership to know, that the threshold to even think about adjuvant chemotherapy in-cludes even the teeny, tiny stage I TNBC. The next important point is that because these are higher risk tumors, we often are utilizing anthracycline and taxane-based adjuvant regimens for even the stage I cancers.

Where there’s variability in clinicians’ treatment patterns and new

EVOLVING MANAGEMENT STRATEGIES FOR TRIPLE-NEGATIVE BREAST CANCER


data is in the neoadjuvant setting. Two large randomized phase 2 studies have supported the use of carboplatin in addition to anthracy-cline and taxane-containing regimens for women with triple negative breast cancer. Now, those trials were Gepar-Sixto and the CALGB 40603 (Alliance) study that Bill Sikov published. Both trials had a primary endpoint of pCR, so right now, all we can say from those two studies is that when platinum chemotherapy was added to an anthra-cycline and taxane-containing regimen, you had a higher likelihood of pCR. Outcomes from both trials consistently looked like platinum chemotherapy helped raise that pCR rate to about 60%, and, in the absence of platinum, the pCR rate was around 30% to 40%.

When interpreting these data, I think we have to be cautious in recognizing there is zero survival data that support adding platinum chemotherapy to an early-stage triple negative regimen. We have no survival data from the neoadjuvant trials, and we lack any adjuvant data for the addition of platinum. There’s really a question about pCR rate serving as a surrogate for survival. We just do not know what magnitude of a difference we need in pCR from these neoad-juvant trials to show any difference in survival in the long run. And if you look at the GeparSixto and CALGB 40603 data in terms of toxicity, the arms that received platinum, in addition to anthracycline and taxane, had much greater rates of adverse events, requirements for dose reductions, and treatment delays. So I think we need to just balance, recognizing that platinum can improve pCR rates; but we have to be cautious in recognizing we do not have long-term survival data to inform decisions about the addition of carboplatin to an ad-juvant regimen.

Moderator: How do you manage patients who receive neoadjuvant therapy, but still have residual disease at the time of surgery? Dr. Traina: This is a very challenging and frustrating situation to be in. It’s disconcerting when a patient has gone through excellent con-ventional cytotoxic therapy, goes on to surgery, and and has residual disease. The standard of care today would suggest that if you’ve given all of your best drugs in the regimen up-front pre-operatively, there’s no data to support administering additional chemotherapy in the adjuvant setting. And it’s quite possible that if there was residual dis-ease, that that cancer may be somewhat resistant to cytotoxic therapy. So the standard of care would not support additional chemotherapy, but I think it’s an excellent opportunity to explore clinical trials. For example, I can think of one ongoing study that is investigating adju-vant olaparib, a PARP inhibitor, in patients with BRCA mutations who have not achieved a pCR with neoadjuvant therapy by the time of surgery. So although the standard of care is to not administer ad-ditional chemotherapy, I would encourage folks to look for clinical trials in their area in the post-neoadjuvant setting.

Moderator: Looking into the near future, how do you see the field of TNBC management evolving in the context of emerging treatment options and prognostic and/or predictive tools we can use to person-alize care in these patients?

Dr. Traina: Good question. I guess the first step is recognizing the heterogeneity of TNBC. It is not all the same and we’ve seen that already with recognizing differences in BRCA-associated TNBC ver-sus other non-BRCA-mutated TNBC. At ASCO earlier this year, our group actually presented data on targeting the subtype of TNBC that is driven by the AR. And I had the pleasure of presenting our data from a large phase 2 study that used an AR antagonist, enzalutamide, to treat AR-positive TNBC. In this trial, we saw a long medical progression-free survival of 40 weeks or so in the setting of having AR-positive disease treated in the first or second-line setting with an endocrine therapy. So, I think a reason to remain optimistic and a take-home message is recognizing heterogeneity and looking toward biomarker development to subtype TNBC to help guide treatment choices.

Many of these targeted therapies are being developed with compan-ion biomarkers, and I think having these biomarkers will be critical in knowing how to choose the best treatment for our patients. Che-motherapy will still remain an important component, but we have immunotherapy; anti-androgen therapy; DNA damaging agents; and PARP inhibition, which is still being actively evaluated. So I think recognizing heterogeneity in TNBC and identifying biomarkers to guide treatment decisions are some of the biggest take-home points. In addition, the field has also begun to move toward tumor genomic profiling to see whether we can identify particular driver mutations that might even help guide clinical trial choice.

REFERENCES1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.2. Boyle P. Triple-negative breast cancer: epidemiological consider-ations and recommendations. Ann Oncol. 2012;23(suppl 6):vi7-vi12.3. Mustacchi G, De Laurentiis M. The role of taxanes in triple-nega-tive breast cancer: literature review. Drug Des Devel Ther. 2015;9:4303-4318.4. Tutt A, Ellis P, Kilburn L, et al. TNT: A randomized phase 3 tri-al of carboplatin (C) compared with docetaxel (D) for patients with metastatic orrecurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Presented at: 37th Annual San Anto-nio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S3-01.5. Rugo HS, Barry WT, Moreno-Aspitia A, et al. Randomized phase 3 trial of paclitaxel once per week compared with nanoparticle albu-min-bound nab-paclitaxel once per week or ixabepilone with bevaci-zumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015;33(21):2361-2369.6. Nanda R, Chow LQ, Dees EC, et al. A phase 1b study of pembroli-zumab (MK-3475 in patients with advanced triple-negative breast cancer. Presented at: 37th Annual San Antonio Breast Cancer Sym-posium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.

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7. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 106th American Association for Cancer Research 106th Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract 2850.8. Traina TA, Miller K, Yardley DA, et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). J Clin Oncol. 2015;33: (suppl; abstr 1003).9. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carbo platin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lan-cet Oncol. 2014;15(7):747–756.10. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week pacli-taxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33(1):13–21.11. Tutt AN, Kaufman B, Gelber RD, et al. OlympiA: A random-ized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and germline BRCA1/2 mutation (gBRCAm). J Clin Oncol. 2015;33:(suppl; abstr TPS1109).

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Mission & ScopeThe American Journal of Hematology/Oncology is a monthly peer-reviewed publication that provides original research, reviews, and editorial/commentaries that address cutting-edge developments in genomics, targeted therapies, molecular diagnostics, and pathways related to on-cological science and clinical practice. As the official publication of Physicians’ Education Resource® (PER®), the Journal’s mission is to advance cancer care through professional education.

The Journal aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practic-ing oncologists gain a better understanding of how these advances have changed the treatment landscape for both solid and hematologic malignancies. Articles published in the Journal will illustrate successes and failures in clinical practice and will provide practical insights into the myriad decisions that oncologists face in everyday clinical prac-tice.

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1. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus ima-tinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial [published online September 4, 2012]. J Clin Oncol. 2012;30(28):3486-3492. 2. Wierda WG, O’Brien S. Chronic lymphoblastic leukemia. In: De-Vita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 3. American Cancer Society. Cancer facts and figures 2014. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfig-ures2014. Accessed March 18, 2015.

Graphic Elements. Use of graphic elements is strongly encouraged, and each article can contain up to 5 graphic elements. All supple-mental data (eg, appendices and lengthy tables) will be posted on the Journal’s website at the time of publication. Authors should indicate what material is intended for Web-exclusive content and include the appropriate reference or callout in the text to these Web-exclusive elements.

Tables. Place each table on a new page. Number tables sequen-tially in the order in which they are cited in the text. Include a title for each table. Special characters, abbreviations, and symbols must be explained in the table key in the following format: “OS indicates overall survival; PFS, progression-free survival.” Footnoted mate-rial in tables should be indicated with superscript, lowercase letters: “a,” “b,” “c,” and so on. Footnotes are listed at the bottom of the table, each on its own line.Figures. The Journal’s production team is available to create fig-ures from sketches provided by the authors. Avoid the use of shad-ing in bar graphs or pie charts—use color or crosshatch patterns instead. Number all figures in the order in which they are mentioned in the text. Any previously published figures must be accompanied by written permission from the publisher and/or copyright holder (see “Permissions” section). Any payment associated with repro-ducing figures is the responsibility of the author(s).

Legends. Legends should include the figure number and a brief description of the graphic. Identify all abbreviations used in the figure at the end of each legend.

Peer Review ProcessEach manuscript is sent to the editor-in-chief for an internal evalua-tion to determine its appropriateness. Manuscripts that do not meet the Journal’s criteria for overall appropriateness, relevance, originality, and scientific merit will be returned promptly (usually within 2 weeks) so that authors may pursue alternate avenues for publication.

Although reviewer selection is ultimately the decision of the edi-

tors, authors may provide the names and e-mail information of pre-ferred and nonpreferred peer reviewers. Manuscripts deemed appro-priate for The American Journal of Hematology/Oncology will be sent to external peer reviewers via a double-blinded review process. Typically, a manuscript will be sent to a minimum of 2 reviewers to provide feedback on the scientific merit of the paper.

Reviewers are requested to complete their evaluation of a manu-script within 2 weeks. They are asked to treat manuscripts as confi-dential communications and not to share their content with anyone (except colleagues whom they ask in confidence to assist in review-ing) or to use the content for their own purposes. The Journal does not send manuscripts to any reviewers who are affiliated with the same institution as any of the authors, and requires that reviewers declare any potential conflicts of interest, such as personal ties to an organization with a vested interest in the content of the manuscript.

Editorial DecisionsThe editors and peer reviewers judge manuscripts on the interest and importance of the topic, the intellectual and scientific strength, the clarity of the presentation, and relevance to readers. We also con-sider the strength of the paper compared with other papers under review, as well as the number of accepted and previously published articles in the same category. Authors of original research and review articles should clearly describe how their findings add to the existing literature.

The editorial office is committed to providing prompt processing times and to communicating timely decisions to authors. While the editorial office makes every effort to notify authors and keep them informed of any delays, most authors can expect a first decision on their manuscript in approximately 4-6 weeks. The editors will com-municate editorial decisions on acceptance or rejection to the cor-responding author only.

Accepted ManuscriptsPage proofs (PDFs) are e-mailed to the corresponding author before publication. Authors can expect to receive proofs approximately 3-4 weeks before the scheduled issue date. All proofs should be returned to the editorial office within 48 hours.

References1. International Committee of Medical Journal Editors. Uniform re-quirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. www.icmje.org/urm_full.pdf. Accessed March 18, 2015. 2. Iverson C, ed. Ethical and legal considerations. In: American Medical Association Manual of Style. 10th ed. New York, NY: Oxford University Press; 2007:125-300.

Editorial Offices:The American Journal of Hematology/OncologyOffice Center at Princeton Meadows, Bldg 400Plainsboro, New Jersey 08536E-mail: [email protected]

Chirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and...

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