Role of chemotherapy Carcinoma colon
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Transcript of Role of chemotherapy Carcinoma colon
ROLE OF CHEMOTHERAPY IN CA COLON
DR ANIL GUPTA
INTRODUCTION Globally, nearly 1,200,000 new CRC cases are believed to occur, which accounts
for approximately10% of all incident cancers, and mortality from CRC is estimated at nearly 609,000.
Third most diagnosed malignancy in USA, responsible for nearly 10% of cancer mortality.
Majority are sporadic cancers, familial CRC are 5% .
Causes includes high fat diet, smoking,sedentary lifestyle, obesity
Familial factors include hereditary nonpolyposis colorectal cancer(HNCC) (3%), Familial adenomatous polyposis(FAP) (1%) hamartomatous polyposis syndromes such as peutz jeughers syndrome, juvenile polyposis, cowden syndrome
Presenting features include lower GI bleeding, change in bowel habits, abdominal pain,weight loss, change in appetite, and weakness, and in particular, obstructive symptoms
Incidence : 35.8/100,000 (USA)
Developing countries < 10/100,000
India: incidence - 7/1,00,000
Median age of diagnosis- 62 yrs
STAGING OF COLON CA
85-95%
30-60%
5%60-80%
The Astler-Coller MODIFICATION
Of historical intrest
AJCC TNM STAGING AJCC 7th edition Adapted from Duke's staging Same for both clinical and pathological staging Not included are staging of appendix, anal CA,
neuroendocrine tumors of colon Based on clinical-radiological and
histopatholgical findings
T STAGING
N STAGING
M STAGING
COMPOSITE STAGE
IN SITU
STAGE I
STAGE II
STAGE III
STAGE IV
PROGNOSTIC FACTORS in colon cancer
Category
I Definitively proven to be of prognostic value based on evidence from multiple statistically robust published trials and used in patient m a n a management.
IIA Factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value but that remains to be validated in statistically robust studies.
IIB Factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA.
III Factors not yet sufficiently studied to determine their prognostic value.
IV Includes factors well studied and shown to have no prognostic significance.
Category I Prognostic factorsCategory I Prognostic factors The local extent of tumor assessed pathologically
Regional lymph node metastasis
Blood or lymphatic vessel invasion ---> poorer prognosis
Residual tumor following surgery with curative intent
Preoperative elevation of carcinoembryonic antigen elevation ---> poorer prognosis
Category IIA Prognostic factorsCategory IIA Prognostic factors Tumor grade --> higher grade poorer prognosis
Radial margin status---> poorer prognosis
Residual tumor in the resection specimen following NACT
Category IIB Prognostic factorsCategory IIB Prognostic factors Histological type ---> signet ring cell and small cell has poor prognosis
Histological features associated with microsatellite instability (MSI)
High degree of MSI (MSI-H),
Loss of heterozygosity at 18q
Tumor border configuration (infiltrating vs pushing border).
STAGE
Category III Prognostic factorsCategory III Prognostic factors
DNA content
All other molecular markers except loss of heterozygosity 18q/DCC and
MSI-H---> eg KRAS, C myc-->insufficient data
Perineural invasion
Microvessel density
Tumor cell–associated proteins or carbohydrates, peritumoral fibrosis, peritumoral inflammatory response, focal neuroendocrine differentiation, nuclear organizing regions, and proliferation indices
Category IV Prognostic factorsCategory IV Prognostic factors Tumor size Not prognostic factors
Gross Tumor configuration.
MICROSATELITE INSTABILITY
Microsatelite instabilty(MSI) is due to gain or loss of repeat units
MSI is due to defective repair gene eg. MLH-1 and MSH2 gene
Known as MSI-H instabilty phenotype
In 15% CRC MSI is found---->a/w, peritumoral lymphocytic infiltration bigger 1º, Node -ve, better prognosis
85% CRC typically have genetic alterations involving loss of hetrozygosity, chromosome amplifications
Known as microsatelite stable tumors/MSS
Poor prognosis
Microsatelites are sections of DNA in which a short sequence of nucleotides are repeated many times
18q deletion Allelic LOH>50% of CRC Involves DCC gene, smad 2 & smad4 Watanabe et al(2006)
Allelic status of 18q Number (N) 5 yr survival
No loss 112 69
Loss 109 50
P=0.005
TUMOR BODY CONFIGURATION
Zlobec et al
MANAGEMENT OF COLON CANCER
Surgery is the mainstay of management of colon cancer
Pedunculated polypPedunculated polyp- polypectomy
Sessile polypSessile polyp- segmental colon resection
Stage II or IIIStage II or III- colectomy with en bloc removal of
regional lymph nodes
Stage IV/Recurrent Stage IV/Recurrent - Convert to resectable disease
f/b surgical debulking in selected
cases
RATIONALE FOR ADJUVANT THERAPY
Routes of spread;- direct spread, transperiotoneal spread, implantation, lymphatic spread, hematogenous spread and venous extension
Cascade hypothesis- metastatic disease develops in discrete steps, first to the liver, then to the lung, and finally to other sites
Stage I, II, III are at risk for having occult stage IV disease The role of adjuvant therapy is to eradicate that microscopic metastatic disease
Despite curative surgery half of these patients suffer incurable tumor recurrence leading to cancer related death
Therefore there is a need of adjuvant therapy to improve recurrence,DFS and OS
ADJUVANT CHEMOTHERAPY THERAPY FOR CARCINOMA IN
SITU AND STAGE I
ADJUVANT THERAPY FOR CARCINOMA IN SITU AND STAGE
I
After curative resection with negative CRM, 5yr survival>95%
Local recurrence 0-3%
NO ADJUVANT THERAPY
MANAGEMENT OF CARCINOMA IN SITU AND STAGE I
ADJUVANT CHEMOTHERAPY IN STAGE II COLON CANCER
STAGE II COLON CANCER
Are at risk for having occult stage IV disease The role of adjuvant therapy is to eradicate that microscopic metastatic disease
5 yr survival rate after curative resection
Target of adjuvant chemotherapy is to prevent recurrence, disease free survival and overall survival
T3N0M0 w/o high risk factors
T3N0M0 with high risk factors /T4N0M0
5 yr survival 70-80% 60-65%
OBSERVATION VS ADJUVANT CHEMOTHERAPY
SEER-Medicare linked SEER-Medicare linked database, Schrag et al (2002) database, Schrag et al (2002)
Erin S. O’Connor et al(2011)Erin S. O’Connor et al(2011)
IMPACT Metanalysis(1999)IMPACT Metanalysis(1999)
Arms Surgery only Adjuvant chemotherapy
5 year survival 75% 78%
Arms Surgery only Adjuvant chemotherapy
5 year survival 80% 82%
Arms Surgery only Adjuvant chemotherapy
5 year survival 75% 78%
HIGH RISK FEATURES- GRADE III OR IV- LVI- BOWEL OBSTRUCTION- <12 LN DISSECTED- PNI- LOCALIZED PERFORATION- UNDETERMINED OR POSITIVE CRM
QUASAR (Quick and Simple and Reliable)(2007)
TRIAL WHICH SUPPORTED ADJUVANT CHEMOTHERAPY IN
STAGE II COLON CANCERNSABP
OBSERVATION 5-YEAR SURVIVAL IN 5-FU+LV
62% 76%
ONGOING TRIAL
WHAT CHEMOTHERAPY SHOULD BE GIVEN??
Groups of Chemotherapy drugs in Colon Cancer
ANTI-METABOLITES
5-Flourouracil Capecitabine Tegafur-uracil
PLATINUM COMPOUNDS
Oxaliplatin
CAMTOTHECIN ANALOGUES
Irinotecan
MONOCLONAL ANTIBODIES
Cetuximab Pantimummab Bevacizumab
TYROSINE KINASE INHIBITORS
Regorafenib
5-Fluorouracil
Virtually the entire history of chemotherapy for CRC has revolved around the use of 5-FU.
Is a source of frustration and humility for investigators working to move beyond it that over 50 years later this agent remains at the very core of most chemotherapeutic approach
Developed by Heidleberger et al and patented in 1957.
Observed that tumor tissue used a larger amount of uracil than non tumor tissues. He therefore substituted a fluorine atom at the number 5 position of the uracil molecule
Cell cycle–specific with activity in the S-phase.
Requires activation to cytotoxic metabolite forms.
MOA
• Alterations in RNA processing and/or mRNA translation.
• Inhibition of DNA synthesis and function.
DISTIRBUTION
After IV administration, is widely distributed to tissues with highest
concentration in GI mucosa, bone marrow, and liver. Penetrates into
third-space fluid collections such as ascites and pleural effusions. Crosses
the blood-brain barrier and distributes into CSF and brain tissue.
METABOLISM
Undergoes extensive enzymatic metabolism intracellularly to cytotoxic metabolites.
Dihydropyrimidine dehydrogenase is the main enzyme responsible for 5-FU catabolism
Must be metabolized before it can exert cytotoxic activity
Greater than 90% of an administered dose of drug is cleared in urine and lungs.
The terminal elimination half-life is short, ranging from 10 to 20 min
TOXICITY Myelosuppression- less frequently observed with infusional
therapy. Neutropenia and thrombocytopenia more common than anemia.
Mucositis and/or diarrhea.-May be severe and dose-limiting for infusional schedules. Nausea and vomiting are mild and rare
Hand-foot syndrome -
Neurologic toxicity manifested by somnolence, confusion, seizures, cerebellar ataxia, and rarely encephalopathy
Cardiac symptoms of chest pain, EKG changes, are rare but increased risk in patients with history of ischemic heart disease
Dry skin, photosensitivity, and pigmentation of the infused vein are common.
Metallic taste in mouth during IV bolus injection. Blepharitis, tear-duct stenosis, acute and chronic conjunctivitis Metallic taste in mouth during IV bolus injection
Discussion of single agent 5-FU regimen
Leucovorin(Citrovorum factor/folinic acid/5-formyl tetrahydrofolate enhances the antitumor activity and toxicity
RATIONALE FOR LEUCOVORIN ADDITIONRATIONALE FOR LEUCOVORIN ADDITION
It potentiates inhibitory effect of 5-FU on TS.It potentiates inhibitory effect of 5-FU on TS.
MAYO REGIMEN
D1-D5, 4 weekly 2 Cycles 5 weeks thereafter
LEUCOVORIN20mg/m2/d
5 FU425mg/m2/d bolus
Poon et al.1989
5-FU+low dose LV(20mg/m2) vs 5-FU+high dose LV(200mg/m2) vs 5-FU+high dose MTX with LV rescue
Survival benefit is similar ,although 5 FU+low dose LV is a/w slightly better survival
5-FU+low dose LV
5-FU+high dose LV
5-FU+MTX with LV rescue
Median survival
12.7 months 12.7 months 8.4 monthsP<0.1
Toxicity
Conclusion- Established efficacy of 5FU with Leucovorin and also concluded that it is not necessary to use high dose leucovorin
5-FU+low dose LV
5-FU+high dose LV
5-FU+MTX with LV rescue
Leukopenia(<2,000/ul)
22% 15% 14%<4000/ul- 77%
Severe Stomatitis
28% 28% -
Severe Diarrhea
19% 16% -
Rate of Hospitalization
15% 5.4% 6.5%
Roswell Park Regimen
2-hour iv infusion weekly for 6 consecutive weeks (on days 1, 8, 15, 22,29 and 36 of the treatment cycle) f/b 2 week rest period
After 1 hour
IV bolus weekly for 6 consecutive weeks (on days 1, 8, 15, 22,29 and 36 of the treatment cycle) f/b 2 week rest period
Patients were to receive three 8-week cycles of therapy for a total treatment duration of 24 weeks (6 months).
Haller et al,1998
LEUCOVORIN(500mg/m2)
5 FLOUROURACIL(500mg/m2)
Original 600mg/m2
Roswell Park Regimen Vs Mayo Regimen
Roswell Park regimen Mayo Regimen
Median response 24.8 wks 23.1 wks
Median survival time
55.1 wks 54.1 wks
Median progression free intervals
29.3 wks 23.1 wks
Grade III diarrhea 36 pts 20 pts
Grade IV diarrhea 4 pts 3 pts
Bolus Vs Continuous Infusion vs Intermittent Infusion
Preclinical evidence suggested that increased duration of exposure could improve efficacy. Because the plasma half-life of 5-FU is short (8 to 20 minutes),
Protracted venous infusion (PVI)/ continuous infusionProtracted venous infusion (PVI)/ continuous infusion
5-FU 300 mg/m2/day by continuous infusion
A meta-analysis (1998) involving 1,219 patients in six trials reported an improved response rate of 22% versus 14% in favor of PVI. Survival with PVI 5-FU was statistically superior, but this survival advantage was less than 1 month.
Interrmittent InfusionInterrmittent Infusion
A larger phase III confirmatory trial compared the weekly high-dose infusion of 2,600 mg/m2, either alone or with 500 mg/m2 of leucovorin, with the Mayo Clinic bolus schedule of 5-FU. No overall survival differences were seen.
LV5FU2 REGIMEN
Both bolus and iv infusion form of 5FU
2 hr infusion D1, D2
D1, D2
22 hr infusion D1, D2
Over 12 cycles with a gap of 2 weeks
LEUCOVORIN(200mg/m2)
5 FLOUROURACIL(400mg)
5 FLOUROURACIL(600mg/m2)
De Gramont et al,1997
LV5FU2 REGIMEN
Mayo regimen vs bimonthly LV+ 5 FU bolus and continuous infusion
Mayo regimen LV5FU2
Response rate 14.4% 32.6%
Median PFS 22 wks 27.6 wks
Median survival times
56.8wks 62wks
P=0.0004P=0.0012P=0.067
Conclusion- The bimonthly regimen (LV5FU2)was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of
increased survival.
Mayo regimen LV5FU2
Grade 3-4 toxicities 23.9% 11.9%
Granulocytopenia 7.3% 1.9%
diarrhea 7.3% 2.9%
mucositis 7.3% 1.9%
CAPECITABINEIs oral precursor of 5-FU
MOAMOA
Inhibition of the target enzyme thymidylate synthase (TS)
Alterations in RNA processing and/or mRNA translation.
Inhibition of DNA synthesis and function.
METABOLISMMETABOLISM
Dihydropyrimidine dehydrogenase is present in liver and extrahepatic tissues such as GI mucosa, WBCs, and the kidneys catabolise into various metabolites which clears through urine
ABSORPTIONABSORPTION
Readily absorbed by the GI tract. Peak plasma levels are reached in 1.5 hours, while peak 5-FU levels are achieved at 2 hours after oral\administration. The rate and extent of absorption are reduced by food.
TOXICITY Diarrhea is dose-limiting, observed in up to 55% of patients. Hand-foot syndrome (palmar-plantar erythrodysesthesia). Severe hand foot
syndrome is seen in 15%–20% of patients.
Nausea and vomiting occur in 15%–53% of patients Myelosuppression is observed less frequently than with IV 5-FU.
Leukopenia more common than thrombocytopenia. Neurologic toxicity manifested by confusion, cerebellar ataxia, and rarely
encephalopathy. Cardiac symptoms of chest pain, EKG changes, and serum enzyme
elevation. Rare event but increased risk in patients with prior history of ischemic heart disease.
Tear-duct stenosis, acute and chronic conjunctivitis.
Elevations in serum bilirubin (20%–40%), alkaline phosphatase, and hepatic transaminases (SGOT, SGPT). Usually transient and clinically asymptomatic.
TEGAFUR-URACIL
Is oral precursor of 5-FU
Combination of two drugs--> Tegafur and Uracil (4:1 molar ratio)
Addition of uracil results in less neurotoxicity, more absorption
Similar toxic profiles as capecitabine
NSABP C-06- Similar efficacy as i.v LV/5 FU(roswell park regimen), both are equitoxic
OXALIPLATIN Platinum Analog
Cell cycle non-specific
MOA:- Inhibhits DNA synthesis
Widely distirbuted in body
ToxicityToxicity
Nausea/ vomiting 65% when used alone, 90% when used with 5FU/LV
Dose limiting- Neurotoxicity
Acute toxicity 80-85% pts- peripheral sensory neuropathy, distal parasethesia within 1-3 days of therapy
Chronic toxicity- if cumulative dose >850 mg- impairment of proprioception
Myelosupression
Should be used with precaution in abnormal renal function
IRINOTECAN
Trade name CPT-11/Camptosar
Topoisomerase I inhibitor
Inactive in its parent form, converted to SN-38 by enzyme carboxylesterase
Cell cycle–nonspecific agent with activity in all phases of the cell cycle
Rationale for use in CRC- Colorectal tumors express higher levels of topoisomerase I than normal colonic mucosa
Given via I.V route
TOXICITY
Highly emetogenic
Early diarrhea- <24 hrs of adminstration
Late diarrhea- >24 hrs of adminstration
Moderate vesicant
Myelosupression
When to start?????
DOES TIMING MATTER?
Traditionally, should be started within 8 weeks of surgery.
Guts et alGuts et al: Meta-analysis of pooled data of 13,158 patients concluded delaying treatment causes inferior survival (RR=1.20)
Czaykowski et alCzaykowski et al: Concluded that delaying adjuvant chemotherapy beyond 8 to 10 weeks appears to be associated with diminished benefit.
CONSENSUS- Should be started within 8 weeks, if no surgical/medical contraindications
For what duration it should be given???
OPTIMAL DURATION OF ADJUVANT CHEMOTHERAPY
INT-0089(2005) INT-0089(2005) - The Intergroup study showed equivalence between 6 months of LV/5-FU and12 months of 5- FU/levamisole adjuvant chemotherapy
GERCOR trial(2007)GERCOR trial(2007)- 6 months of chemotherapy achieved similar results than 9 months of the same chemotherapy
A 6-month chemotherapy duration became, and still is, the standard.
STAGE II CANCER
NCCN
ADJUVANT CHEMOTHERAPY IN STAGE III CANCER
MOSAIC TRIAL
MOSAIC TRIAL SCHEME
RANDOMIZATION
FOLFOX4
LV5FU2
N=1123
N=1123
SII-40%SIII-60%
Oxaliplatin 85mg/m2 on D1 with LV via Y-conncetor, LV5FU2
MOSAIC TRIAL RESULTS3 YR OVERALL SURVIVAL
FOLFOX4 LV5FU2
ALL PATIENTS 77.9% 72.8%
STAGE II PATIENTS
86.6% 83.9%
STAGE III PATIENTS
71.8% 65.5%
ADVERSE EFFECTSFOLFOX-4 LV5FU2
Grade 3-4 neutropenia
41% 5%
Neutropenic fever 1% 0%
Grade 3-4 diarrhea
1% 0%
Grade 3-4 vomiting
11% 7%
Neuropathy, any grade
92% 0%
Neuropathy, grade 3
12% 0%
Persistent neuropathy, grade 2-3, 1 year after t/t
5% 0%
DIFFERENT FOLFOX REGIMENS
mFOLFOX6
FOLFIRI Regimen
LV5FU2 + Irinotecan (180 mg/m2 as a 30- to 90-minute infusion, day 1, every 2 weeks)
More dropouts
More neutropenia
UGTA1A1 Polymorphism
3yr DFS(%)5FULV2 FOLFIRI
ACCORD II 60 51
PETACC 3(2009) 59.9 62.9
XELOX REGIMEN
XELOX FOLFOX 6
3 yr OS 86.9% 87.2%
3 yr DFS 79.8% 79.5%
Pectasides et al, 2010
STAGE III
CHEMOTHERAPY IN METASTATIC/RECURRENCE
COLON CANCER
RECURRENCE Serial elevation/ symptomatic
Suspect recurrence
Workup
Documented metachronus metastases
Resectable Unresectable
Resection adjuvant chemotherapy Convert to resectable
NACT resection adjuvant chemotherapy
UNRESECTABLE METASTATIC DISEASE
Is generally not curable with current technology
Management centers around palliation and control of symptoms, control of tumor growth, and attempts to lengthen progression-free and overall survival.
For palliation risk vs benefit ratio should be taken into account
QOL should be discussed with patient and caregiver
End point of palliative treatment should be good quality of life and if possible convert unresectable to resectable.
Surgical intervention can be a very effective method of palliation and is often indicated in cases of impending obstruction, perforation, bleeding, or pain, however a/w more morbidity
NSABP C-10 concluded that good performance status patients with asymptomatic primaries can be spared initial non curative resection of their primaries
SINGLE AGENT CHEMOTHERAPY
N RR PFS OS
LV5FU2 175 32.6 6.9 month 15.5 month
CAPE 603 26 4.6 month 12.9 month
Bolus FU/LV 604 17 4.7 month 12.8 month
Van Cutsem et al, 2004- Pooled data
SINGLE AGENT CHEMOTHERAPY LV5FU2 better tolerated (less granulocytopenia, diarrhea and mucositis)
and more efficacious than bolus 5 FU (de Gramont et al,1997)
Oral CAPE is superior to bolus 5 FU in first line setting( improved RR, less diarrhea, nausea, stomatitis, alopecia, fewer hospitalizations) but more hyperbilirubinemia and hand foot syndrome ( Van Cutsen et al,2004)
CAPE similar to infusional 5 FU in metastatic setting(Cassidy et al metanalysis,2011)
Adding LV with 5 FU increases OS but high dose LV has no extra benefit(NCCTG, 1989)
No obvious benefit of adding LV to protracted 5 FU(SOCG study,1995)
Single agent oxaliplatin and Irinotecan has limited role in first line setting (Diaz-Rubio et al,1998;Saltz et al ,1998)
With singlet chemotherapy patient can expect 15% to 20% RR, median PFS 5 to 6 months ,median OS 10 to 14 months
DOUBLET CHEMOTHERAPY Combination of 5 FU with Oxaliplatin or Irinotecan has improved RR, OS,
PFS but with more toxicity (de Gramont et al,2000)
CAPOX has similar efficacy to FOLFOX and acceptable safety profile.FOLFOX has mor e neutropenia, CAPOX has more diarrhea (N016996,2011)
FOLFIRI a/w longer PFS than IFL, but less tolerable regimen, no longer used(NAI trial,2006)
FOLFOX, CAPOX has similar efficacy(GERCOR study,2004)
With doublet chemotherapy patient can expect 40% to 50% RR, median PFS 8 to 9 months ,median OS 16 to 19 months
TRIPLET CHEMOTHERAPY FOLFOXIRI – role remains controversial
FOLFOXIRI compared with FOLFIRI by
Irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks
N RR(%) PFS(months) OS (months)
Reference
FOLFOXIRI 122 60 9.8 22.6 Falcone et al,2007
FOLFIRI 122 34 P<0.0001
6.9 P<0.0006 16.7 P=0.32
FOLFOXIRI 137 43 8.4 21.5 Souglakos et al, 2006
FOLFIRI 146 33.6 6.9 19.5
Better results but poor tolerability
ewf
N Febrile neutropenia
Diarrhea Stomatitis Neurotoxicity
Refernce
FOLFIRI 122 28 11 3 0 Falcone et al,2007
FOLFOXIRI 122 50 20 5 2
FOLFIRI 147 28 11 0 0 Souglakos et al, 2006
FOLFOXIRI 138 35 28 6 6
TARGETED THERAPY Monoclonal antibodies against EGFR Monoclonal antibodies against VEGF Multiple tyrosinase kinase inhibitor
VEGF
VEGF receptor-2
Cation channel
Permeability
Antibodies inhibiting VEGF(e.g. bevacizumab)
Antibodies inhibiting VEGF receptors
Soluble VEGF receptors(VEGF-TRAP)
Small-molecules inhibiting VEGF receptors (TKIs)
(e.g. PTK-787)
Ribozymes(Angiozyme)
– P– PP–
P–
– P– P
P– P–
– P– P
P– P–
Migration, permeability, DNA synthesis, survival
LymphangiogenesisAngiogenesis
Agents targeting the VEGF pathway
EGFR EXPRESSION EGFR is involve in progression of mCRC
EGFR is expressed in 75-89% of mCRC Expression is associated with shorter survival Monoclonal antibodies have been developed against
EGFR receptors Inhibition of EGFR signaling pathway results in inhibition of
critical mitogenic and anti-apoptotic signals involved in proliferation, growth, invasion ,metastasis, angiogenesis
Inhibition also enhances response to chemo/radiation therapy
Only for wild KRAS type
EGFR INHIBITORSCetuximabCetuximab (ERBITUX) (ERBITUX) Chimeric antibody
Precise MOA unknown, causes EGFR inhibition
Has nearly 10 fold higher affinity to EGFR than other ligands
400 mg/m2 IV first infusion given over 2 hours, then 250 mg/m2 weekly or 500 mg/m2 IV every 2 weeks
Infusional related toxicity more
PanitumumabPanitumumab (VECTIBIX) (VECTIBIX) Fully humanised antibody
40 fold affinity to EGFR
6 mg/kg IV over 60 minutes every 2 weeks
Lower infusion related toxicity
ASPECCT STUDY(2014)ASPECCT STUDY(2014)Panitumumab vs CetuximabMedian OS 10.4 months vs 10 monthsSimilar toxicity profile but lesser infusion reaction 3% vs 14%
DOUBLET CHEMOTHERAPY + EGFR INHIBITOR
CRYSTAL Trial- FOLFIRI+ Cetuximab
Patients with previously untreated EGFR-expressing metastatic colorectal cancer
The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCR
TRIPLET CHEMOTHERAPY + EGFR INHIBITOR
Folprecht et al, 2010Folprecht et al, 2010
20 patients
FOLFOXIRI+ Cetuximab
RR 75%
PFS 16 months
Median OS 33 months
Median time to response 3 months- potential value for neoajuvant setting
DOUBLET CHEMOTHERAPY + PANITUMUMAB
PRIME STUDY(2010)PRIME STUDY(2010)
FOLFOX4+Panitumumab vs FOLFOX
Median OS 19.3 months vs 15.5 months wild KRAS
PFS 9.6 months vs 8 months
TRIPLET CHEMOTHERAPY + panitumumab
Fornaro et al, 201337 patients
FOLFOXIRI+Panitumumab
RR 89%
Median PFS 11.3 months
Neutropenia 48%
Diarrhea 35%
Asthenia 27%
Stomatitis 14%
Further trials required
VEGF EXPRESSION
Is a predominant angiogenic factor in CRC 70% percent of patients with stage IV CRC had positive VEGF-
1 expression While 50% and 47%, respectively of patients with stage II and
III CRC had positive VEGF-1 expression Patients who died of the disease more frequently had a VEGF-
1-expressing tumour than did those who survived for 10 years
Bendardarf et al(2008)
VEGF INHIBITORSBevacizumabBevacizumab (AVASTIN) (AVASTIN) Recombinant humanized monoclonal antibody directed against
the VEGF
Binding to VEGF prevents subsequent interaction with its receptors subsequently inhibiting VEGFR signalling
Inhibits formation of new blood vessels in primary tumor and metastatic tumors
With FOLFOX it is given as 10mg/kg infusion after a test dose
May cause thromboembolic events,GIT perforations, wound healing complications, hpertension or nephrotic syndrome, Reversible posterior leukoencephalopathy syndrome (RPLS)
DOUBLET CHEMOTHERAPY+ VEGF INHIBITOR
E3200E3200: Response Rates
FOLFOX+ BEVACIZUMAB
FOLFOX+Bevacizumab
FOLFOX Bevacizumab alone10mg/kg
OR 21.8% 9.2% 0%
CR 1.9% 0.7% 0%
FOLFOX+B vs FOLFOX: P < 0.0001
Giantonio BJ, et al. ASCO 2005
TRIPLET CHEMOTHERAPY+ VEGF INHIBITOR
TRIBE STUDYTRIBE STUDY
FOLFIXIRI+BEVACIZUMAB vs FOLFIRI+BEVACIZUMAB
RR 65% vs 53%
PFS 12.2 months vs 9.7 months P=0.0012
More neutropenia
More diarrhea
More stomatitis
Needs Further study
SOLUBLE VEGF RECEPTORS
Ziv-afliberceptZiv-aflibercept (ZALTRAP) (ZALTRAP) Binds to human VEGF-A and VEGF-B Results in inactivation of these growth factors thus causing
decreased neovascularisation and vascular permeabeality Approved as 4mg/kg 1 hr i.v infusion every 2 weeks just
before FOLFIRI regimen for mCRC Has serious adverse effects fistula formation,
thromboembolic events, proteinuria, neutropenia,diarrhea, reversible posterior leukoencephalopathy syndrome
FOLFIRI+ZIV-AFLIBERCEPT
Randomized study done in patients with mCRC where FOLFOX±bevacizumab already tried and it progressed within 6 months
MULTIPLE TYROSINASE KINASE INHIBITOR
RegorafenibRegorafenib (STIVARGA)(STIVARGA) MOA: Inhibition of neoangiogenesis, inhibition of proliferation by
acting on VEGFR1-3 TIE2 receptors
Given as 160mg/day D1-D21 oral tablets
CORRECT Trial;-CORRECT Trial;-
Regorafenib vs placebo:
OS: 6.4 vs 5.0 months, HR=0.77, p=0.0052(17%), grade III fatigue (10%)
DOUBLE TARGETED THERAPY+ CHEMOTHERAPY
CAIRO-2- Randomized phase III Trial
No increase in GI toxicity
Skin related toxicity increased
N RR(%) PFS(month) OS(month)
CAPOX + Bevacizumab
378 50 10.7 20.3
CAPOX + Bevacizumab+ cetuximab
377 52.7 9.4 19.4
IF RECURRENCE IN <12 MONTHS
Chemotherapy for metastatic disease
CHEMOTHERAPY FOR METASTATIC DISEASE
For patient appropriate for intensive therapy
Single agent Single agent cetuximab/ cetuximab/
panitumumabpanitumumab
/regorafenib/regorafenib
VsVs
clinical trialclinical trial
VsVs
best supportive carebest supportive care
Initial therapy 1st progression 2nd progression
If patient is not appropriate for intensive therapy
CHEMOTHERAPY FOR METASTATIC DISEASE
This heterogeneous group of metastatic colon cancer patients, which had been given various modalities of treatment, could be able to achieve a median survival of around 18 months and 2 year PFS of 28%.
Conclusion: So metastatic colon cancer is no longer an acutely fatal disease, rather it is in the ambit of chronic disease.
MANAGEMENT OF DRUG TOXICITY
5 FLUOROURACIL/ CAPECITABINE/ TEGAFUR5 FLUOROURACIL/ CAPECITABINE/ TEGAFUR
Hand and foot syndrome- Vitamin B6 /pyridoxine,Celecoxib ,low-dose nicotine patch , moisturizer
Mucositis- Use of ice chips in mouth 10–15 minutes pre- and 10–15 minutes post-IV bolus injections of 5-FU may reduce the incidence and severity of mucositis
Unexpected severe myelosupression, GI toxicity, Cardiac toxicity -can be due to deficiency of dihydropyrimidine dehydrogenase. Immediately stop treatment.
OXALIPLATINOXALIPLATIN
Neurotoxicity- Reversible on discontinuation for 3 to 4 months
IRINOTECANIRINOTECAN
Diarrhea- Inj.atropine 0.25mg to 1mg, stoppage of treatment beyond gradeIII diarrhea, no laxatives to be used, loperamide, iv antibiotics, adequate rehydration
CETUXIMABCETUXIMAB
Infusion related toxicity- test dose should be give, inj avil, inj dexa should be given, inj adrenaline should be kept prepared
BEVACIZUMABBEVACIZUMAB
Thromboembolic events- drug not to be given in age >65 years and history of angina, stroke, and prior arterial thromboembolic events
GI perforations- drug should be given only after 28 days of surgical intervention, in liver resection should be given after 6-8 weeks
Hypertension- Anti hypertensive drugs, should be permanently discontinued in uncontolled hypertension
Reversible posterior leukoencephalopathy sundrome (RPLS)- self limiting
INVESTIGATIONAL ADJUVANT THERAPIES
Intra hepatic artery chemotherapy(IAHC) Portal vein infusion Intraperitoneal chemotherapy Vaccines Edrecolomab
INTRA ARTERIAL HEPATIC CHEMOTHERAPY(IAHC)
Liver mets derive their blood supply predominantly from hepatic arteries
Wheras normal liver parenchyma has a predominant portal vein supply
IAHC aims to increase drug concentration in liver mets, therby improving response rates
Kemeny et al, 2009
IAHC with oxaliplatin 100mg/m2 with i.v LV5FU2 regimen used in 36 pts with extensive non resectable metastasis, found to have overall response of 90% with 40% downstaged to R0 resection
PORTAL VEIN INFUSION Tumors less than 5 mm in diameter obtain substantial portions of their blood
supply from both the hepatic and portal circulations
Substantially higher doses of 5-FU can be safely given by intraportal than by intravenous infusion
Metanalysis- 4% improvement in 5 yr survival with portal vein infusion
At present, intraportal adjuvant chemotherapy should remain limited to clinical investigations
INTRAPERITONEAL CHEMOTHERAPY
The peritoneal cavity is drained by portal lymphatics into the portal vein
High concentrations of drug to the portal circulation can be delivered, without the need for portal vein canalization
Pharmacokinetic studies of intraperitoneal 5-FU and floxuridine show that intraperitoneal administration of these agents results in intraperitoneal concentrations 200- to 400-fold higher than those achieved systemically
Scheithaueret et al- A randomized trial of 241 pts done ---> No benefit seen in IInd stage colon cancer, however, a 43% reduction in mortality was seen in stage III
Needs further study
VACCINES
Stimulate the patient's immune system to recognize and eradicate the patient's tumor cells
CEA is a commonly expressed antigen in colorectal carcinomas, However it is not very immnunogenic
Vaccines has been developed against CEA---> ALVAC-CEA B7.1, ALVAC-KSA
Administration of ALVAC-CEA B7.1 has been shown to induce CEA-specific T-cell response in patients with advanced adenocarcinoma when given alone
ALVAC-KSA developed a weak T-cell response
Use of vaccine therapy for treatment of resected colon cancer remains highly investigational
EDRECOLOMAB Murine monoclonal IgG2a antibody directed against the cell
surface glycoprotein 17-1A
Shown in nude mice to inhibit growth of human colon cancer xenografts
An initial trial in patients with metastatic disease revealed several minor responses with remarkably little toxicity
A total of 166 patients were randomized to edrecolomab at a dose of 500 mg by 1-hour infusion 2 weeks after surgery, and then 100 mg during 1 hour given every 4 weeks for four doses, or to surgery only
This small trial showed a 32% reduction in mortality for the edrecolomab arm at a median follow-up of 7 years
Similar results not found in larger studies
CONCLUSION Stage II, III are at risk for having occult stage IV disease The
adjuvant therapy is to eradicate that microscopic metastatic diseasemicroscopic metastatic disease
Most effective regimen are based on 5 Flourouracil
Stage IStage I- No adjuvant therapy
Stage IIA with no high risk factorStage IIA with no high risk factor- Observation> 5FU+LV regimen
Stage IIA with high risk factor, IIB, IICStage IIA with high risk factor, IIB, IIC- 5FU+LV regimen
Stage IIIStage III- FOLFOX regimen
Recurrence/Stage IVRecurrence/Stage IV- For Palliation intentFor Palliation intent
Good performance status- FOLFOX± Targeted therapy
Poor performance status – 5FU+LV regimen/ best supportive care
Better patient selection- avoid unnecessary toxicity
There is scope for improvement, participation in clinical trials is encouraged