COLORECTAL CANCER Updated April 2016 by Dr. Doreen Ezeife (PGY-5 Medical Oncology Resident, University of Calgary)

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1 COLORECTAL CANCER Updated April 2016 by Dr. Dreen Ezeife (PGY-5 Medical Onclgy Resident, University f Calgary) Reviewed by Dr. Sctt Berry (Staff Medical Onclgist, University f Trnt) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY-5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: 3 rd highest incidence in Canada (after lung and breast); 49 new cases per 100, Mrtality: 2 nd highest cause f cancer-related mrtality in Canada (after lung); 17.4 deaths per 100, RISK FACTORS - Envirnmental/Chemical/Infectins: abdminal radiatin, renal transplantatin, race African Americans at higher risk, gender men have greater mrtality frm clrectal cancer, besity, red and prcessed meat, tbacc, alchl, use f andrgen deprivatin therapy, diabetes mellitus and insulin resistance - Genetic: Familial adenmatus plypsis (FAP), Lynch syndrme (Hereditary nn-plypsis clrectal cancer (HNPCC), MUTYH-assciated plypsis (MAP), persnal r family histry f spradic clrectal cancers r adenmatus plyps, inflammatry bwel disease (ulcerative clitis and Crhn s disease) acrmegaly PROTECTIVE FACTORS - exercise, high-fiber diet, ASA/NSAIDs, statins: evidence is mixed PREVENTION & SCREENING - Preventin: There is n established chempreventin methd. Althugh NSAIDs have been shwn t have mdest risk reductin in average- and high-risk individuals, clear recmmendatins fr chempreventin - Screening: Average risk individuals: Age > 50 with n ther additinal persnal r familial risk factrs FOBT r FIT testing every 1 t 2 years fr asymptmatic individuals between age 50 t 75 years f age. Psitive FOBT, FIT r flexible sigmidscpy tests shuld be fllwed by endscpy evaluatin f the entire cln. Clnscpy every 10 years Inflammatry Bwel Disease: Guidelines differ slightly but generally recmmend annual surveillance clnscpy beginning after 8 t 10 years f IBD diagnsis Clnscpy shuld be repeated every 1 t 3 years Familial histry: First-degree relative diagnsed age < 60 r >/= 2 first-degree relatives: Screen with clnscpy at age 40 r 10 years befre the yungest relative's diagnsis. Repeat clnscpy every 5 years First-degree relative diagnsed age > 60: Same screening guidelines as fr average risk individuals Familial adenmatus plypsis: Annual flexible sigmidscpy r clnscpy starting at age 10 t 12

2 Lynch syndrme: Use Amsterdam criteria r revised Bethesda guidelines t determine individuals fitting criteria fr Lynch syndrme Screen with clnscpy every 1 t 2 years beginning at age 20 t 25 years, r 2 t 5 years prir t the earliest age f clrectal cancer in the family, whichever cmes first. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Cmmn Symptms: hematchezia, melena, abdminal pain, irn deficiency anemia, change in bwel habits, ccasinally signs f bstructin, rectal cancer can cause tenesmus, rectal pain, and diminished caliber f stls - Cmmn Signs: rectal bleeding, rectal mass n DRE - Cmmn Presentatins: as abve. Uncmmnly, Streptcccus bvis r Clstridium septicum bacteremia are assciated with cln cancer in 10 t 25% f patients. INVESTIGATIONS - Labratry: preperative CEA - Diagnstic Imaging: preperative CT chest, abdmen and pelvis - Diagnstic Prcedures: Cmplete clnscpy fr assessment f the entire bwel and t btain tissue diagnsis, K-ras/N-ras/B-raf testing f tumurs in the metastatic setting, Mismatch repair gene testing f tumurs in lcalized disease (especially in stage II cln cancer) PATHOLOGY & MOLECULAR BIOLOGY - Cmmn Histlgy: Carcinmas are the mst cmmn: adencarcinma (>90%), adensquamus carcinma, spindle cell carcinmas, squamus cell (epidermid) carcinma, undifferentiated carcinma. - Other histlgic types (neurendcrine neplasms, hamartmas, mesenchymal tumrs, lymphmas) are rare. - Cmmn Metastatic Sites: reginal lymph ndes, lungs, liver, and peritneum. Cln cancer typically spreads t liver first because the venus drainage f the intestinal system is via the prtal system. Rectal cancer may spread t lungs first because the inferir rectal vein drains int the inferir vena cava rather than t the prtal system. Therefre, cln cancer drains int the prtal system while rectal cancer drains systemically. - Relevant Mlecular Bilgy: K-ras/N-ras/B-raf testing f tumurs, Mismatch repair genes testing f tumurs, 18q deletins STAGING - TNM: - T1: tumur invades submucsa - T2: tumur invades muscularis prpria - T3: tumur invades thrugh muscularis prpria int periclrectal tissues - T4a/b: tumur penetrates t the surface f visceral peritneum/directly invades ther rgans r structures - N1: metastasis in 1-3 reginal lymph ndes - N2: metastasis in >/=4 reginal lymph ndes - M1a/b: metastasis cnfined t ne rgan r site/metastasis in mre than ne rgan r site r the peritneum - Stage I: T1/2N0M0; Stage IIA: T3N0M0; Stage IIB: T4aN0M0; Stage IIC: T4cN0M0; Stage III: nde psitive disease, M0; Stage IV: M1 disease. C) TREATMENT LOCALIZED / ADJUVANT / LOCALLY ADVANCED COLON CANCER

3 - Bttm Line General Apprach: Stage I: segmental clectmy, n rle fr adjuvant therapy. Stage IIA (T3N0): segmental clectmy, cnsider 6 mnths adjuvant flurpyrimidine in patients with high-risk (at least ne f the high-risk features described belw) T3N0 disease. Stage IIB/C (T4N0): segmental clectmy, cnsider 6 mnths f adjuvant flurpyrimidine r mdified FOLFOX6 in high-risk patients. - High-risk features include: inadequate lymph nde sampling (<12 ndes), T4 disease, clinical perfratin, lymphvascular and/r perineural invasin, cmplete bstructin r pr differentiatin. - Patients with high levels f micrsatellite instability have a better prgnsis. Adjuvant chemtherapy with a flurpyrimidine mntherapy in patients with micrsatellite instability is nt recmmended. - Stage III: segmental clectmy fllwed by 6 mnths f adjuvant chemtherapy with a flurpyrimidine r mdified FOLFOX6. - Stage III cln cancer in patients > 70 years ld: There is n clear benefit f adjuvant FOLFOX chemtherapy in patients > 70 years ld. Hwever, it is reasnable t cnsider FOLFOX chemtherapy in this ppulatin. - N rle fr adjuvant raditherapy. - Prgnsis: Data frm the Surveillance, Epidemilgy, and End Results (SEER) database reprt 5 year survivals f: - Stage I (T1-2N0) 93 percent - Stage IIA (T3N0) 85 percent - Stage IIB (T4N0) 72 percent - Stage IIIA (T1-2 N1) 83 percent - Stage IIIB (T3-4 N1) 64 percent - Stage IIIC (N2) 44 percent - Imprtant Phase III Clinical Trials: Adjuvant chemtherapy versus bservatin in patients with clrectal cancer: a randmised study (QUASAR trial) Lancet Dec 15;370(9604): Regimen 5-FU/flinic acid chemtherapy vs bservatin Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Primary Endpint All-cause mrtality Inclusin/Exclusin Patients with cmplete resectin f cln r rectal cancer withut distant mets N prir chem uncertain indicatin fr chemtherapy (determined by patient s clinicians, 91% f patients deemed t have an uncertain indicatin fr chem had stage II disease). Size (N) 3239 patients Results Survival: Relative risk f death frm any cause frm chem vs bservatin = 0.82 DFS: Relative risk f recurrence with chem vs bservatin = 0.78 Quality f Life: QOL was wrse in the chem grup than the bservatin grup during the curse f chem. Txicity Nausea, ral mucsitis, diarrhea, neutrpenia Cnclusin 5-FU-based chemtherapy can imprve survival in patients with stage II clrectal cancer. The abslute benefit in OS is 2.6%. Other Cmments This trial included bth cln and rectal cancer patients, and sme stage III patients, as well as sme high-risk stage II patients. Amng the patients with cln cancer, there was nly a trend seen in OS.

4 Adjuvant Flururacil, Leucvrin, and Oxaliplatin in Stage II t III Cln Cancer: Updated 10- Year Survival and Outcmes Accrding t BRAF Mutatin and Mismatch Repair Status f the MOSAIC Study. J Clin Oncl Dec 10;33(35): (10 year update with survival data). Original study: J Clin Oncl Jul 1;27(19): Regimen 12 cycles f : Blus + cntinuus infusin 5-FU/leucvrin (LV5FU2) vs. FOLFOX4 (5-FU/leucvrin + xaliplatin) 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Primary Endpint DFS in the riginal study Inclusin/Exclusin Age 18 t 75 Undergne cmplete resectin f histlgically-prven high-risk stage II r stage III cln cancer N prir chemtherapy r raditherapy Treatment started within 7 weeks f surgery Size (N) 2246 patients Results Survival: 10-year OS rates were 67.1% vs 71.7% (LV5FU2 v FOLFOX4, respectively, P = 0.043), 79.5% vs 78.4% fr stage II (P = 0.980) and 59.0% vs 67.1% fr stage III (P = 0.016). BRAF mutatin was nt prgnstic fr OS, but MMR deficient tumurs were an independent prgnstic factr (HR 2.02, P = 0.014). DFS/PFS/TTP: 5yr DFS 73.3% vs 67.4% in FOLFOX4 vs 5FU/leucvrin grup, respectively (in the riginal study). Respnse Rate: nt reprted Quality f Life: nt reprted Txicity Grade 3 peripheral sensry neurpathy in xaliplatin grup Cnclusin Adding xaliplatin t 5FU significantly imprves 5yr DFS and 6yr OS in the stage II and stage III cln cancer patients; FOLFOX shuld be cnsidered after surgery in stage III cln cancer patients. Other Cmments (e.g. any criticisms abut the study) - Other Imprtant Published Data: - Meta-analyses: Efficacy f adjuvant flururacil and flinic acid in cln cancer. Internatinal Multicentre Pled Analysis f Cln Cancer Trials (IMPACT) investigatrs. Lancet. 1995;345(8955):939. Gill S et al. Pled analysis f flururacil-based adjuvant therapy fr stage II and III cln cancer: wh benefits and by hw much? J Clin Oncl. 2004;22(10):1797. Sargent D et al. A pled analysis f adjuvant chemtherapy fr resected cln cancer in elderly patients. NEJM 2001; 345(15): Sargent D et al. Evidence fr cure by adjuvant therapy in cln cancer: Observatins based n individual patient data frm 20,898 patients n 18 randmized trials. JCO 2009;27(6): Other Imprtant Phase III clinical trials:

5 Ythers G et al. Oxaliplatin as adjuvant therapy fr cln cancer: updated results f NSABP C-07 trial, including survival and subset analyses. J Clin Oncl. 2011;29(28):3768. Haller DG et al. Capecitabine plus xaliplatin cmpared with flururacil and flinic acid as adjuvant therapy fr stage III cln cancer. J Clin Oncl. 2011;29(11):1465. Sargent D et al. Defective mismatch repair as a predictive marker fr lack f efficacy f flururacil-based adjuvant therapy in cln cancer. JCO 2010;28(20): Schmll H-J et al. Capecitabine plus xaliplatin (XELOX) versus blus 5- flururacil/leucvrin (5-FU/LV) as adjuvant therapy fr stage III cln cancer: survival fllw-up f study NO16968 (XELOXA). JCO 2012;30(suppl 4):388. Twelves et al. Capecitabine versus 5-flururacil/flinic acid as adjuvant therapy fr stage III cln cancer: final results frm the X-ACT trial with analysis by age and apreliminary evidence f a pharmacdynamics marker f efficacy. Ann Oncl 2012;23: LOCALIZED / ADJUVANT / LOCALLY ADVANCED RECTAL CANCER - Bttm Line General Apprach: Stage I: transabdminal resectin (AR, LAR r APR), n rle fr adjuvant therapy. - Stage II r III: Fr nn-fixed tumurs in the upper tw-thirds f the rectum: neadjuvant shrt-curse radiatin therapy (2500cGy in 5 fractins) LAR r APR within 10 days f first radiatin 6 mnths f adjuvant chemtherapy with capecitabine (fr stage II r III disease) r FOLFOX6 (fr stage III disease). FOLFOX6 is cnsidered ver capecitabine fr patients with nde-psitive disease. Hwever, if the patient presented with advanced clinical stage (bulky T grade r high N stage), but achieved gd dwnstaging, it is reasnable t cnsider either adjuvant capecitabine r FOLFOX6. Lng-curse chemraditherapy may als be used fr stage III disease. Fr fixed rectal tumurs appraching the mesrectal margin and fr tumurs in the distal ne-third f the rectum: neadjuvant lng-curse radiatin therapy (4500cGy in 25 fractins with a pssible bst f 540cGy in 3 fractins) with cncurrent chemtherapy LAR r APR within 6 t 10 weeks after cmpletin f neadjuvant therapy 4 mnths f adjuvant chemtherapy with capecitabine (fr stage II r III disease) r FOLFOX6 (fr stage III disease). FOLFOX6 is cnsidered ver capecitabine fr patients with ndepsitive disease. Hwever, if the patient presented with advanced clinical stage (bulky T grade r high N stage), but achieved gd dwnstaging, it is reasnable t cnsider either adjuvant capecitabine r FOLFOX6. Adjuvant chemtherapy shuld start within 4 weeks pst-p. If a patient with rectal cancer underges upfrnt resectin, referral t a Cancer Centre is recmmended fr cnsideratin f adjuvant chemraditherapy. Preperative versus pstperative chemraditherapy fr rectal cancer (The German Rectal Cancer Study) N Engl J Med. 2004;351(17):1731. Regimen Prep vs pstp chemraditherapy Chemraditherapy in bth grups cnsisted f: 5040 cgy f radiatin therapy (RT) plus 5-FU 1000mg/m2 during weeks 1 and 5 f RT. A bst f 540cGy f RT was added t the pstp grup. One mnth after surgery, fur 5-day cycles f 5-FU were given. 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Primary Endpint OS Inclusin/Exclusin Resectable rectal cancer with the inferir margin within 16cm frm the anal verge N prir chem r raditherapy

6 Age < 75 Size (N) 823 patients Results Survival: 5yr OS was NOT statistically significant (76% in prep treatment grup vs 74% in pstp treatment grup). DFS/PFS/TTP: 5yr DFS was NOT statistically significant (68% in prep treatment grup vs 65% in pstp treatment grup). Lcal Recurrence: The 5 yr incidence f lcal recurrence was 6% in the prep treatment grup and 13% in the pstp treatment grup. This was statistically significant. Quality f Life: nt reprted. Txicity Mre grade 3 r 4 acute txic effects (diarrhea, heme r derm txicities) ccurred with patients in the pstp treatment grup (40%) vs patients in the prep treatment grup (27%). Mre grade 3 r 4 lng term txic effects (GI txicities, strictures, bladder prblems) ccurred in the pstp treatment grup (24%) vs prep treatment grup (14%). Cnclusin Preperative chemrt imprved lcal cntrl and txicity when cmpared t pstp chemrt. N difference in OS. Other Cmments (e.g. any criticisms abut the study) Oxaliplatin added t flururacil-based preperative chemraditherapy and pstperative chemtherapy f lcally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results f the multicentre, pen-label, randmised, phase 3 trial Lancet Oncl Aug;16(8): Regimen Prep and pstp chemraditherapy with 5FU + raditherapy VS prep and pstp chemraditherapy with 5FU + xaliplatin + raditherapy Primary Endpint DFS Inclusin/Exclusin Chemraditherapy in the cntrl grup cnsisted f: 5040 cgy f radiatin therapy (RT) plus 5-FU 1000mg/m2 during weeks 1 and 5 f RT. Pstp chem cnsisted f blus 5-FU 500mg/m2 n days 1-5 and 29. Chemraditherapy in the experimental grup cnsisted f: 5040 cgy f radiatin therapy (RT) plus 5-FU 250mg/m2 n days 1-14 and and xaliplatin 50mg/m2 n days 1, 8, 22 and 29 prep. Pstp chem cnsisted f 8 cycles f xaliplatin 100mg/m2 n days 1 and 15, leucvrin 400mg/m2 n days 1 and 15 and infusinal flururacil 2400mg/m2 n days 1-2 and FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. ct3 r ct4 r cn1-2 rectal cancer with the inferir margin within 12cm frm the anal verge ECOG </= 2 N prir chem r raditherapy t the pelvis Age > 18 Patients with metastatic disease were excluded Size (N) 1265 patients Results Survival: 3yr OS was NOT statistically significant (88.7% in experimental grup vs 88.0% in the cntrl grup). DFS/PFS/TTP: 3yr DFS 76% vs 71% in experimental vs cntrl

7 grup (p = 0.03). Lcreginal Recurrence: The 3 yr incidence f lcal recurrence was 2.9% in the experimental grup and 4.6% in the cntrl grup. Quality f Life: nt reprted. Txicity Diarrhea, sensry neurpathy, fecal incntinence, anastmtic strictures Cnclusin The additin f xaliplatin t neadjuvant and adjuvant chemraditherapy significantly imprved DFS in ct3-4 r cn1-2 rectal cancers in cmparisn t the frmer 5-FU-based chemraditherapy regimen. Other Cmments (e.g. any criticisms abut the study) - Other Imprtant Published Data: - Meta-analyses: - Breugm et al. Adjuvant chemtherapy after preperative (chem)raditherapy and surgery fr patients with rectal cancer: a systematic review and meta-analysis f individual patient data. Lancet Oncl Feb;16(2): Maas et al. Adjuvant chemtherapy in rectal cancer: Defining subgrups wh may benefit after neadjuvant chemradiatin and resectin. Int. J. Cancer: 137, (2015). - Other Phase III clinical trials: Bsset JF et al. Flururacil-based adjuvant chemtherapy after preperative chemraditherapy in rectal cancer: lng-term results f the EORTC randmised study. Lancet Oncl Feb;15(2): Breugm A et al. Adjuvant chemtherapy fr rectal cancer patients treated with preperative (chem)raditherapy and ttal mesrectal excisin: a Dutch Clrectal Cancer Grup (DCCG) randmized phase III trial. Ann Oncl Apr;26(4): Hng et al. Oxaliplatin, flururacil, and leucvrin versus flururacil and leucvrin as adjuvant chemtherapy fr lcally advanced rectal cancer after preperative chemraditherapy (ADORE): an pen-label, multicentre, phase 2, randmised cntrlled trial. Lancet Oncl Oct;15(11): O'Cnnell MJ, Martensn JA, Wieand HS, Krk JE, Macdnald JS, Haller DG, et al. Imprving adjuvant therapy fr rectal cancer by cmbining prtracted-infusin flururacil with radiatin therapy after curative surgery. N Engl J Med 1994 Aug 25;331(8): Hfheinz RD, Wenz F, Pst S, Matzdrff A, Laechelt S, Hartmann JT, et al. Chemraditherapy with capecitabine versus flururacil fr lcally advanced rectal cancer: a randmised, multicentre, nn-inferirity, phase 3 trial. Lancet Oncl 2012 Jun;13(6): Imprved survival with preperative raditherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997 Apr 3;336(14): Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preperative raditherapy cmbined with ttal mesrectal excisin fr resectable rectal cancer. N Engl J Med 2001 Aug 30;345(9): METASTATIC COLORECTAL CANCER - Bttm Line General Apprach: A) Ptentially resectable patients - In select patients, segmental resectin f bstructing r bleeding clrectal primary lesins may be cnsidered. - Palliative raditherapy r steretactic bdy radiatin therapy (SBRT) may be cnsidered. - Liver-nly metastasis r slitary/lbe-cnfined pulmnary mets may be cnsidered fr resectin. Ptentially resectable patients may be treated with neadjuvant chemtherapy until ptimal resectability (please see Unresectable patients sectin fr pssible chemtherapy ptins in these patients). It is preferable t cnsider xaliplatin-based chemtherapy prir t liver metastasectmy as irintecan can cause steathepatitis, which can interfere with surgery.

8 Hwever, irintecan is NOT a cntraindicatin t surgery and can be used if the patient is ineligible fr xaliplatin-based treatment. A limited number f cycles f chemtherapy shuld be delivered t minimize the cnsequences t the liver and adverse effects. - The criteria fr liver resectin are: - at least 2 adjacent lbes (caudate lbe excluded) free f tumur, biliary drainage intact, arterial inflw, nn-thrmbsed prtal vein, 20% r mre liver functinal reserve. B) Unresectable patients - Upn diagnsis f metastatic disease, patients tumurs shuld be tested fr activating mutatins in Ras (Kras and Nras). Patients with knwn Ras mutatins shuld NOT be treated with the EGFR inhibitrs, Panitumumab r Cetuximab. - In patients with unresectable metastatic clrectal cancer, standard first-line palliative chemtherapy ptins are: FOLFIRI CAPOX and FOLFOX6 Capecitabine Irintecan 5-FU FOLFOX r FOLFIRI +/- EGFR inhibitr (Panitumumab r Cetuximab, ONLY in Ras wildtype patients) FOLFIRI +/- Bevacizumab. FOLFOX + Bevacizumab may be cnsidered in select cases. Bevacizumab may als be cnsidered in secnd-line chemtherapy fr thse wh did nt receive it first-line. Patients wh have prgressed n all standard chemtherapy may receive furth-line regrafenib r TAS The chice and sequence f palliative chemtherapy is determined by patient- and diseaserelated factrs, and patient preference as assessed by the medical nclgist. C) Sequential vs Cmbinatin Chemtherapy Strategies - Sequential chemtherapy cnsists f a flurpyrimidine mntherapy fllwed by either: Irintecan mntherapy OR Cmbinatin chemtherapy which cnsists f a dublet f a flurpyrimidine with irintecan r xaliplatin - There is a statistically significant difference in verall survival in favur f cmbinatin chemtherapy ver planned sequential chemtherapy. Hwever, the magnitude f this difference may nt be clinically significant. Additinally, sequential chemtherapy can minimize txicities. Therefre, sequential chemtherapy and upfrnt cmbinatin chemtherapy are bth acceptable standards f care and the chice shuld be made n a case-by-case basis. D) Intermittent vs Cntinuus Chemtherapy Strategies - Intermittent strategies f delivering first-line chemtherapy t patients with unresectable mcrc d nt result in a clinically significant reductin in verall survival and imprve r maintain quality f life in cmparisn t cntinuus chemtherapy. Therefre, cnsideratin f intermittent chemtherapy strategies shuld be part f an infrmed discussin with patients. - Prgnsis: Data frm the Surveillance, Epidemilgy, and End Results (SEER) database reprt 5 year survivals f: - Stage IV 8 percent - Imprtant Phase III Clinical Trials: i) First-line chemtherapy: Irintecan cmbined with flururacil cmpared with flururacil alne as first-line treatment fr metastatic clrectal cancer: a multicenter randmized trial. Duillard D et al. Lancet 2000; 355:

9 Regimen Cntrl: Flururacil + calcium flinate alne Experimental: Irintecan + flururacil + calcium flinate 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Irintecan binds t tpismerase t prevent religatin f the cleaved DNA strand, resulting in DNA breaks and ultimately, terminatin f cellular replicatin. Primary Endpint RR Inclusin/Exclusin Clrectal cancer ECOG 2 r less, life expectancy > 3 mnths N prir chemtherapy fr metastatic disease N CNS mets Adequate rgan functin Size (N) 387 patients Results Survival: mos 17.4 mnths vs 14.1 mnths (p=0.031) in experimental vs cntrl grups. PFS/TTP: mttp was 6.7 mnths vs 4.4 mnths (p<0.001) in experimental vs cntrl grups. Respnse Rate: 49 vs 31% (p<0.001) in experimental vs cntrl grup Quality f Life: There was a significantly later deteriratin in QOL in the irintecan grup. Txicity Grade 3-4 diarrhea, asthenia, neutrpenia and infectin with cncmitant grade 3-4 neutrpenia were significantly mre frequent and severe in the irintecan grup than in the n-irintecan grup Cnclusin First-line irintecan cmbined with flururacil and calcium flinate increased RR, TTP, and OS in patients with metastatic CRC. Other Cmments (e.g. criticisms abut the study) Leucvrin and flururacil with r withut xaliplatin as first-line treatment in advanced clrectal cancer. de Gramnt A et al. J Clin Oncl. 2000;18(16):2938. Regimen FOLFOX4 vs 5-FU/LV alne 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Primary Endpint PFS Inclusin/Exclusin Metastatic unresectable clrectal cancer ECOG 2 r less Age 18 t 75 N prir chemtherapy fr metastatic disease Adequate rgan functin N CNS mets r prir malignancies Size (N) 420 patients

10 Results Survival: mos was numerically better in FOLFOX4 grup (16.2 ms) vs 5-FU/LV alne grup (14.7 ms) but this was NOT statistically signicant. PFS/TTP: mpfs was statistically better in FOLFOX4 grup (9 ms) vs 5-FU/LV alne grup (6.2 ms). Respnse Rate: Objective RR was statistically better in FOLFOX4 grup (49.5%) vs 5-FU/LV alne grup (28.6%). Quality f Life: median QOL scres were cmparable fr bth grups. Txicity Grade 3/4 neutrpenia, diar- rhea, mucsitis, and neurpathy were mre frequent with FOLFOX4. Other grade ¾ txicities were typical 5-FU/LV and xaliplatin txicities. Cnclusin FOLFOX4 is beneficial 1 st -line therapy in mcrc with superir PFS and acceptable tlerability and QOL maintenance. Other Cmments (e.g. criticisms abut the study) Randmized phase III study f capecitabine plus xaliplatin cmpared with flururacil/flinic acid plus xaliplatin as first-line therapy fr metastatic clrectal cancer. Cassidy J et al. JCO 2008;26(12) Regimen Cntrl arm: FOLFOX-4 Experimental arm: XELOX Later amended after bevacizumab data became available t a 2x2 factrial design: - FOLFOX-4 + placeb vs FOLFOX-4 + bevacizumab - XELOX + placeb vs XELOX + bevacizumab 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Capecitabine: an ral prdrug f flururacil. Capecitabine is absrbed intact thrugh the intestinal wall and then cnverted t 5- FU thrugh three enzymatic reactins that take place in the liver, the GI tract and the tumur cell. The final enzymes are present in much higher levels in tumur cells than in nrmal tissue allwing fr enhanced tlerability. Flururacil inhibits thymidylate synthetase t inhibit DNA synthesis. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Primary Endpint PFS Inclusin/Exclusin Unresectable metastatic clrectal cancer ECOG 1 r less, life expectancy mre than 3 mnths N prir chem fr metastatic disease N CNS mets N full-dse anticagulatin r thrmblytics r serius nnhealing wund r severe prteinuria Patients at least 18 years f age Size (N) 634 patients in riginal tw-arm prtin, an additinal 1400 patients

11 after the start f the amended 2 x 2 design. Results Survival: median OS 19.8 mnths with XELOX vs 19.6 mnths with FOLFOX-4 nt significantly different PFS/TTP: median PFS 8.0 mnths with XELOX vs 8.5 mnths with FOLFOX nt significantly different Respnse Rate: XELOX 47% vs FOLFOX 48% nt significantly different Quality f Life: NR Txicity XELOX grup experienced mre grade 3 hand-ft syndrme and diarrhea while the FOLFOX-4 grup had mre grade 3 r 4 neutrpenia/granulcytpenia and febrile neutrpenia/sepsis. Cnclusin XELOX is nninferir t FOLFOX as first-line treatment fr mcrc and shuld be cnsidered in the apprpriate patients. Other Cmments (e.g. criticisms abut the study) ii) Chemtherapy sequencing FOLFIRI fllwed by FOLFOX6 r the reverse sequence in advanced clrectal cancer: a randmized GERCOR study. Turnigand C et al. J Clin Oncl. 2004;22(2):229. (Please als see the cmpanin trial: Clucci JCO 2005; 23(22): ). Regimen Arm A: FOLFIRI Arm B: FOLFOX6 At prgressin, irintecan was replaced by xaliplatin (arm A) r xaliplatin was replaced by irintecan (arm B). 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Irintecan binds t tpismerase t prevent religatin f the cleaved DNA strand, resulting in DNA breaks and ultimately, terminatin f cellular replicatin. Primary Endpint PFS, OS Inclusin/Exclusin Unresectable metastatic CRC ECOG 2 r less N prir chem fr metastatic disease N CNS mets Adequate rgan functin Size (N) 226 patients Results Survival: mos was 21.5 ms fr arm A vs 20.5 ms fr arm B (NOT statistically significant). PFS/TTP: median secnd PFS was 14.2 ms fr arm A vs 10.9 ms fr arm B (NOT statistically significant). Respnse Rate: In 1 st -line therapy, FOLFIRI achieved 56% RR and FOLFOX 54% RR. Quality f Life: nt reprted. Txicity FOLFIRI: mre grade 3 r 4 mucsitis, N/V and alpecia FOLFOX: mre grade 3 r 4 neutrpenia, and neursensry txicity Cnclusin Bth regimens and sequences achieved similar efficacy with different txicity prfiles.

12 Other Cmments (e.g. criticisms abut the study) iii) FOLFOXIRI Phase III trial f infusinal flururacil, leucvrin, xaliplatin, and irintecan (FOLFOXIRI) cmpared with infusinal flururacil, leucvrin, and irintecan (FOLFIRI) as first-line treatment fr metastatic clrectal cancer: the Grupp Onclgic Nrd Ovest. Falcne A et al. J Clin Oncl May 1;25(13): Regimen Arm A: FOLFOXIRI Arm B: FOLFIRI 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Irintecan binds t tpismerase t prevent religatin f the cleaved DNA strand, resulting in DNA breaks and ultimately, terminatin f cellular replicatin. Primary Endpint RR Inclusin/Exclusin Unresectable metastatic CRC N prir chem fr metastatic disease ECOG 2 r less Adequate rgan functin Size (N) 244 patients Results Survival: mos was 22.6 mnths v 16.7 mnths FOLFOXIRI v FOLFIRI, p = PFS/TTP: median PFS 9.8 mnths in FOLFOXIRI grup vs 6.9 mnths in FOLFIRI grup, p = Respnse Rate: 66% v 41% FOLFOXIRI v FOLFIRI, p = Quality f Life: nt significant difference between the tw arms. Txicity Increased grade 2 t 3 peripheral neurtxicity and grade 3 t 4 neutrpenia in the FOLFOXIRI arm. Cnclusin Bth regimens and sequences achieved similar efficacy with different txicity prfiles. Other Cmments (e.g. criticisms abut the study) iv) Surgical candidates Periperative chemtherapy with FOLFOX4 and surgery versus surgery alne fr resectable liver metastases frm clrectal cancer (EORTC Intergrup trial 40983): a randmised cntrlled trial Nrdlinger B et al. Lancet 2008 Mar 22;371(9617):

13 Regimen surgery alne vs 6 cycles f FOLFOX4 surgery 6 cycles f FOLFOX4 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Primary Endpint PFS (HR 0.71 r less) Inclusin/Exclusin Age 18 t 80 years, ECOG 2 r less Histlgically-prven clrectal cancer with ne t fur liver mets that were ptentially resectable and n detectable extrahepatic tumur Primary tumur had t either be already resected (R0 resectin) r judged t be resectable by the hspital multidisciplinary team N prir xaliplatin-based chemtherapy N prir majr liver disease, significant peripheral neurpathy r ther significant majr rgan dysfunctin (detailed in riginal paper). Size (N) 364 patients Results Survival: nt reprted PFS/TTP: median PFS 18.7ms fr perip chem grup vs 11.7 ms fr surgery alne grup Respnse Rate: nt reprted Quality f Life: nt reprted Txicity Reversible pstp cmplicatins ccurred significantly mre frequently in the perip chem grup than in the surgery alne grup. In the perip chem grup, typical FOLFOX chem adverse effects were seen: grade 3 diarrhea, grade 3 stmatitis, grade 3 r 4 neutrpenia, grade 3 sensry neurpathy Cnclusin Perip chemtherapy with FOLFOX4 is cmpatible with liver tumur resectin and imprves PFS in eligible and resected patients. Other Cmments (e.g. criticisms abut the study) v) Bilgic therapy - Anti-VEGF Inhibitrs: Bevacizumab plus Irintecan, Flururacil, and Leucvrin fr Metastatic Clrectal Cancer Hurwitz H et al. N Engl J Med. 2004;350(23):2335.

14 Regimen Irintecan/blus 5-FU/LV plus bevacizumab vs irintecan/blus 5- FU/LV plus placeb 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Bevacizumab: Recmbinant humanized mnclnal antibdy which binds t and inhibits VEGF effectively inhibiting angigenesis and retarding cell grwth in all tissue. Primary Endpint OS Inclusin/Exclusin metastatic CRC ECOG 0 r 1 Age >/= 18 N prir chem r bilgic therapy fr metastatic disease Adequate rgan functin Size (N) 813 patients Results Survival: mos 20.3 ms with bevacizumab vs 15.6 ms withut PFS/TTP: mpfs 10.6ms with bevacizumab vs 6.2 withut Respnse Rate: Overall RR 44.8% with bev vs 34.8% withut Quality f Life: nt reprted Txicity Grade 3 r 4 txicities were higher in the bev grup because f HTN, diarrhea and leukpenia. The ther well-knwn bevacizumab adverse effects (such as prteinuria, GI perfratin, arterial-venus thrmbsis and pr wund healing) ccurred at similar rates in bth grups. Cnclusin Bevacizumab added t 5-FU-based cmbinatin chem results in imprved OS in patients with mcrc. Other Cmments (e.g. criticisms abut the study) Bevacizumab in cmbinatin with xaliplatin-based chemtherapy as first-line therapy in metastatic clrectal cancer: a randmized phase III study. Saltz et al. J Clin Oncl Apr 20;26(12): Regimen 2x2 factrial design: Arm A: XELOX + placeb Arm B: XELOX + bevacizumab Arm C: FOLFOX4 + placeb Arm D: FOLFOX4 + bevacizumab 5-FU: Pyrimidine analg antimetablite that inhibits thymidylate synthetase t deplete thymidine triphsphate and hence, inhibit DNA synthesis. Leucvrin allws 5-FU t frm a stable ternary cmplex with thymidylate synthetase t prlng inhibitin f the enzyme by 5- FU. Bevacizumab: Recmbinant humanized mnclnal antibdy which binds t and inhibits VEGF effectively inhibiting angigenesis and retarding cell grwth in all tissue. Oxaliplatin: alkylating agent that binds t DNA frming crss-links which inhibit DNA replicatin and transcriptin, resulting in cell death. Primary Endpint PFS Inclusin/Exclusin metastatic unresectable CRC ECOG 0 r 1, life expectancy > 3 mnths Age >/= 18

15 N prir systemic therapy fr mcrc r prir xaliplatin r bevacizumab Adequate rgan functin N CNS mets N serius nnhealing wund, significant prteinuria r use f fulldse anticagulants/thrmblytics Size (N) 1401 patients Results Survival: mos 21.3 ms in the bevacizumab grup vs 19.9 ms in the placeb grup, p=0.077 PFS/TTP: mpfs 9.4 in bevacizumab grup vs 8.0 mnths in the placeb grup, p= Respnse Rate: 47% vs 49% in the bevacizumab + chem grup vs placeb + chem grups, respectively, p=0.31. Quality f Life: nt reprted Txicity Grade 3 r 4 txicities were similar in bth arms. Bevacizumab txicities were higher in the bevacizumab arms (16% and 8%). Cnclusin Bevacizumab added t xaliplatin-based chem results in imprved PFS in the first-line setting in patients with mcrc. Other Cmments (e.g. criticisms abut the study) - EGFR-inhibitrs Wild-type KRAS is required fr panitumumab efficacy in patients with metastatic clrectal cancer. Amad RG et al. J Clin Oncl. 2008;26(10):1626. Regimen Panitumumab (P-mab) 6mg/kg plus best supprtive care (BSC) q 2 weeks vs BSC Panitumumab: recmbinant human IgG2 mnclnal antibdy that binds t EGFR cmpetitively inhibiting the binding f EGF t ther ligands. This results in inhibitin f cell grwth, prliferatin and survival. KRAS is a G-prtein dwnstream f EGFR and cells with RAS mutatins are unaffected by EGFR inhibitin. Primary Endpint PFS Inclusin/Exclusin metastatic CRC ECOG 2 r less Age >/= 18 Tw r three prir chemtherapy regimens fr metastatic CRC 1% r mre EGFR-psitive membrane staining in evaluated tumur cells N prir CNS mets Adequate rgan functin Size (N) 427 patients included in KRAS analysis Results Survival: N statistically significant difference was seen amng treatment arms (HR 0.97). With the treatment arms cmbined, wildtype KRAS patients had lnger OS (HR 0.67). PFS/TTP: mpfs in the wildtype KRAS grup was 12.3 weeks fr P- mab vs 7.3 weeks fr BSC. Respnse Rate: RR t P-mab was 17% in the wildtype KRAS grup vs 0% in the mutant KRAS grup. Quality f Life: nt reprted. Txicity Mre grade III diarrhea and rash were seen in P-mab grup Cnclusin Panitumumab mntherapy efficacy in mcrc is restricted t patients with wildtype KRAS tumurs. Patients shuld underg KRAS tumur testing prir t cnsidering P-mab therapy. Other Cmments (e.g. criticisms abut the study)

16 K-ras Mutatins and Benefit frm Cetuximab in Advanced Clrectal Cancer Karapetis et al. NEJM 2008;359: Regimen Arm A: Cetuximab + best supprtive care (BSC) Arm B: BSC alne Cetuximab: recmbinant IgG1 human/muse chimeric mnclnal antibdy that binds t EGFR cmpetitively inhibiting the binding f EGF t ther ligands. This results in inhibitin f cell grwth, prliferatin and survival. KRAS is a G-prtein dwnstream f EGFR and cells with RAS mutatins are unaffected by EGFR inhibitin. Primary Endpint OS Inclusin/Exclusin metastatic CRC expressing EGFR ECOG 2 r less Age >/= 18 Prir chemtherapy with a flurpyrimidine, irintecan, and xaliplatin with n respnse t treatment r had cntraindicatins t treatment with these drugs N prir EGFR inhibitr N prir CNS mets Adequate rgan functin Size (N) 572 randmized Results Survival: In patients with wild-type K-ras tumurs, median OS was 9.5 mnths in the cetuximab grup vs 4.8 mnths in the BSC alne grup, p<0.001). PFS/TTP: mpfs in the wildtype KRAS grup was 3.7 mnths vs 1.9 mnths, p< Respnse Rate: In the cetuximab grup, RR was 12.8% amng patients with wild-type K-ras tumurs vs 1.2% in patients with mutated K-ras tumurs. Quality f Life: Patients with wild-type K-ras tumurs wh received cetuximab had imprvement in glbal health status in cmparisn t BSC alne grup. There was n difference in QOL between the cetuximab and BSC alne grups in the mutated K-ras patients. Txicity Mre rash was seen in cetuximab grup Cnclusin Patients with a clrectal tumur bearing wild-type K-ras had imprved survival with cetuximab therapy while patients with a K-ras mutated clrectal tumur did nt benefit frm cetuximab. The mutatin status f the K-ras gene did nt impact survival in patients treated with BSC alne. Other Cmments (e.g. criticisms abut the study) Panitumumab versus cetuximab in patients with chemtherapy-refractry wild-type KRAS exn 2 metastatic clrectal cancer (ASPECCT): a randmized, multicenter, pen-label, nn-inferirity phase 3 study Price TJ et al. Lancet Oncl 2014;15:

17 Regimen Panitumumab (P-mab) 6mg/kg vs Cetuximab 400mg/m2; 250mg/m2 nce a week thereafter. Panitumumab: recmbinant human IgG2 mnclnal antibdy that binds t EGFR cmpetitively inhibiting the binding f EGF t ther ligands. This results in inhibitin f cell grwth, prliferatin and survival. KRAS is a G-prtein dwnstream f EGFR and cells with RAS mutatins are unaffected by EGFR inhibitin. Cetuximab: recmbinant IgG1 human/muse chimeric mnclnal antibdy that binds t EGFR cmpetitively inhibiting the binding f EGF t ther ligands. This results in inhibitin f cell grwth, prliferatin and survival. KRAS is a G-prtein dwnstream f EGFR and cells with RAS mutatins are unaffected by EGFR inhibitin. Primary Endpint OS fr nn-inferirity Inclusin/Exclusin Chemtherapy-refractry metastatic CRC ECOG 2 r less Age >/= 18 Wild-type KRAS exn 2 status Adequate rgan functin Size (N) 1010 patients Results Survival: 10.4 mnths fr P-mab vs 10.0 mnths fr cetuximab. P- mab was nn-inferir t cetuximab. PFS/TTP: mpfs 4.1 mnths fr P-mab vs 4.4 mnths fr cetuximab. Respnse Rate: RR t P-mab was 22% vs 19.8% in the cetuximab grup. Quality f Life: QOL was similar fr bth grups. Txicity Mre grade III rash and hypmagnesemia were seen in P-mab grup (62% vs 48%). Lwer infusin reactins in the P-mab grup. Cnclusin Panitumumab is nninferir t cetuximab and these therapies prvide similar verall survival benefit. Other Cmments (e.g. criticisms abut the study) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment fr patients with metastatic clrectal cancer (FIRE-3): a randmised, pen-label, phase 3 trial. Lancet Oncl Sep;15(10): Regimen Arm A: FOLFIRI + cetuximab Arm B: FOLFIRI + bevacizumab Cetuximab: recmbinant IgG1 human/muse chimeric mnclnal antibdy that binds t EGFR cmpetitively inhibiting the binding f EGF t ther ligands. This results in inhibitin f cell grwth, prliferatin and survival. KRAS is a G-prtein dwnstream f EGFR and cells with RAS mutatins are unaffected by EGFR inhibitin. Bevacizumab: Recmbinant humanized mnclnal antibdy which binds t and inhibits VEGF effectively inhibiting angigenesis and retarding cell grwth in all tissue. Primary Endpint Objective respnse Inclusin/Exclusin metastatic CRC ECOG 2 r less, life expectancy > 3 mnths Age >/= 18 Wild-type KRAS exn 2 status N prir chemtherapy fr clrectal cancer except fr adjuvant therapy N prir EGFR-targeting agent r bevacizumab N CNS mets Adequate rgan functin

18 N serius nnhealing wund, significant prteinuria r use f fulldse anticagulants/thrmblytics Size (N) 592 patients Results Survival: mos 28.7 mnths in the cetuximab grup vs 25.0 mnths in the bevacizumab grup, p= PFS/TTP: mpfs 10.0 mnths in the cetuximab grup vs 10.3 mnths in the bevacizumab grup, p=0.55. Respnse Rate: bjective RR was 62% in cetuximab grup vs 58% in bevacizumab grup, p=0.18. Quality f Life: QOL was similar fr bth grups. Txicity Mst cmmn grade 3 r wrse adverse event were hemattxicity, skin reactins and diarrhea. Cnclusin Despite similar bjective respnse rates, mos was higher in the cetuximab grup suggesting that this may be the preferred first-line regimen in patients with KRAS exn 2 wild-type mcrc. Other Cmments (e.g. criticisms abut the study) CALGB/SWOG abstract: Phase III trial f FOLFIRI r FOLFOX with Bevacizumab r Cetuximab fr patients with KRAS wild type untreated metastatic adencarcinma f the cln r rectum Venk A et al. Presented at ASCO Regimen Arm A: FOLFOX/FOLFIRI + Bevacizumab Arm B: FOLFOX/FOLFIR + Cetuximab Bevacizumab: Recmbinant humanized mnclnal antibdy which binds t and inhibits VEGF effectively inhibiting angigenesis and retarding cell grwth in all tissue. Cetuximab: recmbinant IgG1 human/muse chimeric mnclnal antibdy that binds t EGFR cmpetitively inhibiting the binding f EGF t ther ligands. This results in inhibitin f cell grwth, prliferatin and survival. KRAS is a G-prtein dwnstream f EGFR and cells with RAS mutatins are unaffected by EGFR inhibitin. Primary Endpint OS Inclusin/Exclusin Untreated metastatic CRC Tumur KRAS wild-type cdns 12 & 13 ECOG 1 r less Age >/= 18 Adequate rgan functin Size (N) 1137 patients Results Survival: Interim analysis - mos 29.9 mnths fr cetuximab grup vs 29.0 mnths fr bevacizumab grup, p=0.34. PFS/TTP: Interim analysis - mpfs 10.4 mnths fr cetuximab vs 10.8 mnths fr bevacizumab, p=0.55. Respnse Rate: Interim analysis ORR 66% fr cetuximab grup vs 57% fr bevacizumab grup. Quality f Life: Higher skin-related QOL scres in bevacizumab grup, p < Txicity Mre grade III rash and diarrhea were seen in cetuximab grup. Mre HTN and VTE in bevacizumab grup. Cnclusin OS is similar in chem/cetuximab and chem/bevacizumab grups in first-line treatment fr patients with KRAS wild-type (cdns 12&13) mcrc. Other Cmments (e.g. criticisms abut the study) vi) Treatment-resistant mcrc

19 Regrafenib mntherapy fr previusly treated metastatic clrectal cancer (CORRECT): an internatinal, multicentre, randmised, placeb-cntrlled, phase 3 trial. Grthey A, et al. Lancet. 2013;381(9863): Regimen Regrafenib 160mg p d plus best supprtive care (BSC) vs BSC plus placeb Regrafenib: a multikinase inhibitr that targets kinases invlved in angigenesis and ncgenesis. The kinases regrafenib targets are: EGF receptrs 1-3, KIT, PDGFR-alpha, PDGFR-beta, RET, FGFR1 and 2, TIE2, DDR2, TrkA, Eph2A, RAF-1. BRAF, BRAFV600E, SAPK2, PTK5, and Abl. Primary Endpint OS Inclusin/Exclusin metastatic CRC ECOG 0 r 1 Age >/= 18 Patients had t have received standard chemtherapy fr mcrc and prgressed within 3 mnths f receiving standard therapy, r have stpped therapy secndary t txicity. Adequate rgan functin Size (N) 760 patients Results Survival: mos 6.4ms in regrafenib grup vs 5.0 ms in placeb grup. PFS/TTP: mpfs was 1.9 ms in regrafenib grup vs 1.7ms in placeb grup. Respnse Rate: bjective RR 1.0% in regrafenib grup vs 0.4% in placeb grup Quality f Life: Bth grups demnstrated a deteriratin in QOL. Txicity Cmmn grade 3 r mre adverse effects in the regrafenib grup were: rash, fatigue, diarrhea, hand-ft syndrme, and HTN. Cnclusin Regrafenib shws survival benefit in patients with mcrc wh have prgressed n all standard therapies. Other Cmments (e.g. criticisms abut the study) Randmized Trial f TAS-102 fr Refractry Metastatic Clrectal Cancer. Mayer RJ et al. N Engl J Med May 14;372(20): Regimen Arm A: TAS mg/m2 bid q4wks + BSC Arm B: Placeb + BSC TAS-102: Cmpsed f trifluridine and tipiracil. Trifluridine is the active cyttxic cmpnent and is a thymidine-based nucleic acid analgue that is incrprated int DNA t interfere with DNA synthesis and inhibit cell prliferatin. Tipiracil is a thymidine phsphrylase inhibitr that prevents the rapid degradatin f trifluridine, allwing fr greater trifluridine expsure in the cell. Primary Endpint OS Inclusin/Exclusin metastatic CRC ECOG 2 r less Age >/= 18 2 r mre prir regimens. Refractry/intlerant f: flurpyrimidine, irintecan r xaliplatin Adequate rgan functin Size (N) 800 patients Results Survival: mos 7.1 mnths in TAS-102 arm vs 5.3 mnths in placeb arm, p<0.0001

20 PFS/TTP: mpfs was 2.0 ms in TAS-102 grup vs 1.7ms in placeb grup, p< Respnse Rate: Quality f Life: Txicity Nausea, vmiting, decreased appetite, fatigue, diarrhea, cytpenias, elevated liver enzymes Cnclusin TAS-102 significantly imprves verall survival in cmparisn t placeb in patients with refractry mcrc. Other Cmments (e.g. criticisms abut the study) - Other Imprtant Published Data: (e.g. meta-analysis, retrspective analyses, phase II) Meta-analysis studying the sequence f therapies in mcrc - Asmis T et al. Strategies f sequential therapies in unresectable mcrc: a meta-analysis. Curr Oncl, Vl 21, pp Phase II trial studying immuntherapy in mcrc - Le et al. PD-1 Blckade in Tumrs with Mismatch-Repair Deficiency. NEJM 2015;372: Awaiting the results f KEYNOTE-164, a Phase II study f Pembrlizumab as mntherapy in patients with refractry mcrc that is mismatch repair deficient r micrsatellite instability-high. - Other imprtant Phase III studies in mcrc: Anther trial cmparing capecitabine t 5-FU/LV in mcrc - Hff PM et al. Cmparisn f ral capecitabine versus intravenus flururacil plus leucvrin as firstline treatment in 605 patients with metastatic clrectal cancer: results f a randmized phase III study. J Clin Oncl. 2001;19(8):2282. Cunningham D et al. Randmised trial f irintecan plus supprtive care versus supprtive care alne after flururacil failure fr patients with metastatic clrectal cancer. Irintecan as a single agent - Lancet. 1998;352(9138): ) Other first line chemtherapy trials: Trials establishing FOLFIRI in 1 st -line mcrc: Saltz LB et al. Irintecan plus flururacil and leucvrin fr metastatic clrectal cancer. Irintecan Study Grup. N Engl J Med. 2000;343(13):905. Köhne CH et al. Phase III study f weekly high-dse infusinal flururacil plus flinic acid with r withut irintecan in patients with metastatic clrectal cancer: Eurpean Organisatin fr Research and Treatment f Cancer Gastrintestinal Grup Study J Clin Oncl. 2005;23(22):4856. Trials establishing FOLFOX in 1 st -line mcrc: - Gldberg RM et al. A randmized cntrlled trial f flururacil plus leucvrin, irintecan, and xaliplatin cmbinatins in patients with previusly untreated metastatic clrectal cancer. J Clin Oncl Jan 1;22(1): Cmpanin trial t the Turnigand trial establishing FOLFIRI/FOLFOX in the 1 st line setting: - Clucci G et al. Phase III randmized trial f FOLFIRI versus FOLFOX4 in the treatment f advanced clrectal cancer: a multicenter study f the Grupp Onclgic Dell'Italia Meridinale. JCO 2005;23(22) ) Other capecitabine cmbinatin trials: Fuchs CS et al. Randmized, cntrlled trial f irintecan plus infusinal, blus, r ral flurpyrimidines in first-line treatment f metastatic clrectal cancer: results frm the BICC-C Study. J Clin Oncl. 2007;25(30):4779.

21 Prschen et al. Capecitabine plus xaliplatin cmpared with flururacil and leucvrin plus xalitain: a randmized cmparisn in mcrc-a final reprt f the AIO Clrectal Study Grup. JCO 2007;25: Diaz-Rubi E et al. Phase III study f capecitabine plus xaliplatin versus cntinuus infusin flururacil plus xaliplatin as first-line therapy in mcrc: final reprt f the Spanish Cperative Grup fr the Treatment f Digestive Tumurs trial. JCO 2007;25: Cmella P et al. Randmised trial cmparing biweekly xaliplatin plus ral capecitabine versus xaliplatin plus i.v. blus flururacil/leucvrin in mcrc patients: results f the Suthern Italy Cperative Onclgy study J Cancer Res Clin Oncl 2009;135: Rthenberg et al. Capecitabine plus xaliplatin (XELOX) versus 5- flururacil/flinic acid plus xaliplain (FOLFOX-4) as secnd-line therapy in mcrc: a randmized phase III nninferirity study. Ann Oncl 2008;19: ) Other FOLFOXIRI trial Suglaks J et al. FOLFOXIRI (flinic acid, 5-flururacil, xaliplatin and irintecan) vs FOLFIRI (flinic acid, 5-flururacil and irintecan) as first-line treatment in metastatic clrectal cancer (MCC): a multicentre randmised phase III trial frm the Hellenic Onclgy Research Grup (HORG). Br J Cancer 2006; 94(6) ) Cntinuus vs Intermittent chemtherapy: This table shws the imprtant clinical trials studying cntinuus vs intermittent chemtherapy strategies in mcrc patients (curtesy f Dr. Sctt Berry): Maughan BMJ 2003 Labianca Ann Oncl 2011 Alexpuls ASCO 2006 Chibaudel ( OPTIMOX2 ) JCO 2009 Adams ( COIN ) Lancet 2011 Kpman ( CAIRO3 ) ASCO 2014 Turnigand ( OPTIMOX1 ) JCO 2006 Grthey ( CONCEPT ) ASCO 2008 n Inductin/Cntinuus Tx 354 5FU Maintenance Tx Primary Outcme OS 337 FOLFIRI OS Nne 216 FOLFOX DDC OS HR (95% CI) 0.87 ( ( p=ns 0.91 ( ) p=nr 39 FOLFIRI NR Nt available 1630 Cape/FOLFOX OS 558 CapeOx+Bev PFS2 620 FOLFOX 5FU DDC 1.14 ( ) p=ns 1.08 ( ) p=nr 1.12 ( ) p=ns 0.93 ( ) p=ns 180 FOLFOX + Bev TTF Nt available Diaz-Rubi ( MACRO ) Onclgist 2012 Tveit ( NORDIC VII ) 480 FOLFOX + Bev Bev PFS 372 Nrdic FLOX + Cetuximab Cetuximab PFS 1.05 ( ) p=ns 1.03 ( ) p=ns