1、Chemotherapy for Metastatic Colon Cancer,Scott Berry Sunnybrook Health Sciences Centre,Where Were We Until 2000?,N H,HN,O,O,F,5-FU,FOLFOX,FOLFIRI,IFL,bevacizumab,cetuximab,PTK 787,Capecitabine,Panitumumab,OS for 1st line Combinations,5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de Gramont) IFL (Gold
2、berg) IFL (Saltz) FOLFIRI (Douillard) FOLFOX (de Gramont) FOLFOX (Goldberg) IFL+ Bevacizumab,0 5 10 15 20 25,Median OS (months),Overview/Objectives,Review key evidence from randomized trials evaluating the chemotherapies and chemotherapy strategies that have emerged for metastatic colorectal cancer
3、looking at both: Efficacy Safety Key Strategies and Questions: Which doublet should be used? ? Should we be using triplet therapy Can capecitabine replace infusional 5FU in doublets? Can sequential monotherapy replace initial doublet therapy? Can toxicity be reduced and efficacy maintained with “on/
4、off” chemotherpay strategies?,Chemotherapy,Case,50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases ECOG 1 some RUQ pain and coughWhat is the optimal chemotherapy choice for her?,CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI,Efficacy of
5、Chemotherapy in First-Line CRC: Phase III Trial Results,Saltz et al. N Engl J Med. 2000;343:905; Douillard et al. Lancet. 2000;355:1041; de Gramont et al. J Clin Oncol. 2000;18:2938,CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI,Phase III Intergroup N9741 Study (Goldberg JCO, 2004),R A N D O
6、 M I Z A T I O N,Irinotecan + Oxaliplatin,IFL,FOLFOX 4,Phase II Sequential,Randomized CrossoverStudy,Tournigand et al JCO 2004,FOLFIRI,FOLFOX 6,N9741/Tournigand Trial: Results,Tournigand Trial: Results,Curative Surgery Rate: 22% FOLFOX , 9% FOLFIRI,FOLFIRI,FOLFOX,0,10,20,30,F. neutropenia,Nausea,Vom
7、iting,Diarrhea,Paresthesia,%,7%,13%,0%,3%,14%,11%,10%,3%,3%,34%,40,Tournigand Toxicity grade 3,P0.05 for Comparisons marked by arrows,Alopecia Any grade 60% vs 28%60-day Mortality: 4% vs 3%,Combination Chemotherapy - Summary,Combination chemotherapy with FOLFIRI or FOLFOX are both acceptable first l
8、ine chemotherapy regimens for people with metastatic colorectal cancerFollow by alternate combination (or single agent Irinotecan after FOLFOX)Considerations: Toxicity profile ? Considering surgery : FOLFOX based on “circumstantial” evidence,2nd Line FOLFOX,FOLFOX 4,OXALI,n=463 2nd line mCRC post IF
9、L,DE GRAMONT,Rothenberg JCO 2003,CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI,Overall survival,Integrated CRC,Capecitabine (n=603)5-FU/LV (n=604),13.1,13.1,0 5 10 15 20 25 30,Time (months),Estimated probability,1.0 0.8 0.6 0.4 0.2 0,What About Capecitabine As a Partner?,Capecitabine + Irin
10、otecan,BICC-C study,FOLFIRI +/- celecoxib,CAPIRI (Cape 1000mg/m2 d1-14) +/- celecoxib,n=430 1st line mCRC,mIFL +/- celecoxib,Slide Courtesy D Jonker from data presented at ASCO 2007,EORTC 40015 study,FOLFIRI +/- celecoxib,CAPIRI (Cape 1000mg/m2 bid x14d)+/- celecoxib,n=85 1st line CRC,Celecoxib vs P
11、lacebo : No Survival difference,Slide Courtesy D Jonker,What About Capecitabine As a Partner?,Capecitabine + Oxaliplatin,Capecitabine + Oxaliplatin Randomized Trials : Efficacy,Second Line,First Line,Capecitabine + Oxaliplatin Randomized Trials : Toxicity,Second Line,First Line,Can Capecitabine Repl
12、ace Infusional 5FU in mCRC?,Capecitabine and Irinotecan At doses studied CapeIri is more toxic and less effective than FOLFIRICapecitabine and Oxaliplatin CapeOx has same efficacy as FOLFOX Differential toxicity profile between CapeOx and FOLFOX,CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI
13、,Triplet Therapy,5-FU/IRI vs FOLFOXIRI: Falcone et al N = 244,FOLFOXIRI,5-FU/Iri Douillard,Randomization,Slide Courtesy of R Goldberg,FOLFOXIRI Schedule,5FU flat continuous infusion 3200mg/m2,L-LV 200 mg/m2,Oxaliplatin 85 mg/m2,2 hours,Repeated every 14 days,CPT-11 165 mg/m2,48 hours,Day 1 Day 2 Day
14、 3,1 hour,Slide Courtesy of R Goldberg,Efficacy,Slide Courtesy of R Goldberg,* p=0.017,Post-ChemoRx Resections (patients with liver mts only),Slide Courtesy of R Goldberg,Grade 3-4 Toxicity,(N=122),(N=122),p =0.0006,Slide Courtesy of R Goldberg,Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.,
15、Survival improves with availability of three active drugs,*,FOLFOXIRI,P=0.0001,Is FOLFOXIRI more active than 5-FU/IRI? Yes, including better resection rates But is comparator arm inferior? More toxic,Monotherapy,Overall survival,Integrated CRC,Capecitabine (n=603)5-FU/LV (n=604),13.1,13.1,0 5 10 15
16、20 25 30,Time (months),Estimated probability,1.0 0.8 0.6 0.4 0.2 0,Monotherapy versus doublets,? Have 3 active chemo agents in mCRC Lead with combination ? Can we use agents sequentially and maintain efficacy and reduce toxicityFOCUS and CAIRO Do both have fatal flaws?,FOCUS,Lancet, 2008,2,135 Untre
17、ated Stage IV patients,A: 5 FU/LV (de Gramont),C: FOLFOX vs FOLFIRI,B: 5 FU/LV (de Gramont),RANDOMI SAT ION,FOCUS UK MRC CR08,IRI,FOLFOX or FOLFIRI,FOCUS UK MRC CR08,Breaks allowed Not before 3 mos Only 4 weeks in 2nd 3 mos After that allowed with re-start of previous regimen as long as progression
18、hadnt occurred within 12 weeks of stopping,FOCUS UK MRC CR08,Up to Dec 02 , recommended salvage in all groups Infusional 5FU and Mit-C Since Dec 02, “balanced salvage“ with CapOx or CapIri Primary Endpoint: Survival,Survival,Table 4,FOCUS,QOL,Mean overall QOL : varied little between arms and regimen
19、s In particular, no differences seen at 3 and 6 mos,FOCUS,Conclude that sequential strategy is a valid option Median Survivals of all arms inferior to FOLFOX arm of N9741 and both arms of Tournigand trial ? Seeing an effect of restricting access to all 3 drugs,Percentage of Patients Receiving All 3
20、Active Drugs,FOCUS,Grothey, JCO, 2004,CAIRO,Randomized study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer,a study of the Dutch Colorectal Cancer Group (DCCG),CJA Punt, M Koopman, J Douma, J Wals, AH Honkoop FLG Erdkamp, RS
21、de Jong, CJ Rodenburg, L Mol, NF Antonini ASCO 2007,CAIRO study CKTO 2002-07,Dose/schedule of drugs all cycles given 3 weekly,Capecitabine monotherapy: 1250 mg/m2 b.i.d. day 1-14 Irinotecan monotherapy: 350 mg/m2 day 1CAPIRI1: capecitabine 1000 mg/m2 b.i.d. day 1-14 + irinotecan 250 mg/m2 day 1CAPOX
22、2: capecitabine 1000 mg/m2 b.i.d. day 1-14 + oxaliplatin 130 mg/m2 day 1,1 Rea et al. Ann Oncol 2005 2 Borner et al. J Clin Oncol 2002,Trial profile,Median overall survival,p = 0.33,Efficacy results,Grade 3-4 toxicities in first line,Quality of life,Participation to this part of the study was propos
23、ed to the first 620 patients entered in the study (QLQ-C30 questionnaire of the EORTC) 403 patients were evaluable for quality of lifeQuality of life scores were comparable between the two arms, except for diarrhoea which was reported more frequently in combination treatment,Conclusions,Combination
24、treatment is not superior in terms of efficacy to sequential treatment in patients with advanced colorectal cancerOur results on median overall survival for sequential treatment are the highest reported when a fluoropyrimidine is administered as monotherapy in 1st lineSequential treatment is a usefu
25、l alternative for combination treatment Our results may be useful for strategies in which chemotherapy is combined with targeted agents,What about use of CapeIri?,62,Back to CAIRO,PFS Capeiri in CAIRO similar to FOLFIRI in BICC-C But OS of 17 mos is less than weve come to expect in sequential double
26、ts Cross trial comparisons CapeIri in CAIRO better tolerated than CapeIri in BICC-C or EORTC trial except for high rates of diarrhea ( double that seen with FOLFIRI in Tournigand or BICC-C)Would Combination arm in CAIRO have done better if FOLFIRI used? No one knows.,63,? Reasons for Results,? Geogr
27、aphic differences in capecitabine metabolism Similar results in Europe ? Celecoxib Results not published for BICC-C? Different dose of cape do better Maybe but not used in this trial,64,Summary,Both CAIRO and FOCUS validate a sequential approach within the context of their study parameters? Would th
28、ey have done so if FOCUS had allowed better access to all 3 chemo drugs and CAIRO had used FOLFIRI?,65,Is Less Chemo More?,Case,50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases ECOG 1 some RUQ pain and coughShe agrees to chemotherapy but asks
29、if there is anyway she can take a break during chemo without reducing the benefits of chemo?,Which of the following strategies has been shown to reduce toxicity without impacting on efficacy?,Induction of FOLFOX for 3 mos followed by infusional 5FU maintanence then reintroduce FOLFOXInduction of FOL
30、FOX for 3 mos followed by no maintanence (complete chemo break) then reintroduce FOLFOX FOLFIRI on for 2 mos, off for 2 mos,Stop and Go concept - OPTIMOX1,Tournigand et al, JCO 2006,(%) FOLFOX4 FOLFOX7 RR 58.5 58.3 PFS 9.0 8.7 DDC 9.0 10.6 OS 19.3 21.2 G3/4 NTox 17.9 13.3,Primary endpoint,F. Maindra
31、ult-Gbel, G. LLedo, B. Chibaudel, L. Mineur, T. Andr, M. Bennamoun, M. Mabro, P.Artru, C. Louvet, A. de Gramont,OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study.,OP
32、TIMOX Studies,OPTIMOX-1,FOLFOX 4 until TF,FOLFOX 7,FOLFOX 7,sLV5FU2,Baseline Progression,t,T size,FOLFOX,FOLFOX,Progression,Baseline progression,Progression at reintroduction,Chemotherapy-free Interval,Duration of Disease Control,t,T size,FOLFOX,FOLFOX,PFS 1,Progression,Baseline progression,PFS 2,Pr
33、ogression at reintroduction,DDC = PFS 1 + PFS 2 (if no PD),ASCO 2001, 146a,Neuropathy,Grade 1 8 %2 21.2 %3 2 %,Grade1 29.4 %2 35.3 %3 5.9 %,Grade1 6.8 %2 15.5 %3 3.9 %,Grade1 36.8 %2 19.2 %3 7 %,Optimox 1,Optimox 2,After the first reintroduction,2 months after FOLFOX,Grade 1 70.7 %2 18.1 %3 0 %,Grad
34、e 1 70.8 %2 16.5 %3 0 %,During C1-C6,Chemotherapy-free Interval,Duration of Disease Control,Overall Survival,Alternating vs continuous FOLFIRI in advanced colorectal cancer (ACC): a randomized GISCAD trial,Roberto Labianca Ospedali Riuniti Bergamo, Italy,Floriani I, Cortesi E, Isa L, Zaniboni A, Mar
35、angolo M, Frontini L, Barni S, Beretta GD, Sobrero A,GISCAD-Trial: Design,Primary endpoint: OS,R,FOLFIRI,Evaluation,4 mos,N=336,PFS,Median f-up: 30 mMedian time to PD: Arm A 6.2 m Arm B 6.5 m,Cox analysis (after adjustment for gender, age and site): HR: 1.01 (0.78-1.27),OS,Median f-up: 30 mMedian su
36、rvival time: Arm A 16.9 m Arm B 17.6 m,Cox analysis (after adjustment for gender, age and site): HR: 1.03 (0.78-1.35),Toxicity,Grade 3/4 toxicities similar in both arms This paradigm of toxicity measurement is not appropriate for this type of trial No QOL analysis,Summary,GISCAD Equivalent DFS, OS, toxicity ? Rationale clinical strategyOPTIMOX2 ? Longer induction needed ? Shorter break before re-introduction? Different maintenance strategy,From OPTIMOX to DREAM,OPTIMOX-1,OPTIMOX-2,Efficacy = Toxicity ,Efficacy decresed Toxicity =,
