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Chemotherapy for Metastatic Colon Cancer

Scott Berry Sunnybrook Health Sciences Centre. Chemotherapy for Metastatic Colon Cancer. Where Were We Until 2000?. O. F. HN. O. N H. 5-FU. oxaliplatin. irinotecan. C. H. 3. C. H. O. 2. O. N. N. N. O. C. O. O. N. H. O. C. H. C. H. 2. 3. NH 2. O. C. Pt. O.

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Chemotherapy for Metastatic Colon Cancer

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  1. Scott Berry Sunnybrook Health Sciences Centre Chemotherapy for Metastatic Colon Cancer

  2. Where Were We Until 2000?

  3. O F HN O N H 5-FU

  4. oxaliplatin irinotecan C H 3 C H O 2 O N N N O C O O N H O C H C H 2 3 NH2 O C Pt O C NH2 O bevacizumab FOLFIRI cetuximab Panitumumab PTK 787 FOLFOX IFL Capecitabine

  5. OS for 1st line Combinations 5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de Gramont) IFL (Goldberg) IFL (Saltz) FOLFIRI (Douillard) FOLFOX (de Gramont) FOLFOX (Goldberg) IFL+ Bevacizumab 0 5 10 15 20 25 Median OS (months)

  6. Overview/Objectives • Review key evidence from randomized trials evaluating the chemotherapies and chemotherapy strategies that have emerged for metastatic colorectal cancer 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/off” chemotherpay strategies?

  7. Chemotherapy

  8. Case • 50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases • ECOG 1 – some RUQ pain and cough • What is the optimal chemotherapy choice for her?

  9. CAPECITABINE • FOLFOX • FOLFIRI • CAPE IRI • CAPE OX • FOLFOXIRI

  10. Efficacy of 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

  11. CAPECITABINE • FOLFOX • FOLFIRI • CAPE IRI • CAPE OX • FOLFOXIRI

  12. Phase III Intergroup N9741 Study(Goldberg JCO, 2004) R A N D O M I Z A T I O N IFL FOLFOX 4 • Irinotecan + Oxaliplatin

  13. Phase II Sequential, Randomized CrossoverStudy FOLFIRI FOLFOX 6 Tournigand et al JCO 2004

  14. N9741/Tournigand Trial: Results

  15. Tournigand Trial: Results Curative Surgery Rate: 22% FOLFOX , 9% FOLFIRI

  16. TournigandToxicity grade >3 P>0.05 for Comparisons marked by arrows % FOLFIRI 40 34% FOLFOX 30 Alopecia Any grade 60% vs 28% 60-day Mortality: 4% vs 3% 20 14% 13% 11% 10% 10 7% 3% 3% 3% 0% 0 Paresthesia Nausea Diarrhea Vomiting F. neutropenia

  17. Combination Chemotherapy - Summary • Combination chemotherapy with FOLFIRI or FOLFOX are both acceptable first line chemotherapy regimens for people with metastatic colorectal cancer • Follow by alternate combination (or single agent Irinotecan after FOLFOX) • Considerations: • Toxicity profile • ? Considering surgery : FOLFOX based on “circumstantial” evidence

  18. CAPECITABINE • FOLFOX • FOLFIRI • CAPE IRI • CAPE OX • FOLFOXIRI

  19. Overall survival Capecitabine (n=603) 5-FU/LV (n=604) 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 13.1 13.1 0 5 10 15 20 25 30 Time (months) Integrated CRC

  20. What About Capecitabine As a Partner? Capecitabine + Irinotecan

  21. BICC-C study FOLFIRI +/- celecoxib n=430 1st line mCRC mIFL +/- celecoxib CAPIRI (Cape 1000mg/m2 d1-14) +/- celecoxib Slide Courtesy D Jonker from data presented at ASCO 2007

  22. EORTC 40015 study FOLFIRI +/- celecoxib n=85 1st line CRC CAPIRI (Cape 1000mg/m2 bid x14d)+/- celecoxib Celecoxib vs Placebo : No Survival difference Slide Courtesy D Jonker

  23. What About Capecitabine As a Partner? Capecitabine + Oxaliplatin

  24. Capecitabine + Oxaliplatin Randomized Trials : Efficacy First Line Second Line

  25. Capecitabine + Oxaliplatin Randomized Trials : Toxicity First Line Second Line

  26. Can Capecitabine Replace Infusional 5FU in mCRC? • Capecitabine and Irinotecan • At doses studied CapeIri is more toxic and less effective than FOLFIRI • Capecitabine and Oxaliplatin • CapeOx has same efficacy as FOLFOX • Differential toxicity profile between CapeOx and FOLFOX

  27. CAPECITABINE • FOLFOX • FOLFIRI • CAPE IRI • CAPE OX • FOLFOXIRI

  28. Triplet Therapy

  29. 5-FU/IRI vs FOLFOXIRI: Falcone et alN = 244 5-FU/Iri Douillard Randomization FOLFOXIRI Slide Courtesy of R Goldberg

  30. FOLFOXIRI Schedule Day 1 Day 2 Day 3 CPT-11 165 mg/m2 Oxaliplatin 85 mg/m2 L-LV 200 mg/m2 5FU flat continuous infusion 3200mg/m2 1 hour 2 hours 48 hours Repeated every 14 days Slide Courtesy of R Goldberg

  31. Efficacy Slide Courtesy of R Goldberg

  32. Post-ChemoRx Resections (patients with liver mts only) * p=0.017 Slide Courtesy of R Goldberg

  33. Grade 3-4 Toxicity (N=122) (N=122) p =0.0006 Slide Courtesy of R Goldberg

  34. Survival improves with availability of three active drugs * FOLFOXIRI P=0.0001 Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.

  35. Is FOLFOXIRI more active than 5-FU/IRI? • Yes, including better resection rates • But is comparator arm inferior? • More toxic

  36. Monotherapy

  37. Overall survival Capecitabine (n=603) 5-FU/LV (n=604) 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 13.1 13.1 0 5 10 15 20 25 30 Time (months) Integrated CRC

  38. Monotherapy versus doublets

  39. ? Have 3 active chemo agents in mCRC • Lead with combination • ? Can we use agents sequentially and maintain efficacy and reduce toxicity • FOCUS and CAIRO • Do both have fatal flaws?

  40. FOCUS Lancet, 2008

  41. FOCUS UK MRC CR08 2,135 Untreated Stage IV patients RANDOMI SAT ION A: 5 FU/LV (de Gramont) IRI FOLFOX or FOLFIRI B: 5 FU/LV (de Gramont) C: FOLFOX vs FOLFIRI

  42. 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 hadn’t occurred within 12 weeks of stopping

  43. 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

  44. Survival

  45. Table 4

  46. FOCUS

  47. QOL • Mean overall QOL : varied little between arms and regimens • In particular, no differences seen at 3 and 6 mos

  48. 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

  49. Percentage of Patients Receiving All 3 Active Drugs

  50. FOCUS Grothey, JCO, 2004

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