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Colo-rectal Cancer

Colo-rectal Cancer. Cancer Society Presentation. Chemotherapy Agents. Fluoropyrimidines 5FU, Capecitabine Oxaliplatin Irinotecan Mitomycin - C Targeted therapies Anti-angiogenic therapies: Bevacizumab EGFR inhibitors: Cetuximab, Panitumumab. Adjuvant therapy. Combination chemotherapy

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Colo-rectal Cancer

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  1. Colo-rectal Cancer Cancer Society Presentation

  2. Chemotherapy Agents Fluoropyrimidines 5FU, Capecitabine Oxaliplatin Irinotecan Mitomycin - C Targeted therapies Anti-angiogenic therapies: Bevacizumab EGFR inhibitors: Cetuximab, Panitumumab

  3. Adjuvant therapy Combination chemotherapy FOLFOX4/ 6 5FU, Folinic Acid and Oxaliplatin MOSAIC; NSABP C-07 Single agent fluoropyrimidine Modulated 5FU Capecitabine

  4. Adjuvant Setting Single Agent Fluoropyrimidine: Benefit in Stage III disease Absolute survival: 17% Rel Risk Reduction for Mortality = 33% Equivalent Schedules for efficacy Weekly 5FU + FA for 6 weeks/8 weeks x 3 (Roswell Park) D1 – D5 monthly for 6 months (Mayo) Oral Capecitabine – 2 weeks on, 1 week off ; 8 cycles

  5. Combination 5FU + Oxaliplatin: MOSAIC 2,246 patients 148 institutions 20 countries FOLFOX4 vs 5FU/LV In Stage II and III disease De Gramont, ASCO 2003 NEJM, 2004:350(23)2343

  6. MOSAIC P < 0.01

  7. MOSAIC Toxicity issues Much higher rates of significant neutropenia (41% vs 5%); emesis; fatigue; port-a-cath Oxaliplatin arm Peripheral neuropathy – affects 95% patients to some degree GD 3 (Functional impairment): 12% (137 patients) At 1 year Gd 3 in only 1%, 47% complete recovery

  8. Adjuvant – NSABP CO-7 2,407 patients randomised, (28.6% II) 5FU/LV (RP) vs FLOX Median F/up 34 months 3 year DFS FLOX 76.5 % vs 71.6% 5FU/LV p = 0.004 ITT, HR 0.79 [0.67 – 0.96] = 21% reduction in the risk of relapse

  9. Adjuvant Avastin No improvement in 3 year DFS.

  10. Stage II Disease Remains controversial Logic – yes but benefit will be smaller, given the rate of recurrence NSABP combined studies; Quasar – benefit seen – 2 -3 % improvement in absolute survival Both the MOSAIC and NSABP C-07 – benefits seen Nordic Study 5FU + levamisole 12 months 19% relative risk reduction Absolute survival benefit: 2 – 3 % Current policy: Limit to High Risk Disease B2 Obstruction, perforation, adherence, poor differentiation, vascular invasion Single agent therapy

  11. Capecitabine Oral Pro-Drug A Carbimate derivative of 5 de-oxyfluorouridine Capable of rapid absorption via intestine Metabolised to 5FU in 3 activation steps. Thymidine phosphorylase is present in high levels in tumour tissue vs healthy tissue (3 – 10x)

  12. How to take • Twice daily after food. • Large glass of water • Usually 14 days then 7 days break. • Missed doses are not made up

  13. Current uses of capecitabine • Single agent • Adjuvant • Metastatic • Rectal Cancer • Combination • Adjuvant • Metastatic

  14. Adjuvant Capecitabine Twelves et al NEJM 2005

  15. Treatment interruptions prevent worsening toxicity • Brief drug interruptions and/or dose adjustments lead to the reinstitution of treatment in most patients • Problem is patients expect toxicities – therefore they don’t want to stop treatment • If Capecitabine is not interrupted at onset of moderate toxicity • toxicity may worsen • may lead to permanent treatment discontinuation • life-threatening consequences

  16. Interrupt Capecitabine for grade  2 toxicities • Diarrhoea • Nausea/vomiting • Stomatitis • Hand-foot syndrome INTERRUPT CAPECITABINE IMMEDIATELY

  17. GI toxicity requires prompt management Diarrhoea grade ≥ 2 • Increase 4-6 stools/day • Moderate increase ostomy output • Not interfering with ADLs STOP taking capecitabine START taking loperamide

  18. Supportive management of diarrhoea: Loperamide and fluids • 4 mg first episode • 2 mg after each unformed stool • IF more than 4 doses in the day – set alarm clock and take 4mg at 12 midnight and 4am • Oncology DN/WBCC check-in after 24 hours

  19. Recommendations All capecitabine patients receive Education prior to starting treatment Written information Loperamide instructions Contact details DN/WBCC/Ward 5 North DANGER signs Prescriptions Loperamide Metoclopramide Aqueous cream Nystatin syrup

  20. Advanced Colo-rectal Cancer Background Median Survival Untreated = 5.6 months (Van Cutsem) History of chemotherapy 5FU Modulated 5FU Infusional 5-FU Irinotecan Oxaliplatin Median Survival in trials of 5FU based therapy = 9 – 12 months

  21. First Line Therapy for Metastatic Disease Routinely combination 5FU + Folinic Acid + Irinotecan (FOLFIRI) 5FU + Oxaliplatin (FOLFOX4) Xelox (Oxaliplatin/Capecitabine) Xeliri

  22. First Line Therapy for Metastatic Disease Goldberg, ASCO, Abs 1009

  23. First Line Therapy for Metastatic Disease Toxicity Profile Balanced: Febrile Neutropenia 4% Gd ¾ nausea or vomiting 3% Oxaliplatin arm: Paresthesiae 18% Irinotecan: Diarrhoea 12%

  24. Advanced Disease Crossover Trials FOLFOX : FOLFIRI FOLFIRI : FOLFOX Early vs Late chemotherapy ANZ Data (incl QOL) 5FU schedules for metastatic disease 168 patients in two trials Overall survival not different No difference in quality of life No difference in overall survival or overall response rate Survival 22 -24 months

  25. Sequential single agent therapy For those of poorer performance status Capecitabine – Response rate: 25% Oxaliplatin – second or third line: 15%* Irinotecan – second or third line:15 – 20%

  26. New Agents Cetuximab EGFR inhibitor EGF Receptor – signalling channel promoting mitogenesis, invasion, angiogenesis Monoclonal antibody Initial data was presented 2002 Phase II extension: patients failing irinotecan were offered continuation with Cetuximab, 22% response rate (Van Cutsem)

  27. Cetuximab In patients with EGFR positive tumours Irinotecan +/- Cetuximab on progression Toxicity – increased irinotecan toxicity Cunningham, ASC0 2003, Abs 1012

  28. Cetuximab Given weekly Intravenous Skin rash Diarrhoea

  29. Bevacizumab Recombinant humanised Monoclonal antibody targeting VEGF ?regression ?stabilisation of vasculature First validation of anti-angiogenic strategy in humans Hurwitz, 2003

  30. Bevacizumab Given three weekly Intravenous Side Effect Profile Hypertension (Class Effect) GI perforation Arterial and venous thrombosis Proteinuria

  31. Targeted Therapy Not a magic bullet Steady incremental improvements This may be individually valuable Cost will be substantial Candidate selection will be crucial Molecular phenotyping Early Pharmacodynamic endpoints

  32. Conclusions Metastatic disease Surgical management where appropriate Clear intention of chemotherapy Response: complete; partial and stable disease Sequential combination therapies: median survivals of 22 – 24 months Adjuvant therapy 17% improvement in overall survival with single agent Additional 5 – 7% with combination therapy with additional toxicity

  33. Progressive improvement in median survival in metastatic colon cancer trials

  34. Referrals Wellington Blood and Cancer Centre 4 Medical Oncologists (Simpson, O’Donnell, Edwards, Barrow) 6 Radiation Oncologists (Johnson, Lamb, Violet, Wilson, Evans, Hamilton) Websites: Cancer Backup UK. NCI-PDQ Fax Number 3855- 984

  35. Post Metastatectomy Chemotherapy Non-surgical Course of Isolated Liver Metastases Small series of patients Median Survival 14 months 5 year survival: 0 – 8% (Scheele, Wagner) Surgical Resection of Liver Metastases

  36. Surgical metastatectomy Extended to lung mets (<5), other solitary sites of disease Evaluate the resectability Evaluate the disease free interval Evaluate the chemosensitivity of the disease

  37. Liver metastases

  38. Drug – Drug Interactions Phenytoin Increased serum concentrations CYP2C9 inhibition thought to be related Increased monitoring recommended Warfarin Increases in the INR and bleeding episodes Mech Unclear: Potentially CYP2C9 inhibition Close monitoring of INR advised

  39. Current Clinical Trials At the Wellington Blood and Cancer Centre Second line: Oxaliplatin/5FU combination with an oral angiogenesis inhibitor (Anti-VEGF) Third line: cetuximab vs cetuximab + brivanib in k Ras wild type patients

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