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Highlights of the Day: Colorectal Cancer

Highlights of the Day: Colorectal Cancer. Charles D. Blanke, M.D. OHSU Cancer Institute. Colorectal Cancer Highlights. Background and epidemiology Key findings in adjuvant treatment of colorectal cancer Key findings in metastatic colorectal cancer Future directions Conclusions.

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Highlights of the Day: Colorectal Cancer

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  1. Highlights of the Day: Colorectal Cancer Charles D. Blanke, M.D. OHSU Cancer Institute

  2. Colorectal Cancer Highlights • Background and epidemiology • Key findings in adjuvant treatment of colorectal cancer • Key findings in metastatic colorectal cancer • Future directions • Conclusions

  3. 2007 Epidemiology of Colorectal Cancer:United States • 3rd leading cause cancer death men and women • 2nd leading cause cancer death Americans • Age-adjusted incidence rates decreasing for 20+ years due to screening • 153,760 cases and 52,180 deaths are expected

  4. 2007 Epidemiology of Colorectal Cancer:United States • 3rd leading cause cancer death men and women • 2nd leading cause cancer death Americans • Age-adjusted incidence rates decreasing for 20+ years due to screening • 153,760 cases and 52,180 deaths are expected

  5. Approved Agents in Metastatic Colorectal Cancer • Breakthroughs have occurred because of new drugs • 5FU: Only approved primary drug 1957 through 1996 • Recently approved chemotherapeutic agents: • Irinotecan and oxaliplatin • Capecitabine • Recently approved biologic agents: • Bevacizumab • Cetuximab, panitumumab

  6. Adjuvant Therapy of Colon Cancer • 6- and 12-month treatment cycles equivalent • 5-FU/lev superior to surgery alone • Irinotecan does not • improve efficacy • 5-FU/LV superior to surgery alone • FOLFOX improves • PFS 1990 1994 1998 2002 2003 2004-5 • Capecitabine more • effective/less toxic than 5FU

  7. ACCENT Database: Background • ACCENT = Adjuvant Colon Cancer Endpoints Group, established 2003 to validate DFS as an adjuvant colon cancer trial endpoint • Disclosure: I represent 1/40th of this group • Included individual data from 18 trials and > 20,800 stage II and III patients • Goals were to “explore” and “inform” re: • Adjuvant therapy benefit • Survival and recurrence • Examination of statistical models with disease-free survival endpoint • A good ASCO for ACCENT: 2 orals and a poster discussion

  8. ACCENT 1: Time-Dependent Patterns of Failure and Treatment Benefit-Dr. D. Sargent HR for Overall Survival Disease-Free Survival

  9. ACCENT 1: Take-Home Points • Risk of event (recurrence) spikes first 2 years • Hazard ratio for treatment only differs between treatment and control for the first four years • After 8 years, recurrence rates overall were < 0.5%/yr • There was a long-term, constant OS 5FU benefit • Treated pts had benefit every single-year • 5FU-based therapy cures, versus just delaying recurrence

  10. ACCENT 2: Prognostic Factors and Survival Following Recurrence-Dr. M O’Connell • Time from randomization on surgical adjuvant protocol to tumor recurrence • Initial stage of colon cancer (II, III) • 5FU-based adjuvant therapy versus surgery alone • Era patient entered onto surgical adjuvant protocol

  11. Time from Recurrence to Death by Year of Recurrence 100 Year 0- 1 (N=1846) Year 1-2 (N=1854) Year 2-3 (N=924) Year 3-4 (N=516) Year 4+ (N=582) Total (N=5722) 80 60 % Alive 40 Log Rank P-Value = <0.0001 20 0 0 1 2 3 4 5 6 7 8 Time (Years)

  12. Time from Recurrence to Death by Stage 100 Stage II (N=1153) Stage III (N=4550) Total (N=5703) 80 60 % Alive Log Rank P-Value = <0.0001 40 20 0 0 1 2 3 4 5 6 7 8 Time (Years)

  13. ACCENT 2: Author Conclusions • Time from surgery and stage of the primary are important prognostic variables • Failing after adjuvant therapy leads to a worse outcome than failing after surgery alone • Survival following recurrence improved over the 15-year period studied

  14. Questions Raised by ACCENT • How do findings change with incorporation of newer drugs/trials? • Which variables are the most important for stratification in future trials? • Should 2-year DFS be the endpoint for Cooperative Group Adjuvant Colon phase III studies? • Should we stop or at least minimize monitoring for recurrence after 5 (8) years?

  15. MOSAIC Adjuvant Trial: Background • 2248 patient phase III trial FOLFOX4 versus LVFU2 in curatively-resected stage II/III colon cancer patients • Safety data reported 2002 • Efficacy data first reported 2003 • With 4-year follow-up, FOLFOX improved DFS by 6.6% over LVFU2, with an insignificant 3.2% augmentation of overall survival1 1PASCO 2005, abstr 3501

  16. MOSAIC 2007 • SStudy now presented with > 5 years follow-up • 6 6% DFS benefit maintained HR = 0.8, p = 0.003

  17. Questions Raised by MOSAIC • There aren’t a lot: FOLFOX clearly represents the SOC for resected node-positive colon cancer patients • How should we treat resected stage II patients adjuvantly? • There were no DFS or OS benefits for node-negative patients • Is this statistics or are they biologically different? • How do we weigh the risk:benefit ratio in this population?

  18. Pooled Analysis Assessing PS in 1st-Line CRC -Goldberg • Phase III studies classically enroll < 10% PS 2 pts • Poor PS = bad prognosis, but lacking sufficient data, oncologists may under- or over-treat • Retrospective analysis of 6286 frontline pts from 9 trials • Primary endpoint was PFS • Secondary endpoints were AEs, 60-day mortality, OS, and ORR

  19. PS Study: Conclusions • Severe N/V worse PS 2 pts; diarrhea, neutropenia not • 60-day mortality greater PS 2 pts (12% vs. 3%) • PFS, OS, ORR all significantly worse PS 2 pts • PFS 4.9 vs 7.6 mo

  20. PFS – Treatment by PS p-value < 0.0001 HR: 0.82 (0.77-0.86) p-value = 0.02 HR: 0.79 (0.66-0.96) Interaction p-value = 0.68

  21. OS – Treatment by PS p-value < 0.0001 HR: 0.87 (0.82-0.93) p-value = 0.21 HR: 0.88 (0.73-1.07) Interaction p-value = 0.41

  22. PS Study: Additional Considerations • Authors concluded “superior” treatment benefits all patients • Study could not definitively address the reason behind poor PS • It is likely eligibility requirements elminated many patients with non-cancer related poor PS • Goldberg’s patients likely had poor PS related to cancer • It is reasonable to treat cancer-related poor PS patients with aggressive chemotherapy, including combinations and new agents • PS 2 patients do terribly, even with therapy (OS < 9 mo; 12% dead within 2 mo) • ?Interesting population for all biologics

  23. OPTIMOX2 Background • Chemo-holidays a hot topic in CRC for last 4 years • 2 randomized trials were presented ASCO 2003 • Phase II salvage study CPT-11 showed no benefit to indefinite therapy vs a fixed number of cycles • OPTIMOX showed stopping oxaliplatin after a fixed number of cycles did not hurt PFS • OPTIMOX2 looked at a complete cessation of chemotherapy after 6 cycles of FOLFOX vs maintenance LVFU2

  24. OPTIMOX2 Results

  25. OPTIMOX2 Results Author conclusions: Maintenance chemotherapy may prolong PFS and OS

  26. OPTIMOX2 Interpretation • This was a smaller than intended and non-definitive trial • Patient numbers downgraded from 600 to 200 • Maintenance chemotherapy looked better, but not statistically so • A more attractive strategy would be biologic maintenance

  27. Circulating tumor cells and survival in metastatic colorectal cancer -Dr. N. Meropol • Assessment of cirulating tumor cells in metastatic CRC patients, correlating with imaging and outcome • Independent predictor of PFS and OS • ???Can we use this information to make early changes to non-effective therapy, hoping to improve outcome???

  28. Randomized study of sequential versus combination chemotherapy -Dr. CJ Punt • Capecitabine followed by irinotecan followed by CapOx versus CapIri followed by CapOx • 36% on sequential arm, versus 53% on combo got all 3 agents • Combo therapy had more toxicity, a 2 month improvement in PFS, and no change in OS • This trial could not say who should get what

  29. REMINDER: Other Exciting Colorectal Cancer Session are Ahead! • Today: General Poster Session S Hall A2 • Today: Education Session on the Continuum of Care in CRC N Hall B1 • Today: Plenary Session Results of Neoadjuvant Chemotherapy for Metastasectomy in Liver Metastases N Hall B1 • Tomorrow: Clinical Science Symposium on EGFR as a Therapeutic Target E Arie Crown

  30. A Phase II Trial of Celecoxib + IFL Chemotherapy in Patients with Advanced Colorectal Cancer R E G I S T E R Treat until: Progression Toxicity Celecoxib + IFL Celecoxib x 2 weeks Celecoxib 400 mg BID Irinotecan 125 mg/m2 weekly x 4 every 43d 5-FU 500 mg/m2 weekly x 4 every 43d LV 20 mg/m2 weekly x 4 every 43d PASCO 2002

  31. What do We Know Now Compared to Before? • Are we moving forward? Schilsky ASCO 2002

  32. NO!!!

  33. Highlights of the Day: Colorectal Cancer Conclusions 2007 • Prior ASCOs have mostly focused on generic use of new drugs • This ASCO did confirm previous findings on a “new” drug-oxaliplatin clearly benefits patients when used after potentially curative resection of colon cancer • Additionally, this seemed to be the ASCO of colorectal cancer “strategy development”

  34. Highlights of the Day: Additional Colorectal Cancer Conclusions 2007 • Large patient databases can help set endpoint guidelines and stratification variables for future large-scale trials • PS 2 patients, if sick from cancer, may benefit from aggressive chemotherapy • Maintenance therapy does not clearly benefit those on chemo-holidays, but I will still use it

  35. What do We Know Now Compared to Before? • Are we moving forward? Blanke ASCO 2007

  36. YES!!!!

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