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oncology symposium future development plans and strategies

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oncology symposium future development plans and strategies

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    1. Oncology SymposiumFuture development plans and strategies for the NCRI Anal cancer working group Dr Arthur Sun Myint Lead Clinician GI Tumour group Clatterbridge Centre for Oncology Association of Coloproctology of Great Britain and Ireland Annual Meeting Oncology Forum – Harrogate 8th June 2009

    2. Thoughts No longer feasible to think that one size fits all in anal cancer (ACT II) So for next studies ?over treating T1/T2 ?under treating T3/T4

    3. Randomised trials ACT 1 585 CRT vs. RT EORTC 110 CRT vs. RT RTOG/ECOG 291 Role of MMC RTOG 98-11 644 Role of NACT/cisplat ACCORD-03 307 Role of NACTcisplat/RT dose ACT 2 940 Role of cisplat vs. MMC + maintenance cisplat EORTC 85 Role of 5FU vs. CDDP 22011-40014 not extended to phase III

    4. Summary of results CRT is better than RT (ACT I and EORTC) CRT needs MMC (RTOG 8704) Neoadjuvant cisplatin not better (ACCORD-03 and RTOG 98-11) Maintenance cisplatin not better (ACTII - James 2009) Increasing dose above 59Gy not better (ACCORD-03)

    6. ACT III Trials Early anal cancer trial Reduce dose Reduce volume Advanced anal cancer trial Neoadjuvant chemo non cross resistant drugs

    7. Failure risk T1/T2 N0 (40%) Local failure <4% Pelvis failure <2% Inguinal failure <5% DFS 85%

    8. ACT III Trials Early anal cancer trial Reduce dose - Original Nigro data used lower dose Reduce volume - Treat primary tumour only and not all the regional lymph nodes

    9. Previous discussions T1/T2 Probably over-treating in terms of RT dose Sequential phase II ? Field size question Omit elective groin node irradiation ? De-escalating RT dose ? Add Biological following CRT

    12. More advanced anal cancers

    22. ACT III Trials Advanced anal cancer trial Increasing RT dose not beneficial Neoadjuvant chemo non cross resistant drugs

    23. Previous discussions T3/T4 Add neoadjuvant docetaxel as in HNSCC Different drugs in CRT (capecitabine) ? Consolidation chemo (await ACT II) Add Biological to RT or following following CRT

    24. Potential population T3/T4 represent 407/940 = 43% of ACT II population 3 year DFS = 66% Easy to define large population with a poor outcome

    25. Capecitabine -We have data From EXTRA phase II Integrated capecitabine and MMC excellent cCR Well tolerated Avoids lines / inpatient Clear data in > 5000 patients randomised and non-randomised trials in rectal cancer of efficacy/tolerability

    26. EXTRA Replacing 5FU in the ACT-II schedule with oral capecitabine, n=31 RT 50.4 Gy/28#/ 38 days in two phases Capecitabine in RT treatment days 825 mg/m2 b.d Full compliance with chemo 68% Full compliance with RT 81% No treatment-related deaths 4 w following CRT 77% clinical CR and 16% PR 3 loco-regional relapses in first 14 m

    27. Possible therapeutic strategies for T3/T4 Intensify Chemoradiation Neoadjuvant chemotherapy (non-cross resistant i.e. taxane) –but very toxic Maintenance/consolidation with different chemotherapy (?gemcitabine/ etoposide) +/- erlotinib Earlier surgical salvage defined by PET

    29. This graph is showing that if patients were going to relapse locally, that this tended to occur within the first couple of years. Very few events occurring after 5 years. Hazard ratio indicates 54% reduction in local relapse if on CMT arm compared to RT alone. P value is showing strongly statistical significant result.This graph is showing that if patients were going to relapse locally, that this tended to occur within the first couple of years. Very few events occurring after 5 years. Hazard ratio indicates 54% reduction in local relapse if on CMT arm compared to RT alone. P value is showing strongly statistical significant result.

    30. Potential strategies – Local ? Advantage to increasing RT phase II dose (local-only failure was only 33% [5/15] of failures in ACT II) (ACCORD-03 dose escalation did not improve DFS and led to more colostomies for necrosis)

    31. Site of recurrence for T3/4 patients

    32. Potential strategies – Systemic Metastases are becoming more of a problem (40% in ACT I) Need systemic therapies to improve DFS? Local failure rate very low. 95% achieve clinical CR in ACT II

    33. Potential randomised Phase II

    34. Potential add on PET at 8 weeks Prospectively examine persistent SUV at this time point Could allow early surgical salvage.

    35. Best Endpoints DFS at 3 years Colostomy free survival at 3 years See results of RTOG 98-11 and ACCORD-03

    36. Potential phase III study Endpoint 3 year DFS Increase DFS from 68% to 77% requires 268 per arm Allowing extra 10% to cover drop out etc 300 per arm = total 600 patients 80% power, 5% alpha 4 years recruitment – 3 year minimum follow-up

    37. Final thoughts So far, DFS has improved from 54% (ACT I) to 74% (ACT II) ACT II is the largest anal cancer trial It took 7 years to complete ACT II Anal cancer MDTs / site specialisation (CNG) has a potential to improve accrual We probably need international collaboration for next studies

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