Oncology Symposium Future development plans and strategies for the NCRI Anal cancer working group

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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

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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

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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

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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)

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UK - ACT III Trials
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ACT III Trials

• Early anal cancer trial
• Reduce dose
• Reduce volume
• Advanced anal cancer trial
• Neoadjuvant chemo
• non cross
  resistant drugs

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Failure risk

• T1/T2 N0 (40)
• Local failure lt4
• Pelvis failure lt2
• Inguinal failure lt5
• DFS 85

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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

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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

NCRN Anal sub-group meeting London 21st May 2009
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More advanced anal cancers
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ACT III Trials

• Advanced anal cancer trial
• Increasing RT dose not beneficial
• Neoadjuvant chemo
• non cross resistant drugs

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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

NCRN Anal sub-group meeting London 21st May 2009
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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

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Capecitabine -We have data

• From EXTRA phase II
• Integrated capecitabine and MMC
• excellent cCR
• Well tolerated
• Avoids lines / inpatient
• Clear data in gt 5000 patients randomised and
  non-randomised trials in rectal cancer of
  efficacy/tolerability

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EXTRA

• Replacing 5FU in the ACT-II schedule with oral
  capecitabine, n31
• 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

Glynne-Jones et al 2008 IJROBP 72119-126
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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

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ACT II - DFS for stage T3/T4
Recurrence-free survival
Patients with T3/T4 (407)
100
80
Recurrence-free survival ()
66
60
40
0
1
2
3
4
5
6
7
8
Time from randomisation (years)
Number at risk
407
273
191
130
85
44
12
1

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Time to first local relapse
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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)

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Site of recurrence for T3/4 patients
PELVIC INCLUDES NODES AS WELL, LOCAL PRIMARY
SITE ONLY
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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

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Potential randomised Phase II
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Potential add on

• PET at 8 weeks
• Prospectively examine persistent SUV at this time
  point
• Could allow early surgical salvage.

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Best Endpoints

• DFS at 3 years
• Colostomy free survival at 3 years
• See results of RTOG 98-11
• and ACCORD-03

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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

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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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