1. Chemotherapy in Anal cancer ?Lessons for vulva ANZGOG 2013 Michelle Vaughan

2. Anal v vulval etiology Anal Vulval Type1Type 2 Age60s35-6555-85 PathAll gradesMore G3More G1 HPV70-85%>60%<15% PrecursorAINVINLichen sclerosis RisksSex/smoking -

3. VULVAL & ANAL CANCER LOCAL CONTROL is dominant aim of treatment Indolent natural history Mets are rare (<10% as a 1 st event) Chemo given to help RT with local control (Uncommon paradigm for chemotherapists!)

4. RCTs in ANAL CANCER nQUESTION 5yr LFR %5yr PFS %5 yr OS % UKCCCR/ACT 1996/2010 585 Add chemo? √ √ - EORTC 1997 110 √√ - RTOG 1996 291 Need MMC? √√ - RTOG 2008/11 644 Cis v MMC? √√√ UKCCCR/ACT (2009) 940 --- ACCORD -03 307Chemo induct? HD RT? ---

5. Does chemo add to RT? nCompared 5yr Local failure % 5yr PFS %5 yr OS % ACT I 585 RT RT + 5FU/MMC - 25 60  35 +15 35  50 ns EORTC 110 - 15 50  35 +20 40  60 ns Arnott Lancet 1996 & Northover BJC 2010, Barteleink JCO 1997 Chemo improves local control & PFS 15-25% Chemo doesn’t affect survival

6. Strong effect on Loco-regional relapse Northover 2010 BJC 102:1123

7. Insignificant survival benefit HR 0.86 CI 0.7 – 1.04 Northover 2010 BJC 102:1123

8. Anal cancer: Is MMC necessary? YES, unfortunately it is. Flam 1996 JCO 14:2527-39 nCompared 4yr Local failure 4yr PFSOS RTOG 291 5FU MMC RT 5FU RT +20% 35  15 -20% 50  70 ns

9. Anal cancer: Is MMC necessary? YES, unfortunately it is. Bother. Flam 1996 JCO 14:2527-39 nCompared 4yr Local failure 4yr PFSOS RTOG 291 5FU MMC RT 5FU RT +20% 35  15 -20% 50  70 ns

10. MMC is toxic …So can we replace it?

11. Cisplatin instead of MMC? MMC + 5FU remains the standard nCompared 5yr LFR5yr PFSOS RTOG 98-11 644 5FU MMC RT 5FU Cis RT + 8% 25  33 -10 58  68 -7 71  78 ACT II UKCCCR 940 5% col7585 Adjani JAMA 2008 & ASCO 2011, James ASCO 2012

12. G3-4 Toxicity: Cis v MMC RTOG 10mg x 2 ACTII 12mg x 1 CISMMCCISMMC Haem44611325 Infection101733 Non haem656174 Severe long1011--

13. Can we reduce the MMC dose? DoseHaem tox G 3-4 RTOG10mg/m 2 D1 + 2961% UKCCCR ACT II12mg/m 2 D125% TOXICITY: Better with D1 only mitomycin EFFICACY???: Who knows?

14. So, What MMC dose? We will never know Either is reasonable If you use the RTOG 10mg/m 2 D1 & D29 remember to: – Do weekly FBC – Dose reduce if nadirs wcc < 2.4!

15. SUMMARY Anal cancer is similar to Vulval cancer In anal cancer several large RCTS say: - Chemo adds PFS to RT - MMC adds PFS to 5FU chemo - MMC is better than cisplatin in 1 of 2 trials - More haem tox ?Argue for 5FU/MMC

16. thank you

17. Delayed deaths problematic Marked excess OTHER deaths in the CRT group, peaking at 5 years (+9% p0.001): – Cancer 2yr3 v 1% (13yr =12 v 6% p= 0.03) – Cardiovasc5 v 3% – Pulmonary 1 v 0% Northover 2010 BJC 102:1123

18. Details of excess deaths: Cardiovascular– Spread in time course, median time about 1 year Second cancers - Mostly lung cancer (reflecting shared etiology), 8 v 2 in 1 st 5 years, 26 v 16 after 5 years SO: Late (+ acute) chemo toxicity possibly cancelling out survival benefit from reduction in anal cancer death in this population

19. ANAL CANCER RCTs (full) nCompared 5yr LFR %5 yr CFS %5yr PFS %5 yr OS % UKCCCR ACT I 1996 Northover 2010 5855FU MMC RT RT - 25 57  32 +10 37  47 +13 34  47 53  58 EORTC 22861 Bartelink 1997 1105FU MMC RT RT - 16 48  32 +32 (45  77) +18 (42  60) 54  58 RTOG 87-04 Flam 1996 2915FU MMC RT 5FU RT -18 34  16* +12 59  71* +22 51  73* 67  76 RTOG 98-11 Ajani 2008/11 6445FU MMC RT 5FU Cis RT - 8 33  25 + 10 # 58  68 + 7 # 71  78 UKCCCR # ACT II 2009 9405FU MMC RT 5FU Cis RT ns 75 3yr? ACCORD-03 # Conroy 2009 3075FU Cis induct HD RT 28837078 P<.001 P <0.01 P<0.05 *4yr # abs only (x)=from graph