Chemotherapy in Anal cancer?Lessons for vulva

ANZGOG 2013Michelle Vaughan

Anal v vulval etiology

Anal VulvalType1 Type 2

Age 60s 35-65 55-85Path All grades More G3 More G1HPV 70-85% >60% <15%Precursor

AIN VIN Lichen sclerosis

Risks Sex/smoking Sex/smoking -

VULVAL & ANAL CANCER

LOCAL CONTROL is dominant aim of treatmentIndolent natural historyMets are rare (<10% as a 1st event)Chemo given to help RT with local control

(Uncommon paradigm for chemotherapists!)

RCTs in ANAL CANCERn QUESTION 5yr LFR % 5yr PFS % 5 yr OS %

UKCCCR/ACT 1996/2010

585Add chemo? √ √ -

EORTC 1997

110 √ √ -

RTOG 1996

291 Need MMC? √ √ -

RTOG 2008/11 644Cis v MMC? √ √ √

UKCCCR/ACT(2009)

940- - -

ACCORD -03 307 Chemo induct?HD RT? - - -

Does chemo add to RT?

n Compared 5yr Local failure %

5yr PFS % 5 yr OS %

ACT I 585 RT

RT + 5FU/MMC

- 2560 35

+1535 50

ns

EORTC 110- 15

50 35

+2040 60

ns

Arnott Lancet 1996 & Northover BJC 2010, Barteleink JCO 1997

Chemo improves local control & PFS 15-25%Chemo doesn’t affect survival

Strong effect on Loco-regional relapse

Northover 2010 BJC 102:1123

Insignificant survival benefit

HR 0.86 CI 0.7 – 1.04

Northover 2010 BJC 102:1123

Anal cancer: Is MMC necessary?

YES, unfortunately it is.

Flam 1996 JCO 14:2527-39

n Compared 4yr Local failure

4yr PFS OS

RTOG 291 5FU MMC RT5FU RT

+20%35 15

-20%50 70

ns

Anal cancer: Is MMC necessary?

YES, unfortunately it is.

Bother.

Flam 1996 JCO 14:2527-39

n Compared 4yr Local failure

4yr PFS OS

RTOG 291 5FU MMC RT5FU RT

+20%35 15

-20%50 70

ns

MMC is toxic

…So can we replace it?

Cisplatin instead of MMC?

MMC + 5FU remains the standard

n Compared 5yr LFR 5yr PFS OS

RTOG 98-11

6445FU MMC RT

5FU Cis RT

+ 8%25 33

-105868

-77178

ACT IIUKCCCR

940 5% col 75 85

Adjani JAMA 2008 & ASCO 2011, James ASCO 2012

G3-4 Toxicity: Cis v MMC

RTOG10mg x 2

ACTII12mg x 1

CIS MMC CIS MMCHaem 44 61 13 25Infection 10 17 3 3Non haem 65 61 74 74Severe long 10 11 - -

Can we reduce the MMC dose?Dose Haem tox G 3-4

RTOG 10mg/m2 D1 + 29 61%

UKCCCR ACT II 12mg/m2 D1 25%

TOXICITY: Better with D1 only mitomycinEFFICACY???: Who knows?

So, What MMC dose?

• We will never know• Either is reasonable• If you use the RTOG 10mg/m2 D1 & D29

remember to: – Do weekly FBC– Dose reduce if nadirs wcc < 2.4!

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

thank you

Delayed deaths problematic

• Marked excess OTHER deaths in the CRT group, peaking at 5 years (+9% p0.001):

– Cancer 2yr 3 v 1% (13yr =12 v 6% p= 0.03)– Cardiovasc 5 v 3%– Pulmonary 1 v 0%

Northover 2010 BJC 102:1123

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 1st 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

ANAL CANCER RCTs (full)n Compared 5yr LFR % 5 yr CFS % 5yr PFS % 5 yr OS %

UKCCCRACT I 1996 Northover 2010

585 5FU MMC RTRT - 25

57 32+1037 47

+1334 47

53 58

EORTC 22861Bartelink 1997

110 5FU MMC RTRT - 16

48 32+32

(4577) +18

(42 60)54 58

RTOG 87-04Flam 1996

291 5FU MMC RT5FU RT -18

34 16*+12

59 71*+22

51 73*67 76

RTOG 98-11Ajani 2008/11

644 5FU MMC RT5FU Cis RT - 8

33 25+ 10#

58 68+ 7#

7178

UKCCCR#

ACT II 2009940 5FU MMC RT

5FU Cis RTns ns 75 3yr ?

ACCORD-03#

Conroy 2009307 5FU Cis induct

HD RT28 83 70 78

P<.001 P <0.01 P<0.05 *4yr #abs only (x)=from graph