Download 5FU MMC - ANZGOG

Chemotherapy in Anal cancer
?Lessons for vulva
ANZGOG 2013
Michelle Vaughan
Anal v vulval etiology
Anal
Age
Path
HPV
60s
All grades
70-85%
Precursor
AIN
Risks
Sex/smoking
Vulval
Type1
35-65
More G3
>60%
Type 2
55-85
More G1
<15%
VIN
Sex/smoking
Lichen sclerosis
-
VULVAL & ANAL CANCER
LOCAL CONTROL is dominant aim of treatment
Indolent natural history
Mets are rare (<10% as a 1st event)
Chemo given to help RT with local control
(Uncommon paradigm for chemotherapists!)
RCTs in ANAL CANCER
n
UKCCCR/ACT
585
Add chemo?
1996/2010
EORTC
QUESTION
110
1997
RTOG
291
Need MMC?
1996
RTOG
644
Cis v MMC?
2008/11
UKCCCR/ACT
940
(2009)
ACCORD -03
307
Chemo induct?
HD RT?
5yr LFR %
5yr PFS %
5 yr OS %
√
√
√
√
√
√
√
√
√
-
-
-
-
-
-
-
-
Does chemo add to RT?
n
Compared
ACT I
585
EORTC
110
5yr Local
failure %
5yr PFS %
5 yr OS %
RT
- 25
+15
60  35
35  50
ns
RT + 5FU/MMC
- 15
+20
50 35
40  60
ns
Chemo improves local control & PFS 15-25%
Chemo doesn’t affect survival
Arnott Lancet 1996 & Northover BJC 2010, Barteleink JCO 1997
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?
RTOG
n
Compared
4yr Local
failure
291
5FU MMC RT
5FU RT
+20% -20%
35  15
4yr PFS
OS
ns
50 70
YES, unfortunately it is.
Flam 1996 JCO 14:2527-39
Anal cancer: Is MMC necessary?
RTOG
n
Compared
4yr Local
failure
291
5FU MMC RT
5FU RT
+20% -20%
35  15
4yr PFS
OS
ns
50 70
YES, unfortunately it is.
Bother.
Flam 1996 JCO 14:2527-39
MMC is toxic
…So can we replace it?
Cisplatin instead of MMC?
n
RTOG
98-11
ACT II
UKCCCR
644
940
Compared
5FU MMC RT
5yr LFR
5yr PFS
OS
+ 8%
-10
-7
25 33
5868
7178
5% col
75
85
5FU Cis RT
MMC + 5FU remains the standard
Adjani JAMA 2008 & ASCO 2011, James ASCO 2012
G3-4 Toxicity: Cis v MMC
Haem
Infection
Non haem
Severe long
RTOG
10mg x 2
CIS
MMC
44
61
10
17
65
61
10
11
ACTII
12mg x 1
CIS
MMC
13
25
3
3
74
74
-
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 mitomycin
EFFICACY???: 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
– Cardiovasc
– Pulmonary
3 v 1%
5 v 3%
1 v 0%
(13yr =12 v 6% p= 0.03)
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)
UKCCCR
n
Compared
585
5FU MMC RT
RT
ACT I 1996
Northover 2010
EORTC 22861
110
Bartelink 1997
RTOG 87-04
291
Flam 1996
RTOG 98-11
644
Ajani 2008/11
UKCCCR#
Conroy 2009
5FU MMC RT
5FU RT
5FU MMC RT
5FU Cis RT
5 yr CFS %
5yr PFS %
5 yr OS %
- 25
+10
+13
57  32
37  47
34  47
53 58
- 16
+32
+18
48 32
(4577)
(42  60)
-18
+12
+22
34 16*
59 71*
51 73*
54  58
67 76
-8
+ 10#
+ 7#
33 25
58  68
7178
940
5FU MMC RT
5FU Cis RT
ns
ns
75 3yr
?
307
5FU Cis induct
HD RT
28
83
70
78
ACT II 2009
ACCORD-03#
5FU MMC RT
RT
5yr LFR %
P<.001 P <0.01 P<0.05
*4yr
#abs
only
(x)=from graph