Transcript Do we need post-operative CHEMOTHERAPY in

Do we need post-operative CHEMOTHERAPY in
patients with PATHOLOGIC Complete Response to
neoadjuvant therapy in RECTAL CANCER ?
Philippe Rougier
ESDO Board(European Society of Digestive Oncology)
SNFGE Past President H
(Société Nationale Française d’Hépatogastro-entérologie)
Paris V Rene Descarte University
Hopital Européen Georges Pompidou ;
75015 Paris ; France
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PROGNOSTIC FACTORS IN RECTAL CANCER
• Size (cT) and site of the primary
• Quality of the surgery
– Mesorectal excision (TME)
– Lateral clearance >1mm
• Stage (T, N, M) and pTNM
• Histopathology (poorly vs mod/well diff)
• Index of proliferation (Ki 67), Ploidy…
• mutations : C-myc, LOH, MSI-H, p53m, K-ras...
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Do we need post-operative CHEMOTHERAPY in
patients with PATHOLOGIC Complete Response
to neoadjuvant therapy in RECTAL CANCER ?
ypT0N0
In other words this question can be translate into:
1. What is the evidence of activity of adjuvant
chemotherapy in rectal cancer?
2. How far can we consider patient with ypT0N0 as
cured?
3. cT2-T3 vs cT4 ?
4. Do they benefit from adjuvant chemotherapy?
ADJUVANT CHEMOTHERAPY IN RECTAL CANCER
• Studies on adjuvant treatments in rectal cancer
– Chemotherapy alone
– radio-chemotherapies combinations
– Meta-analysis
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Adjuvant chemotherapy (CT) CT in rectal cancer
NSABP R-01: (FISHER et al. JNCI 1988)
CT (MOF: FU-MeCCNU) :
379 vs control : 394
5-y survival Adjt vs Surgery
67% vs 59% p=.05 (m > f )
GITSG 7175 : (N Engl J Med 1985 ; 1986)
FU+MeCCNU vs control
48 / 58
Dutch trial (Fan Zoetmulder, ASCO 99, 1021)
FU+levamisole vs control 299
299 rectum / 1029 pts
QUASAR trial (r Gray, Lancet 2007)
3239 patients ’94 -’03
FU+FA or lev vs control
29% rectum = 940 pts
52% vs 46% ; ns
(42 vs 33% at 7 years)
Ns
80.3% vs 77.4 % p 0.02
risk of death: HR 0.82 p=0.008
Japanese trial ((Akasu T et al. Jpn J Clin Oncol 2006 ))
276 patients
Oral FU (UFTR) vs control
Rectum stage III
81% vs 60% (3-y OS)
p=0.005
little
proves of efficacy of Adjuvant CT in rectal cancer ...
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2 Meta-analysis in adjuvant CT in rectal cancer
Risk of death (HR)
- Sakamoto, (4960 pts)
( Jpn J Clin Oncol 1999 ; 29 : 78-86)
Tegafur ou Carmofur oral ;
HR : 0.857 (p<0.049)
RR : 0,83 for rectal K (p<0,02)
- S. Dubé (695 pts)
(Dis Colon Rectum, 1997, 40:35-41)
39 trials :1959-1993 ;
quality score : 49%
rectum : 695 / 12079
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HR : 0.64
(p<.05)
Survival gain + 9%
Adjuvant chemotherapy (5FU) is active as adjuvant TT in
rectal cancer but a poor level of efficacy...
Meta-analysis group of the Japanese Society for Cancer of the Colon
and Rectum and the Meta-analysis Group in Cancer
J Clin Oncol 2004 ; 22: 484-92.
2091 rectal cancer; Cox model
DFS :
HR : 0,73 (p<0,0001)
Overall Survival : HR : 0,82 (p<0,02)
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DFS and OS
Better after adjt CT
Using oral 5FU
The diagnosis and management of rectal cancer:
expert discussion and recommendations (World Congress
on Gastrointestinal Cancer) ; Barcelona, 2007
E. Van Cutsem et al, Annals of Oncology 19 (Supplement 6): vi1–vi8, 2008
• “Most patients who received a preoperative RT or CT-RT
are candidates for postoperative adjuvant chemotherapy.
• The initial staging before the administration of neoadjuvant treatment should dictate the need for adjuvant
chemotherapy. (?)
• Patients with a clinical stage II or stage III rectal cancer
are therefore considered candidates for postoperative
chemotherapy.
• Adjuvant fluoropyrimidine-based chemotherapy is
beneficial to patients that show downstaging (pT1-pT2)
after preoperative CT-RT or RT”.
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BUT
DO WE NEED POSTOPERATIVE CHEMOTHERAPY IN
PATIENTS WITH PATHOLOGIC CR (ypT0N0) TO
NEOADJUVANT THERAPY IN RECTAL CANCER
?
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Do we need post-operative CHEMOTHERAPY in patients
with PATHOLOGIC Complete Response to neoadjuvant
therapy in RECTAL CANCER ?
1. What is the evidence of activity of adjuvant
chemotherapy in rectal cancer?
2. How far can we consider patient with ypT0N0 as
cured?
3. For all patients: cT3 vs cT4 ?
4. Do they benefit from adjuvant chemotherapy?
Rectal cancer pts with a pathologic CR (ypT0N0)
after neoadjuvant tt have an excellent prognosis
- Local recurence rate # 0 - 3% Distant
recurrences <10%
- 5 year DFS in patients ypT0 (n=73) who did
not received adjuvant chemo was 100% in
MSK experience (Govindarajan, Ann Surg Oncol 2011)
- But the risk does exist and is Higher for
cT4 than cT3 and cT2 (RR: 7.3 ; Pucciarelli, DCR 2004)
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Rectal cancer pts with a pathologic CR (ypT0N0)
after neoadjuvant tt have an excellent prognosis
Pooled analysis ; 27 articles (Maas, M, Nelemans PJ, Valentini V et al
Lancet Oncol 2010 ; 11: 835-44)
- ypTONO was reported in 484 pts / 3105 (15.6%)
- 5 year DFS in pCR patients was 83.3%
- Recurrences (distal & local) were reported in 61/419
(14.5%) of pCR and half lower than in absence of pCR
(HR: 0.54)
- Adjusted HR for DFS for administration of adjuvant CT
was 0.91 (ci: 0.73 – 1.12).
- The effect of pCR on DFS was not modified by other
prognostic factors.
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DFS of rectal cancer patients with
ypT0N0 tumor (TRG4) after neoadjuvant RT-CT
« the German experience »
-phase III preop CAO/ARO/AIO-94 arm
n= 385 rectal cancer
-50.4 Gy + 5FU preop (week 1 and5)
• Disease-free survival of 344
patients with rectal carcinoma
after preoperative
chemoradiotherapy and
curative resection (R0
resection), according to tumor
regression grading (TRG).
=> 86% 5-year DFS for TRG4 patients
C Rödel et al. JCO 2005 ; 23 : 8688-96.
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Pronostic of rectal cancer patients
with ypT0N0 tumor after
neoadjuvant RT-CT
« the UK experience »
-phase II NWCOG ; n= 110 rectal cancer
-45 Gy + oral capecitabine + weekly irinotecan
• (A) Metastasis-free survival,
• (B) disease-free survival, and
• (C) overall survival
for patients whose postoperative histology
showed pathologic complete response
(ypCR) or microfoci (mfoci; near-ypCR)
versus other patients without a ypCR or
mfoci.
=> # 90% 5-year survival for ypT0N0 patients
S Gollins et al. JCO 2011 ; 29: 1042-1049
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ypT0N0
Pronostic of rectal cancer patients
with ypT0N0 tumor after
neoadjuvant RT-CT
« the French experience »
-FFCD 9203 phase III trial ; n= 742 T3/T4 rectal C.
-45 Gy /25f +/- 5FU-FA preop (week 1 and5)
• Prognostic value of ypT
stage (A) and tumor
regression grade (B) for local
recurrence-free time, among
patients with gross complete
resection (R0–1).
# 90% 10-year survival without
local recurrence for ypT0 patients
N Methy et al. Ann Oncol 2010 ; 21 : 518-24.
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Do we need post-operative CHEMOTHERAPY in patients
with PATHOLOGIC Complete Response to neoadjuvant
therapy in RECTAL CANCER ?
1. What is the evidence of activity of adjuvant
chemotherapy in rectal cancer?
2. How far can we consider patient with ypT0N0 as
cured?
3. cT3 vs cT4 ?
4. Do they benefit from adjuvant chemotherapy?
The EORTC 22921 trial: Discussion from Germany
Efficacy of adjuvant FU-FA in
ypT0-2 was questionned
by R Fietkau & G Klautke….
(JCO 2008 ; 26: 507).
In the German trial there was
no benefit in adjuvant CT
In ypT0-2 following
neoadjuvant RT-CT as long
as they were N0
(Dis Colon Rectum 2006 ; 49: 1284-92).
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The EORTC 22921 trial
R1
Low
middle
rectum
T3 - T4
surgery
R2
preop RT - CT
no adjuvant
preop RT
adjuvant CT (FU/FA x 4)
(1011 pts)
5 y local Recurrence rate was improved in RT-CT group:p = 0.001
5 y OS
5 y DFS
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no adjuvant
adjuvant
HR
63.2%
67.2%
0.85 ; p = 0.12
52.2%
58.2%
0.87 ; p = 0.13
but survival curves diverge after 5 y…
Bosset JF et al. NEJM 2006 ; 355: 1114-23. Colette L et al. J Clin Oncol 2007 ; 25: 4379-86.
The EORTC 22921 trial
• Exploratory analysis looking at the effect of
adjuvant CT on survival and risk of recurrences (R)
• All pT stage
• ypT0-2
• ypT3-4
effect of adjt CT
on risk of R
-6.7%
ns
- 13.9% p=0.02
+ 7.2% ns
• There was a suggestion of CT efficacy (FU/FA) in
patients responding to neoadjt TT (RT + CT or RT-CT)
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Colette L et al. J Clin Oncol 2007 ; 25: 4379-86.
The EORTC 22921 trial: CT effect on PFS and OS
Analysis focussing on
effect of adjuvant CT
(monthly bolus FU-FA)
in rectal cancer
randomized in the
EORTC trial …
on PFS and OS
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Colette L et al. J Clin Oncol 2007 ; 25: 4379-86.and J Clin Oncol 2008 ; 26: 507-509
The EORTC 22921 trial: CT and Survival (subgroup analysis)
Efficacy of adjuvant
FU-FA on OS in
ypT0-2 sub-population
…
Is apparently high !
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Colette L et al. J Clin Oncol 2007 ; 25: 4379-86.and J Clin Oncol 2008 ; 26: 507-509
The EORTC 22921 trial: CT and survival (subgroup analysis)
Efficacy of adjuvant FU-FA in ypT0-2 on OS is suggested but …
It did not consider patients according to their N status or
the type of preop treatment: RT vs RT-CT
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Colette L et al. J Clin Oncol 2007 ; 25: 4379-86.and J Clin Oncol 2008 ; 26: 507-509
The EORTC 22921 trial:
updated data…
Efficacy of adjuvant
FU-FA in ypT0-2 on OS
Is only seen in the
subgroup of patients
Receving RT alone as
preop tt….
But not in the
subgroup receiving
preop CT-RT
mai-16 L et al. J Clin Oncol 2008 ; 26: 507-509
Colette
Oxaliplatine based regimen for rectal cancer patients
after neoadjuvant RT-CT ?
• Experiences with oxaliplatine based chemotherapy + preop
radiotherapy
– have reported an increased pathological response rate
(ACCORD 12* ; STAR-01**) and
– But have not demonstrated a survival improvement
– And reported an increased toxicity.
• These trials don’t support the use of oxaliplatine based
chemotherapy in adjuvant for all patients in general and for
ypT0N0 patients in particular
* JP Gerad et al. JCO 2010 ; 28: 1638-1644 ; ** C Aschele et al ; JCO 2011 ; 29: 2773-2780)
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Conlusions• There is no proof that adjuvant chemotherapy is usefull in
ypT0N0 patients…
• These patients have an excellent prognostic in most of
the experiences.
• however adjuvant 5FU based chemotherapy is sometimes
discussed for selected patients with cT4 tumor…
• PETACC 6 (XELOX vs XelodaR) will answer the question
on utility of adding oxaliplatin to capecitabine in the
ypT0N0 but not on the utility of 5FU based adjuvant
treatment...
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DO WE NEED POSTOPERATIVE CHEMOTHERAPY
IN PATIENTS WITH PATHOLOGIC CR TO
NEOADJUVANT THERAPY IN RECTAL CANCER ?
NO
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Should we change the
recommendations from the expert
group at the World Congress on
Gastrointestinal Cancer
in Barcelona, 2007 ?
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The diagnosis and management of rectal cancer:
expert discussion and recommendations (World Congress
on Gastrointestinal Cancer) ; Barcelona, 2007
E. Van Cutsem et al, Annals of Oncology 19 (Supplement 6): vi1–vi8, 2008
• “It is, however, not completely clear whether patients that
had a complete response after the neo-adjuvant treatment
should also be offered postoperative adjuvant
chemotherapy [45].
• Adjuvant infusional 5-FU/folinic acid or capecitabine for a
period of 6 months is recommended.
• Oxaliplatin based regimens as postoperative
chemotherapy is considered by some experts, while
waiting the results of phase III trials in rectal cancer and
also in patients in whom 5-FU-based chemoradiotherapy
did not lead to a tumour regression or downsizing. “
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Final Conclusion
We should change the recommendations from the
expert group at the World Congress on
Gastrointestinal Cancer in Barcelona, 2007 ?
Presently there are no clear data supporting the
use of adjuvant chemotherapy in ypT0N0
patients who have an excellent prognosis.
These patients don’t need to be over-treated…
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