Do we need post-operative CHEMOTHERAPY in patients with PATHOLOGIC Complete Response to neoadjuvant therapy in RECTAL CANCER ?

1
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 dHépatogastro-enté
rologie) Paris V Rene Descarte University Hopital
Européen Georges Pompidou 75015 Paris France
2
PROGNOSTIC FACTORS IN RECTAL CANCER

• Size (cT) and site of the primary
• Quality of the surgery
• Mesorectal excision (TME)
• Lateral clearance gt1mm
• 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...

3
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
• What is the evidence of activity of adjuvant
  chemotherapy in rectal cancer?
• How far can we consider patient with ypT0N0 as
  cured?
• cT2-T3 vs cT4 ?
• Do they benefit from adjuvant chemotherapy?

4
ADJUVANT CHEMOTHERAPY IN RECTAL CANCER

• Studies on adjuvant treatments in rectal cancer
• Chemotherapy alone
• radio-chemotherapies combinations
• Meta-analysis

5
Adjuvant chemotherapy (CT) CT in rectal cancer
5-y survival Adjt vs Surgery 67 vs 59 p.05 (m
gt f ) 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 p0.008 81 vs 60 (3-y OS)
p0.005

• NSABP R-01 (FISHER et al. JNCI 1988)
• CT (MOF FU-MeCCNU)
• 379 vs control 394
• GITSG 7175 (N Engl J Med 1985 1986)
• FUMeCCNU vs control
• 48 / 58
• Dutch trial (Fan Zoetmulder, ASCO 99, 1021)
• FUlevamisole vs control 299
• 299 rectum / 1029 pts
• QUASAR trial (r Gray, Lancet 2007)
• 3239 patients 94 -03
• FUFA or lev vs control
• 29 rectum 940 pts
• Japanese trial ((Akasu T et al. Jpn J Clin Oncol
  2006 ))
• 276 patients
• Oral FU (UFTR) vs control
• Rectum stage III

little proves of efficacy of Adjuvant CT in
rectal cancer ...
6
2 Meta-analysis in adjuvant CT in rectal cancer
Risk of death (HR) HR 0.857 (plt0.049) RR
0,83 for rectal K (plt0,02) HR 0.64
(plt.05) Survival gain 9

• Sakamoto, (4960 pts)
• ( Jpn J Clin Oncol 1999 29 78-86)
• Tegafur ou Carmofur oral
• S. Dubé (695 pts)
• (Dis Colon Rectum, 1997, 4035-41)
• 39 trials 1959-1993
• quality score 49
• rectum 695 / 12079

Adjuvant chemotherapy (5FU) is active as adjuvant
TT in rectal cancer but a poor level of
efficacy...
7
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.
DFS and OS Better after adjt CT Using oral 5FU
2091 rectal cancer Cox model DFS HR
0,73 (plt0,0001) Overall Survival HR 0,82
(plt0,02)
8
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.
DFS is Better after adjt CT Using oral
5FU P0.002 Even in Dukes A
9
The diagnosis and management of rectal
cancerexpert discussion and recommendations
(World Congress on Gastrointestinal Cancer)
Barcelona, 2007E. Van Cutsem et al, Annals of
Oncology 19 (Supplement 6) vi1vi8, 2008

• Most patients who received a preoperative RT or
  CT-RT are candidates for postoperative adjuvant
  chemotherapy.
• The initial staging before the administration of
  neo-adjuvant 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.

oct.-20
10

• BUT
• DO WE NEED POSTOPERATIVE CHEMOTHERAPY IN
• PATIENTS WITH PATHOLOGIC CR (ypT0N0) TO
• NEOADJUVANT THERAPY IN RECTAL CANCER
• ?

oct.-20
11
Do we need post-operative CHEMOTHERAPY in
patients with PATHOLOGIC Complete Response to
neoadjuvant therapy in RECTAL CANCER ?

• What is the evidence of activity of adjuvant
  chemotherapy in rectal cancer?
• How far can we consider patient with ypT0N0 as
  cured?
• For all patients cT3 vs cT4 ?
• Do they benefit from adjuvant chemotherapy?

12

• Rectal cancer pts with a pathologic CR (ypT0N0)
  after neoadjuvant tt have an excellent prognosis
• Local recurence rate 0 - 3 Distant recurrences
  lt10
• 5 year DFS in patients ypT0 (n73) 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)

oct.-20
13

• 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.

oct.-20
14
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).

gt 86 5-year DFS for TRG4 patients
C Rödel et al. JCO 2005 23 8688-96.
oct.-20
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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.

ypT0N0
gt 90 5-year survival for ypT0N0 patients
S Gollins et al. JCO 2011 29 1042-1049
oct.-20
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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 (R01).

• 90 10-year survival without
• local recurrence for ypT0 patients

N Methy et al. Ann Oncol 2010 21 518-24.
oct.-20
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Do we need post-operative CHEMOTHERAPY in
patients with PATHOLOGIC Complete Response to
neoadjuvant therapy in RECTAL CANCER ?

• What is the evidence of activity of adjuvant
  chemotherapy in rectal cancer?
• How far can we consider patient with ypT0N0 as
  cured?
• cT3 vs cT4 ?
• Do they benefit from adjuvant chemotherapy?

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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).
oct.-20
19
The EORTC 22921 trial
R1 R2 Low middle preop RT -
CT no adjuvant rectum T3 - T4 preop
RT adjuvant CT (FU/FA x 4) (1011 pts) 5 y
local Recurrence rate was improved in RT-CT
groupp 0.001
surgery
no adjuvant adjuvant HR 5 y OS
63.2 67.2 0.85 p 0.12 5 y
DFS 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.
20
The EORTC 22921 trial

• Exploratory analysis looking at the effect of
  adjuvant CT on survival and risk of recurrences
  (R)
• All pT stage effect of adjt CT -6.7 ns
• ypT0-2 on risk of R - 13.9 p0.02
• ypT3-4 7.2 ns
• There was a suggestion of CT efficacy (FU/FA) in
  patients responding to neoadjt TT (RT CT or
  RT-CT)

Colette L et al. J Clin Oncol 2007 25 4379-86.
21
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
Colette L et al. J Clin Oncol 2007 25
4379-86.and J Clin Oncol 2008 26 507-509
22
The EORTC 22921 trial CT and Survival (subgroup
analysis)
Efficacy of adjuvant FU-FA on OS in ypT0-2
sub-population Is apparently high !
Colette L et al. J Clin Oncol 2007 25
4379-86.and J Clin Oncol 2008 26 507-509
23
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
Colette L et al. J Clin Oncol 2007 25
4379-86.and J Clin Oncol 2008 26 507-509
24
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
Colette L et al. J Clin Oncol 2008 26 507-509
25
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 dont 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)
26
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

28

• Should we change the recommendations from the
  expert group at the World Congress on
  Gastrointestinal Cancer
• in Barcelona, 2007 ?

29
The diagnosis and management of rectal
cancerexpert discussion and recommendations
(World Congress on Gastrointestinal Cancer)
Barcelona, 2007E. Van Cutsem et al, Annals of
Oncology 19 (Supplement 6) vi1vi8, 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 dont need to be over-treated