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 janv.-19

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... janv.-19

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?

ADJUVANT CHEMOTHERAPY IN RECTAL CANCER Studies on adjuvant treatments in rectal cancer Chemotherapy alone radio-chemotherapies combinations Meta-analysis janv.-19

Adjuvant chemotherapy (CT) CT in rectal cancer 5-y survival Adjt vs Surgery 67% vs 59% p=.05 (m > 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 p=0.008 81% vs 60% (3-y OS) p=0.005 NSABP R-01: (FISHER et al. JNCI 1988) CT (MOF: FU-MeCCNU) : 379 vs control : 394 GITSG 7175 : (N Engl J Med 1985 ; 1986) 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 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 ... janv.-19

2 Meta-analysis in adjuvant CT in rectal cancer Risk of death (HR) HR : 0.857 (p<0.049) RR : 0,83 for rectal K (p<0,02) HR : 0.64 (p<.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, 40:35-41) 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... janv.-19

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 (p<0,0001) Overall Survival : HR : 0,82 (p<0,02) janv.-19

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 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”. janv.-19

BUT ? DO WE NEED POSTOPERATIVE CHEMOTHERAPY IN PATIENTS WITH PATHOLOGIC CR (ypT0N0) TO NEOADJUVANT THERAPY IN RECTAL CANCER ? janv.-19

How far can we consider patient with ypT0N0 as cured? 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?

Local recurence rate # 0 - 3% Distant recurrences <10% 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) janv.-19

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. janv.-19

=> 86% 5-year DFS for TRG4 patients 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. janv.-19

=> # 90% 5-year survival for ypT0N0 patients 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 => # 90% 5-year survival for ypT0N0 patients S Gollins et al. JCO 2011 ; 29: 1042-1049 janv.-19

# 90% 10-year survival without local recurrence for ypT0 patients 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. janv.-19

How far can we consider patient with ypT0N0 as cured? cT3 vs cT4 ? 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?

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). janv.-19

no adjuvant adjuvant HR but survival curves diverge after 5 y… 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 group:p = 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… janv.-19 Bosset JF et al. NEJM 2006 ; 355: 1114-23. Colette L et al. J Clin Oncol 2007 ; 25: 4379-86.

All pT stage effect of adjt CT -6.7% ns 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% p=0.02 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) janv.-19 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 janv.-19 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 ! janv.-19 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 janv.-19 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 janv.-19 Colette L et al. J Clin Oncol 2008 ; 26: 507-509

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) janv.-19

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... janv.-19

DO WE NEED POSTOPERATIVE CHEMOTHERAPY IN PATIENTS WITH PATHOLOGIC CR TO NEOADJUVANT THERAPY IN RECTAL CANCER ? NO janv.-19

Should we change the recommendations from the expert group at the World Congress on Gastrointestinal Cancer in Barcelona, 2007 ? janv.-19

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. “ janv.-19

These patients don’t need to be over-treated… 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… janv.-19