Surgery alone vs. chemoradiotherapy followed by surgery for localized esophageal cancer: analysis of a

randomized controlled phase III trial FFCD 9901

C. Mariette, JF Seitz, E Maillard, F Mornex, PA Thomas, JL Raoul, V Boige, D Pezet, C Genet, L Bedenne

French Federation of Digestive Oncology (FFCD)

FRANCE

Background

• Resection = the best treatment for resectable EC• Local recurrence, distant metastasis and poor

survival remain an issue after surgery• In locally advanced EC (T3N+), neoadjuvant CRT

– Often investigated– More and more evidence for survival benefit

• However impact of neoadjuvant CRT in small tumors is unknown

Mariette et al. Lancet Oncol 2005Mariette et al. Lancet Oncol 2007

Aim of the study

• To assess whether preoperative CRT improves outcomes for patients with localized (stages I or II) resectable esophageal carcinomas

• This study complied with the French and European Health guidelines on research involving human subjects

• Registred on clinicaltrials.gov NCT00047112 • Funding source: PHRC program from the French National Cancer Institute

Methods

• Randomized controlled phase III trial • 195 patients randomized by minimization

from 06/2000 to 06/2009• 30 centers in France• Stratification: center, histology, cTNM stage, tumoral

location• Eligibility criteria

– resectable thoracic esophageal SCC or ADC – cTNM stage I or II = T1N0/N+, T2N0/N+, T3N0 M0 (CT scan + EUS)– < 75 years old– OMS status 0 or 1– Weight loss < 15%– Written consent form

Study design• Neoadjuvant CRT + surgery group (CRT+S group, n=97)

45Gy/25F/5 weeks with 2 courses of concomitant CT 5FU 800mg/m2/day D1-D4 + cisplatin 75mg/m2 D1 or D2

• Surgery alone group (S group, n=98)Transthoracic approach with two-field lymphadenectomy

R

SURGERY

SURGERY 5FU-Cis x 2

RT 45 Gy

4 to 6 weeks

Endpoints • Primary endpoint:

Overall survival (time from randomization to all causes of death)

• Secondary endpoints: – Disease free survival (events: first reccurrence, second cancer or

all deaths)

– 30-day postoperative mortality– Postoperative morbidity– R0 resection rate– Prognostic factors identification

Statistical analysis

• To demonstrate an increase of OS from 35% (S group) to 50% (CRT+S group) with α=5% and 1-β=80%380 patients needed (195 deaths)

• Results of a planned interim analysis for primary endpoint after 106 deaths (O’brien-fleming)

• Intention to treat analysis • Median follow-up (reverse kaplan-meier method):

68.7 [60.5-75.9] months

Patient characteristics

CRT +S group N = 98

S group N = 97

Gender

male 87 (88.8%) 80 (82.5%)

female 11 (11.2%) 17 (17.5%)

Mean age 58.4 y 57.3 y

OMS status

0 76 (77.6%) 71 (73.2%)

1 22 (22.4%) 22 (22.7%)

2 0 1 (1%)

unknown 0 3 (3.1%)

Tumor characteristicsCRT +S group

N = 98S group N = 97

Histology

SCC 67 (68.4%) 70 (72.2%)

ADC 30 (30.6%) 27 (27.8%)

undifferenciated 1 (1.0%) 0

UICC clinical stage

stage I 17 (17.3%) 18 (18.6%)

stage IIA 49 (50.0%) 49 (50.5%)

stage IIB 32 (32.7%) 30 (30.9%)

Tumoral location

Above carena 8 (8.2%) 10 (10.3%)

Below carena 90 (91.8%) 87 (89.7%)

Neoadjuvant treatment toxicity

• Patients with at least one grade ¾ toxicity in the CRT + S group10.2% during cycle 1 13.3% during cycle 2

→ mainly leucopenia, neutropenia, thrombocytemia and mucositis

Serious adverse events (SAE)

CRT+S group N = 98

S group N = 97

P

At least one SAE 47 (48.0%) 26 (26.8%) 0.002

No SAE 51 (52.0%) 71 (73.2%)

Total nb of SAE 62 (65.3%) 33 (34.7%) 0.003

Grade ¾ SAE 30/47 (63.8%) 14 /26 (53.8%) 0.59

Causes for no surgery

• Patients who finally underwent surgery– 84/98 = 86% in the CRT + S group– 91/97 = 94% in the S group

CRT +S group N = 14

S group N = 6

TotalN=20

Tumoral progression 4 3 7 (35%)

Treatment toxicity/poor OMS status

4 0 4 (20%)

Cirrhosis 1 1 2 (10%)

Patient’s refusal 2 0 2 (10%)

Others 3 2 5 (25%)

Postoperative course

CRT + S groupN=84

S groupN=91

P

30-day postop mortality

6 (7.1%) 1 (1.1%) 0.054

Postoperative morbidity

37 (44.1%) 45 (49.5%) 0.18

Mean nb of resected nodes

17.7 23.9 <0.001

R0 resection 81 (96.4%) 84 (92.3%) 0.33

pCR 24 (28.6%) - -

Mean LOS (d) 24.8 22.1 0.87

Overall survival

CRT + S group S group P HR

Median survival (months)

31.8 [25.2-72.5] 44.5 [29.8-59.1]0.68 0.92

[0.63-1.35]3-year survival 48.6% 55.2%

With 55% of events and alpha =0.005, the probability of showing a difference between the 2 groups was judged very low, so the trial was stopped for futility(according to O’brien-fleming stopping rule boundaries)

0.00

0.25

0.50

0.75

1.00

Ove

rall

Su

rviv

al

0 12 24 36 48 60 72 84 96 108Time (months)

97 81 55 40 32 21 15 8 3Surgery98 70 50 37 32 26 20 10 4RT/CT + Surgery

Number at risk

Disease free survival

CRT + S group S group P HR

Median DF survival (months)

24.6 [14.9-46.9] 26.0 [22.9-43.1] 0.98 1.01 [0.71-1.43]

3-year survival 41.2% 43.9%

0.00

0.25

0.50

0.75

1.00

Dis

eas

e fr

ee S

urv

ival

97 70 48 33 25 16 10 7 2Surgery98 66 43 32 28 23 19 10 4RT/CT + Surgery

Number at risk

0 12 24 36 48 60 72 84 96 108Time (months)

To summarize

• When comparing CRT+S vs S alone in small EC– High surgical quality (R0, LN, mortality)– Efficacy of the standard CRT regimen (pCR 28.6%)– More SAE but not severe SAE in the CRT+S group– No significant difference regarding postoperative mortality

(p=0.054) but clinically relevant (7-fold increase)

– No survival benefit– No chance for showing any difference in favour of CRT+S,

reason why the trial was stopped even if a relatively small number of patients included

Conclusion

In esophageal cancers

Neoadjuvant CRT followed by surgery does not improve survival for stage I or II tumors

With a trend toward higher postoperative mortality

Discussion

• Were patients overtreated?→ Benefit-risk balance is against neoadjuvant CRT

• Is surgery alone the standard treatment for stage I or II?→ Probably no for N+ patients due to poor survival

• To discuss– Others CT or CRT regimen?– Intensity Modulated Radiation Therapy ? – Tailored approach with neoadjuvant chemo for T1/T2 N+ patients?– Better administation of preoperative treatment regarding patient’s

global health status?

Thanks to• Investigators

– Lille (Prs C Mariette- JP Triboulet)– Marseille (Pr JF Seitz, Pr PA Thomas)– Lyon (Pr F Mornex, Pr J Baulieu)– Rennes (Prs JL Raoul, B Meunier)– Villejuif (Dr V Boige)– Clermont-ferrand (Pr D Pezet)– Limoges (Dr C Genet)– Dijon (Pr L Bedenne)– Besançon ( Pr JF Bosset)– Angers (Pr E Gamelin)– Avignon Clinique (Dr L Mineur)– Boulogne sur mer (Dr J Charneau)– La Roche sur Yon (Dr R Faroux)– Nantes (Pr B Buecher)– Vandoeuvre les Nancy (Pr T Conroy)– Montpellier (Pr M Ychou)– Bourg en bresse (Dr D Pillon)– Bourgoin-Jallieu (Dr N Stremsdoerfer)– Brest (Pr P Lozac’h)– Colmar (Dr B Denis)– Meaux (Dr C Locher)

• Investigators– Mulhouse (Dr B Vedrenne)– Paris G Pompidou (Dr B Landi)– Saint Malo (Dr P Thevenet)– Strasbourg (Dr JC Ollier)– Briis sous forges (Dr MC Clavero-Fabri)– Vannes (Dr V Klein)– Paris (IMM) (Pr B Gayet)

• Biostatisticians E. Maillard, F. Bonnetain

• Research project manager and data manager (M. Moreau, F. Ricard, C. Fuchey)

• Study nurses and the FFCD team

• Patients