In Reply
Authors: Laurent Bedenne, Franck Bonnetain
Journal: Journal of Clinical Oncology (2007)

Dr Ruhstaller et al suggest that our conclusion 1 is not supported by our data and that the trial design has some major limitations.Their first remark is that chemoradiotherapy was not the same in both arms-this is not a bias and simply reflects the essential difference between strategic trials and drug-based trials.When comparing two drugs, everything must be identical in both arms except the study drug, though when comparing two strategies, an experimental strategy is compared with the therapeutic strategy recognized as the reference.Chemoradiotherapy and surgery can be considered as the reference strategy on the basis of three consistent meta-analyses. 2 The experimental strategy may differ considering the doses of chemotherapy or radiotherapy.Indeed, it is not recommended to apply high doses of radiation before surgery, and postoperative chemotherapy or chemoradiotherapy is seldom possible in these patients.Moreover, no randomized studies showed any survival benefit for postoperative adjuvant treatment.As an example, the dissymmetry of treatment schemes between arms was present in the trial by Al-Sarraf et al, 3 which proved the superiority of chemoradiotherapy on radiation alone in inoperable esophageal cancer.The dose of radiation was 64 Gy in the radiotherapy alone arm versus 50 Gy in the chemoradiotherapy arm.The second remark puts forward the problem of inaccurate staging, based on the figure of 75% of the patients having R0 resection in the surgery arm.Staging of esophageal cancer is indeed difficult, and the prediction of R0 resectability is a challenge.However, in the published trials of surgery versus preoperative chemoradiotherapy in patients deemed operable, R0 resection rates vary between 69% and 91% in the surgery arm and between 69% and 96% in the preoperative chemoradiotherapy arm, in intent to treat, which is the only nonbiased way of analyzing a randomized trial. [4]5][6][7] The percentage of R0 resectability in the Fe ´de ´ration Francophone de Cance ´rologie Digestive 9102 was 75% in intent to treat, and is in agreement with the published data, considering that only locally advanced tumors were included in the trial.The R0 resectability rate raised up to 85% if the patients refusing surgery were not taken into account.This figure compares well with the 87% R0 resectability rate in the series at the M.D. Anderson Cancer Center between 1986 and 1996, the period during which FFCD 9102 was conducted. 8 In FFCD 9102, we supported an academic and public health point of view with the aim of reflecting the impact of strategy in clinical practice.It included taking into account (1) the insufficiency of staging by clinicians when they have to decide which treatment to apply and (2) the patient's choice regarding therapeutic decision.Indeed, the interest of randomizing large numbers of patients is to offset possible imbalance resulting from the difficulty of precisely staging esophageal cancer.However, to strengthen our conclusion, we provided in Figure 3 the survival curves in per protocol (ie, removing the patients who refused surgery from the surgery arm and including them in the chemoradiotherapy arm).Overall survivals remained similar.Thus,