Reply to P.S.N. van Rossum et al and J. Shapiro et al
Authors: Christophe Mariette, William B. Robb
Journal: Journal of Clinical Oncology (2014)

gery Study] 4 ), but it is also suggested that this regimen may be responsible for the higher risk of grade 3/4 toxicity and finally for a higher proportion of patients who did not proceed to surgical resection. Even if the therapeutic regimen used in our trial could be responsible for these toxic effects, other factors can also explain the differences observed. The CROSS population had a much higher prevalence of adenocarcinomas, a tumor which is known to have better postoperative outcomes when compared with esophageal squamous cell carcinomas (SCC), in relation with (1) less frequentandlessseverecomorbidities,(2)alowerexposuretoalcoholand tobacco consumption, and (3) a lower risk of malnutrition. In addition, the higher proportion of lower third tumors found in the CROSS trial meant that patients not only received a lower total dose of radiation but also the lung volume spared from radiation was greater. This is a critical point with regards to the development of radiation-induced pneumonitis andsubsequentpostoperativemortality.Eveniftherateofaccrualwaslow in the FFCD trial, related to the relative rarity of patients presenting with early-stage tumors, low case volume per center cannot however be a relevant factor for explaining the higher postoperative mortality rate in the multimodality arm as this figure was only 3.4% in the surgery-only arm with randomization having been stratified by center. Second, regarding efficacy, the 33.3% of pathologic complete response (pCR) is suggested to be low when compared with the SCC population of the CROSS trial. Beside the fact such pCR rate is well within the acceptable range of pCR previously reported, 5 the CROSS trial pCR rate was only 29%, increasing to 49% in the SCC subpopulation that represented only 23% of the overall population. In comparison, SCC represented 70.3% of the overall population in the FFCD trial. Low numbers cannot be used to conclude about the relative efficacy of one regimen over another. Moreover, pCR has not been validated as a reliable surrogate end point in esophageal cancer. We do agree that when considering recurrence, CRT followed by surgery significantly reduced overall and locoregional recurrences in the FFCD trial, as if a subgroup of patients, still to be identified, might benefit from the multimodality regimen. However, any further subgroup analysis of the FFCD database would expose it to multiple testing-related errors, with results more related to chance than scientific relevance. It should be kept in mind that most of the patients died from metastatic disease (70.4% of the recurrence population in the FFCD trial) suggesting that more important than the chemoradiotherapy modalities used, a strategy that will offer a dramatic decrease in the risk of developing metastatic disease is urgently needed. This is not the case with the CROSS regimen, where only a slight decrease of hematogenous recurrences was observed (35% v 29%), the vast majority of patients still experiencing metastatic disease after multimodal treatment (90.5% of the recurrence population). 6 We can hypothetize that the high surgical quality provided in the FFCD 9901 trial, highlighted by the R0 resection rate of 92.1% after surgery alone, when compared with only 69% in the CROSS trial, may be responsible for overcoming the benefits of chemoradiotherapy. This may be specifically true in an early esophageal cancer population where the usual downsizing effect expected from chemoradiotherapy may not influence resection radicality. We believe that before considering the CROSS regimen as the standard of neoadjuvant treatment, several steps should be taken to validate the CROSS results. First, these results should be reproduced in other nonselected populations including earlier tumoral stages, SCC, upper third tumors and patients with poorer performance status. Second, a direct comparison of the FFCD regimen (used worldwide) and CROSS regimen (mainly used in the Netherlands) is needed to better understand which benefits are related to the chemoradiotherapy regimen itself and which benefits are related to patient selection. Such a research program is under investigation in France. All comments issued from comparison of differing populations with differences in perioperative care may be more speculative than scientific.