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Is Surgery Still Part of Local Therapy in Patients With Locally Advanced Esophageal Carcinoma?

Kantonsspital St Gallen, St Gallen, Switzerland

Roger von Moos

Kantonsspital Chur, Chur, Switzerland

To the Editor:

We read with great interest Bedenne et al's long-awaited article, which was published in the April 1, 2007, issue of the Journal of Clinical Oncology.¹ We would like to congratulate Bedenne and his colleagues on successfully conducting a randomized trial in this highly interdisciplinary and complex field of locally advanced esophageal carcinoma. The authors suggested in their conclusion that in patients responding to chemoradiotherapy there is no survival benefit for the addition of surgery compared with the continuation of additional chemoradiotherapy. We do not share the authors' interpretation of the presented results, which we think is not supported by their data for the following reasons.

First, the study, which primarily aimed to compare two local therapy strategies, has a major design problem, as patients randomly assigned to additional chemoradiotherapy received distinctly more systemic therapy compared with patients in the surgery arm. Overall survival, the primary end point of this study, could have been influenced by the misbalance of chemotherapy application both in dose and length between arms.

Second, there are suggestions for a selection of patients with unfavorable characteristics preferring the nonsurgical arm. Of 129 patients randomly assigned to the surgery arm, 32 patients (25%) were not compliant or, finally, not curatively (R0) resectable, though resectability was a major inclusion criterion. At least 19 of these 32 patients were technically inoperable or not R0 resectable, the other 13 patients refused surgery or received no further therapy for unspecified reasons. As only responding patients following chemoradiotherapy were randomly assigned, it is unlikely that one in four patients became unresectable between study inclusion and random assignment. It appears probable that an important number of patients was not accurately staged at study entry, probably understaged, and therefore diluted the possibly positive outcome of the surgery arm. This understaging is not really surprising, as the computed tomography scan and esophagogram were the major investigations for patient selection, whereas endoscopic ultrasonography was only used when available. Inaccurate staging can lead to significant bias and stage migration, especially in this case where the rate of R0 resections is of paramount importance for cure and disease-related survival after surgery.

Third, 43% of the registered and eligible patients for this study were not randomly assigned after chemoradiotherapy because these were qualified as nonresponders. However, the response assessment with the described methods within about 2 weeks after the end of chemoradiotherapy is known to be notoriously difficult and poorly reproducible because of inflammation at the tumor site. It is likely that some responding patients were excluded from random assignment, whereas some nonresponding patients were randomly assigned. This might have added another selection bias, especially as this study was not blinded for obvious reasons. Ilson considered in his editorial,² that a subgroup of the nonrandomized and excluded patients could have had a benefit from salvage surgery. However, the poor survival of the excluded (nonresponding) patients rather suggests that many patients had quite far advanced disease with a high tumor burden. As mentioned earlier, adequate staging is paramount in studies investigating surgery in esophageal carcinoma. In this context, it would be of interest to know whether the response assessment before surgery also was confirmed by the pathology examination.

Fourth, taking into account the therapeutic mortality rate of surgery (11%) in addition to the issues mentioned earlier that prefer the radiotherapy arm, it is quite surprising that patients treated in the surgery arm did not experience a significantly worse outcome. Unfortunately, the authors failed to report data for disease-free-survival. However, the cancer-related death rates mentioned in the publication were 64% (58 of 129) in the surgery arm compared with 79% (72 of 130) in the nonsurgical arm. This suggests that some patients probably benefit from additional surgery, and overall survival alone in this study population might give us insufficient information about all confounding factors regarding outcome and especially about the value of these two treatment strategies.

In summary, we acknowledge the efforts made by Bedenne et al in this highly difficult and complex setting; however, we are convinced that their conclusions are not adequately supported by data because of inherent insufficient methodology. The absence of evidence for a survival benefit by additional surgery in this inadequately staged patient population does not mean that there is enough evidence to abandon surgery as a crucial element in the treatment of patients with locally advanced esophageal cancer. In fact, this study shows again clearly that we need much larger and better designed trials to investigate the optimal use of surgery, radiotherapy, and chemotherapy.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Bedenne L, Michel P, Bouché O, et al: Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 25:1160-1168, 2007[Abstract/Free Full Text]

2. Ilson D: Surgery after primary chemoradiotherapy in squamous cancer of the esophagus: Is the photon mightier than the sword? J Clin Oncol 25:1155-1156, 2007[Free Full Text]

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