To the Editor: We appreciated the commentaries by Drs. Duda, Glimelius, and Willet on our paper “Current Perspectives on Preoperative Integrated Treatments for Locally Advanced Rectal Cancer: A Review of Agreement and Controversies” (August issue of ONCOLOGY). We would like to clarify our thinking on an issue raised by Dr. Glimelius regarding how sphincter preservation (SP) is dealt with in our paper. Dr. Glimelius stresses that long-course radiochemotherapy (LCRTCT) is not superior to short-course (SC) radiotherapy in achieving SP, citing the systematic review published by Bujko et al in 2006 that analyzes 10 randomized trials.
We absolutely agree that there is not sufficient evidence to support such a claim of superiority; indeed, a recent systematic review by Gerard et al analyzing 17 randomized trials, including the latest available, found similar results. We did not intend to assert that there was any significant evidence of superiority of one approach over the other, either in the short remarks on this subject in the body of our paper, or in Table 1. In fact, the issue of SP was not really dealt with in our review, since it would have required a lengthy treatment. It is difficult to analyze in detail all the variables potentially affecting the data from trials on this issue: stage, tumor location, type of neoadjuvant treatment, assessment of surgical operation based on pre- or post-treatment evaluation, the skill of the surgeon, modern surgical techniques, and length of follow-up.[2,3]
We mentioned downstaging and SP as being among the advantages (usual and potential) claimed by authors of LCRTCT reports, much as greater adherence to protocol or reduction of costs and shorter waiting lists are claimed as advantages of SC, even though these results are not seen in every situation and are not seen with statistical significance (Table 1). We wanted to highlight the potential correlation between the higher rate of downstaging and SP because such a correlation might represent a benefit for patients, perhaps more pronounced in some cultural environments, and because it could be considered as an important endpoint deserving of proper evaluation in future research (eg, SC schedules with delayed surgery are under evaluation to test whether these result in higher downstaging rates).
Some data seem to support this view. In the recently published 10-year follow-up of the Lyon R 96-02 randomized trial, the authors conclude that, apart from highly increased doses due to the use of brachytherapy, long-term SP was likely related to clinical response (the effect of downstaging); patients with a major clinical response had a higher rate of SP than did other patients, with a significant difference in the 10-year cumulative rate of permanent colostomy between patients with clinical complete responses, patients with ≥ 50% clinical response, and those with < 50% clinical response (P = .014).
Another aspect to consider is the role of the Biologic Equivalent Dose (BED). Meta-analyses by Glimelius et al and Wong et al have highlighted the fact that a BED ≥ 30 Gy is required to obtain significantly better results. BED is also at the heart of the rationale for the SC schedule. In 2011, Viani et al published a meta-analysis and metaregression evaluating the effect of BED and type of schedule on treatments; they included 21 trials of preoperative SC or LCRTCT vs surgery alone, and in 12 of these they analyzed the effect of radiotherapy on SP. They defined four treatment groups: BED > 30 Gy + short fractionation; BED > 30 Gy + long fractionation; BED < 30 Gy + short fractionation; BED < 30 Gy + long fractionation. In the subgroup analysis of the SP endpoint, the only subgroup showing a benefit with respect to SP was the one in which patients received long-schedule fractionation + BED > 30 Gy (P = .005).
In summary, we agree that there are still insufficient data to support the superiority of one schedule over the other, but in an era of personalized medicine we cannot easily accept that the available trials, which did not properly analyse all the variables involved in SP, constitute conclusive evidence; the absence of data should not be confused with the absence of a proper analysis. We hope that ad hoc trials, with large data base analysis (possibly population-based), and appropriate length of follow-up, will provide a better understanding of this sensitive aspect of quality of life for rectal cancer patients.
Francesco Cellini, MD
Radioterapia Oncologica, Policlinico Universitario Campus Bio Medico, Rome, Italy
Vincenzo Valentini, MD
Radioterapia Oncologica, Policlinico Universitario Agostino Gemelli, Rome, Italy