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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 508-509 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.0938
In Reply:Statistics Department, European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium
Department of Radiation Therapy, University of Franche-Comté, Besançon, France We read with great interest the pertinent comments made by Fietkau and Klautke in reaction to our earlier communication concerning the selection of patients to postoperative chemotherapy (CT) following neoadjuvant radiotherapy (RT) or radiochemotherapy (RCT) in rectal cancer,1 and thank you for giving us the opportunity to reply. We wish to address some of their remarks as follows. Concerning the impact of the type of neoadjuvant treatment, we published in abstract form2 separate results for the group treated neoadjuvantly with RT alone and for the group that received neoadjuvant RCT. However, we elected during the oral presentation at the European Cancer Conference (as well as in the full publication) not to present these results. The reasoning underlying our decision to report only the overall results as double: First, based on statistical reasoning, we considered that separating patients in eight groups (by neoadjuvant treatment, ypT, and postoperative treatment) resulted in small patient numbers. We were able to demonstrate heterogeneity of results in response to adjuvant CT for the pooled groups of patients with ypT1-2 versus ypT3-4 irrespective of neoadjuvant treatment (P = .1; df = 1), but the power is insufficient to definitely determine if the impact of ypT onto the effect of postoperative treatment differs significantly according to the preoperative treatment. On statistical grounds, it seemed therefore more reliable to consider the results for the pooled group rather than to attempt a further specification by neoadjuvant treatment, though indeed, the point estimates for the impact of ypT on the effect of postoperative CT quoted by Fietkau et al and stated in the the European Cancer Conference 10 abstract2 only reached statistical significance for the subgroup of patients who had not received neoadjuvant CT. Thus, we agree with Fietkau and Klautke that the type of neoadjuvant treatment may be important, as it may impact on the predictive value of the classification we proposed. However, the available data thus far do not allow us to firmly conclude whether our findings should be limited to the irradiated patients only nor if for the group of patients with neoadjuvant RCT. Submitting only the patients with ypT0-2 disease to adjuvant CT would be worse than submitting all patients to that treatment, as is done in many centers, when overall adjuvant CT has not showed any benefit.3 To definitively address this question in a trial that randomly assigns patients between two preoperative treatment options, one would need to design the trial with a randomization for the adjuvant treatment taking place after the histopathological results are known, to stratify the randomization upfront for the downstaging effect and the type of preoperative treatment, and to power the trial for assessing the adjuvant treatment effect within the subgroups. Such an undertaking would, however, require an extremely large number of patients. Second, in presenting our results, we explained our belief that the ypT stage achieved at the end of the preoperative treatment is used to "identify a posteriori the good prognostic patients," and that we do not believe there is any causality relating downstaging by preoperative treatment per se to a greater sensitivity to postoperative CT. Our reasoning is that some patients bear good prognostic features that make them more prone to achieve both tumor downstaging by preoperative treatment and improved disease-free survival by adjuvant CT. The observed ypT stage is here used as a posthoc screening for the good prognostic nature of the patients. However, as rightly quoted by Fietkau and Klautke, the likelihood of downstaging was increased after RCT, in comparison to RT alone: 57.8% of patients were downstaged to ypT0-2 after RCT versus 42.7% after RT alone. A proportion of the patients who would not have achieved downstaging with RT alone, thus achieved tumor downstaging with RCT. The consequence of this is that the group of patients achieving ypT1-2 after RT alone is of better prognosis (more strictly selected, 42.7% of the sample) than the group of patients who achieved ypT1-2 after RCT (less strictly selected, 57.8% of the sample). This in turn may explain why the predictive value of the ypT classification is decreased in the group treated neoadjuvantly with RCT, in comparison to the group treated with RT alone: the relative benefit of adjuvant CT for patients with ypT0-2 disease versus those with ypT3-4 disease for overall survival is 2.93 in the neoadjuvant RT subgroup and 1.50 in the neoadjuvant RCT subgroup (Fig 1). For disease-free survival, the corresponding figures are 2.97 (neoadjuvant RT) and 1.33 (neoadjuvant RCT).
As regards the second comment of Fietkau and Klautke, regarding the impact of adjuvant CT in patients with pN0 disease, we followed their suggestion and assessed the benefit of adjuvant CT in the subgroup of pN0 patients with neoadjuvant RCT. Based on 78 deaths, the hazard ratio for adjuvant CT is 1.04 (95% CI, 0.66 to 1.63; Fig 2), and for disease-free survival, based on 102 events, it is 1.01 (95% CI, 0.68 to 1.49; Fig 3).
Finally, we want to stress once more that the response to neoadjuvant treatment is proposed as an imperfect tool for selecting patients who would be more prone to benefit from adjuvant treatment, but that more immediately relevant biologic factors, such as for example classificators based on the analysis of gene expression profiles of the primary tumor, are needed to reliably identify the patients who may benefit from adjuvant fluorouracil-based CT or, more importantly, from adjuvant treatment with more newly targeted agents. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25:4379-4386, 2007 2. Collette L, Calais G, Mineur L, et al: Patients with R0 resection of T3-4 rectal cancer after preoperative radio- or radiochemotherapy: Does anybody benefit of post-operative LV/5-FU chemotherapy? Further results of EORTC trial 22921. Eur J Cancer 3:170, 2005 (suppl; abstr 607) 3. Bosset JF, Collette L, Calais G, et al: Chemotherapy with pre-operative radiotherapy in rectal cancer. N Engl J Med 355:1114-1123, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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