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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1343-1344 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.312
In Reply:Division of Cancer Care and Epidemiology, Queen's Cancer Research Institute, Kingston, Ontario, Canada We are grateful for the opportunity to respond to letters pertaining to our recent article1 on the association between treatment delay and the outcomes of radiotherapy (RT). We agree with Recht's view that higher doses of radiation may diminish the impact of delay in RT on the probability of local recurrence. In theory, a higher dose might be effective in compensating for any increased tumor burden due to delay.2 Furthermore, we concur that the results reported by Schiff et al3 are consistent with that hypothesis. We also agree with both Recht and Blot et al that the impact of delay on the probability of local recurrence will depend on the proportion of patients in whom residual disease is present and on the burden of disease in those patients. Both Blot et al and Hèbert-Croteau et al correctly point out that the results of our meta analyses depend to some extent on which studies are included, and they reasonably question why certain studies were not included in our analysis. Our inclusion criteria were described in the original paper; we excluded studies in which there were significant disease-related or treatment-related differences between the delayed and nondelayed groups, for which we could not control in the analysis. Thus the paper by Nixon et al,4 about which Hèbert-Croteau et al were specifically concerned, was excluded because the extent of the surgical resection was significantly greater among the patients who waited longer for RT, and we were concerned that any association between delay and recurrence might have been confounded by the association between extent of resection and the probability of recurrence. Similarly, the paper by Wallgren5 was excluded because there was a major difference in chemotherapy between the early and late RT groups; the patients who waited longer for RT received six cycles of chemotherapy, whereas those who waited the shorter period received only three cycles of chemotherapy. Hèbert-Croteau et al suggest that data published in abstract form only should not have been included in our analysis. We understand their perspective, but disagree with that conclusion. As we discussed in the original article, we were very concerned about the possibility of publication bias—specifically, that studies that demonstrated a significant association between delay and outcome were more likely to have appeared in a peer-reviewed publication than those that failed to demonstrate such an association. Including only the studies published in peer-reviewed journals would have exposed us to the risk of finding an artificial association between delay and outcome, due only to publication bias. We therefore decided to include all studies that met our basic inclusion criteria in the main analysis and to carry out secondary analysis after excluding the lower-quality studies, to determine the extent to which they influenced the results. We included the results of both primary and secondary analyses to permit readers to reach their own conclusions. Hèbert-Croteau et al conclude that we do not have firm evidence concerning "the specific delay that would have a detrimental effect on outcomes." However, there is no theoretical or empirical basis for believing that there is any specific threshold of delay below which there is no risk, and we did not expect to find one.5 However, there are sound theoretical reasons to suspect that any delay may increase the probability of local failure, and there is a substantial body of empirical data that appears to confirm that there is indeed a measurable incremental risk of recurrence associated with delays of the order of a few weeks. We therefore reiterate our previous recommendation that delays in initiating RT should be as short as is reasonably achievable. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Huang J, Barbera L, Brouwers M, et al: Does delay in starting treatment affect the outcomes of radiotherapy?. A systemic review. J Clin Oncol 21:555-563, 2003 2. Mackillop WJ, Bates JHT, Withers HR: The effect of delay in treatment on local control by radiotherapy. Int J Radiat Oncol Biol Phys 34:243-250, 1996[CrossRef][Medline] 3. Schiff PB, Harrison LB, Strong EW, et al: Impact of the time interval between surgery and postoperative radiation therapy on locoregional control in advanced head and neck cancer. J Surg Oncol 43:203-208, 1990[Medline] 4. Nixon AJ, Recht A, Neuberg D, et al: The relation between the surgery-radiotherapy interval and treatment outcome in patients treated with breast-conserving surgery and radiotherapy without systemic therapy. Int J Radiat Oncol Biol Phys 30:17-21, 1994[Medline] 5. Wallgren A, Bernier J, Gelber RD, et al: Timing of radiotherapy and chemotherapy following breast conserving surgery for patients with node-positive breast cancer. Int J Radiat Oncol Biol Phys 35:649-659, 1996[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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