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Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 6266-6267 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.5040
Sequential or Concurrent Tamoxifen and Radiotherapy: To See or Not to See—That Is the Question!University of Wisconsin Medical School, Department of Human Oncology, Madison, WI
Department of Radiotherapy, The Royal Marsden Hospital, Sutton, Surrey, United Kingdom To the Editor: We read with great interest the three reports1-3 on locoregional control of early-stage breast cancer after sequential versus concurrent tamoxifen and radiotherapy, and the accompanying editorial by Whelan and Levine4 in the January 1, 2005, issue of the Journal of Clinical Oncology. The authors of all three papers are appropriately cautious in interpreting their findings. Whelan and Levine summarize the limitations of the three studies and conclude that the way forward is a large randomized controlled trial. Although we accept their conclusion, we are surprised that Whelan and Levine felt that a meta-analysis was not appropriate. We disagree and on the contrary feel that such an analysis would provide a useful illustration of the statistical power issues involved here. Figure 1 shows a forest plot of the hazard ratios (HR) reported in the three studies on the sequencing of tamoxifen and radiation. With a total of 1,082 patients enrolled onto the three studies, the pooled overall HR was 0.91 with 95% CI 0.52 to 1.61. A useful interpretation of the 95% CI5 is that it represents the set of treatment effects—in this case, effect of scheduling—that cannot be rejected at the 5% level after pooling the outcomes of the three studies. The lower and upper bounds on the 95% CI are perhaps best put in perspective by comparison with the effect of giving tamoxifen at all as estimated from the meta-analysis published by the Early Breast Cancer Trialists' Cooperative Group in 1998.6 The HRs for any type of recurrence (local, contralateral, or distant) after 1, 2, and 5 years of tamoxifen were 0.79, 0.71, and 0.53, respectively. In other words, the difference in HR between the sequential and concurrent radiotherapy and the tamoxifen could be as large as the difference between giving tamoxifen or not. An inferior sequence of the two treatments could be equivalent to a complete abrogation of the reduction in recurrence rate from adjuvant tamoxifen! A randomized controlled trial of sequencing of tamoxifen and radiation would have to be quite large to have sufficient power to give a clinically meaningful statistical resolution in patients with early-stage breast cancer. If we assume a 90% local control rate after radiotherapy alone, and if we further accept that the difference in HR between 2 and 5 years of tamoxifen defines a clinical minimal relevant difference, we estimate that the proposed trial should plan to recruit 7,734 patients to achieve a power of 90% when testing at the 5% level.
A final issue discussed in the January 1, 2005, issue of the Journal1,3,4 is that the two sequences of radiation and tamoxifen may or may not differ with respect to the incidence of late adverse effects. Elucidating this question should also be a research aim of the proposed trial. If, however, the effect of tamoxifen on radiation-induced fibrosis is mediated by a release of transforming growth factor–beta (TGF-ß), as Bentzen et al proposed,7 then the interaction will affect the tissue remodeling rather than the damage induction step of the radiation pathogenesis. In this case, temporal separation of the two modalities may not make much difference in the incidence of fibrosis-related late effects. A few studies have shown that TGF-ß may enhance cellular radiosensitivity in vitro,8-10 whereas other studies suggest the opposite.11 The clinical relevance of these data remains to be demonstrated. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Pierce LJ, Hutchins LF, Green SR, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24-29, 2005
2. Ahn PH, Vu HT, Lannin D, et al: Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol 23:17-23, 2005
3. Harris EE, Christensen VJ, Hwang WT, et al: Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol 23:11-16, 2005
4. Whelan T, Levine M: Radiation therapy and tamoxifen: Concurrent or sequential? That is the question. J Clin Oncol 23:1-4, 2005 5. Bentzen SM: A user's guide to evidence-based oncology. Eur J Cancer Supplements 1:77-91, 2003 (suppl 6) 6. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials.. Lancet 351:1451-1467, 1998[CrossRef][Medline]
7. Bentzen SM, Skoczylas JZ, Overgaard M, et al: Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 88:918-922, 1996 8. Von Pfeil A, Hakenjos L, Herskind C, et al: Irradiated homozygous TGF-beta1 knockout fibroblasts show enhanced clonogenic survival as compared with TGF-beta1 wild-type fibroblasts. Int J Radiat Biol 78:331-339, 2002[CrossRef][Medline]
9. Ahmed MM, Alcock RA, Chendil D, et al: Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2. J Biol Chem 277:2234-2246, 2002 10. Vodovotz Y, Lucia MS, DeLucca AM, et al: Reduced hematopoietic function and enhanced radiosensitivity of transforming growth factor-beta1 transgenic mice. Int J Cancer 90:13-21, 2000[CrossRef][Medline] 11. Kim AH, Lebman DA, Dietz CM, et al: Transforming growth factor-beta is an endogenous radioresistance factor in the esophageal adenocarcinoma cell line OE-33. Int J Oncol 23:1593-1599, 2003[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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