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Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4239-4241 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.00.8623
Radiation Therapy and Tamoxifen: Concurrent or Sequential? It's No Longer the Question!Department of Radiation Oncology, Montpellier, France
Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland To the Editor: In the January 1, 2005, issue of the Journal of Clinical Oncology, three studies1-3 point out the impact of concomitant or sequential use of tamoxifen (TAM) and radiation therapy (RT). We read these articles with great interest and several comments are needed concerning this unresolved question, because the results of a well-conducted randomized trial are not available. In terms of efficacy, none of these studies showed any significant difference in the risk of ipsilateral breast tumor recurrence, disease-free survival, or overall survival in patients receiving concomitant versus sequential TAM and RT. The influence of TAM on local control has already been reported in several retrospective studies, which show that TAM was associated with either no difference or a modest enhancement of local control.4-7 In these studies, the timing and sequencing of TAM administration relative to RT were either variable or not reported. It is reassuring that TAM given concomitantly with RT does not exert a radioprotective effect on the tumor. Therefore, preclinical data obtained with breast cancer cells have to be extrapolated cautiously to the clinical situation.
Regarding the toxicities of the three studies,1-3 only the study reported by Harris et al2 investigated breast and arm edema, pneumonitis, and cosmetic outcomes. No significant differences were reported between groups. We recently published a series of 147 women with breast cancer treated with adjuvant RT, and who were included in the Swiss Cancer League 539-9-1997/778-2-1999 prospective study aimed at evaluating the predictive value of CD4 and CD8 T-lymphocyte apoptosis for the development of radiation-induced late effects.8 TAM (20 mg/d) with concomitant RT was prescribed for 90 hormone receptor–positive patients. There was a statistically significant difference in terms of complication–relapse-free survival (CRFS) rates at 3 years, 48% (95% CI, 37.2% to 57.6%) versus 66% (95% CI, 49.9% to 78.6%), and complication-free survival (CFS) rates at 2 years, 51% (95% CI, 40% to 61%) versus 80% (95% CI, 67% to 89%) in the TAM and no-TAM groups, respectively. In each of these groups, the CRFS rates were significantly lower for patients with low levels of CD8-radiation–induced apoptosis, 20% (95% CI, 10% to 31.9%), 66% (95% CI, 51.1% to 77.6%), and 79% (95% CI, 55% to 90.9%) for CD8 Our finding with regard to the influence of TAM on subcutaneous fibrosis, particularly in radiosensitive patients, is new. Wazer et al9 showed a borderline significant trend, indicating an adverse impact of TAM on cosmetic appearance, but these preliminary results were not confirmed in their updated analysis.10 Fowble et al4 reported on 154 patients treated with TAM, and found no major adverse effects on cosmesis or complications. The timing between TAM and the initiation of RT was unknown for 111 patients. Twenty-three patients received TAM during RT, and 20 patients began TAM after the completion of RT. Taylor et al11 showed that the use of adjuvant TAM did not appear to diminish the excellent cosmetic outcomes, irrespective of whether it was administered concurrently or sequentially with RT. In a recent prospective randomized study comparing breast pain after breast-conserving surgery plus TAM with or without RT,12 the incidence and severity of breast symptoms were similar at baseline in patients subsequently randomized to the RT and no-RT arms of the study. With lung fibrosis as an end point, contradictory reports have indicated that TAM could result in potentiation of postradiation normal-tissue reactions.13-15 The dominant cause of cosmetic failure in the patients treated with irradiation and TAM appeared to be retractive fibrosis. Although not immediately apparent, there may be a mechanistic link between TAM therapy and postradiation normal tissue changes. TAM stimulates in vitro the secretion in human fibroblasts of the fibroblast mitogen transforming growth factor ß (TGF-ß).16 Evidence suggests that radiation-induced fibrosis is, in part, mediated by TGF-ß. Another interesting question is whether subcutaneous fibrosis can be prevented, or at least reduced. First, our predictive radiation-induced lymphocyte apoptosis assay seems to be highly specific and sensitive to discriminate subgroups of patients as a function of their intrinsic radiosensitivity. Further prospective studies are still necessary before using this test in routine daily practice. Second, preliminary results have shown that TGF-ß antagonists may inhibit or reduce the action of this growth factor.17-20 The significant reduction of chronic RT damage obtained with the pentoxifylline and alpha-tocopherol combination20 challenges the dogma that established RT sequelae such as radiation-induced subcutaneous fibrosis are irreversible. Third, evidence from the first analysis of the Arimidex, Tamoxifen Alone or in Combination Trialists Group (ATAC) trial supports the use of aromatase inhibitors such as anastrozole for the adjuvant treatment of early breast cancer in postmenopausal women.21,22 Our data showed that especially in radiosensitive patients TAM should be delayed after completion of RT. Another approach could be to replace TAM by an aromatase inhibitor. Recently, we demonstrated the radiosensitization of breast cancer cells transfected with the aromatase gene by the nonsteroidal aromatase inhibitor letrozole.23 In conclusion, there is no clinical evidence that concomitant TAM and RT could reduce the efficacy of RT alone or in sequential schedule with TAM. The main question concerns higher lung and subcutaneous fibrosis incidence, particularly in radiosensitive patients, and not in the entire treated population. In the era of intensive research on aromatase inhibitors in the adjuvant setting,21,22,24-26 and in disagreement with Whelan et al,27 we are convinced that it is irrelevant to design a randomized trial comparing concurrent versus sequential TAM and RT. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. 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 23:10.1200/JCO. 2005.09.048 2. Harris EER, Christensen VJ, Hwang W-T, et al: Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol 23:10.1200/JCO. 2005.09.056 3. 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 23:10.1200/JCO. 2005.01.198 4. Fowble B, Fein DA, Hanlon AL, et al: The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer. Int J Radiat Oncol Biol Phys 35:669-677, 1996[CrossRef][Medline] 5. Leborgne F, Leborgne JH, Ortega B, et al: Breast conservation treatment of early stage breast cancer: Patterns of failure. Int J Radiat Oncol Biol Phys 31:765-775, 1995[CrossRef][Medline] 6. Rutqvist LE, Cedermark B, Glas U, et al: Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer: Stockholm Breast Cancer Study Group. Acta Oncol 31:265-270, 1992[Medline] 7. Azria D, Lemanski C, Zouhair A, et al: Adjuvant treatment of breast cancer by concomitant hormonotherapy and radiotherapy: State of the art. Cancer Radiother 8:188-196, 2004[Medline] 8. Azria D, Gourgou S, Sozzi WJ, et al: Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients. Br J Cancer 91:1251-1260, 2004[CrossRef][Medline]
9. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al: Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 10:356-363, 1992 10. Wazer DE, Morr J, Erban JK, et al: The effects of postradiation treatment with tamoxifen on local control and cosmetic outcome in the conservatively treated breast. Cancer 80:732-740, 1997[CrossRef][Medline] 11. Taylor ME, Perez CA, Halverson KJ, et al: Factors influencing cosmetic results after conservation therapy for breast cancer. Int J Radiat Oncol Biol Phys 31:753-764, 1995[CrossRef][Medline] 12. Rayan G, Dawson LA, Bezjak A, et al: Prospective comparison of breast pain in patients participating in a randomized trial of breast-conserving surgery and tamoxifen with or without radiotherapy. Int J Radiat Oncol Biol Phys 55:154-161, 2003[CrossRef][Medline]
13. Bentzen SM, Skoczylas JZ, Overgaard M, et al: Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 88:918-922, 1996 14. Huang EY, Wang CJ, Chen HC, et al: Multivariate analysis of pulmonary fibrosis after electron beam irradiation for postmastectomy chest wall and regional lymphatics: Evidence for non-dosimetric factors. Radiother Oncol 57:91-96, 2000[CrossRef][Medline] 15. Koc M, Polat P, Suma S: Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol 64:171-175, 2002[CrossRef][Medline] 16. Colletta AA, Wakefield LM, Howell FV, et al: Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 62:405-409, 1990[Medline] 17. Border WA, Okuda S, Languino LR, et al: Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 346:371-374, 1990[CrossRef][Medline] 18. Shah M, Foreman DM, Ferguson MW: Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 339:213-214, 1992[CrossRef][Medline]
19. Delanian S, Balla-Mekias S, Lefaix JL: Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 17:3283-3290, 1999
20. Delanian S, Porcher R, Balla-Mekias S, et al: Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol 21:2545-2550, 2003 21. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 22. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline] 23. Azria D, Larbouret C, Cunat S, et al: Letrozole (Femara) sensitizes breast cancer cells to ionizing irradiation. Breast Cancer Res 7:R156-R163, 2005[CrossRef][Medline]
24. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003
25. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 26. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:10.1200/JCO. 2005.09.121 27. Whelan T, Levine M: Radiation therapy and tamoxifen: Concurrent or sequential? That is the question. J Clin Oncol 23:10.1200/JCO. 2005.08.955
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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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16%, 16% to 24%, and more than 24%, respectively. Similar results were observed for the CFS rates. The concomitant use of TAM with RT was significantly associated with an increased incidence of grade 2 or more subcutaneous fibrosis, particularly for radiosensitive patients. 
