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Originally published as JCO Early Release 10.1200/JCO.2005.08.955 on November 15 2004 © 2005 American Society of Clinical Oncology.
Radiation Therapy and Tamoxifen: Concurrent or Sequential? That Is the QuestionDepartments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, and the Juravinski Cancer Centre, Hamilton, Ontario, Canada Randomized controlled trials have had an important impact on the treatment of women with early breast cancer. Many women routinely receive breast-conserving surgery plus radiation therapy, adjuvant chemotherapy, or hormonal therapy based on the results of randomized trials. However, despite the extensive use of combinations of chemotherapy, hormonal therapy, and radiation therapy, the optimal sequencing of these different adjuvant treatments for patients with early breast cancer remains unclear. Unfortunately, there have been few randomized trials addressing this important issue. In a randomized trial by Recht et al,1 the optimal sequencing of radiation and chemotherapy in patients treated with breast-conserving surgery was evaluated. Of 244 patients, 122 were allocated to receive radiation therapy before anthracycline-based chemotherapy and 122 were allocated to receive radiation therapy after the same chemotherapy. The median length of follow-up was 58 months. Although the study was relatively small by today’s standards, there was a trend for an increased risk of distant recurrence for patients treated with radiation therapy first (36% v 25%; hazard ratio [HR], 1.62; 95% CI, 1.01 to 2.62; P = .05). As a result, breast irradiation is now usually given after anthracycline-based chemotherapy. In early 1990s, investigators from the North American Breast Intergroup conducted a randomized trial in postmenopausal women with node-positive, hormone receptor–positive breast cancer, which compared tamoxifen, administered concurrently with cyclophosphamide, doxorubicin, and fluorouracil (n = 550) with tamoxifen given after the completion of the same chemotherapy (n = 566).2 This was an important clinical question because there was some concern that the cytostatic effect of concurrent tamoxifen might interfere with the cytotoxic effects of chemotherapy on cancer cells. Preclinical data had demonstrated that human breast tumor cells in culture pretreated with tamoxifen were protected from the cytotoxicity of chemotherapy.3 This concern was not shared by all investigators; several cooperative groups recommended the concurrent use of chemotherapy and tamoxifen in trials evaluating these agents. Furthermore, it had already been observed that combined chemotherapy and tamoxifen increased the risk of thromboembolic complications in patients.4 With a median follow-up of 8.5 years, the results of the Intergroup study were presented at the 2000 American Society of Clinical Oncology Annual Meeting. The 8-year disease-free survival estimates were 67% for patients treated with sequential chemotherapy and tamoxifen compared with 62% for patients treated with concurrent chemotherapy and tamoxifen (P < .05).2 This study led to important changes in clinical practice. The question of optimal scheduling of hormonal therapy and radiation is equally important. Preclinical studies have suggested that concurrent treatment with tamoxifen may result in decreased efficacy of radiation therapy. In cell culture studies, tamoxifen causes arrest of breast cancer cells in culture in the relatively radioresistant G0/G1 phases of the cell cycle.5 Although some basic studies have demonstrated reduced radiosensitivity of human tumor cells pretreated with tamoxifen,6,7 the effect has not been uniform; some studies have demonstrated no effect8 and others have suggested enhanced radiosensitivity.9 In addition to concerns regarding decreased efficacy of concurrent tamoxifen and radiation therapy, clinical studies have reported increased pulmonary and breast fibrosis from the combination. It has been hypothesized that these effects may be mediated through locally increased concentrations of transforming growth factor ß induced by tamoxifen. In a subgroup of patients who participated in a randomized trial, 38 patients received concurrent tamoxifen and postmastectomy radiation therapy, and 46 received postmastectomy radiation therapy only.10 Optical density changes in pre- and post-treatment chest x-rays were used to assess for the development of apical lung fibrosis. Although the incidence of radiologic changes consistent with fibrosis was increased from 13% to 36% in patients treated with the combination, clinically significant differences in symptomatic pneumonitis were not reported. In a prospective cohort study, 74 patients treated with concurrent tamoxifen and postmastectomy radiation therapy were compared with 37 patients treated with radiation only.11 Patients were assessed by serial computed tomography scans. The incidence of pulmonary fibrosis was increased from 14% to 35% (P < .01), but only 1% of patients had symptoms that required treatment. Another prospective study failed to confirm these findings.12 In a retrospective case series, Wazer et al13 reported a trend for an adverse cosmetic outcome associated with breast fibrosis in patients treated with tamoxifen and breast irradiation given either concurrently or sequentially (P = .06). This association was not observed in another retrospective case series.14 Although these studies are interesting, their interpretation is limited by a number of factors, including small numbers of patients, the lack of a controlled comparison to sequential radiation therapy and tamoxifen, and the generalizability of the findings to patients treated with breast-conserving therapy. In view of the continued uncertainty of the optimal scheduling of tamoxifen and radiation therapy in women with early breast cancer, the results of three studies published in this issue of the Journal of Clinical Oncology should be viewed with considerable interest.15-17 All three studies used a retrospective cohort design, rather than a randomized trial, to compare the effects of concurrent tamoxifen and radiation therapy with the effects of radiation therapy followed sequentially by tamoxifen. In a randomized trial, treatment groups are usually similar for known (and unknown) prognostic factors, and therefore any difference in outcomes can be attributed to the different interventions received. In a retrospective cohort study, there is little control over how patients receive different interventions—the physician usually selects treatment, often resulting in a difference in prognostic factors. Even when there is an attempt to correct for differences between known prognostic factors using a multivariate analysis, potential differences in unknown factors in groups may lead to erroneous results. An additional problem with a retrospective design is that, by its very nature, it is not a planned experiment. As a result, sample sizes may be too small to detect important clinical differences. Finally, important clinical outcomes may not be measured routinely or evaluated systematically, increasing the risk of bias. Let us review these studies, keeping in mind these methodological considerations.
The largest study, by Ahn et al15 from Yale (New Haven, CT), identified 495 patients treated with concurrent tamoxifen and radiation therapy (n = 254) or radiation therapy followed sequentially by tamoxifen (n = 241). Patients were identified over a 23-year period (1976 to 1999), during which time there were considerable changes in the staging and treatment of breast cancer. The study observed no significant differences in the risk of ipsilateral breast tumor recurrence, disease-free survival, or overall survival. In addition, there were imbalances in the treatment groups for potentially important prognostic factors, in that patients who received radiation therapy followed sequentially by tamoxifen were slightly younger and more likely to receive chemotherapy. Younger age would likely increase the cohorts’ risk for ipsilateral breast tumor recurrence, whereas the use of chemotherapy would lower the risk. The latter association is also important, given that patients who received chemotherapy were reportedly more likely to receive tamoxifen after chemotherapy, again potentially prejudicing them to a better outcome.2 Another important difference between the treatment groups in this study was the length of follow-up. Patients treated with radiation therapy followed sequentially by tamoxifen were observed for a shorter period of time (9.9 v 11 years; P The second study, by Harris et al,16 compared 174 patients treated with concurrent tamoxifen and radiation therapy, with 104 patients treated with radiation therapy followed sequentially by tamoxifen. Patients were accrued throughout a long period between 1980 and 1995. No significant differences in ipsilateral breast tumor recurrence, disease-free survival, or overall survival were observed between groups. However, important differences between the treatment groups were noted, in that patients treated with radiation therapy followed sequentially by tamoxifen were again more likely to be younger and to have received chemotherapy. In this study, the HR for ipsilateral breast tumor recurrence (radiation therapy followed sequentially by tamoxifen v concurrent tamoxifen and radiation therapy) was 1.23 (95% CI, 0.33 to 4.49; P = .78). Again, such a result is consistent with either a beneficial or a detrimental effect of radiation therapy followed sequentially by tamoxifen, compared with concurrent tamoxifen and radiation therapy. In contrast to the previous study, important morbidity outcomes such as breast and arm edema, pneumonitis, and cosmetic outcome were collected; no important differences were observed between groups. However, this assessment was performed by the treating radiation oncologist, who was not blinded to treatment received; consequently, there could have been bias in the assessment of this outcome. The third study, by Pierce et al,17 identified two cohorts of patients from a randomized trial of different adjuvant systemic therapy regimens. Patients were randomly assigned to cyclophosphamide, doxorubicin, and fluorouracil (CAF), CAF followed by tamoxifen; cyclophosphamide, methotrexate, and fluorouracil (CMF); or CMF followed by tamoxifen. Eligibility criteria for the trial included patients with high-risk, node-negative breast cancer, which was defined as hormone receptor-negative or hormone receptor (estrogen or progesterone receptor) –positive, and tumor larger than 2 cm or with a high S phase. Patients treated with breast-conserving surgery were treated with radiation either before adjuvant chemotherapy or after chemotherapy was completed. Of 1,345 patients randomly assigned to a chemotherapy regimen followed by tamoxifen, only 23% were treated with breast-conserving surgery or radiation. Of these, 202 patients received concurrent tamoxifen and radiation therapy and 107 received radiation therapy followed sequentially by tamoxifen. In this study, no differences were noted in the risk of ipsilateral breast tumor recurrence, disease-free survival, or survival between radiation therapy followed sequentially by tamoxifen and concurrent tamoxifen and radiation therapy. Despite prospective data collection, this analysis was performed retrospectively. Although the groups were similar for age and all received chemotherapy, 45% of patients had hormone receptor–negative disease, which limits the generalizability of this study. Important imbalances in favor of radiation therapy followed sequentially by tamoxifen were observed in hormone receptor–positive status between the groups. In addition, all patients treated with radiation therapy followed sequentially by tamoxifen received radiation before chemotherapy, resulting in increased delay in receiving chemotherapy in this group. Patients who received concurrent tamoxifen and radiation therapy were more likely to receive radiation after chemotherapy, with less delay. The HR for risk of ipsilateral breast tumor recurrence (radiation therapy followed sequentially by tamoxifen v concurrent tamoxifen and radiation therapy) was 0.73, but again, rather wide confidence intervals were obtained (95% CI, 0.26 to 2.04; P = .54). Limited data were collected on radiation toxicity. In view of the small patient numbers in each of these three studies, one might be tempted to combine the data in a meta-analysis. We do not believe this is appropriate because of the inherent limitations of combining results from retrospective studies. Although a meta-analysis may partially address the issue of power, it cannot correct for the other methodologic limitations. What can we conclude from these studies? Because of the inherent limitations of the research design, it is hard to make any firm conclusions regarding the relative effectiveness of sequential or concurrent tamoxifen and radiation therapy. The only way to address this question adequately in the least biased way possible is through a large randomized controlled trial. Is it worth the effort and considerable cost to do so? We believe it is. Combined use of radiation and hormonal therapy is increasingly common with the popularity of breast-conserving therapy and adjuvant treatment. Relevant outcomes potentially affected by sequencing of the treatment include radiation pneumonitis, breast fibrosis and cosmesis, local recurrence, and distant recurrence. This latter outcome could be affected by delay in initiation of hormonal therapy.1 Recent randomized trials suggest that breast irradiation is quite effective in patients treated with tamoxifen.18-20 In these studies, it would appear that a substantial number of patients received tamoxifen concurrently with breast irradiation.18,19 Although physicians may be tempted to delay tamoxifen therapy until completion of radiation therapy to avoid possible toxicity, it is not clear that this is the most effective approach. An argument against performing a randomized trial is that even if sequential tamoxifen and radiation therapy were truly better than concurrent therapy in terms of preventing local recurrence (exhibited by an HR as low as 0.5), this would result in a decrease in 10-year local recurrence from approximately 8% to 4%. Although such differences may appear modest, they are comparable to that seen with other interventions in current use, such as boost irradiation,21 and are of a magnitude that could potentially influence overall survival.22 This question of sequencing of hormonal therapy and radiation is likely to remain relevant despite the increasing use of the third-generation aromatase inhibitors23 and accelerated breast irradiation.24,25 Like tamoxifen, aromatase inhibitors appear to cause G1 cell cycle arrest, suggesting that concurrent administration of these drugs with radiation could lead to decreased radiation sensitivity. Recent studies in cell culture, however, suggest that breast cancer cells pretreated with aromatase inhibitors may have increased radiation sensitivity.26 Even with accelerated radiation therapy schedules, if concurrent therapy remained more effective with acceptable or equivalent toxicity, it would likely be preferred. The three studies reported in this issue have identified a gap in our knowledge regarding the modern treatment of breast cancer. An important question has been asked. The onus is now on investigators to answer it with the most rigorous design possible. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
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13. Wazer D, 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 14. Fowble B, Fein D, Hanlon A, 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]
15. Ahn P, Thanh H, 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
16. Harris E, Christensen V, Twang W, 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
17. Pierce L, Hutchins L, Green S, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24-29, 2005
18. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:4141-4149, 2002
19. Fyles A, McCready D, Manchul L, et al: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351:963-970, 2004
20. Hughes K, Schnaper L, Berry D, et al: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early stage breast carcinoma. N Engl J Med 351:971-977, 2004
21. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378-1387, 2001
22. Vinh-Hung V, Verschraegen C: Breast-conserving surgery with or without radiotherapy: Pooled-analysis for risks for ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 96:115-121, 2004 23. The ATAC Trialists’ Group: 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 randomized trial. Lancet 359:2131-2139, 2002[CrossRef][Medline]
24. Whelan T, MacKenzie R, Julian J, et al: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 94:1143-1150, 2002
25. Vicini F, Kestin L, Chen P, et al: Limited-field radiation therapy in the management of early-stage breast cancer. J Natl Cancer Inst 95:1205-1211, 2003 26. Azia D, Larbouret C, Cunat S, et al: Letrozole sensitizes aromatase-expressing breast tumour cells to gamma irradiation. Breast Cancer Res Treat 82:S41, 2003 (abstr 174) Related Articles
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.02), suggesting that they were from a later cohort and could have a better outcome as a result of the increasing use of new interventions such as screening mammography (smaller tumors), chemotherapy (as observed), and possibly other interventions (for example, 5 years rather than 2 years of tamoxifen). Even though a multivariate analysis was used in an attempt to adjust for a number of observed differences, such an analysis is unable to correct for other unknown factors. The second major point for consideration is sample size. Although this was the largest of the three studies, fewer than 500 patients were evaluated. The HR for ipsilateral breast tumor recurrence comparing sequential with concurrent tamoxifen and radiation therapy was 0.93 (95% CI, 0.42 to 2.05; P = .86). Such a result is consistent with sequential therapy being either better or worse. Finally, important morbidity outcomes were not reported. 
