Impact of Concurrent Versus Sequential Tamoxifen With Radiation Therapy in Early-Stage Breast Cancer Patients Undergoing Breast Conservation
http://www.100md.com
《临床肿瘤学》
the Department of Radiation Oncology, Center for Clinical Epidemiology and Biostatistics, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
ABSTRACT
PATIENTS AND METHODS: This retrospective study evaluates the effect of the sequence of tamoxifen with RT on outcomes in stage I to II breast cancer patients who underwent breast-conservation treatment (BCT) and received adjuvant tamoxifen, with or without adjuvant chemotherapy. Patients were grouped as concurrent (tamoxifen given during RT followed by continued tamoxifen; 174 patients) and sequential (RT followed by tamoxifen; 104 patients).
RESULTS: Median follow-up after RT was 8.6 years for both groups. The pathologic T and N stage, race, estrogen and progesterone status, number of positive nodes, and RT were comparable between the two groups (all P ≥ .08). More women age 49 years or younger and women who received chemotherapy were in the sequential group than the concurrent group (6% and 25%, respectively; P < .0001). The sequence of tamoxifen therapy did not influence 10-year local recurrence rates (sequential, 7%; concurrent, 3%; P = .52), overall survival (sequential, 86%; concurrent, 81%; P = .64), or relapse-free survival (sequential, 76%; concurrent, 85%; P = .35). When adjusting age and chemotherapy use in the multivariable Cox model, hazard ratios comparing sequential versus concurrent tamoxifen therapy were 1.56 (95% CI, 0.87 to 2.79), 1.23 (95% CI, 0.63 to 2.41), and 1.22 (95% CI, 0.33 to 4.49) for the overall survival, relapse-free survival, and local recurrence, respectively.
CONCLUSION: The therapeutic regimens of tamoxifen given concurrently or sequentially with RT both appear to be reasonable options for patients treated with BCT.
INTRODUCTION
Radiation therapy and systemic chemotherapy are usually given sequentially. Several agents used in breast cancer treatment are radiosensitizers, and concurrent administration of drugs such as doxorubicin and methotrexate are associated with an increased risk of radiation complications. The optimal sequencing of radiation and tamoxifen has not been established. Tamoxifen has no significant radiosensitizing properties; therefore, it often has been given concurrently with radiation. However, tamoxifen is a cytostatic drug that arrests cells in G1, a relatively radioresistant cell cycle phase.1 The possibility of an increased risk of adverse effects in patients receiving concurrent tamoxifen and radiation is of concern. In addition, concurrent tamoxifen and chemotherapy has been associated an increased risk of thromboembolic events,2 and with a lower disease-free survival than sequential regimens.3 Therefore, we conducted this retrospective study at the University of Pennsylvania (Philadelphia, PA) to determine whether the timing of tamoxifen with radiation affected outcomes or complications in women with early-stage breast cancer receiving both treatment modalities.
PATIENTS AND METHODS
The patient characteristics for both the concurrent and sequential study groups of patients are shown in Table 1. Of 1,234 patients with stage I and II breast cancer who received BCT during the study period, there were 330 women (27%) who received tamoxifen as adjuvant therapy. From this cohort, 52 patients for whom tamoxifen sequencing data were not available were excluded; therefore, a total of 278 patients (84% of those receiving tamoxifen) were assessable.
Study Design
Patients were divided for comparison of outcomes into two groups: sequential and concurrent. The sequential group was defined as having tamoxifen therapy administered after the completion of all radiation therapy. The concurrent group was defined as receiving concurrent tamoxifen and radiation for at least 1 day of concurrent treatment. The sequential group had 104 patients, and the concurrent group had 174 patients, when concurrent was thus defined as any number of days of concurrent tamoxifen with radiation. Although most patients in the concurrent group received tamoxifen during the entire course of their treatment, 14 patients (5%) received concurrent tamoxifen for less than 21 days, or less than half the overall radiation treatment time. A separate analysis was performed moving these 14 patients into the sequential group, and the same results were seen (data not shown).
Outcomes for the two groups were compared for any local recurrence, relapse-free survival, and overall survival. Cosmesis was assessed by a radiation oncologist at each follow-up visit using a cosmetic scale of excellent, good, fair, and poor, as previously described.5,6 Complications were also assessed during treatment and at each follow-up appointment, and included breast edema, arm edema, pneumonitis, rib fracture, and axillary vein thrombosis, which were graded according to the Radiation Therapy Oncology Group Late Toxicity Criteria.7
Statistical Methods
Statistical comparisons of clinical, pathologic, and treatment-related factors, cosmesis, and complications were performed by Pearson {chi}2 statistic and by analysis of variance. Five and 10-year overall survival, relapse-free survival, and local failure curves were calculated using the Kaplan-Meier estimates, with time beginning at the initiation of radiation.8 Comparisons for survival curves are based on the log-rank test.9 Cox proportional hazards models and logistic regressions were used to assess the impact of tamoxifen sequence on outcomes while adjusting for other patient variables. The assumptions for the Cox proportional hazards model for overall survival, local recurrence, and relapse-free survival were satisfied based on a global test using the multivariate model. Statistical comparisons between curves were conferred by P ≤ .05.10
RESULTS
Outcomes were compared for local recurrence, overall survival, and relapse-free survival, with no significant differences between the concurrent and sequential groups (Table 2). The 5- and 10-year actuarial local recurrence in the concurrent group was 2% and 3%, and in the sequential group was 2% and 7%, respectively (hazard ratio, 1.22; 95% CI, 0.33 to 4.49; P = .52). There were a total of seven local recurrences in 174 patients in the concurrent group, and five local recurrences in 104 patients in the sequential group. The 5- and 10-year relapse-free survival was 92% and 85% in the concurrent group, and 89% and 76% in the sequential group, respectively (hazard ratio, 1.23; 95% CI, 0.63 to 2.41; P = .35). The 5- and 10-year overall survival for the concurrent group was 94% and 81%, and in the sequential group was 90% and 86%, respectively (hazard ratio, 1.56; 95% CI, 0.87 to 2.79; P = .64; Fig 1).
Multivariate models for local recurrence, relapse-free survival, and overall survival were performed adjusting for age and use of chemotherapy, the factors that differed between the sequential and concurrent groups. For the multivariate model, overall survival for sequential in comparison with the concurrent group was associated with a hazard ratio of 1.56 (95% CI, 0.87 to 2.79; P = .14). The multivariate model for relapse-free survival produced a hazard ratio of 1.22 (95% CI, 0.63 to 2.41; P = .54) when sequential versus concurrent tamoxifen therapy were compared, and a hazard ratio of 1.23 (95% CI, 0.33 to 4.49; P = .78) for local recurrence. Although imbalances in the baseline characteristics including the use of chemotherapy and age were controlled for in the distribution, there were a small number of local recurrence events. The use of chemotherapy was not associated with a lower 10-year local recurrence rate in the sequential group (7%), which had the higher rate of chemotherapy use than the concurrent group (3%; P = .52).
Complications between the sequential and concurrent groups were compared (Table 3). Complications assessed included breast edema, arm edema, pneumonitis, and rib fracture. Only 5% of patients in both groups had grade 3 to 4 breast edema (P = .96). For all other complications, including arm edema, pneumonitis, and rib fracture, there was no significant difference between the concurrent and sequential groups (all P ≥ .31). Grade 3 to 4 arm edema occurred in 2% of the concurrent group and 3% of the sequential group. Pneumonitis and rib fracture were rare in both groups (P = .53 and .31, respectively). There was no impact of the effect of tamoxifen sequence on complications when the analysis was performed adjusting for age and chemotherapy use.
Cosmesis was assessed and scored at each follow-up and cosmesis scores for each group were compared at 3 and 5 years after the completion of treatment. At 3 years, data were available for 86% of patients in the sequential group and 74% of patients in the concurrent group. At 5 years, data were available for 53% and 52%, respectively. In both groups, 95% of patients had excellent or good cosmesis at 3 years (P = .92), and 94% had excellent or good cosmesis at 5 years (P = .83). There was no impact on the effect of tamoxifen sequence on cosmesis when the analysis was adjusted for age and chemotherapy use.
DISCUSSION
Tamoxifen is a cytostatic drug that arrests the progression of cells in G1, a relatively radioresistant phase of the cell cycle.1 This effect could theoretically compromise the efficacy of the radiation treatment. Contradictory results have been noted in in vitro studies using breast cancer cell lines treated with tamoxifen and radiation. One study found that irradiated MCF-7 cells treated with tamoxifen were less radiosensitive, with a widened shoulder on the cell survival curve.21 However, a similar study also with MCF-7 cells irradiated and then incubated with 4-hydroxytamoxifen, the antiestrogenic metabolite of tamoxifen, showed no alteration in radiosensitivity.22 One clinical study showed a detrimental effect of concurrent tamoxifen with chemotherapy. In a randomized trial of patients receiving multiagent chemotherapy followed by tamoxifen versus chemotherapy with concurrent tamoxifen, the sequential systemic treatment had a disease-free survival of 67% v 62% for patients receiving concurrent treatment, which was of borderline statistical significance (P = .045).3 In light of these concerns, for women receiving radiation therapy after the completion of systemic chemotherapy or for breast conservation patients who are not receiving any systemic chemotherapy, the question of whether tamoxifen influences local recurrence or complications rates arises.
Two articles in this issue of the Journal of Clinical Oncology examining the effect of tamoxifen sequence showed no adverse effect on local or systemic control in sequential versus concurrent tamoxifen and radiation patients. Pierce et al23 reported on 309 patients who received radiation before or concurrently with tamoxifen, all of whom also had chemotherapy. When the sequential and concurrent groups were compared, there were similar local relapse rates (4.7% v 6.4%, respectively; P = .53), 10-year disease-free survival (83% v 82%, respectively; P = .76), and overall survival (90% v 88%, respectively; P = .65). Ahn et al24 examined 475 patients treated with breast conservation therapy who took tamoxifen during or subsequent to radiation. They reported that the women in the concurrent group were significantly older and less likely to receive chemotherapy than were those in the sequential group—the same pattern that was noted in our study. For the sequential versus concurrent group, 10-year overall survival, distant metastasis-free rate, and local relapse rates were 80% v 85%, 78% v 84%, and 12% v 10%, respectively (P values not given). The outcomes in both studies are entirely consistent with the findings in this analysis that there is no difference in outcome associated with the sequencing of tamoxifen and radiation, although neither reported on the impact of sequence on complications or cosmetic outcome.
In this retrospective study of patients diagnosed with early-stage breast cancer and treated with breast conservation therapy, the patients who received concurrent tamoxifen with radiation were more often older (P < .0001), and those in the sequential group were more likely to have received any chemotherapy (P < .0001). Despite these imbalances between the two groups, the sequence of tamoxifen had no impact on local recurrence rates. A higher percentage of women age 50 or older received chemotherapy in the sequential group (40%) than in the concurrent group (21%). This was also true for patients age 49 or younger, for whom 76% in the sequential group received chemotherapy compared with 49% in the concurrent group. This suggests that the use of chemotherapy tended to be associated with a delay in the initiation of tamoxifen.
The sequence of tamoxifen had no impact on the local recurrence rates. The sequential group, which had a younger median age and a higher rate of chemotherapy use, actually had a higher rate of 10-year local recurrence (7%) than the concurrent group (3%), which was not statistically significant. Overall, there were a small number of local recurrence events (five of 104 patients in the sequential tamoxifen group and seven of 174 patients in the concurrent tamoxifen group); therefore, the power to detect a small difference in local recurrence by sequence is limited. However, given that the use of chemotherapy was controlled for in the analysis, it is unlikely that the use of chemotherapy had an impact on the lack of difference between the sequential and concurrent tamoxifen groups.
As expected, this study did not find any difference in either relapse-free or overall survival by sequence of tamoxifen use. Given that tamoxifen is a long-term cytostatic systemic therapy, the exact timing of initiation in the initial course of therapy would not be expected to influence survival outcomes. However, the major limitation of this study is the small sample size as illustrated by the 95% CIs for the hazard ratios, creating the potential to miss a small difference between the different sequence groups.
There are little data on the risk of complications when tamoxifen and radiation are given. One study reported that in postmastectomy patients receiving radiotherapy and tamoxifen, there was an increased risk of lung fibrosis.25 However, in another study, chest computed tomography scans were performed before radiation and 4 months after completion to quantify radiographic changes in the lungs of irradiated patients and correlate these with radiation technique and symptomatic pneumonitis.26 That study found no correlation with lung density changes and the use of concurrent tamoxifen. Overall, concerns regarding the interaction of tamoxifen with radiation have led some clinicians to advocate their sequential use. Therefore, this study also assessed the risk of complications and the overall cosmetic outcome with respect to the timing of tamoxifen with radiation. There was no difference in the rates of breast edema, arm edema, symptomatic pneumonitis, or rib fracture between the two groups. The rates of excellent and good cosmesis at both 3 and 5 years after radiation were also identical for each group. These results suggest that there is no increased risk of developing fibrosis in the lungs or in the treated breast when tamoxifen is given concurrently with radiation, although subtle differences would not be readily detected with the sample size in this study.
In conclusion, there is no clinical impact on local recurrence, overall survival, relapse-free survival, cosmesis, or significant complications associated with the sequence of tamoxifen and radiation. Therefore, it is reasonable to use either concurrent or sequential regimens when tamoxifen and radiation are both indicated in patients undergoing breast conservation therapy.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Presented in part at the 39th American Society of Clinical Oncology Meeting, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Osborne C, Boldt D, Clark G, et al: Effects of tamoxifen on human breast cancer cell cycle kinetics: Accumulation of cells in early G1 phase. Cancer Res 43:3583-3585, 1983
2. Pritchard KI, Paterson AH, Paul N, et al: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer: National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14:2731-2737, 1996
3. Albain K, Green J, Ravdin P, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100. Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143)
4. Fleming ID, Cooper JS, Henson DE, eds, et al: American Joint Committee on Cancer AJCC Cancer Staging Manual (ed 5). Philadelphia, PA, JB Lippincott, 1997
5. Fowble B, Solin LJ, Schultz DJ: Conservative surgery and radiation for early breast cancer, in Fowble B, Goodman RL, Glick JH, et al (eds): Breast Cancer Treatment: A Comprehensive Guide to Management. St Louis, MO, Mosby Year Book, 1991, pp 105-149
6. Harris JR, Levene MB, Svensson G, et al: Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys 5:257-261, 1979
7. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995
8. Kaplan EL, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958
9. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966
10. Kirkwood BR: Essentials of Medical Statistics. Osney Mead, Oxford, United Kingdom, Blackwell Science Ltd, 1988, pp 39-40
11. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002
12. Veronesi U, Banfi A, Salvadori B, et al: Breast conservation is the treatment of choice in small breast cancer: Long-term results of a randomized trial. Eur J Cancer 26:668-670, 1990
13. Poggi MM, Danforth DN, Sciuto LC, et al: Eighteen year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: The National Cancer Institute Randomized Trail. Cancer 98:697-702, 2003
14. van Dongen JA, Voogd AC, Fentiman IS, et al: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92:1143-1150, 2000
15. Blichert-Toft M, Rose C, Andersen JA, et al: Danish randomized trial comparing breast conservation therapy with mastectomy: Six years of life-table analysis—Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 11:19-25, 1992
16. Sarrazin D, Le MG, Arriagada R, et al: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14:177-184, 1989
17. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989
18. Dalberg K, Johansson H, Johansson U, et al: A randomized trial of long term adjuvant tamoxifen plus postoperative radiation therapy versus radiation therapy alone for patients with early stage breast carcinoma treated with breast-conserving surgery: Stockholm Breast Cancer Study Group. Cancer 82:2204-2211, 1998
19. Anonymous: Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer: Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 88:1543-1549, 1996
20. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer—An overview of the randomized trials. Lancet 351:1451-1467, 1998
21. Wazer DE, Tercilla OF, Lin PS, et al: Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17-estradiol and tamoxifen. Br J Radiol 62:1079-1083, 1989
22. Sarkaria JN, Miller EM, Parker CJ, et al: 4-Hydroxytamoxifen, an active metabolite of tamoxifen, does not alter the radiation sensitivity of MCF-7 breast carcinoma cells irradiated in vitro. Breast Cancer Res Treat 30:159-165, 1994
23. Pierce LJ, Hutchins L, Green SJ, 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
24. Ahn PH, Vu HT, Lannin D, et al: Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not effect local relapse rates. J Clin Oncol 23:10.1200/JCO.2005.09.048
25. Bentzen S, Skoczylas J, Overgaard M, et al: Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 88:918-922, 1996
26. Wennberg B, Gagliardi G, Sundbom L, et al: Early response of lung in breast cancer irradiation: Radiologic density changes measured by CT and symptomatic radiation pneumonitis. Int J Radiat Oncol Biol Phys 52:1196-1206, 2002(Eleanor E.R. Harris, Vast)
ABSTRACT
PATIENTS AND METHODS: This retrospective study evaluates the effect of the sequence of tamoxifen with RT on outcomes in stage I to II breast cancer patients who underwent breast-conservation treatment (BCT) and received adjuvant tamoxifen, with or without adjuvant chemotherapy. Patients were grouped as concurrent (tamoxifen given during RT followed by continued tamoxifen; 174 patients) and sequential (RT followed by tamoxifen; 104 patients).
RESULTS: Median follow-up after RT was 8.6 years for both groups. The pathologic T and N stage, race, estrogen and progesterone status, number of positive nodes, and RT were comparable between the two groups (all P ≥ .08). More women age 49 years or younger and women who received chemotherapy were in the sequential group than the concurrent group (6% and 25%, respectively; P < .0001). The sequence of tamoxifen therapy did not influence 10-year local recurrence rates (sequential, 7%; concurrent, 3%; P = .52), overall survival (sequential, 86%; concurrent, 81%; P = .64), or relapse-free survival (sequential, 76%; concurrent, 85%; P = .35). When adjusting age and chemotherapy use in the multivariable Cox model, hazard ratios comparing sequential versus concurrent tamoxifen therapy were 1.56 (95% CI, 0.87 to 2.79), 1.23 (95% CI, 0.63 to 2.41), and 1.22 (95% CI, 0.33 to 4.49) for the overall survival, relapse-free survival, and local recurrence, respectively.
CONCLUSION: The therapeutic regimens of tamoxifen given concurrently or sequentially with RT both appear to be reasonable options for patients treated with BCT.
INTRODUCTION
Radiation therapy and systemic chemotherapy are usually given sequentially. Several agents used in breast cancer treatment are radiosensitizers, and concurrent administration of drugs such as doxorubicin and methotrexate are associated with an increased risk of radiation complications. The optimal sequencing of radiation and tamoxifen has not been established. Tamoxifen has no significant radiosensitizing properties; therefore, it often has been given concurrently with radiation. However, tamoxifen is a cytostatic drug that arrests cells in G1, a relatively radioresistant cell cycle phase.1 The possibility of an increased risk of adverse effects in patients receiving concurrent tamoxifen and radiation is of concern. In addition, concurrent tamoxifen and chemotherapy has been associated an increased risk of thromboembolic events,2 and with a lower disease-free survival than sequential regimens.3 Therefore, we conducted this retrospective study at the University of Pennsylvania (Philadelphia, PA) to determine whether the timing of tamoxifen with radiation affected outcomes or complications in women with early-stage breast cancer receiving both treatment modalities.
PATIENTS AND METHODS
The patient characteristics for both the concurrent and sequential study groups of patients are shown in Table 1. Of 1,234 patients with stage I and II breast cancer who received BCT during the study period, there were 330 women (27%) who received tamoxifen as adjuvant therapy. From this cohort, 52 patients for whom tamoxifen sequencing data were not available were excluded; therefore, a total of 278 patients (84% of those receiving tamoxifen) were assessable.
Study Design
Patients were divided for comparison of outcomes into two groups: sequential and concurrent. The sequential group was defined as having tamoxifen therapy administered after the completion of all radiation therapy. The concurrent group was defined as receiving concurrent tamoxifen and radiation for at least 1 day of concurrent treatment. The sequential group had 104 patients, and the concurrent group had 174 patients, when concurrent was thus defined as any number of days of concurrent tamoxifen with radiation. Although most patients in the concurrent group received tamoxifen during the entire course of their treatment, 14 patients (5%) received concurrent tamoxifen for less than 21 days, or less than half the overall radiation treatment time. A separate analysis was performed moving these 14 patients into the sequential group, and the same results were seen (data not shown).
Outcomes for the two groups were compared for any local recurrence, relapse-free survival, and overall survival. Cosmesis was assessed by a radiation oncologist at each follow-up visit using a cosmetic scale of excellent, good, fair, and poor, as previously described.5,6 Complications were also assessed during treatment and at each follow-up appointment, and included breast edema, arm edema, pneumonitis, rib fracture, and axillary vein thrombosis, which were graded according to the Radiation Therapy Oncology Group Late Toxicity Criteria.7
Statistical Methods
Statistical comparisons of clinical, pathologic, and treatment-related factors, cosmesis, and complications were performed by Pearson {chi}2 statistic and by analysis of variance. Five and 10-year overall survival, relapse-free survival, and local failure curves were calculated using the Kaplan-Meier estimates, with time beginning at the initiation of radiation.8 Comparisons for survival curves are based on the log-rank test.9 Cox proportional hazards models and logistic regressions were used to assess the impact of tamoxifen sequence on outcomes while adjusting for other patient variables. The assumptions for the Cox proportional hazards model for overall survival, local recurrence, and relapse-free survival were satisfied based on a global test using the multivariate model. Statistical comparisons between curves were conferred by P ≤ .05.10
RESULTS
Outcomes were compared for local recurrence, overall survival, and relapse-free survival, with no significant differences between the concurrent and sequential groups (Table 2). The 5- and 10-year actuarial local recurrence in the concurrent group was 2% and 3%, and in the sequential group was 2% and 7%, respectively (hazard ratio, 1.22; 95% CI, 0.33 to 4.49; P = .52). There were a total of seven local recurrences in 174 patients in the concurrent group, and five local recurrences in 104 patients in the sequential group. The 5- and 10-year relapse-free survival was 92% and 85% in the concurrent group, and 89% and 76% in the sequential group, respectively (hazard ratio, 1.23; 95% CI, 0.63 to 2.41; P = .35). The 5- and 10-year overall survival for the concurrent group was 94% and 81%, and in the sequential group was 90% and 86%, respectively (hazard ratio, 1.56; 95% CI, 0.87 to 2.79; P = .64; Fig 1).
Multivariate models for local recurrence, relapse-free survival, and overall survival were performed adjusting for age and use of chemotherapy, the factors that differed between the sequential and concurrent groups. For the multivariate model, overall survival for sequential in comparison with the concurrent group was associated with a hazard ratio of 1.56 (95% CI, 0.87 to 2.79; P = .14). The multivariate model for relapse-free survival produced a hazard ratio of 1.22 (95% CI, 0.63 to 2.41; P = .54) when sequential versus concurrent tamoxifen therapy were compared, and a hazard ratio of 1.23 (95% CI, 0.33 to 4.49; P = .78) for local recurrence. Although imbalances in the baseline characteristics including the use of chemotherapy and age were controlled for in the distribution, there were a small number of local recurrence events. The use of chemotherapy was not associated with a lower 10-year local recurrence rate in the sequential group (7%), which had the higher rate of chemotherapy use than the concurrent group (3%; P = .52).
Complications between the sequential and concurrent groups were compared (Table 3). Complications assessed included breast edema, arm edema, pneumonitis, and rib fracture. Only 5% of patients in both groups had grade 3 to 4 breast edema (P = .96). For all other complications, including arm edema, pneumonitis, and rib fracture, there was no significant difference between the concurrent and sequential groups (all P ≥ .31). Grade 3 to 4 arm edema occurred in 2% of the concurrent group and 3% of the sequential group. Pneumonitis and rib fracture were rare in both groups (P = .53 and .31, respectively). There was no impact of the effect of tamoxifen sequence on complications when the analysis was performed adjusting for age and chemotherapy use.
Cosmesis was assessed and scored at each follow-up and cosmesis scores for each group were compared at 3 and 5 years after the completion of treatment. At 3 years, data were available for 86% of patients in the sequential group and 74% of patients in the concurrent group. At 5 years, data were available for 53% and 52%, respectively. In both groups, 95% of patients had excellent or good cosmesis at 3 years (P = .92), and 94% had excellent or good cosmesis at 5 years (P = .83). There was no impact on the effect of tamoxifen sequence on cosmesis when the analysis was adjusted for age and chemotherapy use.
DISCUSSION
Tamoxifen is a cytostatic drug that arrests the progression of cells in G1, a relatively radioresistant phase of the cell cycle.1 This effect could theoretically compromise the efficacy of the radiation treatment. Contradictory results have been noted in in vitro studies using breast cancer cell lines treated with tamoxifen and radiation. One study found that irradiated MCF-7 cells treated with tamoxifen were less radiosensitive, with a widened shoulder on the cell survival curve.21 However, a similar study also with MCF-7 cells irradiated and then incubated with 4-hydroxytamoxifen, the antiestrogenic metabolite of tamoxifen, showed no alteration in radiosensitivity.22 One clinical study showed a detrimental effect of concurrent tamoxifen with chemotherapy. In a randomized trial of patients receiving multiagent chemotherapy followed by tamoxifen versus chemotherapy with concurrent tamoxifen, the sequential systemic treatment had a disease-free survival of 67% v 62% for patients receiving concurrent treatment, which was of borderline statistical significance (P = .045).3 In light of these concerns, for women receiving radiation therapy after the completion of systemic chemotherapy or for breast conservation patients who are not receiving any systemic chemotherapy, the question of whether tamoxifen influences local recurrence or complications rates arises.
Two articles in this issue of the Journal of Clinical Oncology examining the effect of tamoxifen sequence showed no adverse effect on local or systemic control in sequential versus concurrent tamoxifen and radiation patients. Pierce et al23 reported on 309 patients who received radiation before or concurrently with tamoxifen, all of whom also had chemotherapy. When the sequential and concurrent groups were compared, there were similar local relapse rates (4.7% v 6.4%, respectively; P = .53), 10-year disease-free survival (83% v 82%, respectively; P = .76), and overall survival (90% v 88%, respectively; P = .65). Ahn et al24 examined 475 patients treated with breast conservation therapy who took tamoxifen during or subsequent to radiation. They reported that the women in the concurrent group were significantly older and less likely to receive chemotherapy than were those in the sequential group—the same pattern that was noted in our study. For the sequential versus concurrent group, 10-year overall survival, distant metastasis-free rate, and local relapse rates were 80% v 85%, 78% v 84%, and 12% v 10%, respectively (P values not given). The outcomes in both studies are entirely consistent with the findings in this analysis that there is no difference in outcome associated with the sequencing of tamoxifen and radiation, although neither reported on the impact of sequence on complications or cosmetic outcome.
In this retrospective study of patients diagnosed with early-stage breast cancer and treated with breast conservation therapy, the patients who received concurrent tamoxifen with radiation were more often older (P < .0001), and those in the sequential group were more likely to have received any chemotherapy (P < .0001). Despite these imbalances between the two groups, the sequence of tamoxifen had no impact on local recurrence rates. A higher percentage of women age 50 or older received chemotherapy in the sequential group (40%) than in the concurrent group (21%). This was also true for patients age 49 or younger, for whom 76% in the sequential group received chemotherapy compared with 49% in the concurrent group. This suggests that the use of chemotherapy tended to be associated with a delay in the initiation of tamoxifen.
The sequence of tamoxifen had no impact on the local recurrence rates. The sequential group, which had a younger median age and a higher rate of chemotherapy use, actually had a higher rate of 10-year local recurrence (7%) than the concurrent group (3%), which was not statistically significant. Overall, there were a small number of local recurrence events (five of 104 patients in the sequential tamoxifen group and seven of 174 patients in the concurrent tamoxifen group); therefore, the power to detect a small difference in local recurrence by sequence is limited. However, given that the use of chemotherapy was controlled for in the analysis, it is unlikely that the use of chemotherapy had an impact on the lack of difference between the sequential and concurrent tamoxifen groups.
As expected, this study did not find any difference in either relapse-free or overall survival by sequence of tamoxifen use. Given that tamoxifen is a long-term cytostatic systemic therapy, the exact timing of initiation in the initial course of therapy would not be expected to influence survival outcomes. However, the major limitation of this study is the small sample size as illustrated by the 95% CIs for the hazard ratios, creating the potential to miss a small difference between the different sequence groups.
There are little data on the risk of complications when tamoxifen and radiation are given. One study reported that in postmastectomy patients receiving radiotherapy and tamoxifen, there was an increased risk of lung fibrosis.25 However, in another study, chest computed tomography scans were performed before radiation and 4 months after completion to quantify radiographic changes in the lungs of irradiated patients and correlate these with radiation technique and symptomatic pneumonitis.26 That study found no correlation with lung density changes and the use of concurrent tamoxifen. Overall, concerns regarding the interaction of tamoxifen with radiation have led some clinicians to advocate their sequential use. Therefore, this study also assessed the risk of complications and the overall cosmetic outcome with respect to the timing of tamoxifen with radiation. There was no difference in the rates of breast edema, arm edema, symptomatic pneumonitis, or rib fracture between the two groups. The rates of excellent and good cosmesis at both 3 and 5 years after radiation were also identical for each group. These results suggest that there is no increased risk of developing fibrosis in the lungs or in the treated breast when tamoxifen is given concurrently with radiation, although subtle differences would not be readily detected with the sample size in this study.
In conclusion, there is no clinical impact on local recurrence, overall survival, relapse-free survival, cosmesis, or significant complications associated with the sequence of tamoxifen and radiation. Therefore, it is reasonable to use either concurrent or sequential regimens when tamoxifen and radiation are both indicated in patients undergoing breast conservation therapy.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Presented in part at the 39th American Society of Clinical Oncology Meeting, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Osborne C, Boldt D, Clark G, et al: Effects of tamoxifen on human breast cancer cell cycle kinetics: Accumulation of cells in early G1 phase. Cancer Res 43:3583-3585, 1983
2. Pritchard KI, Paterson AH, Paul N, et al: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer: National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14:2731-2737, 1996
3. Albain K, Green J, Ravdin P, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100. Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143)
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