Sequence of Radiotherapy With Tamoxifen in Conservatively Managed Breast Cancer Does Not Affect Local Relapse Rates
http://www.100md.com
《临床肿瘤学》
the Albert Einstein College of Medicine of Yeshiva University, Bronx
Long Island Jewish Hospital, Long Island Campus of the Albert Einstein College of Medicine, New Hyde Park, NY
Yale University School of Medicine, New Haven, CT
ABSTRACT
METHODS: Between 1976 and 1999, 1,649 patients with stage I or II breast cancer were treated with CS plus RT at Yale-New Haven Hospital (New Haven, CT). TAM was administered to 500 patients. The timing of TAM relative to RT was documented for each patient. Of the 500 patients, the timing of TAM was unclear in five patients, was administered concurrently with RT in 254 patients (CON-TAM), and was administered sequentially after completion of RT in 241 patients (SEQ-TAM).
RESULTS: There were no differences between the CON-TAM and SEQ-TAM group in T stage, estrogen and progesterone status, nodal status, histology, or margin status. The CON-TAM group was slightly older than the SEQ-TAM group (62 v 58 years) and received chemotherapy in addition to TAM less frequently (14% v 38%). As of September 2002, with a median follow-up of 10.0 years, there were no significant differences between the CON-TAM and SEQ-TAM groups in overall survival (84% v 82%; hazard ratio [HR], 1.234; 95% CI, 0.42 to 2.05; P = .45), distant–metastasis-free rate (82% v 78%; HR, 1.55; 95% CI, 0.89 to 2.68; P = .12), ipsilateral breast-relapse–free rate (90% v 86%; HR, 0.932; 95% CI, 0.42 to 2.05; P = .86), or contralateral breast-relapse–free rate (95% v 93%; HR, 0.892; 95% CI, 0.53 to 1.48; P = .66).
CONCLUSION: Although the concurrent use of TAM with RT may theoretically render cancer cells less responsive to RT, this retrospective study suggests that in practical application, concurrent administration of TAM with RT does not compromise local control.
INTRODUCTION
Despite the frequent use of TAM in combination with RT in the conservative management of breast cancer, there is considerable confusion among clinicians and patients regarding the optimal timing of TAM with respect to the administration of RT. Although the timing of RT with cytotoxic chemotherapy has been evaluated extensively in retrospective and prospective randomized studies, there is a paucity of data regarding the timing of TAM with RT and its impact on local control.8,11,18-21
A recent randomized study that evaluated the sequencing of chemotherapy with TAM demonstrated superior results when TAM was administered after chemotherapy, as opposed to concurrently with chemotherapy, with respect to disease-free survival (DFS) and overall survival.22 Theoretically, this might be due to concurrent use of TAM rendering cells less sensitive to the cytotoxic effects of chemotherapy.23,24 Similar arguments could be made regarding the concurrent administration of RT and TAM. Results from laboratory studies demonstrate that pretreatment or concurrent treatment of breast cancer cells with TAM leads to increased radioresistance.25-28 On the basis of these laboratory data, in combination with the recent clinical evidence that concurrent TAM and chemotherapy compromise outcomes, one might hypothesize that concurrent administration of RT and TAM could decrease rates of local control. To address this issue, this study was undertaken to evaluate the effect on local control of the sequencing of TAM with RT in the conservatively managed breast cancer patient. To our knowledge, this issue has not been explored in the clinical setting.
METHODS
Radiation oncology charts and tumor registry data were reviewed in detail on all 1,649 conservatively managed patients; particular attention was paid to the timing of systemic therapy and RT. A total of 500 patients who received TAM as a component of their adjuvant systemic therapy serve as the focus of the current analysis. Barring discontinuation because of adverse effects or initiation of another type of hormonal therapy, patients were generally treated with TAM for a total of 5 years. In the earlier years, patients were treated for varying lengths of time ranging from 2 years to indefinitely. A minority of patients continued to receive TAM for longer than 5 years. In this retrospective review, it was difficult to ascertain the precise duration of TAM in all patients. In those patients in whom the use of TAM was clearly documented, fewer than 10% continued to receive the medication for longer than 5 years.
Of the 500 patients who were treated with TAM, 254 were identified as having started TAM before RT or concurrently with RT (CON-TAM), whereas 241 received TAM sequentially after RT was completed (SEQ-TAM). In only five patients (1%), the sequence of TAM and RT could not be identified. The following analysis excludes the five patients in whom TAM sequencing could not be determined.
Measured outcomes included rates of local failure, contralateral breast recurrence, distant metastasis, cause-specific survival, and overall survival. Local failure was defined as biopsy-documented recurrence of disease in the treated, ipsilateral breast, whether it occurred at the original lumpectomy site or elsewhere within the treated breast. Breast cancer developing in the opposite untreated breast was scored as a contralateral event. Length of follow-up and other temporal parameters were determined by listing the date of first surgery as time zero. For all measured end points, patients were censored at the time of the specific event. Therefore, patients with ipsilateral relapse before distant metastasis were censored at the time of breast relapse, with respect to the ipsilateral breast-relapse–free rate.
Tests for statistical significance were performed using the {chi}2 statistic for categoric variables. Survival curves were generated using the Cox life-table regression model with use of the Mantel-Haenszel statistic. Multivariate analysis was performed using a proportional hazards regression model.
RESULTS
As of September 2002, median follow-up on the entire cohort of patients was 10.4 years. Median age for all patients receiving TAM was 61 years. Table 2 summarizes the outcomes of the patients, broken down by sequencing of TAM. Of the 254 patients in the CON-TAM group, there were 23 overall deaths; in the 218 patients in the SEQ-TAM group, there were 21 deaths. Relapse in the ipsilateral breast was observed in 13 of the CON-TAM patients, whereas 14 patients in the SEQ-TAM group experienced local relapse. Eight patients in the CON-TAM group had contralateral breast cancer develop, whereas seven patients in the SEQ-TAM group developed contralateral breast cancer. Distant metastasis developed in 21 patients in the CON-TAM group compared with 29 patients in the SEQ-TAM group.
The actuarial 10-year overall survival of the two groups was similar (84% for the CON-TAM group and 80% for the SEQ-TAM group; hazard ratio [HR], 1.234; 95% CI, 0.72 to 2.12; P = .45; Fig 1.). There was no difference in 10-year survival free of ipsilateral breast recurrence (90% v 86%; HR, 0.932; 95% CI, 0.42 to 2.05; P = .86; Fig 2), contralateral breast recurrence (95% v 93%; HR, 0.892; 95% CI, 0.53 to 1.48; P = .66), or in freedom from disease-specific mortality (92% v 89%; HR, 1.163; 95% CI, 0.56 to 2.41; P = .68).
Although not statistically significant, there was a trend toward decreased distant–relapse-free survival in patients who started TAM after RT was completed (80% for the CON-TAM group and 77% for the SEQ-TAM group at 10 years; HR, 1.55; 95% CI, 0.89 to 2.68; P = .12). However, this is likely because patients in the SEQ-TAM group had more aggressive disease and were more frequently treated with chemotherapy.
As noted above, the SEQ-TAM group was more likely to receive chemotherapy and had a slightly younger age, both of which have been shown to influence local relapse rates. A multivariate proportional hazards regression model, which took into account stage, age, use of chemotherapy, margin status, histology, and sequencing of TAM, failed to reveal any effect of TAM sequencing on any of the outcomes measures, including local control.
Because of the differences in age and use of chemotherapy between the CON-TAM and SEQ-TAM cohorts, we conducted a subset analysis of those patients receiving TAM alone (without chemotherapy) as adjuvant therapy. A total of 362 patients in this subset analysis received TAM alone, without chemotherapy as adjuvant systemic treatment. As noted in Table 3, there were no differences between the two cohorts with respect to age, nodal status, receptor status, or margins. Follow-up was slightly longer in the CON-TAM group, given that a delay in TAM therapy was a frequent practice in more recent years; however, this difference was not statistically significant. The CON-TAM group had a slightly larger mean tumor size than the SEQ-TAM group (1.56 v 1.31 cm; P < .01). In this subset analysis, outcomes at 10 years between the CON-TAM and SEQ-TAM groups were similar, with an ipsilateral breast cancer–relapse-free rate of 92% v 89% (HR, 1.11; 95% CI, 0.43 to 2.87; P = .82), distant–metastasis-free rate of 84% v 79% (HR, 1.38; 95% CI, 0.69 to 2.78; P = .36), and contralateral breast–relapse-free rate of 96% v 95% (HR, 1.09; 95% CI, 0.63 to 1.9; P = .75).
DISCUSSION
There has been great interest in the optimal sequencing of chemotherapeutic and hormonal systemic therapies relative to each other and to RT after breast-conserving surgery. In the in vitro setting, pretreatment with TAM has antagonistic effects on fluorouracil and doxorubicin for both ER-positive and ER-negative cell lines.23 A recent randomized controlled study of TAM with respect to chemotherapy showed that concurrent administration led to decreased DFS at 8 years compared with when TAM was administered after cyclophosphamide, doxorubicin, and fluorouracil in ER-positive postmenopausal women. Concurrent TAM was found to decrease the effectiveness of cyclophosphamide, doxorubicin, and fluorouracil in improving DFS.22 The National Surgical Adjuvant Breast and Bowel Project B-20 study found that this could be due in part to patient intolerance of systemic therapies when chemotherapy and hormone therapy are given concurrently, at least in lymph node-negative and ER-positive postmenopausal women treated with cyclophosphamide, methotrexate, and fluorouracil, or doxorubicin and cyclophosphamide in conjunction with TAM.35 Another randomized controlled trial found that administration of low-dose chemotherapy concurrently with TAM had neither a positive nor negative effect on survival compared with TAM alone, although most of these patients were treated with radical surgery instead of CS + RT.24
The findings that breast cancer patients might fare worse with concurrent administration of TAM and chemotherapy raises the possibility that concurrent administration of TAM and RT could lead to worse outcomes. The experience with the optimal timing of chemotherapy and RT has been instructive: instituting chemotherapy before or during RT reduced rates of distant relapse, but produced a tendency toward decreased local control.11,20,21,36
In agreement with other published studies, we observed a decrease in local relapse rate associated with the use of TAM in the adjuvant setting. In our experience, however, starting TAM before or during RT, or after completion of RT, did not affect rates of local relapse, distant metastasis, contralateral breast relapse, or overall survival in a statistically significant manner.
It should be noted that the group starting TAM after completion of RT was more likely to receive chemotherapy and initiated use of TAM after completion of RT and chemotherapy, in accordance with standard practice in the community. Although the two cohorts of CON-TAM and SEQ-TAM are similar in most respects, they demonstrate significant differences in age and in the administration of chemotherapy. Both differences might artificially lead to deviations from the true effect of sequencing of therapy. The difference in mean age was only 4 years, but was significant. One of the most consistently reported prognostic factors for in-breast relapses reported in the literature is the increased local relapse rate with decreasing age.
Given that the SEQ-TAM group had a significantly younger age, one might expect, if anything, a slightly higher local relapse rate with SEQ-TAM. Given that the relapse rates were the same for the slightly older CON-TAM group, one cannot totally exclude a slight detrimental effect with the concurrent use of TAM. However, a multivariate analysis failed to reveal any differences in local control as a function of sequencing.
To further investigate this issue, we conducted a subset analysis, in which we eliminated the patients receiving any chemotherapy. In this subset analysis, the CON-TAM and SEQ-TAM groups had similar ages, follow-up, receptor status, and margin status. The slightly larger primary tumor size in the CON-TAM group could conceivably bias the CON-TAM group, yielding a slightly higher relapse rate, both systemically and locally. However, even in this subset analysis, the in-breast relapse rates were not significantly different. Specifically, the concurrent use of TAM appears to have no adverse effect on the in-breast relapse rates.
Because of the nonrandomized nature of this retrospective study, and the inherent biases with respect to the use of chemotherapy and more aggressive disease in the SEQ-TAM cohort, we can reach no firm conclusions regarding the effects of the sequencing of TAM with respect to survival or distant metastasis. With respect to the effects on local control, although there are caveats, it appears that administration of TAM during RT did not result in a compromise of local control, compared with delaying TAM until all RT was completed.
Clearly, there are limitations in interpreting this retrospective study. Although we cannot state with certainty that concurrent administration of TAM with RT has no adverse effect on local control, our observed data would indicate that any theoretical compromise is not of any meaningful clinical significance. Although the follow-up (median of approximately 10 years) and patient numbers (approximately 250 in each cohort) in this series are respectable, we would not have the power to detect a small 5% to 10% difference in local control. With just more than 200 patients in each arm, this retrospective analysis would have approximately 80% power to detect a 15% difference in local control as a function of TAM sequencing. We would need a much larger sample size of nearly 800 patients to detect a smaller 5% to 10% difference in local control. Another limitation in this study is a lack of precise data regarding the duration of TAM in each patient. Although we attempted to document starting and stopping dates for TAM in each patient, the nature of the review does not lend itself well to precision and accuracy with respect to the duration of TAM. In those patients in whom we were confident in the accuracy of the duration of TAM, we observed no differences between the two cohorts.
Since completion of our study, two other studies, reported in abstract form at the 2003 American Society of Clinical Oncology annual meeting, observed similar findings.37,38 Although these studies were also nonrandomized retrospective analyses with respect to the sequencing of TAM and were subject to similar limitations as those of our own analysis, taken together they appear to offer some reassurance that the concurrent use of RT with TAM does not lead to a clinically significant compromise in local control.
For future studies, a multicenter randomized controlled trial would be desirable for greater scientific validity and to confirm these retrospective observations. At this point, barring any additional examination of this issue and given the limitations inherent in this study, we cannot recommend any particular sequence of TAM relative to RT. Until more definitive randomized data are available, patient and physician preferences regarding the sequencing of TAM with RT will continue to be a reasonable standard.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. National Institutes of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 2001:5-15, 2001
2. Fisher B, Anderson S, Redmond CK, et al: Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 333:1456-1461, 1995
3. Veronesi U: NIH consensus meeting on early breast cancer. Eur J Cancer 26:843-844, 1990
4. Veronesi U, Marubini E, Mariani L, et al: Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of a randomized trial. Ann Oncol 12:997-1003, 2001
5. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19:931-942, 2001
6. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 320:822-828, 1989
7. Fowble B: Ipsilateral breast tumor recurrence following breast-conserving surgery for early-stage invasive cancer. Acta Oncol 38:9-17, 1999 (suppl 13)
8. Haffty BG: Who's on first Sequencing chemotherapy and radiation therapy in conservatively managed node-negative breast cancer. Cancer J Sci Am 5:147-149, 1999
9. Haffty BG, Fischer D, Rose M, et al: Prognostic factors for local recurrence in the conservatively treated breast cancer patient: A cautious interpretation of the data. J Clin Oncol 9:997-1003, 1991
10. Haffty BG, Wilmarth L, Wilson L, et al: Adjuvant systemic chemotherapy and hormonal therapy: Effect on local recurrence in the conservatively treated breast cancer patient. Cancer 73:2543-2548, 1994
11. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996
12. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases: Anglian Breast Cancer Study Group. Br J Cancer 83:1301-8130, 2000
13. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451-1467, 1998
14. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998
15. 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
16. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study—Hereditary Breast Cancer Clinical Study Group. Lancet 356:1876-1881, 2000
17. Veronesi U, Marubini E, Del Vecchio M, et al: Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst 87:19-27, 1995
18. Recht A, Harris JR, Come SE: Sequencing of irradiation and chemotherapy for early-stage breast cancer. Oncology (Huntingt) 8:19-37, 1994
19. Buchholz TA, Hunt KK, Amosson CM, et al: Sequencing of chemotherapy and radiation in lymph node-negative breast cancer. Cancer J Sci Am 5:159-164, 1999
20. Buchholz TA, Austin-Seymour MM, Moe RE, et al: Effect of delay in radiation in the combined modality treatment of breast cancer. Int J Radiat Oncol Biol Phys 26:23-35, 1993
21. Wallgren A, Bernier J, Gelber RD, et al: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer: International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35:649-659, 1996
22. Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be given sequential instead of concurrent: Initial results from Intergroup trial 0100 (SWOG-88-14). J Clin Oncol 21:37a, 2002 (suppl)
23. Hug V, Hortobagyi GN, Drewinko B, et al: Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro. J Clin Oncol 3:1672-1677, 1985
24. Jakesz R, Hausmaninger H, Haider K, et al: Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer. J Clin Oncol 17:1701-1709, 1999
25. Kantorowitz DA, Thompson HJ, Furmanski P: Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma. Int J Radiat Oncol Biol Phys 26:89-94, 1993
26. Wazer DE, Tercilla OF, Lin PS, et al: Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17-beta-estradiol and tamoxifen. Br J Radiol 62:1079-1083, 1989
27. Paulsen GH, Strickert T, Marthinsen AB, et al: Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro. Acta Oncol 35:1011-1019, 1996
28. Villalobos M, Aranda M, Nunez MI, et al: Interaction between ionizing radiation, estrogens and antiestrogens in the modification of tumor microenvironment in estrogen dependent multicellular spheroids. Acta Oncol 34:413-417, 1995
29. Haffty BG, Fischer D, Fischer JJ: Regional nodal irradiation in the conservative treatment of breast cancer. Int J Radiat Oncol Biol Phys 19:859-865, 1990
30. Schmidt-Ullrich RK, Valerie K, Chan W, et al: Expression of oestrogen receptor and transforming growth factor-alpha in MCF-7 cells after exposure to fractionated irradiation. Int J Radiat Biol 61:405-415, 1992
31. Buchholz TA, Wazer DE: Molecular biology and genetics of breast cancer development: A clinical perspective. Semin Radiat Oncol 12:285-295, 2002
32. Wazer DE, Band V: Molecular and anatomic considerations in the pathogenesis of breast cancer. Radiat Oncol Investig 7:1-12, 1999
33. Hall EJ: Radiobiology for the Radiologist (ed 4). Philadelphia, JB Lippincott, 1994
34. Ellis PA, Saccani-Jotti G, Clarke R, et al: Induction of apoptosis by tamoxifen and ICI 182780 in primary breast cancer. Int J Cancer 72:608-613, 1997
35. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997
36. Recht A: Radiotherapy-chemotherapy integration in breast-conservation therapy. Front Radiat Ther Oncol 27:89-102, 1993
37. 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
38. Harris EER, Christensen VJ, Hwang W-T, et al: The 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(Peter H. Ahn, Ha Thanh Vu)
Long Island Jewish Hospital, Long Island Campus of the Albert Einstein College of Medicine, New Hyde Park, NY
Yale University School of Medicine, New Haven, CT
ABSTRACT
METHODS: Between 1976 and 1999, 1,649 patients with stage I or II breast cancer were treated with CS plus RT at Yale-New Haven Hospital (New Haven, CT). TAM was administered to 500 patients. The timing of TAM relative to RT was documented for each patient. Of the 500 patients, the timing of TAM was unclear in five patients, was administered concurrently with RT in 254 patients (CON-TAM), and was administered sequentially after completion of RT in 241 patients (SEQ-TAM).
RESULTS: There were no differences between the CON-TAM and SEQ-TAM group in T stage, estrogen and progesterone status, nodal status, histology, or margin status. The CON-TAM group was slightly older than the SEQ-TAM group (62 v 58 years) and received chemotherapy in addition to TAM less frequently (14% v 38%). As of September 2002, with a median follow-up of 10.0 years, there were no significant differences between the CON-TAM and SEQ-TAM groups in overall survival (84% v 82%; hazard ratio [HR], 1.234; 95% CI, 0.42 to 2.05; P = .45), distant–metastasis-free rate (82% v 78%; HR, 1.55; 95% CI, 0.89 to 2.68; P = .12), ipsilateral breast-relapse–free rate (90% v 86%; HR, 0.932; 95% CI, 0.42 to 2.05; P = .86), or contralateral breast-relapse–free rate (95% v 93%; HR, 0.892; 95% CI, 0.53 to 1.48; P = .66).
CONCLUSION: Although the concurrent use of TAM with RT may theoretically render cancer cells less responsive to RT, this retrospective study suggests that in practical application, concurrent administration of TAM with RT does not compromise local control.
INTRODUCTION
Despite the frequent use of TAM in combination with RT in the conservative management of breast cancer, there is considerable confusion among clinicians and patients regarding the optimal timing of TAM with respect to the administration of RT. Although the timing of RT with cytotoxic chemotherapy has been evaluated extensively in retrospective and prospective randomized studies, there is a paucity of data regarding the timing of TAM with RT and its impact on local control.8,11,18-21
A recent randomized study that evaluated the sequencing of chemotherapy with TAM demonstrated superior results when TAM was administered after chemotherapy, as opposed to concurrently with chemotherapy, with respect to disease-free survival (DFS) and overall survival.22 Theoretically, this might be due to concurrent use of TAM rendering cells less sensitive to the cytotoxic effects of chemotherapy.23,24 Similar arguments could be made regarding the concurrent administration of RT and TAM. Results from laboratory studies demonstrate that pretreatment or concurrent treatment of breast cancer cells with TAM leads to increased radioresistance.25-28 On the basis of these laboratory data, in combination with the recent clinical evidence that concurrent TAM and chemotherapy compromise outcomes, one might hypothesize that concurrent administration of RT and TAM could decrease rates of local control. To address this issue, this study was undertaken to evaluate the effect on local control of the sequencing of TAM with RT in the conservatively managed breast cancer patient. To our knowledge, this issue has not been explored in the clinical setting.
METHODS
Radiation oncology charts and tumor registry data were reviewed in detail on all 1,649 conservatively managed patients; particular attention was paid to the timing of systemic therapy and RT. A total of 500 patients who received TAM as a component of their adjuvant systemic therapy serve as the focus of the current analysis. Barring discontinuation because of adverse effects or initiation of another type of hormonal therapy, patients were generally treated with TAM for a total of 5 years. In the earlier years, patients were treated for varying lengths of time ranging from 2 years to indefinitely. A minority of patients continued to receive TAM for longer than 5 years. In this retrospective review, it was difficult to ascertain the precise duration of TAM in all patients. In those patients in whom the use of TAM was clearly documented, fewer than 10% continued to receive the medication for longer than 5 years.
Of the 500 patients who were treated with TAM, 254 were identified as having started TAM before RT or concurrently with RT (CON-TAM), whereas 241 received TAM sequentially after RT was completed (SEQ-TAM). In only five patients (1%), the sequence of TAM and RT could not be identified. The following analysis excludes the five patients in whom TAM sequencing could not be determined.
Measured outcomes included rates of local failure, contralateral breast recurrence, distant metastasis, cause-specific survival, and overall survival. Local failure was defined as biopsy-documented recurrence of disease in the treated, ipsilateral breast, whether it occurred at the original lumpectomy site or elsewhere within the treated breast. Breast cancer developing in the opposite untreated breast was scored as a contralateral event. Length of follow-up and other temporal parameters were determined by listing the date of first surgery as time zero. For all measured end points, patients were censored at the time of the specific event. Therefore, patients with ipsilateral relapse before distant metastasis were censored at the time of breast relapse, with respect to the ipsilateral breast-relapse–free rate.
Tests for statistical significance were performed using the {chi}2 statistic for categoric variables. Survival curves were generated using the Cox life-table regression model with use of the Mantel-Haenszel statistic. Multivariate analysis was performed using a proportional hazards regression model.
RESULTS
As of September 2002, median follow-up on the entire cohort of patients was 10.4 years. Median age for all patients receiving TAM was 61 years. Table 2 summarizes the outcomes of the patients, broken down by sequencing of TAM. Of the 254 patients in the CON-TAM group, there were 23 overall deaths; in the 218 patients in the SEQ-TAM group, there were 21 deaths. Relapse in the ipsilateral breast was observed in 13 of the CON-TAM patients, whereas 14 patients in the SEQ-TAM group experienced local relapse. Eight patients in the CON-TAM group had contralateral breast cancer develop, whereas seven patients in the SEQ-TAM group developed contralateral breast cancer. Distant metastasis developed in 21 patients in the CON-TAM group compared with 29 patients in the SEQ-TAM group.
The actuarial 10-year overall survival of the two groups was similar (84% for the CON-TAM group and 80% for the SEQ-TAM group; hazard ratio [HR], 1.234; 95% CI, 0.72 to 2.12; P = .45; Fig 1.). There was no difference in 10-year survival free of ipsilateral breast recurrence (90% v 86%; HR, 0.932; 95% CI, 0.42 to 2.05; P = .86; Fig 2), contralateral breast recurrence (95% v 93%; HR, 0.892; 95% CI, 0.53 to 1.48; P = .66), or in freedom from disease-specific mortality (92% v 89%; HR, 1.163; 95% CI, 0.56 to 2.41; P = .68).
Although not statistically significant, there was a trend toward decreased distant–relapse-free survival in patients who started TAM after RT was completed (80% for the CON-TAM group and 77% for the SEQ-TAM group at 10 years; HR, 1.55; 95% CI, 0.89 to 2.68; P = .12). However, this is likely because patients in the SEQ-TAM group had more aggressive disease and were more frequently treated with chemotherapy.
As noted above, the SEQ-TAM group was more likely to receive chemotherapy and had a slightly younger age, both of which have been shown to influence local relapse rates. A multivariate proportional hazards regression model, which took into account stage, age, use of chemotherapy, margin status, histology, and sequencing of TAM, failed to reveal any effect of TAM sequencing on any of the outcomes measures, including local control.
Because of the differences in age and use of chemotherapy between the CON-TAM and SEQ-TAM cohorts, we conducted a subset analysis of those patients receiving TAM alone (without chemotherapy) as adjuvant therapy. A total of 362 patients in this subset analysis received TAM alone, without chemotherapy as adjuvant systemic treatment. As noted in Table 3, there were no differences between the two cohorts with respect to age, nodal status, receptor status, or margins. Follow-up was slightly longer in the CON-TAM group, given that a delay in TAM therapy was a frequent practice in more recent years; however, this difference was not statistically significant. The CON-TAM group had a slightly larger mean tumor size than the SEQ-TAM group (1.56 v 1.31 cm; P < .01). In this subset analysis, outcomes at 10 years between the CON-TAM and SEQ-TAM groups were similar, with an ipsilateral breast cancer–relapse-free rate of 92% v 89% (HR, 1.11; 95% CI, 0.43 to 2.87; P = .82), distant–metastasis-free rate of 84% v 79% (HR, 1.38; 95% CI, 0.69 to 2.78; P = .36), and contralateral breast–relapse-free rate of 96% v 95% (HR, 1.09; 95% CI, 0.63 to 1.9; P = .75).
DISCUSSION
There has been great interest in the optimal sequencing of chemotherapeutic and hormonal systemic therapies relative to each other and to RT after breast-conserving surgery. In the in vitro setting, pretreatment with TAM has antagonistic effects on fluorouracil and doxorubicin for both ER-positive and ER-negative cell lines.23 A recent randomized controlled study of TAM with respect to chemotherapy showed that concurrent administration led to decreased DFS at 8 years compared with when TAM was administered after cyclophosphamide, doxorubicin, and fluorouracil in ER-positive postmenopausal women. Concurrent TAM was found to decrease the effectiveness of cyclophosphamide, doxorubicin, and fluorouracil in improving DFS.22 The National Surgical Adjuvant Breast and Bowel Project B-20 study found that this could be due in part to patient intolerance of systemic therapies when chemotherapy and hormone therapy are given concurrently, at least in lymph node-negative and ER-positive postmenopausal women treated with cyclophosphamide, methotrexate, and fluorouracil, or doxorubicin and cyclophosphamide in conjunction with TAM.35 Another randomized controlled trial found that administration of low-dose chemotherapy concurrently with TAM had neither a positive nor negative effect on survival compared with TAM alone, although most of these patients were treated with radical surgery instead of CS + RT.24
The findings that breast cancer patients might fare worse with concurrent administration of TAM and chemotherapy raises the possibility that concurrent administration of TAM and RT could lead to worse outcomes. The experience with the optimal timing of chemotherapy and RT has been instructive: instituting chemotherapy before or during RT reduced rates of distant relapse, but produced a tendency toward decreased local control.11,20,21,36
In agreement with other published studies, we observed a decrease in local relapse rate associated with the use of TAM in the adjuvant setting. In our experience, however, starting TAM before or during RT, or after completion of RT, did not affect rates of local relapse, distant metastasis, contralateral breast relapse, or overall survival in a statistically significant manner.
It should be noted that the group starting TAM after completion of RT was more likely to receive chemotherapy and initiated use of TAM after completion of RT and chemotherapy, in accordance with standard practice in the community. Although the two cohorts of CON-TAM and SEQ-TAM are similar in most respects, they demonstrate significant differences in age and in the administration of chemotherapy. Both differences might artificially lead to deviations from the true effect of sequencing of therapy. The difference in mean age was only 4 years, but was significant. One of the most consistently reported prognostic factors for in-breast relapses reported in the literature is the increased local relapse rate with decreasing age.
Given that the SEQ-TAM group had a significantly younger age, one might expect, if anything, a slightly higher local relapse rate with SEQ-TAM. Given that the relapse rates were the same for the slightly older CON-TAM group, one cannot totally exclude a slight detrimental effect with the concurrent use of TAM. However, a multivariate analysis failed to reveal any differences in local control as a function of sequencing.
To further investigate this issue, we conducted a subset analysis, in which we eliminated the patients receiving any chemotherapy. In this subset analysis, the CON-TAM and SEQ-TAM groups had similar ages, follow-up, receptor status, and margin status. The slightly larger primary tumor size in the CON-TAM group could conceivably bias the CON-TAM group, yielding a slightly higher relapse rate, both systemically and locally. However, even in this subset analysis, the in-breast relapse rates were not significantly different. Specifically, the concurrent use of TAM appears to have no adverse effect on the in-breast relapse rates.
Because of the nonrandomized nature of this retrospective study, and the inherent biases with respect to the use of chemotherapy and more aggressive disease in the SEQ-TAM cohort, we can reach no firm conclusions regarding the effects of the sequencing of TAM with respect to survival or distant metastasis. With respect to the effects on local control, although there are caveats, it appears that administration of TAM during RT did not result in a compromise of local control, compared with delaying TAM until all RT was completed.
Clearly, there are limitations in interpreting this retrospective study. Although we cannot state with certainty that concurrent administration of TAM with RT has no adverse effect on local control, our observed data would indicate that any theoretical compromise is not of any meaningful clinical significance. Although the follow-up (median of approximately 10 years) and patient numbers (approximately 250 in each cohort) in this series are respectable, we would not have the power to detect a small 5% to 10% difference in local control. With just more than 200 patients in each arm, this retrospective analysis would have approximately 80% power to detect a 15% difference in local control as a function of TAM sequencing. We would need a much larger sample size of nearly 800 patients to detect a smaller 5% to 10% difference in local control. Another limitation in this study is a lack of precise data regarding the duration of TAM in each patient. Although we attempted to document starting and stopping dates for TAM in each patient, the nature of the review does not lend itself well to precision and accuracy with respect to the duration of TAM. In those patients in whom we were confident in the accuracy of the duration of TAM, we observed no differences between the two cohorts.
Since completion of our study, two other studies, reported in abstract form at the 2003 American Society of Clinical Oncology annual meeting, observed similar findings.37,38 Although these studies were also nonrandomized retrospective analyses with respect to the sequencing of TAM and were subject to similar limitations as those of our own analysis, taken together they appear to offer some reassurance that the concurrent use of RT with TAM does not lead to a clinically significant compromise in local control.
For future studies, a multicenter randomized controlled trial would be desirable for greater scientific validity and to confirm these retrospective observations. At this point, barring any additional examination of this issue and given the limitations inherent in this study, we cannot recommend any particular sequence of TAM relative to RT. Until more definitive randomized data are available, patient and physician preferences regarding the sequencing of TAM with RT will continue to be a reasonable standard.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. National Institutes of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 2001:5-15, 2001
2. Fisher B, Anderson S, Redmond CK, et al: Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 333:1456-1461, 1995
3. Veronesi U: NIH consensus meeting on early breast cancer. Eur J Cancer 26:843-844, 1990
4. Veronesi U, Marubini E, Mariani L, et al: Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of a randomized trial. Ann Oncol 12:997-1003, 2001
5. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19:931-942, 2001
6. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 320:822-828, 1989
7. Fowble B: Ipsilateral breast tumor recurrence following breast-conserving surgery for early-stage invasive cancer. Acta Oncol 38:9-17, 1999 (suppl 13)
8. Haffty BG: Who's on first Sequencing chemotherapy and radiation therapy in conservatively managed node-negative breast cancer. Cancer J Sci Am 5:147-149, 1999
9. Haffty BG, Fischer D, Rose M, et al: Prognostic factors for local recurrence in the conservatively treated breast cancer patient: A cautious interpretation of the data. J Clin Oncol 9:997-1003, 1991
10. Haffty BG, Wilmarth L, Wilson L, et al: Adjuvant systemic chemotherapy and hormonal therapy: Effect on local recurrence in the conservatively treated breast cancer patient. Cancer 73:2543-2548, 1994
11. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996
12. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases: Anglian Breast Cancer Study Group. Br J Cancer 83:1301-8130, 2000
13. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451-1467, 1998
14. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998
15. 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
16. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study—Hereditary Breast Cancer Clinical Study Group. Lancet 356:1876-1881, 2000
17. Veronesi U, Marubini E, Del Vecchio M, et al: Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst 87:19-27, 1995
18. Recht A, Harris JR, Come SE: Sequencing of irradiation and chemotherapy for early-stage breast cancer. Oncology (Huntingt) 8:19-37, 1994
19. Buchholz TA, Hunt KK, Amosson CM, et al: Sequencing of chemotherapy and radiation in lymph node-negative breast cancer. Cancer J Sci Am 5:159-164, 1999
20. Buchholz TA, Austin-Seymour MM, Moe RE, et al: Effect of delay in radiation in the combined modality treatment of breast cancer. Int J Radiat Oncol Biol Phys 26:23-35, 1993
21. Wallgren A, Bernier J, Gelber RD, et al: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer: International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35:649-659, 1996
22. Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be given sequential instead of concurrent: Initial results from Intergroup trial 0100 (SWOG-88-14). J Clin Oncol 21:37a, 2002 (suppl)
23. Hug V, Hortobagyi GN, Drewinko B, et al: Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro. J Clin Oncol 3:1672-1677, 1985
24. Jakesz R, Hausmaninger H, Haider K, et al: Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer. J Clin Oncol 17:1701-1709, 1999
25. Kantorowitz DA, Thompson HJ, Furmanski P: Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma. Int J Radiat Oncol Biol Phys 26:89-94, 1993
26. Wazer DE, Tercilla OF, Lin PS, et al: Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17-beta-estradiol and tamoxifen. Br J Radiol 62:1079-1083, 1989
27. Paulsen GH, Strickert T, Marthinsen AB, et al: Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro. Acta Oncol 35:1011-1019, 1996
28. Villalobos M, Aranda M, Nunez MI, et al: Interaction between ionizing radiation, estrogens and antiestrogens in the modification of tumor microenvironment in estrogen dependent multicellular spheroids. Acta Oncol 34:413-417, 1995
29. Haffty BG, Fischer D, Fischer JJ: Regional nodal irradiation in the conservative treatment of breast cancer. Int J Radiat Oncol Biol Phys 19:859-865, 1990
30. Schmidt-Ullrich RK, Valerie K, Chan W, et al: Expression of oestrogen receptor and transforming growth factor-alpha in MCF-7 cells after exposure to fractionated irradiation. Int J Radiat Biol 61:405-415, 1992
31. Buchholz TA, Wazer DE: Molecular biology and genetics of breast cancer development: A clinical perspective. Semin Radiat Oncol 12:285-295, 2002
32. Wazer DE, Band V: Molecular and anatomic considerations in the pathogenesis of breast cancer. Radiat Oncol Investig 7:1-12, 1999
33. Hall EJ: Radiobiology for the Radiologist (ed 4). Philadelphia, JB Lippincott, 1994
34. Ellis PA, Saccani-Jotti G, Clarke R, et al: Induction of apoptosis by tamoxifen and ICI 182780 in primary breast cancer. Int J Cancer 72:608-613, 1997
35. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997
36. Recht A: Radiotherapy-chemotherapy integration in breast-conservation therapy. Front Radiat Ther Oncol 27:89-102, 1993
37. 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
38. Harris EER, Christensen VJ, Hwang W-T, et al: The 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(Peter H. Ahn, Ha Thanh Vu)