Sequencing of Tamoxifen and Radiotherapy After Breast-Conserving Surgery in Early-Stage Breast Cancer
http://www.100md.com
《临床肿瘤学》
the Southwest Oncology Group, San Antonio
Baylor College of Medicine, Houston, TX
University of Michigan School of Medicine, Ann Arbor, MI
University of Arkansas Medical Center, Little Rock, AR
Fred Hutchinson Cancer Research Center
University of Washington, Seattle, WA
Loyola University Medical Center, Maywood, IL
ABSTRACT
PATIENTS AND METHODS: Southwest Oncology Group trial 8897 (Intergroup 0102) randomly assigned node-negative women with T1-3 breast cancers to cyclophosphamide, doxorubicin, fluorouracil (CAF); CAF -> TAM; cyclophosphamide, methotrexate, fluorouracil (CMF); and CMF -> TAM. For this analysis, data are reported only in the TAM groups. RT was allowed either before adjuvant therapy (sequential [SEQ] RT; 107 patients) or after chemotherapy but concurrent with TAM (concurrent [CONC] RT; 202 patients). Survival data were adjusted for receptor status, age, and tumor size.
RESULTS: With a median follow-up of 10.3 years, 10-year DFS values were 83% and 83% for CONC versus SEQ RT groups (log-rank P = .73; P = .76 adjusted for patient characteristics), and 10-year overall survivals were 88% and 90%, respectively (log-rank P = .59; adjusted P = .65). Patterns of failure showed no increase in in-breast recurrence rates between CONC RT and SEQ RT groups, with 10-year local recurrence rates of 7% for CONC RT and 5% for SEQ RT (hazard ratio, 0.73; 95% CI, 0.26 to 2.04; P = .54).
CONCLUSION: The current analysis does not suggest an adverse effect on local or systemic control with CONC versus SEQ TAM and RT in node-negative breast cancer. A randomized trial is encouraged to validate these results.
INTRODUCTION
PATIENTS AND METHODS
High-risk patients were eligible for random assignment, whereas low-risk patients were observed after local therapy. The criteria for high risk included the presence of estrogen receptor- and progesterone receptor-negative disease; an estrogen receptor-positive and/or progesterone receptor-positive tumor that was ≥ 2 cm in size; an estrogen receptor-positive cancer measuring less than 2 cm associated with an S phase fraction ≥ 4.4 for diploid tumors and ≥ 7.0 for aneuploid tumors; or S phase fraction unknown for a tumor greater than 1 cm. Low-risk was defined as an estrogen receptor- and/or progesterone receptor-positive tumor measuring less than 2 cm with a % S phase less than 4.4 for diploid cancers or less than 7.0 for aneuploid tumors; or cancers ≤ 1 cm and % S phase unknown.
Patients with low-risk disease were observed without systemic therapy; patients with high-risk disease were randomly assigned to one of four treatments, as shown in Fig 1. For purposes of this analysis, data were reported only for those high-risk patients receiving TAM who underwent breast-conserving therapy. The timing of breast RT was not specified in the trial. It was left to the discretion of the treating physician whether to deliver the RT to the breast before adjuvant therapy was started (before registration) or after adjuvant chemotherapy was completed. Therefore, RT was given either before TAM (SEQ RT) or after chemotherapy concurrent with TAM (CONC RT). Systemic therapy consisted of either cyclophosphamide, methotrexate, and fluorouracil (CMF) for six 28-day cycles followed by TAM (cyclophosphamide 100 mg/m2 orally qd for 14 days, methotrexate 40 mg/m2 intravenously [IV] on days 1 and 8, fluorouracil 600 mg/m2 IV on days 1 and 8, and tamoxifen 20 mg daily for 5 years starting on day 29 of the last chemotherapy cycle); or cyclophosphamide, doxorubicin, and fluorouracil (CAF) for six 28-day cycles followed by TAM (cyclophosphamide 100 mg/m2 orally qd for 14 days, doxorubicin 30 mg/m2 IV on days 1 and 8, fluorouracil 500 mg/m2 IV on days 1 and 8, and tamoxifen 20 mg daily for 5 years starting on day 29 of the last cycle). According to the cooperative group standard for this era of adjuvant trials, tamoxifen was prescribed for both receptor-positive and receptor-negative disease.
Patients electing breast conservation underwent an excisional biopsy of the primary lesion with microscopically negative margins. If the excision resulted in microscopically involved margins, a re-excision was required to clear the margins. Patients with multicentric disease either clinically or mammographically were excluded from study. All patients underwent an axillary dissection and were required to be node-negative for study eligibility.
RT was given to all patients who received breast-conserving surgery either before adjuvant chemotherapy was delivered or after chemotherapy was completed, concurrent with TAM. For patients treated with RT before adjuvant chemotherapy, RT had to be completed within 12 weeks of the primary surgery. In patients treated with RT after chemotherapy, RT started after patients recovered from the toxicity of the last cycle of chemotherapy, approximately day 29.
The breast only was irradiated using tangential fields with the dose calculated to the midplane of the central axis: 45 to 50 Gy was delivered over 5 to 5.5 weeks. Areas of dose inhomogeneity were limited to ± 10% of the central axis dose. Lung correction was allowed but not required. The decision whether to use a boost to the tumor bed was left to the physician. When a boost was employed, either an electron boost or an iridium implant was acceptable, and the total tumor bed dose was 60 to 65 Gy. Regional node irradiation was not permitted.
The rate of local recurrence as the first site of recurrence was calculated as a cumulative incidence at 10 years and as the number of local recurrences per 100 person-years of follow-up, with the difference tested using the binomial distribution.3 Local failure as first failure included concurrent regional or distant failure. Regional failures as first failure included concurrent distant failures. Failures reported as distant were distant only as first failure. A {chi}2 test was used to compare the distribution of first sites of recurrence in the two groups. For DFS and overall survival, the method of Kaplan and Meier was used for estimation, and Cox modeling was used to test CONC RT versus SEQ RT, adjusting for receptor status (positive v negative), age (< 65 v ≥ 65 years), and tumor size (< 2 v ≥ 2 cm).
RESULTS
With a median follow-up of 10.3 years, 10-year estimates of IBTR as first failure were similar for each group, with a 7% risk of IBTR among patients treated with CONC RT versus 5% for patients treated with SEQ RT (hazard ratio [HR], 0.73; 95% CI, 0.26 to 2.04; P = .54). Rate estimates were 0.67/100 person-years of follow-up for CONC RT and 0.49/100 person-years follow-up for SEQ RT (P = .17). Ten-year rates of IBTR in patients with hormone receptor-positive disease only were 4% in the CONC RT group and 6% in the SEQ RT group (P = .51). Patterns of first failure showed no evidence of an increase in IBTR with CONC RT compared with SEQ RT, with 13 local recurrences of 32 recurrences (41%) as a component of first failure with CONC therapy versus five of 15 recurrences (33%) among patients treated with SEQ therapies (P = .63). Ten-year rates of regional failure as first failure were 0.5% and 0.8% for CONC RT and SEQ RT, respectively (P = .76), and 10-year rates of distant failure only as first failure were 8% and 9% for CONC RT and SEQ RT, respectively (P = .66).
Ten-year DFS was 82% and 83% for the CONC and SEQ RT groups, respectively (HR, 0.91; 95% CI, 0.51 to 1.63; log-rank P = .73; adjusted P = .76), as shown in Fig 2A. The DFS analyses restricted to the hormone receptor-positive groups were 84% and 84% (P = .90). Ten-year overall survivals were 88% and 90% for the CONC and SEQ RT groups, respectively (HR, 0.84; 95% CI, 0.40 to 1.78; log-rank P = .59; adjusted P = .65), as shown in Figure 2B. Overall survivals in the receptor-positive groups only were 91% for CONC RT and 90% for SEQ RT (P = 1.0).
Toxicities were reviewed by the sequence of TAM and RT. No significant differences were observed in grade 3 or 4 hematologic toxicity between the two cohorts, with 21% of CONC RT patients having a grade 3% and 50% having a grade 4 granulocytopenia compared with 18% and 47%, respectively, for SEQ RT (P = .22). Although there were no occurrences of grade 4 pulmonary toxicity in either group, one occurrence of grade 3 pulmonary toxicity was reported in the CONC RT group.
DISCUSSION
Radiosensitivity is known to vary throughout the mitotic cycle, with cells most sensitive to RT at or close to mitosis, and resistance observed in both the latter part of the S phase and early G1 when prolonged.6 Although apoptosis after RT is an important treatment response, other mechanisms of cell injury, specifically the induction of sublethal and potentially lethal damage, can be reversed depending on factors such as postradiation cellular conditions, dose-rate effects, phase of the cell cycle, and position of cell cycle checkpoints.6 Thus, agents that alter cell cycle kinetics and prolong G1 can increase cell damage repair and reduce cell death caused by radiation. Wazer et al7 demonstrated reduced radiosensitivity in MCF-7 cells treated in physiologic concentrations of TAM, evidenced by a widened shoulder on cell survival curves after incubation with TAM compared with that of controls. Although other studies have reproduced these findings,8-10 some series have not shown changes in radiosensitivity with the addition of TAM.11,12 Using defined hormonal conditions, Sarkaria et al11 demonstrated inhibition of MCF-7 cells by 4-hydroxytamoxifen but no significant alteration in radiation sensitivity. A recent report by Singla et al12 also found no difference in MCF-7 cell survival when concurrent and delayed TAM administration were compared. Therefore, although some preclinical studies suggest an antagonistic effect of TAM on radiosensitivity, these findings have not been observed uniformly.
Preclinical studies have also been performed to assess the in vitro effect of TAM on mammary epithelial cells exposed to cytotoxic chemotherapy. Hug et al13 studied the effect of fluorouracil and doxorubicin with tamoxifen citrate on estrogen receptor-positive MCF-7 cells and estrogen receptor-negative MDA-468 tumor cells. Tamoxifen citrate protected cells from the cytotoxicity of both chemotherapy agents, with a greater protective effect against fluorouracil.
Data from recent randomized trials have demonstrated a clinically antagonistic effect of TAM on concurrent cytotoxic chemotherapy that is consistent with in vitro results.2,14 Results from Southwest Oncology Group 8814 (INT 0100) phase III trial assessing the impact of sequential adjuvant chemotherapy plus hormonal therapy in node-positive, receptor-positive disease demonstrated a significantly greater DFS with sequential CAF plus TAM compared with concurrent CAF plus TAM followed by TAM, with 8-year estimates of 67% and 62%, respectively (P = .045).2 These results support the practice of withholding TAM until completion of adjuvant chemotherapy. Results from a second, smaller phase III trial comparing epirubicin and cyclophosphamide with sequential versus concurrent TAM also were recently reported.14 With minimum follow-up of only 15 months, no significant difference was seen between the groups but the DFS curves suggest a trend in favor of the sequential arm. Additional follow-up is needed.
In contrast to these systemic therapy phase III trials directly comparing outcome by timing of TAM, no randomized trials to date have studied sequencing of TAM and RT. Extensive data are available, however, on rates of in-breast tumor control after breast-conserving surgery and RT in patients receiving TAM that show reduction in recurrence with TAM compared with treatment without TAM.15-17 Ten-year results from the low-risk, node-negative patients entered on the Stockholm Adjuvant Tamoxifen Trial demonstrated a 60% reduction in ipsilateral breast tumor recurrence with TAM and RT compared with patients randomly assigned to RT alone (P = .02).15 Tamoxifen was started within 4 to 6 weeks of surgery and RT was initiated usually 1 month postoperatively. Although the exact number of patients who received concurrent TAM and RT is unclear, it appears that the majority of patients randomly assigned to TAM received at least a portion of their treatment concurrently with RT, and results demonstrate a highly significant improvement in local control. Similar findings were seen in the National Surgical Adjuvant Breast and Bowel Project B-21 study in patients with invasive cancer of one centimeter or less randomized to TAM, RT, or both.16 Radiotherapy usually began 14 days after surgery while TAM was started within 35 days after lumpectomy. Eight-year results demonstrated a further reduction in rates of in-breast tumor recurrence by the addition of TAM to breast RT, with a 63% reduction in the hazard rate of IBTR with TAM compared to a 49% reduction without TAM (P = .01). Findings from the National Surgical Adjuvant Breast and Bowel Project B-24 in the treatment of ductal carcinoma-in-situ also confirmed a reduction in IBTR by the addition of TAM to breast RT.17 Although the timing of TAM relative to RT was not specified in these studies, it is clear there was significant overlap of treatments. These studies, however, do not address whether an additional reduction in IBTR could be observed with sequential TAM and RT.
With comparable rates of local control irrespective of the timing of TAM and RT demonstrated in this and other reports,18,19 potential differences in complication rates by sequencing of therapy could factor into management decisions. Some reports have noted increased rates of pulmonary and breast fibrosis after TAM with RT.20-22 In a study of patients entered onto a prospective Danish trial, Bentzen et al22 found a significantly increased risk of lung fibrosis in patients treated concurrently with TAM and RT compared with RT alone, and hypothesized that TAM mediated this risk through the induction of transforming growth factor beta secretion. It was unclear, however, whether the predominant effect was due to the induction of radiation injury or to postradiation treatment processing of radiation injury, and whether there would be any amelioration of the effect by delaying TAM until after RT was completed.
Conflicting reports exist regarding the impact of TAM on breast fibrosis and cosmesis. Fowble et al23 did not find an adverse effect of TAM use on breast fibrosis, whereas Wazer et al24 found a trend suggesting poorer cosmesis in patients receiving TAM, with a greater incidence of fibrosis, telangiectasia, and hyperpigmentation associated with TAM use (P = .06). Because of the multi-institutional nature of the present Intergroup trial results, radiation complications were not available for analysis; therefore, no statements can be made regarding the impact of TAM on pulmonary and breast fibrosis in this study. Clearly, additional studies of potential complications related to the sequencing of TAM and RT are warranted.
We recognize the substantial limitations of this investigation. Although our results do not suggest differences in rates of tumor control in the irradiated breast irrespective of the timing of TAM and RT, these results should be interpreted with caution. The CI for the HR does not rule out a large benefit or detriment for either approach. In addition, as previously stated, this is a retrospective analysis of patients entered onto a prospective trial not designed to study the sequencing of TAM and RT. Given the nonrandomized nature of this report, imbalances in patient characteristics exist between groups. These imbalances, such as a higher percentage of receptor-positive patients in the SEQ group relative to the CONC group, could affect results. In addition, information was not available on the percent of patients in each group who received a boost dose of radiation to the tumor bed. Therefore, it is possible that a disproportionate number of women received this treatment in the two groups. Given that subsequent trials have proven a significant reduction in local failure with the use of a boost,25,26 patterns of failure in the present study could have been altered by its discretionary use.
Few events occurred in this node-negative group, limiting the power of our observations; minimal data were available regarding complications. Only 309 women of 2,690 eligible patients received breast-conserving surgery and RT with TAM and thus were available for analysis. This small sample size reflects the low rate of breast conservation previously reported in high-risk, node-negative patients at the time the trial was conducted,27 as well as the restriction of this analysis to the patients in the trial randomly assigned to receive TAM. As the indications for TAM and other selective estrogen receptor modulators continue to increase, it will be important to answer definitively the question regarding the optimal sequencing of selective estrogen-receptor modulators and RT with respect to rates of in-breast tumor control and complications in a randomized trial specifically designed to address the sequencing question. Data from such a trial could not only validate the current results, but also provide reassurance to the increasing number of women receiving endocrine therapies (including aromatase inhibitors) who are desirous of breast preservation, and yield valuable correlative tumor biology information in hormone receptor-positive disease. Discussions regarding the feasibility of conducting such a trial are currently in progress.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA27057, CA37981, CA20319, CA46282.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
2. Albain K, Green S, 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 Onc 21:37a, 2002 (abstr 143)
3. Kalbfleish J, Prentiss R: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley & Sons, 1980
4. Sutherland R, Hall R, Taylor I: Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res 43:3998-4006, 1983
5. Osborne C, Boldt D, Estrada P: Human breast cancer cell cycle synchronization by estrogens and antiestrogens in culture. Cancer Res 44:1433-1439, 1984
6. Hall E: Radiobiology for the Radiologist. Philadelphia, PA, Lippincott Williams and Wilkins, 2000, pp 67-79
7. Wazer D, Tercila O, Lin S, et al: Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17B-estradiol and tamoxifen. Br J Radiol 62:1079-1083, 1989
8. Bhning K, Busch M, Rave-Frank M, et al: Effect of tamoxifen and estrogen treatment on the radiosensitivity of MCF-7 breast cancer cells. Onkologie 19:163-169, 1996
9. Villalobos M, Aranda M, Nunez M, 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
10. Paulsen G, Strickert T, Marthinsen A, 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
11. Sarkaria J, Miller E, Parker C, 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
12. Singla R, Albuquerque K, Creech S, et al: The presence and timing of tamoxifen and its effect on the radiosensitivity of MCF-7 breast cancer cells. Breast Cancer Res Treat 82:S161, 2003 (abstr 664)
13. Hug V, Hortobagyi G, Drewinko B, et al: Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro. J Clin Oncol 3:1672-1677, 1985
14. Pico C, Martin M, Jara C, et al: Epirubicin-cyclophosphamide (EC) chemotherapy plus tamoxifen (T) administered concurrent (Con) versus sequential (Sec): randomized phase III trial in postmenopausal node-positive breast cancer (BC) patients. Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 144)
15. 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. Cancer 82:2204-2211, 1998
16. Fisher B, Bryant J, Dignam J, 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
17. Fisher B, Digman J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993-2000, 1999
18. Ahn P, Thanh Vu H, Burtness B, et al: Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer. Proc 85th Annual Meeting of the American Radium Society, 2003
19. Christensen V, Harris E, Hwang W, et al: The impact of concurrent versus sequential tamoxifen and radiation therapy in breast cancer patients undergoing breast conservation therapy. Proc Am Soc Clin Onc 22:40, 2003 (abstr)
20. Koc M, Polat P, Suma S: Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol 64:171-175, 2002
21. Huang E, Wang C, Chen H, et al: Multivariate analysis of pulmonary fibrosis after electron beam irradiation for postmastectomy chest wall and regional lymphatics: Evidence for non-dosimetric factors. Radiother Oncol 57:91-96, 2000
22. Bentzen S, Skoczylas J, Overgaard M, et al: Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 88:918-922, 1996
23. 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 Rad Oncol Biol Phys 35:669-677, 1996
24. Wazer D, DiPetrillo T, Schmidt-Ulrich 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
25. Bartelink H, Horiot J, 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
26. Romestaing P, Lehingue Y, Carrie C, et al: Role of a 10-Gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol 15:963-968, 1997
27. Albain KS, Green SR, Lichter AS, et al: The influence of patient characteristics, socioeconomic factors, geography and systemic risk on the use of breast sparing treatment in women enrolled on Intergroup adjuvant breast cancer studies. J Clin Oncol 14:3009-3017, 1996(Lori J. Pierce, Laura F. )
Baylor College of Medicine, Houston, TX
University of Michigan School of Medicine, Ann Arbor, MI
University of Arkansas Medical Center, Little Rock, AR
Fred Hutchinson Cancer Research Center
University of Washington, Seattle, WA
Loyola University Medical Center, Maywood, IL
ABSTRACT
PATIENTS AND METHODS: Southwest Oncology Group trial 8897 (Intergroup 0102) randomly assigned node-negative women with T1-3 breast cancers to cyclophosphamide, doxorubicin, fluorouracil (CAF); CAF -> TAM; cyclophosphamide, methotrexate, fluorouracil (CMF); and CMF -> TAM. For this analysis, data are reported only in the TAM groups. RT was allowed either before adjuvant therapy (sequential [SEQ] RT; 107 patients) or after chemotherapy but concurrent with TAM (concurrent [CONC] RT; 202 patients). Survival data were adjusted for receptor status, age, and tumor size.
RESULTS: With a median follow-up of 10.3 years, 10-year DFS values were 83% and 83% for CONC versus SEQ RT groups (log-rank P = .73; P = .76 adjusted for patient characteristics), and 10-year overall survivals were 88% and 90%, respectively (log-rank P = .59; adjusted P = .65). Patterns of failure showed no increase in in-breast recurrence rates between CONC RT and SEQ RT groups, with 10-year local recurrence rates of 7% for CONC RT and 5% for SEQ RT (hazard ratio, 0.73; 95% CI, 0.26 to 2.04; P = .54).
CONCLUSION: The current analysis does not suggest an adverse effect on local or systemic control with CONC versus SEQ TAM and RT in node-negative breast cancer. A randomized trial is encouraged to validate these results.
INTRODUCTION
PATIENTS AND METHODS
High-risk patients were eligible for random assignment, whereas low-risk patients were observed after local therapy. The criteria for high risk included the presence of estrogen receptor- and progesterone receptor-negative disease; an estrogen receptor-positive and/or progesterone receptor-positive tumor that was ≥ 2 cm in size; an estrogen receptor-positive cancer measuring less than 2 cm associated with an S phase fraction ≥ 4.4 for diploid tumors and ≥ 7.0 for aneuploid tumors; or S phase fraction unknown for a tumor greater than 1 cm. Low-risk was defined as an estrogen receptor- and/or progesterone receptor-positive tumor measuring less than 2 cm with a % S phase less than 4.4 for diploid cancers or less than 7.0 for aneuploid tumors; or cancers ≤ 1 cm and % S phase unknown.
Patients with low-risk disease were observed without systemic therapy; patients with high-risk disease were randomly assigned to one of four treatments, as shown in Fig 1. For purposes of this analysis, data were reported only for those high-risk patients receiving TAM who underwent breast-conserving therapy. The timing of breast RT was not specified in the trial. It was left to the discretion of the treating physician whether to deliver the RT to the breast before adjuvant therapy was started (before registration) or after adjuvant chemotherapy was completed. Therefore, RT was given either before TAM (SEQ RT) or after chemotherapy concurrent with TAM (CONC RT). Systemic therapy consisted of either cyclophosphamide, methotrexate, and fluorouracil (CMF) for six 28-day cycles followed by TAM (cyclophosphamide 100 mg/m2 orally qd for 14 days, methotrexate 40 mg/m2 intravenously [IV] on days 1 and 8, fluorouracil 600 mg/m2 IV on days 1 and 8, and tamoxifen 20 mg daily for 5 years starting on day 29 of the last chemotherapy cycle); or cyclophosphamide, doxorubicin, and fluorouracil (CAF) for six 28-day cycles followed by TAM (cyclophosphamide 100 mg/m2 orally qd for 14 days, doxorubicin 30 mg/m2 IV on days 1 and 8, fluorouracil 500 mg/m2 IV on days 1 and 8, and tamoxifen 20 mg daily for 5 years starting on day 29 of the last cycle). According to the cooperative group standard for this era of adjuvant trials, tamoxifen was prescribed for both receptor-positive and receptor-negative disease.
Patients electing breast conservation underwent an excisional biopsy of the primary lesion with microscopically negative margins. If the excision resulted in microscopically involved margins, a re-excision was required to clear the margins. Patients with multicentric disease either clinically or mammographically were excluded from study. All patients underwent an axillary dissection and were required to be node-negative for study eligibility.
RT was given to all patients who received breast-conserving surgery either before adjuvant chemotherapy was delivered or after chemotherapy was completed, concurrent with TAM. For patients treated with RT before adjuvant chemotherapy, RT had to be completed within 12 weeks of the primary surgery. In patients treated with RT after chemotherapy, RT started after patients recovered from the toxicity of the last cycle of chemotherapy, approximately day 29.
The breast only was irradiated using tangential fields with the dose calculated to the midplane of the central axis: 45 to 50 Gy was delivered over 5 to 5.5 weeks. Areas of dose inhomogeneity were limited to ± 10% of the central axis dose. Lung correction was allowed but not required. The decision whether to use a boost to the tumor bed was left to the physician. When a boost was employed, either an electron boost or an iridium implant was acceptable, and the total tumor bed dose was 60 to 65 Gy. Regional node irradiation was not permitted.
The rate of local recurrence as the first site of recurrence was calculated as a cumulative incidence at 10 years and as the number of local recurrences per 100 person-years of follow-up, with the difference tested using the binomial distribution.3 Local failure as first failure included concurrent regional or distant failure. Regional failures as first failure included concurrent distant failures. Failures reported as distant were distant only as first failure. A {chi}2 test was used to compare the distribution of first sites of recurrence in the two groups. For DFS and overall survival, the method of Kaplan and Meier was used for estimation, and Cox modeling was used to test CONC RT versus SEQ RT, adjusting for receptor status (positive v negative), age (< 65 v ≥ 65 years), and tumor size (< 2 v ≥ 2 cm).
RESULTS
With a median follow-up of 10.3 years, 10-year estimates of IBTR as first failure were similar for each group, with a 7% risk of IBTR among patients treated with CONC RT versus 5% for patients treated with SEQ RT (hazard ratio [HR], 0.73; 95% CI, 0.26 to 2.04; P = .54). Rate estimates were 0.67/100 person-years of follow-up for CONC RT and 0.49/100 person-years follow-up for SEQ RT (P = .17). Ten-year rates of IBTR in patients with hormone receptor-positive disease only were 4% in the CONC RT group and 6% in the SEQ RT group (P = .51). Patterns of first failure showed no evidence of an increase in IBTR with CONC RT compared with SEQ RT, with 13 local recurrences of 32 recurrences (41%) as a component of first failure with CONC therapy versus five of 15 recurrences (33%) among patients treated with SEQ therapies (P = .63). Ten-year rates of regional failure as first failure were 0.5% and 0.8% for CONC RT and SEQ RT, respectively (P = .76), and 10-year rates of distant failure only as first failure were 8% and 9% for CONC RT and SEQ RT, respectively (P = .66).
Ten-year DFS was 82% and 83% for the CONC and SEQ RT groups, respectively (HR, 0.91; 95% CI, 0.51 to 1.63; log-rank P = .73; adjusted P = .76), as shown in Fig 2A. The DFS analyses restricted to the hormone receptor-positive groups were 84% and 84% (P = .90). Ten-year overall survivals were 88% and 90% for the CONC and SEQ RT groups, respectively (HR, 0.84; 95% CI, 0.40 to 1.78; log-rank P = .59; adjusted P = .65), as shown in Figure 2B. Overall survivals in the receptor-positive groups only were 91% for CONC RT and 90% for SEQ RT (P = 1.0).
Toxicities were reviewed by the sequence of TAM and RT. No significant differences were observed in grade 3 or 4 hematologic toxicity between the two cohorts, with 21% of CONC RT patients having a grade 3% and 50% having a grade 4 granulocytopenia compared with 18% and 47%, respectively, for SEQ RT (P = .22). Although there were no occurrences of grade 4 pulmonary toxicity in either group, one occurrence of grade 3 pulmonary toxicity was reported in the CONC RT group.
DISCUSSION
Radiosensitivity is known to vary throughout the mitotic cycle, with cells most sensitive to RT at or close to mitosis, and resistance observed in both the latter part of the S phase and early G1 when prolonged.6 Although apoptosis after RT is an important treatment response, other mechanisms of cell injury, specifically the induction of sublethal and potentially lethal damage, can be reversed depending on factors such as postradiation cellular conditions, dose-rate effects, phase of the cell cycle, and position of cell cycle checkpoints.6 Thus, agents that alter cell cycle kinetics and prolong G1 can increase cell damage repair and reduce cell death caused by radiation. Wazer et al7 demonstrated reduced radiosensitivity in MCF-7 cells treated in physiologic concentrations of TAM, evidenced by a widened shoulder on cell survival curves after incubation with TAM compared with that of controls. Although other studies have reproduced these findings,8-10 some series have not shown changes in radiosensitivity with the addition of TAM.11,12 Using defined hormonal conditions, Sarkaria et al11 demonstrated inhibition of MCF-7 cells by 4-hydroxytamoxifen but no significant alteration in radiation sensitivity. A recent report by Singla et al12 also found no difference in MCF-7 cell survival when concurrent and delayed TAM administration were compared. Therefore, although some preclinical studies suggest an antagonistic effect of TAM on radiosensitivity, these findings have not been observed uniformly.
Preclinical studies have also been performed to assess the in vitro effect of TAM on mammary epithelial cells exposed to cytotoxic chemotherapy. Hug et al13 studied the effect of fluorouracil and doxorubicin with tamoxifen citrate on estrogen receptor-positive MCF-7 cells and estrogen receptor-negative MDA-468 tumor cells. Tamoxifen citrate protected cells from the cytotoxicity of both chemotherapy agents, with a greater protective effect against fluorouracil.
Data from recent randomized trials have demonstrated a clinically antagonistic effect of TAM on concurrent cytotoxic chemotherapy that is consistent with in vitro results.2,14 Results from Southwest Oncology Group 8814 (INT 0100) phase III trial assessing the impact of sequential adjuvant chemotherapy plus hormonal therapy in node-positive, receptor-positive disease demonstrated a significantly greater DFS with sequential CAF plus TAM compared with concurrent CAF plus TAM followed by TAM, with 8-year estimates of 67% and 62%, respectively (P = .045).2 These results support the practice of withholding TAM until completion of adjuvant chemotherapy. Results from a second, smaller phase III trial comparing epirubicin and cyclophosphamide with sequential versus concurrent TAM also were recently reported.14 With minimum follow-up of only 15 months, no significant difference was seen between the groups but the DFS curves suggest a trend in favor of the sequential arm. Additional follow-up is needed.
In contrast to these systemic therapy phase III trials directly comparing outcome by timing of TAM, no randomized trials to date have studied sequencing of TAM and RT. Extensive data are available, however, on rates of in-breast tumor control after breast-conserving surgery and RT in patients receiving TAM that show reduction in recurrence with TAM compared with treatment without TAM.15-17 Ten-year results from the low-risk, node-negative patients entered on the Stockholm Adjuvant Tamoxifen Trial demonstrated a 60% reduction in ipsilateral breast tumor recurrence with TAM and RT compared with patients randomly assigned to RT alone (P = .02).15 Tamoxifen was started within 4 to 6 weeks of surgery and RT was initiated usually 1 month postoperatively. Although the exact number of patients who received concurrent TAM and RT is unclear, it appears that the majority of patients randomly assigned to TAM received at least a portion of their treatment concurrently with RT, and results demonstrate a highly significant improvement in local control. Similar findings were seen in the National Surgical Adjuvant Breast and Bowel Project B-21 study in patients with invasive cancer of one centimeter or less randomized to TAM, RT, or both.16 Radiotherapy usually began 14 days after surgery while TAM was started within 35 days after lumpectomy. Eight-year results demonstrated a further reduction in rates of in-breast tumor recurrence by the addition of TAM to breast RT, with a 63% reduction in the hazard rate of IBTR with TAM compared to a 49% reduction without TAM (P = .01). Findings from the National Surgical Adjuvant Breast and Bowel Project B-24 in the treatment of ductal carcinoma-in-situ also confirmed a reduction in IBTR by the addition of TAM to breast RT.17 Although the timing of TAM relative to RT was not specified in these studies, it is clear there was significant overlap of treatments. These studies, however, do not address whether an additional reduction in IBTR could be observed with sequential TAM and RT.
With comparable rates of local control irrespective of the timing of TAM and RT demonstrated in this and other reports,18,19 potential differences in complication rates by sequencing of therapy could factor into management decisions. Some reports have noted increased rates of pulmonary and breast fibrosis after TAM with RT.20-22 In a study of patients entered onto a prospective Danish trial, Bentzen et al22 found a significantly increased risk of lung fibrosis in patients treated concurrently with TAM and RT compared with RT alone, and hypothesized that TAM mediated this risk through the induction of transforming growth factor beta secretion. It was unclear, however, whether the predominant effect was due to the induction of radiation injury or to postradiation treatment processing of radiation injury, and whether there would be any amelioration of the effect by delaying TAM until after RT was completed.
Conflicting reports exist regarding the impact of TAM on breast fibrosis and cosmesis. Fowble et al23 did not find an adverse effect of TAM use on breast fibrosis, whereas Wazer et al24 found a trend suggesting poorer cosmesis in patients receiving TAM, with a greater incidence of fibrosis, telangiectasia, and hyperpigmentation associated with TAM use (P = .06). Because of the multi-institutional nature of the present Intergroup trial results, radiation complications were not available for analysis; therefore, no statements can be made regarding the impact of TAM on pulmonary and breast fibrosis in this study. Clearly, additional studies of potential complications related to the sequencing of TAM and RT are warranted.
We recognize the substantial limitations of this investigation. Although our results do not suggest differences in rates of tumor control in the irradiated breast irrespective of the timing of TAM and RT, these results should be interpreted with caution. The CI for the HR does not rule out a large benefit or detriment for either approach. In addition, as previously stated, this is a retrospective analysis of patients entered onto a prospective trial not designed to study the sequencing of TAM and RT. Given the nonrandomized nature of this report, imbalances in patient characteristics exist between groups. These imbalances, such as a higher percentage of receptor-positive patients in the SEQ group relative to the CONC group, could affect results. In addition, information was not available on the percent of patients in each group who received a boost dose of radiation to the tumor bed. Therefore, it is possible that a disproportionate number of women received this treatment in the two groups. Given that subsequent trials have proven a significant reduction in local failure with the use of a boost,25,26 patterns of failure in the present study could have been altered by its discretionary use.
Few events occurred in this node-negative group, limiting the power of our observations; minimal data were available regarding complications. Only 309 women of 2,690 eligible patients received breast-conserving surgery and RT with TAM and thus were available for analysis. This small sample size reflects the low rate of breast conservation previously reported in high-risk, node-negative patients at the time the trial was conducted,27 as well as the restriction of this analysis to the patients in the trial randomly assigned to receive TAM. As the indications for TAM and other selective estrogen receptor modulators continue to increase, it will be important to answer definitively the question regarding the optimal sequencing of selective estrogen-receptor modulators and RT with respect to rates of in-breast tumor control and complications in a randomized trial specifically designed to address the sequencing question. Data from such a trial could not only validate the current results, but also provide reassurance to the increasing number of women receiving endocrine therapies (including aromatase inhibitors) who are desirous of breast preservation, and yield valuable correlative tumor biology information in hormone receptor-positive disease. Discussions regarding the feasibility of conducting such a trial are currently in progress.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA27057, CA37981, CA20319, CA46282.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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