|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4691-4699 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.129 Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and MastectomyFrom the Departments of Radiation Oncology, Biomathematics, Surgical Oncology, Breast Medical Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Thomas A. Buchholz, MD, Department of Radiation Oncology, Box 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: tbuchhol{at}mdanderson.org
PURPOSE: To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. PATIENTS AND METHODS: We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation.
RESULTS: Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage CONCLUSION: After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.
Treatment recommendations for radiation therapy in the setting of neoadjuvant chemotherapy and mastectomy are under considerable debate. A consensus was not established in the current guidelines of the American Society of Clinical Oncology regarding postmastectomy radiation because there were not enough data concerning the efficacy of radiation in this setting to adequately provide answers.1 In fact, currently there are no large retrospective or prospective studies addressing this issue. This question has become increasingly important because the use of neoadjuvant chemotherapy is rapidly becoming standard treatment for many subsets of patients with breast cancer.2 The value of postmastectomy radiation in conjunction with adjuvant chemotherapy has been established by three randomized trials and two recent meta-analyses.3-7 These data have shown that, for properly selected populations, radiation can improve local-regional control rates by approximately 20% and survival rates by 10%. In general, the selection of patients for postmastectomy radiation is made on the basis of the pathological information concerning the extent of local-regional disease. For patients treated with surgery before chemotherapy, postmastectomy radiation is indicated for those with four or more positive axillary nodes and for those with clinical stage III disease or T3 tumors.1,8 The role of postmastectomy radiation after neoadjuvant chemotherapy, however, remains unclear. Most patients treated with neoadjuvant chemotherapy have significant treatment-related changes in the pathological extent of disease. For patients who receive this treatment sequencing, additional data are needed to determine which subsets of patients can benefit from radiation. To address these questions, we recently reported our institutional experience on 150 patients treated with neoadjuvant chemotherapy and mastectomy without radiation therapy and identified factors predictive of local-regional recurrence (LRR).9 To build on those findings, in this report, we retrospectively compared the outcomes of 542 patients who received radiation after neoadjuvant chemotherapy and mastectomy versus the outcomes of the patients from the previously published cohort who were treated on the same prospective clinical trials. Our purpose was to evaluate the efficacy of postmastectomy radiation in terms of local-regional control and survival in the setting of neoadjuvant chemotherapy and determine which subsets of these patients benefited from radiation treatment.
Patient Population We retrospectively analyzed the data from six consecutive prospective clinical trials conducted at The University of Texas M.D. Anderson Cancer Center (Houston, TX) that investigated the role of doxorubicin-based neoadjuvant chemotherapy for patients with nonmetastatic, noninflammatory breast cancer. The institutional review board approved each protocol, and participating patients gave written informed consent. The review board also approved this retrospective analysis. From 1974 to 2000, 744 of the patients enrolled in these trials were treated with neoadjuvant chemotherapy and mastectomy. We compared the data from the 557 of these patients who received postmastectomy radiation treatment (37 received preoperative radiation because of refractory disease) to the data from the 150 patients who did not receive radiation. The initial outcomes of the cohort who did not receive radiation were previously reported,9 but these data were updated for the purpose of the current study. Some patients did not receive radiation because of disease progression. To minimize this potential bias between comparative groups, all patients with disease recurrence within 2 months after mastectomy or completion of adjuvant chemotherapy were excluded: 15 (3%) in the irradiated group and 16 (11%) in the nonirradiated group. The remaining 676 patients formed the study population for this review. All patients were prospectively clinically staged according to the 1988 American Joint Committee on Cancer Staging and End Results Reporting guidelines. Only patients without systemic metastases were eligible for these trials. The patients designated as having stage IV disease represent patients with ipsilateral supraclavicular lymph node involvement without systemic metastases.
Treatment Details
We limited our study to the patients in these trials who were treated with mastectomy. The median number of recovered axillary lymph nodes after mastectomy was 15. For the 542 patients treated with postmastectomy radiation, treatment volumes typically included the chest wall and draining lymphatics (median dose, 50 Gy), followed by a chest wall boost (median dose, 10 Gy). Radiation treatment was delivered at an outside institution for 94 patients. Radiation treatment was not a randomized variable in the trials studied. The decisions to undergo radiation and/or mastectomy (rather than breast-conserving surgery) were determined by the patient and her physicians, and thus are subject to selection biases. After neoadjuvant chemotherapy and mastectomy, 640 patients (95%) received adjuvant chemotherapy. These regimens changed over the period of time of the clinical trials and initially began with FAC (similar to the preoperative regimen). The historical strategy was to use cyclophosphamide, methotrexate, fluorouracil (CMF). Thereafter, either vinblastine and methotrexate, or vinblastine, methotrexate, fluorouracil was used. Finally, the most recent approach adopted for this cohort investigated the use of taxanes. Additionally, 233 patients (34%) also received adjuvant tamoxifen.
Statistical Analysis
Patient Characteristics The median follow-up times of all irradiated and nonirradiated patients were 73 and 66 months, respectively (median time for all patients was 69 months). Table 2 presents the comparisons of clinical, pathological, and treatment characteristics between these two cohorts. When compared with patients who did not receive radiation, a greater percentage of irradiated patients had more advanced clinical T-stage, clinical N-stage, combined clinical stage (1988 AJCC), poorer clinical response to neoadjuvant chemotherapy, higher numbers of pathologically positive nodes, and close or positive surgical margins (P  .01 for all comparisons). There were no differences between the two groups with respect to age, use of tamoxifen, use of adjuvant chemotherapy, pathological tumor size, number of dissected axillary nodes, or percentage of estrogen receptor-negative tumors.
LRR Rates According to Use of Radiation and Disease Extent Despite the imbalance in prognostic features between the two groups, the 10-year actuarial rate of LRR was higher in the patients not treated with postmastectomy radiation (22% v 11%, P = .0001; Fig 1). The 10-year rate of isolated LRR (the first site of failure) was also significantly reduced with radiation (20% v 8%, P = .0002). Table 3 presents data concerning the use of radiation and LRR for various subsets of patients. Radiation reduced LRR for patients with clinical T3 or T4 tumors and clinical N2 to N3 stage disease (P .002 for all comparisons). For combined clinical stage, patients with stage IIB or greater disease had lower rates of LRR if treated with radiation (10-year rates, 26% v 11%; P < .0001). With respect to pathological features, radiation reduced LRR rates for patients with residual tumors larger than 2 cm and for patients with four or more positive nodes (P .001 for both comparisons).
Radiation also significantly reduced LRR rates for patients who initially presented with clinical stage III or IV advanced disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy (10-year rates, 3% v 33%; P = .006; Fig 2). For patients presenting with early stage I to stage II disease who achieved a pathological complete response, no difference in LRR rates was observed (P = .22). In addition, in the subset of patients with clinical stage II disease with one to three positive lymph nodes after chemotherapy, no difference in LRR rates was observed (P = .79, n = 55).
On multivariate Cox regression analysis of factors associated with LRR (Table 4), radiation use was the most significant variable, with a hazard ratio for no radiation of 4.7 (95% CI, 2.7 to 8.1; P < .0001). Other factors found to be significant for developing LRR included: 20% or more positive axillary nodes, clinical stage IIIB to stage IV disease, no tamoxifen use, estrogen receptor-negative disease, and minimal or worse clinical response to neoadjuvant chemotherapy (P .033 for all comparisons). Both forward and backward stepwise analysis confirmed that these same six risk factors were significantly associated with developing LRR. On univariate analyses of the entire study population, achievement of a clinical complete response (6% v 14%, P = .050) or a pathological complete response (2% v 12%, P = .088) were associated with lower LRR. However, neither clinical nor pathological complete response to neoadjuvant chemotherapy was independently associated with LRR in the multivariate model.
Survival Rates According to Use of Radiation and Disease Extent The 10-year actuarial rates of OS in the two groups were not significantly different (54% for radiation v 47% for no radiation, P = .063). Because a greater percentage of patients who did not receive radiation died of intercurrent disease, we focused our analyses on CSS. The 10-year actuarial rates of CSS were nearly identical in the two groups (58% for radiation v 55% for no radiation, P = .85). Table 5 presents the associations between radiation treatment and CSS for various subgroups. On univariate analysis, radiation improved CSS rates in patients with clinical stage IIIB to stage IV disease, clinical T4 tumors, or four or more positive nodes (P .007 for all comparisons; Figs 3A to C). For these three subgroups, the benefit of radiation with respect to OS was also highly significant (42% v 20%, 42% v 20%, and 38% v 15%; P .0002 for all comparisons).
Multivariate Cox regression analysis of factors associated with CSS for all 676 patients (Table 6) revealed that the hazard ratio for lack of radiation treatment was 2.0 (95% CI, 1.4 to 2.9; P < .0001). Other factors found to be significant for worse CSS included: clinical stage IIIB to stage IV disease, residual pathological tumor involvement after chemotherapy, four or more positive nodes, minimal or worse clinical response to neoadjuvant chemotherapy, fewer than 10 axillary nodes sampled, no tamoxifen, and estrogen receptor-negative disease (P .03 for all comparisons). On univariate analyses of the entire study population, achievement of a clinical complete response (79% v 54%, P < .001) or a pathological complete response (95% v 55%, P < .001) were associated with higher CSS. However, neither clinical nor pathological complete response to neoadjuvant chemotherapy was independently associated with CSS in the multivariate model.
A separate analysis was completed (n = 713), which included the 37 patients who were treated with preoperative radiation. The results of this analysis continued to show significant differences with the irradiated cohort and its subgroups having lower rates of LRR and higher rates of CSS.
This report is the first large series investigating the efficacy of postmastectomy radiation for patients treated with neoadjuvant chemotherapy. The results represent a single institution's experience with all patients treated on prospective clinical trials with doxorubicin-based chemotherapy, mastectomy including a level I and II axillary dissection (median number of nodes recovered = 15), and radiation techniques comparable to modern standards of care. The results of this study suggest that the addition of radiation to neoadjuvant chemotherapy and mastectomy reduces the rate of LRR and may improve CSS for selected patients with locally advanced disease at presentation or with four or more positive lymph nodes after neoadjuvant treatment. Multivariate analysis revealed that lack of radiation treatment was the greatest hazard associated with developing LRR (hazard ratio, 4.7). Radiation therapy reduced the relative risk for LRR two-fold for patients who presented with clinical stage IIB or greater disease, clinical T3 or T4 tumors, or clinical N2 to N3 disease (10-year rates, 11% v 26%, 8% v 22%, and 12% v 40%, respectively). In addition, patients who presented with clinically advanced stage III to stage IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (33% v 3%). Analyzing pathological factors from mastectomy, we found that radiation significantly reduced the risk of developing LRR for patients with four or more positive nodes or with tumor sizes greater than 2 cm (10-year rates, 16% v 59%, 14% v 31%, respectively). The reduction in LRR rates in this study with radiation is similar in magnitude to data regarding the efficacy of postmastectomy radiation after mastectomy and adjuvant chemotherapy. We recently reported the LRR outcome of 1,500 patients treated with mastectomy and adjuvant chemotherapy and found that radiation reduced the 10-year LRR rate from 19% to 10% (P < .0001).14 In addition, three randomized trials investigating postmastectomy radiation in patients treated with systemic therapy demonstrated a reduction in LRR rates from approximately 30% to 10%.3-5 It was not surprising that the benefits of postmastectomy radiation in the current study were similar to those reported after adjuvant chemotherapy. One would not anticipate that the sequencing of chemotherapy and surgery would necessarily affect the efficacy of radiation; however, until this report, there have been no published data to support this hypothesis. Whether radiation therapy benefits patients with stage II breast cancer with one to three positive lymph nodes remains an area of controversy. In this study, we did not find that radiation provided any benefit to these patients; however, the sample size was limited. In our previous study investigating radiation after mastectomy and adjuvant chemotherapy, radiation reduced the 10-year LRR rate for patients with stage II breast cancer and one to three positive lymph nodes from 13% to 3%, P = .003.14 Clearly, more data from clinical trials are needed to guide treatment recommendations regarding this group of patients. In addition to reducing LRR rates, we also found that radiation may improve survival from breast cancer death in certain subsets of patients. Lack of radiation treatment was independently associated with higher breast cancer mortality (hazard ratio 2.0). For patients with clinical stage IIIB to stage IV disease, clinical T4 tumors, or four or more pathologically positive nodes, the addition of radiation after neoadjuvant chemotherapy and mastectomy resulted in an absolute CSS advantage of approximately 20% (44% v 22%, 45% v 24%, and 44% v 18%, respectively). The potential for LRR therapy, in conjunction with systemic therapy, to reduce metastases and deaths from breast cancer has long been recognized. The meta-analysis published by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that radiation treatment improved 20-year CSS rates by 13% (P = .0001), despite the fact that most of the trials included in the analysis used obsolete radiation techniques and did not include systemic treatment.15,16 However, this CSS advantage of radiation therapy was historically counterbalanced by an increase in the number of deaths from other causes, particularly cardiovascular, which mitigated any OS benefit. Since the time of those early trials, modern radiation techniques have progressed significantly and overcome limitations associated with cardiovascular dose toxicity. Indeed, the two Danish trials have demonstrated that postmastectomy radiation, using more modern techniques, did not increase the risk of ischemic heart disease-related morbidity or mortality.17 Correspondingly, the three most recent randomized trials investigating postmastectomy radiation have demonstrated an improvement in OS.3-5 In general, the absolute survival benefit in these trials was about half as great as the absolute reduction in the rate of LRR. For the patients with four or more positive nodes, clinical T4 tumors, or stage IIIB to stage IV disease, our results showed a similar magnitude of benefit. The absolute reduction in LRR for these subsets of patients ranged from 30% to 40% (Table 3), and the absolute benefit in CSS was approximately 20% (Table 5). As previously stated, we chose to focus our analysis on CSS in this study rather than OS because patients who did not receive radiation more often died of nonbreast cancer-related causes. It is important to recognize the limitations of this review. Foremost, this was a retrospective analysis where radiation was not a randomized variable. In an effort to reduce the potential for selection biases that may have affected whether patients were treated or not treated with radiation, we excluded any patients who had a recurrence within 2 months after mastectomy or completion of adjuvant chemotherapy. Because radiation was not a randomized variable, the two cohorts had significant differences in many factors that affected LRR and survival. The variables we identified that affected outcome biased the irradiated cohort to have a worse expected outcome; however, it is possible that there are other selection biases that we did not take into account. In addition, because of the limited number of patients in some subgroup analyses, we cannot conclude a lack of benefit from radiation, particularly for patients with earlier stage disease or lesser pathological extent of disease. Finally, our series had a median follow-up period of 69 months. Longer follow-up may help define other subsets of patients who can benefit from radiation therapy, particularly with respect to survival. An update of the Early Breast Cancer Trialists' Collaborative Group meta-analysis that extended follow-up from 10 to 20 years demonstrated an increasingly significant CSS benefit from radiation in the second decade after treatment (P = .03 v P = .0001).15,16 In conclusion, postmastectomy radiation plays an important role in the management of patients receiving neoadjuvant chemotherapy and mastectomy for locally advanced breast cancer. Radiation was found to benefit both local control and survival in patients presenting with clinical T3 tumors or stage III to stage IV disease, and in patients with four or more positive nodes after chemotherapy. Radiation treatment should be considered for these patients regardless of their response to initial chemotherapy.
The authors indicated no potential conflicts of interest.
Supported in part by National Cancer Institute grants CA16672 and T32CA77050. Presented at the 2003 Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 19-23, 2003, Salt Lake City, UT. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiation: Guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1539-1569, 2001 2. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcomes of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract]
3. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997 4. Overgaard M, Jensen M-J, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet 353:1641-1648, 1999[CrossRef][Medline]
5. Ragaz J, Jackson S, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997
6. Whelan TJ, Julian J, Wright J, et al: Does local-regional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000 7. De Steene JV, Soete G, Storme G: Adjuvant radiotherapy for breast cancer significantly improves overall survival: The missing link. Radiother Oncol 55:263-272, 2000[CrossRef][Medline] 8. Harris JR, Halpin-Murphy P, McNeese M, et al: Consensus statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 44:989-990, 1999[CrossRef][Medline]
9. Buchholz TA, Tucker SL, Masullo L, et al: Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol 20:17-23, 2002 10. Buzdar AU, Singletary SE, Booser DJ, et al: Combined modality treatment of stage III and inflammatory breast cancer: M.D. Anderson Cancer Center experience. Surg Oncol Clin N Am 4:715-734, 1995[Medline]
11. Buzdar AU, Singletary SE, Theriault RL, et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412-3417, 1999 12. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507-2516, 1998 13. Harris E, Albert A: Survivorship analysis for clinical studies. New York, NY, Dekker, 1991 14. Woodward WA, Strom EA, Tucker SL, et al: Locoregional recurrence after doxorubicin-based chemotherapy and postmastectomy: Implications for breast cancer patients with early-stage disease and predictors for recurrence after postmastectomy radiation. Int J Radiat Oncol Biol Phys 57:336-344, 2003[CrossRef][Medline]
15. Early Breast Cancer Trialists' Collaborative Group: Effects of radiotherapy and surgery in early breast cancer. N Engl J Med 333:1444-1456, 1995 16. Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival for radiotherapy for early breast cancer: An overview of the randomized trials. Lancet 355:1757-1770, 2000[CrossRef][Medline] 17. Højris I, Overgaard M, Christensen JJ, et al: Morbidity and mortality of ischemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: Analysis of DBCG 82b and 82c randomized trials. Lancet 354:1425-1430, 1999[CrossRef][Medline] Submitted November 21, 2003; accepted August 18, 2004.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P 
2 test for dichotomized variables and the Mann-Whitney test for continuous variables. LRR was defined as disease recurrence on the ipsilateral chest wall or in the ipsilateral axillary, supraclavicular, infraclavicular, or internal mammary lymph nodes. Any other site of recurrence was considered distant metastasis. All LRR were considered as events, irrespective of their timing relative to distant metastases. The 5- and 10-year actuarial rates of LRR, isolated LRR (the first site of failure), overall survival (OS), and cause-specific survival (CSS) were calculated according to the Kaplan-Meier method, and comparisons between the two patient groups were made using the log-rank test.
