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Originally published as JCO Early Release 10.1200/JCO.2004.01.042 on September 27 2004 © 2004 American Society of Clinical Oncology. Patterns of Locoregional Failure in Patients With Operable Breast Cancer Treated by Mastectomy and Adjuvant Chemotherapy With or Without Tamoxifen and Without Radiotherapy: Results From Five National Surgical Adjuvant Breast and Bowel Project Randomized Clinical TrialsFrom the National Surgical Adjuvant Breast and Bowel Project Operations and Biostatistical Centers, National Surgical Adjuvant Breast and Bowel Project; Department of Biostatistics, University of Pittsburgh, Graduate School of Public Health; and Department of Radiation Oncology, University of Pittsburgh Medical Center Presbyterian, Pittsburgh, PA; Department of Radiation Oncology, Massachusetts General Hospital/Boston Medical Center, Boston, MA; and Aultman Cancer Center, Canton, OH Address reprint requests to Alphonse Taghian, MD, PhD, Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114; e-mail: ataghian{at}partners.org
PURPOSE: To assess patterns of locoregional failure (LRF) in lymph node–positive (LN+) breast cancer patients treated with mastectomy and adjuvant chemotherapy (± tamoxifen) and without postmastectomy radiotherapy (PMRT) in five National Surgical Adjuvant Breast and Bowel Project trials.
PATIENTS AND METHODS: We examined 5,758 patients enrolled onto the B-15, B-16, B-18, B-22, and B-25 trials. Median follow-up time was 11.1 years. Distribution of pathologic tumor size was
RESULTS: The overall 10-year cumulative incidences of isolated LRF, LRF with or without distant failure (DF), and DF alone as first event were 12.2%, 19.8%, and 43.3%, respectively. Cumulative incidences for LRF as first event with or without DF for patients with one to three, four to nine, and CONCLUSION: In patients with large tumors and four or more LN+, LRF as first event remains a significant problem. Although PMRT is currently recommended for patients with four or more LN+, it may also have value in selected patients with one to three LN+. However, in the absence of a randomized trial examining the worth of radiotherapy in this group of patients, the value of PMRT remains unknown.
During the last 50 years, a number of randomized clinical trials have been carried out to test the merit of postmastectomy radiotherapy (PMRT) in patients with breast cancer.1,2 The great majority of these trials did not include adjuvant chemotherapy and were not confined to high-risk patients.2-4 These studies showed that the addition of radiotherapy (RT) resulted in a significant reduction in locoregional failure (LRF) but no improvement in overall survival.1 However, in patients with a higher risk of local failure who have undergone adjuvant chemotherapy as well as modern RT, locoregional RT after surgery has been found to reduce mortality.2 Recent randomized trials of PMRT in node-positive patients5-7 have stimulated discussion about the generalizability of their findings to current practice, particularly because the benefit in survival demonstrated in these studies has been found in patients with one to three and with four or more positive lymph nodes (LN+). However, in those studies, cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy was used in node-positive patients. In the United States and Canada, the great majority of patients with LN+ would be treated with doxorubicin-based chemotherapy.8 In the Danish trials, axillary lymph node (LN) dissection was considered substandard because only an average of seven LNs were removed6,7 compared with 15 to 17 LNs removed in other studies.9-11 Furthermore, the rate of total LRF in patients with one to three LN+ who did not receive PMRT in these trials was higher than the rate in these series9-11 (30% to 31%5-7 v 13% to 19.7%,9-11 respectively). Thus, the applicability of findings from these trials to current practice in the United States regarding the use of PMRT in patients treated by doxorubicin-based chemotherapy and with adequate axillary LN dissection has been questioned. Recently, three large studies9-11 reported a pattern of LRF after modified radical mastectomy (MRM) in patients receiving adjuvant chemotherapy. Recht et al9 reported the pattern of failure in more than 2,000 patients in Eastern Cooperative Oncology Group (ECOG) trials who received CMF chemotherapy. Katz et al10 reported it in the M.D. Anderson Cancer Center (MDA) experience with 1,031 patients who received doxorubicin-based chemotherapy, and Wallgren et al11 reported it in patients enrolled onto the International Breast Cancer Study Group (IBCSG). In the present study, we examine the pattern of LRF in 5,758 patients enrolled onto the following five randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP): trials B-15, B-16, B-18, B-22, and B-25.12-16 Only patients who were treated by MRM, had at least one LN+ removed, and received adjuvant chemotherapy with or without tamoxifen and no PMRT were included in this analysis.
Study Population Patients included in this report were treated in five NSABP studies (B-15, B-16, B-18, B-22, and B-25) evaluating adjuvant chemotherapy but not allowing adjuvant PMRT. To be included in this analysis, patients must have had follow-up information, satisfied the eligibility requirements for the studies, undergone MRM, and had at least one pathologically positive axillary LN but did not receive PMRT. A brief summary of each of the five trials is provided in Table 1. Also, treatment details, outcome, and other aspects of each trial are explained in the previous publications.12-16
Statistical Methods In NSABP studies, local failure (LF) is defined as any recurrence of tumor in the ipsilateral chest wall or in mastectomy scars. Regional failure (RF) is defined as any recurrence of tumor in the ipsilateral supraclavicular, infraclavicular, axillary, or internal mammary nodes. Recurrence in any other site in this study was considered as distant failure (DF). For our study, isolated LF (ILF) was defined as any first LF without evidence of simultaneous DF. Here, simultaneous DF is defined as any subsequent DF that occurred within 4 months after the diagnosis of the first LF. Isolated RF (IRF) was defined similarly as any RF as a first event without evidence of simultaneous DF. Isolated LRF (ILRF) was defined as any first LF or RF without evidence of simultaneous DF. The occurrence of contralateral events and other second primary cancers was ignored in the determination of (isolated) local, regional, or locoregional recurrences. LRF with or without DF (LRF ± DF) was defined as any first LRF with or without any subsequent DF. Time to ILF was defined as time from definitive surgery to the first diagnosis of an ILF. Time to other LF with a simultaneous DF was also defined as time from surgery to the first LF, not time to a subsequent DF. Time to a RF or LRF with or without simultaneous DF was similarly defined. Time to DF and death were defined as time from surgery to the first DF and death, respectively. If LF or RF occurred without a subsequent DF but with the additional follow-up time being less than 4 months, we counted this event as an isolated event.
The nonparametric method17 was used to estimate 10-year cumulative incidence for ILF, IRF, ILRF, LRF ± DF, and DF alone. For the analysis of cumulative incidence for each end point, competing events were defined as any first isolated recurrence, any first other recurrence followed by a DF within 4 months, any first DF, and any death without evidence of previous recurrence. Gray's K-sample statistic was used to test whether any statistical significance of differences existed in cumulative incidence among groups stratified by protocols (univariate analysis).18 The proportional hazard model19 was used to test the association between cause-specific hazard functions and selected patient and tumor characteristics and to estimate the magnitude of such association, stratified by protocols. All P values were two-tailed, and a P
Study Population and Patient and Tumor Characteristics A total of 5,758 patients from the five studies met the predetermined criteria and are included in this analysis (Table 1). All patients were treated between 1984 and 1994. Patient and tumor characteristics are listed in Table 2.
Rates of LRF ± DF The median follow-up time without any first recurrence for all patients was 11.1 years (range, 0.003 to 18.0 years). The median follow-up time for patients who were alive was 11.9 years (range 0.43 to 18.0 years). The numbers of patients at risk for any first recurrence at 5 and 10 years were 3,188 and 1,674, respectively. Of the 5,758 patients, 715 (12.4%) presented with ILRF as first event. An additional 442 patients (7.7%) presented with LRF followed by a subsequent DF within 4 months, and 1,673 patients (29.1%) presented with DF as a first event. The overall cumulative incidence of LRF ± DF at 10 years was 19.8%, stratified by protocol. The 10-year cumulative incidence of DF alone as a first event was 43.3%. The median times to develop ILRF and DF were 2.0 and 2.9 years, respectively. The majority (71%) of LRF occurred within the first 4 years, and 21.4%, 6.5%, and 1.0% of LRF occurred at 4 to 8, 8 to 12, and more than 12 years of follow-up, respectively.
Rates of LRF According to Patient and Tumor Characteristics: Univariate Analysis
Frequency Distribution of Sites of LRF As First Events The majority of recurrences occurred in the chest wall and around the mastectomy scar (56.9% of patients). Supraclavicular LN recurrence represented 22.6% of all LRF, and axillary failure represented 11.7%. Both of parasternal and subclavicular failures were less than 1% of the total LRF.
Rates of LRF According to Patient and Tumor Characteristics: Multivariate Analysis
Three other large studies evaluating patterns of LRF in patients treated with mastectomy and adjuvant systemic therapy but without RT have been published recently.9-11 In the ECOG9and the IBCSG11 studies, patients received adjuvant CMF, but in the MDA study, 10 anthracycline-based adjuvant chemotherapy was used. In our study, 90.3% of patients received anthracycline-based chemotherapy, and 9.7% received CMF (NSABP B-15).12 Although similar patterns of LRF were observed in our study and in these three other studies with regard to the effect of tumor size and number of involved LNs, the rate of LRF in the group of patients with greater than 5-cm tumors who had one to three LN+ seemed somewhat lower in our study (11.4% v 16% to 31.4%, respectively). Certainly, patient selection and differences in eligibility criteria in the various adjuvant trials included in these reports can account for the differences. However, in the three previous reports9-11 and in the present study, rates of LRF were lower than those reported in the three randomized trials of PMRT5-7 (Table 6). The average number of axillary LNs dissected in the four series (ECOG,9 MDA,10 IBCSG,11 and this current study) was fairly similar (between 15 and 17 LNs removed). However, in the Danish6,7 and Canadian trials,5 the average number of LNs removed was seven and 11, respectively. This difference in the number of removed LNs could explain, at least in part, the higher rates of LRF observed in the randomized trials.5-7
The value of locoregional PMRT has been the subject of long-standing intense controversy for more than a quarter of a century, and the controversy has evolved significantly over the past several years as results from new randomized trials have become available.5-7 Although the majority of randomized trials conducted to date consistently show a reduction in local recurrence rates with the addition of RT to surgery or to surgery plus systemic therapy,1,2,4 it was not until recently that a survival benefit was demonstrated as well.5-7 This benefit was shown in two studies in which PMRT was added to surgery plus systemic adjuvant chemotherapy.5,6 Because adjuvant chemotherapy has been shown to improve survival,20 the great majority of node-positive patients would currently be treated with adjuvant chemotherapy. Therefore, extrapolation on the value of PMRT from trials that did not use adjuvant chemotherapy would not necessarily be applicable to current practice. However, there are also significant differences between the recently disclosed randomized trials of PMRT5-7 and other studies3,9,10,13,21,22 that have dictated standards of care in the United States, particularly as these differences relate to the extent of axillary LN dissection, the type of chemotherapy used, and the rates of LRF observed in patients who did not receive PMRT. These differences make the generalizability of the results from those trials somewhat questionable for patients treated today. Even more controversial than the role of PMRT in node-positive patients is the role of this intervention in patients with one to three LN+. In a survey addressed to radiation oncologists in the United States, Ceilley et al23 showed that only 58% of responders would use PMRT in this group of patients. In the NSABP currently ongoing LN+ trials (B-30 and B-31), in which the use of PMRT is left to the discretion of the treating physician, 39% to 44% of patients with one to three LN+ are receiving PMRT (unpublished data). In the randomized trials,5-7 the 10-year rate of LRF in patients with one to three LN+ who did not receive RT varied between 30% and 33% (the Canadian study5 presented 15-year rates). In the three series from ECOG,22 MDA,10 and IBCSG11 and in our series, these rates were substantially lower and varied between 13% and 19.7% (Table 6). The reasons for this discrepancy are unclear, although the differences in surgical techniques and the possible inadequacy of the LN dissection in the Danish study have been put forward as plausible explanations. The proportion of LRF that occurred in the axilla in the Danish study was 45% compared with 14% and 11.8% in the MDA and NSABP studies, respectively. The number of LNs dissected could not fully explain this discrepancy because, in the Danish study, the rate of LRF remained high (27%) in the group of patients who had more than nine LNs removed and who did not receive RT. However, the number of patients in this group was relatively small (only 25% of patients had > nine LNs removed). Other explanations have been also discussed by Recht et al,9 such as differences in the scoring of LRF between trials or in the type of statistical analysis used.
In the MDA analysis, Katz et al10 identified a subset of patients with one to three LN+ at higher risk of LRF. This included patients with larger tumors and extranodal extension Although the LRF ± DF rates in patients with four or more LN+ were lower in the ECOG, MDA, and the IBCSG studies9-11 compared with the randomized trials, these rates are still considerably high. The rates varied between 42% and 46% in the randomized studies and between 24% and 38% in the other series9-11 (Table 6). In the guidelines of the American Society of Clinical Oncology,22 PMRT was recommended for this group of patients. In the Ceilley et al23 survey, 95% of radiation oncologists who responded to the survey would recommend PMRT for this group of patients. In the NSABP trials (B-30 and B-31), in which PMRT is left to the discretion of the investigator, 84% to 90% of patients with four or more LN+ are receiving PMRT (unpublished data). PMRT in this group of patients would have a significant effect on local control, with approximately a two-thirds reduction in local recurrence,1 thus decreasing the LRF rate to approximately 6% to 10%, and a possible effect on survival.
One of the criticisms of the randomized trials5,6 relates to the use of CMF in which the cyclophosphamide is administered intravenously as opposed to orally administered cyclophosphamide in the CMF regimen9,11,13,25 or the more commonly used anthracycline-containing regimens for patients with positive nodes.8 The 1998 overview analysis demonstrated that anthracycline-containing regimens have superior activity when compared with nonanthracycline-containing regimens in terms of reducing recurrence and mortality.20 In our study, the pattern of failure data from the B-15 trial12 demonstrates that, although the LRF ± DF was slightly higher in the oral CMF group for patients with four to nine and
The number of removed axillary LNs has been found to have an impact on the rates of LRF in several studies.6,9,10 In the Danish study,6 the LRF rate increased from 27% in patients who had more than nine LNs recovered to 40% in patients who had zero to three LNs recovered. In our study, the 10-year cumulative incidence of ILRF was significantly higher in patients who had one to five LNs removed; the rates were 19.7%, 12.9%, and 11.9% for patients who had one to five, six to nine, and
In the majority of studies, RF is reported as part of LRF.5-7,10,11 To potentially identify subgroups of patients with a low risk for RF who might not benefit from regional radiation, we reported the rates of ILF and IRF as first event separately. The 10-year cumulative incidence of IRF for patients with one to three LN+ varied between 2.3% and 3.5% for various tumor sizes (Table 4). The most common approach of PMRT includes the area of the chest wall and regional LNs. The risk of radiation pneumonitis increases with the increase in the lung volume irradiated as well as with the use of chemotherapy.27,28 In addition, the risk for arm lymphedema increases when RT includes the axilla.29 All these facts together raise the question of the need for regional radiation in the absence of survival benefit. Should radiation be used in this group of patients? In patients with four to nine LN+, the 10-year cumulative incidence of IRF as a first event varied between 5.4% and 8.7%. This risk increased up to 10.9% in patients with In a study including 1,703 premenopausal patients, de la Rochefordiere et al30 showed that younger age was an independent significant prognostic factor in disease-free survival and overall survival. However, the authors did not report information about LRF. In the Recht et al9 (629 patients < 44 years old) and Katz et al10 (226 patients < 40 years old) studies, age was not found to be a significant predictor of LRF. In contrast, in our study (1,131 patients < 40 years old), the LRF ± DF was significantly higher in patients 20 to 39 years of age (26.1%) compared with patients more than 60 years old (14.1%; Table 3). This difference was highly statistically significant (P < .0001). In fact, in our study, age was also found to be an independent prognostic factor for ILF and IRF, LRF ± DF, and DF as a first event. However, it should be noted that, in our trials, women older than 50 years received tamoxifen independent of their ER status. In conclusion, our study of 5,758 patients demonstrates that the incidence and pattern of failure in patients with LN+ treated with mastectomy and adjuvant chemotherapy with or without tamoxifen and without PMRT are similar to those found in the ECOG,9 MDA,10and IBCSG studies11 but are different from those found in the Danish and Canadian randomized trials.5-7 The 10-year cumulative incidence of LRF ± DF in patients in our study who had four or more LN+ is substantial enough to warrant the consideration of adjuvant PMRT for these patients. On the basis of the tumor size, the group with one to three LN+ in our study had an incidence of LRF ± DF varying between 10.6% and 15.3%, which was much lower than the 30% to 33% rates reported in the Danish and Canadian randomized trials. The overall lower rates found in the ECOG, MDA, and IBCSG series, as well as in our study, do not justify the routine use of PMRT in this group of patients, and only the results of future randomized trials will eventually settle the question.
The authors indicated no potential conflicts of interest.
We thank Barbara C. Good, PhD, for editorial assistance with this manuscript.
Supported by Public Health Service Grant Nos. U10CA-12027, U10CA-69974, and U10CA-69651-10 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD. Presented at the 43rd American Society of Therapeutic Radiology and Oncology Meeting, San Francisco, CA, November 4-8, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757-1770, 2000[CrossRef][Medline]
2. Whelan T, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000
3. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002 4. Auquier A, Rutqvist L, Host H, et al: Post-mastectomy megavoltage radiotherapy: The Oslo and Stockholm trials. Eur J Cancer 28:433-437, 1992
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. Overgaard M, Hansen P, 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 7. Overgaard M, Hansen P, 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] 8. Adjuvant Therapy for Breast Cancer. NIH Consensus Statement Online November 1-3, 2000; 17:1-23. http://consensus.nih.gov/cons/114/114_statement.htm
9. Recht A, Gray R, Davidson N, et al: Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689-1700, 1999
10. Katz A, Strom E, Buchholz TA, et al: Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 18:2817-2827, 2000
11. Wallgren A, Bonetti M, Gelber RD, et al: Risk factors for locoregional recurrence among breast cancer patients: Results from International Breast Cancer Study Group Trials I through VII. J Clin Oncol 21:1205-1213, 2003 12. Fisher B, Brown A, Dimitrov N, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of CMF in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the NSABP B-15. J Clin Oncol 8:1483-1496, 1990[Abstract] 13. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990[Abstract]
14. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483-2493, 1997
15. Fisher B, Anderson P, Wickerman D, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from NSABP Project B-22. J Clin Oncol 15:1858-1869, 1997
16. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from the National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374-3388, 1999 17. Kalbfleisch J, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley and Sons, 1980 18. Gray R: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988 19. Cox D: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 20. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline] 21. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract]
22. Recht A, Edge S, Solin LJ, et al: Postmastectomy radiotherapy: Guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1539-1569, 2001 23. Ceilley E, Goldberg S, Kachnic L, et al: The radiotherapeutic management of breast cancer: Treatment practice in the United States. Int J Radiat Oncol Biol Phys 51:110, 2001 (abstr)[Medline] 24. Southwest Oncology Group (SWOG): Randomized trial of post-mastectomy radiotherapy in stage II breast cancer in women with one to three positive axillary nodes, phase III (SWOG 9927). http://swog.org/visitors/ViewProtocolDetails.asp?ProtocolID=1807 25. Levine M, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651-2658, 1998[Abstract] 26. Taghian A, Jeong J, Anderson S, et al: Relationship between number of lymph node dissected and the risk of axillary/supraclavicular failure in patients with breast cancer treated by mastectomy and chemotherapy (+/– tamoxifen) without radiation: Results from five NSABP trials. Int J Radiat Oncol Biol Phys 54:89, 2002 (abstr) 27. Lingos T, Recht A, Vicini F, et al: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21:355-360, 1991[Medline]
28. Taghian A, Assaad S, Niemierko A, et al: Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel. J Natl Cancer Inst 93:1806-1811, 2001 29. Coen JJ, Taghian AG, Kachnic L, et al: Risk of lymphedema after regional nodal irradiation with breast conservation therapy. Int J Radiat Oncol Biol Phys 55:1209-1215, 2003[CrossRef][Medline] 30. de la Rochefordiere A, Asselain B, Campana F, et al: Age as a prognostic factor in premenopausal breast carcinoma. Lancet 341:1039-1043, 1993[CrossRef][Medline] Submitted January 7, 2004; accepted June 8, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 cm, 2.1 to 5 cm, and more than 5 cm in 30%, 52%, and 11% of patients, respectively. Distribution of the number of LN+ was one to three, four to nine, and 
10 in 51%, 32%, and 16% of patients, respectively. Ninety percent of patients received doxorubicin-based chemotherapy. 
