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© 2000 American Society for Clinical Oncology Locoregional Recurrence Patterns After Mastectomy and Doxorubicin-Based Chemotherapy: Implications for Postoperative IrradiationFrom the Departments of Radiation Oncology, Biomathematics, Medical Oncology, and Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Eric A. Strom, MD, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 97, Houston, TX 77030; email estrom{at}notes.mdacc.tmc.edu
PURPOSE: The objective of this study was to determine locoregional recurrence (LRR) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation. PATIENTS AND METHODS: A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospective trials. Median follow-up time was 116 months. Rates of isolated and total LRR (± distant metastasis) were calculated by Kaplan-Meier analysis.
RESULTS: The 10-year actuarial rates of isolated LRR were 4%, 10%, 21%, and 22% for patients with zero, one to three, four to nine, or
CONCLUSION: Patients with tumors
RANDOMIZED TRIALS that date back to the early 1970s have established that adjuvant radiation therapy after mastectomy reduces the incidence of locoregional recurrence (LRR) of breast cancer by approximately two thirds.1-11 Two more recent trials now suggest that the improved locoregional control achieved by using postmastectomy irradiation in appropriately selected patients improves survival rates.10,11 The patients most likely to benefit from adjuvant radiotherapy are presumed to be those with an increased risk of locoregional failure. Their identification requires analysis of the patterns of failure after standard modified radical mastectomy and adjuvant systemic therapy. In one such analysis, Fowble et al12 reviewed the recurrence patterns of 627 patients treated with mastectomy and cyclophosphamide/methotrexate/fluorouracil (CMF) chemotherapy on Eastern Cooperative Oncology Group trials. Factors predictive of high rates of LRR were identified as four or more involved nodes, tumor size greater than 5 cm, the presence of tumor necrosis, negative estrogen receptor status, and involvement of the pectoral fascia. A recent update by Recht et al13 that included over 2,000 patients treated with CMF on Eastern Cooperative Oncology Group trials suggested that the combination of prognostic factors, particularly tumor size and nodal involvement, was most predictive of the risk of LRR. These two reports of LRR patterns after mastectomy and CMF therapy remain the only large series in the literature. However, there is little information concerning recurrence patterns after other forms of systemic therapy, including anthracycline-based chemotherapy, which growing evidence suggests is superior to CMF for node-positive patients.14 In this report, we examine LRR patterns in 1,031 patients treated on prospective trials at the University of Texas M.D. Anderson Cancer Center with mastectomy and doxorubicin-based chemotherapy without irradiation. Our goal was to identify subgroups of patients at significant risk of LRR who might benefit from the addition of postmastectomy irradiation.
Patient, Tumor, and Treatment Characteristics Between 1975 and 1994, 1,805 patients were treated with doxorubicin-based adjuvant systemic therapy with or without tamoxifen after mastectomy on prospective clinical trials at the University of Texas M.D. Anderson Cancer Center.15-21 Each protocol was reviewed and approved by an institutional review board. Each participant gave written informed consent according to institutional guidelines. Referral for postoperative irradiation was at the discretion of the treating medical oncologists in most of these trials. A fraction of the patients on one protocol were randomized to receive postmastectomy irradiation. The results of this trial were previously published.16 This report comprises the data from the records of the 1,031 patients who did not receive radiotherapy. Eligibility criteria for these trials included resectable stages II and IIIA disease. Patients older than 75 years, those with evidence of distant dissemination at diagnosis, and those with a prior or concurrent malignancy were not eligible for inclusion in these trials. Informed consent was required before protocol entry. Patient, tumor, and treatment characteristics are listed in Table 1. The median age for all patients was 48 years (interquartile range, 42 to 56 years). Four hundred ninety-three (48%) of the patients were premenopausal, and 525 (51%) were postmenopausal; menopausal status was not recorded for 13 patients.
Pathology for each patient was reviewed at M.D. Anderson Cancer Center before treatment. Information concerning pathologic findings was obtained from the M.D. Anderson pathology reports; however, pathology materials were not re-examined for the purpose of this study. Pathologic tumor size was determined by postoperative gross and microscopic examination. The median tumor size was 2.5 cm, with an interquartile range of 1.9 to 3.9 cm. The median number of nodes examined was 17 (interquartile range, 13 to 22), and the median number of involved nodes was three (interquartile range, one to six). Nine hundred eighteen patients (89%) had 10 or more nodes examined. Nine patients (1%) had fewer than five nodes removed, and 91 (9%) had between five and nine nodes removed. The median pathologic size of the largest involved node was 1.6 cm (interquartile range, 1.0 to 2.5 cm). Extranodal extension was described as focal (  2 mm), gross (> 2 mm), present, not otherwise specified, or absent. Patients underwent radical mastectomy (n = 5) or modified radical mastectomy (n = 1,026) before adjuvant systemic therapy. They were then randomized to one of several treatment arms (Table 1), each of which consisted of combination chemotherapy that included doxorubicin. Each protocol stipulated a minimum of six cycles of fluorouracil/doxorubicin/cyclophosphamide and a minimum doxorubicin dose of 40 to 50 mg/m2 per cycle. No patients received preoperative chemotherapy in these trials. The median number of chemotherapy cycles was seven (interquartile range, six to 10). In addition to chemotherapy, 318 patients (31%) who were estrogen receptor– and/or progesterone receptor–positive also received tamoxifen.
Follow-Up, End Points, and Statistical Analysis All LRRs were recorded, as were the date and site of first distant metastasis. LRRs consisted of ipsilateral chest wall, axillary, supraclavicular, infraclavicular, or internal mammary node failures. Recurrence of any other site was considered distant metastasis.
Five- and 10-year actuarial rates of overall survival (OS), disease-free survival (DFS), distant metastasis, isolated LRR, and total LRR were calculated by the Kaplan-Meier method, with comparisons among groups performed using two-sided log-rank tests.22 Total LRR consisted of all LRRs with or without prior or simultaneous distant metastasis. For the purpose of this study, an isolated LRR was defined as an LRR without prior or simultaneous distant metastasis. Multivariate analysis was performed using Cox logistic regression analysis.22 All P values were two-tailed, with a value of
Overall Results OS and DFS for all patients at 10 years were 65% and 55%, respectively. The actuarial rates of isolated and total LRR for the entire cohort were 14% and 19%, respectively, at 10 years (crude rates, 12% and 17%, respectively). Table 2 lists the sites of LRR. The chest wall and supraclavicular fossa were the most common sites of locoregional failure, which represents a component of failure in 68% and 40%, respectively, of those who experienced an LRR. Axillary, infraclavicular, and internal mammary node chain (IMC) recurrences were much less common, although the rates for these may be underreported because most patients were not routinely screened for regional recurrences with ultrasound or thoracic CT scans. Seventy-nine percent of recurrences were biopsy proven. Although the median interval to LRR was 29 months, 42% of failures occurred after 3 years and 21% after 5 years. The median interval to chest wall recurrence was 27 months, which was shorter than the interval to detection of regional nodal recurrence (median, 44 months). The 10-year actuarial rate of distant metastasis–free survival was 64%.
LRR With Regard to Prognostic and Treatment-Related Factors The probability of isolated and total LRR was analyzed with regard to prognostic and treatment-related factors (Table 3). Increasing T stage, as well as 1-cm increments in tumor size, were predictive of both isolated and total LRR on univariate analysis (P < .0001). The number of involved nodes was also a significant predictor of the risk of LRR. The 10-year actuarial rate of isolated LRR was 4% for node-negative patients. Corresponding rates of isolated LRR for patients with one to three, four to nine, or  10 involved nodes were 10%, 21%, and 22%, respectively, at 10 years (P < .0001). The 10-year actuarial rate of total LRR was 7% for node-negative patients and 14%, 25%, and 33% for patients with one to three, four to nine, and 10 involved nodes, respectively (P < .0001). The probability of isolated and total LRR as a function of the number of axillary lymph nodes that contained tumor is displayed in Figs 1 and 2. Primary tumor size and number of nodes that contained tumor were interactive parameters predictive of LRR. Table 4 lists 10-year actuarial rates of isolated and total LRR with regard to traditional categories of tumor size and nodal status.
Pathologic size of the largest involved lymph node, of which 90% were less than 3 cm, was recorded in 564 patients. In these patients, the size of the largest involved axillary lymph node did not predict the risk of LRR. The degree of extranodal extension was predictive of the risk of both isolated and total LRR. Focal extranodal extension was associated with a minimally increased risk of LRR. However, extranodal extension of 2 mm was associated with a significantly greater risk (27% risk of isolated LRR and 33% of total LRR). This increased rate of LRR was not entirely explained by an increased incidence of axillary failure. Axillary recurrences as a component of failure made up only 8% of all LRRs in the patients with extranodal extension 2 mm. This rate of axillary failure was not significantly different from that of the overall sample. There was no association between age or menopausal status and the risk of isolated or total LRR. Neither histology nor estrogen receptor status, alone or when stratified by the addition of hormonal therapy to chemotherapy, was a significant prognostic factor for LRR. Central or inner quadrant tumors were marginally associated with increased risk of total LRR when compared with outer quadrant lesions (24% v 16%; P = .04). There were no significant differences in the rates of total or isolated LRR with regard to the specific regimen of combination chemotherapy, the number of cycles of chemotherapy, or the use of hormonal therapy.
On multivariate analysis by forward stepwise Cox logistic regression, significant predictors of isolated LRR included T stage (P < .0001), number of involved nodes (P < .0001), and extranodal extension
LRR Patterns for Patients With One to Three Involved Nodes
Patients with T2 tumors were significantly more likely to experience an isolated LRR or LRR with or without distant metastasis than were patients with T1 tumors (P = .02 and .01, respectively). The risk of isolated LRR increased with primary tumor size grouped in 1-cm increments. Patients with tumors 2 cm had the lowest rates of isolated LRR (< 10%), those with tumors 2.1 to 4.0 cm had intermediate rates (10% to 13%), and those with tumors 4.1 to 5.0 cm had the highest rates (26%). These values reached marginal significance (P = .05), although there were few patients in the last group. There were no significant differences in LRR patterns with regard to other potential prognostic or treatment-related variables, including age, menopausal status, estrogen receptor status, tumor location, histology, grade, chemotherapy regimen, or the use of hormonal therapy.
On multivariate analysis by forward stepwise Cox logistic regression, significant predictors of isolated LRR for patients with one to three involved nodes included extranodal extension
The history of postmastectomy radiation can be characterized as one of conflicting data and extensive debate. Since the 1950s, a variety of prospective trials with conflicting results have been conducted.1-11 After the publication in 1987 of a meta-analysis by Cuzick et al23 that reported increased mortality in women who had received postmastectomy radiotherapy as a component of their treatment, its use was intensely challenged. An update published in 1994 reported no significant difference in overall mortality. A decrease in breast cancer–related deaths in those treated with radiation was offset by increased cardiac mortality.24 A similar reduction in breast cancer mortality, as well as a two thirds reduction in LRR, was reported in a third meta-analysis, which was published by the Early Breast Cancer Trialists’ Collaborative Group.1 These authors also reported an increase in non–breast cancer deaths, which was most evident for women older than 60 years and which resulted in no difference in OS. These meta-analyses were strongly influenced by the results of several early trials, which were hampered by poor radiation technique, improper patient selection, and the infrequent use of adjuvant systemic therapy.25 More recently, two trials published in the New England Journal of Medicine have demonstrated superior locoregional control, DFS, and OS with the addition of postoperative radiotherapy to mastectomy and chemotherapy. The Danish 82b trial evaluated the use of postoperative radiotherapy in 1,708 high-risk premenopausal women treated with mastectomy and CMF.8,9 At 10 years, there was a decrease in LRR from 32% to 9% in the patients who received radiation to the chest wall and regional lymphatics (P < .001). This translated into improvements in both DFS (48% v 34%; P = .001) and OS (54% v 45%; P < .001). Most surprising was the observation that these significant improvements in DFS and OS were evident for all subgroups of patients, including patients with one to three involved nodes. A second trial from British Columbia also reported improvements in locoregional control (87% v 67%; P = .003) and DFS (50% v 33%; P = .007) in node-positive premenopausal women treated with adjuvant radiation after mastectomy and CMF.11 Similar benefits in postmenopausal women treated with mastectomy and tamoxifen were recently reported by the Danish Breast Cancer Cooperative Group.10 Together, these trials have demonstrated that the improvement in locoregional control observed with adjuvant irradiation translates into an improvement in OS. It is, therefore, imperative to identify those patients at significant risk of LRR who are most likely to realize the benefit of adjuvant irradiation. Unfortunately, few published data exist concerning LRR patterns in patients treated with modern chemotherapy. The only large series reported to date includes patients treated with various CMF-related regimens.12,13 There is growing evidence that anthracycline-based chemotherapy is the treatment of choice for women with node-positive breast cancer.14 Only a handful of small series have reported LRR rates after mastectomy and anthracycline-containing regimens.14,16,21,26-38 Unlike these previous series, this report focuses specifically on prognostic factors predictive of LRR in patients treated with anthracycline-based chemotherapy after mastectomy and represents the largest data set currently available in this cohort of breast cancer patients. Our analysis of recurrence patterns in 1,031 patients found that doxorubicin-based adjuvant systemic therapy does not obviate the need for postmastectomy irradiation for subsets of breast cancer patients at substantial risk of LRR. Patients with tumors larger than 4 cm or involvement of four or more axillary lymph nodes experienced rates of isolated LRR in excess of 20%. The results of the Danish trial demonstrated that the reduction in LRR observed with the addition of radiotherapy in patients with comparable LRR rates translated into an absolute benefit in DFS of 10% and an absolute benefit in OS of approximately 6%. This survival benefit is similar in magnitude to that achievable with adjuvant systemic therapy. Together, these data suggest that all patients with tumors larger than 4 cm or with four or more involved axillary lymph nodes should be offered postoperative radiotherapy. The risk of LRR and, thus, the value of postmastectomy radiotherapy in patients with one to three involved nodes remain controversial. Although the Danish group observed an improvement in OS for this subset of patients, the reported LRR rate of 30%8,9 was much greater than that reported in other studies, in which it ranged from 5% to 20%.12,13,31,32,35,39-42 One possible explanation for the discrepancy in the LRR rates is the limited nature of axillary dissections performed in the Danish trial. The median number of nodes removed was seven, compared with the median of 17 in our series, which is more consistent with standard practice in the United States. Also, the proportion of LRRs that were axillary failures in the Danish trial (45% of LRRs) was also much greater than that observed in our report (14% of LRRs). Interestingly, patients with one to three involved nodes and fewer than 10 nodes examined in our cohort were at significantly increased risk of both isolated LRR and LRR with or without distant metastasis. One possible reason these patients are at increased LRR risk is that the axillary dissection is too limited and underestimates the actual disease extent.
As a group, patients with stage II breast cancer and one to three involved nodes experienced a low risk of LRR (10% isolated LRR and 14% total LRR). However, there were subsets of these patients who were observed to have a much higher risk of LRR. These include patients with tumors larger than 4.0 cm (26% isolated LRR risk) or with lymph node disease displaying extranodal extension Consistent with most previous reports,12,13 our study found that the chest wall and supraclavicular fossa are the most common sites of LRR. The low overall rates of axillary recurrence do not support the routine supplementation of axillary dose beyond that delivered by the supraclavicular/axillary apex field and the chest wall tangents. Although the rate of documented IMC failures in our cohort was quite low, CT scans and ultrasound were not routinely performed as screening procedures in these patients, many of whom were treated before the routine use of CT scans. It is, therefore, possible that many IMC recurrences went undetected. Indeed, despite the observation that these clinical recurrences are rare,12,43-47 autopsy and surgical reports have documented microscopic involvement of the IMC nodes in up to 25% of node-positive patients with outer quadrant tumors and 50% of those with central/inner quadrant tumors.48 Whether subclinical involvement of these nodes is a source of seeding for distant metastasis is also unknown. The indications for treatment to the regional lymphatics, particularly the use of a posterior axillary supplemental field and targeting of the IMC nodes, remain questions worthy of further study. There has been considerable debate over the most appropriate method for reporting failure patterns such as LRR.49-51 The Kaplan-Meier statistical methodology we used may overestimate true rates of recurrence by assuming that patients who die from a competing risk, such as distant metastatic disease, have a projected risk of LRR equivalent to that of the overall population in the study. This may not be the case, given that these patients may have more aggressive disease by nature and that additional systemic therapy delivered after the diagnosis of a distant metastasis potentially alters the subsequent risk of LRR. However, we have chosen to use the Kaplan-Meier methodology because it does provide useful information for clinicians interested in estimations of total actuarial risk of an event independent of a competing risk. Although there are limitations to any method of analysis of outcome other than survival, Kaplan-Meier analysis addresses most closely the clinical situation that physicians face in discussing the role of adjuvant therapy with their patients. Crude recurrence rates are also reported to allow readers to compare these results with other series in the literature. Given the long duration of follow-up in our study, the crude rates of LRR do not differ dramatically from the rates calculated by the Kaplan-Meier method, which indicates that this is a fair approximation of the true risk.
The results of this analysis demonstrate that doxorubicin-based chemotherapy does not obviate the need for postmastectomy irradiation. Patients with zero, one to three, four to nine, and 10 or more involved nodes experience isolated LRR rates of 4%, 10%, 21%, and 22%, respectively. The corresponding rates of total LRR are 7%, 14%, 25%, and 34%, respectively. Because of the longer duration of follow-up and precise definition of isolated and total LRR in the current series, these rates are consistent with previous reports from our institution. Our results also support the recently published recommendations of the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus statement regarding the indications for postmastectomy irradiation.52 We conclude that patients with stage II disease and four or more involved nodes or stage III disease are at the greatest risk of isolated LRR and are most likely to derive a benefit from the addition of postmastectomy irradiation. Taken as a whole, patients with stage II breast cancer and one to three involved lymph nodes are at low risk of LRR, and the corresponding absolute benefit in survival derived from postmastectomy irradiation is likely to be small. However, there may be a subset of these patients who are also at a significant risk of LRR and for whom adjuvant irradiation should be considered. These include patients with large tumors, those with extranodal extension The question of whether radiation benefits subgroups of stage II patients with one to three involved nodes takes on increased importance with the growing evidence that modern radiotherapy has the potential to improve survival in properly selected patients. Because our experience does not reproduce the findings of the recent prospective trials, it is difficult to justify the routine use of postmastectomy irradiation in patients with one to three involved nodes unless other risk factors are present. The results of this study support the need for a prospective, randomized trial to specifically assess the role of postmastectomy irradiation in this patient group.
Supported by a generous grant from the Stanford and Joan Alexander Foundation, Houston, TX. We thank Jessica Erwin and Ramani Krishnan for their contribution to the database from which this analysis was conducted.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
