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Journal of Clinical Oncology, Vol 23, No 8 (March 10), 2005: pp. 1706-1717 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.08.109
The Use of Radiotherapy After Mastectomy: A Review of the Literature
From the Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI Address reprint requests to Lori J. Pierce, MD, Department of Radiation Oncology, University of Michigan, 1500 E. Medical Center Drive, Room 4308, Ann Arbor, MI 48109; e-mail: ljpierce{at}umich.edu.
Postmastectomy radiotherapy (PMRT) has been shown to significantly reduce the risk of locoregional failure (LRF) and to improve disease-specific survival in high-risk women with early-stage breast cancer.1-7 Studies have also confirmed its importance in maintaining optimal locoregional control in patients with locally advanced disease.8,9 Historically, PMRT was delivered before the availability of systemic therapies. However, this review will emphasize the role of PMRT in the presence of adjuvant (or neoadjuvant) systemic therapy. The content of this review is based upon critical examination of all published randomized trials of mastectomy and systemic therapy with or without radiotherapy (RT), meta-analyses of all PMRT randomized trials, and the published guidelines for PMRT from the National Institutes of Health, the American Society of Therapeutic Radiology and Oncology, the American College of Radiology, the American Society of Clinical Oncology, and Health Canada.10-14 The outcomes emphasized are LRF, breast cancer–specific survival, overall survival, and non–breast-cancer deaths. Whenever possible, recommendations were based upon controlled investigations rather than uncontrolled observational studies. The levels of evidence for treatment recommendations were adapted from the criteria proposed by Sackett.15 Briefly, level I evidence was based on results from large randomized trials with clear outcomes (high power, low risk of error), and/or meta-analyses of well-designed clinical trials; level II was based on small randomized trial results of low power (moderate to high risk of error); level III represented nonrandomized, concurrent cohort comparisons of contemporaneous controls; level IV consisted of reports from nonrandomized comparisons between current patients and historical controls; and level V represented case reports with no historic controls.
Virtually every PMRT randomized trial to date has demonstrated a reduction in the risk of LRF with the use of comprehensive RT.1,2 Prevention of LRF is an important goal in oncology management as, on average, only approximately 50% of locoregional recurrences can be subsequently controlled.16 Despite the consistent improvements in locoregional control, evidence of a benefit in survival attributed to PMRT has been elusive until recent years.3-5 Conceptually, for PMRT to improve survival, RT must be able to sterilize residual locoregional disease which, if left untreated, could lead to distant tumor spread. The patients who would potentially benefit are those without micrometastatic disease at presentation or patients with micrometastatic disease effectively treated by systemic therapy. Appropriate patient selection would require identification of factors predicting residual locoregional disease after mastectomy as discussed in Patient Selection for PMRT: Defining Risk.
As shown in Table 1, randomized trials have shown inconsistent reductions in the rates of LRF with systemic therapies.17-31 Almost all agents, particularly hormonal, have resulted in some risk reduction; however, the absolute rates of isolated LRF have remained 15% or higher in most node-positive series, depending upon the baseline estimate of risk (level II evidence).
Recent studies suggest that dose-dense regimens and newer systemic agents do not significantly reduce the risk of LRF beyond that achieved with standard chemotherapy (level II evidence).32-39 In the Cancer and Leukemia Group B (CALGB) 8541 trial in node-positive breast cancer, randomization between high-, standard-, and low-intensity cyclophosphamide, doxorubicin, and fluorouracil (CAF) resulted in comparable levels of LRF following high- and standard-intensity chemotherapy (ie, 14% and 17% total recurrences, respectively) compared to 27% following low-intensity CAF.32 Similarly, intensification of cyclophosphamide in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-22 trial did not result in any reduction in the rate of LRF over standard doxorubicin and cyclophosphamide (AC), with 10% risk of LRF with all regimens at 5 years.33 Retrospective analyses also demonstrate LRF rates of approximately 33% to 40% in the absence of RT despite administration of high-dose chemotherapy with peripheral stem-cell support.34-36 The impact of taxanes on LRF has not been extensively studied, however, results of locoregional control following AC with or without paclitaxel among patients entered on CALGB 9344 did not demonstrate a significant benefit following paclitaxel in patients treated with mastectomy at 5 years, with rates of isolated locoregional recurrence of 10.8% with AC and 8.8% with AC + paclitaxel without RT (P = .28), and 4.3% and 3.5% with RT, respectively (P = .87).37 Results of dose-dense versus conventional AC + paclitaxel (CALGB 9741) showed no difference in risk of LRF by regimen.39 Collectively, these reports suggest that while systemic therapy can reduce rates of LRF, considerable risk for recurrence persists particularly in high-risk patients.
Randomized trials have consistently shown a highly significant two-thirds reduction in LRF with the addition of PMRT (level I evidence).6,7 This reduction has been observed despite inclusion of older studies insufficiently powered to demonstrate a benefit and use of RT techniques and targets inadequate by current standards.1,2,40 Despite the benefit in locoregional control, the effect of PMRT on disease-specific and overall survival has varied. Early analyses suggested decreased survival with PMRT.41,42 A later report of cause-specific mortality in 4,309 10-year survivors demonstrated that the excess of cardiac deaths associated with RT was offset by a reduction in deaths due to breast cancer, suggesting a benefit from PMRT beyond the established improvement in local control.43 The 1995 meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) demonstrated a significant reduction in breast cancer deaths due to RT (odds ratio [OR], 0.94) and also an increased risk of non–breast-cancer deaths (OR, 1.24), resulting in overall mortality rates of 40.3% with RT versus 41.4% without RT (2.6% ± 2.5% reduction in the odds of death).6 The 2000 EBCTCG overview provided 20-year results of 20,000 women entered into 40 randomized RT trials.7 Rates of isolated local recurrence were significantly reduced with RT by two thirds (10.4% RT v 30.1% control; 2P < .00001). Breast cancer mortality was significantly reduced by RT (2P = .0001) but this benefit was counterbalanced by a significant increase in non–breast-cancer deaths (2P = .0003), primarily vascular in origin. In the final analysis, RT resulted in a nonsignificant benefit in overall survival, that is, a 3.9% reduction in the annual death rate (2P = .06; level I evidence). Other meta-analyses have been performed, emphasizing the more clinically relevant PMRT trials.1,2,40 Van de Steene et al44 categorized the meta-analysis data by factors that could influence survival and found a significant survival benefit with RT in the more recent trials, as well as trials that utilized standard RT fractionation, and those trials with a favorable baseline crude survival. Whelan et al45 performed a meta-analysis of the 18 trials in which all patients received systemic therapy. RT significantly reduced the risk of any recurrence (OR, 0.69; P = .00004), local recurrence (OR, 0.25; P < .00001), and mortality (OR, 0.83; P = .004). Even when the two largest trials, Danish Breast Cancer Collaborative Group (DBCCG) 82b and 82c, were excluded,3,4 PMRT resulted in an 11% reduction in mortality (P = .17). Therefore, using specific criteria to select appropriate studies, these analyses demonstrated improvement in overall survival with postoperative RT (level I evidence). While meta-analyses help to provide evidence to support clinical strategies, large randomized controlled trials are still considered the gold standard when evaluating the relative merits of clinical therapies (level I evidence).46 The results of the published trials of mastectomy and adjuvant systemic therapy, with or without RT, are presented in Table 2.3-5,8,9,47-54 Based upon trial size and/or length of follow-up, the DBCCG trials 82b and 82c and the British Columbia Cancer Agency (BCCA) trial provide the greatest level I evidence of a significant benefit of PMRT upon survival.3-5 In DBCCG 82b, 1,708 premenopausal, high-risk patients with pathologic stage II/III breast cancer were randomly assigned to receive either nine cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) or eight cycles with PMRT.3 As only 8% of patients in the study were node negative, this trial constitutes a predominately node-positive study. With median follow-up of 114 months, PMRT significantly reduced LRF (9% v 32%; P < .001), significantly improved disease-free survival (DFS; 48% v 34%; P < .001), and significantly improved overall survival (54% v 45%; P < .001; Fig 1). Multivariate analysis for any type of recurrence or death from any cause revealed a benefit of PMRT in all patients randomly assigned, regardless of tumor size and number of axillary nodes involved. In the recently updated BCCA trial,5 318 premenopausal women with node-positive breast cancer were randomly assigned to either 12 months of CMF (later reduced to 6 months) or to CMF with PMRT. At 20-year follow-up, PMRT significantly reduced the crude risk of isolated LRF from 26% to 10% (relative risk [RR] = 0.36; P = .002) and improved breast cancer–specific survival (53% v 38%; RR = 0.67; P = .008) and overall survival (47% v 37%; RR = 0.73; P = .03; Fig 2). In DBCCG 82c, 1,375 postmenopausal high-risk women with stage II/III disease were randomly assigned to tamoxifen 30 mg for 1 year or tamoxifen with PMRT.4 With median follow-up of 123 months, PMRT significantly reduced LRF (8% v 35%; P < .001) and improved DFS (36% v 24%; P < .001) and survival (45% v 36%; P = .03; level I evidence; Fig 3).
Clinical and pathologic factors predicting high- (ie, > 20%), moderate- (10% to 20%), and low-risk (< 10%) for LRF are used to categorize the potential locoregional benefit from comprehensive PMRT. Extent of axillary involvement has been shown to predict LRF risk (level II and III evidence). As shown in Table 3, increasing risk of LRF is associated with increasing axillary involvement in the presence of adjuvant systemic therapy.3-5,48,51,55-57 There is now consistent agreement that patients with  four positive nodes should receive PMRT.10-14,58,59
The recommendations are less clear in patients with one to three positive nodes. Despite the evidence from the DBCCG and the BCCA studies in support of a survival benefit with PMRT in all node-positive patients, debate remains regarding the applicability of their findings to moderate-risk patients (ie, women with one to three positive nodes). Concerns raised include the incompleteness of the surgical resections, use of older methotexate-based regimens (DBCCG 82b and BCCA trials), use of 1 year only of tamoxifen (DBCCG 82c), and the lack of estrogen receptor data in patient recruitment and data analysis (DBCCG 82c). Other studies, however, suggest comparable rates of LRF with doxorubicin-based and methotrexate-based regimens,55,56 and preliminary results do not suggest a significant reduction of LRF with the addition of taxanes.37 The rate of overall LRF in the control patients in the DBCCG trials (approximately 30%) was higher than that observed in other series (less than 20%),48,55,56,60 and analyses of the combined DBCCG studies demonstrated a 13% rate of axillary failures,61 higher than the 0% to 3% rate commonly observed with a level I/II dissection.60,62,63 These high rates of LRF reflect, in part, the inability to identify those patients with only one to three positive nodes, given that in the Danish trials, only a median of seven nodes were removed.64 Thus, while the relative risk reduction for LRF with PMRT in patients with one to three positive nodes may be similar to that with four nodes positive,7 the absolute benefit in women with one to three positive nodes may not warrant its routine use when balanced against the potential for radiation-associated morbidities. Some argue, however, that the benefit in locoregional control from PMRT may underestimate the potential survival gains from treatment, and strongly advocate for its use in moderate-risk patients.65 At this time, insufficient evidence exists to recommend routine use of PMRT with one to three positive nodes. In the 2000 EBCTCG overview, women with node-negative disease treated with mastectomy and axillary clearance had the lowest risk of LRF without RT.7 Despite the highly significant two-thirds reduction in risk of isolated LRF with RT (ie, 9.2% in controls and 2.7% with RT; 2P < .00001), the risk of any recurrence was not significantly reduced (30.2% control and 28.2% with RT; 2P > .1; level I evidence).7 Therefore, PMRT is not routinely recommended in cancers less than 5 cm with negative nodes. Recent analyses of results from the International Breast Cancer Study Group trials I through VII suggest, however, that certain tumor-related factors are associated with increased rates of LRF in node-negative disease.66 Vascular invasion and tumor size greater than 2 cm in premenopausal women and vascular invasion only in postmenopausal women increased the risk of LRF as first failure to approximately 15% to 20% compared to 8% without these factors. Additional trials of PMRT are needed in node-negative breast cancer. Tumor size appears to be an independent predictor for LRF in most series, with higher failure rates with T3 lesions compared to T1 and T2 disease (level II evidence).3,4,55,67,68 Rates of failure for pathologic T3N0 cancers, an uncommon presentation, have been reported between 15% and 60% in the presence of systemic therapy (level V evidence).53,55,69 More recently, tumor size and extent of axillary involvement have been combined to predict cumulative incidences of LRF.56 Invasion of the skin or pectoral fascia have been associated with increased rates of LRF.3,4,60 While these factors were used for eligibility criteria as high risk in both DBCCG 82b and 82c, outcome results were only reported in 82c, where RT reduced LRF in the presence of deep fascia invasion from 45% to 6%, and 34% to 8% with skin invasion (level II evidence).4 The extent of axillary surgery appears to affect rates of LRF.56,61 Recht et al56 demonstrated increasing LRF with decreasing number of nodes examined in the Eastern Cooperative Oncology Group trials. Extracapsular extension is associated with increasing rates of LRF attributable to the correlation with the extent of axillary involvement.70-74 However, the impact of extracapsular extension upon systemic failure and the potential reduction of that risk by locoregional RT is unclear.75-78 The effect of close/positive margins on LRF is also not well defined.79-82 A recent paper suggests that a combination of clinicopathologic factors, in addition to positive margin assessment, is needed to predict rates of approximately 20% LRF.83 At present, insufficient data are available to recommend PMRT based upon these and other clinicopathologic factors, including patient age, estrogen and progesterone receptor status, HER-2/neu status, tumor grade, lymphovascular invasion, and p53 overexpression.84-90
The choice of RT fields has generally been based upon patterns of LRF. Most mastectomy series show that more than 50% of LRF occur on the chest wall, with the mastectomy scar at greatest risk for recurrence.91-93 Therefore, treatment to the chest wall is recommended for all PMRT patients. The second most common site of LRF is the supraclavicular/infraclavicular (axillary apex) region. As many as 33% of LRF occur in this region, with absolute rates of first failure reported in up to 18% of patients, depending upon extent of axillary involvement and tumor size (level IV evidence).91,94,95 While supraclavicular/axillary apex failures are uncommon in patients with one to three positive axillary nodes, failure rates increase in patients with four positive nodes.56,90 Therefore, PMRT, including a supraclavicular field, is recommended in patients with four positive axillary nodes. Data are insufficient, however, to recommend a third field in patients with one to three positive nodes based strictly upon patterns of failure. However, the survival gains realized after PMRT in the Danish and British Columbia trials were obtained in patients treated with a supraclavicular field, which supports the routine use of a third field whenever PMRT is delivered. Whether the survival benefit can be attributed to the regional irradiation is unknown. Two current randomized trials of regional RT (European Organisation for Research and Treatment of Cancer [EORTC] 22922 and the National Cancer Institute of Canada Clinical Trials [NCIC GTC] Group MA.20 trial) will address this question. Patterns of failure data suggest the risk of axillary failure to be 0% to 3% after a complete axillary dissection,53-55 with increasing axillary failures after inadequate surgery (level III evidence).56,61,96 As the risk of axillary failure is low in an adequately dissected axilla, and the risk of lymphedema increases with the addition of axillary RT,97,98 routine full axillary irradiation is strongly discouraged following a level I to III dissection. Whether to irradiate the internal mammary nodes (IMN) remains unclear. Clinically evident IMN recurrences are uncommon.91,99,100 No randomized trials to date have demonstrated a survival benefit from IMN treatment, however, subset analyses suggest survival benefits with treatment in certain subgroups.101-104 The IMN were included in the treated volume in the Danish and British Columbia trials, but as previously noted, whether treatment of these nodes contributed to the improvement in survival is not clear. The EORTC and NCIC CTG MA.20 trials should provide insight into the effect of IMN RT upon survival.
Lymphedema While a general discussion of potential complications associated with PMRT is beyond the scope of this article, three complications—arm lymphedema, pneumonitis/pulmonary fibrosis, and chronic cardiac toxicity—will be presented. Two factors consistently shown to impact lymphedema risk are extent of axillary surgery and use of axillary RT (level V evidence).97,98 While each of these factors can separately result in risk less than 10%, the additive risk can be as high as 40% following complete (I to III) axillary dissection and full axillary RT.97,98 Limitation of the regional fields to include only the supraclavicular region and axillary apex appears to reduce this risk (level V evidence),74,105 and use of computed tomography planning allows identification of the nodal regions and design of conformal fields that may further reduce arm and shoulder morbidity.106
Pneumonitis and Pulmonary Fibrosis
Cardiac Toxicity Three-dimensional, computed tomography–based treatment planning allows individualized planning and utilization of nonaxial beams to ensure coverage of clinical targets while minimizing critical normal tissue exposure.110 Examples of advantages using three- versus two-dimensional planning are shown in Figures 4 and 5. As shown in Figure 4A, the 95% isodose line encompasses the chest wall volume using standard (two-dimensional) tangents; however, IMN coverage is compromised. Three-dimensional planning allows incorporation of the IMN in the target volume if desired (Fig 4B), while shaping the field to minimize additional lung RT. Depending upon body habitus and heart position in the thorax, chest wall coverage with standard tangents can include a portion of the heart in the RT field (Fig 5A). Three-dimensional planning can provide field-shaping capabilities to eliminate the heart from the RT field while maintaining chest wall coverage (Fig 5B). Newer strategies such as intensity-modulated radiotherapy (IMRT) may provide greater beam conformality while maximizing dose homogeneity and limiting normal tissue exposure.121
No randomized trials have evaluated the optimal sequencing of chemotherapy and PMRT. Information has been extrapolated from breast conservation trials. In a randomized trial of a 12-week course of chemotherapy sequenced before or after RT, no significant differences in time to failure or overall survival were observed by treatment arm (level II evidence).122 Preliminary results of other sequencing studies also show no difference, but longer follow-up is needed.123,124 Sequencing options include sequential versus concurrent therapies. Concurrent chemotherapy and RT has been associated with increased complications compared with sequential treatments.125,126 While strategies have been proposed to decrease the risk of complications with concurrent therapies,127,128 in general, sequential therapies have been better tolerated. Options for sequential therapies include administration of chemotherapy first, RT first, or a "sandwich" approach where RT is given between cycles of chemotherapy. In a series from Grenada, Spain, rates of LRF were 18%, 10%, and 5% at 10 years with chemotherapy first, RT first, and sandwich approach, respectively, with rates of DFS of 46%, 41%, and 57% and overall survival 47%, 48%, and 57%, respectively (P = .05; level III evidence).129 In both DBCCG 82b and BCCA trials,3,5 PMRT was delivered between successive cycles of chemotherapy and these trials have shown the greatest survival benefit for PMRT. Whether sequencing affected the outcome is unknown. In the meta-analysis by Whelan et al,45 a multivariate analysis indicated benefit in mortality when RT was started within 6 months of surgery. However, retrospective studies have not suggested an adverse effect on outcome when longer chemotherapy schedules were given first.105 Clearly, the optimal timing of RT has yet to be defined. Of note, dose-dense chemotherapy regimens allow initiation of PMRT earlier than traditional schedules.39 It will be important to compare rates of LRF following dose-dense schedules. Similarly, the optimal sequencing of hormonal therapies and RT has not been defined. Retrospective series suggest similar rates of in-breast tumor control with tamoxifen administration either after or concurrent with RT130-133; however, randomized comparisons are lacking. In the two randomized PMRT studies with tamoxifen,4,53 tamoxifen was given concurrently with RT, and rates of LRF were significantly reduced with RT (level II evidence). Whether LRF could have been further reduced by sequential administration is unknown.
Whether patients with high-risk, node-negative disease or one to three positive nodes should receive PMRT remains an issue of debate. A randomized trial for PMRT in patients with one to three positive nodes previously open in the United States was closed secondary to inadequate accrual. The Scottish Cancer Trials Breast Group will open a similar trial that will also include high-risk, node-negative women (I. Kunkler, personal communication, January 2005). The primary end point will be overall survival, with secondary end points of disease-free survival, metastasis-free survival, and acute and late morbidity. Information regarding the benefits of regional RT, applicable to both breast conservation and mastectomy patients, will be obtained from the EORTC 22922 and the NCIC CTG MA.20 trials. Accrual to the MA.20 continues, while accrual for EORTC 22922 was completed in January 2004 with 4,004 patients; the first planned analysis is scheduled for approximately 8 years after closure (H. Bartelink, personal communication, August 2004).
Information is needed to define the indications for PMRT following neoadjuvant chemotherapy. Retrospective analyses of patients treated with neoadjuvant chemotherapy suggest that clinical T3 disease, pathologic involvement of Another area of needed research is defining the optimal integration of breast reconstruction and PMRT. Increasing reports have demonstrated adverse cosmetic results in irradiated expander-implant reconstructions137-139; better results appear to be obtained with autologous procedures (level V evidence).140,141 However, since not all patients are candidates for autologous reconstruction, information to improve the outcome of expander implants and PMRT, and to further optimize the sequencing of RT and autologous reconstructions is needed. Multidisciplinary input is indicated for optimal care of these patients and prospective studies of adequate power are needed to control for potential confounding clinical variables. Finally, continued research and implementation of technical advances in RT treatment planning are needed. While three-dimensional treatment planning systems are readily available for use, practice pattern surveys suggest gradual integration into routine clinical care.142 Advances in treatment planning such as IMRT and/or active breathing control121,143 may further improve target coverage while limiting normal tissue exposure. While it is logical that by further reducing treatment-related morbidity, gains in survival will be realized, outcome studies are needed to validate these assumptions.
The National Institutes of Health Consensus Panel on Adjuvant Therapy of Operable Breast Cancer and consensus statements from the American Society of Therapeutic Radiology and Oncology, American College of Radiology, American Society of Clinical Oncology, and Health Canada recommend the use of PMRT for patients with four positive axillary nodes, T3 or T4 lesions, and/or tumor invading the skin or adjacent musculature.10-14 These groups concur that there is insufficient evidence to recommend PMRT in patients with one to three positive nodes (or high-risk node-negative disease). These patients are strongly encouraged to participate in any available research studies that randomly assign women to the use of PMRT. In the absence of a study, both the potential expected proportional reduction and the absolute reduction in recurrence secondary to PMRT, and the possible improvement in survival, should be discussed with each patient and weighed against the potential for toxicity from treatment.
The author indicated no potential conflicts of interest.
Author's disclosures of potential conflicts of interest are found at the end of this article.
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INTRODUCTION
RATIONALE FOR PMRT
, and Bcl-2 proteins and benefit from adjuvant radiotherapy in breast cancer. J Natl Cancer Inst 89:639-645, 1997
