- Email: [email protected]
Postmastectomy Radiation Therapy for Patients With Locally Advanced Breast Cancer
Postmastectomy Radiation Therapy for Patients With Locally Advanced Breast Cancer Reshma Jagsi, MD, DPhil, and Lori Pierce, MD Radiation therapy is an integral component of the multimodal treatment of locally advanced breast cancer. Even after mastectomy and systemic therapy, occult residual disease in the chest wall and/or regional lymph nodes may serve as the source of morbid locoregional recurrence as well as the source of distant seeding or reseeding of metastases. Thus, postmastectomy radiation therapy offers substantial benefits in appropriately selected patients. This review article summarizes the data from randomized trials revealing a significant benefit from postmastectomy radiation therapy in patients with locally advanced disease as well as results from other relevant studies. It concludes with a summary of consensus guideline recommendations in this important area. Semin Radiat Oncol 19:236-243 © 2009 Elsevier Inc. All rights reserved.
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or patients with pathologic stage III breast cancer either historically defined1 or as defined in the current 6th edition of the American Joint Committee on Cancer’s Cancer Staging Manual,2 radiation therapy is an integral component of multimodal treatment. Even after mastectomy and systemic therapy, occult disease may remain in the chest wall and/or regional lymph nodes. This residual disease may serve not only as a source of potentially morbid locoregional recurrence but also as an important reservoir from which distant metastases may be seeded or reseeded after the initial elimination of distant disease by sophisticated modern systemic therapies. Interest in postmastectomy radiation therapy (PMRT) stems from the concept that when an isolated locoregional reservoir of tumor cells remains after surgery and systemic therapy, if radiation therapy is able to eliminate this reservoir, PMRT may contribute both to the improvement of local control and also to the reduction of breast cancer-related mortality. In 2005, the Oxford Early Breast Cancer Trialists’ Collaborative Group published a landmark update of their comprehensive meta-analysis, considering data from 8,505 women with lymph node-positive disease treated with mastectomy and axillary clearance and enrolled on randomized trials of PMRT. In this update, which included patients enrolled on trials initiated through 1995, the 5-year local recurrence risk was reduced with radiotherapy from 22.8% to 5.8%, with 15-year breast cancer mortality risks of 54.7% v 60.1% (re-
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. Address reprint requests to Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, UHB2C490, SPC 5010, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5010. E-mail: [email protected]
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1053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2009.05.009
duction 5.4%, 2P ⫽ .0002) and an overall mortality reduction of 4.4% (64.2% v 59.8%, 2P ⫽ .0009).3 Figure 1 shows these findings. Thus, there has now been documented not only substantial improvement in local control but also a clear overall survival (OS) advantage because of the use of PMRT in node-positive patients. These findings provide a strong rationale for the use of radiation therapy in the management of patients with locally advanced breast cancer. In this article, we first review the evidence gathered from the randomized trials of PMRT regarding the relative reduction in risk of locoregional recurrence afforded by radiotherapy and associated effects on survival, including a detailed discussion of the issues of appropriate patient selection that continue to generate debate in the field. We then turn to the particular complexities introduced into the decision-making process when neoadjuvant chemotherapy has been used. Finally, we conclude by presenting a summary of the consensus statements issued by various professional societies and organizations to guide practice in this area.
Evidence From Randomized Trials PMRT has been a subject of considerable study over the past several decades. Multiple randomized trials have consistently revealed a substantial reduction in the risk of locoregional recurrence of breast cancer with the use of PMRT.4-6 However, most early studies failed to show an improvement in OS, and meta-analyses suggested that the benefits of PMRT in cancer control were offset by treatment-related tox-
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Figure 1 Early Breast Cancer Trialists’ Collaboratve Group meta-analysis results regarding effects of PMRT in nodepositive patients. (Reprinted with permission.3)
icity, especially cardiotoxicity.7 Outdated radiation techniques, such as anterior “hockey stick” photon fields, led large volumes of the heart to receive high doses of radiation in many older studies. Therefore, the salutary effect of PMRT upon OS was not convincingly established until large studies utilizing modern techniques of radiotherapy matured. The Eastern Cooperative Oncology Group conducted a trial from 1982 to 1987 focusing exclusively on patients with operable locally advanced disease as defined by 1978 American Joint Committee on Cancer staging treated with both mastectomy and systemic therapy.8 It included patients with pathologic T4 lesions excluding T4d disease, T3 lesions with positive nodes, N2 disease (defined as metastases to ipsilateral lymph nodes fixed to one another or to other structures), or earlier stage lesions fixed to underlying muscle. Patients underwent modified or standard radical mastectomy with grossly tumor-free margins and had examination of at least 8 axillary nodes. Patients went on to receive 6 courses of cyclophosphamide, doxorubicin, fluorouracil, tamoxifen, and fluoxymesterone (CAFTH) systemic therapy and were then randomized to PMRT or observation. By focusing on a group at high risk of locoregional recurrence, all of whom received systemic therapy in the hopes of addressing any distant micrometastatic disease that existed on presentation, and by using relatively modern techniques and doses of radiotherapy, this study attempted to address many of the concerns of critics of the previous trials. Unfortunately, high rates of noncompliance with treatment assignment and insufficient numbers of patients analyzed with relatively short follow-up to allow detection of a modest survival difference ultimately limited the impact of the study.9 The analysis of outcomes in the 312 randomized patients, after a median follow-up of 9 years, revealed a significant and substantial reduction in locoregional recurrence as a component of initial failure in patients who were assigned to radiotherapy PMRT (15% v 24%). However, PMRT had no detectable im-
pact on overall time to relapse or survival in this series of locally advanced breast cancer patients. In contrast, randomized trials from Denmark and British Columbia, initially published in 1997, did finally show a significant survival benefit from PMRT. The British Columbia trial randomized 318 premenopausal patients with pathologically positive lymph nodes, status post modified radical mastectomy with axillary lymph node dissection, to CMF chemotherapy alone or chemotherapy and PMRT to the chest wall and regional lymph nodes.10 In this study, PMRT both reduced locoregional failure (from 28% to 10%) and improved OS (20-year OS improved from 37% to 47%, P ⫽ .03). The Danish 82b trial randomized 1,708 premenopausal women with high-risk breast cancer (defined as involvement of the axillary nodes, tumor size ⬎5 cm, or invasion of the skin or pectoral fascia), status post total mastectomy and axillary dissection, to CMF chemotherapy and PMRT to the chest wall and regional lymph nodes v CMF chemotherapy alone.11 In this study, PMRT also led to both a reduction in locoregional failure (from 32% to 9%) and an improvement in OS (10-year OS improved from 45% to 54%, P ⬍ .001). The Danish 82c trial randomized 1,375 postmenopausal high-risk breast cancer patients younger than 70 years of age, status post total mastectomy and axillary dissection, to radiation therapy plus tamoxifen v tamoxifen alone.12 Again, PMRT reduced locoregional recurrence (from 35% to 8%) and improved OS (10-year OS improved from 36% to 45%, P ⫽ .03). Of note, in each of these 3 trials, PMRT benefited not only patients with 4 or more axillary nodes involved but also those with 1 to 3 nodes positive. Together, these studies have been extremely influential in shifting opinion in favor of PMRT, at least for patients at high risk of locoregional recurrence, such as those presenting with locally advanced disease by current staging. These studies met with certain criticisms, however. These included concerns about the adequacy of the surgery performed. The median number of lymph nodes removed in the
R. Jagsi and L. Pierce
238 Danish study was only 7, lower than that expected from a standard level I/II axillary dissection, prompting the concern that inadequate regional surgery may have led to the underestimation of the true extent of axillary disease in these patients and possibly also contributed to an increased incidence of locoregional failures. Because locoregional recurrence rates after mastectomy (and without PMRT) in retrospective American series of patients with 1 to 3 positive lymph nodes have been lower (13% in large series from Eastern Cooperative Oncology Group13 and the National Surgical Adjuvant Breast and Bowel Project (NSABP)14) than those observed in the Danish and British Columbia studies, some have questioned the role of PMRT for American patients with only 1 to 3 lymph nodes involved. Indeed, consensus panels convened in this country around the turn of the millennium concluded that the evidence to support PMRT was only strong enough to sustain a recommendation for patients with 4 or more lymph nodes involved as well as a suggestion for treatment for patients with T3, node-positive disease.15 For patients with 1 to 3 lymph nodes involved, these panels concluded there was insufficient evidence to make suggestions or recommendations for the routine use of PMRT, and practice in the United
States became divided between radiation oncologists who routinely treat and those who routinely observe this subgroup of patients.16 Unfortunately, the Intergroup’s randomized study designed to assess the role of PMRT in American patients with 1 to 3 positive lymph nodes failed to accrue and closed in 2003. More recently, however, increasing evidence has accumulated in support of a role for PMRT even among patients with 1 to 3 lymph nodes involved. The Danish studies were pooled and reanalyzed to include only the 1152 node-positive patients with 8 or more lymph nodes removed. A survival benefit of the same absolute magnitude (9%) was observed in patients with 1 to 3 lymph nodes involved as among patients with 4 or more lymph nodes involved, even though the locoregional recurrence rates were lower among the former group (Fig. 2).17 This led the authors to note that the survival benefit of PMRT is likely related to the ability of systemic therapy to eliminate any existing metastatic deposits at the time of diagnosis; therefore, PMRT may be particularly important in the subgroup of patients with less extensive nodal involvement in whom the burden of distant disease at diagnosis is likely to be less substantial (and potentially more
Figure 2 Findings from the subset analysis of the Danish postmastectomy trials. (Reprinted with permission.17)
Postmastectomy radiation therapy amenable to elimination by systemic therapies) or absent. Further compelling findings have emerged from the Oxford Early Breast Cancer Trialists’ Collaborative Group’s metaanalysis, as discussed earlier. Although the participants in the Danish and Canadian trials were primarily patients with node-positive disease, patients with large or advanced primaries and node-negative disease were included in the Danish trials and may also benefit from PMRT. Patients with node-negative disease who have large or otherwise locally advanced primary tumors, although uncommon, have traditionally been considered at high risk for locoregional recurrence after mastectomy in the absence of radiation therapy.18,19 Moreover, in the Danish trials, not only the node-positive patients but also patients with node-negative high risk disease (ie, tumor size greater than 5 cm and/or invasion to skin or pectoral fascia) appeared to benefit from radiotherapy. More specifically, among the 135 node-negative patients in the 82b randomized trial, locoregional recurrence was 3% among patients treated with chemotherapy and radiation and 17% in those treated with chemotherapy alone; 10-year disease-free survival was 74% in patients treated with radiation and chemotherapy and 62% in those treated with chemotherapy alone, and 10-year OSs were 82% and 70%, respectively.11 In the 82c randomized trial, among the 132 node-negative patients included, local recurrence as first recurrence occurred in 6% of the patients treated with radiation and tamoxifen and 23% in those treated with tamoxifen alone; 10-year disease-free survival was 43% in patients treated with radiation and tamoxifen and 40% in those treated with tamoxifen alone, and 10-year OS was 56% and 55%, respectively.12 Given these findings, we continue to advocate the routine use of PMRT in women with large or locally advanced primary tumors and node-negative disease. We should note, however, that the use of radiotherapy in patients with small, node-negative T3 lesions warrants discussion. Recent studies have suggested that rates of locoregional recurrence may be lower than expected among patients with node-negative, borderline T3 (stage II) disease. A recent retrospective study of 70 patients treated at 3 institutions by mastectomy and systemic therapy (but no PMRT) for T2-3, N0 disease (with mean tumor size of 6 cm) revealed a 5-year locoregional recurrence rate of only 7.6%.20 Another recent study examined the long-term outcomes of 313 stage II node-negative patients with tumors greater than or equal to 5 cm (with a median tumor size of 5.5 cm) who underwent mastectomy but not PMRT in 5 NSABP trials.21 The investigators found that the overall 10-year cumulative incidence of isolated locoregional failure was 7.1%, and the incidence of locoregional failure with or without distant failure in this population was 10.0%. They were unable to identify any statistically significant prognostic factors for locoregional failure. With such low incidences of locoregional failure over an extended follow-up period, the authors recommended that patients with T2-3 primaries and negative axillae not undergo PMRT. It is important to note, however, that these were small, retrospective series, and the median size of the tumors in these studies was on the smaller end of the spec-
239 trum for T3 tumors so that relatively fewer tumors of extremely large size were included. Patients with T3N0 tumors still warrant consultation with a radiation oncologist who may discuss these data with the patient as well as the prospective data showing benefit after the use of PMRT in patients with large or advanced primary tumors and node-negative disease. Furthermore, in light of evidence from several other retrospective studies of node-negative patients that included patients with smaller primary tumors,22-24 it may be prudent to consider a number of other potential prognostic features, including patient age, tumor size, margin status, presence of lymphovascular invasion, use of systemic therapy, and nuclear grade, when determining whether to use PMRT in patients with node-negative disease without clearly advanced primary tumors for whom the risk of locoregional failure appears to be less substantial. Further prospective studies are ongoing and necessary to quantify the potential benefits of PMRT in this group.25 Ultimately, all patients with locally advanced breast cancer merit consultation with radiation oncology because there is strong consensus regarding the need for treatment in patients with stage III disease. Patients with stage II disease should be counseled regarding their estimated risks of locoregional recurrence in the absence of radiotherapy, the estimated benefit in terms of locoregional control expected from radiotherapy, and the estimated impact on OS associated with this treatment so that they may determine whether they wish to receive treatment.
Patients Treated With Neoadjuvant Chemotherapy Because none of the patients enrolled on the randomized trials of PMRT just discussed were treated with neoadjuvant systemic therapy, appropriate patient selection for PMRT after neoadjuvant therapy is more complicated than when pathologic staging has been unaffected by disease response to systemic agents. In the absence of prospective trials, decisions regarding the role of PMRT in patients treated with neoadjuvant chemotherapy have largely been guided by retrospective analyses. Investigators at the M. D. Anderson Cancer Center have conducted a series of retrospective studies seeking to illuminate these issues. Their data suggest that both the initial clinical stage and final pathologic extent of disease are independently predictive of the risk of locoregional failure in the setting of neoadjuvant chemotherapy and that radiation therapy is effective at reducing this risk. For example, in one analysis, they compared the outcomes of 542 patients treated with neoadjuvant chemotherapy, mastectomy, and PMRT with the outcomes of a control group of 134 patients not treated with PMRT. At 10 years, local-regional recurrence rates were significantly lower for irradiated patients at 11% compared with 22%.26 The small subset of patients who presented with clinical stage III disease who subsequently achieved a complete pathologic response to systemic therapy also had a significantly reduced locoregional recurrence rate
240 compared with patients not treated with PMRT. At 10 years, these patients had a 3% rate of locoregional recurrence (1 event among 35 patients) v 33% (3 events among 11 patients) in nonirradiated patients. Postmastectomy radiation also improved cause-specific survival in patients with stage IIIB disease, clinical T4 tumors, and greater than 4 positive lymph nodes. The authors suggested that PMRT should be considered for patients in all of these subsets, regardless of their response to preoperative systemic chemotherapy. A follow-up retrospective review of the same series of 542 patients was published in 2005 examining the risk factors associated with locoregional recurrence after PMRT.27 The authors remarked on the importance of disease staging both before and after neoadjuvant chemotherapy because several risk factors were associated with either the pretreatment or posttreatment extent of disease. For the patients who were treated with PMRT after neoadjuvant chemotherapy and mastectomy, supraclavicular nodal involvement on presentation was associated with a higher risk of locoregional recurrence after treatment. On postneoadjuvant chemotherapy assessment, evidence of skin or nipple involvement and extracapsular invasion were also strongly correlated with LRR. The lack of tamoxifen use postoperatively was also associated with increased LRR, but, because of the preponderance of patients with ER-negative disease with increased LRR, it was believed to be of little clinical significance. Of note, ER-receptor negative disease was the strongest predictor of LRR in this group. Patients with 1 or none of these factors had a 4% 10-year LRR rate, but this rate jumped to 28% with the presence of 3 or more risk factors. The NSABP trials of neoadjuvant chemotherapy, in which PMRT was not administered, also offer an opportunity to determine which patients face substantial risks of locoregional failure in the absence of PMRT. In the B18 study, among patients undergoing mastectomy, multivariate analysis of risk factors for locoregional recurrence were similar in both the pre- and postoperative chemotherapy arms with respect to age less than 50 years (related to the use of tamoxifen only in women ⱖ50 years of age) and pathologically positive axillary nodes. Breast tumor response was also significantly associated with local control in patients receiving neoadjuvant chemotherapy.28 A pooled analysis of the B18 and B27 trials, conducted by Mamounas,29 reveals an 8-year risk of locoregional recurrence of 15% for 447 patients with residual positive lymph nodes on pathologic evaluation after neoadjuvant chemotherapy (Fig. 3). In 2008, a multidisciplinary expert panel organized by the National Cancer Institute published a statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer.30 That statement concludes that PMRT should be considered for patients presenting with clinical stage III disease or with histologically positive lymph nodes after preoperative chemotherapy. It further concludes that there is a need for prospective trials to evaluate the benefits of PMRT in patients with clinical stage II disease who have negative lymph nodes after preoperative chemotherapy. In any case, given the complexities of assessing risks based on prechemotherapy clinical data and postchemotherapy pa-
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Figure 3 Eight-year cumulative incidence of locoregional failure among patients treated with mastectomy and without radiotherapy on NSABP neoadjuvant chemotherapy studies B18 and B27 (E. Mamounas, unpublished data).
thology in patients treated with neoadjuvant chemotherapy, treatment in a multidisciplinary context with radiation oncology consultation before any treatment commences would be especially prudent in these cases.
Consensus Guidelines The complexities of the data described earlier motivated several professional societies to develop practice guidelines regarding the use of PMRT. The American Society of Clinical Oncology (ASCO) Health Services Research Committee commissioned a multidisciplinary panel of breast cancer experts for an in-depth review of worldwide data on locoregional failure from breast cancer and the ability of PMRT to reduce risk of locoregional as well as distant relapse.31 When evidence-based data were inadequate, the expert panel was charged with using their expert opinion to assess the utility of PMRT. The panel’s systematic, graded review of all published evidence regarding PMRT was assembled into a clinical practice guideline as summarized in Table 1. Of note, the language used to express the guidelines has very specific implications. “Recommendation” refers to guidelines based on level I or level II data. Level I data are derived from meta-analyses of multiple well-designed, controlled studies or from highly powered, randomized trials. Level II data are based on at least 1 well-designed experimental trial and low-powered randomized trials. “Suggestion” refers to guidelines based on data from levels III, IV, or V. Data in these levels are weaker so these guidelines are based in some part on consensus from the ASCO panel. “Insufficient evidence” denotes a lack of either evidence or panel consensus regarding the population in question. The ASCO PMRT practice guideline includes recommendations for the routine use of PMRT in cases of highest-risk breast cancer, as defined by disease with at least 4 metastatic lymph nodes. PMRT was suggested for cases of operable stage III disease. The panel concluded that data regarding net ben-
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Table 1 2001 ASCO Practice Guidelines for the Use of PMRT 1. Patients with 4 or more positive axillary nodes 2. Patients with 1 to 3 positive axillary nodes 3. Patients with T3N1 or Stage III tumors 4. Patients undergoing preoperative systemic therapy 5. 6. 7. 8.
9.
10. 11.
12.
13. 14.
15.
PMRT is recommended for patients with 4 or more positive axillary lymph nodes. There is insufficient evidence to make recommendations regarding patients with T1/T2 tumors and 1 to 3 positive axillary nodes. PMRT is suggested for patients with T3 tumors with positive axillary nodes and patients with operable stage III tumors. There is insufficient evidence to make recommendations whether patients initially treated with preoperative systemic therapy should be given PMRT after surgery. Modification of these guidelines for There is insufficient evidence for modifying the above guidelines based on other special patient subgroups tumor-related, patient-related, or treatment-related factors. Chest wall irradiation In patients given PMRT, the panel suggests that adequately treating the chest wall is mandatory. Details of chest wall irradiation There is insufficient evidence for the panel to recommend aspects of chest wall irradiation, such as total dose, fraction size, bolus use, and scar boosts. Axillary nodal irradiation The panel suggests that full axillary radiotherapy not be given routinely to patients undergoing complete or level I/level II axillary dissection. There is insufficient evidence to suggest whether some patient subgroups may benefit from axillary irradiation. Supraclavicular nodal irradiation for The incidence of clinical supraclavicular failure is sufficiently great in patients patients with 4 or more positive with four or more positive axillary nodes that the panel suggests axillary nodes supraclavicular field radiation in all such patients. Supraclavicular irradiation for patients There is insufficient evidence to state whether supraclavicular radiation should with 1-3 positive axillary nodes or should not be used in patients with one to three positive axillary nodes. Internal mammary nodal irradiation There is insufficient evidence to make recommendations on whether deliberate internal mammary nodal irradiation should or should not be used in any patient subgroup. Sequencing of PMRT and systemic There is insufficient evidence to recommend the optimal sequencing of therapy chemotherapy, tamoxifen, and PMRT. The panel does suggest, given the available evidence regarding toxicities, that doxorubicin not be administered concurrently with PMRT. Integration of PMRT and There is insufficient evidence to make recommendations with regard to the reconstructive surgery integration of PMRT and reconstructive surgery. Long-term toxicities The potential long-term risks of PMRT include lymphedema, brachial plexopathy, radiation pneumonitis, rib fractures, cardiac toxicity, and radiation-induced second neoplasms. There is sufficient evidence for the panel to suggest that, in general, the risk of serious toxicity of PMRT (when performed using modern techniques) is low enough that such considerations should not limit its use when otherwise indicated. However, follow-up in patients treated with current radiotherapy techniques is insufficient to rule out the possibility of very late cardiac toxicity. Toxicity consideration for special There is insufficient evidence to make recommendations that PMRT should not patient subgroups be used for some subgroups of patients because of increased rates of toxicity (such as radiation carcinogenesis) compared with the rest of the population.
efits of PMRT in cases of T1 to 2 tumors and 1 to 3 metastatic nodes were insufficient to make suggestions or recommendations for its routine use. Similarly, the panel assessed the available evidence on using patient factors (such as age or menopausal status) and primary tumor features (such as lymphovascular invasion) and concluded that there was insufficient evidence to make recommendations or suggestions for modifying the guidelines based on these factors. Most of the panel favored the routine use of PMRT in breast cancer cases receiving neoadjuvant chemotherapy because patients with relatively more advanced clinical stages of disease constitute the population most likely to be referred for this treatment sequence. However, the panel acknowledged the paucity of clinical trial data to address this issue and concluded that no
definitive recommendation could be offered for this patient population. Furthermore, neoadjuvant chemotherapy is used increasingly for patients with T2 tumors as a strategy for improving lumpectomy eligibility, and this treatment sequence is no longer restricted to cases of locally advanced disease. Additional evidence from retrospective analyses conducted after the time of the ASCO panel was considered by the National Cancer Institute’s consensus panel on neoadjuvant therapy, as described earlier, and its recommendations should be considered in addition to those of the ASCO panel for this subset of patients. Similar guidelines have been developed by the American Society for Therapeutic Radiology and Oncology,32 the American College of Radiology,33 and the Canadian Commit-
242 tee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.34 Of note, all expert panels recommended the use of PMRT in patients with 4 or more positive axillary nodes. They also all acknowledged the lesser clarity surrounding patients with 1 to 3 positive axillary nodes. Of note, the ASTRO experts stated, “The data regarding patient selection for survival advantage are less clear, but the most recent evidence suggests that the greatest survival benefit is seen in node-positive patients with low tumor burdens (i.e., fewer positive nodes or smaller tumors). Radiation therapy in these patients for survival benefit is worthy of consideration, pending more definitive data . . . . Consultation with a radiation oncologist should occur in node-positive patients treated with mastectomy to help patients assess the risks and benefits of PMRT.” The ACR recommendations echo this statement. Since the time of these reports, additional published analyses have shown benefit from PMRT in patients with 1 to 3 positive nodes. Thus, discussion of the pros and cons of PMRT is warranted in these patients. As clinical studies continue to mature, the oncology community continues to debate the potential value of PMRT for categories of “intermediate-risk” breast cancer in which data were insufficient to warrant definitive recommendations by expert panels. However, there is a strong consensus regarding the role of PMRT in patients with truly locally advanced disease. Indeed, a survey of radiation oncologists found that the vast majority (⬎98%) reported that they would offer radiation to at least the chest wall in patients with 4 or more involved lymph nodes, although there was less consensus in the cases of T3N0 disease (in which 88.3% would offer PMRT to the chest wall) and even less so for cases in which 1 to 3 lymph nodes were involved (with 85.2% offering PMRT to at least the chest wall if extracapsular extension was noted and 61.7% offering it if it were absent).16 Thus, all patients with locally advanced breast cancer merit referral to radiation oncology, and PMRT is considered an integral component of their multimodal management.
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concerning locoregional treatments after preoperative chemotherapy for breast cancer: A National Cancer Institute conference. J Clin Oncol 26:791-797, 2008 Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1539-1569, 2001 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 Taylor ME, Haffty BG, Shank BM, et al: Postmastectomy radiotherapy; American College of Radiology, ACR: Appropriateness criteria. Radiology 215:1153-1170, 2000 (suppl) Truong PT, Olivotto NA, Whelan TJ, et al: Clinical practice guidelines for the care and treatment of breast cancer. 16. Locoregional postmastectomy radiotherapy. CMAJ 170:1263-1273, 2004
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or patients with pathologic stage III breast cancer either historically defined1 or as defined in the current 6th edition of the American Joint Committee on Cancer’s Cancer Staging Manual,2 radiation therapy is an integral component of multimodal treatment. Even after mastectomy and systemic therapy, occult disease may remain in the chest wall and/or regional lymph nodes. This residual disease may serve not only as a source of potentially morbid locoregional recurrence but also as an important reservoir from which distant metastases may be seeded or reseeded after the initial elimination of distant disease by sophisticated modern systemic therapies. Interest in postmastectomy radiation therapy (PMRT) stems from the concept that when an isolated locoregional reservoir of tumor cells remains after surgery and systemic therapy, if radiation therapy is able to eliminate this reservoir, PMRT may contribute both to the improvement of local control and also to the reduction of breast cancer-related mortality. In 2005, the Oxford Early Breast Cancer Trialists’ Collaborative Group published a landmark update of their comprehensive meta-analysis, considering data from 8,505 women with lymph node-positive disease treated with mastectomy and axillary clearance and enrolled on randomized trials of PMRT. In this update, which included patients enrolled on trials initiated through 1995, the 5-year local recurrence risk was reduced with radiotherapy from 22.8% to 5.8%, with 15-year breast cancer mortality risks of 54.7% v 60.1% (re-
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. Address reprint requests to Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, UHB2C490, SPC 5010, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5010. E-mail: [email protected]
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1053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2009.05.009
duction 5.4%, 2P ⫽ .0002) and an overall mortality reduction of 4.4% (64.2% v 59.8%, 2P ⫽ .0009).3 Figure 1 shows these findings. Thus, there has now been documented not only substantial improvement in local control but also a clear overall survival (OS) advantage because of the use of PMRT in node-positive patients. These findings provide a strong rationale for the use of radiation therapy in the management of patients with locally advanced breast cancer. In this article, we first review the evidence gathered from the randomized trials of PMRT regarding the relative reduction in risk of locoregional recurrence afforded by radiotherapy and associated effects on survival, including a detailed discussion of the issues of appropriate patient selection that continue to generate debate in the field. We then turn to the particular complexities introduced into the decision-making process when neoadjuvant chemotherapy has been used. Finally, we conclude by presenting a summary of the consensus statements issued by various professional societies and organizations to guide practice in this area.
Evidence From Randomized Trials PMRT has been a subject of considerable study over the past several decades. Multiple randomized trials have consistently revealed a substantial reduction in the risk of locoregional recurrence of breast cancer with the use of PMRT.4-6 However, most early studies failed to show an improvement in OS, and meta-analyses suggested that the benefits of PMRT in cancer control were offset by treatment-related tox-
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Figure 1 Early Breast Cancer Trialists’ Collaboratve Group meta-analysis results regarding effects of PMRT in nodepositive patients. (Reprinted with permission.3)
icity, especially cardiotoxicity.7 Outdated radiation techniques, such as anterior “hockey stick” photon fields, led large volumes of the heart to receive high doses of radiation in many older studies. Therefore, the salutary effect of PMRT upon OS was not convincingly established until large studies utilizing modern techniques of radiotherapy matured. The Eastern Cooperative Oncology Group conducted a trial from 1982 to 1987 focusing exclusively on patients with operable locally advanced disease as defined by 1978 American Joint Committee on Cancer staging treated with both mastectomy and systemic therapy.8 It included patients with pathologic T4 lesions excluding T4d disease, T3 lesions with positive nodes, N2 disease (defined as metastases to ipsilateral lymph nodes fixed to one another or to other structures), or earlier stage lesions fixed to underlying muscle. Patients underwent modified or standard radical mastectomy with grossly tumor-free margins and had examination of at least 8 axillary nodes. Patients went on to receive 6 courses of cyclophosphamide, doxorubicin, fluorouracil, tamoxifen, and fluoxymesterone (CAFTH) systemic therapy and were then randomized to PMRT or observation. By focusing on a group at high risk of locoregional recurrence, all of whom received systemic therapy in the hopes of addressing any distant micrometastatic disease that existed on presentation, and by using relatively modern techniques and doses of radiotherapy, this study attempted to address many of the concerns of critics of the previous trials. Unfortunately, high rates of noncompliance with treatment assignment and insufficient numbers of patients analyzed with relatively short follow-up to allow detection of a modest survival difference ultimately limited the impact of the study.9 The analysis of outcomes in the 312 randomized patients, after a median follow-up of 9 years, revealed a significant and substantial reduction in locoregional recurrence as a component of initial failure in patients who were assigned to radiotherapy PMRT (15% v 24%). However, PMRT had no detectable im-
pact on overall time to relapse or survival in this series of locally advanced breast cancer patients. In contrast, randomized trials from Denmark and British Columbia, initially published in 1997, did finally show a significant survival benefit from PMRT. The British Columbia trial randomized 318 premenopausal patients with pathologically positive lymph nodes, status post modified radical mastectomy with axillary lymph node dissection, to CMF chemotherapy alone or chemotherapy and PMRT to the chest wall and regional lymph nodes.10 In this study, PMRT both reduced locoregional failure (from 28% to 10%) and improved OS (20-year OS improved from 37% to 47%, P ⫽ .03). The Danish 82b trial randomized 1,708 premenopausal women with high-risk breast cancer (defined as involvement of the axillary nodes, tumor size ⬎5 cm, or invasion of the skin or pectoral fascia), status post total mastectomy and axillary dissection, to CMF chemotherapy and PMRT to the chest wall and regional lymph nodes v CMF chemotherapy alone.11 In this study, PMRT also led to both a reduction in locoregional failure (from 32% to 9%) and an improvement in OS (10-year OS improved from 45% to 54%, P ⬍ .001). The Danish 82c trial randomized 1,375 postmenopausal high-risk breast cancer patients younger than 70 years of age, status post total mastectomy and axillary dissection, to radiation therapy plus tamoxifen v tamoxifen alone.12 Again, PMRT reduced locoregional recurrence (from 35% to 8%) and improved OS (10-year OS improved from 36% to 45%, P ⫽ .03). Of note, in each of these 3 trials, PMRT benefited not only patients with 4 or more axillary nodes involved but also those with 1 to 3 nodes positive. Together, these studies have been extremely influential in shifting opinion in favor of PMRT, at least for patients at high risk of locoregional recurrence, such as those presenting with locally advanced disease by current staging. These studies met with certain criticisms, however. These included concerns about the adequacy of the surgery performed. The median number of lymph nodes removed in the
R. Jagsi and L. Pierce
238 Danish study was only 7, lower than that expected from a standard level I/II axillary dissection, prompting the concern that inadequate regional surgery may have led to the underestimation of the true extent of axillary disease in these patients and possibly also contributed to an increased incidence of locoregional failures. Because locoregional recurrence rates after mastectomy (and without PMRT) in retrospective American series of patients with 1 to 3 positive lymph nodes have been lower (13% in large series from Eastern Cooperative Oncology Group13 and the National Surgical Adjuvant Breast and Bowel Project (NSABP)14) than those observed in the Danish and British Columbia studies, some have questioned the role of PMRT for American patients with only 1 to 3 lymph nodes involved. Indeed, consensus panels convened in this country around the turn of the millennium concluded that the evidence to support PMRT was only strong enough to sustain a recommendation for patients with 4 or more lymph nodes involved as well as a suggestion for treatment for patients with T3, node-positive disease.15 For patients with 1 to 3 lymph nodes involved, these panels concluded there was insufficient evidence to make suggestions or recommendations for the routine use of PMRT, and practice in the United
States became divided between radiation oncologists who routinely treat and those who routinely observe this subgroup of patients.16 Unfortunately, the Intergroup’s randomized study designed to assess the role of PMRT in American patients with 1 to 3 positive lymph nodes failed to accrue and closed in 2003. More recently, however, increasing evidence has accumulated in support of a role for PMRT even among patients with 1 to 3 lymph nodes involved. The Danish studies were pooled and reanalyzed to include only the 1152 node-positive patients with 8 or more lymph nodes removed. A survival benefit of the same absolute magnitude (9%) was observed in patients with 1 to 3 lymph nodes involved as among patients with 4 or more lymph nodes involved, even though the locoregional recurrence rates were lower among the former group (Fig. 2).17 This led the authors to note that the survival benefit of PMRT is likely related to the ability of systemic therapy to eliminate any existing metastatic deposits at the time of diagnosis; therefore, PMRT may be particularly important in the subgroup of patients with less extensive nodal involvement in whom the burden of distant disease at diagnosis is likely to be less substantial (and potentially more
Figure 2 Findings from the subset analysis of the Danish postmastectomy trials. (Reprinted with permission.17)
Postmastectomy radiation therapy amenable to elimination by systemic therapies) or absent. Further compelling findings have emerged from the Oxford Early Breast Cancer Trialists’ Collaborative Group’s metaanalysis, as discussed earlier. Although the participants in the Danish and Canadian trials were primarily patients with node-positive disease, patients with large or advanced primaries and node-negative disease were included in the Danish trials and may also benefit from PMRT. Patients with node-negative disease who have large or otherwise locally advanced primary tumors, although uncommon, have traditionally been considered at high risk for locoregional recurrence after mastectomy in the absence of radiation therapy.18,19 Moreover, in the Danish trials, not only the node-positive patients but also patients with node-negative high risk disease (ie, tumor size greater than 5 cm and/or invasion to skin or pectoral fascia) appeared to benefit from radiotherapy. More specifically, among the 135 node-negative patients in the 82b randomized trial, locoregional recurrence was 3% among patients treated with chemotherapy and radiation and 17% in those treated with chemotherapy alone; 10-year disease-free survival was 74% in patients treated with radiation and chemotherapy and 62% in those treated with chemotherapy alone, and 10-year OSs were 82% and 70%, respectively.11 In the 82c randomized trial, among the 132 node-negative patients included, local recurrence as first recurrence occurred in 6% of the patients treated with radiation and tamoxifen and 23% in those treated with tamoxifen alone; 10-year disease-free survival was 43% in patients treated with radiation and tamoxifen and 40% in those treated with tamoxifen alone, and 10-year OS was 56% and 55%, respectively.12 Given these findings, we continue to advocate the routine use of PMRT in women with large or locally advanced primary tumors and node-negative disease. We should note, however, that the use of radiotherapy in patients with small, node-negative T3 lesions warrants discussion. Recent studies have suggested that rates of locoregional recurrence may be lower than expected among patients with node-negative, borderline T3 (stage II) disease. A recent retrospective study of 70 patients treated at 3 institutions by mastectomy and systemic therapy (but no PMRT) for T2-3, N0 disease (with mean tumor size of 6 cm) revealed a 5-year locoregional recurrence rate of only 7.6%.20 Another recent study examined the long-term outcomes of 313 stage II node-negative patients with tumors greater than or equal to 5 cm (with a median tumor size of 5.5 cm) who underwent mastectomy but not PMRT in 5 NSABP trials.21 The investigators found that the overall 10-year cumulative incidence of isolated locoregional failure was 7.1%, and the incidence of locoregional failure with or without distant failure in this population was 10.0%. They were unable to identify any statistically significant prognostic factors for locoregional failure. With such low incidences of locoregional failure over an extended follow-up period, the authors recommended that patients with T2-3 primaries and negative axillae not undergo PMRT. It is important to note, however, that these were small, retrospective series, and the median size of the tumors in these studies was on the smaller end of the spec-
239 trum for T3 tumors so that relatively fewer tumors of extremely large size were included. Patients with T3N0 tumors still warrant consultation with a radiation oncologist who may discuss these data with the patient as well as the prospective data showing benefit after the use of PMRT in patients with large or advanced primary tumors and node-negative disease. Furthermore, in light of evidence from several other retrospective studies of node-negative patients that included patients with smaller primary tumors,22-24 it may be prudent to consider a number of other potential prognostic features, including patient age, tumor size, margin status, presence of lymphovascular invasion, use of systemic therapy, and nuclear grade, when determining whether to use PMRT in patients with node-negative disease without clearly advanced primary tumors for whom the risk of locoregional failure appears to be less substantial. Further prospective studies are ongoing and necessary to quantify the potential benefits of PMRT in this group.25 Ultimately, all patients with locally advanced breast cancer merit consultation with radiation oncology because there is strong consensus regarding the need for treatment in patients with stage III disease. Patients with stage II disease should be counseled regarding their estimated risks of locoregional recurrence in the absence of radiotherapy, the estimated benefit in terms of locoregional control expected from radiotherapy, and the estimated impact on OS associated with this treatment so that they may determine whether they wish to receive treatment.
Patients Treated With Neoadjuvant Chemotherapy Because none of the patients enrolled on the randomized trials of PMRT just discussed were treated with neoadjuvant systemic therapy, appropriate patient selection for PMRT after neoadjuvant therapy is more complicated than when pathologic staging has been unaffected by disease response to systemic agents. In the absence of prospective trials, decisions regarding the role of PMRT in patients treated with neoadjuvant chemotherapy have largely been guided by retrospective analyses. Investigators at the M. D. Anderson Cancer Center have conducted a series of retrospective studies seeking to illuminate these issues. Their data suggest that both the initial clinical stage and final pathologic extent of disease are independently predictive of the risk of locoregional failure in the setting of neoadjuvant chemotherapy and that radiation therapy is effective at reducing this risk. For example, in one analysis, they compared the outcomes of 542 patients treated with neoadjuvant chemotherapy, mastectomy, and PMRT with the outcomes of a control group of 134 patients not treated with PMRT. At 10 years, local-regional recurrence rates were significantly lower for irradiated patients at 11% compared with 22%.26 The small subset of patients who presented with clinical stage III disease who subsequently achieved a complete pathologic response to systemic therapy also had a significantly reduced locoregional recurrence rate
240 compared with patients not treated with PMRT. At 10 years, these patients had a 3% rate of locoregional recurrence (1 event among 35 patients) v 33% (3 events among 11 patients) in nonirradiated patients. Postmastectomy radiation also improved cause-specific survival in patients with stage IIIB disease, clinical T4 tumors, and greater than 4 positive lymph nodes. The authors suggested that PMRT should be considered for patients in all of these subsets, regardless of their response to preoperative systemic chemotherapy. A follow-up retrospective review of the same series of 542 patients was published in 2005 examining the risk factors associated with locoregional recurrence after PMRT.27 The authors remarked on the importance of disease staging both before and after neoadjuvant chemotherapy because several risk factors were associated with either the pretreatment or posttreatment extent of disease. For the patients who were treated with PMRT after neoadjuvant chemotherapy and mastectomy, supraclavicular nodal involvement on presentation was associated with a higher risk of locoregional recurrence after treatment. On postneoadjuvant chemotherapy assessment, evidence of skin or nipple involvement and extracapsular invasion were also strongly correlated with LRR. The lack of tamoxifen use postoperatively was also associated with increased LRR, but, because of the preponderance of patients with ER-negative disease with increased LRR, it was believed to be of little clinical significance. Of note, ER-receptor negative disease was the strongest predictor of LRR in this group. Patients with 1 or none of these factors had a 4% 10-year LRR rate, but this rate jumped to 28% with the presence of 3 or more risk factors. The NSABP trials of neoadjuvant chemotherapy, in which PMRT was not administered, also offer an opportunity to determine which patients face substantial risks of locoregional failure in the absence of PMRT. In the B18 study, among patients undergoing mastectomy, multivariate analysis of risk factors for locoregional recurrence were similar in both the pre- and postoperative chemotherapy arms with respect to age less than 50 years (related to the use of tamoxifen only in women ⱖ50 years of age) and pathologically positive axillary nodes. Breast tumor response was also significantly associated with local control in patients receiving neoadjuvant chemotherapy.28 A pooled analysis of the B18 and B27 trials, conducted by Mamounas,29 reveals an 8-year risk of locoregional recurrence of 15% for 447 patients with residual positive lymph nodes on pathologic evaluation after neoadjuvant chemotherapy (Fig. 3). In 2008, a multidisciplinary expert panel organized by the National Cancer Institute published a statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer.30 That statement concludes that PMRT should be considered for patients presenting with clinical stage III disease or with histologically positive lymph nodes after preoperative chemotherapy. It further concludes that there is a need for prospective trials to evaluate the benefits of PMRT in patients with clinical stage II disease who have negative lymph nodes after preoperative chemotherapy. In any case, given the complexities of assessing risks based on prechemotherapy clinical data and postchemotherapy pa-
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Figure 3 Eight-year cumulative incidence of locoregional failure among patients treated with mastectomy and without radiotherapy on NSABP neoadjuvant chemotherapy studies B18 and B27 (E. Mamounas, unpublished data).
thology in patients treated with neoadjuvant chemotherapy, treatment in a multidisciplinary context with radiation oncology consultation before any treatment commences would be especially prudent in these cases.
Consensus Guidelines The complexities of the data described earlier motivated several professional societies to develop practice guidelines regarding the use of PMRT. The American Society of Clinical Oncology (ASCO) Health Services Research Committee commissioned a multidisciplinary panel of breast cancer experts for an in-depth review of worldwide data on locoregional failure from breast cancer and the ability of PMRT to reduce risk of locoregional as well as distant relapse.31 When evidence-based data were inadequate, the expert panel was charged with using their expert opinion to assess the utility of PMRT. The panel’s systematic, graded review of all published evidence regarding PMRT was assembled into a clinical practice guideline as summarized in Table 1. Of note, the language used to express the guidelines has very specific implications. “Recommendation” refers to guidelines based on level I or level II data. Level I data are derived from meta-analyses of multiple well-designed, controlled studies or from highly powered, randomized trials. Level II data are based on at least 1 well-designed experimental trial and low-powered randomized trials. “Suggestion” refers to guidelines based on data from levels III, IV, or V. Data in these levels are weaker so these guidelines are based in some part on consensus from the ASCO panel. “Insufficient evidence” denotes a lack of either evidence or panel consensus regarding the population in question. The ASCO PMRT practice guideline includes recommendations for the routine use of PMRT in cases of highest-risk breast cancer, as defined by disease with at least 4 metastatic lymph nodes. PMRT was suggested for cases of operable stage III disease. The panel concluded that data regarding net ben-
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Table 1 2001 ASCO Practice Guidelines for the Use of PMRT 1. Patients with 4 or more positive axillary nodes 2. Patients with 1 to 3 positive axillary nodes 3. Patients with T3N1 or Stage III tumors 4. Patients undergoing preoperative systemic therapy 5. 6. 7. 8.
9.
10. 11.
12.
13. 14.
15.
PMRT is recommended for patients with 4 or more positive axillary lymph nodes. There is insufficient evidence to make recommendations regarding patients with T1/T2 tumors and 1 to 3 positive axillary nodes. PMRT is suggested for patients with T3 tumors with positive axillary nodes and patients with operable stage III tumors. There is insufficient evidence to make recommendations whether patients initially treated with preoperative systemic therapy should be given PMRT after surgery. Modification of these guidelines for There is insufficient evidence for modifying the above guidelines based on other special patient subgroups tumor-related, patient-related, or treatment-related factors. Chest wall irradiation In patients given PMRT, the panel suggests that adequately treating the chest wall is mandatory. Details of chest wall irradiation There is insufficient evidence for the panel to recommend aspects of chest wall irradiation, such as total dose, fraction size, bolus use, and scar boosts. Axillary nodal irradiation The panel suggests that full axillary radiotherapy not be given routinely to patients undergoing complete or level I/level II axillary dissection. There is insufficient evidence to suggest whether some patient subgroups may benefit from axillary irradiation. Supraclavicular nodal irradiation for The incidence of clinical supraclavicular failure is sufficiently great in patients patients with 4 or more positive with four or more positive axillary nodes that the panel suggests axillary nodes supraclavicular field radiation in all such patients. Supraclavicular irradiation for patients There is insufficient evidence to state whether supraclavicular radiation should with 1-3 positive axillary nodes or should not be used in patients with one to three positive axillary nodes. Internal mammary nodal irradiation There is insufficient evidence to make recommendations on whether deliberate internal mammary nodal irradiation should or should not be used in any patient subgroup. Sequencing of PMRT and systemic There is insufficient evidence to recommend the optimal sequencing of therapy chemotherapy, tamoxifen, and PMRT. The panel does suggest, given the available evidence regarding toxicities, that doxorubicin not be administered concurrently with PMRT. Integration of PMRT and There is insufficient evidence to make recommendations with regard to the reconstructive surgery integration of PMRT and reconstructive surgery. Long-term toxicities The potential long-term risks of PMRT include lymphedema, brachial plexopathy, radiation pneumonitis, rib fractures, cardiac toxicity, and radiation-induced second neoplasms. There is sufficient evidence for the panel to suggest that, in general, the risk of serious toxicity of PMRT (when performed using modern techniques) is low enough that such considerations should not limit its use when otherwise indicated. However, follow-up in patients treated with current radiotherapy techniques is insufficient to rule out the possibility of very late cardiac toxicity. Toxicity consideration for special There is insufficient evidence to make recommendations that PMRT should not patient subgroups be used for some subgroups of patients because of increased rates of toxicity (such as radiation carcinogenesis) compared with the rest of the population.
efits of PMRT in cases of T1 to 2 tumors and 1 to 3 metastatic nodes were insufficient to make suggestions or recommendations for its routine use. Similarly, the panel assessed the available evidence on using patient factors (such as age or menopausal status) and primary tumor features (such as lymphovascular invasion) and concluded that there was insufficient evidence to make recommendations or suggestions for modifying the guidelines based on these factors. Most of the panel favored the routine use of PMRT in breast cancer cases receiving neoadjuvant chemotherapy because patients with relatively more advanced clinical stages of disease constitute the population most likely to be referred for this treatment sequence. However, the panel acknowledged the paucity of clinical trial data to address this issue and concluded that no
definitive recommendation could be offered for this patient population. Furthermore, neoadjuvant chemotherapy is used increasingly for patients with T2 tumors as a strategy for improving lumpectomy eligibility, and this treatment sequence is no longer restricted to cases of locally advanced disease. Additional evidence from retrospective analyses conducted after the time of the ASCO panel was considered by the National Cancer Institute’s consensus panel on neoadjuvant therapy, as described earlier, and its recommendations should be considered in addition to those of the ASCO panel for this subset of patients. Similar guidelines have been developed by the American Society for Therapeutic Radiology and Oncology,32 the American College of Radiology,33 and the Canadian Commit-
242 tee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.34 Of note, all expert panels recommended the use of PMRT in patients with 4 or more positive axillary nodes. They also all acknowledged the lesser clarity surrounding patients with 1 to 3 positive axillary nodes. Of note, the ASTRO experts stated, “The data regarding patient selection for survival advantage are less clear, but the most recent evidence suggests that the greatest survival benefit is seen in node-positive patients with low tumor burdens (i.e., fewer positive nodes or smaller tumors). Radiation therapy in these patients for survival benefit is worthy of consideration, pending more definitive data . . . . Consultation with a radiation oncologist should occur in node-positive patients treated with mastectomy to help patients assess the risks and benefits of PMRT.” The ACR recommendations echo this statement. Since the time of these reports, additional published analyses have shown benefit from PMRT in patients with 1 to 3 positive nodes. Thus, discussion of the pros and cons of PMRT is warranted in these patients. As clinical studies continue to mature, the oncology community continues to debate the potential value of PMRT for categories of “intermediate-risk” breast cancer in which data were insufficient to warrant definitive recommendations by expert panels. However, there is a strong consensus regarding the role of PMRT in patients with truly locally advanced disease. Indeed, a survey of radiation oncologists found that the vast majority (⬎98%) reported that they would offer radiation to at least the chest wall in patients with 4 or more involved lymph nodes, although there was less consensus in the cases of T3N0 disease (in which 88.3% would offer PMRT to the chest wall) and even less so for cases in which 1 to 3 lymph nodes were involved (with 85.2% offering PMRT to at least the chest wall if extracapsular extension was noted and 61.7% offering it if it were absent).16 Thus, all patients with locally advanced breast cancer merit referral to radiation oncology, and PMRT is considered an integral component of their multimodal management.
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