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The Role of Radiation Therapy in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy
The Role of Radiation Therapy in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy Thomas A. Buchholz, MD,* and Lawrence J. Solin, MD† Radiation therapy is an important component of multi-modality therapy for most patients with nonmetastatic breast cancer. However, most data concerning the efficacy of radiation therapy and the indications for its use have been obtained in patients who received surgical treatment as their initial therapy. The increasing use of neoadjuvant chemotherapy has sparked many new questions, largely because this treatment sequence affects the surgical pathology findings, and because these pathological findings are one of the most important factors that guide radiation treatment decisions. However, data are now emerging that are answering some of these questions. For example, a number of studies have now shown that breast conservation surgery plus radiation therapy can make breast preservation possible in carefully selected patients with advanced disease who respond favorably to neoadjuvant chemotherapy. In addition, although no randomized trials have been conducted that assess the benefits of radiation therapy in patients also treated with neoadjuvant chemotherapy and mastectomy, data from single-institution studies do suggest that postmastectomy radiation therapy reduces the probability of local-regional recurrence and may improve survival in patients with locally advanced disease. Furthermore, data suggest that indications for postmastectomy radiation therapy should be based both on the initial clinical extent of disease and the residual extent of pathological disease, rather than just considering either factor alone. Semin Breast Dis 7:129 –134 © 2004 Elsevier Inc. All rights reserved.
T
he percentage of breast cancer patients that are treated with chemotherapy before definitive surgery is increasing. Treatment with neoadjuvant chemotherapy was initially investigated in patients with advanced inoperable, local-regional disease and patients with inflammatory breast cancer. After high response rates were noted in the patients in these early studies, this approach began to be used in patients with operable breast cancer. There are a number of potential benefits for sequencing chemotherapy before surgery, including offering the possibility of breast conservation therapy for selected patients with T3 or T4 primary tumors. This benefit and others have come with the tradeoff of raising a number of questions among radiation oncologists with regard to defining the proper selection criteria for breast conservation, determining the indications for regional lymphatic irradiation,
*Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. †Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA. Address reprint requests and correspondence to: Thomas A. Buchholz, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: [email protected]
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.02.002
and defining the appropriate indications for postmastectomy radiation therapy. To date, few data are available from studies that have investigated the role of and indications for radiation therapy in patients treated with neoadjuvant chemotherapy. Correspondingly, there remain many areas of controversy concerning the radiotherapeutic management of such patients. This article will provide answers to some of these questions and explore some of the controversies in hopes of providing a rational framework in which to make clinical decisions.
Radiation Therapy as a Component of Breast Conservation after Neoadjuvant Chemotherapy The clearest proven clinical benefit of neoadjuvant chemotherapy is that it can make breast conservation possible in select patients with advanced disease. Results from two randomized trials comparing neoadjuvant chemotherapy with adjuvant chemotherapy in patients with Stage II and Stage III breast cancer indicated that breast conservation rates were 129
T.A. Buchholz and L.J. Solin
130
Figure 1 Various pathological responses that occur after neoadjuvant chemotherapy. As shown, in some instances, malignant cells become clustered around a residual nidus, whereas in other cases, residual tumor cells become scattered over the residual volume of disease. A breast-conserving surgical procedure that is directed at removing a central nidus might therefore leave different volumes of residual disease. (From Buchholz TA, Hunt KK, Whitman GJ, et al: Neoadjuvant chemotherapy for breast cancer: a multidisciplinary discussion of benefits and risks. Cancer 98:11501160, 2003. Copyright © 2003 American Cancer Society. Reproduced with permission of John Wiley & Sons, Inc.)
increased when chemotherapy was given before surgery.1,2 This increase in breast conservation rates resulted because approximately 80% of the patients in these studies had a favorable response to neoadjuvant chemotherapy. After responding, a breast-conserving surgical approach could then be directed at removing the postchemotherapy residual nidus of disease, allowing for an esthetically acceptable outcome. While this approach is attractive in that it avoids mastectomy, concerns have been raised over whether the risk of local recurrence will be greater in these patients. This is because most advanced breast cancers are infiltrative and some tumors do not shrink concentrically to a solitary nidus in response to neoadjuvant chemotherapy. Fig. 1 shows the various ways in which a cancer can respond to neoadjuvant chemotherapy.3 As shown in this figure, sometimes a microscopic residuum of disease spread out over the initial volume of the primary tumor can be left. Thus, surgery directed at the primary core may leave a high burden of microscopic disease around the tumor bed site, which may lead to breast cancer recurrence. This theoretical concern has been reinforced by some clinical data showing higher rates of breast cancer recurrence in patients with advanced tumors who have been treated with breast conservation after neoadjuvant chemotherapy. For example, in the National Surgical Adjuvant Breast and Bowel Project B-18 trial, four cycles of neoadjuvant chemotherapy were compared with four cycles of adjuvant chemotherapy.
The overall 9-year rate of recurrence of ipsilateral breast cancer was slightly higher in the patients treated with neoadjuvant chemotherapy (10.7% versus 7.6%, respectively, P ⫽ 0.12).1 Furthermore, the rate of recurrence of breast cancer in the group treated with neoadjuvant chemotherapy was higher in those who were mastectomy candidates at diagnosis than in those who were breast conservation candidates at diagnosis (15.7% versus 9.9%, respectively, P ⫽ 0.04). One can interpret these data as showing that the recurrence rate in patients with large primary tumors in whom a response to neoadjuvant chemotherapy allowed a breast conservation surgery was twice that in patients with smaller tumors treated with surgery first (15.7% versus 7.6%, respectively). A number of other series have also shown relatively high breast cancer recurrence rates in patients who receive neoadjuvant chemotherapy. Table 1 gives data from a number of these series and also from series in which the breast cancer recurrence rates were relatively low.1,4-10 One difficulty in interpreting these data, however, is that the selection criteria for breast conservation after chemotherapy and the local treatment strategies varied across studies. In the aggregate, however, the data do allow some general conclusions to be drawn: ● ●
breast conservation procedures are more complex in patients who have surgery first multidisciplinary coordination is likely important
Radiation after neoadjuvant chemotherapy for breast cancer
131
Table 1 Rates of Local or Local–Regional Recurrence in Patients Treated with Neoadjuvant Chemotherapy and Breast Conservation First Author (ref.)
No. of Patients
Local Recurrence
Comments
Wolmark (1) Mauriac (4)
503 84
11% @ 9 yrs 29% @ 10 yrs
Rouizer (5)
257
21% @ 10 yrs
Ring (6)
69
21% @ 5 yrs
Merajver (7)
25
18% @ 5 yrs
71 456 340
11% @ 5 yrs 7% @ 8 yrs 5% @ 5 yrs
B-18 trial, Stage II or III disease French multi-institution trial, 52% treated with radiation without surgery French multi-institution trial, 28% with close/positive margins All with CR to chemotherapy and with no surgery performed All with CR to chemotherapy with no surgery performed All patients had surgery All patients had surgery All patients had surgery, only 4% had positive margins
Vines (8) Bonadonna (9) Chen (10) Note. CR, complete response.
● ●
proper patient selection for breast conservation is critical radiation therapy as a sole modality is likely less effective than the combination of breast-conserving surgery and radiation therapy
Investigators at The University of Texas M.D. Anderson Cancer Center recently published the results of one of the largest studies investigating breast conservation after neoadjuvant chemotherapy.10 In this study, the outcome in 340 patients who were carefully selected by a multidisciplinary team to undergo breast conservation after showing a favorable response to chemotherapy was analyzed. Patient selection criteria for a breast-conserving approach included: ● ● ● ● ●
no postoperative residual malignant calcifications no residual T4 breast skin abnormalities negative surgical margins no multicentric disease ability to undergo a course of radiation therapy
Although 72% of patients in this study had clinical Stage IIB or III disease, the 5- and 10-year breast recurrence rates were only 5% and 10%, respectively. This favorable outcome is likely attributable to the selection criteria used and the close multidisciplinary coordination of care. These authors also identified factors associated with breast recurrence and local-regional recurrence (LRR) in an effort to further refine the selection criteria. The factors they identified included clinical N2 or N3 disease, lymphovascular space invasion in the primary tumor biopsy specimen, a multifocal pattern of residual disease, and residual disease greater than 2 cm in diameter. The clinical T-stage, however, did not correlate with breast recurrence, indicating that when careful selection criteria are used, patients with advanced primary tumors can be successfully treated with breast conservation. Interestingly, the 5-year breast cancer recurrence rate was only 3% in patients with T3/T4 tumors that formed a solitary nidus in response to neoadjuvant chemotherapy. However, the breast cancer recurrence rate was 20% in patients with T3/T4 tu-
mors that broke up and left a multifocal pattern of residual disease in response to neoadjuvant chemotherapy.10 When breast conservation is being considered in patients with Stage III breast cancer, it is important to also recognize that treatment with mastectomy does not preclude LRR. Indeed, many of the factors that correlate with LRR in patients treated with breast conservation are the same as those that correlate with LRR in patients treated with mastectomy followed by radiation therapy. Furthermore, patients with advanced disease are at a significant competing risk of distant metastases, which is an additional incentive to avoiding removing the breast.
Radiation Treatment Fields The radiation treatment fields and dosages of radiation used in patients treated with breast conservation surgery after neoadjuvant chemotherapy do not differ significantly from those used in patients who undergo surgery before chemotherapy. These recommended radiation treatment fields and dosages are extrapolated from the setting of standard breast conservation treatment (ie, using breast conserving surgery first, without neoadjuvant chemotherapy). Typically, 45 to 50 Gy is delivered to the breast over 5 weeks and then the tumor bed is given a supplemental dose of 10 to 16 Gy. However, neoadjuvant chemotherapy use has led to new questions concerning when to add fields to treat lymphatic regions, and the use of nodal radiation for some patients treated with neoadjuvant chemotherapy remains a major area of controversy. In patients treated with surgery first, there is a consensus that the supraclavicular fossa and axillary apex should be included in the field when four or more axillary lymph nodes contain disease, when there is lymph node involvement with gross extracapsular extension, or there is extensive lymphovascular space invasion. In patients treated with surgery first who have zero to three positive lymph nodes without extracapsular extension, many radiation oncologists treat the breast only because the risk of disease in the supraclavicular
T.A. Buchholz and L.J. Solin
132 fossa is low enough to not justify the associated morbidity of this treatment. Radiation to the supraclavicular fossa may be considered for selected patients with one to three positive axillary lymph nodes, and radiation to the full axilla may be considered for selected patients with four or more positive axillary lymph nodes. Finally, the use of internal mammary nodal (IMN) radiation also remains controversial. It is unclear whether to add regional nodal irradiation in patients with clinical Stage I or II disease who have 0 to 3 positive axillary lymph nodes after neoadjuvant chemotherapy. Some of these patients likely had 4 or more positive lymph nodes at the time chemotherapy was started, and nodal irradiation would have been recommended had they been treated with surgery first. There are currently insufficient data regarding the failure patterns in patients with Stage II disease with 1 to 3 positive lymph nodes after chemotherapy to answer this question. In one of the only studies that has investigated this issue, Garg and coworkers11 recently reported that, of 42 patients with clinical stage II breast cancer who had 1 to 3 positive lymphs nodes after chemotherapy, the local–regional treatment of these patients was mastectomy without radiation. Disease recurred in the supraclavicular fossa/axillary apex in only 1 of these 42 patients, and this patient had a simultaneous chest wall recurrence. The median follow-up for this report was only 46 months. For patients with locally advanced breast cancer, most radiation oncologists currently advocate irradiating both the breast and the axillary apex/supraclavicular fossa, even if the response to neoadjuvant chemotherapy permits a breast conservation surgery.
Indications for Radiation Therapy after Neoadjuvant Chemotherapy Followed by Mastectomy Perhaps the most important question concerning radiation treatment that has been raised as a result of the move toward using neoadjuvant chemotherapy concerns the indications for postmastectomy radiation therapy. In patients treated with mastectomy first, the decision to administer radiation
therapy is made on the basis of the pathological extent of disease. Consensus statements issued by the American Society of Therapeutic Radiology Oncology and the American Society of Clinical Oncology have both recommended postmastectomy radiation therapy for patients with four or more positive lymph nodes.12,13 However, both of these consensus statements have indicated that there are insufficient data to guide treatment recommendations in such patients who are treated with neoadjuvant chemotherapy. Data accumulated over the past 50 years indicate that postmastectomy radiation therapy reduces the risk of LRR by approximately two-thirds.14 In addition, recent prospective trials have shown that postmastectomy radiation therapy improved overall survival in various patient subgroups in which the 10-year LRR rate without radiation therapy was approximately 25% to 30%.15-17 In these trials, the LRR with the addition of postmastectomy radiation was less than 10%. A number of recent studies have attempted to define which patient subgroups have a clinically relevant risk of LRR after mastectomy and adjuvant chemotherapy, which would thus make them candidates for radiation.18-21 These studies have predominantly used the pathological extent of disease as the basis for this risk stratification and have shown that patients with American Joint Commission of Cancer 2003 Stage III disease (which includes T3N1 disease and disease with 4 or more positive lymph nodes) have a 20% to 30% risk of LRR if they do not receive radiation therapy. These studies have also shown that the risk of LRR is much lower (⬍15%) in patients with Stage II breast cancer with one to three positive lymph nodes.18-21 Accordingly, the use of postmastectomy radiation therapy in women with Stage II breast cancer with one to three positive lymph nodes remains an area of controversy. One important consideration is that neoadjuvant chemotherapy changes the extent of pathological disease in 80% to 90% of cases, so how pathological information should guide decisions regarding radiation therapy is less clear. Adding to this problem is the fact that there are significantly fewer data regarding how clinical and pathological features of disease correlate with LRR after mastectomy in patients treated with neoadjuvant chemotherapy compared with those treated with adjuvant chemotherapy. One study that examined this issue investigated LRR in 150 patients treated with neoadju-
Table 2 LRR Rates and CSS Rates for Patients with Advanced Breast Cancer Treated with Neoadjuvant Chemotherapy According to the Use of Postmastectomy Radiation Therapy (Data from Huang et al. 24) Extent of Disease Clinical Stage T4 primary tumor Clinical Stage IIIB/C >4 ⴙ LN after neoadjuvant chemotherapy
Postmastectomy Radiation Therapy
10-yr LRR rate
P value
10-yr CSS rate
P value
No Yes No Yes No Yes
46% 16% 51% 16% 59% 17%
P < 0.0001
22% 44% 22% 44% 18% 39%
P ⴝ 0.015
CSS, cause-specific survival; LRR, local–regional recurrence; LN, lymph node.
P < 0.0001 P < 0.0001
P ⴝ 0.002 P ⴝ 0.011
Radiation after neoadjuvant chemotherapy for breast cancer vant chemotherapy and modified radical mastectomy but not radiation therapy. The important finding from this study was that both the initial clinical stage and the final pathological extent of disease independently affected the LRR risk.22 In particular, the study showed that patients with primary tumors that exceeded 5 cm in diameter, T4 primary disease, or extensive adenopathy at the time of diagnosis were at high risk of LRR even if they had had an excellent response to treatment. In addition, the LRR rate remained relatively high (19%, 95% CI: 6%– 48%) in a subset of patients who achieved a pathological complete remission.22 A high LRR rate (46%) was also noted in a group of patients who initially had clinically T3 or T4 primary tumors but had tumors less than 5 cm in diameter and only one to three positive lymph nodes after chemotherapy.22 These authors then compared the risk of LRR according to the pathological extent of disease between patients treated with neoadjuvant chemotherapy and mastectomy and patients treated with mastectomy and adjuvant chemotherapy.23 Not surprisingly, for any given pathological extent of disease, the LRR risk was higher in patients treated with neoadjuvant chemotherapy, in whom the pathological extent of disease represented residual disease after chemotherapy, compared with patients treated with surgery first, in whom the pathological extent of disease represented the initial volume of disease before any systemic treatment.23 The interesting finding of this article was that the difference in the LRR risk in these groups was much greater in terms of any given pathological primary tumor size than in terms of any class of number of positive lymph nodes. This finding likely reflects the fact that neoadjuvant chemotherapy changes the primary tumor size in the vast majority of cases but much less frequently changes the number of positive lymph nodes. Recently, data have become available regarding the efficacy of radiation therapy in patients treated with mastectomy after neoadjuvant chemotherapy. This study compared the outcome of 579 patients who received neoadjuvant chemotherapy, mastectomy, and radiation therapy with that of 136 patients who were treated with neoadjuvant chemotherapy and mastectomy alone.24 Although the patients in this study were treated on single institutional prospective trials, radiation therapy was not a randomized variable in these trials. Thus, there were significant imbalances in the prognostic factors between the two groups, with those receiving radiation therapy having worse disease features. Despite these imbalances, the LRR rate was significantly lower in the patients treated with postmastectomy radiation therapy than in those treated with neoadjuvant chemotherapy and mastectomy alone (10-year LRR rates were 8% and 22%, respectively, P ⫽ 0.001). More importantly, treatment with radiation therapy was associated with better overall and cause-specific survival rates in selected groups of patients with high-risk disease (Table 2). In addition, a multivariate analysis for the endpoint of cause-specific survival showed that treatment with radiation therapy was independently associated with a better outcome, with the hazard ratio in patients who do not receive radiation therapy being 2.03 (95% CI, 1.41-2.92, P ⬍ 0.0001).
133 On the basis of these data, it is currently reasonable to recommend postmastectomy radiation therapy for all patients with clinical T3 or T4 tumors or clinical Stage III disease, regardless of their response to the chemotherapy regimen. In terms of clinical Stage I or II breast cancer, postmastectomy radiation therapy should be recommended for patients with four or more positive lymph nodes after chemotherapy and the unusual patient in whom the disease progresses and the primary tumor exceeds 5 cm in diameter. It is clear, however, that additional studies are needed that quantify the LRR risk in patients who present with T1 or T2 disease and have one to three positive lymph nodes after neoadjuvant chemotherapy. The radiation fields and the radiation dose used in patients who have undergone only mastectomy are similar to those used in patients treated with mastectomy followed by adjuvant chemotherapy. In general, the treatment volume should include the chest wall, undissected axilla, and supraclavicular fossa. Whether to also include components of the dissected axilla and/or the internal mammary lymph nodes is controversial, as the chest wall is the most common site of LRR after neoadjuvant chemotherapy and mastectomy. Indeed, in a series of such patients in which LRR patterns were examined, the chest wall was a component of the LRR in 79%, the supraclavicular lymph nodes were a component in 32%, the axilla was a component in 20%, the infraclavicular region was a component in 9%, and the internal mammary lymph nodes were a component in 3%.22 This study did not assess recurrences in sites less accessible to clinical examination, such as the internal mammary artery region, so some of these percentages may be underestimations.
Conclusions While neoadjuvant chemotherapy has a number of clinical benefits, its adoption into clinical practice has also raised questions within all disciplines that treat cancer, including radiation oncology. One particular benefit of neoadjuvant chemotherapy is that it can make breast conservation surgery an option in select patients with advanced primary tumors, but the success of this strategy depends on the use of careful selection criteria and the close coordination of multidisciplinary care. Radiation therapy also plays an important role in patients with locally advanced disease who are treated with neoadjuvant chemotherapy and mastectomy. Nonetheless, some questions remain unanswered with regard to radiation field design and indications for postmastectomy radiation therapy in patients with early-stage disease who receive neoadjuvant chemotherapy. It is hoped that as more experience with this approach is gained, additional data will become available to help guide rationale treatment decisions.
References 1. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 30:96-102, 2001 2. van der Hage JA, Cornelis JH, van de Velde CJ, et al: Preoperative
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134
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19:4224-4237, 2001 Buchholz TA, Hunt KK, Whitman GJ, et al: Neoadjuvant chemotherapy for breast cancer: a multidisciplinary discussion of benefits and risks. Cancer 98:1150-1160, 2003 Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for operable breast cancer larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Ann Oncol 10:47-52, 1999 Rouzier R, Extra JM, Carton M, et al: Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol 19:3795-3804, 2001 Ring A, Webb A, Ashley S, et al: Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol 21:4540-4555, 2003 Merajver SD, Weber BL, Cody R, et al: Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience. J Clin Oncol 15:2873-2881, 1997 Vines EF, Hepp R, Campos M, et al: Analysis of local failure after breast conserving therapy (BCT) for locally advanced breast cancer (LABC). Int J Radiat Oncol Biol Phys 57:S238-S239, 2003 (suppl 2) Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93-100, 1998 Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast-conserving therapy after neoadjuvant chemotherapy: The M.D. Anderson Cancer Center experience J Clin Oncol 22:2303-2312, 2004 Garg AK, Strom EA, McNeese MD, et al: T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for localregional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiation. Int J Radiat Oncol Biol Phys 59:138-145, 2004 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 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 Early Breast Cancer Trialists’ Collaborative Group: Favourable and un-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
favourable effects on long-term survival for radiotherapy for early breast cancer: an overview of the randomized trials. Lancet 355:1757-1770, 2000 Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997 Overgaard M, Hansen S, Rose P, et al: Randomized trial evaluating postoperative radiotherapy in high risk postmenopausal breast cancer patients given adjuvant tamoxifen: results from the DBCG 82c trial. Radiother Oncol 48:S78, 1998 Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node- positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997 Recht A, Gray R, Davidson NE, et al: Locoregional failure ten years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689-1700, 1999 Katz A, Strom EA, Buchholz TA, et al: Locoregional recurrence patterns following mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation. J Clin Oncol 18:2817-2827, 2000 Wallgren A, Bonetti M, Gelber RD, et al: Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group trials I through VII. J Clin Oncol 21:12051213, 2003 Taghian AG, Jeong JH, Anderson S, et al: Pattern of loco-regional and distant failure in patients with breast cancer treated with mastectomy and chemotherapy (⫹/⫺ tamoxifen) without radiation: results from five NSABP randomized trials. Int J Rad Oncol Biol Phys 51:106-107, 2002 (suppl 1) Buchholz TA, Tucker SL, Masullo L, et al: Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol 20:17-23, 2002 Buchholz TA, Katz A, Strom EA, et al: Pathological factors that predict for local-regional recurrences after mastectomy are different for breast cancer patients treated with neoadjuvant versus adjuvant chemotherapy. Int J Radiat Oncol Biol Phys 53:880-888, 2001 Huang EH, Tucker SL, Strom EA, et al: Radiation treatment improves local-regional control and cause-specific survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol 22:4691– 4699, 2004
T
he percentage of breast cancer patients that are treated with chemotherapy before definitive surgery is increasing. Treatment with neoadjuvant chemotherapy was initially investigated in patients with advanced inoperable, local-regional disease and patients with inflammatory breast cancer. After high response rates were noted in the patients in these early studies, this approach began to be used in patients with operable breast cancer. There are a number of potential benefits for sequencing chemotherapy before surgery, including offering the possibility of breast conservation therapy for selected patients with T3 or T4 primary tumors. This benefit and others have come with the tradeoff of raising a number of questions among radiation oncologists with regard to defining the proper selection criteria for breast conservation, determining the indications for regional lymphatic irradiation,
*Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. †Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA. Address reprint requests and correspondence to: Thomas A. Buchholz, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: [email protected]
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.02.002
and defining the appropriate indications for postmastectomy radiation therapy. To date, few data are available from studies that have investigated the role of and indications for radiation therapy in patients treated with neoadjuvant chemotherapy. Correspondingly, there remain many areas of controversy concerning the radiotherapeutic management of such patients. This article will provide answers to some of these questions and explore some of the controversies in hopes of providing a rational framework in which to make clinical decisions.
Radiation Therapy as a Component of Breast Conservation after Neoadjuvant Chemotherapy The clearest proven clinical benefit of neoadjuvant chemotherapy is that it can make breast conservation possible in select patients with advanced disease. Results from two randomized trials comparing neoadjuvant chemotherapy with adjuvant chemotherapy in patients with Stage II and Stage III breast cancer indicated that breast conservation rates were 129
T.A. Buchholz and L.J. Solin
130
Figure 1 Various pathological responses that occur after neoadjuvant chemotherapy. As shown, in some instances, malignant cells become clustered around a residual nidus, whereas in other cases, residual tumor cells become scattered over the residual volume of disease. A breast-conserving surgical procedure that is directed at removing a central nidus might therefore leave different volumes of residual disease. (From Buchholz TA, Hunt KK, Whitman GJ, et al: Neoadjuvant chemotherapy for breast cancer: a multidisciplinary discussion of benefits and risks. Cancer 98:11501160, 2003. Copyright © 2003 American Cancer Society. Reproduced with permission of John Wiley & Sons, Inc.)
increased when chemotherapy was given before surgery.1,2 This increase in breast conservation rates resulted because approximately 80% of the patients in these studies had a favorable response to neoadjuvant chemotherapy. After responding, a breast-conserving surgical approach could then be directed at removing the postchemotherapy residual nidus of disease, allowing for an esthetically acceptable outcome. While this approach is attractive in that it avoids mastectomy, concerns have been raised over whether the risk of local recurrence will be greater in these patients. This is because most advanced breast cancers are infiltrative and some tumors do not shrink concentrically to a solitary nidus in response to neoadjuvant chemotherapy. Fig. 1 shows the various ways in which a cancer can respond to neoadjuvant chemotherapy.3 As shown in this figure, sometimes a microscopic residuum of disease spread out over the initial volume of the primary tumor can be left. Thus, surgery directed at the primary core may leave a high burden of microscopic disease around the tumor bed site, which may lead to breast cancer recurrence. This theoretical concern has been reinforced by some clinical data showing higher rates of breast cancer recurrence in patients with advanced tumors who have been treated with breast conservation after neoadjuvant chemotherapy. For example, in the National Surgical Adjuvant Breast and Bowel Project B-18 trial, four cycles of neoadjuvant chemotherapy were compared with four cycles of adjuvant chemotherapy.
The overall 9-year rate of recurrence of ipsilateral breast cancer was slightly higher in the patients treated with neoadjuvant chemotherapy (10.7% versus 7.6%, respectively, P ⫽ 0.12).1 Furthermore, the rate of recurrence of breast cancer in the group treated with neoadjuvant chemotherapy was higher in those who were mastectomy candidates at diagnosis than in those who were breast conservation candidates at diagnosis (15.7% versus 9.9%, respectively, P ⫽ 0.04). One can interpret these data as showing that the recurrence rate in patients with large primary tumors in whom a response to neoadjuvant chemotherapy allowed a breast conservation surgery was twice that in patients with smaller tumors treated with surgery first (15.7% versus 7.6%, respectively). A number of other series have also shown relatively high breast cancer recurrence rates in patients who receive neoadjuvant chemotherapy. Table 1 gives data from a number of these series and also from series in which the breast cancer recurrence rates were relatively low.1,4-10 One difficulty in interpreting these data, however, is that the selection criteria for breast conservation after chemotherapy and the local treatment strategies varied across studies. In the aggregate, however, the data do allow some general conclusions to be drawn: ● ●
breast conservation procedures are more complex in patients who have surgery first multidisciplinary coordination is likely important
Radiation after neoadjuvant chemotherapy for breast cancer
131
Table 1 Rates of Local or Local–Regional Recurrence in Patients Treated with Neoadjuvant Chemotherapy and Breast Conservation First Author (ref.)
No. of Patients
Local Recurrence
Comments
Wolmark (1) Mauriac (4)
503 84
11% @ 9 yrs 29% @ 10 yrs
Rouizer (5)
257
21% @ 10 yrs
Ring (6)
69
21% @ 5 yrs
Merajver (7)
25
18% @ 5 yrs
71 456 340
11% @ 5 yrs 7% @ 8 yrs 5% @ 5 yrs
B-18 trial, Stage II or III disease French multi-institution trial, 52% treated with radiation without surgery French multi-institution trial, 28% with close/positive margins All with CR to chemotherapy and with no surgery performed All with CR to chemotherapy with no surgery performed All patients had surgery All patients had surgery All patients had surgery, only 4% had positive margins
Vines (8) Bonadonna (9) Chen (10) Note. CR, complete response.
● ●
proper patient selection for breast conservation is critical radiation therapy as a sole modality is likely less effective than the combination of breast-conserving surgery and radiation therapy
Investigators at The University of Texas M.D. Anderson Cancer Center recently published the results of one of the largest studies investigating breast conservation after neoadjuvant chemotherapy.10 In this study, the outcome in 340 patients who were carefully selected by a multidisciplinary team to undergo breast conservation after showing a favorable response to chemotherapy was analyzed. Patient selection criteria for a breast-conserving approach included: ● ● ● ● ●
no postoperative residual malignant calcifications no residual T4 breast skin abnormalities negative surgical margins no multicentric disease ability to undergo a course of radiation therapy
Although 72% of patients in this study had clinical Stage IIB or III disease, the 5- and 10-year breast recurrence rates were only 5% and 10%, respectively. This favorable outcome is likely attributable to the selection criteria used and the close multidisciplinary coordination of care. These authors also identified factors associated with breast recurrence and local-regional recurrence (LRR) in an effort to further refine the selection criteria. The factors they identified included clinical N2 or N3 disease, lymphovascular space invasion in the primary tumor biopsy specimen, a multifocal pattern of residual disease, and residual disease greater than 2 cm in diameter. The clinical T-stage, however, did not correlate with breast recurrence, indicating that when careful selection criteria are used, patients with advanced primary tumors can be successfully treated with breast conservation. Interestingly, the 5-year breast cancer recurrence rate was only 3% in patients with T3/T4 tumors that formed a solitary nidus in response to neoadjuvant chemotherapy. However, the breast cancer recurrence rate was 20% in patients with T3/T4 tu-
mors that broke up and left a multifocal pattern of residual disease in response to neoadjuvant chemotherapy.10 When breast conservation is being considered in patients with Stage III breast cancer, it is important to also recognize that treatment with mastectomy does not preclude LRR. Indeed, many of the factors that correlate with LRR in patients treated with breast conservation are the same as those that correlate with LRR in patients treated with mastectomy followed by radiation therapy. Furthermore, patients with advanced disease are at a significant competing risk of distant metastases, which is an additional incentive to avoiding removing the breast.
Radiation Treatment Fields The radiation treatment fields and dosages of radiation used in patients treated with breast conservation surgery after neoadjuvant chemotherapy do not differ significantly from those used in patients who undergo surgery before chemotherapy. These recommended radiation treatment fields and dosages are extrapolated from the setting of standard breast conservation treatment (ie, using breast conserving surgery first, without neoadjuvant chemotherapy). Typically, 45 to 50 Gy is delivered to the breast over 5 weeks and then the tumor bed is given a supplemental dose of 10 to 16 Gy. However, neoadjuvant chemotherapy use has led to new questions concerning when to add fields to treat lymphatic regions, and the use of nodal radiation for some patients treated with neoadjuvant chemotherapy remains a major area of controversy. In patients treated with surgery first, there is a consensus that the supraclavicular fossa and axillary apex should be included in the field when four or more axillary lymph nodes contain disease, when there is lymph node involvement with gross extracapsular extension, or there is extensive lymphovascular space invasion. In patients treated with surgery first who have zero to three positive lymph nodes without extracapsular extension, many radiation oncologists treat the breast only because the risk of disease in the supraclavicular
T.A. Buchholz and L.J. Solin
132 fossa is low enough to not justify the associated morbidity of this treatment. Radiation to the supraclavicular fossa may be considered for selected patients with one to three positive axillary lymph nodes, and radiation to the full axilla may be considered for selected patients with four or more positive axillary lymph nodes. Finally, the use of internal mammary nodal (IMN) radiation also remains controversial. It is unclear whether to add regional nodal irradiation in patients with clinical Stage I or II disease who have 0 to 3 positive axillary lymph nodes after neoadjuvant chemotherapy. Some of these patients likely had 4 or more positive lymph nodes at the time chemotherapy was started, and nodal irradiation would have been recommended had they been treated with surgery first. There are currently insufficient data regarding the failure patterns in patients with Stage II disease with 1 to 3 positive lymph nodes after chemotherapy to answer this question. In one of the only studies that has investigated this issue, Garg and coworkers11 recently reported that, of 42 patients with clinical stage II breast cancer who had 1 to 3 positive lymphs nodes after chemotherapy, the local–regional treatment of these patients was mastectomy without radiation. Disease recurred in the supraclavicular fossa/axillary apex in only 1 of these 42 patients, and this patient had a simultaneous chest wall recurrence. The median follow-up for this report was only 46 months. For patients with locally advanced breast cancer, most radiation oncologists currently advocate irradiating both the breast and the axillary apex/supraclavicular fossa, even if the response to neoadjuvant chemotherapy permits a breast conservation surgery.
Indications for Radiation Therapy after Neoadjuvant Chemotherapy Followed by Mastectomy Perhaps the most important question concerning radiation treatment that has been raised as a result of the move toward using neoadjuvant chemotherapy concerns the indications for postmastectomy radiation therapy. In patients treated with mastectomy first, the decision to administer radiation
therapy is made on the basis of the pathological extent of disease. Consensus statements issued by the American Society of Therapeutic Radiology Oncology and the American Society of Clinical Oncology have both recommended postmastectomy radiation therapy for patients with four or more positive lymph nodes.12,13 However, both of these consensus statements have indicated that there are insufficient data to guide treatment recommendations in such patients who are treated with neoadjuvant chemotherapy. Data accumulated over the past 50 years indicate that postmastectomy radiation therapy reduces the risk of LRR by approximately two-thirds.14 In addition, recent prospective trials have shown that postmastectomy radiation therapy improved overall survival in various patient subgroups in which the 10-year LRR rate without radiation therapy was approximately 25% to 30%.15-17 In these trials, the LRR with the addition of postmastectomy radiation was less than 10%. A number of recent studies have attempted to define which patient subgroups have a clinically relevant risk of LRR after mastectomy and adjuvant chemotherapy, which would thus make them candidates for radiation.18-21 These studies have predominantly used the pathological extent of disease as the basis for this risk stratification and have shown that patients with American Joint Commission of Cancer 2003 Stage III disease (which includes T3N1 disease and disease with 4 or more positive lymph nodes) have a 20% to 30% risk of LRR if they do not receive radiation therapy. These studies have also shown that the risk of LRR is much lower (⬍15%) in patients with Stage II breast cancer with one to three positive lymph nodes.18-21 Accordingly, the use of postmastectomy radiation therapy in women with Stage II breast cancer with one to three positive lymph nodes remains an area of controversy. One important consideration is that neoadjuvant chemotherapy changes the extent of pathological disease in 80% to 90% of cases, so how pathological information should guide decisions regarding radiation therapy is less clear. Adding to this problem is the fact that there are significantly fewer data regarding how clinical and pathological features of disease correlate with LRR after mastectomy in patients treated with neoadjuvant chemotherapy compared with those treated with adjuvant chemotherapy. One study that examined this issue investigated LRR in 150 patients treated with neoadju-
Table 2 LRR Rates and CSS Rates for Patients with Advanced Breast Cancer Treated with Neoadjuvant Chemotherapy According to the Use of Postmastectomy Radiation Therapy (Data from Huang et al. 24) Extent of Disease Clinical Stage T4 primary tumor Clinical Stage IIIB/C >4 ⴙ LN after neoadjuvant chemotherapy
Postmastectomy Radiation Therapy
10-yr LRR rate
P value
10-yr CSS rate
P value
No Yes No Yes No Yes
46% 16% 51% 16% 59% 17%
P < 0.0001
22% 44% 22% 44% 18% 39%
P ⴝ 0.015
CSS, cause-specific survival; LRR, local–regional recurrence; LN, lymph node.
P < 0.0001 P < 0.0001
P ⴝ 0.002 P ⴝ 0.011
Radiation after neoadjuvant chemotherapy for breast cancer vant chemotherapy and modified radical mastectomy but not radiation therapy. The important finding from this study was that both the initial clinical stage and the final pathological extent of disease independently affected the LRR risk.22 In particular, the study showed that patients with primary tumors that exceeded 5 cm in diameter, T4 primary disease, or extensive adenopathy at the time of diagnosis were at high risk of LRR even if they had had an excellent response to treatment. In addition, the LRR rate remained relatively high (19%, 95% CI: 6%– 48%) in a subset of patients who achieved a pathological complete remission.22 A high LRR rate (46%) was also noted in a group of patients who initially had clinically T3 or T4 primary tumors but had tumors less than 5 cm in diameter and only one to three positive lymph nodes after chemotherapy.22 These authors then compared the risk of LRR according to the pathological extent of disease between patients treated with neoadjuvant chemotherapy and mastectomy and patients treated with mastectomy and adjuvant chemotherapy.23 Not surprisingly, for any given pathological extent of disease, the LRR risk was higher in patients treated with neoadjuvant chemotherapy, in whom the pathological extent of disease represented residual disease after chemotherapy, compared with patients treated with surgery first, in whom the pathological extent of disease represented the initial volume of disease before any systemic treatment.23 The interesting finding of this article was that the difference in the LRR risk in these groups was much greater in terms of any given pathological primary tumor size than in terms of any class of number of positive lymph nodes. This finding likely reflects the fact that neoadjuvant chemotherapy changes the primary tumor size in the vast majority of cases but much less frequently changes the number of positive lymph nodes. Recently, data have become available regarding the efficacy of radiation therapy in patients treated with mastectomy after neoadjuvant chemotherapy. This study compared the outcome of 579 patients who received neoadjuvant chemotherapy, mastectomy, and radiation therapy with that of 136 patients who were treated with neoadjuvant chemotherapy and mastectomy alone.24 Although the patients in this study were treated on single institutional prospective trials, radiation therapy was not a randomized variable in these trials. Thus, there were significant imbalances in the prognostic factors between the two groups, with those receiving radiation therapy having worse disease features. Despite these imbalances, the LRR rate was significantly lower in the patients treated with postmastectomy radiation therapy than in those treated with neoadjuvant chemotherapy and mastectomy alone (10-year LRR rates were 8% and 22%, respectively, P ⫽ 0.001). More importantly, treatment with radiation therapy was associated with better overall and cause-specific survival rates in selected groups of patients with high-risk disease (Table 2). In addition, a multivariate analysis for the endpoint of cause-specific survival showed that treatment with radiation therapy was independently associated with a better outcome, with the hazard ratio in patients who do not receive radiation therapy being 2.03 (95% CI, 1.41-2.92, P ⬍ 0.0001).
133 On the basis of these data, it is currently reasonable to recommend postmastectomy radiation therapy for all patients with clinical T3 or T4 tumors or clinical Stage III disease, regardless of their response to the chemotherapy regimen. In terms of clinical Stage I or II breast cancer, postmastectomy radiation therapy should be recommended for patients with four or more positive lymph nodes after chemotherapy and the unusual patient in whom the disease progresses and the primary tumor exceeds 5 cm in diameter. It is clear, however, that additional studies are needed that quantify the LRR risk in patients who present with T1 or T2 disease and have one to three positive lymph nodes after neoadjuvant chemotherapy. The radiation fields and the radiation dose used in patients who have undergone only mastectomy are similar to those used in patients treated with mastectomy followed by adjuvant chemotherapy. In general, the treatment volume should include the chest wall, undissected axilla, and supraclavicular fossa. Whether to also include components of the dissected axilla and/or the internal mammary lymph nodes is controversial, as the chest wall is the most common site of LRR after neoadjuvant chemotherapy and mastectomy. Indeed, in a series of such patients in which LRR patterns were examined, the chest wall was a component of the LRR in 79%, the supraclavicular lymph nodes were a component in 32%, the axilla was a component in 20%, the infraclavicular region was a component in 9%, and the internal mammary lymph nodes were a component in 3%.22 This study did not assess recurrences in sites less accessible to clinical examination, such as the internal mammary artery region, so some of these percentages may be underestimations.
Conclusions While neoadjuvant chemotherapy has a number of clinical benefits, its adoption into clinical practice has also raised questions within all disciplines that treat cancer, including radiation oncology. One particular benefit of neoadjuvant chemotherapy is that it can make breast conservation surgery an option in select patients with advanced primary tumors, but the success of this strategy depends on the use of careful selection criteria and the close coordination of multidisciplinary care. Radiation therapy also plays an important role in patients with locally advanced disease who are treated with neoadjuvant chemotherapy and mastectomy. Nonetheless, some questions remain unanswered with regard to radiation field design and indications for postmastectomy radiation therapy in patients with early-stage disease who receive neoadjuvant chemotherapy. It is hoped that as more experience with this approach is gained, additional data will become available to help guide rationale treatment decisions.
References 1. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 30:96-102, 2001 2. van der Hage JA, Cornelis JH, van de Velde CJ, et al: Preoperative
T.A. Buchholz and L.J. Solin
134
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19:4224-4237, 2001 Buchholz TA, Hunt KK, Whitman GJ, et al: Neoadjuvant chemotherapy for breast cancer: a multidisciplinary discussion of benefits and risks. Cancer 98:1150-1160, 2003 Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for operable breast cancer larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Ann Oncol 10:47-52, 1999 Rouzier R, Extra JM, Carton M, et al: Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol 19:3795-3804, 2001 Ring A, Webb A, Ashley S, et al: Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol 21:4540-4555, 2003 Merajver SD, Weber BL, Cody R, et al: Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience. J Clin Oncol 15:2873-2881, 1997 Vines EF, Hepp R, Campos M, et al: Analysis of local failure after breast conserving therapy (BCT) for locally advanced breast cancer (LABC). Int J Radiat Oncol Biol Phys 57:S238-S239, 2003 (suppl 2) Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93-100, 1998 Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast-conserving therapy after neoadjuvant chemotherapy: The M.D. Anderson Cancer Center experience J Clin Oncol 22:2303-2312, 2004 Garg AK, Strom EA, McNeese MD, et al: T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for localregional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiation. Int J Radiat Oncol Biol Phys 59:138-145, 2004 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 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 Early Breast Cancer Trialists’ Collaborative Group: Favourable and un-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
favourable effects on long-term survival for radiotherapy for early breast cancer: an overview of the randomized trials. Lancet 355:1757-1770, 2000 Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997 Overgaard M, Hansen S, Rose P, et al: Randomized trial evaluating postoperative radiotherapy in high risk postmenopausal breast cancer patients given adjuvant tamoxifen: results from the DBCG 82c trial. Radiother Oncol 48:S78, 1998 Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node- positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997 Recht A, Gray R, Davidson NE, et al: Locoregional failure ten years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689-1700, 1999 Katz A, Strom EA, Buchholz TA, et al: Locoregional recurrence patterns following mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation. J Clin Oncol 18:2817-2827, 2000 Wallgren A, Bonetti M, Gelber RD, et al: Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group trials I through VII. J Clin Oncol 21:12051213, 2003 Taghian AG, Jeong JH, Anderson S, et al: Pattern of loco-regional and distant failure in patients with breast cancer treated with mastectomy and chemotherapy (⫹/⫺ tamoxifen) without radiation: results from five NSABP randomized trials. Int J Rad Oncol Biol Phys 51:106-107, 2002 (suppl 1) Buchholz TA, Tucker SL, Masullo L, et al: Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol 20:17-23, 2002 Buchholz TA, Katz A, Strom EA, et al: Pathological factors that predict for local-regional recurrences after mastectomy are different for breast cancer patients treated with neoadjuvant versus adjuvant chemotherapy. Int J Radiat Oncol Biol Phys 53:880-888, 2001 Huang EH, Tucker SL, Strom EA, et al: Radiation treatment improves local-regional control and cause-specific survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol 22:4691– 4699, 2004