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Breast Conservation Therapy for Patients With Locally Advanced Breast Cancer
Breast Conservation Therapy for Patients With Locally Advanced Breast Cancer Mohamed A. Alm El-Din, MD,*,† and Alphonse G. Taghian, MD, PhD* Neoadjuvant chemotherapy achieves high response rates in patients with breast cancer and has been used to reduce tumor size and allow for breast conservation in individuals who initially required mastectomy. The goals of this approach are to achieve optimal locoregional control together with acceptable cosmesis. In the setting of locally advanced disease, breast preservation appears to be feasible for appropriately selected patients whose tumors show adequate downstaging in response to induction chemotherapy. Nevertheless, further prospective randomized trials are warranted to better evaluate the results of this approach as compared with mastectomy. Semin Radiat Oncol 19:229-235 © 2009 Elsevier Inc. All rights reserved. KEYWORDS breast cancer, locally advanced, breast conservation
M
astectomy followed by postmastectomy radiation has been the standard of treatment for patients with locally advanced breast cancer (LABC) in that a breast-conserving approach for patients with larger primary tumors may not have been technically feasible, may not have been as effective, and may have resulted in significant cosmetic deformity. However, since the introduction of neoadjuvant chemotherapy (NACT), a large number of patients with locally advanced primary disease have enjoyed a conservative approach. This review addresses some of the issues and concerns related to the use of this approach.
Success Rates of Breast Conservation After NACT A number of studies and clinical trials have shown that breast conservation after NACT is possible for selected patients who otherwise would require mastectomy. A study from M. D. Anderson Cancer Center was one of the early reports that investigated the feasibility of breast conservation after induction chemotherapy in patients with locally advanced dis-
*Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. †Department of Radiation Oncology, Tanta University Hospitals, Tanta Faculty of Medicine, Tanta, Egypt. Address reprint requests to Alphonse G. Taghian, MD, PhD, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street Cox Building 302, Boston, MA 02114. E-mail: [email protected].
1053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2009.05.005
ease.1 Mastectomy specimens from 143 patients with stage IIB and III breast cancer (77% stage IIIA or IIIB) were retrospectively analyzed after NACT. A complete response was observed in 16%, whereas 86% were considered as partial responders. The authors were able to define strict selection criteria for breast conservation on the basis of the pathologic assessment of mastectomy specimens. These criteria included complete resolution of skin edema, residual tumor size of less than 5 cm, no evidence of multicentric lesions, and the absence of extensive intramammary lymphatic invasion or extensive microcalcifications. The authors found that 23% of this study cohort would have been eligible for conservative surgery rather than modified radical mastectomy on the basis of these criteria. Two randomized prospective trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial and European organization of research and treatment of cancer (EORTC) 10902 trial, which compared preoperative versus postoperative chemotherapy, have showed that a higher percentage of patients among preoperative chemotherapy arms underwent breast-conserving surgery.2-4 Among the B18 trial, there was an overall increase in lumpectomies by 12% in the preoperative chemotherapy group. The improvement in lumpectomy rate was more pronounced, with 7-fold increase, in patients with tumors ⱖ5 cm. In the 10902 trial, 57 patients (23%), among the preoperative chemotherapy group, underwent breast-conserving surgery and not the planned mastectomy. Other smaller studies have also indicated that breast conservation is feasible after NACT. In a study involving 97 229
M.A. Alm El-Din and A.G. Taghian
230 Table 1 Local Recurrence Rate for Breast-Conserving Surgery After NACT Study al10
McIntoch, et Chen, et al12 Shen, et al11 Clark, et al8 Hunt, et al9 NSABP B184 Asoglu, et al13 Mauriac, et al14
Population
Stage
Number of BCS
LRR (%)
Median Follow-up (mo)
173* 340 33 34 93 1531 28 272
T2 > 4 cm, T3, T4 or N2 I-III IIIB and IIIC T3/T4, N0-2 IIA-IV† T1-3, N0-1 IIB-IIIB T2 > 3 cm/T3, N0-1
44 340 33 15 86 503‡ 28 40
2 5§ 6§ 6.6 9.7 10.7 14 22.5§
62 60 60 30 55 114 60 124
Abbreviations: BCS, breast-conserving surgery; LRR, locoregional recurrence rate; NSABP, National Surgical Adjuvant Breast and Bowel Project. *Data available for 166. †Supraclavicular metastases only. ‡The number of lumpectomies among patients who had preoperative chemotherapy. §The rate of ipsilateral breast tumor recurrence.
patients with LABC, the addition of docetaxel to CVAP (cyclophosphamide, vincristine, doxorubicin, and prednisone) as opposed to further CVAP as induction chemotherapy resulted in higher complete clinical and pathologic response, and this translated into a higher breast conservation rate (67% v 48%).5 In another study on a small cohort of patients with LABC (n ⫽ 29) who received NACT, Lebowitz et al6 found that 59% underwent breast conservation, whereas only 13% were considered eligible for this type of surgery at presentation. In the NSABP B27 trial, 2,411 patients with operable breast cancer were randomized to anthracyclines with or without taxanes.7 Although the pathologic complete response was doubled (26.1% v 13.7%), there was no significant improvement with regard to the rate of the breast conservation rate (61.6% v 63.7%) or the overall survival. Several studies have documented acceptable rates of local recurrence in patients with breast cancer undergoing breast conservation after NACT (Table 1).4,8-12 However, when interpreting such data, it is important to consider that some of these studies included both patients with early stage and those with locally advanced disease. In the NSABP B18, there was no significant difference in the rates of ipsilateral breast tumor recurrence (IBTR) between women treated with lumpectomy in the setting of preoperative versus postoperative chemotherapy. However, the rate of IBTR among patients who underwent breast conservation after their tumors had been downstaged by NACT was significantly higher compared with that encountered among those who were initially candidates for breast conservation (15.9% v 9.9%, P ⬍ .04).4 It is important to note that the selection of type of surgery was not randomized in the B18 study, which might affect the accuracy of the results. Asoglu et al13 reported slightly higher locoregional recurrence (LRR) rate in a group of patients with LABC who were treated by induction chemotherapy followed by surgery. Most of this study cohort (75%) was stage III (Table 1). Mauriac et al14 also reported a higher rate of isolated local recurrence among breast cancer patients with operable tumors larger than 3 cm who were treated by initial chemotherapy (Table 1). Buchholz et al15 suggested that higher rates of local recurrence among patients undergoing breast conservation after
NACT could be explained by the small volume of resection that might not be appropriate for a large tumor that has responded to induction chemotherapy. Several prospective clinical trials have addressed the issue of survival in patients with early stage or LABC receiving preoperative chemotherapy versus those receiving postoperative chemotherapy.2,4,14,16-20 These trials have confirmed overall survival equivalence for the two approaches further emphasizing the safety of the NACT. Based on these results together with the advantage of improving tumor resectability, induction chemotherapy followed by surgery and radiation has become the preferred approach for patients with bulky, locally advanced disease at the time of diagnosis. Furthermore, Kuerer et al21 and Schwartz et al17 reported better disease-free and overall survival in patients with LABC undergoing breast conservation after NAC. However, when the responders were stratified with regard to age, there was no difference in survival between the mastectomy arm and the breast conversation arm. In addition, the studies with better survival in patients with LABC undergoing breast conservation after induction chemotherapy as compared with those undergoing mastectomy might represent selection bias because the breast conservation group likely includes patients who achieve a good response to chemotherapy.
Concerns Over This Approach/Volume of Resection As shown in several pathologic studies, the pattern of response to induction chemotherapy is not uniform but rather heterogeneous, with some cases leaving clusters of viable tumor cells at a distance from the central residual tumor site.3,22 This might explain the discrepancy between the clinical and the pathologic response to induction chemotherapy that was reported in several studies.3,21,23-25 In a retrospective study by Clouth et al,26 101 patients with LABC underwent NACT. Twenty-five patients (25%) achieved a complete clinical and radiologic response and were subjected to multiple core biopsies centrally and at all four quadrants. Pathologic examination revealed pathologic
Breast conservation therapy complete response in 16 patients, and they received adjuvant radiotherapy with no further surgery. Most of the patients (8/9) who had residual disease underwent mastectomy indicating the existence of tumor in more than one quadrant despite achieving complete clinical and radiologic response after NACT. In another study of 226 patients with tumors ⬎3 cm (87% had tumors between 3 and 5 cm) receiving NACT followed by surgery, the histopathology showed multifocality in the primary tumor in 37 patients (16.3%) and complete pathologic response was seen in only 8 patients (3.5%).22 Therefore, the assessment of tumor response to induction chemotherapy with the elimination of patients with multifocal disease is crucial when offering breast conservation in patients with LABC undergoing NACT.
Appropriate Selection Criteria Several institutions have reported their experience regarding the role of breast conservation following induction chemotherapy for LABC, nevertheless the fraction of patients offered breast conservation varies tremendously due to variability of methods utilized as well as the inconsistence of selection criteria. The eligibility criteria for breast conservation after induction chemotherapy in LABC are similar to those applied in early-stage breast cancer. Presence of multicentric disease, extensive micro-calcification, extensive skin changes, and lymphatic permeation are generally considered as contraindications for breast conservation in those patients.27 Mathew et al28 suggested that breast conservation should be performed for selected group of patients with LABC particularly those who achieve pathological complete response after NACT. Nevertheless, patients who respond partially with a significant downstaging of the tumor size, as long as lumpectomy is technically feasible, could also be candidates for conservative surgery after NACT. In the study from M. D. Anderson Cancer Center, 110 of 143 patients were not considered as good candidates for breast conservation after induction chemotherapy.1 Among those patients, 55 (50%) had tumor in other quadrants. The factors most commonly associated with multiple quadrant involvement were persistent skin edema, residual tumor size larger than 4 cm, extensive intramammary lymphatic invasion and mammographic evidence of multicentric disease. The patient desire for breast preservation is an important issue and should be also considered. Magnetic resonance imaging (MRI) may also play an important role in better identification of patients who would be good candidates for breast conservation following NACT. Multiple studies have addressed the benefit of MRI in patients with known breast cancer reporting that approximately 9% will be found to have multicentric disease that was not detected by conventional imaging.29-33 Evaluation of disease response to chemotherapy is another potential role of breast MRI in the setting of preoperative chemotherapy. Several studies have suggested a greater agreement between MRI and extent of residual disease as compared to that achieved with physical examination or conventional imaging.34-38 Yet, the
231 role of breast MRI to evaluate the feasibility of breast conservation after NACT has to be defined. Concerns regarding the sensitivity, the availability and the cost of MRI should be also considered. Positron emission tomography scans, as predictors of pathological response, have been also tried but the data remain immature and require further validation.39
Importance of Prechemotherapy Clip Placement Localization of the tumor within the breast following NACT appears to be challenging particularly in the subset of patients who achieve a complete clinical or radiological response. In a study by Edeiken et al,40 implantation of metallic markers guided by ultrasound has shown to be optimal in localization of the tumor bed in case complete response occurs following NACT. In 23 patients (47%), the metallic markers were the only remaining marker for the tumor bed following NACT. The authors added that the metallic markers showed no evidence of migration as comparisons were made on mammograms after implantation and shortly before surgery. The position of the markers was also confirmed on histopathological examination by proximity to fibrosis or scar tissue related to post-chemotherapy changes. In a recent study from M. D. Anderson Cancer Center, the omission of radio-opaque clip placement in patients undergoing preoperative chemotherapy was associated with increased incidence of local recurrence.41 The 5-year rate of local control was 98.6% in patients who had radio-opaque clips placed versus 91.7% in patients who did not have tumor marker clips placed (P ⫽ .02). The authors recommended placement of radio-opaque clips in the tumor bed before or during NACT to facilitate accurate tumor bed localization and to reduce the risk of breast tumor recurrence. However, clip placement may not be required for lesions associated with microcalcifications as they have an inherent target for subsequent localization. Skin tattooing has been shown to be effective in identification of the tumor bed as suggested by Veronesi et al.22 Nevertheless, localization by metallic markers has been more popular among surgeons particularly with the advent of recent imaging modalities.
Radiotherapy After Breast Conservation in LABC As in early breast cancer, postoperative radiotherapy is an integral part in the management of patients with LABC undergoing breast conservation. The technique of irradiation is generally the same; however, existing data are limited regarding whether comprehensive irradiation is absolutely necessary to achieve optimal locoregional control in patients whose tumors achieve substantial degree of downstaging in response to chemotherapy. The results of surgical pathology have been traditionally used to estimate the odds of locoregional recurrence following surgery in breast cancer patients and hence identifying those who would benefit from nodal irradiation. However,
232 this could not be applied for patients undergoing preoperative chemotherapy with an expected response rate up to 80%. The investigators at M. D. Anderson Cancer Center suggest that, in the preoperative chemotherapy setting, both the initial clinical stage and the final pathologic extent of the disease independently predict the risk of a locoregional recurrence.42 After NACT and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage lll-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes.43 The 5-year locoregional recurrence rate in 12 patients with stage III disease who achieved a pathologic complete remission, remained high when radiation was not used (33.3% ⫾ 15.7%).44 Therefore, for selected patients undergoing breast conservation after NACT, irradiation of the supraclavicular and may be the upper internal mammary nodes might be considered in conjunction with breast radiotherapy regardless the response to systemic treatment. Mauriac et al14 highlighted the role of surgery for axillary control as they reported higher nodal relapse in patients undergoing preoperative chemotherapy who were treated exclusively by nodal irradiation as compared to those who had axillary dissection (10 v 1, respectively). The data from NSABP B-18 & B-27 and M. D. Anderson Cancer Center suggest that patients with clinical stage II disease who have negative lymph nodes after induction chemotherapy have an 8-year risk of LRR after mastectomy that is less than 10%.45,46 Given that local or regional radiotherapy was not given in the above mentioned studies, the rate of LRR does not appear to justify nodal irradiation in this subset of patients. The power of such conclusions is limited and needs further confirmation in prospective randomized trials especially all patients from the above mentioned studies underwent axillary dissections (with or without sentinel lymph node surgery). Another challenge in the setting of postoperative radiotherapy in patients with LABC undergoing NACT is the boost volume. The question is whether or not the pre-chemotherapy volume should be irradiated particularly in patients whose tumors show significant or complete response to induction chemotherapy. Although the issue of irradiating the pre- or post-chemotherapy is still controversial, the majority of institutions consider the pre-chemotherapy size. However, the cosmetic results of irradiating such large volume, in some cases, need to be addressed because a large portion of the breast will be included in the treatment portals.
Predictors of Locoregional Failure The investigators at M. D. Anderson Cancer Center reported the results of NACT and breast conversation in 340 women, of whom 130 (38%) were stage III.12 At a median follow-up period of 60 months, the 5-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Rates of IBTR and LRR were correlated with clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multi-
M.A. Alm El-Din and A.G. Taghian focal pattern of residual disease, and lymphovascular invasion. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Nevertheless, the authors concluded that breast conservation is an acceptable modality of treatment after induction chemotherapy for patients with stage III disease. The previously mentioned four parameters were incorporated into a classification system that can be used in clinical decision-making and to counsel patients treated with this multimodality approach.47 The M. D. Anderson Prognostic Index (MDAPI) was developed by assigning scores of 0 (favorable) or 1 (unfavorable) for each of these four variables and using the total to give an overall MDAPI score of 0-4. Using the MDAPI score, patients who undergo breast conservation after NACT can be stratified into a low, intermediate, or high-risk group for IBTR and LRR. Patients with a score of 3 to 4, LRR was ⬎60% after breast conservation and was ⬍0% with mastectomy.48 The authors suggested that according to MDAPI score, patients at higher risk of recurrence may benefit from alternative locoregional treatment strategies. Asoglu et al13 suggested that negative surgical margins following breast conservation in patients undergoing NACT could be more important than clinical and histological parameters in terms of prediction of local recurrence rate.
Predictors of Disease-Free and Overall Survival The NSABP B-18 trial confirmed the association between the category of clinical response to induction chemotherapy and survival in operable breast cancer.4 Of the 682 patients, 247 (36%) had complete clinical response and 88 (13%) had complete pathological response. At 9 years of follow-up, the rates of disease-free survival was 64% in patients with complete clinical response compared to 46% in non-responders (stable disease and progressive disease; P ⫽ 0.0008). The overall survival was similarly better (75% v 65%, P ⫽ 0.005). In this study, histological response was found to be better predictor of outcome. At 9 years, the disease-free survival in patients who achieved complete pathological response was 75% compared to 58% for incomplete responders (P ⫽ 0.0005). For overall survival the rates were 85% and 73% (P ⫽ .00008). In a randomized controlled trial including patients with LABC, Heys et al5 reported significant increase in disease-free survival at 3 years in those with better clinical and pathological response (90% v 77%, P ⫽ 0.03). Another study of 200 patients with LABC, 17.6% had complete clinical response and 12.2% had complete pathological response.49 Patients with complete clinical response had better recurrence-free and overall survival as compared to those with partial response (79% and 85%, v 40% and 52%, respectively; P ⫽ 0.0001). The recurrence-free and overall survival were also significantly better for patients with complete pathological response (85% for both) as compared to those with incomplete response (52% and 59%, respectively; P ⫽ 0.0001). In
Breast conservation therapy the prospective study by Kuerer et al21 that included 372 patients with LABC receiving NACT, the 5-year disease-free and overall survival of the patients who achieved complete pathological response (87% and 89%, respectively) was significantly better than that of patients who did not respond completely to chemotherapy (58% and 64%, respectively; P ⬍ 0.01). The residual disease in the axilla following NACT has been reported to be a poor prognostic factor for the outcome.22,50,51 Rouzier et al50 reported an interesting finding on multivariate analysis of the data of 152 patients with T1 to T3 tumors with cytologically proven metastasis in the axilla. The authors found that conversion of positive to negative nodes (occurred in 23%) was a strong predictor of survival (P ⬍ 0.01) where complete pathological response in the breast was a marker of pathological axillary conversion following chemotherapy rather than a predictor of survival by itself.
Is Breast Surgery Necessary? The choice of local treatment modality after NACT has been always an area of major controversy particularly in patients with complete clinical response. After NACT, surgery and radiotherapy have been tried solely or in combination in the context of multidisciplinary approach. Touboul et al52 treated 147 patients with tumors more than 3 cm with four cycles of chemotherapy. Ninety-five patients were eligible for breast conservation (48; complete response and 47; residual disease). Patients with complete response received only radiotherapy boost where those with residual disease underwent wide excision and received two more cycles of chemotherapy followed by radiotherapy. The 5-year overall survival in the patients who underwent wide excision and radiotherapy was 81% as compared to 65% in the radiotherapy alone group. For those who underwent mastectomy, the 5-year survival was 76%. Another French study reported extremely high rate of locoregional recurrence (34%) in a group of breast cancer patients who were treated by initial chemotherapy followed by breast and nodal irradiation with no surgery.14 The results of two meta-analyses stressed on the potential role of surgery in breast cancer patients receiving NACT. The first meta-analysis evaluated the results of nine randomized studies, including a total of 3946 patients with breast cancer.53 Among the included studies, the tumor size ranged from T0 to T4b where the nodal status ranged from N0 to N2. Primary outcomes were death, disease progression, distant disease failure, and locoregional disease recurrence. The authors reported no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (risk ratio [RR] ⫽ 1.00; 95% confidence interval [CI], 0.90 to 1.12), disease progression (RR ⫽ 0.99; 95% CI, 0.91 to 1.07), or distant disease failure (RR ⫽ 0.94; 95% CI, 0.83 to 1.06). However, the risk of locoregional disease recurrences (RR ⫽ 1.22; 95% CI, 1.04 to 1.43) was significantly higher in neoadjuvant therapy compared with adjuvant therapy, particularly in trials where more patients in the neoadjuvant arm received radiation
233 therapy without surgery (RR ⫽ 1.53; 95% CI, 1.11 to 2.10). The authors recommended avoiding the use of radiotherapy without any surgical treatment, even in the presence of an apparently good clinical response to NACT. More recently, the rates of breast conservation as well as the rates of local recurrence were examined in those receiving NACT compared to those receiving adjuvant chemotherapy in meta-analysis of 11 studies including over 5000 patients with operable breast cancer.54 Despite the significantly decreased rates of mastectomy among the neoadjuvant group, the local recurrence rates were significantly higher among the same group. In the three studies, which account for more than one third of the patients, radiotherapy was the only modality of local treatment as surgery was not done after complete response. After exclusion of the results of these studies, there was no significant difference between the two groups with regard to local recurrence (Hazard Ratio 1.12; 95% CI, 0.92-1.37). Resection is also essential for documenting chemotherapy response and achieving locoregional control.55 Surgery, therefore, remains the mainstay in management of patients with LABC receiving NACT as clinical assessment could be deceiving.
Review of Data In summary, breast conservation after NACT appears to be feasible in patients with LABC because it offers an acceptable rate of disease control. The proper selection of patients who are candidates for this modality is crucial because it will affect the treatment outcome in terms of locoregional control rate, disease-free survival, and overall survival. Pre-chemotherapy clip placement is an integral part if breast conservation is to be considered after NACT, especially for those patients who might achieve complete clinical and radiologic responses. Frozen section and histopathological examination at the time of breast-conserving surgery could be important because the findings from the pathology might reveal a high probability of multicentricity, which would preclude the use of a conservative approach.
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Reviewing the State of the Science and Exploring New Research Directions. National Cancer Institute, March 26, 2007, Bethesda, MD Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation after neoadjuvant chemotherapy. Cancer 103:689-695, 2005 Huang EH, Strom EA, Perkins GH, et al: Comparison of risk of localregional recurrence after mastectomy or breast conservation therapy for patients treated with neoadjuvant chemotherapy and radiation stratified according to a prognostic index score. Int J Radiat Oncol Biol Phys 66:352-357, 2006 Thomas E, Holmes FA, Smith TL, et al: The use of alternate, non-crossresistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol 22:2294-2302, 2004 Rouzier R, Extra JM, Klijanienko J, et al: Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol 20:1304-1310, 2002
235 51. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 176:502-509, 1998 52. Touboul E, Lefranc JP, Blondon J, et al: Primary chemotherapy and preoperative irradiation for patients with stage II larger than 3 cm or locally advanced non-inflammatory breast cancer. Radiother Oncol 42: 219-229, 1997 53. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst 97:188-194, 2005 54. Mieog JS, van der Hage JA, van de Velde CJ: Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev CD005002, 2007 55. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507-2516, 1988
M
astectomy followed by postmastectomy radiation has been the standard of treatment for patients with locally advanced breast cancer (LABC) in that a breast-conserving approach for patients with larger primary tumors may not have been technically feasible, may not have been as effective, and may have resulted in significant cosmetic deformity. However, since the introduction of neoadjuvant chemotherapy (NACT), a large number of patients with locally advanced primary disease have enjoyed a conservative approach. This review addresses some of the issues and concerns related to the use of this approach.
Success Rates of Breast Conservation After NACT A number of studies and clinical trials have shown that breast conservation after NACT is possible for selected patients who otherwise would require mastectomy. A study from M. D. Anderson Cancer Center was one of the early reports that investigated the feasibility of breast conservation after induction chemotherapy in patients with locally advanced dis-
*Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. †Department of Radiation Oncology, Tanta University Hospitals, Tanta Faculty of Medicine, Tanta, Egypt. Address reprint requests to Alphonse G. Taghian, MD, PhD, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street Cox Building 302, Boston, MA 02114. E-mail: [email protected].
1053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2009.05.005
ease.1 Mastectomy specimens from 143 patients with stage IIB and III breast cancer (77% stage IIIA or IIIB) were retrospectively analyzed after NACT. A complete response was observed in 16%, whereas 86% were considered as partial responders. The authors were able to define strict selection criteria for breast conservation on the basis of the pathologic assessment of mastectomy specimens. These criteria included complete resolution of skin edema, residual tumor size of less than 5 cm, no evidence of multicentric lesions, and the absence of extensive intramammary lymphatic invasion or extensive microcalcifications. The authors found that 23% of this study cohort would have been eligible for conservative surgery rather than modified radical mastectomy on the basis of these criteria. Two randomized prospective trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial and European organization of research and treatment of cancer (EORTC) 10902 trial, which compared preoperative versus postoperative chemotherapy, have showed that a higher percentage of patients among preoperative chemotherapy arms underwent breast-conserving surgery.2-4 Among the B18 trial, there was an overall increase in lumpectomies by 12% in the preoperative chemotherapy group. The improvement in lumpectomy rate was more pronounced, with 7-fold increase, in patients with tumors ⱖ5 cm. In the 10902 trial, 57 patients (23%), among the preoperative chemotherapy group, underwent breast-conserving surgery and not the planned mastectomy. Other smaller studies have also indicated that breast conservation is feasible after NACT. In a study involving 97 229
M.A. Alm El-Din and A.G. Taghian
230 Table 1 Local Recurrence Rate for Breast-Conserving Surgery After NACT Study al10
McIntoch, et Chen, et al12 Shen, et al11 Clark, et al8 Hunt, et al9 NSABP B184 Asoglu, et al13 Mauriac, et al14
Population
Stage
Number of BCS
LRR (%)
Median Follow-up (mo)
173* 340 33 34 93 1531 28 272
T2 > 4 cm, T3, T4 or N2 I-III IIIB and IIIC T3/T4, N0-2 IIA-IV† T1-3, N0-1 IIB-IIIB T2 > 3 cm/T3, N0-1
44 340 33 15 86 503‡ 28 40
2 5§ 6§ 6.6 9.7 10.7 14 22.5§
62 60 60 30 55 114 60 124
Abbreviations: BCS, breast-conserving surgery; LRR, locoregional recurrence rate; NSABP, National Surgical Adjuvant Breast and Bowel Project. *Data available for 166. †Supraclavicular metastases only. ‡The number of lumpectomies among patients who had preoperative chemotherapy. §The rate of ipsilateral breast tumor recurrence.
patients with LABC, the addition of docetaxel to CVAP (cyclophosphamide, vincristine, doxorubicin, and prednisone) as opposed to further CVAP as induction chemotherapy resulted in higher complete clinical and pathologic response, and this translated into a higher breast conservation rate (67% v 48%).5 In another study on a small cohort of patients with LABC (n ⫽ 29) who received NACT, Lebowitz et al6 found that 59% underwent breast conservation, whereas only 13% were considered eligible for this type of surgery at presentation. In the NSABP B27 trial, 2,411 patients with operable breast cancer were randomized to anthracyclines with or without taxanes.7 Although the pathologic complete response was doubled (26.1% v 13.7%), there was no significant improvement with regard to the rate of the breast conservation rate (61.6% v 63.7%) or the overall survival. Several studies have documented acceptable rates of local recurrence in patients with breast cancer undergoing breast conservation after NACT (Table 1).4,8-12 However, when interpreting such data, it is important to consider that some of these studies included both patients with early stage and those with locally advanced disease. In the NSABP B18, there was no significant difference in the rates of ipsilateral breast tumor recurrence (IBTR) between women treated with lumpectomy in the setting of preoperative versus postoperative chemotherapy. However, the rate of IBTR among patients who underwent breast conservation after their tumors had been downstaged by NACT was significantly higher compared with that encountered among those who were initially candidates for breast conservation (15.9% v 9.9%, P ⬍ .04).4 It is important to note that the selection of type of surgery was not randomized in the B18 study, which might affect the accuracy of the results. Asoglu et al13 reported slightly higher locoregional recurrence (LRR) rate in a group of patients with LABC who were treated by induction chemotherapy followed by surgery. Most of this study cohort (75%) was stage III (Table 1). Mauriac et al14 also reported a higher rate of isolated local recurrence among breast cancer patients with operable tumors larger than 3 cm who were treated by initial chemotherapy (Table 1). Buchholz et al15 suggested that higher rates of local recurrence among patients undergoing breast conservation after
NACT could be explained by the small volume of resection that might not be appropriate for a large tumor that has responded to induction chemotherapy. Several prospective clinical trials have addressed the issue of survival in patients with early stage or LABC receiving preoperative chemotherapy versus those receiving postoperative chemotherapy.2,4,14,16-20 These trials have confirmed overall survival equivalence for the two approaches further emphasizing the safety of the NACT. Based on these results together with the advantage of improving tumor resectability, induction chemotherapy followed by surgery and radiation has become the preferred approach for patients with bulky, locally advanced disease at the time of diagnosis. Furthermore, Kuerer et al21 and Schwartz et al17 reported better disease-free and overall survival in patients with LABC undergoing breast conservation after NAC. However, when the responders were stratified with regard to age, there was no difference in survival between the mastectomy arm and the breast conversation arm. In addition, the studies with better survival in patients with LABC undergoing breast conservation after induction chemotherapy as compared with those undergoing mastectomy might represent selection bias because the breast conservation group likely includes patients who achieve a good response to chemotherapy.
Concerns Over This Approach/Volume of Resection As shown in several pathologic studies, the pattern of response to induction chemotherapy is not uniform but rather heterogeneous, with some cases leaving clusters of viable tumor cells at a distance from the central residual tumor site.3,22 This might explain the discrepancy between the clinical and the pathologic response to induction chemotherapy that was reported in several studies.3,21,23-25 In a retrospective study by Clouth et al,26 101 patients with LABC underwent NACT. Twenty-five patients (25%) achieved a complete clinical and radiologic response and were subjected to multiple core biopsies centrally and at all four quadrants. Pathologic examination revealed pathologic
Breast conservation therapy complete response in 16 patients, and they received adjuvant radiotherapy with no further surgery. Most of the patients (8/9) who had residual disease underwent mastectomy indicating the existence of tumor in more than one quadrant despite achieving complete clinical and radiologic response after NACT. In another study of 226 patients with tumors ⬎3 cm (87% had tumors between 3 and 5 cm) receiving NACT followed by surgery, the histopathology showed multifocality in the primary tumor in 37 patients (16.3%) and complete pathologic response was seen in only 8 patients (3.5%).22 Therefore, the assessment of tumor response to induction chemotherapy with the elimination of patients with multifocal disease is crucial when offering breast conservation in patients with LABC undergoing NACT.
Appropriate Selection Criteria Several institutions have reported their experience regarding the role of breast conservation following induction chemotherapy for LABC, nevertheless the fraction of patients offered breast conservation varies tremendously due to variability of methods utilized as well as the inconsistence of selection criteria. The eligibility criteria for breast conservation after induction chemotherapy in LABC are similar to those applied in early-stage breast cancer. Presence of multicentric disease, extensive micro-calcification, extensive skin changes, and lymphatic permeation are generally considered as contraindications for breast conservation in those patients.27 Mathew et al28 suggested that breast conservation should be performed for selected group of patients with LABC particularly those who achieve pathological complete response after NACT. Nevertheless, patients who respond partially with a significant downstaging of the tumor size, as long as lumpectomy is technically feasible, could also be candidates for conservative surgery after NACT. In the study from M. D. Anderson Cancer Center, 110 of 143 patients were not considered as good candidates for breast conservation after induction chemotherapy.1 Among those patients, 55 (50%) had tumor in other quadrants. The factors most commonly associated with multiple quadrant involvement were persistent skin edema, residual tumor size larger than 4 cm, extensive intramammary lymphatic invasion and mammographic evidence of multicentric disease. The patient desire for breast preservation is an important issue and should be also considered. Magnetic resonance imaging (MRI) may also play an important role in better identification of patients who would be good candidates for breast conservation following NACT. Multiple studies have addressed the benefit of MRI in patients with known breast cancer reporting that approximately 9% will be found to have multicentric disease that was not detected by conventional imaging.29-33 Evaluation of disease response to chemotherapy is another potential role of breast MRI in the setting of preoperative chemotherapy. Several studies have suggested a greater agreement between MRI and extent of residual disease as compared to that achieved with physical examination or conventional imaging.34-38 Yet, the
231 role of breast MRI to evaluate the feasibility of breast conservation after NACT has to be defined. Concerns regarding the sensitivity, the availability and the cost of MRI should be also considered. Positron emission tomography scans, as predictors of pathological response, have been also tried but the data remain immature and require further validation.39
Importance of Prechemotherapy Clip Placement Localization of the tumor within the breast following NACT appears to be challenging particularly in the subset of patients who achieve a complete clinical or radiological response. In a study by Edeiken et al,40 implantation of metallic markers guided by ultrasound has shown to be optimal in localization of the tumor bed in case complete response occurs following NACT. In 23 patients (47%), the metallic markers were the only remaining marker for the tumor bed following NACT. The authors added that the metallic markers showed no evidence of migration as comparisons were made on mammograms after implantation and shortly before surgery. The position of the markers was also confirmed on histopathological examination by proximity to fibrosis or scar tissue related to post-chemotherapy changes. In a recent study from M. D. Anderson Cancer Center, the omission of radio-opaque clip placement in patients undergoing preoperative chemotherapy was associated with increased incidence of local recurrence.41 The 5-year rate of local control was 98.6% in patients who had radio-opaque clips placed versus 91.7% in patients who did not have tumor marker clips placed (P ⫽ .02). The authors recommended placement of radio-opaque clips in the tumor bed before or during NACT to facilitate accurate tumor bed localization and to reduce the risk of breast tumor recurrence. However, clip placement may not be required for lesions associated with microcalcifications as they have an inherent target for subsequent localization. Skin tattooing has been shown to be effective in identification of the tumor bed as suggested by Veronesi et al.22 Nevertheless, localization by metallic markers has been more popular among surgeons particularly with the advent of recent imaging modalities.
Radiotherapy After Breast Conservation in LABC As in early breast cancer, postoperative radiotherapy is an integral part in the management of patients with LABC undergoing breast conservation. The technique of irradiation is generally the same; however, existing data are limited regarding whether comprehensive irradiation is absolutely necessary to achieve optimal locoregional control in patients whose tumors achieve substantial degree of downstaging in response to chemotherapy. The results of surgical pathology have been traditionally used to estimate the odds of locoregional recurrence following surgery in breast cancer patients and hence identifying those who would benefit from nodal irradiation. However,
232 this could not be applied for patients undergoing preoperative chemotherapy with an expected response rate up to 80%. The investigators at M. D. Anderson Cancer Center suggest that, in the preoperative chemotherapy setting, both the initial clinical stage and the final pathologic extent of the disease independently predict the risk of a locoregional recurrence.42 After NACT and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage lll-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes.43 The 5-year locoregional recurrence rate in 12 patients with stage III disease who achieved a pathologic complete remission, remained high when radiation was not used (33.3% ⫾ 15.7%).44 Therefore, for selected patients undergoing breast conservation after NACT, irradiation of the supraclavicular and may be the upper internal mammary nodes might be considered in conjunction with breast radiotherapy regardless the response to systemic treatment. Mauriac et al14 highlighted the role of surgery for axillary control as they reported higher nodal relapse in patients undergoing preoperative chemotherapy who were treated exclusively by nodal irradiation as compared to those who had axillary dissection (10 v 1, respectively). The data from NSABP B-18 & B-27 and M. D. Anderson Cancer Center suggest that patients with clinical stage II disease who have negative lymph nodes after induction chemotherapy have an 8-year risk of LRR after mastectomy that is less than 10%.45,46 Given that local or regional radiotherapy was not given in the above mentioned studies, the rate of LRR does not appear to justify nodal irradiation in this subset of patients. The power of such conclusions is limited and needs further confirmation in prospective randomized trials especially all patients from the above mentioned studies underwent axillary dissections (with or without sentinel lymph node surgery). Another challenge in the setting of postoperative radiotherapy in patients with LABC undergoing NACT is the boost volume. The question is whether or not the pre-chemotherapy volume should be irradiated particularly in patients whose tumors show significant or complete response to induction chemotherapy. Although the issue of irradiating the pre- or post-chemotherapy is still controversial, the majority of institutions consider the pre-chemotherapy size. However, the cosmetic results of irradiating such large volume, in some cases, need to be addressed because a large portion of the breast will be included in the treatment portals.
Predictors of Locoregional Failure The investigators at M. D. Anderson Cancer Center reported the results of NACT and breast conversation in 340 women, of whom 130 (38%) were stage III.12 At a median follow-up period of 60 months, the 5-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Rates of IBTR and LRR were correlated with clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multi-
M.A. Alm El-Din and A.G. Taghian focal pattern of residual disease, and lymphovascular invasion. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Nevertheless, the authors concluded that breast conservation is an acceptable modality of treatment after induction chemotherapy for patients with stage III disease. The previously mentioned four parameters were incorporated into a classification system that can be used in clinical decision-making and to counsel patients treated with this multimodality approach.47 The M. D. Anderson Prognostic Index (MDAPI) was developed by assigning scores of 0 (favorable) or 1 (unfavorable) for each of these four variables and using the total to give an overall MDAPI score of 0-4. Using the MDAPI score, patients who undergo breast conservation after NACT can be stratified into a low, intermediate, or high-risk group for IBTR and LRR. Patients with a score of 3 to 4, LRR was ⬎60% after breast conservation and was ⬍0% with mastectomy.48 The authors suggested that according to MDAPI score, patients at higher risk of recurrence may benefit from alternative locoregional treatment strategies. Asoglu et al13 suggested that negative surgical margins following breast conservation in patients undergoing NACT could be more important than clinical and histological parameters in terms of prediction of local recurrence rate.
Predictors of Disease-Free and Overall Survival The NSABP B-18 trial confirmed the association between the category of clinical response to induction chemotherapy and survival in operable breast cancer.4 Of the 682 patients, 247 (36%) had complete clinical response and 88 (13%) had complete pathological response. At 9 years of follow-up, the rates of disease-free survival was 64% in patients with complete clinical response compared to 46% in non-responders (stable disease and progressive disease; P ⫽ 0.0008). The overall survival was similarly better (75% v 65%, P ⫽ 0.005). In this study, histological response was found to be better predictor of outcome. At 9 years, the disease-free survival in patients who achieved complete pathological response was 75% compared to 58% for incomplete responders (P ⫽ 0.0005). For overall survival the rates were 85% and 73% (P ⫽ .00008). In a randomized controlled trial including patients with LABC, Heys et al5 reported significant increase in disease-free survival at 3 years in those with better clinical and pathological response (90% v 77%, P ⫽ 0.03). Another study of 200 patients with LABC, 17.6% had complete clinical response and 12.2% had complete pathological response.49 Patients with complete clinical response had better recurrence-free and overall survival as compared to those with partial response (79% and 85%, v 40% and 52%, respectively; P ⫽ 0.0001). The recurrence-free and overall survival were also significantly better for patients with complete pathological response (85% for both) as compared to those with incomplete response (52% and 59%, respectively; P ⫽ 0.0001). In
Breast conservation therapy the prospective study by Kuerer et al21 that included 372 patients with LABC receiving NACT, the 5-year disease-free and overall survival of the patients who achieved complete pathological response (87% and 89%, respectively) was significantly better than that of patients who did not respond completely to chemotherapy (58% and 64%, respectively; P ⬍ 0.01). The residual disease in the axilla following NACT has been reported to be a poor prognostic factor for the outcome.22,50,51 Rouzier et al50 reported an interesting finding on multivariate analysis of the data of 152 patients with T1 to T3 tumors with cytologically proven metastasis in the axilla. The authors found that conversion of positive to negative nodes (occurred in 23%) was a strong predictor of survival (P ⬍ 0.01) where complete pathological response in the breast was a marker of pathological axillary conversion following chemotherapy rather than a predictor of survival by itself.
Is Breast Surgery Necessary? The choice of local treatment modality after NACT has been always an area of major controversy particularly in patients with complete clinical response. After NACT, surgery and radiotherapy have been tried solely or in combination in the context of multidisciplinary approach. Touboul et al52 treated 147 patients with tumors more than 3 cm with four cycles of chemotherapy. Ninety-five patients were eligible for breast conservation (48; complete response and 47; residual disease). Patients with complete response received only radiotherapy boost where those with residual disease underwent wide excision and received two more cycles of chemotherapy followed by radiotherapy. The 5-year overall survival in the patients who underwent wide excision and radiotherapy was 81% as compared to 65% in the radiotherapy alone group. For those who underwent mastectomy, the 5-year survival was 76%. Another French study reported extremely high rate of locoregional recurrence (34%) in a group of breast cancer patients who were treated by initial chemotherapy followed by breast and nodal irradiation with no surgery.14 The results of two meta-analyses stressed on the potential role of surgery in breast cancer patients receiving NACT. The first meta-analysis evaluated the results of nine randomized studies, including a total of 3946 patients with breast cancer.53 Among the included studies, the tumor size ranged from T0 to T4b where the nodal status ranged from N0 to N2. Primary outcomes were death, disease progression, distant disease failure, and locoregional disease recurrence. The authors reported no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (risk ratio [RR] ⫽ 1.00; 95% confidence interval [CI], 0.90 to 1.12), disease progression (RR ⫽ 0.99; 95% CI, 0.91 to 1.07), or distant disease failure (RR ⫽ 0.94; 95% CI, 0.83 to 1.06). However, the risk of locoregional disease recurrences (RR ⫽ 1.22; 95% CI, 1.04 to 1.43) was significantly higher in neoadjuvant therapy compared with adjuvant therapy, particularly in trials where more patients in the neoadjuvant arm received radiation
233 therapy without surgery (RR ⫽ 1.53; 95% CI, 1.11 to 2.10). The authors recommended avoiding the use of radiotherapy without any surgical treatment, even in the presence of an apparently good clinical response to NACT. More recently, the rates of breast conservation as well as the rates of local recurrence were examined in those receiving NACT compared to those receiving adjuvant chemotherapy in meta-analysis of 11 studies including over 5000 patients with operable breast cancer.54 Despite the significantly decreased rates of mastectomy among the neoadjuvant group, the local recurrence rates were significantly higher among the same group. In the three studies, which account for more than one third of the patients, radiotherapy was the only modality of local treatment as surgery was not done after complete response. After exclusion of the results of these studies, there was no significant difference between the two groups with regard to local recurrence (Hazard Ratio 1.12; 95% CI, 0.92-1.37). Resection is also essential for documenting chemotherapy response and achieving locoregional control.55 Surgery, therefore, remains the mainstay in management of patients with LABC receiving NACT as clinical assessment could be deceiving.
Review of Data In summary, breast conservation after NACT appears to be feasible in patients with LABC because it offers an acceptable rate of disease control. The proper selection of patients who are candidates for this modality is crucial because it will affect the treatment outcome in terms of locoregional control rate, disease-free survival, and overall survival. Pre-chemotherapy clip placement is an integral part if breast conservation is to be considered after NACT, especially for those patients who might achieve complete clinical and radiologic responses. Frozen section and histopathological examination at the time of breast-conserving surgery could be important because the findings from the pathology might reveal a high probability of multicentricity, which would preclude the use of a conservative approach.
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