Ann Surg Oncol (2015) 22:1434–1440 DOI 10.1245/s10434-015-4402-x
CONTINUING EDUCATION – BREAST ONCOLOGY
Influence of Neoadjuvant Chemotherapy on Radiotherapy for Breast Cancer Amit K. Garg, MD and Thomas A. Buchholz, MD Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
ABSTRACT Neoadjuvant chemotherapy is a standard treatment option for patients with locally advanced operable breast cancer and is increasingly used in early breast cancer. Initial randomized trials of neoadjuvant chemotherapy established equivalency to adjuvant chemotherapy in terms of survival, but they also demonstrated improved rates of breast conservation and the ability to modify the risk of locoregional recurrence after a favorable response to chemotherapy. High-quality nonrandomized data have helped to tailor radiotherapy treatment recommendations after neoadjuvant chemotherapy and breast-conserving surgery or mastectomy. Results from an ongoing phase 3 randomized trial (NSABP B-51/ RTOG 1304) will help to clarify the value of locoregional
Acknowledgment: This educational review series, ‘‘Neoadjuvant Therapy in Breast Cancer’’ is supported by an educational grant from Genentech, Inc. The Society of Surgical Oncology offers CME/MOC for this educational review series. Visit moc.surgonc.org for additional information. Annals of Surgical Oncology educational reviews represent the journal’s commitment to the peer review and publication of high quality research necessary to define the safety, toxicity, or effectiveness of potential therapeutic agents compared with conventional alternatives. This Educational Review Series may include information regarding the use of medications that may be outside the approved labeling for these products. Physicians should consult the current prescribing information for these products. Authors of Annals of Surgical Oncology educational reviews are provided at the time of article solicitation with this statement regarding off-label pharmaceutical information and research. Ó Society of Surgical Oncology 2015 First Received: 28 August 2014; Published Online: 2 March 2015 A. K. Garg, MD e-mail: [email protected]
radiotherapy for patients with clinical N1 disease that becomes node negative after neoadjuvant chemotherapy.
The use of neoadjuvant chemotherapy significantly influences radiotherapy recommendations after surgery for breast cancer by potentially changing the locoregional recurrence (LRR) risk according to clinical stage. Specifically, it can decrease this risk for the subset of patients with clinically positive lymph nodes or advanced primary disease who experience a favorable pathologic response. This can then potentially lead to the question of whether these favorable subsets of patients benefit from radiation or whether radiation should be reserved for patients with greater degrees of residual disease.1–3 Moreover, response rates continue to improve in molecular subtypes of breast cancer that may benefit from more recently available targeted therapies.4,5 Although radiotherapy for breast cancer has been shown to improve locoregional control and improve survival for selected breast cancer patients who undergo breast conservation or mastectomy, these initial trials did not include patients treated with neoadjuvant chemotherapy.6–11 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 and the European Organisation for Research and Treatment of Cancer (EORTC) 10902 compared neoadjuvant chemotherapy to adjuvant chemotherapy in patients with mostly early breast cancer T1–3N0–1 who underwent breast conservation or mastectomy.2,12 Radiotherapy in these trials was limited to the whole breast after breast conservation or not performed at all after mastectomy. Therefore, the value of these trials in helping to tailor radiotherapy treatment recommendations after mastectomy is based mainly on information of LRR risk in the absence of radiotherapy. Many of the studies demonstrating the benefit of radiotherapy in patients treated with neoadjuvant chemotherapy come from data collected retrospectively at
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Clinical T stage 1 -3, N1
nonrandomized studies have demonstrated that neoadjuvant chemotherapy followed by BCS and radiotherapy leads to excellent results in properly selected patients. The NSABP B-18 and EORTC 10902 randomized trials compared neoadjuvant chemotherapy to adjuvant chemotherapy in operable breast cancer patients and found no difference in overall survival, but they did find a higher rate of breast conservation in the neoadjuvant chemotherapy arms (68 vs. 60 % in NSABP B-18 and 35 vs. 22 % in EORTC 10902).2–4 These improvements in breast conservation rates were not associated with an increase in longterm LRR between the arms (13 vs. 10 % in NSABP B-18 and 20 vs. 20 % in EORTC 10902). Not surprisingly, patients with T3 tumors were most likely to benefit from a change of surgical approach from mastectomy to breast conservation after a favorable response to neoadjuvant chemotherapy.1 A meta-analysis of 14 randomized trials that included 5,500 patients who underwent neoadjuvant versus adjuvant chemotherapy found a 17 % lower rate of mastectomy in patients who received neoadjuvant chemotherapy and no difference in locoregional control or survival based on timing of chemotherapy.24 In a recent update of 1,100 patients who underwent breast conservation after neoadjuvant chemotherapy on the NSABP B-18 and B-27 trials, the 10-year LRR rate was 10.3 %.1 Independent predictors of LRR included age \50 years, positive clinical nodal status, and pathologically positive lymph node status and lack of complete response in the breast. Taken together, these randomized data suggest that BCS followed by whole breast radiotherapy is a safe and effective approach after neoadjuvant chemotherapy for select patients, and that both clinical and pathologic factors are important predictors of LRR. Consideration of nodal radiation in high-risk subsets is also warranted. Nonrandomized data of breast conservation after neoadjuvant chemotherapy have helped to further define subsets of patients at risk for recurrence. In 2004, MD Anderson Cancer Center investigators reported on 340 patients, the majority with IIB or III disease (72 %), who underwent BCS and radiotherapy after neoadjuvant chemotherapy and found that clinical N2 or N3 disease, lymphovascular invasion, multifocal pattern of residual disease, and residual primary tumor [2 cm predicted local recurrence.16 Nodal radiation was used at the discretion of the treating physicians. Although overall 5- and 10-year local recurrence rates were 5 and 10 %, respectively, recurrence rates were as high as 45 % when three of the above factors were present. These four prognostic factors were subsequently used in studies that compared outcomes in patients who received neoadjuvant chemotherapy and breast conservation or mastectomy followed by radiation.13,19
Neoadjuvant Chemotherapy
Mastectomy
pN+
pN-
No radiotherapy
XRT to chest wall + regional LN*
Breast Conservation
pN-
pN+
Whole Breast XRT
Whole breast XRT + regional LN*
*regional lymph nodes include supraclavicular fossa, internal mammary chain, undissected axilla
FIG. 1 Currently accruing NSABP B-51/RTOG 1304 phase 3 randomized trial. Asterisk regional lymph nodes include supraclavicular fossa, internal mammary chain, and undissected axilla
MD Anderson from 1974 to the present.13–22 These series help to quantify LRR risk with and without radiotherapy for a variety of patient subgroups that underwent neoadjuvant chemotherapy and either breast-conserving surgery (BCS) or mastectomy. Taken together, these studies have provided a strong rationale for the provision of postoperative radiotherapy to the breast or chest wall as well as the regional lymph nodes for patients with clinical stage III or greater disease at presentation as well as select patients with stage II disease and high-risk features after neoadjuvant chemotherapy. The NSABP B-51/Radiation Therapy Oncology Group (RTOG) 1304 randomized phase 3 trial will provide valuable data to assess whether it is safe to limit the extent of radiotherapy in stage II/III breast cancer patients who present with clinical N1 disease and become node negative after neoadjuvant chemotherapy (Fig. 1). BREAST CONSERVATION AFTER NEOADJUVANT CHEMOTHERAPY Neoadjuvant chemotherapy is increasingly used to help shrink primary breast tumors that would otherwise not be amenable to up-front BCS based on large tumor size or unfavorable breast/tumor size ratio. When this approach is successful, less breast tissue is required to be removed at the time of surgery and therefore cosmesis is potentially improved.23 Whole breast radiotherapy is used as part of breast conservation in this setting to eradicate microscopic disease and improve local control. Randomized and high-quality
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A recent report from MD Anderson evaluated the impact of chemotherapy timing in a large review of 2,984 patients who underwent BCS and whole breast radiotherapy, 652 of whom received neoadjuvant chemotherapy.25 Despite more advanced disease, younger age, and a higher proportion of high-grade disease and estrogen receptor–negative tumors, patients who received neoadjuvant chemotherapy and breast-conservation therapy had low rates of 5- and 10-year LRR (7 and 10 %, respectively), although this was statistically significantly higher than LRR rates in patients who underwent initial surgery (3 and 6 % for 5- and 10-year LRR, respectively). Multivariate analysis revealed age \50 years, clinical stage III disease, estrogen receptor negativity, lack of use of hormone therapy in estrogen receptor–positive tumors, residual multifocal disease on pathology, lymphovascular invasion, and close or positive margins to be predictive of recurrence. When adjusting for clinical stage at presentation, there was no difference in LRR between patients treated with neoadjuvant versus adjuvant chemotherapy. Furthermore, neoadjuvant chemotherapy downstaged 52 % of patients with stage II/III disease to pathologic 0/I disease. The authors concluded that tumor biology and initial stage were the driving factors of local recurrence, rather than timing of chemotherapy relative to surgery.
POSTMASTECTOMY RADIOTHERAPY AFTER NEOADJUVANT CHEMOTHERAPY Many women undergo mastectomy after neoadjuvant chemotherapy for a variety of reasons, including inadequate response to chemotherapy or perceived higher risk of LRR compared to breast conservation based on the presence of adverse prognostic factors. Although randomized trials have helped to guide postmastectomy radiotherapy decisions after initial surgery, no randomized studies exist that compare outcomes with or without radiotherapy after neoadjuvant chemotherapy and mastectomy.6,7,9–11 Patients enrolled in NSABP B-18 and B-27 had clinical stage T1–T3N0–N1 disease, and those who received mastectomy after neoadjuvant chemotherapy were not permitted to receive postmastectomy radiation.1 However, valuable insight into predictors of LRR in patients treated on these trials without radiation as well as retrospective data collected from prospective studies at MD Anderson have helped to guide postmastectomy radiation decisions thus far. In the pooled analysis of the NSABP B-18 and B-27 studies, the 10-year cumulative incidence of LRR in the 1,947 patients who underwent mastectomy after neoadjuvant chemotherapy was 12.6 %.1 Predictors of LRR in this group were clinical tumor size ([5 vs. \5 cm), clinical
A. K. Garg, T. A. Buchholz
nodal involvement, and pathologic nodal status/breast tumor response. These results are consistent with an earlier report from MD Anderson on 150 patients treated on prospective trials from 1974 to 1998 with neoadjuvant chemotherapy and mastectomy without radiation that found that both clinical presentation and pathologic extent after neoadjuvant chemotherapy were important predictors of LRR.14 Specifically, more advanced T stage at presentation, more advanced combined clinical stage at presentation, larger tumor size after chemotherapy, and increasing number of positive lymph nodes after chemotherapy were predictive of LRR. Subgroup analysis found that clinical IIB or higher stage at presentation, pathologically involved lymph nodes after neoadjuvant chemotherapy, and clinical T3 or T4 disease without pathologically involved lymph nodes were all groups associated with a high enough locoregional risk ([15 %) to warrant consideration of risk-reduction with postmastectomy radiotherapy to the chest wall and draining lymphatics. In 2004, MD Anderson investigators reported outcomes from a comparison of 542 patients treated with neoadjuvant doxorubicin-based protocols from 1974 to 2000 who received mastectomy and postmastectomy radiation with 134 similarly treated patients who did not receive postmastectomy radiation.20 Comprehensive postmastectomy radiation was typically used, which included treatment to the chest wall and draining lymphatics, including the supraclavicular fossa and internal mammary chain. They found both clinical and pathologic factors to be predictive of locoregional and cause-specific survival benefit from postmastectomy radiotherapy, including clinical T3 or higher disease at presentation, clinical N2–3 disease at presentation, pathologic tumor size at the time of resection, and four or more positive lymph nodes involved at resection. Additional retrospective studies from MD Anderson have sought to identify subgroups of patients who may benefit from postmastectomy radiotherapy after neoadjuvant chemotherapy and mastectomy. An initial study in stage I or II breast cancer patients found that clinical T3 disease at presentation, age 40 or younger, and four or more lymph nodes positive at surgery predicted for LRR after neoadjuvant chemotherapy and mastectomy.18 A more recent analysis of clinical T3 node-negative breast cancer also found an improvement in 5-year LRR with postmastectomy radiation after neoadjuvant chemotherapy and surgery.22 The benefit of radiotherapy was of borderline significance in the 89 patients who remained nodenegative after surgery (2 vs. 14 % with and without radiation, respectively, p = 0.06). Analysis of clinical T3 node-negative patients treated in NSABP B-18 and B-27 suggested that rates of LRR were higher than 10 % when
Influence of Chemotherapy on Radiotherapy
there was an absence of complete response in the breast or when axillary nodes were positive at the time of surgery but that they remained low (\7 %) when a complete pathologic response was seen in both the breast and axilla.1 Although data for clinical T3 node negative breast cancer are mixed, it remains MD Anderson’s practice to consider postmastectomy radiation in this subset of patients, regardless of response to neoadjuvant chemotherapy. In a series of 107 patients younger than 35 who received neoadjuvant chemotherapy and mastectomy, postmastectomy radiotherapy was associated with reduced 5-year LRR (12 vs. 37 %, p = 0.001) and improved survival (67 vs. 48 %, p = 0.031) compared to those who did not receive radiotherapy despite more advanced disease features in patients who received radiation.17 The authors concluded that young age is an important factor when considering postmastectomy radiotherapy, especially in those with stage IIB or higher disease.
BREAST CONSERVATION VERSUS MASTECTOMY WITH RADIATION AFTER NEOADJUVANT CHEMOTHERAPY No randomized studies have compared breast conservation versus mastectomy in advanced breast cancer patients who receive neoadjuvant chemotherapy and radiation. However, MD Anderson investigators retrospectively compared BCS and mastectomy in patients who received neoadjuvant chemotherapy and radiation according to a model of four prognostic criteria (clinical N2 or N3 disease, lymphovascular space invasion, a multifocal pattern of residual disease, and residual primary tumor larger than 2 cm) that were independently predictive of LRR in a previous study of neoadjuvant chemotherapy and breast conservation.13,19 In the initial study published in 2006, 815 patients underwent neoadjuvant chemotherapy, surgery, and radiation, and those with 3 or 4 of the prognostic factors had significantly lower 10-year LRR with mastectomy than those who underwent breast conservation (19 vs. 61 %, respectively, p = 0.009).19 A more recent study from MD Anderson using an independent data set of 551 patients treated similarly with neoadjuvant chemotherapy, surgery, and radiation found similar rates of LRR between breast conservation and mastectomy when 2 or fewer adverse prognostic factors were present, but the study found lower rates of LRR with mastectomy when 3 or 4 factors were present (7 vs. 31 %, p = 0.007).13 Taken together, these retrospective results and data suggest that selecting patients for breast conservation or mastectomy after neoadjuvant chemotherapy requires careful multidisciplinary assessment of clinical and pathologic factors.
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INDIVIDUALIZING RADIOTHERAPY BASED ON PATHOLOGIC RESPONSE Significant debate exists regarding the recurrence risk and thus the benefit of postsurgical radiotherapy in subgroups of breast cancer patients who experience a favorable response in the breast and/or axilla after neoadjuvant chemotherapy. With modern chemotherapy regimens, approximately 40 % of patients who present with involved axillary lymph nodes are node negative at surgery after neoadjuvant chemotherapy, and this percentage may be significantly higher in the breast and/or axilla depending on the molecular subtype of disease.26–29 The pooled analysis of all three arms of NSABP B-27 and the preoperative arm of B-18 provides important insight into LRR risk for subgroups of patients for whom the benefit of radiation is questioned. Specifically, patients with clinically involved lymph nodes before neoadjuvant chemotherapy who became pathologically node negative at surgery had low rates of LRR (approximately 10 % or below) regardless of surgical approach.1 Rates of recurrence were even lower when a complete response was concurrently seen in the breast. Highest rates of recurrence were seen in patients who remained node positive after neoadjuvant chemotherapy. Limitations of the data from NSABP B-27 and B-18 include the absence of histologic confirmation of pretreatment lymph nodes, low pathologic complete response rates, and challenges in the assessment of LRR that may have understated locoregional failure.30 Moreover, it is important to emphasize that most patients had stage I or II breast cancer, with only 30 % having clinical N1 disease. Because these trials were initiated before a survival benefit was demonstrated in node-positive patients with postmastectomy radiotherapy or nodal radiation plus whole breast radiotherapy, no radiation was permitted in patients undergoing mastectomy, and only whole breast radiation was used in breast conservation patients.7,10,11,31 Recent retrospective studies from Korea and France have also contributed to the hypothesis that recurrence risk may be sufficiently low to omit radiotherapy in select patients with stage II-III breast cancer after a favorable response to neoadjuvant chemotherapy and mastectomy.32,33 In the Korean study, no statistically significant differences in outcomes were seen in 46 patients with pathologic node-negative status at surgery who did not receive postmastectomy radiotherapy, when compared to 105 patients also with pathologic node-negative disease who received radiotherapy. Similarly, the French study found no difference in local-regional recurrence rates or overall survival in 56 patients with pathologic node-negative disease after neoadjuvant chemotherapy who did not receive postmastectomy radiotherapy when compared to
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the 78 pathologic node-negative patients who did receive radiotherapy. An important caveat for both of these retrospective studies is that clinical N1 and N2 disease were grouped together, and thus the impact of more advanced nodal disease at presentation on recurrence rates after neoadjuvant chemotherapy and mastectomy remained unanswered. The ongoing NSABP B-51/RTOG 1304 randomized trial is designed to assess the value of nodal radiotherapy in patients with biopsy-proven clinical N1 axillary nodal disease before neoadjuvant chemotherapy that becomes pathologically node negative at the time of surgery (see Fig. 1). The results from this trial will help to quantify the benefit, if any, of locoregional radiotherapy in the setting of pathologic response to neoadjuvant chemotherapy in stage I to IIIA breast cancer. Importantly, patients with locally or regionally advanced disease including T4 disease or N2/N3 disease are not eligible, as the significant benefit of comprehensive postsurgical radiotherapy has been previously demonstrated even when a complete pathologic response is seen after neoadjuvant chemotherapy and maximal surgery.21 PRACTICAL CONSIDERATIONS AND RADIOTHERAPY TECHNIQUE The results above place an emphasis on accurate clinical staging before neoadjuvant chemotherapy and warrant careful multidisciplinary assessment of clinical and pathologic risk factors that help inform postsurgical radiotherapy recommendations in select patients. At MD Anderson, it is standard to obtain a mammogram and ultrasound of the breast and regional lymph nodes (axilla, supraclavicular, infraclavicular) and biopsy (fine-needle aspiration) of any suspicious lymph nodes before the initiation of neoadjuvant chemotherapy. Patients who may be eligible for breast conservation have clips placed at the site of the primary tumor, and imaging is done to make sure any suspicious calcifications or residual disease are removed before radiotherapy. Systemic staging is performed in select patients with positive lymph nodes. Sentinel node biopsy is typically performed after neoadjuvant chemotherapy in clinically node-negative patients, and full axillary dissection is performed after neoadjuvant chemotherapy in patients with clinically positive lymph nodes. It should be noted that sentinel lymph node biopsy after neoadjuvant chemotherapy in clinically node-positive patients may still have a role and thus may also influence radiotherapy discussion and technique in the future.34,35 The currently accruing ALLIANCE A011202 phase 3 study is designed to answer the question of whether axillary node dissection or targeted axillary nodal radiation provides similar control in patients with a
A. K. Garg, T. A. Buchholz
positive sentinel lymph node after completion of neoadjuvant chemotherapy. At MD Anderson, comprehensive nodal radiation to the supraclavicular fossa and internal mammary chain is considered for clinically node-positive patients after neoadjuvant chemotherapy and surgery. Findings at the time of surgery, including response to chemotherapy, number of lymph nodes involved and examined, and presence of high-risk factors (lymphovascular invasion, extranodal extension, high-grade disease), help tailor recommendations. In patients with positive sentinel nodes after neoadjuvant chemotherapy who do not undergo further surgery, the undissected axilla is also a target. The chest wall and draining lymphatics typically receive 50 Gy over 5 weeks with a 10 Gy boost to the chest wall if margins are negative. In node-negative patients who receive breast conservation, an abbreviated course of whole breast radiotherapy is considered a standard option. Respiratory gating is a technique that is also used in leftsided breast cancers that may benefit from additional protection to the heart and lungs.36 In patients with clinically positive infraclavicular, supraclavicular, or internal mammary lymph nodes, these regions receive an additional radiation boost of 10–16 Gy, depending on response to neoadjuvant chemotherapy. Accelerated partial breast irradiation is not currently considered appropriate after neoadjuvant chemotherapy. Because radiotherapy in breast cancer is not without its risks, including cardiopulmonary toxicity, lymphedema, and secondary malignancy, quality assurance is considered a key element in its proper delivery.37–42 Finally, the complex interplay between breast reconstruction and radiotherapy technique and toxicity is also an important consideration that warrants careful multidisciplinary engagement.37,43 CONCLUSIONS Neoadjuvant chemotherapy has significantly influenced radiotherapy management decisions in patients who undergo breast conservation or mastectomy. Both clinical and pathologic characteristics contribute to LRR risk after neoadjuvant chemotherapy. Consideration of radiotherapy to the breast and regional nodes or chest wall and regional nodes is warranted in patients with stage IIIA or higher breast cancer after neoadjuvant chemotherapy and breast conservation or mastectomy. Treatment is commonly tailored for those with stage II breast cancer based on clinical factors, the presence or absence of high-risk features, and response to chemotherapy. Upcoming results from the NSABP B-51/RTOG 1304 trial will also help to assess the benefit of locoregional radiotherapy for clinical N1 breast
Influence of Chemotherapy on Radiotherapy
cancers that become node negative after neoadjuvant chemotherapy. DISCLOSURE
The authors declare no conflict of interest.
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1439 15. Buchholz TA, Tucker SL, Masullo L, et al. Predictors of localregional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol. 2002;20:17–23. 16. Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer center experience. J Clin Oncol. 2004;22:2303–12. 17. Garg AK, Oh JL, Oswald MJ, et al. Effect of postmastectomy radiotherapy in patients \35 years old with stage II–III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy. Int J Radiat Oncol Biol Phys. 2007;69:1478–83. 18. Garg AK, Strom EA, McNeese MD, et al. T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for locoregional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59:138–45. 19. Huang EH, Strom EA, Perkins GH, et al. Comparison of risk of local-regional 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. 2006;66:352–7. 20. Huang EH, Tucker SL, Strom EA, et al. Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol. 2004;22: 4691–9. 21. McGuire SE, Gonzalez-Angulo AM, Huang EH, et al. Postmastectomy radiation improves the outcome of patients with locally advanced breast cancer who achieve a pathologic complete response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1004–9. 22. Nagar H, Mittendorf EA, Strom EA, et al. Local-regional recurrence with and without radiation therapy after neoadjuvant chemotherapy and mastectomy for clinically staged T3N0 breast cancer. Int J Radiat Oncol Biol Phys. 2011;81:782–7. 23. Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg. 2006; 244:464–70. 24. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg. 2007;94: 1189–200. 25. Mittendorf EA, Buchholz TA, Tucker SL, et al. Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy. Ann Surg. 2013;257:173–9. 26. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2–positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13:228–33. 27. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2negative cohort. Lancet. 2010;375(9712):377–84. 28. Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg. 1999;230:72–8. 29. Mamounas EP, Brown A, Anderson S, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from
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A. K. Garg, T. A. Buchholz 36. Wang X, Pan T, Pinnix C, et al. Cardiac motion during deep-inspiration breath-hold: implications for breast cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2012;82:708–14. 37. Buchholz TA, Lehman CD, Harris JR, et al. Statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer: a National Cancer Institute conference. J Clin Oncol. 2008;26:791–7. 38. Cutter DJ, Darby SC, Yusuf SW. Risks of heart disease after radiotherapy. Tex Heart Inst J. 2011;38:257–8. 39. Jagsi R, Griffith KA, Koelling T, Roberts R, Pierce LJ. Rates of myocardial infarction and coronary artery disease and risk factors in patients treated with radiation therapy for early-stage breast cancer. Cancer. 2007;109:650–7. 40. Kong FM, Pan C, Eisbruch A, Ten Haken RK. Physical models and simpler dosimetric descriptors of radiation late toxicity. Semin Radiat Oncol. 2007;17:108–20. 41. McGale P, Darby SC, Hall P, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol. 2011;100:167–75. 42. Parkin DM, Darby SC. Cancers in 2010 attributable to ionising radiation exposure in the UK. Br J Cancer. 2011;105:S57–65. 43. Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction: a critical review of the literature. Plast Reconstr Surg. 2009;124:395–408.
CONTINUING EDUCATION – BREAST ONCOLOGY
Influence of Neoadjuvant Chemotherapy on Radiotherapy for Breast Cancer Amit K. Garg, MD and Thomas A. Buchholz, MD Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
ABSTRACT Neoadjuvant chemotherapy is a standard treatment option for patients with locally advanced operable breast cancer and is increasingly used in early breast cancer. Initial randomized trials of neoadjuvant chemotherapy established equivalency to adjuvant chemotherapy in terms of survival, but they also demonstrated improved rates of breast conservation and the ability to modify the risk of locoregional recurrence after a favorable response to chemotherapy. High-quality nonrandomized data have helped to tailor radiotherapy treatment recommendations after neoadjuvant chemotherapy and breast-conserving surgery or mastectomy. Results from an ongoing phase 3 randomized trial (NSABP B-51/ RTOG 1304) will help to clarify the value of locoregional
Acknowledgment: This educational review series, ‘‘Neoadjuvant Therapy in Breast Cancer’’ is supported by an educational grant from Genentech, Inc. The Society of Surgical Oncology offers CME/MOC for this educational review series. Visit moc.surgonc.org for additional information. Annals of Surgical Oncology educational reviews represent the journal’s commitment to the peer review and publication of high quality research necessary to define the safety, toxicity, or effectiveness of potential therapeutic agents compared with conventional alternatives. This Educational Review Series may include information regarding the use of medications that may be outside the approved labeling for these products. Physicians should consult the current prescribing information for these products. Authors of Annals of Surgical Oncology educational reviews are provided at the time of article solicitation with this statement regarding off-label pharmaceutical information and research. Ó Society of Surgical Oncology 2015 First Received: 28 August 2014; Published Online: 2 March 2015 A. K. Garg, MD e-mail: [email protected]
radiotherapy for patients with clinical N1 disease that becomes node negative after neoadjuvant chemotherapy.
The use of neoadjuvant chemotherapy significantly influences radiotherapy recommendations after surgery for breast cancer by potentially changing the locoregional recurrence (LRR) risk according to clinical stage. Specifically, it can decrease this risk for the subset of patients with clinically positive lymph nodes or advanced primary disease who experience a favorable pathologic response. This can then potentially lead to the question of whether these favorable subsets of patients benefit from radiation or whether radiation should be reserved for patients with greater degrees of residual disease.1–3 Moreover, response rates continue to improve in molecular subtypes of breast cancer that may benefit from more recently available targeted therapies.4,5 Although radiotherapy for breast cancer has been shown to improve locoregional control and improve survival for selected breast cancer patients who undergo breast conservation or mastectomy, these initial trials did not include patients treated with neoadjuvant chemotherapy.6–11 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 and the European Organisation for Research and Treatment of Cancer (EORTC) 10902 compared neoadjuvant chemotherapy to adjuvant chemotherapy in patients with mostly early breast cancer T1–3N0–1 who underwent breast conservation or mastectomy.2,12 Radiotherapy in these trials was limited to the whole breast after breast conservation or not performed at all after mastectomy. Therefore, the value of these trials in helping to tailor radiotherapy treatment recommendations after mastectomy is based mainly on information of LRR risk in the absence of radiotherapy. Many of the studies demonstrating the benefit of radiotherapy in patients treated with neoadjuvant chemotherapy come from data collected retrospectively at
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Clinical T stage 1 -3, N1
nonrandomized studies have demonstrated that neoadjuvant chemotherapy followed by BCS and radiotherapy leads to excellent results in properly selected patients. The NSABP B-18 and EORTC 10902 randomized trials compared neoadjuvant chemotherapy to adjuvant chemotherapy in operable breast cancer patients and found no difference in overall survival, but they did find a higher rate of breast conservation in the neoadjuvant chemotherapy arms (68 vs. 60 % in NSABP B-18 and 35 vs. 22 % in EORTC 10902).2–4 These improvements in breast conservation rates were not associated with an increase in longterm LRR between the arms (13 vs. 10 % in NSABP B-18 and 20 vs. 20 % in EORTC 10902). Not surprisingly, patients with T3 tumors were most likely to benefit from a change of surgical approach from mastectomy to breast conservation after a favorable response to neoadjuvant chemotherapy.1 A meta-analysis of 14 randomized trials that included 5,500 patients who underwent neoadjuvant versus adjuvant chemotherapy found a 17 % lower rate of mastectomy in patients who received neoadjuvant chemotherapy and no difference in locoregional control or survival based on timing of chemotherapy.24 In a recent update of 1,100 patients who underwent breast conservation after neoadjuvant chemotherapy on the NSABP B-18 and B-27 trials, the 10-year LRR rate was 10.3 %.1 Independent predictors of LRR included age \50 years, positive clinical nodal status, and pathologically positive lymph node status and lack of complete response in the breast. Taken together, these randomized data suggest that BCS followed by whole breast radiotherapy is a safe and effective approach after neoadjuvant chemotherapy for select patients, and that both clinical and pathologic factors are important predictors of LRR. Consideration of nodal radiation in high-risk subsets is also warranted. Nonrandomized data of breast conservation after neoadjuvant chemotherapy have helped to further define subsets of patients at risk for recurrence. In 2004, MD Anderson Cancer Center investigators reported on 340 patients, the majority with IIB or III disease (72 %), who underwent BCS and radiotherapy after neoadjuvant chemotherapy and found that clinical N2 or N3 disease, lymphovascular invasion, multifocal pattern of residual disease, and residual primary tumor [2 cm predicted local recurrence.16 Nodal radiation was used at the discretion of the treating physicians. Although overall 5- and 10-year local recurrence rates were 5 and 10 %, respectively, recurrence rates were as high as 45 % when three of the above factors were present. These four prognostic factors were subsequently used in studies that compared outcomes in patients who received neoadjuvant chemotherapy and breast conservation or mastectomy followed by radiation.13,19
Neoadjuvant Chemotherapy
Mastectomy
pN+
pN-
No radiotherapy
XRT to chest wall + regional LN*
Breast Conservation
pN-
pN+
Whole Breast XRT
Whole breast XRT + regional LN*
*regional lymph nodes include supraclavicular fossa, internal mammary chain, undissected axilla
FIG. 1 Currently accruing NSABP B-51/RTOG 1304 phase 3 randomized trial. Asterisk regional lymph nodes include supraclavicular fossa, internal mammary chain, and undissected axilla
MD Anderson from 1974 to the present.13–22 These series help to quantify LRR risk with and without radiotherapy for a variety of patient subgroups that underwent neoadjuvant chemotherapy and either breast-conserving surgery (BCS) or mastectomy. Taken together, these studies have provided a strong rationale for the provision of postoperative radiotherapy to the breast or chest wall as well as the regional lymph nodes for patients with clinical stage III or greater disease at presentation as well as select patients with stage II disease and high-risk features after neoadjuvant chemotherapy. The NSABP B-51/Radiation Therapy Oncology Group (RTOG) 1304 randomized phase 3 trial will provide valuable data to assess whether it is safe to limit the extent of radiotherapy in stage II/III breast cancer patients who present with clinical N1 disease and become node negative after neoadjuvant chemotherapy (Fig. 1). BREAST CONSERVATION AFTER NEOADJUVANT CHEMOTHERAPY Neoadjuvant chemotherapy is increasingly used to help shrink primary breast tumors that would otherwise not be amenable to up-front BCS based on large tumor size or unfavorable breast/tumor size ratio. When this approach is successful, less breast tissue is required to be removed at the time of surgery and therefore cosmesis is potentially improved.23 Whole breast radiotherapy is used as part of breast conservation in this setting to eradicate microscopic disease and improve local control. Randomized and high-quality
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A recent report from MD Anderson evaluated the impact of chemotherapy timing in a large review of 2,984 patients who underwent BCS and whole breast radiotherapy, 652 of whom received neoadjuvant chemotherapy.25 Despite more advanced disease, younger age, and a higher proportion of high-grade disease and estrogen receptor–negative tumors, patients who received neoadjuvant chemotherapy and breast-conservation therapy had low rates of 5- and 10-year LRR (7 and 10 %, respectively), although this was statistically significantly higher than LRR rates in patients who underwent initial surgery (3 and 6 % for 5- and 10-year LRR, respectively). Multivariate analysis revealed age \50 years, clinical stage III disease, estrogen receptor negativity, lack of use of hormone therapy in estrogen receptor–positive tumors, residual multifocal disease on pathology, lymphovascular invasion, and close or positive margins to be predictive of recurrence. When adjusting for clinical stage at presentation, there was no difference in LRR between patients treated with neoadjuvant versus adjuvant chemotherapy. Furthermore, neoadjuvant chemotherapy downstaged 52 % of patients with stage II/III disease to pathologic 0/I disease. The authors concluded that tumor biology and initial stage were the driving factors of local recurrence, rather than timing of chemotherapy relative to surgery.
POSTMASTECTOMY RADIOTHERAPY AFTER NEOADJUVANT CHEMOTHERAPY Many women undergo mastectomy after neoadjuvant chemotherapy for a variety of reasons, including inadequate response to chemotherapy or perceived higher risk of LRR compared to breast conservation based on the presence of adverse prognostic factors. Although randomized trials have helped to guide postmastectomy radiotherapy decisions after initial surgery, no randomized studies exist that compare outcomes with or without radiotherapy after neoadjuvant chemotherapy and mastectomy.6,7,9–11 Patients enrolled in NSABP B-18 and B-27 had clinical stage T1–T3N0–N1 disease, and those who received mastectomy after neoadjuvant chemotherapy were not permitted to receive postmastectomy radiation.1 However, valuable insight into predictors of LRR in patients treated on these trials without radiation as well as retrospective data collected from prospective studies at MD Anderson have helped to guide postmastectomy radiation decisions thus far. In the pooled analysis of the NSABP B-18 and B-27 studies, the 10-year cumulative incidence of LRR in the 1,947 patients who underwent mastectomy after neoadjuvant chemotherapy was 12.6 %.1 Predictors of LRR in this group were clinical tumor size ([5 vs. \5 cm), clinical
A. K. Garg, T. A. Buchholz
nodal involvement, and pathologic nodal status/breast tumor response. These results are consistent with an earlier report from MD Anderson on 150 patients treated on prospective trials from 1974 to 1998 with neoadjuvant chemotherapy and mastectomy without radiation that found that both clinical presentation and pathologic extent after neoadjuvant chemotherapy were important predictors of LRR.14 Specifically, more advanced T stage at presentation, more advanced combined clinical stage at presentation, larger tumor size after chemotherapy, and increasing number of positive lymph nodes after chemotherapy were predictive of LRR. Subgroup analysis found that clinical IIB or higher stage at presentation, pathologically involved lymph nodes after neoadjuvant chemotherapy, and clinical T3 or T4 disease without pathologically involved lymph nodes were all groups associated with a high enough locoregional risk ([15 %) to warrant consideration of risk-reduction with postmastectomy radiotherapy to the chest wall and draining lymphatics. In 2004, MD Anderson investigators reported outcomes from a comparison of 542 patients treated with neoadjuvant doxorubicin-based protocols from 1974 to 2000 who received mastectomy and postmastectomy radiation with 134 similarly treated patients who did not receive postmastectomy radiation.20 Comprehensive postmastectomy radiation was typically used, which included treatment to the chest wall and draining lymphatics, including the supraclavicular fossa and internal mammary chain. They found both clinical and pathologic factors to be predictive of locoregional and cause-specific survival benefit from postmastectomy radiotherapy, including clinical T3 or higher disease at presentation, clinical N2–3 disease at presentation, pathologic tumor size at the time of resection, and four or more positive lymph nodes involved at resection. Additional retrospective studies from MD Anderson have sought to identify subgroups of patients who may benefit from postmastectomy radiotherapy after neoadjuvant chemotherapy and mastectomy. An initial study in stage I or II breast cancer patients found that clinical T3 disease at presentation, age 40 or younger, and four or more lymph nodes positive at surgery predicted for LRR after neoadjuvant chemotherapy and mastectomy.18 A more recent analysis of clinical T3 node-negative breast cancer also found an improvement in 5-year LRR with postmastectomy radiation after neoadjuvant chemotherapy and surgery.22 The benefit of radiotherapy was of borderline significance in the 89 patients who remained nodenegative after surgery (2 vs. 14 % with and without radiation, respectively, p = 0.06). Analysis of clinical T3 node-negative patients treated in NSABP B-18 and B-27 suggested that rates of LRR were higher than 10 % when
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there was an absence of complete response in the breast or when axillary nodes were positive at the time of surgery but that they remained low (\7 %) when a complete pathologic response was seen in both the breast and axilla.1 Although data for clinical T3 node negative breast cancer are mixed, it remains MD Anderson’s practice to consider postmastectomy radiation in this subset of patients, regardless of response to neoadjuvant chemotherapy. In a series of 107 patients younger than 35 who received neoadjuvant chemotherapy and mastectomy, postmastectomy radiotherapy was associated with reduced 5-year LRR (12 vs. 37 %, p = 0.001) and improved survival (67 vs. 48 %, p = 0.031) compared to those who did not receive radiotherapy despite more advanced disease features in patients who received radiation.17 The authors concluded that young age is an important factor when considering postmastectomy radiotherapy, especially in those with stage IIB or higher disease.
BREAST CONSERVATION VERSUS MASTECTOMY WITH RADIATION AFTER NEOADJUVANT CHEMOTHERAPY No randomized studies have compared breast conservation versus mastectomy in advanced breast cancer patients who receive neoadjuvant chemotherapy and radiation. However, MD Anderson investigators retrospectively compared BCS and mastectomy in patients who received neoadjuvant chemotherapy and radiation according to a model of four prognostic criteria (clinical N2 or N3 disease, lymphovascular space invasion, a multifocal pattern of residual disease, and residual primary tumor larger than 2 cm) that were independently predictive of LRR in a previous study of neoadjuvant chemotherapy and breast conservation.13,19 In the initial study published in 2006, 815 patients underwent neoadjuvant chemotherapy, surgery, and radiation, and those with 3 or 4 of the prognostic factors had significantly lower 10-year LRR with mastectomy than those who underwent breast conservation (19 vs. 61 %, respectively, p = 0.009).19 A more recent study from MD Anderson using an independent data set of 551 patients treated similarly with neoadjuvant chemotherapy, surgery, and radiation found similar rates of LRR between breast conservation and mastectomy when 2 or fewer adverse prognostic factors were present, but the study found lower rates of LRR with mastectomy when 3 or 4 factors were present (7 vs. 31 %, p = 0.007).13 Taken together, these retrospective results and data suggest that selecting patients for breast conservation or mastectomy after neoadjuvant chemotherapy requires careful multidisciplinary assessment of clinical and pathologic factors.
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INDIVIDUALIZING RADIOTHERAPY BASED ON PATHOLOGIC RESPONSE Significant debate exists regarding the recurrence risk and thus the benefit of postsurgical radiotherapy in subgroups of breast cancer patients who experience a favorable response in the breast and/or axilla after neoadjuvant chemotherapy. With modern chemotherapy regimens, approximately 40 % of patients who present with involved axillary lymph nodes are node negative at surgery after neoadjuvant chemotherapy, and this percentage may be significantly higher in the breast and/or axilla depending on the molecular subtype of disease.26–29 The pooled analysis of all three arms of NSABP B-27 and the preoperative arm of B-18 provides important insight into LRR risk for subgroups of patients for whom the benefit of radiation is questioned. Specifically, patients with clinically involved lymph nodes before neoadjuvant chemotherapy who became pathologically node negative at surgery had low rates of LRR (approximately 10 % or below) regardless of surgical approach.1 Rates of recurrence were even lower when a complete response was concurrently seen in the breast. Highest rates of recurrence were seen in patients who remained node positive after neoadjuvant chemotherapy. Limitations of the data from NSABP B-27 and B-18 include the absence of histologic confirmation of pretreatment lymph nodes, low pathologic complete response rates, and challenges in the assessment of LRR that may have understated locoregional failure.30 Moreover, it is important to emphasize that most patients had stage I or II breast cancer, with only 30 % having clinical N1 disease. Because these trials were initiated before a survival benefit was demonstrated in node-positive patients with postmastectomy radiotherapy or nodal radiation plus whole breast radiotherapy, no radiation was permitted in patients undergoing mastectomy, and only whole breast radiation was used in breast conservation patients.7,10,11,31 Recent retrospective studies from Korea and France have also contributed to the hypothesis that recurrence risk may be sufficiently low to omit radiotherapy in select patients with stage II-III breast cancer after a favorable response to neoadjuvant chemotherapy and mastectomy.32,33 In the Korean study, no statistically significant differences in outcomes were seen in 46 patients with pathologic node-negative status at surgery who did not receive postmastectomy radiotherapy, when compared to 105 patients also with pathologic node-negative disease who received radiotherapy. Similarly, the French study found no difference in local-regional recurrence rates or overall survival in 56 patients with pathologic node-negative disease after neoadjuvant chemotherapy who did not receive postmastectomy radiotherapy when compared to
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the 78 pathologic node-negative patients who did receive radiotherapy. An important caveat for both of these retrospective studies is that clinical N1 and N2 disease were grouped together, and thus the impact of more advanced nodal disease at presentation on recurrence rates after neoadjuvant chemotherapy and mastectomy remained unanswered. The ongoing NSABP B-51/RTOG 1304 randomized trial is designed to assess the value of nodal radiotherapy in patients with biopsy-proven clinical N1 axillary nodal disease before neoadjuvant chemotherapy that becomes pathologically node negative at the time of surgery (see Fig. 1). The results from this trial will help to quantify the benefit, if any, of locoregional radiotherapy in the setting of pathologic response to neoadjuvant chemotherapy in stage I to IIIA breast cancer. Importantly, patients with locally or regionally advanced disease including T4 disease or N2/N3 disease are not eligible, as the significant benefit of comprehensive postsurgical radiotherapy has been previously demonstrated even when a complete pathologic response is seen after neoadjuvant chemotherapy and maximal surgery.21 PRACTICAL CONSIDERATIONS AND RADIOTHERAPY TECHNIQUE The results above place an emphasis on accurate clinical staging before neoadjuvant chemotherapy and warrant careful multidisciplinary assessment of clinical and pathologic risk factors that help inform postsurgical radiotherapy recommendations in select patients. At MD Anderson, it is standard to obtain a mammogram and ultrasound of the breast and regional lymph nodes (axilla, supraclavicular, infraclavicular) and biopsy (fine-needle aspiration) of any suspicious lymph nodes before the initiation of neoadjuvant chemotherapy. Patients who may be eligible for breast conservation have clips placed at the site of the primary tumor, and imaging is done to make sure any suspicious calcifications or residual disease are removed before radiotherapy. Systemic staging is performed in select patients with positive lymph nodes. Sentinel node biopsy is typically performed after neoadjuvant chemotherapy in clinically node-negative patients, and full axillary dissection is performed after neoadjuvant chemotherapy in patients with clinically positive lymph nodes. It should be noted that sentinel lymph node biopsy after neoadjuvant chemotherapy in clinically node-positive patients may still have a role and thus may also influence radiotherapy discussion and technique in the future.34,35 The currently accruing ALLIANCE A011202 phase 3 study is designed to answer the question of whether axillary node dissection or targeted axillary nodal radiation provides similar control in patients with a
A. K. Garg, T. A. Buchholz
positive sentinel lymph node after completion of neoadjuvant chemotherapy. At MD Anderson, comprehensive nodal radiation to the supraclavicular fossa and internal mammary chain is considered for clinically node-positive patients after neoadjuvant chemotherapy and surgery. Findings at the time of surgery, including response to chemotherapy, number of lymph nodes involved and examined, and presence of high-risk factors (lymphovascular invasion, extranodal extension, high-grade disease), help tailor recommendations. In patients with positive sentinel nodes after neoadjuvant chemotherapy who do not undergo further surgery, the undissected axilla is also a target. The chest wall and draining lymphatics typically receive 50 Gy over 5 weeks with a 10 Gy boost to the chest wall if margins are negative. In node-negative patients who receive breast conservation, an abbreviated course of whole breast radiotherapy is considered a standard option. Respiratory gating is a technique that is also used in leftsided breast cancers that may benefit from additional protection to the heart and lungs.36 In patients with clinically positive infraclavicular, supraclavicular, or internal mammary lymph nodes, these regions receive an additional radiation boost of 10–16 Gy, depending on response to neoadjuvant chemotherapy. Accelerated partial breast irradiation is not currently considered appropriate after neoadjuvant chemotherapy. Because radiotherapy in breast cancer is not without its risks, including cardiopulmonary toxicity, lymphedema, and secondary malignancy, quality assurance is considered a key element in its proper delivery.37–42 Finally, the complex interplay between breast reconstruction and radiotherapy technique and toxicity is also an important consideration that warrants careful multidisciplinary engagement.37,43 CONCLUSIONS Neoadjuvant chemotherapy has significantly influenced radiotherapy management decisions in patients who undergo breast conservation or mastectomy. Both clinical and pathologic characteristics contribute to LRR risk after neoadjuvant chemotherapy. Consideration of radiotherapy to the breast and regional nodes or chest wall and regional nodes is warranted in patients with stage IIIA or higher breast cancer after neoadjuvant chemotherapy and breast conservation or mastectomy. Treatment is commonly tailored for those with stage II breast cancer based on clinical factors, the presence or absence of high-risk features, and response to chemotherapy. Upcoming results from the NSABP B-51/RTOG 1304 trial will also help to assess the benefit of locoregional radiotherapy for clinical N1 breast
Influence of Chemotherapy on Radiotherapy
cancers that become node negative after neoadjuvant chemotherapy. DISCLOSURE
The authors declare no conflict of interest.
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A. K. Garg, T. A. Buchholz 36. Wang X, Pan T, Pinnix C, et al. Cardiac motion during deep-inspiration breath-hold: implications for breast cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2012;82:708–14. 37. Buchholz TA, Lehman CD, Harris JR, et al. Statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer: a National Cancer Institute conference. J Clin Oncol. 2008;26:791–7. 38. Cutter DJ, Darby SC, Yusuf SW. Risks of heart disease after radiotherapy. Tex Heart Inst J. 2011;38:257–8. 39. Jagsi R, Griffith KA, Koelling T, Roberts R, Pierce LJ. Rates of myocardial infarction and coronary artery disease and risk factors in patients treated with radiation therapy for early-stage breast cancer. Cancer. 2007;109:650–7. 40. Kong FM, Pan C, Eisbruch A, Ten Haken RK. Physical models and simpler dosimetric descriptors of radiation late toxicity. Semin Radiat Oncol. 2007;17:108–20. 41. McGale P, Darby SC, Hall P, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol. 2011;100:167–75. 42. Parkin DM, Darby SC. Cancers in 2010 attributable to ionising radiation exposure in the UK. Br J Cancer. 2011;105:S57–65. 43. Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction: a critical review of the literature. Plast Reconstr Surg. 2009;124:395–408.
