Surgical Oncology 24 (2015) 5e8
Contents lists available at ScienceDirect
Surgical Oncology journal homepage: www.elsevier.com/locate/suronc
Commentary
Lumpectomy margins: Everything old is new again? Eleftherios P. Mamounas*, Tomas Dvorak University of Florida Health Cancer Center-Orlando Health, Orlando, FL, USA
The controversy on the optimal width of tumor resection margins following breast conserving surgery is as old as the procedure itself. Even from the time of inception of this procedure, two divergent approaches emerged, the procedure of lumpectomy, as pioneered and evaluated in the US by the NSABP B-06 and subsequent clinical trials [1e3] and the procedure of quadrantectomy, as pioneered and evaluated in Italy by the Milan group [4,5]. These two procedures were diametrically opposed on their approach to the width of lumpectomy margins. Lumpectomy was designed as the removal of the breast tumor with a limited normal rim of tissue around it. Pathologically negative margins were declared if on microscopic examination there was “no ink on tumor”. On the other hand, quadrantectomy was the removal of the quadrant where the tumor resided along with the overlying skin and underlying fascia en block. As a result, quadrantectomy was generally associated with widely negative margins and was originally intended as a procedure for which the addition of breast radiotherapy was not necessary for local control. However, the benefit from breast radiotherapy in reducing in-breast recurrence was eventually demonstrated with both procedures, further fueling the debate on the optimal width of resection margins [4]. Over the past three decades the uncertainty on the optimal width of resection margins continued unabated, leading to great variability in perceptions and attitudes of what constitutes an acceptable margin following breast conserving surgery [6e9]. Reasons for this continuing uncertainty included the retrospective nature of most of the available evidence, the option of selective reexcision at the discretion of the treating physician, and the potential for varying the extent/dose of radiotherapy and adjuvant systemic therapy based on margin width, thus potentially blunting the true effect of a close margin on rates of in-breast recurrence [10,11]. Consequently, approximately one in four women who undergo breast conserving surgery also undergo a re-excision, often performed with the intent of obtaining more widely clear margins [12,13]. Re-excisions can potentially result in additional discomfort, increase surgical complications, compromise the cosmetic result, increase patient anxiety and health care costs and lead to more frequent use of mastectomy [14]. * Corresponding author. 1400 S. Orange Avenue, Orlando, FL 32806, USA. Tel.: þ1 321 841 1851; fax: þ1 407 649 6994. E-mail address: [email protected] (E.P. Mamounas). http://dx.doi.org/10.1016/j.suronc.2014.11.006 0960-7404/© 2014 Elsevier Ltd. All rights reserved.
To that extent, development of a consensus guideline on optimal margin width following breast conserving surgery is much needed and has the potential to have a great impact on clinical management. In order to develop such a consensus guideline [15e17], the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) convened a multidisciplinary margins panel (MP) that used as primary evidence a study-level metaanalysis of margin width and ipsilateral breast tumor recurrence (IBTR) that included 33 studies, 28,162 patients and 1506 IBTRs. Additional topic-specific literature reviews were conducted by participants for questions not addressed in the meta-analysis. The systematic review/meta-analysis included studies of patients with stage I/II BC (no neoadjuvant chemotherapy) treated with local excision and whole breast radiotherapy and reported IBTR in relation to microscopic margin widths, with a minimum follow-up of 4 years (because of the increased incidence of IBTR over time) [18]. Almost all publications included in the meta-analysis (except for two) [19,20] were retrospective and provided observational data at the study level [18,21]. The primary question that was addressed was: “What margin width minimizes the risk of IBTR in patients with invasive cancer receiving whole breast radiotherapy?” With median follow-up of 79.2 months (6.6 years), the median prevalence of IBTR was 5.3% (interquartile range, 2.3%e7.6%) [18]. Presence of positive margins (ink on invasive carcinoma or ductal carcinoma in situ) was associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk was not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins did not significantly decrease the rate of IBTR compared with no ink on tumor. There was no evidence that more widely clear margins reduced risk for IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component. Based on these findings from the meta-analysis, the MP concluded that the use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. The above recommendations from the MP provide a much needed guidance regarding margin assessment following breast conserving surgery. As clinicians who treat early-stage breast cancer digest and apply these recommendations into their everyday
6
E.P. Mamounas, T. Dvorak / Surgical Oncology 24 (2015) 5e8
practice, it is important to examine some of the strengths and limitations of the recommendations, as well some of the issues raised following publication of the new guidelines. The MP recognized some of the limitations of the guideline: it applies to patients with invasive breast cancer treated with whole breast radiotherapy; the findings cannot be extrapolated to patients with pure DCIS, to those treated with neoadjuvant chemotherapy or accelerated partial breast irradiation, or to those not receiving radiotherapy. On the other hand, there are important clinical observations that provide assurance when attempting to apply the MP's recommendations. Since the adoption of breast conserving surgery and whole breast radiotherapy more than two decades ago, the landscape of breast cancer presentation and treatment has evolved considerably and advances in screening/diagnostic imaging techniques, surgical treatment, radiotherapy and adjuvant systemic therapy have resulted in a dramatic decline in the rates of IBTR [22e24]. Arguably, adjuvant systemic therapy has had the largest impact in decreasing IBTR rates, particularly when combined with breast radiotherapy. In the NSABP B-06 trial, nodepositive women who received chemotherapy and breast radiotherapy had significantly lower IBTR rates than node-negative patients who received only breast radiotherapy (20 years, 8.8% vs. 17% respectively) [1]. This was despite the fact that node-positive patients had a higher rate of IBTR than node-negative patients if breast radiotherapy was not used (20 years, 44.2% vs. 36.2% respectively). Thus, the effect of breast radiotherapy was more pronounced in patients with positive lymph nodes, who also received adjuvant chemotherapy per protocol specification. Since then, further improvements in distant recurrence and overall survival with new, subtype-directed systemic therapy agents have also resulted in further declines in IBTR rates both in the adjuvant [12,22,23,25e29] as well as in the neoadjuvant setting, where achievement of pathologic complete response has been associated with significantly lower rates of IBTR [30]. Thus, decreasing IBTR rates with adjuvant or neoadjuvant systemic therapy could minimize the impact of margin width on IBTR. This last observation begs the question of whether the new recommendations can eventually be extended to patients treated with neoadjuvant chemotherapy. Besides the limitations identified by the MP additional concerns have been raised following the publication of the consensus guideline. Those mainly relate to the strength of the evidence included in the meta-analysis that was used as the foundation for the MP's recommendations [6,16], the observation that close margins were associated with increased risk of IBTR compared to negative margins, the strength of the evidence for selection of “no tumor on ink” as the minimum required margin versus 1 mm or more [31] and the applicability of these recommendations to all patients that fall under the guideline criteria vs. the option for individualizing surgical treatment in selected clinical circumstances [6,32]. The limitation of using retrospective observational data in a study-level meta-analysis vs. using data from prospective clinical trials in a patient-level meta-analysis is a legitimate one that can only be partially addressed. There are no prospective clinical trials (randomized or non-randomized) evaluating IBTR rates according to margin width and it is unlikely that such trials will ever be conducted. However, performing patient-level meta-analysis on the existing observational studies -although difficult-may provide useful information that would strengthen the evidence for the MP's recommendations. In the meta-analysis used for the development of the guideline, the use of study-specified margin definitions (close, positive, negative) was associated with a significant increase in the odds of IBTR with close margins (OR, 1.74; 95% CI, 1.42e2.15) or positive margins (OR, 2.44; 95% CI, 1.97e3.03) vs. negative margins
(P < .001). However, the MP felt that because of the heterogeneity between study definitions of close vs. positive margins, the analysis of specific quantitative margin widths (1 vs. 2 vs. 5 mm) that showed no significant association with IBTR superseded this finding [17]. In addition, the MP commented on technical issues that confound the meaningful differentiation of 1e2 mm of margin width and can affect the relationship between margin width and IBTR such as narrowing of margins ex vivo, flattening from lack of supportive tissue and specimen radiography, tracking of surface ink into deeper portions of the specimen and observations that tumorto-ink distance on any single slide may not necessarily be representative of the entire specimen, particularly since even with total sequential embedding only < 1% of the specimen margins are being examined [17,33,34]. The MP further commented that despite the variability in margin assessment, the lack of association between specific margin widths (1, 2, 5 mm) and IBTR is reassuring [17]. They further stated that with an overall median IBTR rate of 5.3% across all 33 studies in the meta-analysis, the possible absolute reduction in IBTR with 5-mm margins is approximately 1%e2% and that this difference is virtually eliminated after adjusting for treatment. Dixon and Thomas [31] have argued that although in the metaanalysis, used for the development of the guideline, 1 mm was as good as wider margins, the data on margins >0 mm were limited; nonetheless, “pairwise comparison between distance categories for negative margins (in the adjusted models) showed that the odds of IBTR were higher for studies using >0 mm relative to 5 mm”. They further commented that the logic of using no ink on tumor as a negative margin by the MP because of difficulties with analyzing and inking margins, should also apply to all the studies included in the meta-analysis. Citing data from a Danish study of over 12,000 women confirming that 1 mm margin was as good as wider, they argued that the MP may be right that no ink on margin is sufficient, but that the evidence to support this is much less convincing than the evidence suggesting that close margins increase IBTR and that a margin width of 1 mm is optimal. In reply to Dixon and Thomas [35], the authors of the margin guideline argue that the overall conclusion for using >0 mm as adequate margin is supported by a large body of evidence including a recent study of 86,598 patients from phase 3 clinical trials (conducted between 1990 and 2011) in which the proportion of loco-regional recurrences diminished from 30% to 15% (P < .001) with modern adjuvant systemic therapy [36]. They further commented that in the absence of patient-level evidence clearly demonstrating a difference in IBTR with margins of >0 mm versus 1 mm and in the context of the difficulty for pathologists to reproducibly distinguishing margin widths of >0 mm and 1 mm, the definition of >0 mm was adopted with the hope of ultimately reducing unnecessary re-excisions based solely on minute margin widths. However, they also state that the above arguments are not meant to indicate that wider margins (than no ink on tumor) are not ever appropriate and that the interpretation of the meta-analysis results needs to be viewed in the context of the accumulated clinical experience with breast-conserving therapy as well as other existing published literature [35]. Lastly, others have argued that application of these guidelines should enhance rather than supplant the process of shared decision making between physicians and patients [6,32] and that there are circumstances in which close or even negative margins may still warrant re-excision. Such circumstances would include patients in whom imaging studies underestimate the extent of disease and pathology reveals multiple foci of disease not identified preoperatively, patients who may not want to receive adjuvant systemic therapy and of course patients who are not candidates to receive breast XRT. The ASTRO/SSO consensus guidelines on lumpectomy margins provide useful guidance that will have considerable impact on the
E.P. Mamounas, T. Dvorak / Surgical Oncology 24 (2015) 5e8
surgical management of early-stage breast cancer. Although after many years of debate regarding optimal margin width these guidelines bring us back full circle to the original “no tumor on ink” concept put forward by the NSAPB in the pivotal B-06 trial that first opened in 1976, they take place in a considerably different environment. So, where do we go from here in the local management of early-stage breast cancer? There are several avenues worth exploring. First, we will need a similar guideline for patients with DCIS and for patients who undergo neoadjuvant chemotherapy and efforts are under way to clarify these indications. Second, we need to ensure that the margin is in fact “negative” during the initial surgery. Both intraoperative imprint cytology (IC) and intraoperative frozen section analysis (FSA) have been shown in a recent systematic review to significantly reduce the rate of re-excision [37], and merit consideration for possible implementation in routine clinical practice. Optical image-guided surgery has long been in development, and at last significant progress may be under way in this arena as a means to better distinguish tumor from normal tissue [38]. Third, we are entering a new era of cancer management, where biology rather than anatomy becomes the dominant factor that dictates our approach to local management of the disease. This was recently exemplified in cancers of head & neck, where identification of biological subtypes driven by smoking history and HPV status is leading to a de-escalation of concurrent radiation therapy with chemotherapy, after decades of continued escalation of treatment for all patients [39]. Similarly, in breast cancer we are identifying various molecular subtypes, some of which may need less aggressive local treatment, while others may benefit from further intensification. This may include omission of radiation altogether, omission of a radiation boost, change in radiation fractionation schema, or conversely further escalation of a boost, and possibly concurrent chemoradiotherapy. And finally, we need to be mindful of health care costs, and the “value” of care as a relationship between efficacy, toxicity, and cost. Reducing the number of re-excisions, which may cost $15,000e$25,000 each, is likely going to have a significant cumulative impact on breast cancer spending, including prevention of potentially unnecessary mastectomies and costly reconstructive surgeries. But as with the adoption of any new guidelines, the practicing clinicians should have a clear understanding of the strengths and limitations of the evidence behind the guidelines and always leave room for individualization when the clinical circumstances dictate it. References [1] Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233e41. [2] Fisher B, Redmond C, Poisson R, Margolese R, Wolmark N, Wickerham L, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822e8. [3] Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol e Off J Am Soc Clin Oncol 2002;20:4141e9. [4] Veronesi U, Saccozzi R, Del Vecchio M, Banfi A, Clemente C, De Lena M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med 1981;305:6e11. [5] Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twentyyear follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347: 1227e32. [6] Jagsi R, Smith BD, Sabel M, Pierce L. Individualized, patient-centered application of consensus guidelines to improve the quality of breast cancer care. Int J Radiat Oncol Biol Phys 2014;88:535e6. [7] Taghian A, Mohiuddin M, Jagsi R, Goldberg S, Ceilley E, Powell S, et al. Current perceptions regarding surgical margin status after breast-conserving therapy: results of a survey. Ann Surg 2005;241:629e39.
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[8] Azu M, Abrahamse P, Katz SJ, Jagsi R, Morrow M. What is an adequate margin for breast-conserving surgery? Surgeon attitudes and correlates. Ann Surg Oncol 2010;17:558e63. [9] Jagsi R, Abrahamse P, Morrow M, Hamilton AS, Graff JJ, Katz SJ, et al. Coordination of breast cancer care between radiation oncologists and surgeons: a survey study. Int J Radiat Oncol Biol Phys 2012;82:2072e8. [10] Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 2012;48: 3342e54. [11] Wazer DE, Schmidt-Ullrich RK, Ruthazer R, Schmid CH, Graham R, Safaii H, et al. Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 1998;40:851e8. [12] Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707e16. [13] Morrow M, Jagsi R, Alderman AK, Griggs JJ, Hawley ST, Hamilton AS, et al. Surgeon recommendations and receipt of mastectomy for treatment of breast cancer. Jama 2009;302:1551e6. [14] King TA, Sakr R, Patil S, Gurevich I, Stempel M, Sampson M, et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol e Off J Am Soc Clin Oncol 2011;29:2158e64. [15] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Ann Surg Oncol 2014;21: 704e16. [16] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol e Off J Am Soc Clin Oncol 2014;32:1507e15. [17] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Int J Radiat Oncol Biol Phys 2014;88:553e64. [18] Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014;21:717e30. [19] Bellon JR, Come SE, Gelman RS, Henderson IC, Shulman LN, Silver BJ, et al. Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol e Off J Am Soc Clin Oncol 2005;23:1934e40. [20] Voogd AC, Nielsen M, Peterse JL, Blichert-Toft M, Bartelink H, Overgaard M, et al. Differences in risk factors for local and distant recurrence after breastconserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials. J Clin Oncol e Off J Am Soc Clin Oncol 2001;19:1688e97. [21] Houssami N, Macaskill P, Marinovich ML, Dixon JM, Irwig L, Brennan ME, et al. Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 2010;46:3219e32. [22] Anderson SJ, Wapnir I, Dignam JJ, Fisher B, Mamounas EP, Jeong JH, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 2009;27:2466e73. [23] Wapnir IL, Anderson SJ, Mamounas EP, Geyer CE, Jeong JH, Tan-Chiu E, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project nodepositive adjuvant breast cancer trials. J Clin Oncol e Off J Am Soc Clin Oncol 2006;24:2028e37. [24] Cabioglu N, Hunt KK, Buchholz TA, Mirza N, Singletary SE, Kuerer HM, et al. Improving local control with breast-conserving therapy: a 27-year singleinstitution experience. Cancer 2005;104:20e9. [25] Mamounas EP, Tang G, Liu Q. The importance of systemic therapy in minimizing local recurrence after breast-conserving surgery: the NSABP experience. J Surg Oncol 2014;110:45e50. [26] Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L, et al. Hormonal therapies for early breast cancer: systematic review and economic evaluation. Health Technol Assess 2007;11:1e134. iii-iv, ix-xi. [27] Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29e36. [28] Romond EH, Perez EA, Bryant J, Suman VS, Geyer CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673e84. [29] Mannino M, Yarnold JR. Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld? Radiother Oncol e J Eur Soc Ther Radiol Oncol 2009;90: 14e22.
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[30] Mamounas EP, Anderson SJ, Dignam JJ, Bear HD, Julian TB, Geyer CE, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol e Off J Am Soc Clin Oncol 2012;30:3960e6. [31] Dixon JM, Thomas J. In regard to Moran et al. Int J Radiat Oncol Biol Phys 2014;89:1139. [32] Hunt KK, Sahin AA. Too much, too little, or just right? Tumor margins in women undergoing breast-conserving surgery. J Clin Oncol e Off J Am Soc Clin Oncol 2014;32:1401e6. [33] Graham RA, Homer MJ, Katz J, Rothschild J, Safaii H, Supran S. The pancake phenomenon contributes to the inaccuracy of margin assessment in patients with breast cancer. Am J Surg 2002;184:89e93. [34] Carter D. Margins of “lumpectomy” for breast cancer. Hum pathol 1986;17: 330e2.
[35] Moran MS, Houssami N, Schnitt SJ, Morrow M. In reply to Dixon and Thomas. Int J Radiat Oncol Biol Phys 2014;89:1139e41. [36] Bouganim N, Tsvetkova E, Clemons M, Amir E. Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research. Breast Cancer Res Treat 2013;139:603e6. [37] Esbona K, Li Z, Wilke LG. Intraoperative imprint cytology and frozen section pathology for margin assessment in breast conservation surgery: a systematic review. Ann Surg Oncol 2012;19:3236e45. [38] Keereweer S, Van Driel PB, Snoeks TJ, Kerrebijn JD, Baatenburg de Jong RJ, Vahrmeijer AL, et al. Optical image-guided cancer surgery: challenges and limitations. Clin Cancer Res e Off J Am Assoc Cancer Res 2013;19:3745e54. [39] Mirghani H, Amen F, Blanchard P, Moreau E, Guigay J, Hartl DM, et al. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives. Int J Cancer e J Int du Cancer 2014.
Contents lists available at ScienceDirect
Surgical Oncology journal homepage: www.elsevier.com/locate/suronc
Commentary
Lumpectomy margins: Everything old is new again? Eleftherios P. Mamounas*, Tomas Dvorak University of Florida Health Cancer Center-Orlando Health, Orlando, FL, USA
The controversy on the optimal width of tumor resection margins following breast conserving surgery is as old as the procedure itself. Even from the time of inception of this procedure, two divergent approaches emerged, the procedure of lumpectomy, as pioneered and evaluated in the US by the NSABP B-06 and subsequent clinical trials [1e3] and the procedure of quadrantectomy, as pioneered and evaluated in Italy by the Milan group [4,5]. These two procedures were diametrically opposed on their approach to the width of lumpectomy margins. Lumpectomy was designed as the removal of the breast tumor with a limited normal rim of tissue around it. Pathologically negative margins were declared if on microscopic examination there was “no ink on tumor”. On the other hand, quadrantectomy was the removal of the quadrant where the tumor resided along with the overlying skin and underlying fascia en block. As a result, quadrantectomy was generally associated with widely negative margins and was originally intended as a procedure for which the addition of breast radiotherapy was not necessary for local control. However, the benefit from breast radiotherapy in reducing in-breast recurrence was eventually demonstrated with both procedures, further fueling the debate on the optimal width of resection margins [4]. Over the past three decades the uncertainty on the optimal width of resection margins continued unabated, leading to great variability in perceptions and attitudes of what constitutes an acceptable margin following breast conserving surgery [6e9]. Reasons for this continuing uncertainty included the retrospective nature of most of the available evidence, the option of selective reexcision at the discretion of the treating physician, and the potential for varying the extent/dose of radiotherapy and adjuvant systemic therapy based on margin width, thus potentially blunting the true effect of a close margin on rates of in-breast recurrence [10,11]. Consequently, approximately one in four women who undergo breast conserving surgery also undergo a re-excision, often performed with the intent of obtaining more widely clear margins [12,13]. Re-excisions can potentially result in additional discomfort, increase surgical complications, compromise the cosmetic result, increase patient anxiety and health care costs and lead to more frequent use of mastectomy [14]. * Corresponding author. 1400 S. Orange Avenue, Orlando, FL 32806, USA. Tel.: þ1 321 841 1851; fax: þ1 407 649 6994. E-mail address: [email protected] (E.P. Mamounas). http://dx.doi.org/10.1016/j.suronc.2014.11.006 0960-7404/© 2014 Elsevier Ltd. All rights reserved.
To that extent, development of a consensus guideline on optimal margin width following breast conserving surgery is much needed and has the potential to have a great impact on clinical management. In order to develop such a consensus guideline [15e17], the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) convened a multidisciplinary margins panel (MP) that used as primary evidence a study-level metaanalysis of margin width and ipsilateral breast tumor recurrence (IBTR) that included 33 studies, 28,162 patients and 1506 IBTRs. Additional topic-specific literature reviews were conducted by participants for questions not addressed in the meta-analysis. The systematic review/meta-analysis included studies of patients with stage I/II BC (no neoadjuvant chemotherapy) treated with local excision and whole breast radiotherapy and reported IBTR in relation to microscopic margin widths, with a minimum follow-up of 4 years (because of the increased incidence of IBTR over time) [18]. Almost all publications included in the meta-analysis (except for two) [19,20] were retrospective and provided observational data at the study level [18,21]. The primary question that was addressed was: “What margin width minimizes the risk of IBTR in patients with invasive cancer receiving whole breast radiotherapy?” With median follow-up of 79.2 months (6.6 years), the median prevalence of IBTR was 5.3% (interquartile range, 2.3%e7.6%) [18]. Presence of positive margins (ink on invasive carcinoma or ductal carcinoma in situ) was associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk was not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins did not significantly decrease the rate of IBTR compared with no ink on tumor. There was no evidence that more widely clear margins reduced risk for IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component. Based on these findings from the meta-analysis, the MP concluded that the use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. The above recommendations from the MP provide a much needed guidance regarding margin assessment following breast conserving surgery. As clinicians who treat early-stage breast cancer digest and apply these recommendations into their everyday
6
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practice, it is important to examine some of the strengths and limitations of the recommendations, as well some of the issues raised following publication of the new guidelines. The MP recognized some of the limitations of the guideline: it applies to patients with invasive breast cancer treated with whole breast radiotherapy; the findings cannot be extrapolated to patients with pure DCIS, to those treated with neoadjuvant chemotherapy or accelerated partial breast irradiation, or to those not receiving radiotherapy. On the other hand, there are important clinical observations that provide assurance when attempting to apply the MP's recommendations. Since the adoption of breast conserving surgery and whole breast radiotherapy more than two decades ago, the landscape of breast cancer presentation and treatment has evolved considerably and advances in screening/diagnostic imaging techniques, surgical treatment, radiotherapy and adjuvant systemic therapy have resulted in a dramatic decline in the rates of IBTR [22e24]. Arguably, adjuvant systemic therapy has had the largest impact in decreasing IBTR rates, particularly when combined with breast radiotherapy. In the NSABP B-06 trial, nodepositive women who received chemotherapy and breast radiotherapy had significantly lower IBTR rates than node-negative patients who received only breast radiotherapy (20 years, 8.8% vs. 17% respectively) [1]. This was despite the fact that node-positive patients had a higher rate of IBTR than node-negative patients if breast radiotherapy was not used (20 years, 44.2% vs. 36.2% respectively). Thus, the effect of breast radiotherapy was more pronounced in patients with positive lymph nodes, who also received adjuvant chemotherapy per protocol specification. Since then, further improvements in distant recurrence and overall survival with new, subtype-directed systemic therapy agents have also resulted in further declines in IBTR rates both in the adjuvant [12,22,23,25e29] as well as in the neoadjuvant setting, where achievement of pathologic complete response has been associated with significantly lower rates of IBTR [30]. Thus, decreasing IBTR rates with adjuvant or neoadjuvant systemic therapy could minimize the impact of margin width on IBTR. This last observation begs the question of whether the new recommendations can eventually be extended to patients treated with neoadjuvant chemotherapy. Besides the limitations identified by the MP additional concerns have been raised following the publication of the consensus guideline. Those mainly relate to the strength of the evidence included in the meta-analysis that was used as the foundation for the MP's recommendations [6,16], the observation that close margins were associated with increased risk of IBTR compared to negative margins, the strength of the evidence for selection of “no tumor on ink” as the minimum required margin versus 1 mm or more [31] and the applicability of these recommendations to all patients that fall under the guideline criteria vs. the option for individualizing surgical treatment in selected clinical circumstances [6,32]. The limitation of using retrospective observational data in a study-level meta-analysis vs. using data from prospective clinical trials in a patient-level meta-analysis is a legitimate one that can only be partially addressed. There are no prospective clinical trials (randomized or non-randomized) evaluating IBTR rates according to margin width and it is unlikely that such trials will ever be conducted. However, performing patient-level meta-analysis on the existing observational studies -although difficult-may provide useful information that would strengthen the evidence for the MP's recommendations. In the meta-analysis used for the development of the guideline, the use of study-specified margin definitions (close, positive, negative) was associated with a significant increase in the odds of IBTR with close margins (OR, 1.74; 95% CI, 1.42e2.15) or positive margins (OR, 2.44; 95% CI, 1.97e3.03) vs. negative margins
(P < .001). However, the MP felt that because of the heterogeneity between study definitions of close vs. positive margins, the analysis of specific quantitative margin widths (1 vs. 2 vs. 5 mm) that showed no significant association with IBTR superseded this finding [17]. In addition, the MP commented on technical issues that confound the meaningful differentiation of 1e2 mm of margin width and can affect the relationship between margin width and IBTR such as narrowing of margins ex vivo, flattening from lack of supportive tissue and specimen radiography, tracking of surface ink into deeper portions of the specimen and observations that tumorto-ink distance on any single slide may not necessarily be representative of the entire specimen, particularly since even with total sequential embedding only < 1% of the specimen margins are being examined [17,33,34]. The MP further commented that despite the variability in margin assessment, the lack of association between specific margin widths (1, 2, 5 mm) and IBTR is reassuring [17]. They further stated that with an overall median IBTR rate of 5.3% across all 33 studies in the meta-analysis, the possible absolute reduction in IBTR with 5-mm margins is approximately 1%e2% and that this difference is virtually eliminated after adjusting for treatment. Dixon and Thomas [31] have argued that although in the metaanalysis, used for the development of the guideline, 1 mm was as good as wider margins, the data on margins >0 mm were limited; nonetheless, “pairwise comparison between distance categories for negative margins (in the adjusted models) showed that the odds of IBTR were higher for studies using >0 mm relative to 5 mm”. They further commented that the logic of using no ink on tumor as a negative margin by the MP because of difficulties with analyzing and inking margins, should also apply to all the studies included in the meta-analysis. Citing data from a Danish study of over 12,000 women confirming that 1 mm margin was as good as wider, they argued that the MP may be right that no ink on margin is sufficient, but that the evidence to support this is much less convincing than the evidence suggesting that close margins increase IBTR and that a margin width of 1 mm is optimal. In reply to Dixon and Thomas [35], the authors of the margin guideline argue that the overall conclusion for using >0 mm as adequate margin is supported by a large body of evidence including a recent study of 86,598 patients from phase 3 clinical trials (conducted between 1990 and 2011) in which the proportion of loco-regional recurrences diminished from 30% to 15% (P < .001) with modern adjuvant systemic therapy [36]. They further commented that in the absence of patient-level evidence clearly demonstrating a difference in IBTR with margins of >0 mm versus 1 mm and in the context of the difficulty for pathologists to reproducibly distinguishing margin widths of >0 mm and 1 mm, the definition of >0 mm was adopted with the hope of ultimately reducing unnecessary re-excisions based solely on minute margin widths. However, they also state that the above arguments are not meant to indicate that wider margins (than no ink on tumor) are not ever appropriate and that the interpretation of the meta-analysis results needs to be viewed in the context of the accumulated clinical experience with breast-conserving therapy as well as other existing published literature [35]. Lastly, others have argued that application of these guidelines should enhance rather than supplant the process of shared decision making between physicians and patients [6,32] and that there are circumstances in which close or even negative margins may still warrant re-excision. Such circumstances would include patients in whom imaging studies underestimate the extent of disease and pathology reveals multiple foci of disease not identified preoperatively, patients who may not want to receive adjuvant systemic therapy and of course patients who are not candidates to receive breast XRT. The ASTRO/SSO consensus guidelines on lumpectomy margins provide useful guidance that will have considerable impact on the
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surgical management of early-stage breast cancer. Although after many years of debate regarding optimal margin width these guidelines bring us back full circle to the original “no tumor on ink” concept put forward by the NSAPB in the pivotal B-06 trial that first opened in 1976, they take place in a considerably different environment. So, where do we go from here in the local management of early-stage breast cancer? There are several avenues worth exploring. First, we will need a similar guideline for patients with DCIS and for patients who undergo neoadjuvant chemotherapy and efforts are under way to clarify these indications. Second, we need to ensure that the margin is in fact “negative” during the initial surgery. Both intraoperative imprint cytology (IC) and intraoperative frozen section analysis (FSA) have been shown in a recent systematic review to significantly reduce the rate of re-excision [37], and merit consideration for possible implementation in routine clinical practice. Optical image-guided surgery has long been in development, and at last significant progress may be under way in this arena as a means to better distinguish tumor from normal tissue [38]. Third, we are entering a new era of cancer management, where biology rather than anatomy becomes the dominant factor that dictates our approach to local management of the disease. This was recently exemplified in cancers of head & neck, where identification of biological subtypes driven by smoking history and HPV status is leading to a de-escalation of concurrent radiation therapy with chemotherapy, after decades of continued escalation of treatment for all patients [39]. Similarly, in breast cancer we are identifying various molecular subtypes, some of which may need less aggressive local treatment, while others may benefit from further intensification. This may include omission of radiation altogether, omission of a radiation boost, change in radiation fractionation schema, or conversely further escalation of a boost, and possibly concurrent chemoradiotherapy. And finally, we need to be mindful of health care costs, and the “value” of care as a relationship between efficacy, toxicity, and cost. Reducing the number of re-excisions, which may cost $15,000e$25,000 each, is likely going to have a significant cumulative impact on breast cancer spending, including prevention of potentially unnecessary mastectomies and costly reconstructive surgeries. But as with the adoption of any new guidelines, the practicing clinicians should have a clear understanding of the strengths and limitations of the evidence behind the guidelines and always leave room for individualization when the clinical circumstances dictate it. References [1] Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233e41. [2] Fisher B, Redmond C, Poisson R, Margolese R, Wolmark N, Wickerham L, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822e8. [3] Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol e Off J Am Soc Clin Oncol 2002;20:4141e9. [4] Veronesi U, Saccozzi R, Del Vecchio M, Banfi A, Clemente C, De Lena M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med 1981;305:6e11. [5] Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twentyyear follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347: 1227e32. [6] Jagsi R, Smith BD, Sabel M, Pierce L. Individualized, patient-centered application of consensus guidelines to improve the quality of breast cancer care. Int J Radiat Oncol Biol Phys 2014;88:535e6. [7] Taghian A, Mohiuddin M, Jagsi R, Goldberg S, Ceilley E, Powell S, et al. Current perceptions regarding surgical margin status after breast-conserving therapy: results of a survey. Ann Surg 2005;241:629e39.
7
[8] Azu M, Abrahamse P, Katz SJ, Jagsi R, Morrow M. What is an adequate margin for breast-conserving surgery? Surgeon attitudes and correlates. Ann Surg Oncol 2010;17:558e63. [9] Jagsi R, Abrahamse P, Morrow M, Hamilton AS, Graff JJ, Katz SJ, et al. Coordination of breast cancer care between radiation oncologists and surgeons: a survey study. Int J Radiat Oncol Biol Phys 2012;82:2072e8. [10] Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 2012;48: 3342e54. [11] Wazer DE, Schmidt-Ullrich RK, Ruthazer R, Schmid CH, Graham R, Safaii H, et al. Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 1998;40:851e8. [12] Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707e16. [13] Morrow M, Jagsi R, Alderman AK, Griggs JJ, Hawley ST, Hamilton AS, et al. Surgeon recommendations and receipt of mastectomy for treatment of breast cancer. Jama 2009;302:1551e6. [14] King TA, Sakr R, Patil S, Gurevich I, Stempel M, Sampson M, et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol e Off J Am Soc Clin Oncol 2011;29:2158e64. [15] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Ann Surg Oncol 2014;21: 704e16. [16] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol e Off J Am Soc Clin Oncol 2014;32:1507e15. [17] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Int J Radiat Oncol Biol Phys 2014;88:553e64. [18] Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014;21:717e30. [19] Bellon JR, Come SE, Gelman RS, Henderson IC, Shulman LN, Silver BJ, et al. Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol e Off J Am Soc Clin Oncol 2005;23:1934e40. [20] Voogd AC, Nielsen M, Peterse JL, Blichert-Toft M, Bartelink H, Overgaard M, et al. Differences in risk factors for local and distant recurrence after breastconserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials. J Clin Oncol e Off J Am Soc Clin Oncol 2001;19:1688e97. [21] Houssami N, Macaskill P, Marinovich ML, Dixon JM, Irwig L, Brennan ME, et al. Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 2010;46:3219e32. [22] Anderson SJ, Wapnir I, Dignam JJ, Fisher B, Mamounas EP, Jeong JH, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 2009;27:2466e73. [23] Wapnir IL, Anderson SJ, Mamounas EP, Geyer CE, Jeong JH, Tan-Chiu E, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project nodepositive adjuvant breast cancer trials. J Clin Oncol e Off J Am Soc Clin Oncol 2006;24:2028e37. [24] Cabioglu N, Hunt KK, Buchholz TA, Mirza N, Singletary SE, Kuerer HM, et al. Improving local control with breast-conserving therapy: a 27-year singleinstitution experience. Cancer 2005;104:20e9. [25] Mamounas EP, Tang G, Liu Q. The importance of systemic therapy in minimizing local recurrence after breast-conserving surgery: the NSABP experience. J Surg Oncol 2014;110:45e50. [26] Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L, et al. Hormonal therapies for early breast cancer: systematic review and economic evaluation. Health Technol Assess 2007;11:1e134. iii-iv, ix-xi. [27] Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29e36. [28] Romond EH, Perez EA, Bryant J, Suman VS, Geyer CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673e84. [29] Mannino M, Yarnold JR. Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld? Radiother Oncol e J Eur Soc Ther Radiol Oncol 2009;90: 14e22.
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[30] Mamounas EP, Anderson SJ, Dignam JJ, Bear HD, Julian TB, Geyer CE, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol e Off J Am Soc Clin Oncol 2012;30:3960e6. [31] Dixon JM, Thomas J. In regard to Moran et al. Int J Radiat Oncol Biol Phys 2014;89:1139. [32] Hunt KK, Sahin AA. Too much, too little, or just right? Tumor margins in women undergoing breast-conserving surgery. J Clin Oncol e Off J Am Soc Clin Oncol 2014;32:1401e6. [33] Graham RA, Homer MJ, Katz J, Rothschild J, Safaii H, Supran S. The pancake phenomenon contributes to the inaccuracy of margin assessment in patients with breast cancer. Am J Surg 2002;184:89e93. [34] Carter D. Margins of “lumpectomy” for breast cancer. Hum pathol 1986;17: 330e2.
[35] Moran MS, Houssami N, Schnitt SJ, Morrow M. In reply to Dixon and Thomas. Int J Radiat Oncol Biol Phys 2014;89:1139e41. [36] Bouganim N, Tsvetkova E, Clemons M, Amir E. Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research. Breast Cancer Res Treat 2013;139:603e6. [37] Esbona K, Li Z, Wilke LG. Intraoperative imprint cytology and frozen section pathology for margin assessment in breast conservation surgery: a systematic review. Ann Surg Oncol 2012;19:3236e45. [38] Keereweer S, Van Driel PB, Snoeks TJ, Kerrebijn JD, Baatenburg de Jong RJ, Vahrmeijer AL, et al. Optical image-guided cancer surgery: challenges and limitations. Clin Cancer Res e Off J Am Assoc Cancer Res 2013;19:3745e54. [39] Mirghani H, Amen F, Blanchard P, Moreau E, Guigay J, Hartl DM, et al. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives. Int J Cancer e J Int du Cancer 2014.
