VOLUME 32 䡠 NUMBER 32 䡠 NOVEMBER 10 2014
JOURNAL OF CLINICAL ONCOLOGY
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New Information Prompts Old Question: Is Sentinel Lymph Node Sampling Equivalent to Axillary Lymph Node Dissection? Richard Cedric Zellars, Johns Hopkins University, Baltimore, MD See accompanying article on page 3600
In 2010, the results of American College of Surgeons Oncology Group Z0011 trial were published in Annals of Surgery.1 A second publication appeared in Journal of the American Medical Association the following year.2 Z0011 concluded, in a select population and using a noninferiority design, that axillary lymph node dissection (ALND) did not provide any clinical advantage over sentinel lymph node sampling (SLNS) alone. Thus, it was felt that SLNS can replace an ALND (SLNS ⫽ ALND) in a select population. Although some called for caution in the acceptance of this conclusion due to concerns about the details of the study, surgeons quickly began omitting routine ALND in patients with positive SLNS. In fact, much has been written acknowledging the astonishing alacrity at which the results of this trial influenced practice.3-5 Now, with the systematic review of the Z0011 radiation records by Jagsi et al,6 published with this editorial, one must ask if the results of Z0011 are still valid and wonder if the rapid acceptance of Z0011, despite critical absence of treatment information, was because the conclusions reached were indeed accurate or because the results of this trial simply agreed with preconceptions of the practitioners. Briefly, in Z0011 women undergoing breast-conserving therapy (BCT) with fewer than three positive sentinel lymph nodes (SLN) were randomly assigned to ALND or not. All patients were to receive whole-breast irradiation only (2 fields). Specifically, nodal-directed or third-field radiation was prohibited. Although powered for 1,900 patients, this noninferiority study accrued only 891 patients. The study concluded that there was no significant difference between the ALND and SLNS cohorts with respect to locoregional, disease-free survival (DFS), and overall survival. Z0011 was criticized for not meeting its accrual goal, having too many patients lost to follow-up, and lacking radiation therapy details. Some suspected that radiation oncologists adjusted their breast tangents (high tangents) to cover more nodal tissue in patients known to have an undissected axilla, which could have resulted in an unfair advantage to the SLNS arm. Jagsi et al6 undertook the tedious process of reviewing the radiation records to determine how often patients were treated with high tangents. A surprise finding awaited the investigators. Radiation case report forms were available for 605 of the 856 evaluable patients on the study. From the 605 case report forms, 89 of 540 patients, who Journal of Clinical Oncology, Vol 32, No 32 (November 10), 2014: pp 3583-3585
received whole-breast radiation, also received a protocolprohibited treatment to the supraclavicular field. To further evaluate the radiation delivered, Jagsi et al requested detailed records for all evaluable patients. Although they only received 29% of the requested charts, this quality control evaluation revealed that 18.9% of patients received ⱖ three fields of radiation. This protocol violation was present in both cohorts at not significantly different rates. Interestingly, when categorized by the number of nodes positive, the SLNS cohort was more likely to receive the extra field of radiation in each category. Jagsi et al conclude that further study may be necessary to answer the question posed by Z0011 and suggest that standardized collection of locoregional treatment common data elements, as developed by the NCI Breast Oncology-Local Disease (BOLD) Task Force, would allow better monitoring of treatment delivered in clinical trials.7 The revelation that ⱖ three fields were used in a subset of patients provides evidence that should compel the re-examination of Z0011. Although, the third-field protocol violation rate did not differ significantly between cohorts, there is no solace to be found in this fact. It is the undissected axilla that is far more likely to benefit from additional radiation than the dissected axilla. This previously unrecognized third-field radiation finding may explain the apparent equivalence between the treatment arms. In response to criticisms, Z0011 results are said to be similar to those of National Surgical Adjuvant Breast and Bowel Project B-04. It has even been referred to as a “contemporary reaffirmation” of B-04.8 In B-04, clinically node-negative patients were randomly assigned to radical mastectomy, total mastectomy (TM) with axillary radiation, or TM alone.9,10 Based on the rate of positive nodes in the dissected axilla, it was estimated that 40% of the TM-only patients had positive axillary nodes. However, only approximately 20% developed clinically evident axillary recurrences. B-04 implies that not all axillary disease will manifest itself—a finding the Z0011 investigators suggest supports the validity of their study. What is often overlooked when referencing B-04 is the fact that it too suffered from significant protocol violations. One third of the patients in B-04 who were randomly assigned to no ALND actually did have axillary nodes removed. The unauthorized removal of these nodes could have influenced the axillary recurrence rate in © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY MICHIGAN on June 17, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 141.211.4.224
3583
Editorial
the TM-alone patients. One must wonder if the similar results in B-04 and Z0011 are because both studies faced similar problems with protocol adherence. Despite the best efforts of principal investigators, protocol violations are common in clinical trials. A widely accepted statistical technique to address protocol violations is the intention-to-treat (ITT) analysis.11 ITT analysis evaluates all patients randomly assigned to treatment including those who did not adhere to protocol prescribed therapy. By including nonadherent patients, ITT analyses result in a conservative estimate of the difference between treatment arms. While ITT analyses are widely accepted in superiority trials, they are more controversial in noninferiority trials, because ITT analyses “tend to bias the results toward equivalence.”12(p20) An alternative analytic method is the per-protocol (PP) analysis.11,13 PP analyses exclude participants who did not adhere to the protocol prescribed therapy and therefore PP analyses are more likely to detail differences between treatment arms. It has been recommended that with respect to noninferiority trials there should be both ITT and PP analyses.11,13 If both analyses agree, one could be more confident about the results. Employing this combination of analyses, the Z0011 investigators presented a PP or treatment-received analysis excluding the 5% of patients who did not have the appropriate surgical procedure. However, no such analyses were presented excluding the 15% to 19% of patients who had an extra radiation field or the 30% (251 of 856)2 who did not have whole-breast radiation. Since radiation therapy has been shown repeatedly to influence locoregional control in breast cancer, PP analyses excluding patients with major radiation protocol deviations are not only necessary but also likely to be illuminating. Unfortunately, all this may be for naught given the Early Breast Cancer Trialists’ Collaborate Group (EBCTCG) 2014 meta-analysis update, and other recently presented clinical trial results. The EBCTCG meta-analysis again showed that there was a recurrence-free and breast cancer–specific survival benefit associated with regional nodal irradiation (RNI) in women with one to three positive nodes.14 Z0011, in which 85% of the ALND patients had one to three positive nodes, concluded that there was no significant difference in locoregional failure, disease-free survival (DFS), and overall survival (OS) between ALND and SLNS. Thus,asstatedearlier,Z0011concludesthatSLNSisnotinferiortoALND (ALND ⴝ SLNS). In the recently presented AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, patients with cT1-2 SLNpositive breast cancer were randomly assigned to an ALND or axillary radiation therapy (ART).15,16 Nearly 90% of the patients had BCT and 87% of those in the ALND arm had one to three positive nodes. With 6.1-year median follow-up, the 5-year axillary recurrence rates were 0.54% versus 1.03% in the ALND and ART arms respectively and there was no significant difference in DFS and OS between arms. AMAROS concludes that SLNS plus ART is equivalent to an ALND with respect to cancer outcomes (ALND ⴝ SLNS ⫹ ART). In the National Cancer Institute of Canada - Clinical Trials Group MA.20 trial, women undergoing BCT who had a positive node on ALND, or other high-risk features, were randomly assigned to RNI or not.17 In this study 85% of participants had one to three positive nodes. With 5-year median follow-up, there was a statisticallysignificantimprovementinlocoregionalfailureandDFSanda trend toward improved OS in those patients receiving RNI. MA.20 concludesthatALNDplusRNIisbetterwithrespecttodiseaseoutcomesthan ALND alone (ALND ⬍ ALND ⫹ RNI). Given the standard caveats when comparingtrials,onecouldhypothesizethatSLNSwithorwithoutARTis 3584
© 2014 by American Society of Clinical Oncology
equivalent to ALND, and that ALND is less effective than ALND plus RNI (SLNS ⫾ ART ⴝ ALND ⬍ ALND ⫹ RNI). MA.20 suggests that both arms of Z0011 are inferior to ALND and RNI. This summary hypothesis is based on and limited by the results of these current clinical trials. The clinical details of MA.20 and AMAROS have not been fully published; therefore a thorough analysis of patient and tumor characteristics across these studies is problematic. Nonetheless, this hypothesis may also explain why there is no clear difference in outcomes between the two arms of Z0011. Much credit should be given to Jagsi et al6 (some of whom were primary investigators on Z0011) for bravely bringing forward this additional information. Although all the radiation records for the patients on Z0011 were not available, there is certainly enough information to justify re-evaluation of the data with an analytic technique to address protocol nonadherence. The Z0011 primary investigators, collectively and individually, have modernized local regional therapy for breast cancer. They have rightly earned the gratitude of millions of patients with breast cancer and should be lauded for their past and current efforts. However, it behooves them now to gather all the radiation data from each Z0011 patient and re-evaluate the results of their seminal study. Decreasing the frequency of ALND and its attendant toxicity is an important goal. The difficulty lies in defining the person in whom an ALND could be safely avoided. Given the Jagsi et al6 article in conjunction with the studies discussed herein, questions remain as to whether patients with positive SLNs can safely forgo both ALND and RNI. While the published results of Z0011 may agree with our preconceived notions, which arose from studies such as B-04, further analysis of Z0011 is still needed. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Giuliano AE, McCall L, Beitsch P, et al: Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: The American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 252:426-432, 2010 2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011 3. Cody HS 3rd: Does the rapid acceptance of ACOSOG Z0011 compromise selection of systemic therapy? Ann Surg Oncol 19:3643-3645, 2012 4. Gainer SM, Hunt KK, Beitsch P, et al: Changing behavior in clinical practice in response to the ACOSOG Z0011 trial: A survey of the American Society of Breast Surgeons. Ann Surg Oncol 19:3152-3158, 2012 5. Massimino KP, Hessman CJ, Ellis MC, et al: Impact of American College of Surgeons Oncology Group Z0011 and National Surgical Adjuvant Breast and Bowel Project B-32 trial results on surgeon practice in the Pacific Northwest. Am J Surg 203:618-622, 2012 6. Jagsi R, Chadha M, Moni J, et al: Radiation field design on the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 32:3600-3606, 2014 7. National Cancer Institute: Breast Cancer Steering Committee. http:// www.cancer.gov/aboutnci/organization/ccct/steering-committees/breast-cancer 8. Cady B: Discussions of Z0011. Ann Surg 252:432, 2010 9. Fisher B, Montague E, Redmond C, et al: Comparison of radical mastectomy with alternative treatments for primary breast cancer: A first report of results from a prospective randomized clinical trial. Cancer 39:2827-2839, 1977 (suppl 6) 10. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002 11. Gupta SK: Intention-to-treat concept: A review. Perspect Clin Res 2:109112, 2011 12. Snapinn SM: Noninferiority trials. Curr Control Trials Cardiovasc Med 1:19-21, 2000 JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY MICHIGAN on June 17, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 141.211.4.224
Editorial
13. Jones B, Jarvis P, Lewis JA, et al: Trials to assess equivalence: The importance of rigorous methods. BMJ 313:36-39, 1996 14. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383:2127-2135, 2014 15. Rutgers EJ: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023). J Clin Oncol 31:43s, 2013 (suppl; abstr LBA1001)
16. Straver ME, Meijnen P, van Tienhoven G, et al: Role of axillary clearance after a tumor-positive sentinel node in the administration of adjuvant therapy in early breast cancer. J Clin Oncol 28:731-737, 2010 17. Whelan TJ, NCIC-CTG MA. 20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol 29:80s, 2011 (suppl; abstr LBA1003)
DOI: 10.1200/JCO.2014.57.9946; published online ahead of print at www.jco.org on September 29, 2014
■ ■ ■
Be the First to Hear When New Clinical Cancer Research Is Published Online By signing up for JCO’s Early Release Notification, you will be alerted and have access to new articles posted online every Monday, weeks before they appear in print. All Early Release articles are searchable and citable, and are posted on jco.org in advance of print publication. Simply go to jco.org/earlyrelease, sign in, select “Early Release Notification,” and click the SUBMIT button. Stay informed—sign up today!
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY MICHIGAN on June 17, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 141.211.4.224
3585
JOURNAL OF CLINICAL ONCOLOGY
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New Information Prompts Old Question: Is Sentinel Lymph Node Sampling Equivalent to Axillary Lymph Node Dissection? Richard Cedric Zellars, Johns Hopkins University, Baltimore, MD See accompanying article on page 3600
In 2010, the results of American College of Surgeons Oncology Group Z0011 trial were published in Annals of Surgery.1 A second publication appeared in Journal of the American Medical Association the following year.2 Z0011 concluded, in a select population and using a noninferiority design, that axillary lymph node dissection (ALND) did not provide any clinical advantage over sentinel lymph node sampling (SLNS) alone. Thus, it was felt that SLNS can replace an ALND (SLNS ⫽ ALND) in a select population. Although some called for caution in the acceptance of this conclusion due to concerns about the details of the study, surgeons quickly began omitting routine ALND in patients with positive SLNS. In fact, much has been written acknowledging the astonishing alacrity at which the results of this trial influenced practice.3-5 Now, with the systematic review of the Z0011 radiation records by Jagsi et al,6 published with this editorial, one must ask if the results of Z0011 are still valid and wonder if the rapid acceptance of Z0011, despite critical absence of treatment information, was because the conclusions reached were indeed accurate or because the results of this trial simply agreed with preconceptions of the practitioners. Briefly, in Z0011 women undergoing breast-conserving therapy (BCT) with fewer than three positive sentinel lymph nodes (SLN) were randomly assigned to ALND or not. All patients were to receive whole-breast irradiation only (2 fields). Specifically, nodal-directed or third-field radiation was prohibited. Although powered for 1,900 patients, this noninferiority study accrued only 891 patients. The study concluded that there was no significant difference between the ALND and SLNS cohorts with respect to locoregional, disease-free survival (DFS), and overall survival. Z0011 was criticized for not meeting its accrual goal, having too many patients lost to follow-up, and lacking radiation therapy details. Some suspected that radiation oncologists adjusted their breast tangents (high tangents) to cover more nodal tissue in patients known to have an undissected axilla, which could have resulted in an unfair advantage to the SLNS arm. Jagsi et al6 undertook the tedious process of reviewing the radiation records to determine how often patients were treated with high tangents. A surprise finding awaited the investigators. Radiation case report forms were available for 605 of the 856 evaluable patients on the study. From the 605 case report forms, 89 of 540 patients, who Journal of Clinical Oncology, Vol 32, No 32 (November 10), 2014: pp 3583-3585
received whole-breast radiation, also received a protocolprohibited treatment to the supraclavicular field. To further evaluate the radiation delivered, Jagsi et al requested detailed records for all evaluable patients. Although they only received 29% of the requested charts, this quality control evaluation revealed that 18.9% of patients received ⱖ three fields of radiation. This protocol violation was present in both cohorts at not significantly different rates. Interestingly, when categorized by the number of nodes positive, the SLNS cohort was more likely to receive the extra field of radiation in each category. Jagsi et al conclude that further study may be necessary to answer the question posed by Z0011 and suggest that standardized collection of locoregional treatment common data elements, as developed by the NCI Breast Oncology-Local Disease (BOLD) Task Force, would allow better monitoring of treatment delivered in clinical trials.7 The revelation that ⱖ three fields were used in a subset of patients provides evidence that should compel the re-examination of Z0011. Although, the third-field protocol violation rate did not differ significantly between cohorts, there is no solace to be found in this fact. It is the undissected axilla that is far more likely to benefit from additional radiation than the dissected axilla. This previously unrecognized third-field radiation finding may explain the apparent equivalence between the treatment arms. In response to criticisms, Z0011 results are said to be similar to those of National Surgical Adjuvant Breast and Bowel Project B-04. It has even been referred to as a “contemporary reaffirmation” of B-04.8 In B-04, clinically node-negative patients were randomly assigned to radical mastectomy, total mastectomy (TM) with axillary radiation, or TM alone.9,10 Based on the rate of positive nodes in the dissected axilla, it was estimated that 40% of the TM-only patients had positive axillary nodes. However, only approximately 20% developed clinically evident axillary recurrences. B-04 implies that not all axillary disease will manifest itself—a finding the Z0011 investigators suggest supports the validity of their study. What is often overlooked when referencing B-04 is the fact that it too suffered from significant protocol violations. One third of the patients in B-04 who were randomly assigned to no ALND actually did have axillary nodes removed. The unauthorized removal of these nodes could have influenced the axillary recurrence rate in © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY MICHIGAN on June 17, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 141.211.4.224
3583
Editorial
the TM-alone patients. One must wonder if the similar results in B-04 and Z0011 are because both studies faced similar problems with protocol adherence. Despite the best efforts of principal investigators, protocol violations are common in clinical trials. A widely accepted statistical technique to address protocol violations is the intention-to-treat (ITT) analysis.11 ITT analysis evaluates all patients randomly assigned to treatment including those who did not adhere to protocol prescribed therapy. By including nonadherent patients, ITT analyses result in a conservative estimate of the difference between treatment arms. While ITT analyses are widely accepted in superiority trials, they are more controversial in noninferiority trials, because ITT analyses “tend to bias the results toward equivalence.”12(p20) An alternative analytic method is the per-protocol (PP) analysis.11,13 PP analyses exclude participants who did not adhere to the protocol prescribed therapy and therefore PP analyses are more likely to detail differences between treatment arms. It has been recommended that with respect to noninferiority trials there should be both ITT and PP analyses.11,13 If both analyses agree, one could be more confident about the results. Employing this combination of analyses, the Z0011 investigators presented a PP or treatment-received analysis excluding the 5% of patients who did not have the appropriate surgical procedure. However, no such analyses were presented excluding the 15% to 19% of patients who had an extra radiation field or the 30% (251 of 856)2 who did not have whole-breast radiation. Since radiation therapy has been shown repeatedly to influence locoregional control in breast cancer, PP analyses excluding patients with major radiation protocol deviations are not only necessary but also likely to be illuminating. Unfortunately, all this may be for naught given the Early Breast Cancer Trialists’ Collaborate Group (EBCTCG) 2014 meta-analysis update, and other recently presented clinical trial results. The EBCTCG meta-analysis again showed that there was a recurrence-free and breast cancer–specific survival benefit associated with regional nodal irradiation (RNI) in women with one to three positive nodes.14 Z0011, in which 85% of the ALND patients had one to three positive nodes, concluded that there was no significant difference in locoregional failure, disease-free survival (DFS), and overall survival (OS) between ALND and SLNS. Thus,asstatedearlier,Z0011concludesthatSLNSisnotinferiortoALND (ALND ⴝ SLNS). In the recently presented AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, patients with cT1-2 SLNpositive breast cancer were randomly assigned to an ALND or axillary radiation therapy (ART).15,16 Nearly 90% of the patients had BCT and 87% of those in the ALND arm had one to three positive nodes. With 6.1-year median follow-up, the 5-year axillary recurrence rates were 0.54% versus 1.03% in the ALND and ART arms respectively and there was no significant difference in DFS and OS between arms. AMAROS concludes that SLNS plus ART is equivalent to an ALND with respect to cancer outcomes (ALND ⴝ SLNS ⫹ ART). In the National Cancer Institute of Canada - Clinical Trials Group MA.20 trial, women undergoing BCT who had a positive node on ALND, or other high-risk features, were randomly assigned to RNI or not.17 In this study 85% of participants had one to three positive nodes. With 5-year median follow-up, there was a statisticallysignificantimprovementinlocoregionalfailureandDFSanda trend toward improved OS in those patients receiving RNI. MA.20 concludesthatALNDplusRNIisbetterwithrespecttodiseaseoutcomesthan ALND alone (ALND ⬍ ALND ⫹ RNI). Given the standard caveats when comparingtrials,onecouldhypothesizethatSLNSwithorwithoutARTis 3584
© 2014 by American Society of Clinical Oncology
equivalent to ALND, and that ALND is less effective than ALND plus RNI (SLNS ⫾ ART ⴝ ALND ⬍ ALND ⫹ RNI). MA.20 suggests that both arms of Z0011 are inferior to ALND and RNI. This summary hypothesis is based on and limited by the results of these current clinical trials. The clinical details of MA.20 and AMAROS have not been fully published; therefore a thorough analysis of patient and tumor characteristics across these studies is problematic. Nonetheless, this hypothesis may also explain why there is no clear difference in outcomes between the two arms of Z0011. Much credit should be given to Jagsi et al6 (some of whom were primary investigators on Z0011) for bravely bringing forward this additional information. Although all the radiation records for the patients on Z0011 were not available, there is certainly enough information to justify re-evaluation of the data with an analytic technique to address protocol nonadherence. The Z0011 primary investigators, collectively and individually, have modernized local regional therapy for breast cancer. They have rightly earned the gratitude of millions of patients with breast cancer and should be lauded for their past and current efforts. However, it behooves them now to gather all the radiation data from each Z0011 patient and re-evaluate the results of their seminal study. Decreasing the frequency of ALND and its attendant toxicity is an important goal. The difficulty lies in defining the person in whom an ALND could be safely avoided. Given the Jagsi et al6 article in conjunction with the studies discussed herein, questions remain as to whether patients with positive SLNs can safely forgo both ALND and RNI. While the published results of Z0011 may agree with our preconceived notions, which arose from studies such as B-04, further analysis of Z0011 is still needed. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Giuliano AE, McCall L, Beitsch P, et al: Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: The American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 252:426-432, 2010 2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011 3. Cody HS 3rd: Does the rapid acceptance of ACOSOG Z0011 compromise selection of systemic therapy? Ann Surg Oncol 19:3643-3645, 2012 4. Gainer SM, Hunt KK, Beitsch P, et al: Changing behavior in clinical practice in response to the ACOSOG Z0011 trial: A survey of the American Society of Breast Surgeons. Ann Surg Oncol 19:3152-3158, 2012 5. Massimino KP, Hessman CJ, Ellis MC, et al: Impact of American College of Surgeons Oncology Group Z0011 and National Surgical Adjuvant Breast and Bowel Project B-32 trial results on surgeon practice in the Pacific Northwest. Am J Surg 203:618-622, 2012 6. Jagsi R, Chadha M, Moni J, et al: Radiation field design on the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 32:3600-3606, 2014 7. National Cancer Institute: Breast Cancer Steering Committee. http:// www.cancer.gov/aboutnci/organization/ccct/steering-committees/breast-cancer 8. Cady B: Discussions of Z0011. Ann Surg 252:432, 2010 9. Fisher B, Montague E, Redmond C, et al: Comparison of radical mastectomy with alternative treatments for primary breast cancer: A first report of results from a prospective randomized clinical trial. Cancer 39:2827-2839, 1977 (suppl 6) 10. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002 11. Gupta SK: Intention-to-treat concept: A review. Perspect Clin Res 2:109112, 2011 12. Snapinn SM: Noninferiority trials. Curr Control Trials Cardiovasc Med 1:19-21, 2000 JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY MICHIGAN on June 17, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 141.211.4.224
Editorial
13. Jones B, Jarvis P, Lewis JA, et al: Trials to assess equivalence: The importance of rigorous methods. BMJ 313:36-39, 1996 14. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383:2127-2135, 2014 15. Rutgers EJ: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023). J Clin Oncol 31:43s, 2013 (suppl; abstr LBA1001)
16. Straver ME, Meijnen P, van Tienhoven G, et al: Role of axillary clearance after a tumor-positive sentinel node in the administration of adjuvant therapy in early breast cancer. J Clin Oncol 28:731-737, 2010 17. Whelan TJ, NCIC-CTG MA. 20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol 29:80s, 2011 (suppl; abstr LBA1003)
DOI: 10.1200/JCO.2014.57.9946; published online ahead of print at www.jco.org on September 29, 2014
■ ■ ■
Be the First to Hear When New Clinical Cancer Research Is Published Online By signing up for JCO’s Early Release Notification, you will be alerted and have access to new articles posted online every Monday, weeks before they appear in print. All Early Release articles are searchable and citable, and are posted on jco.org in advance of print publication. Simply go to jco.org/earlyrelease, sign in, select “Early Release Notification,” and click the SUBMIT button. Stay informed—sign up today!
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY MICHIGAN on June 17, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 141.211.4.224
3585
![[Sentinel node invasion: is it necessary to perform axillary lymph node dissection? Randomized trial SERC].](/assets/img/hold.png)
