VOLUME
32
䡠
NUMBER
34
䡠
DECEMBER
1
2014
JOURNAL OF CLINICAL ONCOLOGY
Recommendation for Omitting Axillary Lymph Node Dissection Should Be Individualized in Patients With Breast Cancer With One or Two Positive Sentinel Lymph Nodes TO THE EDITOR: We would like to comment on the recommendation 2.1 of the revised American Society of Clinical Oncology guideline on sentinel lymph node (SLN) biopsy for patients with early-stage breast cancer.1 The guideline advises against recommending completion axillary lymph node dissection (ALND) for patients with T1or T2 primary lesions and one or two positive axillary SLNs. This recommendation is based on data from one randomized trial, the American College of Surgeons Oncology Group Z00112 (the other randomized trial available with a similar clinical question, the International Breast Cancer Study Group 23-01, addresses a different population with only micrometastatic node disease3). Z0011 randomly assigned 891 (from a planned 1,900) patients with T1 or T2 breast cancers and one or two positive axillary SLN to further ALND or no further surgical treatment. It was able to demonstrate the noninferiority of no further surgical treatment. Z0011 had shortcomings, which were partially reviewed previously.4 The two groups had slight inequalities in several prognostic characteristics (T stage, grade, lymphovascular invasion), all favoring the SLN group. Moreover, micrometastatic-only node disease was present in a statistically significant higher percentage of patients in the SLN group (44.8% v 37.5%). Despite these inequalities, overall survival (OS) and disease-free survival were similar. The study had a high rate of loss to follow-up (166 of 891 patients; 18.6%), a source of potential bias. Human epidermal growth factor receptor 2 (HER2) testing was not standard at the time of the study and was not reported. The LN tumor burden in the studied population was low, with 21% of patients in the ALND group having additional positive nodes. One can predict that a similar percentage of patients in the SLN group would have additional disease. The low tumor burden is also depicted in the higher OS rates in the study compared with the rate of 80% anticipated. Available models predict that patients who meet the eligibility criteria of Z0011 may have much higher probabilities of additional positive nodes. For example, one model predicts that a patient with a grade 3 tumor of 5 cm and two positive SLNs may have a probability of ⬎ 90% for additional positive nodes.5 The question remains whether patients with higher axillary LN burdens will have similar outcome without ALND. An additional question is the generalizability of results to subtypes of breast cancer not well represented or not studied in Z0011 (estrogen receptor negative and HER2 positive). The authors recognized this shortcoming and performed an exploratory analysis of subgroups that showed no statistically significant differences. Nevertheless, this represents weak evidence. Overall, for the less common subtypes of breast cancer such as triple negative and HER2 positive Journal of Clinical Oncology, Vol 32, No 34 (December 1), 2014: pp 3901-3902
C O R R E S P O N D E N C E
there is little evidence to support omitting ALND. This is particularly worrisome in triple-negative patients, for whom there is currently no proven targeted therapy to control residual disease. Moreover, for HER2-positive patients who have available efficacious targeted therapies, these can produce only small percentages of complete responses in the presence of significant disease.6,7 The same is true for radiation therapy. A final issue is the length of follow-up. As the authors of Z0011 noted, it would have taken more than 20 years to observe the prespecified 500 deaths. Although the fact that no differences were observed in OS and local recurrences at 6 years is reassuring, concerns remain. The population studied with mainly ER-positive disease often has an indolent course, and thus 6 years may be too short a period to evaluate OS. Moreover, local recurrence rates display some discernible differences between the two groups.8 The ALND group had numerically more (3.6% v 1.9% in the SLN group) in-breast recurrences. These recurrences should not have been influenced by the treatment assigned and probably reflect the aforementioned baseline differences in the two groups. In contrast, axillary recurrences were more prevalent in the SLN group (0.9% v 0.5% in the ALND group). Although this difference was not statistically significant, it may imply that the two treatments are not equal in controlling axillary disease. Increased axillary tumor burden may accentuate such differences. In conclusion, we believe that available data from only one randomized study are not sufficient for clinicians to recommend omitting completion ALND in all patients with T1/T2 disease and up to two positive SLNs who will undergo lumpectomy and whole-breast irradiation. On the basis of Z0011, it would be more prudent to recommend routine consideration of ALND omission only in postmenopausal patients, ductal carcinomas, clinically negative axilla, no extranodal extension, and estrogen receptor/progesterone receptor– positive disease. In other patients with one or more deviations from the studied population the standard should remain completion ALND, and an individualized decision should be reached, optimally with involvement of the patient, in anticipation of more confirmatory data.
Ioannis A. Voutsadakis and Sylvana Spadafora Sault Area Hospital, Sault Ste Marie, Ontario, Canada
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Lyman GH, Temin S, Edge SB, et al: Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 32:1365-1383, 2014 2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel lymph node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011 3. Galimberti V, Cole BF, Zurrida S, et al: Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): A phase 3 randomized controlled trial. Lancet Oncol 14:297-305, 2013 4. Shah-Khan M, Boughey JC: Evolution of axillary nodal staging in breast cancer: Clinical implications of the ACOSOG Z0011 trial. Cancer Control 19:267276, 2012
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at University of Manitoba Libraries on June 10, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 130.179.16.201
3901
Correspondence
5. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al: A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 10:1140-1151, 2003 6. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against Her2 for metastatic breast cancer that overexpresses Her2. N Engl J Med 344:783-792, 2001 7. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012
8. 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 252:426-433, 2010
DOI: 10.1200/JCO.2014.57.1190; published online ahead of print at www.jco.org on September 22, 2014
■ ■ ■
3902
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at University of Manitoba Libraries on June 10, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 130.179.16.201
32
䡠
NUMBER
34
䡠
DECEMBER
1
2014
JOURNAL OF CLINICAL ONCOLOGY
Recommendation for Omitting Axillary Lymph Node Dissection Should Be Individualized in Patients With Breast Cancer With One or Two Positive Sentinel Lymph Nodes TO THE EDITOR: We would like to comment on the recommendation 2.1 of the revised American Society of Clinical Oncology guideline on sentinel lymph node (SLN) biopsy for patients with early-stage breast cancer.1 The guideline advises against recommending completion axillary lymph node dissection (ALND) for patients with T1or T2 primary lesions and one or two positive axillary SLNs. This recommendation is based on data from one randomized trial, the American College of Surgeons Oncology Group Z00112 (the other randomized trial available with a similar clinical question, the International Breast Cancer Study Group 23-01, addresses a different population with only micrometastatic node disease3). Z0011 randomly assigned 891 (from a planned 1,900) patients with T1 or T2 breast cancers and one or two positive axillary SLN to further ALND or no further surgical treatment. It was able to demonstrate the noninferiority of no further surgical treatment. Z0011 had shortcomings, which were partially reviewed previously.4 The two groups had slight inequalities in several prognostic characteristics (T stage, grade, lymphovascular invasion), all favoring the SLN group. Moreover, micrometastatic-only node disease was present in a statistically significant higher percentage of patients in the SLN group (44.8% v 37.5%). Despite these inequalities, overall survival (OS) and disease-free survival were similar. The study had a high rate of loss to follow-up (166 of 891 patients; 18.6%), a source of potential bias. Human epidermal growth factor receptor 2 (HER2) testing was not standard at the time of the study and was not reported. The LN tumor burden in the studied population was low, with 21% of patients in the ALND group having additional positive nodes. One can predict that a similar percentage of patients in the SLN group would have additional disease. The low tumor burden is also depicted in the higher OS rates in the study compared with the rate of 80% anticipated. Available models predict that patients who meet the eligibility criteria of Z0011 may have much higher probabilities of additional positive nodes. For example, one model predicts that a patient with a grade 3 tumor of 5 cm and two positive SLNs may have a probability of ⬎ 90% for additional positive nodes.5 The question remains whether patients with higher axillary LN burdens will have similar outcome without ALND. An additional question is the generalizability of results to subtypes of breast cancer not well represented or not studied in Z0011 (estrogen receptor negative and HER2 positive). The authors recognized this shortcoming and performed an exploratory analysis of subgroups that showed no statistically significant differences. Nevertheless, this represents weak evidence. Overall, for the less common subtypes of breast cancer such as triple negative and HER2 positive Journal of Clinical Oncology, Vol 32, No 34 (December 1), 2014: pp 3901-3902
C O R R E S P O N D E N C E
there is little evidence to support omitting ALND. This is particularly worrisome in triple-negative patients, for whom there is currently no proven targeted therapy to control residual disease. Moreover, for HER2-positive patients who have available efficacious targeted therapies, these can produce only small percentages of complete responses in the presence of significant disease.6,7 The same is true for radiation therapy. A final issue is the length of follow-up. As the authors of Z0011 noted, it would have taken more than 20 years to observe the prespecified 500 deaths. Although the fact that no differences were observed in OS and local recurrences at 6 years is reassuring, concerns remain. The population studied with mainly ER-positive disease often has an indolent course, and thus 6 years may be too short a period to evaluate OS. Moreover, local recurrence rates display some discernible differences between the two groups.8 The ALND group had numerically more (3.6% v 1.9% in the SLN group) in-breast recurrences. These recurrences should not have been influenced by the treatment assigned and probably reflect the aforementioned baseline differences in the two groups. In contrast, axillary recurrences were more prevalent in the SLN group (0.9% v 0.5% in the ALND group). Although this difference was not statistically significant, it may imply that the two treatments are not equal in controlling axillary disease. Increased axillary tumor burden may accentuate such differences. In conclusion, we believe that available data from only one randomized study are not sufficient for clinicians to recommend omitting completion ALND in all patients with T1/T2 disease and up to two positive SLNs who will undergo lumpectomy and whole-breast irradiation. On the basis of Z0011, it would be more prudent to recommend routine consideration of ALND omission only in postmenopausal patients, ductal carcinomas, clinically negative axilla, no extranodal extension, and estrogen receptor/progesterone receptor– positive disease. In other patients with one or more deviations from the studied population the standard should remain completion ALND, and an individualized decision should be reached, optimally with involvement of the patient, in anticipation of more confirmatory data.
Ioannis A. Voutsadakis and Sylvana Spadafora Sault Area Hospital, Sault Ste Marie, Ontario, Canada
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Lyman GH, Temin S, Edge SB, et al: Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 32:1365-1383, 2014 2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel lymph node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011 3. Galimberti V, Cole BF, Zurrida S, et al: Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): A phase 3 randomized controlled trial. Lancet Oncol 14:297-305, 2013 4. Shah-Khan M, Boughey JC: Evolution of axillary nodal staging in breast cancer: Clinical implications of the ACOSOG Z0011 trial. Cancer Control 19:267276, 2012
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at University of Manitoba Libraries on June 10, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 130.179.16.201
3901
Correspondence
5. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al: A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 10:1140-1151, 2003 6. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against Her2 for metastatic breast cancer that overexpresses Her2. N Engl J Med 344:783-792, 2001 7. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012
8. 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 252:426-433, 2010
DOI: 10.1200/JCO.2014.57.1190; published online ahead of print at www.jco.org on September 22, 2014
■ ■ ■
3902
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at University of Manitoba Libraries on June 10, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 130.179.16.201
