Journal of Surgical Oncology 48:217-219 (1991)
EDITORIAL COMMENTS
Axillary Dissection in Breast Cancer: When, Why, How Much, and for How Long? Another Operation Soon to be Extinct? PETER J. DECKERS, MD From the Department of Surgery, University of Connecticut Health Center, Farrnington, and the Department of Surgery, Hartford Hospital, Hartford, Connecticut
KEYWORDS:internal mammary nodes, en bloc dissection, radiation therapy, adjuvant therapy
The prognostic significance of tumor size and location of the primary tumor in the breast as well as the pathologic status of the axillary lymph nodes in patients with invasive primary breast cancer have been thoroughly studied. A direct adverse relationship between increasing tumor size and prognosis is well established. Likewise, even though 50% of invasive tumors are located in the upper outer quadrant of the breast, it is unusual to find statistically significant differences in survival based on quadrant location alone. Although the American College of Surgeons’ (ACS) National Survey in 1978 [ 11 and even earlier data from Fisher et al. [2] both indicate that women with medial tumors and negative nodes do somewhat worse than patients with lateral tumors and negative nodes, this difference is, at most, 5%. Moreover, the prognosis for patients with positive nodes was not statistically different based on tumor location. However, the likelihood of axillary lymph node involvement is influenced by location of the primary tumor in the breast. In the ACS survey, 43% of patients with tumors in the lateral half of the breast had positive axillary nodes, compared with 35% for patients with medial-half tumors. Fisher has observed that 52% of patients with lateral-half tumors had positive nodes, compared with 29% of patients with medial-half tumors. This tendency occurs independent of tumor size. Axillary node involvement is directly related to the size of the primary lesion. The larger the primary tumor, the greater the risk of axillary node involvement [3-51. Even invasive tumors of less than 1 cm have a risk of axillary involvement which may approach 10-15%. Detection of axillary involvement by physical examination is inaccurate. When axillary lymph nodes are palpable and suspicious for cancer, histologic evidence of metastatic disease is found in only 70-73%. Conversely, 0 1991 Wiley-Liss, Inc.
when axillary nodes are not palpable, histologic involvement is detected in approximately 3 5 4 0 % [6]. These figures indicate the shortcomings of clinical evaluation. Moreover, since histologic involvement of axillary nodes has a high correlation with prognosis and in 1991 is still critical for effective treatment planning, it is imperative that thorough axillary dissection (10 or more nodes removed) rather than an axillary sampling be performed in all patients [7]. Patients with histologically negative axillary nodes have a markedly better survival than do patients with histologic involvement. Furthermore, patients with one to three positive nodes do better than patients with four or more positive nodes. Prognosis appears to be directly related to the number of positive axillary nodes. Patients with negative nodes can be expected to have a 70% I0-year survival; patients with one to three positive nodes, a 39% 10-year survival; and patients with 6 1 0 positive nodes, a 14% I0-year survival. The axilla is commonly divided into three levels: level 1 is defined as tissue inferior and lateral to the edge of the pectoralis minor muscle; level 2 is tissue directly beneath the pectoralis minor muscle; and level 3 is tissue superior and medial to the pectoralis minor muscle. Prognosis is related to the level of axillary involvement. Nodal disease in level 3 carries a far more ominous prognosis than nodal disease in level 1 . In fact, disease at level 3 was, at one time, a criterion for inoperability in patients with invasive breast cancer. The most important issue, however, is not the level in which positive nodes are found, but rather the Accepted for publication July 3, 1991. Address reprint requests to Peter J . Deckers, MD, Professor and Chairman, Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-9984.
218
Deckers
total number of lymph nodes involved histologically with metastatic breast cancer. Micrometastatic involvement of axillary lymph nodes may not be associated with the poor prognosis seen with macrometastatic involvement. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has demonstrated that when patients with axillary metastases measuring 2 mm or less in greatest diameter (micrometastases) were compared with patients with metastases larger than 2 cm, or with those without nodal metastases, survival rates for patients with micrometastases and for those without nodal metastases were similar [8]. Both groups exhibited a significantly higher likelihood of survival than did patients with macrometastases. Axillary lymph node involvement is more common than internal mammary node involvement. On the other hand, internal mammary node involvement is much more common when axillary nodes are involved and, as would be expected, internal mammary node involvement is more common for medial lesions than for lateral lesions [9]. However, even in patients with inner or central primary lesions, axillary involvement is more common than internal mammary node involvement. The most consistent finding regarding internal mammary node involvement is its relationship to axillary node involvement. When axillary nodes are negative, internal mammary node involvement is uncommon (approximately 10%). When axillary nodes are positive, internal mammary node involvement is approximately 30%. Furthermore, the greater the extent of axillary node involvement, the greater the likelihood of internal mammary node involvement. Today, most agree that the axilla is the most important site of nodal involvement. The critical issue is to determine whether or not local-regional treatment of the axillary lymph node areas is important in prolonging disease-free survival and survival in patients with invasive breast cancer. Most data today indicate that treatment of regional nodal areas has at most only little, if any, impact on the likelihood of long-term survival. The determination of axillary and internal mammary node involvement today is used chiefly as a means of assessing prognosis and establishing appropriate treatment plans. The presence and extent of axillary node involvement are the most important means of assessing prognosis. This is best achieved by complete axillary dissection. However, it is established that thorough dissection of level 3 is associated with increased morbidity, especially in relationship to arm swelling. In addition, there is little evidence that increased prognostic data are gained by this complete axillary dissection or that the increased prognostic data outweigh the increased morbidity compared with subtotal (levels 1 and 2) dissection. In fact, today most patients undergo an axillary dissection that is limited to levels 1 and 2. This seems most appropriate.
Protocol B-04 of the NSABP is an important study in evaluating the therapeutic efficacy of en bloc dissection (axillary lymph node dissection) in cancer surgery [ 101. This protocol was specifically designed to determine whether, in patients with clinically negative axillary nodes, 1) total mastectomy followed by delayed axillary dissection for those patients who subsequently develop positive nodes is as effective a therapy as radical mastectomy including (in continuity) synchronous, prophylactic axillary dissection, and 2) total mastectomy with postoperative regional radiation is as effective a treatment as radical mastectomy with synchronous axillary dissection, or total mastectomy with delayed axillary dissection for patients who subsequently develop positive nodes. Conversely, the primary aim in patients with clinically positive nodes was to determine whether radical mastectomy with synchronous therapeutic axillary dissection and total mastectomy with regional radiation are equivalent procedures. This study accrued 1,665 eligible patients between July 1971 and September 1974, and results are now available to 180 months of observation. Survival data fail to demonstrate any advantage for particular treatment groups among either the clinically negative or clinically positive node groups. The percent survival without disease at 5, 10, and 15 years is also similar, even though examination of the site of first-reported recurrence reveals that the incidence of local treatment failure among negative node patients is somewhat less in the groups treated with radiotherapy. Sixty-eight patients ( I 8%) assigned to the total mastectomy group have had a delayed positive axillary dissection. The median time to positive biopsy in this group has been 14.8 months, with a range of 3-134.5 months. Eighty-one percent of dissections occurred within 30 months. Fifty-eight of these 68 patients (85%) have had a systemic failure subsequent to axillary dissection, with a median time to treatment failure of 17.2 months post dissection. The data in patients with clinically negative nodes fail to show any advantage to prophylactic axillary dissection when compared with patients who undergo delayed axillary dissection when and if their axillary nodes become suspicious for metastatic disease. Furthermore, in patients with negative axillary nodes, radiation was given to the axilla, supraclavicular fossa, chest wall, and internal mammary nodes. Therefore, this group represents the only group in the negative node patients in which any type of treatment was delivered to nodal areas other than the axilla. Recurrence in the axilla after radiation therapy was similar to that observed after surgical axillary dissection (2%) and was significantly different than the recurrence rate observed in patients with similarly sized tumors treated by mastectomy alone (18%). This indicates that radiation therapy to lymph node-bearing areas is effective in destroying tumor cells
Axillary Dissection in Breast Cancer
219
in these lymph nodes. Therefore, if treatment of the Is it not reasonable to conjecture that soon all women supraclavicular or internal mammary nodes had any with breast cancer could receive adjuvant chemotherapy effect on survival, one would expect that the total with the same multiagent regimen? Adjuvant tamoxifen mastectomy and radiation therapy group would show an therapy might be advocated after completion of a short improved survival compared with the other two groups, intensive chemotherapy regimen for all women with since this was the only group in which the supraclavicular estrogen receptor-positive primary tumors or for all and internal mammary nodes, as well as the chest wall, women over 50 years of age. If this unified approach to were treated. Survival, however, is exactly the same in adjuvant systemic therapy is established, axillary dissecall three groups. These data are strongly suggestive that tion might be offered only to women with grossly positive lymph node metastases are indicators of systemic spread axillae to most effectively establish local-regional conand that the disease is no longer a local-regional event. trol. The operation would have no utility in patients with The future of axillary dissection is not secure. It offers ductal carcinoma in situ or in women with palpable no therapeutic advantage in women with palpable T1 and invasive tumors and clinically negative axillae. It would T2 invasive tumors and a negative axilla on clinical truly be another of an increasingly long list of operations examination. This procedure does establish prognosis, threatened with extinction. but few would deny the seriousness of breast cancer even in women with negative nodes. It is effective in decreasREFERENCES ing the incidence of axillary recurrence when compared 1. Nemoto T, Natarajan N, Bedwani R, et al.: Breast cancer in the with women treated by mastectomy alone (1 8% -+ 2%). medial half results of the 1978 national survey of the American College of Surgeons. Cancer 51:1333-1338, 1983. However, irradiation to the axilla after mastectomy alone 2. Fisher B, Slack NH, Ausman RK, et al.: Location of breast is equally effective, and the full local-regional effects of carcinoma and prognosis. Surg Gynecol Obstet 129:705-7 16, adjuvant chemotherapy and/or hormonal therapy remain 1969. 3. Koscielny S, Tubiana M, Le MG, et al.: Breast cancer: relationto be explored. In 1991, adjuvant systemic treatment ship between the size of the primary tumor and the probability of strategies for women with positive and negative axillary metastatic dissemination. Br J Cancer 49:709-715, 1984. nodes as well as positive and negative estrogen receptors, 4. Schottenfeld D, Nash AG, Robbins GF, et al.: Ten-year results of the treatment of primary operable breast carcinoma. Cancer respectively, remain different. This fact, therefore, es38:1001-1007, 1976. tablishes the continued usefulness of axillary dissection 5. Fisher B, Slack NH, Bross IDJ, et al.: Cancer of the breast: size as a diagnostic tool useful for adjuvant treatment planof neoplasm and prognosis. Cancer 24:1071-1080, 1969. 6. Fisher ER, Sass R, Fisher B, et al.: Pathologic findings from the ning. However, it is established that multiagent, AdriNational Surgical Adjuvant Project for breast cancers. Cancer amycin-based chemotherapy regimens are competitive, if 53:712-723,7984. not consensus, therapy for women with positive nodes. 7. Fisher B. Wolmark N. Bauer M. et al.: The accuracv of clinical nodal staging and of limited axillary dissection as a deienninant of Moreover, chemotherapy is effective in prolonging dishistologic nodal status in carcinoma of the breast. Surg Gynecol ease-free survival in women with negative nodes. Trials Obstet 152:765-772, 1981. testing Adriamycin-based chemotherapy regimens in 8. Fisher ER, Swamidoss S, Lee CH, et al.: Detection and significance of occult axillary node metastases in patients with invasive women with negative nodes are now in progress. Soon breast cancer. Cancer 42:2025-2031, 1978. we should be able to reliably intercorrelate and interpret 9. Veronesi U , Cascinelli N , Greco M, et al.: Prognosis of breast prognostic factors such as tumor size, histologic and cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 202:702-707, 1985. nuclear grades, estrogen receptor status, proliferative Fisher B, Redmund C, Fisher ER, et al.: Ten-year results of a rate, ploidy, HER-2 oncogene, and cathepsin-D, thereby 10. randomized clinical trial comparing radical mastectomy and total predicting those women at higher risk for recurrence mastectomy with or without radiation. N Engl J Med 312:674681, 1985. independent of nodal status.
EDITORIAL COMMENTS
Axillary Dissection in Breast Cancer: When, Why, How Much, and for How Long? Another Operation Soon to be Extinct? PETER J. DECKERS, MD From the Department of Surgery, University of Connecticut Health Center, Farrnington, and the Department of Surgery, Hartford Hospital, Hartford, Connecticut
KEYWORDS:internal mammary nodes, en bloc dissection, radiation therapy, adjuvant therapy
The prognostic significance of tumor size and location of the primary tumor in the breast as well as the pathologic status of the axillary lymph nodes in patients with invasive primary breast cancer have been thoroughly studied. A direct adverse relationship between increasing tumor size and prognosis is well established. Likewise, even though 50% of invasive tumors are located in the upper outer quadrant of the breast, it is unusual to find statistically significant differences in survival based on quadrant location alone. Although the American College of Surgeons’ (ACS) National Survey in 1978 [ 11 and even earlier data from Fisher et al. [2] both indicate that women with medial tumors and negative nodes do somewhat worse than patients with lateral tumors and negative nodes, this difference is, at most, 5%. Moreover, the prognosis for patients with positive nodes was not statistically different based on tumor location. However, the likelihood of axillary lymph node involvement is influenced by location of the primary tumor in the breast. In the ACS survey, 43% of patients with tumors in the lateral half of the breast had positive axillary nodes, compared with 35% for patients with medial-half tumors. Fisher has observed that 52% of patients with lateral-half tumors had positive nodes, compared with 29% of patients with medial-half tumors. This tendency occurs independent of tumor size. Axillary node involvement is directly related to the size of the primary lesion. The larger the primary tumor, the greater the risk of axillary node involvement [3-51. Even invasive tumors of less than 1 cm have a risk of axillary involvement which may approach 10-15%. Detection of axillary involvement by physical examination is inaccurate. When axillary lymph nodes are palpable and suspicious for cancer, histologic evidence of metastatic disease is found in only 70-73%. Conversely, 0 1991 Wiley-Liss, Inc.
when axillary nodes are not palpable, histologic involvement is detected in approximately 3 5 4 0 % [6]. These figures indicate the shortcomings of clinical evaluation. Moreover, since histologic involvement of axillary nodes has a high correlation with prognosis and in 1991 is still critical for effective treatment planning, it is imperative that thorough axillary dissection (10 or more nodes removed) rather than an axillary sampling be performed in all patients [7]. Patients with histologically negative axillary nodes have a markedly better survival than do patients with histologic involvement. Furthermore, patients with one to three positive nodes do better than patients with four or more positive nodes. Prognosis appears to be directly related to the number of positive axillary nodes. Patients with negative nodes can be expected to have a 70% I0-year survival; patients with one to three positive nodes, a 39% 10-year survival; and patients with 6 1 0 positive nodes, a 14% I0-year survival. The axilla is commonly divided into three levels: level 1 is defined as tissue inferior and lateral to the edge of the pectoralis minor muscle; level 2 is tissue directly beneath the pectoralis minor muscle; and level 3 is tissue superior and medial to the pectoralis minor muscle. Prognosis is related to the level of axillary involvement. Nodal disease in level 3 carries a far more ominous prognosis than nodal disease in level 1 . In fact, disease at level 3 was, at one time, a criterion for inoperability in patients with invasive breast cancer. The most important issue, however, is not the level in which positive nodes are found, but rather the Accepted for publication July 3, 1991. Address reprint requests to Peter J . Deckers, MD, Professor and Chairman, Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-9984.
218
Deckers
total number of lymph nodes involved histologically with metastatic breast cancer. Micrometastatic involvement of axillary lymph nodes may not be associated with the poor prognosis seen with macrometastatic involvement. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has demonstrated that when patients with axillary metastases measuring 2 mm or less in greatest diameter (micrometastases) were compared with patients with metastases larger than 2 cm, or with those without nodal metastases, survival rates for patients with micrometastases and for those without nodal metastases were similar [8]. Both groups exhibited a significantly higher likelihood of survival than did patients with macrometastases. Axillary lymph node involvement is more common than internal mammary node involvement. On the other hand, internal mammary node involvement is much more common when axillary nodes are involved and, as would be expected, internal mammary node involvement is more common for medial lesions than for lateral lesions [9]. However, even in patients with inner or central primary lesions, axillary involvement is more common than internal mammary node involvement. The most consistent finding regarding internal mammary node involvement is its relationship to axillary node involvement. When axillary nodes are negative, internal mammary node involvement is uncommon (approximately 10%). When axillary nodes are positive, internal mammary node involvement is approximately 30%. Furthermore, the greater the extent of axillary node involvement, the greater the likelihood of internal mammary node involvement. Today, most agree that the axilla is the most important site of nodal involvement. The critical issue is to determine whether or not local-regional treatment of the axillary lymph node areas is important in prolonging disease-free survival and survival in patients with invasive breast cancer. Most data today indicate that treatment of regional nodal areas has at most only little, if any, impact on the likelihood of long-term survival. The determination of axillary and internal mammary node involvement today is used chiefly as a means of assessing prognosis and establishing appropriate treatment plans. The presence and extent of axillary node involvement are the most important means of assessing prognosis. This is best achieved by complete axillary dissection. However, it is established that thorough dissection of level 3 is associated with increased morbidity, especially in relationship to arm swelling. In addition, there is little evidence that increased prognostic data are gained by this complete axillary dissection or that the increased prognostic data outweigh the increased morbidity compared with subtotal (levels 1 and 2) dissection. In fact, today most patients undergo an axillary dissection that is limited to levels 1 and 2. This seems most appropriate.
Protocol B-04 of the NSABP is an important study in evaluating the therapeutic efficacy of en bloc dissection (axillary lymph node dissection) in cancer surgery [ 101. This protocol was specifically designed to determine whether, in patients with clinically negative axillary nodes, 1) total mastectomy followed by delayed axillary dissection for those patients who subsequently develop positive nodes is as effective a therapy as radical mastectomy including (in continuity) synchronous, prophylactic axillary dissection, and 2) total mastectomy with postoperative regional radiation is as effective a treatment as radical mastectomy with synchronous axillary dissection, or total mastectomy with delayed axillary dissection for patients who subsequently develop positive nodes. Conversely, the primary aim in patients with clinically positive nodes was to determine whether radical mastectomy with synchronous therapeutic axillary dissection and total mastectomy with regional radiation are equivalent procedures. This study accrued 1,665 eligible patients between July 1971 and September 1974, and results are now available to 180 months of observation. Survival data fail to demonstrate any advantage for particular treatment groups among either the clinically negative or clinically positive node groups. The percent survival without disease at 5, 10, and 15 years is also similar, even though examination of the site of first-reported recurrence reveals that the incidence of local treatment failure among negative node patients is somewhat less in the groups treated with radiotherapy. Sixty-eight patients ( I 8%) assigned to the total mastectomy group have had a delayed positive axillary dissection. The median time to positive biopsy in this group has been 14.8 months, with a range of 3-134.5 months. Eighty-one percent of dissections occurred within 30 months. Fifty-eight of these 68 patients (85%) have had a systemic failure subsequent to axillary dissection, with a median time to treatment failure of 17.2 months post dissection. The data in patients with clinically negative nodes fail to show any advantage to prophylactic axillary dissection when compared with patients who undergo delayed axillary dissection when and if their axillary nodes become suspicious for metastatic disease. Furthermore, in patients with negative axillary nodes, radiation was given to the axilla, supraclavicular fossa, chest wall, and internal mammary nodes. Therefore, this group represents the only group in the negative node patients in which any type of treatment was delivered to nodal areas other than the axilla. Recurrence in the axilla after radiation therapy was similar to that observed after surgical axillary dissection (2%) and was significantly different than the recurrence rate observed in patients with similarly sized tumors treated by mastectomy alone (18%). This indicates that radiation therapy to lymph node-bearing areas is effective in destroying tumor cells
Axillary Dissection in Breast Cancer
219
in these lymph nodes. Therefore, if treatment of the Is it not reasonable to conjecture that soon all women supraclavicular or internal mammary nodes had any with breast cancer could receive adjuvant chemotherapy effect on survival, one would expect that the total with the same multiagent regimen? Adjuvant tamoxifen mastectomy and radiation therapy group would show an therapy might be advocated after completion of a short improved survival compared with the other two groups, intensive chemotherapy regimen for all women with since this was the only group in which the supraclavicular estrogen receptor-positive primary tumors or for all and internal mammary nodes, as well as the chest wall, women over 50 years of age. If this unified approach to were treated. Survival, however, is exactly the same in adjuvant systemic therapy is established, axillary dissecall three groups. These data are strongly suggestive that tion might be offered only to women with grossly positive lymph node metastases are indicators of systemic spread axillae to most effectively establish local-regional conand that the disease is no longer a local-regional event. trol. The operation would have no utility in patients with The future of axillary dissection is not secure. It offers ductal carcinoma in situ or in women with palpable no therapeutic advantage in women with palpable T1 and invasive tumors and clinically negative axillae. It would T2 invasive tumors and a negative axilla on clinical truly be another of an increasingly long list of operations examination. This procedure does establish prognosis, threatened with extinction. but few would deny the seriousness of breast cancer even in women with negative nodes. It is effective in decreasREFERENCES ing the incidence of axillary recurrence when compared 1. Nemoto T, Natarajan N, Bedwani R, et al.: Breast cancer in the with women treated by mastectomy alone (1 8% -+ 2%). medial half results of the 1978 national survey of the American College of Surgeons. Cancer 51:1333-1338, 1983. However, irradiation to the axilla after mastectomy alone 2. Fisher B, Slack NH, Ausman RK, et al.: Location of breast is equally effective, and the full local-regional effects of carcinoma and prognosis. Surg Gynecol Obstet 129:705-7 16, adjuvant chemotherapy and/or hormonal therapy remain 1969. 3. Koscielny S, Tubiana M, Le MG, et al.: Breast cancer: relationto be explored. In 1991, adjuvant systemic treatment ship between the size of the primary tumor and the probability of strategies for women with positive and negative axillary metastatic dissemination. Br J Cancer 49:709-715, 1984. nodes as well as positive and negative estrogen receptors, 4. Schottenfeld D, Nash AG, Robbins GF, et al.: Ten-year results of the treatment of primary operable breast carcinoma. Cancer respectively, remain different. This fact, therefore, es38:1001-1007, 1976. tablishes the continued usefulness of axillary dissection 5. Fisher B, Slack NH, Bross IDJ, et al.: Cancer of the breast: size as a diagnostic tool useful for adjuvant treatment planof neoplasm and prognosis. Cancer 24:1071-1080, 1969. 6. Fisher ER, Sass R, Fisher B, et al.: Pathologic findings from the ning. However, it is established that multiagent, AdriNational Surgical Adjuvant Project for breast cancers. Cancer amycin-based chemotherapy regimens are competitive, if 53:712-723,7984. not consensus, therapy for women with positive nodes. 7. Fisher B. Wolmark N. Bauer M. et al.: The accuracv of clinical nodal staging and of limited axillary dissection as a deienninant of Moreover, chemotherapy is effective in prolonging dishistologic nodal status in carcinoma of the breast. Surg Gynecol ease-free survival in women with negative nodes. Trials Obstet 152:765-772, 1981. testing Adriamycin-based chemotherapy regimens in 8. Fisher ER, Swamidoss S, Lee CH, et al.: Detection and significance of occult axillary node metastases in patients with invasive women with negative nodes are now in progress. Soon breast cancer. Cancer 42:2025-2031, 1978. we should be able to reliably intercorrelate and interpret 9. Veronesi U , Cascinelli N , Greco M, et al.: Prognosis of breast prognostic factors such as tumor size, histologic and cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 202:702-707, 1985. nuclear grades, estrogen receptor status, proliferative Fisher B, Redmund C, Fisher ER, et al.: Ten-year results of a rate, ploidy, HER-2 oncogene, and cathepsin-D, thereby 10. randomized clinical trial comparing radical mastectomy and total predicting those women at higher risk for recurrence mastectomy with or without radiation. N Engl J Med 312:674681, 1985. independent of nodal status.
