A cost-effectiveness analysis of axillary node dissection in postmenopausal woman with estrogen receptor–positive breast cancer and clinically negative axillary nodes

Abstract

It is becoming fashionable (and appropriate) to evaluate cost-effectiveness of medical care. Often this evaluation is an assessment of the value of an additional test or therapy. As examples, are both a computed tomographic scan and a magnetic resonance imaging procedure necessary in certain circumstances? Is the addition of intraperitoneal chemotherapy of value as an adjunct for certain intra-abdominal malignancies? Implicit also in the results of a cost-effectiveness evaluation is the possible deletion of a standard treatment for a patient. For example, should life-support systems be withdrawn if there remains a 5% chance of survival? Orr et al (Surgery 1999;126:568-76) have agreed that a 5% survival advantage might be gained from axillary node dissection in patients with breast cancer. This figure comes from another analysis done by Orr published earlier this year.1Orr RK. The impact of prophylactic axillary node dissection on breast cancer survival. A Bayesian meta-analysis.Ann Surg Oncol. 1999; 6: 109-116Crossref PubMed Scopus (306) Google Scholar The analysis evaluated 6 trials that justifiably compare total mastectomy with axillary node dissection to total mastectomy without axillary node dissection or with inadequate treatment to the axilla (ie, inadequate radiation therapy). Axillary node dissection improved survival rates from 4% to 16%, and in 3 of the trials this improvement was significant. The only “head-to-head” trial of axillary node dissection versus no axillary node treatment was the NSABP BO-4 trial. In it, 35% of the control patients had 1 or more lymph nodes removed at the time of total mastectomy.2Fisher B Wolmark N Bauer M et al.The accuracy of clinical nodal staging and of limited axillary dissection as a determinant of histologic nodal status in carcinoma of the breast.Surg Gynecol Obstet. 1981; 152: 765-772PubMed Google Scholar We now know from data from sentinel lymph node studies in breast cancer that a positive sentinel node is often the only positive lymph node that is an axillary metastasis from small breast cancers.3Albertini J Lyman G Cox C et al.Lymphatic mapping and sentinel node biopsy in the patient with breast cancer.JAMA. 1996; 276: 1818-1822Crossref PubMed Google Scholar Possibly the sentinel node with micrometastasis was removed from patients in the control group of the BO-4 trial, and that may be the reason the axillary failure rates were no different in the control group of the study. (Failure rates were 21% when no nodes were removed, 8% when 1 to 5 nodes were removed, and 0% when 6 or more nodes were removed.)Consequently, to date there are no prospective randomized trials that directly compare adequate surgical dissection of the axilla to no axillary treatment. All conclusions of the value of axillary node dissection to survival must be made from inference from other studies.The incidence of positive axillary lymph nodes resulting from T1a breast cancers approximates 7%, as gleaned from the multiple published series evaluating this subject.4Recht A Houlihan MJ. Axillary lymph nodes and breast cancer.Cancer. 1995; 76: 1491-1512Crossref PubMed Scopus (293) Google Scholar Mustafa and Bland,5Mustafa IA Cole B Wanebo HJ et al.The impact of histopathology on nodal metastases in minimal breast cancer.Arch Surg. 1997; 132: 384-391Crossref PubMed Scopus (63) Google Scholar however, recently reviewed 2185 patients from the Rhode Island Tumor Registry who had breast lesions of less than 1 cm. They identified risk factors to determine the incidence of axillary metastasis within this group: age (<40 years vs >40 years = 31.2% vs 15.6%), size (<.5 cm vs >.5 cm = 11.3% vs 17%), and histologic grade (1, 2, or 3 = 9.5%, 17.2%, or 22.3%). Orr et al, using their cost-effectiveness model, recommend axillary node dissection for women who have a 20% or greater chance of having axillary metastasis. Consequently, the data of Mustafa and Bland would indicate that Orr et al would recommend axillary dissection for women under 40 years of age with a histologic grade III 1-cm breast cancer. Yet Orr et al state: “Because of the lower risk of nodal metastasis, patients with 1-cm, nonpalpable tumors experience minimal benefit at markedly higher incremental costs….” Interestingly, in the Guy's Hospital trial,6Hayward J Caleffi M. The significance of local control in the primary treatment of breast cancer.Arch Surg. 1987; 122: 1244-1247Crossref PubMed Scopus (129) Google Scholar patients with T1 lesions had a survival advantage because axillary node dissections were performed; whereas, patients with T2 lesions did not. No doubt, patient selection contributed to this difference. (T1 patients probably had multiple poor-risk factors.)I go into this detail to point out the difficulty for models such as the one used by Orr et al to replace clinical judgment based on all data available to the clinician. I agree that patients who benefit least from axillary node dissection are those older than 40 years of age who have an invasive T1 breast cancer that is hormone receptor positive, HER-2 neu negative, histologic grade 1 with no endovascular space invasion, and which has a DNA index of 1 with an S-phase of less than 7%. Risk factor variability within this group, however, still requires clinical judgment rather than a formula-driven approach for axillary node dissection, or a treatment that improves survival, albeit small, may be withheld from a patient. Likewise, there is mounting evidence that patients with potential for residual chest-wall disease after adequate surgical therapy are at a greater risk for distant metastasis unless they are treated with adjuvant chest-wall radiation therapy.7Overgaard M Hansen PS Overgaard J et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy.N Engl J Med. 1997; 337: 949-955Crossref PubMed Scopus (2184) Google Scholar, 8Ragaz J Jackson SM Le N et al.Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.N Engl J Med. 1997; 337: 956-962Crossref PubMed Scopus (1473) Google Scholar In other words, an aggressive attempt to eradicate any residual microscopic disease on the chest wall results in an improved chance of survival. Once again, it can be inferred that adequate axillary clearance at the time of appropriate treatment of the primary lesion might improve the patient's chances of survival.The technique of sentinel lymph node biopsy allows identification of those patients who do not need to have a full axillary dissection. It would appear that this technique is ideally suited for patients who have T1 breast cancers. The false-negative rate from this procedure, however, is reported to be 11.4% in a multiinstitutional study published by Krag et al.9Krag D Weaver D Ashikaga T et al.The sentinel node in breast cancer.N Engl J Med. 1998; 339: 941-946Crossref PubMed Scopus (1810) Google Scholar Let us assume that the incidence of positive axillary lymph nodes in a patient with a breast cancer of less than 1 cm is approximately 10%. Then only 1 of 100 patients with a T1 breast cancer with good biological markers would have disease left behind in the axilla after sentinel lymph node biopsy (10 positive axillae × .114 false-negative rate = 1 positive axilla missed). Nevertheless, each surgeon accepting a sentinel lymph node biopsy as an adequate representation of the pathological status of the axilla should compare the pathological results of the sentinel lymph node with the remainder of the axillary specimen in an appropriate number of patients before considering the technique accurate. The sentinel lymph node trial sponsored by the American College of Surgeons Oncology Group should establish the proper role for sentinel lymphadenectomy and axillary node dissection in the surgical armamentarium in the treatment of breast cancer. In the meantime, treatment algorithms based on risk factors such as those evaluated by Mustafa and Bland are necessary to determine the need for axillary dissection. Likewise, the surgeon who is a novice at sentinel lymph node biopsy might apply the technique initially to those patients less likely to have axillary metastasis since the false-negative rate should be lowest in this group. For now, caution should be used when abandoning established oncological principles based on cost-effective analysis. It is becoming fashionable (and appropriate) to evaluate cost-effectiveness of medical care. Often this evaluation is an assessment of the value of an additional test or therapy. As examples, are both a computed tomographic scan and a magnetic resonance imaging procedure necessary in certain circumstances? Is the addition of intraperitoneal chemotherapy of value as an adjunct for certain intra-abdominal malignancies? Implicit also in the results of a cost-effectiveness evaluation is the possible deletion of a standard treatment for a patient. For example, should life-support systems be withdrawn if there remains a 5% chance of survival? Orr et al (Surgery 1999;126:568-76) have agreed that a 5% survival advantage might be gained from axillary node dissection in patients with breast cancer. This figure comes from another analysis done by Orr published earlier this year.1Orr RK. The impact of prophylactic axillary node dissection on breast cancer survival. A Bayesian meta-analysis.Ann Surg Oncol. 1999; 6: 109-116Crossref PubMed Scopus (306) Google Scholar The analysis evaluated 6 trials that justifiably compare total mastectomy with axillary node dissection to total mastectomy without axillary node dissection or with inadequate treatment to the axilla (ie, inadequate radiation therapy). Axillary node dissection improved survival rates from 4% to 16%, and in 3 of the trials this improvement was significant. The only “head-to-head” trial of axillary node dissection versus no axillary node treatment was the NSABP BO-4 trial. In it, 35% of the control patients had 1 or more lymph nodes removed at the time of total mastectomy.2Fisher B Wolmark N Bauer M et al.The accuracy of clinical nodal staging and of limited axillary dissection as a determinant of histologic nodal status in carcinoma of the breast.Surg Gynecol Obstet. 1981; 152: 765-772PubMed Google Scholar We now know from data from sentinel lymph node studies in breast cancer that a positive sentinel node is often the only positive lymph node that is an axillary metastasis from small breast cancers.3Albertini J Lyman G Cox C et al.Lymphatic mapping and sentinel node biopsy in the patient with breast cancer.JAMA. 1996; 276: 1818-1822Crossref PubMed Google Scholar Possibly the sentinel node with micrometastasis was removed from patients in the control group of the BO-4 trial, and that may be the reason the axillary failure rates were no different in the control group of the study. (Failure rates were 21% when no nodes were removed, 8% when 1 to 5 nodes were removed, and 0% when 6 or more nodes were removed.) Consequently, to date there are no prospective randomized trials that directly compare adequate surgical dissection of the axilla to no axillary treatment. All conclusions of the value of axillary node dissection to survival must be made from inference from other studies. The incidence of positive axillary lymph nodes resulting from T1a breast cancers approximates 7%, as gleaned from the multiple published series evaluating this subject.4Recht A Houlihan MJ. Axillary lymph nodes and breast cancer.Cancer. 1995; 76: 1491-1512Crossref PubMed Scopus (293) Google Scholar Mustafa and Bland,5Mustafa IA Cole B Wanebo HJ et al.The impact of histopathology on nodal metastases in minimal breast cancer.Arch Surg. 1997; 132: 384-391Crossref PubMed Scopus (63) Google Scholar however, recently reviewed 2185 patients from the Rhode Island Tumor Registry who had breast lesions of less than 1 cm. They identified risk factors to determine the incidence of axillary metastasis within this group: age (<40 years vs >40 years = 31.2% vs 15.6%), size (<.5 cm vs >.5 cm = 11.3% vs 17%), and histologic grade (1, 2, or 3 = 9.5%, 17.2%, or 22.3%). Orr et al, using their cost-effectiveness model, recommend axillary node dissection for women who have a 20% or greater chance of having axillary metastasis. Consequently, the data of Mustafa and Bland would indicate that Orr et al would recommend axillary dissection for women under 40 years of age with a histologic grade III 1-cm breast cancer. Yet Orr et al state: “Because of the lower risk of nodal metastasis, patients with 1-cm, nonpalpable tumors experience minimal benefit at markedly higher incremental costs….” Interestingly, in the Guy's Hospital trial,6Hayward J Caleffi M. The significance of local control in the primary treatment of breast cancer.Arch Surg. 1987; 122: 1244-1247Crossref PubMed Scopus (129) Google Scholar patients with T1 lesions had a survival advantage because axillary node dissections were performed; whereas, patients with T2 lesions did not. No doubt, patient selection contributed to this difference. (T1 patients probably had multiple poor-risk factors.) I go into this detail to point out the difficulty for models such as the one used by Orr et al to replace clinical judgment based on all data available to the clinician. I agree that patients who benefit least from axillary node dissection are those older than 40 years of age who have an invasive T1 breast cancer that is hormone receptor positive, HER-2 neu negative, histologic grade 1 with no endovascular space invasion, and which has a DNA index of 1 with an S-phase of less than 7%. Risk factor variability within this group, however, still requires clinical judgment rather than a formula-driven approach for axillary node dissection, or a treatment that improves survival, albeit small, may be withheld from a patient. Likewise, there is mounting evidence that patients with potential for residual chest-wall disease after adequate surgical therapy are at a greater risk for distant metastasis unless they are treated with adjuvant chest-wall radiation therapy.7Overgaard M Hansen PS Overgaard J et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy.N Engl J Med. 1997; 337: 949-955Crossref PubMed Scopus (2184) Google Scholar, 8Ragaz J Jackson SM Le N et al.Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.N Engl J Med. 1997; 337: 956-962Crossref PubMed Scopus (1473) Google Scholar In other words, an aggressive attempt to eradicate any residual microscopic disease on the chest wall results in an improved chance of survival. Once again, it can be inferred that adequate axillary clearance at the time of appropriate treatment of the primary lesion might improve the patient's chances of survival. The technique of sentinel lymph node biopsy allows identification of those patients who do not need to have a full axillary dissection. It would appear that this technique is ideally suited for patients who have T1 breast cancers. The false-negative rate from this procedure, however, is reported to be 11.4% in a multiinstitutional study published by Krag et al.9Krag D Weaver D Ashikaga T et al.The sentinel node in breast cancer.N Engl J Med. 1998; 339: 941-946Crossref PubMed Scopus (1810) Google Scholar Let us assume that the incidence of positive axillary lymph nodes in a patient with a breast cancer of less than 1 cm is approximately 10%. Then only 1 of 100 patients with a T1 breast cancer with good biological markers would have disease left behind in the axilla after sentinel lymph node biopsy (10 positive axillae × .114 false-negative rate = 1 positive axilla missed). Nevertheless, each surgeon accepting a sentinel lymph node biopsy as an adequate representation of the pathological status of the axilla should compare the pathological results of the sentinel lymph node with the remainder of the axillary specimen in an appropriate number of patients before considering the technique accurate. The sentinel lymph node trial sponsored by the American College of Surgeons Oncology Group should establish the proper role for sentinel lymphadenectomy and axillary node dissection in the surgical armamentarium in the treatment of breast cancer. In the meantime, treatment algorithms based on risk factors such as those evaluated by Mustafa and Bland are necessary to determine the need for axillary dissection. Likewise, the surgeon who is a novice at sentinel lymph node biopsy might apply the technique initially to those patients less likely to have axillary metastasis since the false-negative rate should be lowest in this group. For now, caution should be used when abandoning established oncological principles based on cost-effective analysis.