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Impact of nodal status on indication for adjuvant treatment in clinically node negative breast cancer
Annals of Oncology 11: 1137-1140, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Impact of nodal status on indication for adjuvant treatment in clinically node negative breast cancer M. Greco,1 M. Gennaro,1 P.Valagussa,2 R. Agresti,1 C. Ferraris,1 B. Ferrari,3 C. Urban4 & L. Gianni5 for the Istituto Nazionale per lo Studio e la Cura dei Tumori 1 Breast Unit, 2Scientific Direction, Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano, Milan, Italy; 3Breast Pathology, Gynecology Service, Provincial Hospital of Rosario, Argentina; " Surgical Oncology, Universidade Federal do Parana, Brazil; 5 Medical Oncology A, Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano, Milan, Italy
Summary
We addressed the problem of the need for axillary dissection in clinically node-negative breast cancer by determining how the information provided by the dissection suggests a different treatment to that indicated by primary tumour characteristics and age alone. We examined retrospectively 260 cases of clinically node negative early breast cancer all of whom underwent breast surgery, radiotherapy and axillary dissection. We assigned adjuvant therapy according to accepted guidelines with and without consideration of pathological node status and compared the difference. Fifty-six patients had involved axillary nodes. There was no change in adjuvant chemotherapy indication for the 44 cases over 65 years. The change in indication for the remaining 216 cases was 18.5% to 6%, depending on whether none or all of the intermediate risk
Introduction Early invasive breast cancer is managed by surgery and radiotherapy with adjuvant systemic treatment given in selected cases. Surgery, which increasingly is conservative, treats and stages the loco-regional disease and provides prognostic information: Pathological tumour size, grading, and hormonal receptor status are assessed, together with the patient's age, to determine the risk of recurrence and need for adjuvant systemic treatment. Axillary dissection is also considered by many to provide important, if not vital prognostic information in breast cancer. Increasingly however the need for prophylactic axillary node dissection has been questioned particularly since in early breast cancer only a minority of patients are found to have metastatic nodes [1-3]. Our own experience is that for tumours up to 2 cm without clinical evidence of axillary involvement, axillary metastases are absent in nearly 80% of patients undergoing axillary dissection. In such cases the dissection is useless as a treatment yet at the same time is associated with significant risk of morbidity. We decided to approach the problem of whether
patients were originally assigned chemotherapy (all were originally assigned tamoxifen). Since the trend is for most intermediate risk patients is to be assigned adjuvant chemotherapy, and since tamoxifen is anyway considered effective therapy for low and intermediate risk patients, we conclude that the information provided by axillary dissection is probably not necessary if guidelines recommending wide application of systemic adjuvant chemotherapy are applied. Satisfactory prognostic information can be obtained by consideration of primary tumour characteristics, while new prognostic markers are likely to further refine prognostic precision in the near future. Key words: adjuvant chemotherapy, breast neoplasms, carcinoma infiltrating, lymphatic metastasis, lymph node excision, risk assessment
axillary dissection is necessary by performing a study designed to answer a specific question: In clinically nodenegative breast cancer patients, can the information provided by axillary dissection suggest a different treatment to that indicated by assessment of primary tumour characteristics and age alone [4]? To do this we retrospectively analysed the pathological features of 260 pTl breast cancer patients, using accepted guidelines [5] to assign adjuvant treatment, first without and then with the histopathological data provided by complete axillary dissection, and analysed the differences.
Patients and methods In 1996, 325 women were treated at the National Cancer Institute of Milan for unifocal Tl breast carcinoma without previous malignancy and with no evidence of metastases at diagnosis. Forty-eight were Nl or N2 and 277 were clinically node negative at diagnosis. Of the latter, 267 patients received total axillary dissection and all nodes were examined pathologically. Of these, seven had microinvasive carcinoma (pTlmic) and were excluded. The remaining 260 cases were analysed retrospectively and form the subject of this study. They were arbitrarily divided into two age classes ^ 65 years and > 65 years, since treatment protocols differ between young and elderly patients.
1138 Table 1. Axillary lymph node status in relation to tumour size in 260 women with Tl breast cancer. Nodal status
NN+ 1-3N+ 4-9 N+ >9N+
Tumour size pTla, « = 25 (%)
pTlb, n = 69 (%)
pTlc, n = 166 (%)
20 (80) 5(20) 4 1 0
57 (82.6) 12(17.4) 11 1 0
127(76.5) 39 (23.5) 34 3 2
We used the guidelines of the 6th International Conference on Adjuvant Therapy of Primary Breast Cancer [5] to assign the younger cases ( < 6 5 years) to risk categories, initially without considering information on node status (i.e., assuming all were pNO) and subsequently considering pathological nodal status. Based on the risk categories, treatments were reassigned and differences in proposed treatments were compared to identify the influence of axillary dissection in planning adjuvant therapy. For low risk patients the guidelines state that endocrine therapy is optional and chemotherapy is not indicated. For intermediate risk patients endocrine therapy is indicated but chemotherapy is optional. In high risk, as well as node-positive patients, chemotherapy is mandatory and should be associated with endocrine therapy in patients with positive ER. Sequential anthracyclines and CMF based regimens are accepted as standard chemotherapy. Doseintensive regimens, high-dose chemotherapy and taxanes all remain investigational in the adjuvant setting [5, 6). According to the guidelines standard treatments for elderly patients differ somewhat from those in younger women: Tamoxifen is the first choice adjuvant treatment in the low, intermediate and ER positive high-risk groups, even when the nodes are involved. If the tumour is ER negative, chemotherapy should be considered even when the nodes are free from metastases [5].
Results The median age of the 260 patients was 56 years (range 31-81), 44 (16.9%) were >65 years and 216 were <65 years; 243 received conservative breast surgery and 17 received modified radical mastectomy. None had chest wall or skin involvement (pT4) and none had received neoadjuvant chemotherapy. Twenty-five tumours were pTla, 69 pTlb and 166 pTlc; 226 (86.9%) were ER positive and 163 (62.7%) were PgR positive. The cancer was well or moderately differentiated in 215 (82.7%) cases and poorly differentiated in 45 (17.3%). Nodal involvement was found on pathological examination in 56 (21.5%) patients, 50 of whom were ^65 years of age (Table 1). These features allowed attribution of each case to single-risk category. Seventy-eight patients were attributed to the low-risk group, 123 to the intermediate risk group and 59 to the high risk group. For low risk patients ^ 65 years endocrine therapy is optional; however, since tamoxifen may prevent breast cancer in women at risk for the disease, it should be given in the absence of contraindications [7, 8]. We therefore assigned all low risk cases to tamoxifen treatment. For the intermediate risk group, chemotherapy is
Table 2. Adjuvant treatments to assigned to 216 patients <65 years old without axillary node information. Treatment assigned considering intermediate risk patients firstly as low-risk and secondly as high-risk patients.
Intermediate-risk patients considered low risk I ntermediate-risk patients considered high risk
Hormone therapy
Chemotherapy
Chemotherapy plus hormone therapy
168
27
21
70
27
119
Table 3 Lymph-node metastases in patients ^ 65 years according to risk category as determined from of tumour characteristics only. Risk group
Number of patients ^ 65 years with lymph node metastases
Low Intermediate High
13 27 10
optional and depends on the patient's general condition, socio-economic circumstances and preference, as well as the toxicity of the regimen. Furthermore, the NSABP B-20 study showed that no subgroup of patients failed to benefit from chemotherapy (in addition to tamoxifen) in terms of disease-free survival, distant disease-free survival and overall survival, in afive-yearfollow-up [9]. We therefore performed a double assignment for the intermediate risk group: either to receive hormonal therapy alone (in effect treating them as low-risk patients) or assigning them to chemotherapy plus hormone therapy (treating them as high-risk patients). The numbers of patients ^ 65 years old assigned to each of the three adjuvant treatment regimens by both these methods is shown in Table 2. The original risk group distribution of the 50 patients ^65 years old found to have nodal metastases on histological examination is shown in Table 3. Thirteen (6%) cases previously assigned to the low-risk group had axillary node metastases, and were therefore re-assigned to chemotherapy as well as hormone therapy. Twentyseven of the intermediate risk group (12.5% of the total) would been reassigned to chemotherapy if not assigned it previously. Thus the change in indication for chemotherapy ranged from 6%-18.5% in the series of 216 ^65-year-old cases in the light of pathological node status, depending on the original adjuvant treatment assignment. Histological node status did not influence the treatment of the 44 patients over 65, since the 37 (84%) ER positive cases were initially assigned tamoxifen, and the 7 (16%) ER negative cases were assigned chemotherapy. Five (13.5%) and one (14.3%) had node metastases in the ER positive and ER negative subgroups respectively.
1139 Discussion The need for prophylactic axillary dissection in patients with a clinically negative axilla was questioned more than 30 years ago. A prospective clinical trial (B-04) published in 1977 showed identical survival in a group receiving immediate axillary surgery or radiotherapy, compared with untreated patients who did not receive axillary surgery unless and until there was a relapse [10]. A Cancer Research Campaign trial published in the same year concluded that untreated axillary nodes did "not appear to act as a source of tertiary spread" [11]. A recent overview of the problem argued that the intervention has little or no impact on overall survival in early breast cancer [12]. Moreover two large studies in which axillary dissection was not performed also found that in selected patients long term outcome was not influenced by whether or not prophylactic axillary dissection was performed [13,14]. Axillary dissection provides prognostic information considered vital for planning adjuvant therapy. However, this aspect is less important today than in the recent past, not only because breast cancer is diagnosed earlier and there is less chance of axillary involvement, but also because modern treatment protocols assign adjuvant chemotherapy to most node-negative patients, as well as those with involved nodes [5]. The status of the internal mammary chain nodes is highly predictive of prognosis [15, 16]. Furthermore a percentage from 6.7%—12.7%, depending on age, of a series of 588 Tl patients with uninvolved axillary lymph nodes had metastases in the internal mammary nodes [16]. Nevertheless this surgical procedure has shown no benefit in terms of local control or overall survival [16] and, in spite of its importance in prognosis, it has been neglected. Sentinel node biopsy has recently become popular as a minimally invasive method of obtaining information on state of the axilla [17-19]. However this desire for prognostic information might be better satisfied by perfection of the completely non-invasive PET techniques that have shown promise in this area [20]. Another approach is to use the characteristics of the primary tumour to determine the metastatic potential of the disease and select patients for chemotherapy. In a study on 851 breast cancer patients, univariate and multivariate analyses showed that the commonly used biologic tumour markers did not predict nodal status [21]. However, a prognostic score obtained by consideration of several markers together correlated well with overall survival. Interestingly a good score seemed to be an indicator of good prognosis even when there was nodal involvement [22]. In the present study the histopathological information provided by axillary dissection indicated that, at the most, an additional 18.5% (40 of 216) of the «£ 65-year-old cases in the low- and intermediate-risk categories should have been given systemic chemotherapy, otherwise they would have been undertreated according the guidelines.
If chemotherapy is widely adopted, as the guidelines allow, cases in the intermediate-risk group would have been assigned adjuvant chemotherapy at the outset; in that case only 6% of cases would have changed from no adjuvant to adjuvant chemotherapy based on the histology of the axillary nodes, and again all would have anyway received tamoxifen. In conclusion, to answer the question posed in introduction, our findings suggest that lack of knowledge of axillary node status is unlikely to lead to undertreatment in younger patients (in this series ^ 65 years of age) with early breast cancer, especially when adjuvant chemotherapy is applied widely as modern treatment guidelines allow. Elderly patients do not benefit at all from node status information in terms of adjuvant chemotherapy planning, according to these guidelines. These findings therefore raise doubts as to the need for axillary lymph node dissection in clinically node negative patients. Many new biological markers are being tested on primary tumours and it is likely that some of them, singly or in combination will be able to predict outcome and the response to available therapies. It is our opinion these developments will definitively supersede axillary dissection as a means of obtaining prognostic information in clinically node negative patients. Clearly, however, clinical trials will be required to demonstrate the effectiveness of systemic therapies allocated on the basis of such factors (i.e., without axillary information).
Acknowledgements
Francesca Falcetti and Luisa Morandi, Controlled Clinical Trials Operative Office, Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano. References 1. Tabar L, Fagerberg C, Duffy SW et al. Update of the Swedish two-country program of mammographic screening for breast cancer. Radiol Clin North Am 1992; 30: 187-210. 2. Veronesi U, Salvadori B, Luini A et al. Breast conservation is a safe method in patients with small cancer of the breast. Longterm results of three randomized trials on 1973 patients. Eur J Cancer 1995; 31 (10): 1574-9. 3. Baxter N, McCready D, Chapman JA et al. Clinical behavior of untreated axillary nodes after local treatment for primary breast cancer. Ann Surg Oncol 1996; 3 (3): 235 40. 4. Dees EC, Shulman LN, Souba WW, Smith BL. Does information from axillary dissection change treatment in clinically nodenegative patients with breast cancer? Ann Surg 1997; 226 (3): 279-87. 5. Goldhirsch A, Glick JH, Gelber RD, Seen HJ. Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998; 90 (21): 1601-8. 6. Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998; 339 (14): 974-84. 7. Veronesi U, Maisonneuve P, Costa A et al. Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Lancet 1998; 352: 93-7. 8. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for
1140
9. 10.
11. 12. 13. 14. 15. 16. 17.
prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-l study. J Natl Cancer Inst 1998; 90 (18): 1371-88. Fisher B, Dignam J, Wolmark N et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997; 89 (22): 1673-82. Fisher B, Montague E, Redmond C. Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from prospective randomized clinical trial. Cancer 1977; 29: 2827-39. Baum M, Coyle PJ. Simple mastectomy for early breast cancer and the behaviour of the untreated axillary nodes. Bull Cancer 1977; 218: 603-10. Cady B. Is axillary lymph node dissection necessary in routine management of breast cancer? No. Important Adv Oncol 1996; 251-65. Greco M, Agresti R, Raselli R et al. Axillary dissection can be avoided in selected breast cancer patients: Analysis of 401 cases. Anticancer Res 1996; 16: 3913-8. Haffty BG, Ward B, Pathare P et al. Reappraisal of the role of axillary lymph node dissection in the conservative treatment of the breast cancer. J Clin Oncol 1997; 15 (2)- 691-700. Cody HS, Urban JA. Internal mammary node status: A major prognosticator in axillary node-negative breast cancer. Ann Sufg Oncol 1995; 2 (1): 32-7. Veronesi U, Cascinelli N, Greco M et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 1985; 202 (6): 702-7. Olilla DW, Brennan MB, Giuliano AE. Therapeutic effect of
18. 19. 20. 21. 22.
sentinel lymphadenectomy in Tl breast cancer. Arch Surg 1998; 133: 647-51. Krag D, Weaver D, Ashikaga Tet al. The sentinel node in breast cancer. A multicenter validation study. N Engl J Med 1998; 339 (14): 941-6. Veronesi U, Paganelli G, Viale G et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: Results in a large series. J Natl Cancer Inst 1999; 91 (4): 368-73. Cnppa F, Agresti R, Seregni E et al. Prospective evaluation of fluorine-18-FDG PET in presurgical staging of the axilla in breast cancer. J Nucleic Med 1998; 39 (1): 4-8. Velanovich V, Szymanscki W. Lymph node metastasis in breast cancer: Common prognostic markers lack predictive value. Ann Surg Oncol 1998; 5 (7): 613-9. Menard S, Bufalino R, Rilke F et al. Prognosis based on primary breast carcinoma instead of pathological nodal status. Br J Cancer 1994; 70: 709-12.
Received 3 March 2000; accepted 14 June 2000.
Correspondence to: M. Greco, MD Breast Unit Istituto Nazionale per lo Studio e la Cura dei Tumon di Milano Via Venezian 1 20133 Milan Italy
Original article Impact of nodal status on indication for adjuvant treatment in clinically node negative breast cancer M. Greco,1 M. Gennaro,1 P.Valagussa,2 R. Agresti,1 C. Ferraris,1 B. Ferrari,3 C. Urban4 & L. Gianni5 for the Istituto Nazionale per lo Studio e la Cura dei Tumori 1 Breast Unit, 2Scientific Direction, Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano, Milan, Italy; 3Breast Pathology, Gynecology Service, Provincial Hospital of Rosario, Argentina; " Surgical Oncology, Universidade Federal do Parana, Brazil; 5 Medical Oncology A, Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano, Milan, Italy
Summary
We addressed the problem of the need for axillary dissection in clinically node-negative breast cancer by determining how the information provided by the dissection suggests a different treatment to that indicated by primary tumour characteristics and age alone. We examined retrospectively 260 cases of clinically node negative early breast cancer all of whom underwent breast surgery, radiotherapy and axillary dissection. We assigned adjuvant therapy according to accepted guidelines with and without consideration of pathological node status and compared the difference. Fifty-six patients had involved axillary nodes. There was no change in adjuvant chemotherapy indication for the 44 cases over 65 years. The change in indication for the remaining 216 cases was 18.5% to 6%, depending on whether none or all of the intermediate risk
Introduction Early invasive breast cancer is managed by surgery and radiotherapy with adjuvant systemic treatment given in selected cases. Surgery, which increasingly is conservative, treats and stages the loco-regional disease and provides prognostic information: Pathological tumour size, grading, and hormonal receptor status are assessed, together with the patient's age, to determine the risk of recurrence and need for adjuvant systemic treatment. Axillary dissection is also considered by many to provide important, if not vital prognostic information in breast cancer. Increasingly however the need for prophylactic axillary node dissection has been questioned particularly since in early breast cancer only a minority of patients are found to have metastatic nodes [1-3]. Our own experience is that for tumours up to 2 cm without clinical evidence of axillary involvement, axillary metastases are absent in nearly 80% of patients undergoing axillary dissection. In such cases the dissection is useless as a treatment yet at the same time is associated with significant risk of morbidity. We decided to approach the problem of whether
patients were originally assigned chemotherapy (all were originally assigned tamoxifen). Since the trend is for most intermediate risk patients is to be assigned adjuvant chemotherapy, and since tamoxifen is anyway considered effective therapy for low and intermediate risk patients, we conclude that the information provided by axillary dissection is probably not necessary if guidelines recommending wide application of systemic adjuvant chemotherapy are applied. Satisfactory prognostic information can be obtained by consideration of primary tumour characteristics, while new prognostic markers are likely to further refine prognostic precision in the near future. Key words: adjuvant chemotherapy, breast neoplasms, carcinoma infiltrating, lymphatic metastasis, lymph node excision, risk assessment
axillary dissection is necessary by performing a study designed to answer a specific question: In clinically nodenegative breast cancer patients, can the information provided by axillary dissection suggest a different treatment to that indicated by assessment of primary tumour characteristics and age alone [4]? To do this we retrospectively analysed the pathological features of 260 pTl breast cancer patients, using accepted guidelines [5] to assign adjuvant treatment, first without and then with the histopathological data provided by complete axillary dissection, and analysed the differences.
Patients and methods In 1996, 325 women were treated at the National Cancer Institute of Milan for unifocal Tl breast carcinoma without previous malignancy and with no evidence of metastases at diagnosis. Forty-eight were Nl or N2 and 277 were clinically node negative at diagnosis. Of the latter, 267 patients received total axillary dissection and all nodes were examined pathologically. Of these, seven had microinvasive carcinoma (pTlmic) and were excluded. The remaining 260 cases were analysed retrospectively and form the subject of this study. They were arbitrarily divided into two age classes ^ 65 years and > 65 years, since treatment protocols differ between young and elderly patients.
1138 Table 1. Axillary lymph node status in relation to tumour size in 260 women with Tl breast cancer. Nodal status
NN+ 1-3N+ 4-9 N+ >9N+
Tumour size pTla, « = 25 (%)
pTlb, n = 69 (%)
pTlc, n = 166 (%)
20 (80) 5(20) 4 1 0
57 (82.6) 12(17.4) 11 1 0
127(76.5) 39 (23.5) 34 3 2
We used the guidelines of the 6th International Conference on Adjuvant Therapy of Primary Breast Cancer [5] to assign the younger cases ( < 6 5 years) to risk categories, initially without considering information on node status (i.e., assuming all were pNO) and subsequently considering pathological nodal status. Based on the risk categories, treatments were reassigned and differences in proposed treatments were compared to identify the influence of axillary dissection in planning adjuvant therapy. For low risk patients the guidelines state that endocrine therapy is optional and chemotherapy is not indicated. For intermediate risk patients endocrine therapy is indicated but chemotherapy is optional. In high risk, as well as node-positive patients, chemotherapy is mandatory and should be associated with endocrine therapy in patients with positive ER. Sequential anthracyclines and CMF based regimens are accepted as standard chemotherapy. Doseintensive regimens, high-dose chemotherapy and taxanes all remain investigational in the adjuvant setting [5, 6). According to the guidelines standard treatments for elderly patients differ somewhat from those in younger women: Tamoxifen is the first choice adjuvant treatment in the low, intermediate and ER positive high-risk groups, even when the nodes are involved. If the tumour is ER negative, chemotherapy should be considered even when the nodes are free from metastases [5].
Results The median age of the 260 patients was 56 years (range 31-81), 44 (16.9%) were >65 years and 216 were <65 years; 243 received conservative breast surgery and 17 received modified radical mastectomy. None had chest wall or skin involvement (pT4) and none had received neoadjuvant chemotherapy. Twenty-five tumours were pTla, 69 pTlb and 166 pTlc; 226 (86.9%) were ER positive and 163 (62.7%) were PgR positive. The cancer was well or moderately differentiated in 215 (82.7%) cases and poorly differentiated in 45 (17.3%). Nodal involvement was found on pathological examination in 56 (21.5%) patients, 50 of whom were ^65 years of age (Table 1). These features allowed attribution of each case to single-risk category. Seventy-eight patients were attributed to the low-risk group, 123 to the intermediate risk group and 59 to the high risk group. For low risk patients ^ 65 years endocrine therapy is optional; however, since tamoxifen may prevent breast cancer in women at risk for the disease, it should be given in the absence of contraindications [7, 8]. We therefore assigned all low risk cases to tamoxifen treatment. For the intermediate risk group, chemotherapy is
Table 2. Adjuvant treatments to assigned to 216 patients <65 years old without axillary node information. Treatment assigned considering intermediate risk patients firstly as low-risk and secondly as high-risk patients.
Intermediate-risk patients considered low risk I ntermediate-risk patients considered high risk
Hormone therapy
Chemotherapy
Chemotherapy plus hormone therapy
168
27
21
70
27
119
Table 3 Lymph-node metastases in patients ^ 65 years according to risk category as determined from of tumour characteristics only. Risk group
Number of patients ^ 65 years with lymph node metastases
Low Intermediate High
13 27 10
optional and depends on the patient's general condition, socio-economic circumstances and preference, as well as the toxicity of the regimen. Furthermore, the NSABP B-20 study showed that no subgroup of patients failed to benefit from chemotherapy (in addition to tamoxifen) in terms of disease-free survival, distant disease-free survival and overall survival, in afive-yearfollow-up [9]. We therefore performed a double assignment for the intermediate risk group: either to receive hormonal therapy alone (in effect treating them as low-risk patients) or assigning them to chemotherapy plus hormone therapy (treating them as high-risk patients). The numbers of patients ^ 65 years old assigned to each of the three adjuvant treatment regimens by both these methods is shown in Table 2. The original risk group distribution of the 50 patients ^65 years old found to have nodal metastases on histological examination is shown in Table 3. Thirteen (6%) cases previously assigned to the low-risk group had axillary node metastases, and were therefore re-assigned to chemotherapy as well as hormone therapy. Twentyseven of the intermediate risk group (12.5% of the total) would been reassigned to chemotherapy if not assigned it previously. Thus the change in indication for chemotherapy ranged from 6%-18.5% in the series of 216 ^65-year-old cases in the light of pathological node status, depending on the original adjuvant treatment assignment. Histological node status did not influence the treatment of the 44 patients over 65, since the 37 (84%) ER positive cases were initially assigned tamoxifen, and the 7 (16%) ER negative cases were assigned chemotherapy. Five (13.5%) and one (14.3%) had node metastases in the ER positive and ER negative subgroups respectively.
1139 Discussion The need for prophylactic axillary dissection in patients with a clinically negative axilla was questioned more than 30 years ago. A prospective clinical trial (B-04) published in 1977 showed identical survival in a group receiving immediate axillary surgery or radiotherapy, compared with untreated patients who did not receive axillary surgery unless and until there was a relapse [10]. A Cancer Research Campaign trial published in the same year concluded that untreated axillary nodes did "not appear to act as a source of tertiary spread" [11]. A recent overview of the problem argued that the intervention has little or no impact on overall survival in early breast cancer [12]. Moreover two large studies in which axillary dissection was not performed also found that in selected patients long term outcome was not influenced by whether or not prophylactic axillary dissection was performed [13,14]. Axillary dissection provides prognostic information considered vital for planning adjuvant therapy. However, this aspect is less important today than in the recent past, not only because breast cancer is diagnosed earlier and there is less chance of axillary involvement, but also because modern treatment protocols assign adjuvant chemotherapy to most node-negative patients, as well as those with involved nodes [5]. The status of the internal mammary chain nodes is highly predictive of prognosis [15, 16]. Furthermore a percentage from 6.7%—12.7%, depending on age, of a series of 588 Tl patients with uninvolved axillary lymph nodes had metastases in the internal mammary nodes [16]. Nevertheless this surgical procedure has shown no benefit in terms of local control or overall survival [16] and, in spite of its importance in prognosis, it has been neglected. Sentinel node biopsy has recently become popular as a minimally invasive method of obtaining information on state of the axilla [17-19]. However this desire for prognostic information might be better satisfied by perfection of the completely non-invasive PET techniques that have shown promise in this area [20]. Another approach is to use the characteristics of the primary tumour to determine the metastatic potential of the disease and select patients for chemotherapy. In a study on 851 breast cancer patients, univariate and multivariate analyses showed that the commonly used biologic tumour markers did not predict nodal status [21]. However, a prognostic score obtained by consideration of several markers together correlated well with overall survival. Interestingly a good score seemed to be an indicator of good prognosis even when there was nodal involvement [22]. In the present study the histopathological information provided by axillary dissection indicated that, at the most, an additional 18.5% (40 of 216) of the «£ 65-year-old cases in the low- and intermediate-risk categories should have been given systemic chemotherapy, otherwise they would have been undertreated according the guidelines.
If chemotherapy is widely adopted, as the guidelines allow, cases in the intermediate-risk group would have been assigned adjuvant chemotherapy at the outset; in that case only 6% of cases would have changed from no adjuvant to adjuvant chemotherapy based on the histology of the axillary nodes, and again all would have anyway received tamoxifen. In conclusion, to answer the question posed in introduction, our findings suggest that lack of knowledge of axillary node status is unlikely to lead to undertreatment in younger patients (in this series ^ 65 years of age) with early breast cancer, especially when adjuvant chemotherapy is applied widely as modern treatment guidelines allow. Elderly patients do not benefit at all from node status information in terms of adjuvant chemotherapy planning, according to these guidelines. These findings therefore raise doubts as to the need for axillary lymph node dissection in clinically node negative patients. Many new biological markers are being tested on primary tumours and it is likely that some of them, singly or in combination will be able to predict outcome and the response to available therapies. It is our opinion these developments will definitively supersede axillary dissection as a means of obtaining prognostic information in clinically node negative patients. Clearly, however, clinical trials will be required to demonstrate the effectiveness of systemic therapies allocated on the basis of such factors (i.e., without axillary information).
Acknowledgements
Francesca Falcetti and Luisa Morandi, Controlled Clinical Trials Operative Office, Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano. References 1. Tabar L, Fagerberg C, Duffy SW et al. Update of the Swedish two-country program of mammographic screening for breast cancer. Radiol Clin North Am 1992; 30: 187-210. 2. Veronesi U, Salvadori B, Luini A et al. Breast conservation is a safe method in patients with small cancer of the breast. Longterm results of three randomized trials on 1973 patients. Eur J Cancer 1995; 31 (10): 1574-9. 3. Baxter N, McCready D, Chapman JA et al. Clinical behavior of untreated axillary nodes after local treatment for primary breast cancer. Ann Surg Oncol 1996; 3 (3): 235 40. 4. Dees EC, Shulman LN, Souba WW, Smith BL. Does information from axillary dissection change treatment in clinically nodenegative patients with breast cancer? Ann Surg 1997; 226 (3): 279-87. 5. Goldhirsch A, Glick JH, Gelber RD, Seen HJ. Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998; 90 (21): 1601-8. 6. Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998; 339 (14): 974-84. 7. Veronesi U, Maisonneuve P, Costa A et al. Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Lancet 1998; 352: 93-7. 8. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for
1140
9. 10.
11. 12. 13. 14. 15. 16. 17.
prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-l study. J Natl Cancer Inst 1998; 90 (18): 1371-88. Fisher B, Dignam J, Wolmark N et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997; 89 (22): 1673-82. Fisher B, Montague E, Redmond C. Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from prospective randomized clinical trial. Cancer 1977; 29: 2827-39. Baum M, Coyle PJ. Simple mastectomy for early breast cancer and the behaviour of the untreated axillary nodes. Bull Cancer 1977; 218: 603-10. Cady B. Is axillary lymph node dissection necessary in routine management of breast cancer? No. Important Adv Oncol 1996; 251-65. Greco M, Agresti R, Raselli R et al. Axillary dissection can be avoided in selected breast cancer patients: Analysis of 401 cases. Anticancer Res 1996; 16: 3913-8. Haffty BG, Ward B, Pathare P et al. Reappraisal of the role of axillary lymph node dissection in the conservative treatment of the breast cancer. J Clin Oncol 1997; 15 (2)- 691-700. Cody HS, Urban JA. Internal mammary node status: A major prognosticator in axillary node-negative breast cancer. Ann Sufg Oncol 1995; 2 (1): 32-7. Veronesi U, Cascinelli N, Greco M et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 1985; 202 (6): 702-7. Olilla DW, Brennan MB, Giuliano AE. Therapeutic effect of
18. 19. 20. 21. 22.
sentinel lymphadenectomy in Tl breast cancer. Arch Surg 1998; 133: 647-51. Krag D, Weaver D, Ashikaga Tet al. The sentinel node in breast cancer. A multicenter validation study. N Engl J Med 1998; 339 (14): 941-6. Veronesi U, Paganelli G, Viale G et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: Results in a large series. J Natl Cancer Inst 1999; 91 (4): 368-73. Cnppa F, Agresti R, Seregni E et al. Prospective evaluation of fluorine-18-FDG PET in presurgical staging of the axilla in breast cancer. J Nucleic Med 1998; 39 (1): 4-8. Velanovich V, Szymanscki W. Lymph node metastasis in breast cancer: Common prognostic markers lack predictive value. Ann Surg Oncol 1998; 5 (7): 613-9. Menard S, Bufalino R, Rilke F et al. Prognosis based on primary breast carcinoma instead of pathological nodal status. Br J Cancer 1994; 70: 709-12.
Received 3 March 2000; accepted 14 June 2000.
Correspondence to: M. Greco, MD Breast Unit Istituto Nazionale per lo Studio e la Cura dei Tumon di Milano Via Venezian 1 20133 Milan Italy