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© 2003 American Society for Clinical Oncology Long-Term Survival of Patients With Supraclavicular Metastases at Diagnosis of Breast CancerFrom the Breast Cancer Outcomes Unit and Radiation and Systemic Therapy Programs of the British Columbia Cancer Agency, Victoria, and University of British Columbia, Vancouver, British Columbia, Canada. Address reprint requests to I.A. Olivotto, MD, British Columbia Cancer Agency-Vancouver Island Centre, 2410 Lee Ave, Victoria, British Columbia, Canada, V8R 6V5; email: iolivott{at}bccancer.bc.ca.
Background: Patients with supraclavicular metastases at diagnosis of breast cancer were classified between 1987 and 2002 as having stage M1 breast cancer according to the tumor-node-metastasis (TNM) system. The 2003 edition of the TNM staging guidelines has classified such patients as having stage IIIC disease. To determine relative prognosis, we compared long-term survival in a population-based cohort of patients with isolated supraclavicular metastases (nodal-M1) to outcomes of patients with stage IIIB or M1 (other) disease at presentation. Materials and Methods: Among patients with breast cancer and known tumor stage referred to the British Columbia Cancer Agency from 1976 to 1985, 336 IIIB, 233 M1, and 51 nodal-M1 patients were identified. Actuarial overall and breast cancer–specific survival rates were determined to 20 years. Results: Overall survival at 20 years was 13.2% for nodal-M1 cases (95% confidence interval [CI], 5% to 26%), 9.4% for IIIB cases (95% CI, 6% to 14%), and 1.3% for M1 (other) cases (95% CI, 0.4% to 3.5%; log-rank P < .0005). Overall survival was similar between nodal-M1 and IIIB cases (P = .27). Breast cancer–specific survival at 20 years was 24.1% for nodal-M1 cases (95% CI, 13% to 37%), 30.2% for IIIB cases (95% CI, 23% to 38%), and 3.9% for M1 (other) cases (95% CI, 2% to 8%; log-rank P < .0005). Breast cancer–specific survival was significantly different for nodal-M1 cases compared with either IIIB or M1 (other) cases (P = .008 for both). Conclusion: Patients with supraclavicular metastases at diagnosis have significantly better outcomes than patients with M1 (other) disease and overall survival similar to patients with IIIB disease. Reclassification as stage IIIC is appropriate for patients with breast cancer who present with supraclavicular nodal metastases alone.
PATIENTS WITH breast cancer who present with supraclavicular metastases have a poor prognosis, especially when treated with surgery or radiation therapy (RT) alone.1–3 The presence of supraclavicular metastases was one of the original signs of inoperability identified by Haagensen and Stout.4 In 1987, the International Union Against Cancer/American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system changed the classification of patients with supraclavicular metastases from N3 to M1 to reflect the poor prognosis of patients with this presentation.5 Recently, Brito et al6 reported on a pooled analysis of three M.D. Anderson Hospital protocols and found that patients with regional stage IV disease had better outcomes than patients with visceral stage IV disease. The protocols included patients fit enough to receive doxorubicin-based chemotherapy. Recently, the AJCC has further amended the staging classification to include patients with supraclavicular metastases at diagnosis in the IIIC category.7 This staging change came into effect January 1, 2003. To determine differences in long-term outcome, this study evaluated survival rates in a population-based cohort of patients with primary breast cancer presenting with IIIB disease, isolated supraclavicular metastases, or other distant metastases.
Patients included women with invasive breast cancer diagnosed in British Columbia (BC) and referred to the BC Cancer Agency (BCCA) between 1976 and 1985 and presenting with isolated supraclavicular metastases (N3 in International Union Against Cancer TNM staging, before 1987) or IIIB disease (T4, N0 to N3, M0, including inflammatory breast cancer) or with clinical or radiographic evidence of more widespread metastases (stage M1).8,9 Date of diagnosis; prospectively collected T, N, and M stage at diagnosis; and date and cause of death or date of last follow-up were obtained from the BCCA electronic database. Patients without IIIB, supraclavicular, or M1 (other) disease and those with unknown stage were excluded. Patients with both supraclavicular and M1 disease were included with the M1 patients. All patients had a pathologic diagnosis of breast cancer. A chart review was conducted to determine method of diagnosis and initial treatment of the patients with supraclavicular metastases. The BCCA has the mandate for cancer control in BC, including maintenance of the BC Cancer Registry, operation of regional cancer centers providing all radiation therapy in the province, and management of the budget for all antineoplastic drugs. Approximately 70% of all newly diagnosed patients with breast cancer in BC are referred to the BCCA within 1 year of diagnosis. The referral rate is higher for patients with indications for radiation or systemic therapy than for patients without such indications.10 The treatment of patients with breast cancer evolved over the interval of this study. Systemic therapy included ovarian ablation and infrequent use of single-agent chemotherapy in the early part of the study, but by the early 1980s, patients with locally advanced disease received multiagent, neoadjuvant doxorubicin-based chemotherapy, followed by definitive local-regional therapy and, if their tumors were estrogen receptor–positive, tamoxifen.11 Before 1987, BCCA policy for patients with IIIB or with supraclavicular disease but no evidence of distant metastases was to offer treatment with systemic therapy and wide-field radiotherapy to the breast or chest wall, axilla, supraclavicular, and internal mammary nodes with or without mastectomy. Patients with clinical or radiographic evidence of distant metastases were treated with palliative intent. They received sequential hormonal and chemotherapy and selective use of RT to symptomatic areas at the discretion of their treating oncologist.12,13
Statistical Consideration
There were 5,368 patients with invasive breast cancer with known stage referred to the BCCA between January 1, 1976, and December 31, 1985. A total of 51 (1%) had supraclavicular but no other metastases, 336 (6.3%) had IIIB disease, and 233 (4.3%) had distant M1 disease at diagnosis and form the study groups. There were more subjects in 1981 to 1985 compared with 1976 to 1980 in part because of more complete recording of stage in the later years (Table 1  ). All patients with IIIB disease had T4 disease, and more than 50% of cases in the other groups had T3/4 primary disease. The median interval from diagnosis to first visit at the cancer center was 15, 21, and 12 days for the supraclavicular, IIIB, and M1 (other) cases, respectively. The median age was 57 years (range, 29 to 95 years) for the supraclavicular patients, 66 years (range, 29 to 95 years) for IIIB cases, and 63 years (range, 29 to 95 years) for M1 (other) cases. The age distributions were significantly different (P = .003).
The 51 patients with supraclavicular metastases and no evidence of distant metastases had the supraclavicular disease diagnosed clinically (n = 34), at open biopsy (n = 16), or by fine-needle aspiration cytology (n = 1). Local therapy was mastectomy (n = 13) or biopsy alone. Forty patients (78%) received local-regional RT. Overall, 42 patients (82%) received initial systemic therapy including chemotherapy alone (n = 18), hormone therapy alone (n = 10), or both (n = 14). Chemotherapy was anthracycline-based in 72%. Hormonal therapy included tamoxifen in 71%, ovarian ablation in 17%, or other agents in 12%.
Figures 1
Patients presenting with supraclavicular metastases have a poor prognosis.1–3 More than 50% succumb to disease within 3 years of diagnosis. However, this study demonstrated that a significant minority, approximately 13%, may be long-term survivors. Breast cancer–specific survival for patients with supraclavicular disease at diagnosis was intermediate between survival of patients presenting with IIIB and M1 (other) disease through the first decade of follow-up. Between 10 and 20 years after diagnosis, the overall and breast cancer–specific survivals of the supraclavicular and IIIB patients converge and remain significantly better than cases presenting with M1 (other) disease. The observed differences in survival are not explained by a poorer than average survival of patients with M1 disease. The survival experience of patients with M1 disease in this study was similar to that of survival rates reported by others.14–16 The differences between either the supraclavicular or IIIB cases and the M1 (other) cases is also not likely to be explained simply by differences in the pace of disease at diagnosis or by a lead-time effect, because the difference persists through 20 years of follow-up. A limitation of the study is that the majority of patients with supraclavicular metastases had the diagnosis made clinically. Such cases were only included if review of the initial oncology consultation at the BCCA had a clear description of a hard mass, consistent with metastases in the supraclavicular region. There was usually concurrence in the clinical description between several examiners for each patient. However, it is possible that patients without supraclavicular metastases could have been misclassified, and this could have spuriously increased the apparent survival outcomes for the study group. Patients presenting with isolated supraclavicular nodal metastases were, on average, younger than patients with IIIB or M1 (other) disease. If younger patients and those with visceral metastases were more likely to receive chemotherapy, the age differences between groups may tend to reduce outcome differences between the supraclavicular and IIIB patients while increasing differences between supraclavicular and M1 (other) patients. However, previous analyses from our group have shown that survival from the date of first recurrence was independent of age,17 and age did not influence recurrence-free or overall survival for patients with stage I and II disease.10,18,19 Therefore, the observed differences in median age between groups are unlikely to have significantly affected survival outcomes. During the era of this study, the policy of the BCCA was to treat patients with locally advanced or supraclavicular lymph node metastases with radical intent.12,13 This included systemic therapy and wide-field RT with or without mastectomy. The treatment intent was recognized to be palliative for patients presenting with distant metastases. The treatment policy was to individualize therapy to optimize quality of life.12,13 Definitive treatment may well have contributed to the survival improvement seen for the IIIB and supraclavicular cases compared with those with M1 (other) disease, but this cannot be proven with the available data. Better 10-year survival for patients with supraclavicular lymph node metastases compared with those having other metastases has been reported.6 That study included patients suitable for treatment with doxorubicin-based chemotherapy and definitive local-regional therapy. Approximately 31% of patients with regional stage IV disease were 10-year survivors. This rate is comparable to the 26% overall and 29% 10-year breast cancer–specific survival rates observed for patients presenting with supraclavicular lymph node metastases in this study. Patients with stage IIIB disease had better outcomes at 10 years. Breast cancer–specific survival rate was 42% for patients with stage IIIB disease compared with just 6% for patients with M1 (other) disease. The current population-based cohort study confirms that a significant proportion of patients presenting with stage IIIB or supraclavicular disease and without other evidence of distant metastases may achieve long-term disease control. It therefore seems appropriate that patients with metastases confined to the supraclavicular lymph nodes should be treated with radical intent. Treatment should include neoadjuvant, multiagent chemotherapy, definitive treatment to the local-regional area including RT, and if rendered operable, mastectomy. Tamoxifen is also advised for patients with estrogen receptor–positive disease. Therapeutic nihilism and sequential palliative interventions alone may well be insufficient unless the patient’s performance status indicates that radical treatment will not be tolerated. It also seems appropriate to reclassify the formal stage grouping of such patients. In any stage grouping, there is some heterogeneity of outcome. Patients with supraclavicular lymph node metastases but no other evidence of spread have outcomes more similar to those traditionally classified as stage IIIB (locally advanced, inoperable) rather than patients with stage IV disease. The 2003 revision of the AJCC breast cancer TNM staging system has appropriately reclassified patients presenting with supraclavicular metastases from M1 to a new category, IIIC.7
1. Jackson SM: Carcinoma of the breast: The significance of supraclavicular lymph node metastases. Clin Radiol 17:107–114, 1966[CrossRef][Medline] 2. Debois JM: The significance of a supraclavicular node metastasis in patients with breast cancer: A literature review. Strahlenther Onkol 173:1–12, 1997[Medline] 3. Strom EA, McNeese MD, Fletcher GH, et al: Results of mastectomy and postoperative irradiation in the management of locoregionally advanced carcinoma of the breast. Int J Radiat Oncol Biol Phys 21:319–323, 1991[Medline] 4. Haagensen CD, Stout AP: Carcinoma of the breast: Criteria of inoperability. Ann Surg 118:859–870, 1943[Medline] 5. Hermanek P, Sobin LH (eds): TNM Classification of Malignant Tumours: International Union Against Cancer (ed 4). New York, NY, Springer, 1987
6. Brito RA, Valero V, Buzdar AU, et al: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19:628–633, 2001
7. Singletary SE, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628–3636, 2002 8. International Union Against Cancer Committee on TNM Classification: TNM Classification of Malignant Tumours (ed 2). Geneva, Switzerland, International Union Against Cancer, 1974 9. Harmer MH (ed): TNM Classification of Malignant Tumours (ed 3). Geneva, Switzerland, International Union Against Cancer, 1978 10. Olivotto IA, Mates D, Kan L, et al: Prognosis, treatment, and recurrence of breast cancer for women attending or not attending the Screening Mammography Program of British Columbia. Breast Cancer Res Treat 54:73–81, 1999[CrossRef][Medline] 11. Ragaz J, Manji M, Plenderleith IH, et al: Impact of residual disease in stage III breast cancer patients treated with preoperative (neoadjuvant) chemotherapy, radiotherapy and mastectomy: The 10-year analysis of the British Columbia study. Proc Am Soc Clin Oncol 13:71, 1994 (abstr 88) 12. Cancer Control Agency of British Columbia: Treatment policies: The Agency. Vancouver, Canada, Cancer Control Agency of British Columbia, 1977 13. Cancer Control Agency of British Columbia: Cancer treatment policies: The Agency (ed 2). Vancouver, Canada, Cancer Control Agency of British Columbia, 1983 14. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia: A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol 4:186–193, 1986[Abstract] 15. Muss HB, Case LD, Richards F, et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer: The Piedmont Oncology Association. N Engl J Med 325:1342–1348, 1991[Abstract]
16. Joensuu H, Holli K, Heikkinen M, et al: Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: A prospective randomized trial. J Clin Oncol 16:3720–3730, 1998 17. Wai ES, Trevisan CH, Taylor SCM, et al: Health system costs of metastatic breast cancer. Breast Cancer Res Treat 65:233–240, 2001[CrossRef][Medline]
18. Weir L, Speers C, D’yachkova Y, et al: Prognostic significance of the number of axillary lymph nodes removed in patients with node-negative breast cancer. J Clin Oncol 20:1793–1799, 2002
19. Lohrisch C, Jackson J, Jones A, et al: Relationship between tumor location and relapse in 6781 women with early invasive breast cancer. J Clin Oncol 18:2828–2835, 2000 Submitted November 21, 2001; accepted November 8, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
