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© 2002 American Society for Clinical Oncology
Can We Cure Limited Metastatic Breast Cancer?The University of Texas M.D. Anderson Cancer Center, Houston, TX AN ARTICLE in this issue of the Journal of Clinical Oncology provides an opportunity to review the state of our knowledge about overt metastatic breast cancer limited to a single organ site, and mostly to a single lesion.1,2 Oligometastasis is certainly an appropriate name for it. A somewhat similar situation, in which a solitary recurrence or metastatic lesion is resected surgically or treated with radiotherapy at curative doses, has been referred to as stage IV NED (no evidence of disease).3-7 It is a generally held belief that once the patient with breast cancer develops clinically detectable metastases beyond the regional lymph nodes, the disease is incurable.8 Let’s evaluate the evidence in support for and against this belief. Clearly, untreated breast cancer eventually leads to death, unless intercurrent causes intervene.9,10 Competing causes of death are frequent in breast cancer, and their frequency increases with age.11,12 The breast cancer literature includes a large number of reports about prospective clinical trials that examine the effects of endocrine therapy, chemotherapy, or both. However, most of these trials have relatively brief follow-up, with a minority of patients having died by the time of the analysis. Long-term follow-up, beyond 3 to 5 years, is exceptional in the metastatic breast cancer literature. Because the median survival for patients with metastatic breast cancer ranges between 2 and 4 years, this is not inappropriate; however, not pursuing long-term follow-up studies reduces our understanding of the clinical course of breast cancer among the minority of patients who survive longer than 3 to 5 years. A few reports have presented 5-, 10-, and even 15-year follow-up data.13,15 These analyses have demonstrated that, while most patients with metastatic breast cancer respond transiently to conventional treatments, the majority develop evidence of progressive disease within 12 to 24 months of initiating treatment.16,17 However, some patients who achieve a complete remission after chemotherapy remain in this state for prolonged periods of time, with some even beyond 20 years.13,14 These long-term survivors are usually young, have excellent performance status, and have limited metastatic disease. Although this fraction represents a numerically small group of patients (between 1% and 3%), this finding challenges the commonly held belief that metastatic breast cancer is universally fatal. Another group of breast cancer patients relevant to this discussion are those who present with very limited metastatic disease, often with a single lesion. Patients with solitary skin, lymph node, lung, liver, or brain metastases have been treated with surgical resection (therefore providing histologic confirmation of metastatic disease), sometimes with diagnostic but often with curative intent.18-20 Although most of the reports addressing this issue are based on retrospective analyses, it is apparent that a subset of these patients remains without ever developing additional metastatic deposits. Five- to 10-year follow-up of these patients indicates that some remain without recurrence.18-20 Patients with a solitary lung metastasis constitute the majority of reported cases, along with chest wall and lymph node metastases. Patients with liver metastases or other visceral lesions seldom survive without additional metastases after surgical resection, with or without the addition of radiation therapy. In the absence of systemic therapy, one would have to hypothesize that these patients indeed had a solitary metastatic deposit, without other tumorigenic micrometastases, and that the surgical resection might have been curative. Our group at The University of Texas M.D. Anderson Cancer Center started a prospective, single-arm clinical trial in 1974 to evaluate the effect of adjuvant systemic therapy after surgical resection and, when possible, radiation therapy of solitary metastases.3-6,21 Systemic therapy was added, assuming that micrometastases existed in the majority of them and that systemic therapy might eliminate micrometastases in at least some patients, in a manner similar to adjuvant chemotherapy or hormone therapy in patients with high-risk primary breast cancer. Because it was considered that the great majority of patients would develop additional metastases if treated with regional treatment only, a simultaneous control arm was not considered appropriate. The 5-, 10- and 15-year disease-free survival rates of the 134 patients treated with the combined-modality regimen were 36%, 26%, and 24%, respectively.6 With a maximum follow-up of 26 years, only two additional events occurred after the 15th year of follow-up.21 These results were compared with a group of historical controls treated at the same institution. The 62 control patients with solitary recurrence or metastasis were treated with surgery, with or without radiotherapy, between 1967 and 1976. Their 5-, 10-, and 15-year disease-free survival rates were 7%, 4%, and 3%, respectively. Although more than half of the metastases included in both the control and experimental groups represented chest wall recurrences, many others had classical visceral metastases to lung, brain, and liver, or bone and distant soft tissue metastases. With the usual caveats associated with historical controls, these differences between the groups treated with and without adjuvant systemic therapy seemed substantial. Two additional cohorts of patients, treated with more dose-intensive chemotherapy programs6 and the addition of adjuvant hormonal therapy for hormone receptor–positive tumors,21 have confirmed the original observations and expanded the group of patients with stage IV NED treated at our institution to 231 patients. Subsequently, several investigators and research groups, including ours at the University of Texas M.D. Anderson Cancer Center, have attempted to test this hypothesis in the context of a prospective randomized clinical trial. Borner et al22 hypothesized that combining surgical resection of the locoregional recurrence with adjuvant tamoxifen would decrease the odds of recurrence and death. One hundred sixty-seven patients with isolated first locoregional recurrence were registered in this randomized trial of complete excision and radiotherapy, with or without tamoxifen. After a median follow-up of 6.3 years, the authors reported a significant prolongation of disease-free survival (26 v 82 months; P = .007); however, no significant change in survival could be demonstrated (5-year overall survival, 74% and 76%; P = .77). However, at the time of the report, only 45 of the 167 patients had died, so there were too few events for a mature survival analysis. To my knowledge, all other randomized trials designed to test this hypothesis with chemotherapy have failed to complete the targeted accrual. The experience from the University of Colorado Health Sciences Center includes 62 patients (60 assessable).1 These patients were treated with surgical resection and/or radiation therapy when possible (58 patients); in addition, 10 patients had positive selection of hematopoietic stem cells used for support in an attempt to purge the stem-cell collection from malignant cell contamination. All received high-dose chemotherapy. With a median follow-up of 62 months, 51.6% of patients remain without evidence of active disease. On the surface, these results seem to confirm the results of the earlier M.D. Anderson Cancer Center reports. Because no simultaneous controls are available for either trial, definitive conclusions are unwarranted. Although there seems to be little difference in the 5-year results between the two single-institution experiences, there were important differences between the University of Colorado and the M.D. Anderson patient groups: 10 of the former group and none of the latter had bone marrow involvement; 84% of the former and none of the latter had received prior adjuvant chemotherapy. Therefore, the group of patients treated in the M.D. Anderson protocol represented a more favorable group. From these observations, it is difficult to ascertain the role of high-dose chemotherapy, or any other component, in the overall combined-modality treatment program. However, the observation common to both experiences is that 5 years after regional treatment of a recurrent or metastatic lesion, 36% to 52% of patients remain not only alive but without evidence of metastatic disease. This is remarkable, because it is contrary to all other experience in metastatic breast cancer. The other observation common to these studies and the ones reported by Greenberg14 and Tomiak13 is that the long-term disease-free survivors were young, had good performance status, and had limited metastatic disease. The favorable prognostic effect of HER2 negativity is in keeping with other reports.23 The article by Nieto et al1 presents an analysis of prognostic factors for a group of 60 patients with limited recurrent or metastatic disease (oligometastases) treated with regional therapy (surgery with or without radiotherapy), high-dose chemotherapy, and autologous hematopoietic stem-cell support. The 5-year relapse-free and overall survival rates were 52% and 62%, respectively. The investigators correlated baseline characteristics of these 60 patients with outcome measures, relapse-free survival, and overall survival. They concluded that HER2 status and number of involved sites identified three distinct prognostic groups of patients in this population. Why is this article worthy of editorial comment? Normally, an analysis of clinical material for prognostic factors requires a large population of patients to have sufficient statistical power for reliable conclusions. Furthermore, the development of prognostic models requires that the model developed from the original patient population be tested or validated in a different, unrelated patient population. Only in that manner can one determine whether the prognostic model is valid and useful. Otherwise, it leads to a circular argument for validity. The article by Nieto et al fulfills neither of these requirements. The use of high-dose chemotherapy for any subset of breast cancer continues under study,24 and the design of the clinical trial that recruited the 60 patients who form the basis for this prognostic analysis does not permit any conclusions regarding the contribution of this treatment strategy to outcome.2 The experience with two decades of single-arm trials with high-dose chemotherapy and autologous stem-cell support indicates that patient selection and stage migration resulting from extensive staging procedures can affect substantially the outcome of therapy and highlights the importance of randomized trials to ensure comparability of baseline characteristics, extent of staging, and frequency of monitoring. Therefore, it would be very important to design and complete a large, controlled trial to confirm the hypothesis that multimodality therapy administered to a group of patients with limited metastatic breast cancer can produce long-term disease-free survival or cure in a subset of patients. This is particularly important because this is the group of patients most likely to be given palliative hormonal therapy first, because they are asymptomatic and perceived to have a good prognosis. Yet, the data described above would suggest that this is the group that would benefit the most from more aggressive, multidisciplinary therapy. These reports show that 3% to 30% of selected patients with biopsy-proven distant metastases from breast cancer and who can be rendered disease-free with multidisciplinary treatments are probably curable. Does a 20-year disease-free survival represent cure? With the chronic history and not infrequent late relapses of breast cancer, it would be unwise to state (and probably unlikely) that all these patients are cured. However, it is probable that of those, some will achieve a personal cure. The Holmes et al,6 Rivera et al,21 and Nieto et al1 reports provide level III evidence in support of the hypothesis that metastatic breast cancer might be curable with a multidisciplinary approach in selected patients with limited metastases; the tamoxifen trial results represent level II evidence. Optimal clinical decisions require level I evidence for integration into standard practice. If the possibility of curative multidisciplinary therapy exists for patients with limited metastatic breast cancer, the hypothesis must be formally tested in prospective controlled trials. If proven, we should offer such treatment to all eligible patients. If the hypothesis cannot be proven, we will have resolved another controversy in the field. Because patients with a solitary metastasis represent only 1% to 3% of patients, we need a large multicenter collaboration to accomplish this task. We were able to accomplish much with such collaborations in primary operable breast cancer. We must be able to do it in this instance, too. The clinical consequences of confirming this hypothesis would be considerable. First, it would suggest that a selected subset of patients with metastatic breast cancer should be approached with curative, not palliative, intent. Second, that intensive postoperative monitoring to diagnose metastatic breast cancer early should be revisited. Finally, prognostic models to identify the optimal candidates for curative treatment of metastatic breast cancer should be developed on the basis of long-term follow-up of large numbers of patients treated in prospective trials. REFERENCES
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Nieto Y, Nawaz S, Jones RB, et al: Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer. J Clin Oncol 20: 707-718, 2002
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Nieto Y, Cagnoni PJ, Shpall EJ, et al: Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease. Clin.Cancer Res 5: 1731-1737, 1999 3. Blumenschein GR, Buzdar AU, Tashima CK, et al: Adjuvant chemoimmunotherapy of stage IV (NED) breast cancer, in Salmon SE, Jones SE (eds): Adjuvant Therapy of Cancer. Amsterdam, the Netherlands, Elsevier North-Holland Publishing Co, 1977, pp 147-152 4. Buzdar AU, Blumenschein GR, Smith TL, et al: Adjuvant chemoimmunotherapy following regional therapy for isolated recurrences of breast cancer (stage IV NED). J Surg Oncol 12: 27-40, 1979[Medline] 5. Buzdar AU, Blumenschein GR, Montague ED, et al: Combined modality approach in breast cancer with isolated or multiple metastases. Am J Clin Oncol 7: 45-50, 1984[Medline] 6. Holmes FA, Buzdar AU, Kau SW, et al: Combined-modality approach for patients with isolated recurrences of breast cancer (IV-NED): The M.D. Anderson experience. Breast Disease 7: 7-20, 1994 7. Juan O, Lluch A, de Paz L, et al: Prognostic factors in patients with isolated recurrences of breast cancer (stage IV-NED). Breast Cancer Res Treat 53: 105-112, 1999[CrossRef][Medline] 8. Henderson IC: Chemotherapy for Metastatic disease, in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases (ed 2). Philadelphia, PA, J.B. Lippincott Company, 1991, pp 604-665 9. Bloom HJG, Richardson WW, Harries EJ: Natural history of untreated breast cancer (1805-1933): Comparison of untreated and treated cases according to histological grade of malignancy. BMJ 213-221:1962 10. Bloom HJ: The natural history of untreated breast cancer. Ann NY Acad Sci 114: 747-754, 1964[Medline] 11. Yancik R: Cancer burden in the aged: An epidemiologic and demographic overview. Cancer 80: 1273-1283, 1997 (review article)[CrossRef][Medline]
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Satariano WA, Ragland DR: The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 120: 104-110, 1994 13. Tomiak E, Piccart M, Mignolet F, et al: Characterisation of complete responders to combination chemotherapy for advanced breast cancer: A retrospective EORTC Breast Group study. Eur J Cancer 32A: 1876-1887, 1996[CrossRef] 14. Greenberg PA, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197-2205, 1996[Abstract] 15. Falkson G, Holcroft C, Gelman RS, et al: Ten-year follow-up study of premenopausal women with metastatic breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 13: 1453-1458, 1995[Abstract]
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Diaz-Canton EA, Valero V, Rahman Z, et al: Clinical course of breast cancer patients with metastases confined to the lungs treated with chemotherapy: The University of Texas M.D. Anderson Cancer Center experience and review of the literature. Ann Oncol 9: 413-418, 1998 17. Rahman ZU, Frye DK, Smith TL, et al: Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: A reference. Cancer 85: 104-111, 1999[CrossRef][Medline] 18. Girard P, Baldeyrou P, le Chevalier T, et al: Surgery for pulmonary metastases. Cancer 74: 2791-2797, 1994[CrossRef][Medline] 19. McKenna RJ Jr, McMurtrey MJ, Larson DL, et al: A perspective on chest wall resection in patients with breast cancer. Ann Thorac Surg 38: 482-487, 1984[Abstract] 20. Temple WJ, Ketcham AS: Surgical management of isolated systemic metastases. Semin Oncol 7: 468-480, 1980[Medline] 21. Rivera E, Holmes FA, Buzdar AU, et al: Fluorouracil, doxorubicin, and cyclophosphamide followed by tamoxifen as adjuvant treatment for patients with stage IV breast cancer who have no evidence of disease. Breast J (in press)
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Borner M, Bacchi M, Goldhirsch A, et al: First isolated locoregional recurrence following mastectomy for breast cancer: Results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation—Swiss Group for Clinical Cancer Research. J Clin Oncol 12: 2071-2077, 1994 23. Ross JS, Fletcher JA: HER-2/neu (c-erb-B2) gene and protein in breast cancer. Am.J.Clin.Pathol 112: S53-S67, 1999 (review article)[Medline]
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Antman KH, Heitjan DF, Hortobagyi GN: High-dose chemotherapy for breast cancer. JAMA 282: 1701-1703, 1999 This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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