|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 16 (August 15), 2004: pp. 3302-3308 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.095 Breast Cancer With Synchronous Metastases: Trends in Survival During a 14-Year PeriodFrom the Breast Cancer Unit, Institut Gustave Roussy, Villejuif; Department of Medicine, Centre Leon Berard, Lyon; and Department of Medicine, Centre Antoine Lacassagne, Nice, France Address reprint requests to Fabrice Andre, MD, Breast Cancer Unit, Comite 050, Institut Gustave Roussy, 39 Rue C Desmoulins, 94805 Villejuif, France; e-mail: fandre{at}igr.fr
PURPOSE: Although new drugs were approved during the 1990s for the treatment of metastatic breast cancer, it is not clear whether their use has changed the outcome of patients in daily practice. This study sought to determine whether survival has improved over time for breast cancer patients who had metastases at diagnosis.
PATIENTS AND METHODS: A total of 724 patients have been treated in three French cancer centers for an initially metastatic breast cancer between 1987 and 2000; 343 were diagnosed between 1987 and 1993, and 381 were diagnosed between 1994 and 2000. Tumor characteristics, treatments, and outcomes of these patients were compared by RESULTS: Characteristics were not different between the patients diagnosed from 1987 to 1993 and those diagnosed from 1994 to 2000. Ten percent of patients treated from 1987 to 1994 and 58% of patients treated from 1994 to 2000 have received either a taxane or a new aromatase inhibitor. The 3-year overall survival rates were 27% for patients treated from 1987 to 1993 and 44% for patients treated from 1994 to 2000 (P < .001). The treatment period (1994 to 2000 v 1987 to 1993) was a prognostic factor in multivariate analysis (relative risk, 0.6; P < .001). CONCLUSION: The survival of breast cancer patients presenting with metastases at diagnosis has improved over time. This study strongly suggests that this improvement is related to treatment.
Six percent to 10% of breast cancer patients present with metastasis at diagnosis.1,2 Once metastases are detected, median survival ranges between 18 and 24 months,3,4 and the treatment is considered palliative. During the last decade, a series of new drugs have been developed and approved for daily practice in this setting. These new drugs include vinorelbine,5 paclitaxel,6 docetaxel,7 letrozole,8 anastrozole,9 and exemestane.10 More recently, monoclonal antibodies (trastuzumab)11 and oral fluorouracil derivatives (capecitabine)12 have been added to this list. The approval of these drugs has been based on results of phase II and III trials. These trials showed that new drugs induce tumor response rates that range from 20% to 70% and increase progression-free survival. In some of these trials, new drugs increased overall survival (OS).6-9,11,12 Although the magnitude of the effect on survival remains unclear, there is a consensus that these treatments exhibit antitumor activity for metastatic breast cancer.13 In addition to new antineoplastic drugs, some advances have been made in supportive care. Indeed, bisphosphonates are now widely used for patients with bone metastasis,14 and granulocyte colony-stimulating factor and new antibiotics have improved the management of neutropenia.15 Advances have also been made in the fields of surgery and radiotherapy for palliative situations (such as spinal cord compression).16 Although clinical trials suggest that some advances have been made in the management of metastatic breast cancer during the 1990s, it is not clear whether survival of these patients has improved in a context of daily practice. In this study, we analyzed the evolution of the survival of breast cancer patients with metastases at diagnosis over time. Two time periods have been compared: before and after the year of approval of paclitaxel for treatment of metastatic breast cancer in France.
Patient Selection This study includes 724 consecutive breast cancer patients with metastases at diagnosis (stage IV). These patients have been treated in three French cancer centers (Institut Gustave Roussy, Villejuif; Centre Leon Berard, Lyon; and Centre Antoine Lacassagne, Nice) between 1987 and 2000. During this period, the identity and clinical file, including tumor-node-metastasis system status, of all patients were included prospectively in the hospital database. Patients were included in the study to present a TXNXM+ breast cancer at diagnosis according to 1987 TNM system classification of tumor response.17 Patients presenting with isolated ipsilateral supraclavicular lymph nodes were excluded from the study because it has been shown that their prognoses are similar to those of patients with stage III breast cancer.18 Patient characteristics were recorded prospectively in the hospital database, except hormonal receptors (HRs), which were verified retrospectively in the medical chart. Although data were prospectively recorded in hospital database, their accuracy was validated for each patient using the medical chart. The institutional review boards approved the acquisition and report of the data from these patients. To be included, breast adenocarcinoma must have been proven histologically or cytologically. A biopsy of metastasis was not required for inclusion in the study group.
Staging
Variables
Statistical Analysis
Patient Characteristics A total of 724 patients were included in the study. Three hundred forty-three patients were diagnosed from 1987 to 1993 and 381 patients were diagnosed from 1994 to 2000. This represents 4.2% and 3.5% of overall breast cancer patients referred in these institutes from 1987 to 1993 (n = 8,167) and from 1994 to 2000 (n = 10,886), respectively. Median follow-up of survivors was 51 months for the overall population, 60 months for the patients treated from 1987 to 1993, and 45 months for the patients treated from 1994 to 2000. The diagnosis of metastatic disease was provided by MRI in 16 (5%) and 35 (9%) patients during the two periods, respectively. Patient characteristics are listed in Table 1. Briefly, 28% of patients presented with liver metastasis and 54% of tumors were coded as HR-positive. Characteristics did not differ between patients diagnosed from 1987 to 1993 and those diagnosed from 1994 to 2000 (Table 1), except there was a higher rate of unknown HR status in patients diagnosed from 1987 to 1993. Forty percent (n = 62) and 27% (n = 105) of patients with HR-negative and HR-positive tumors presented with liver involvement, respectively (P < .05). Thirty-seven percent (n = 58) and 51% (n = 196) of patients with HR-negative and HR-positive tumors presented with nonvisceral involvement, respectively. Twenty-seven percent (n = 38) and 47% (n = 67) of patients with unknown receptor status presented with liver involvement and a nonvisceral involvement, respectively.
Treatments According to the Treatment Period Treatments are listed in Table 1. Ten percent of patients treated from 1987 to 1993 and 58% of patients treated from 1994 to 2000 received a new medical treatment, as defined in Patients and Methods (P < .001). Thirty-eight percent of patients diagnosed from 1994 to 2000 were treated with either paclitaxel or docetaxel, and 39% were treated with a new aromatase inhibitor, as defined in Patients and Methods. For comparison, 6% of patients diagnosed from 1987 to 1993 were treated with taxanes and 5% were treated with a new aromatase inhibitor, as defined in Patients and Methods (Table 1). No differences were noted between the two periods regarding the locoregional treatment of primary tumors (Table 1). One patient diagnosed from 1987 to 1993 and five patients diagnosed from 1994 to 2000 were treated by surgical resection of metastases. One hundred fifteen patients diagnosed from 1987 to 1993 (33%) and 106 patients diagnosed from 1994 to 2000 (28%) received radiation therapy for bone metastases. One patient was treated with hepatic artery infusion of chemotherapy for liver metastases in each period.
Survival of Initially Metastatic Breast Cancer Patients According to Time Period
A multivariate analysis that included age, visceral involvement, number of organs involved, HR status, center, and time period was performed. The presence of visceral metastases (ie, liver and/or brain metastases), the involvement of multiple organs, HR status, and time period were found to be prognostic factors in multivariate analysis (Table 2). There was no interaction between HR status and site of metastasis in the multivariate analysis of survival (P = .39). To model the impact of positive hormone receptor status on the outcome of patients in each period, a multivariate analysis was performed for patients treated from 1987 to 1993 and for those treated from 1994 to 2000. The positive HR status remained a prognostic factor in each period. Its impact was more pronounced in the period 1994 to 2000 (hazard ratio for HR-positive tumors during the period from 1994 to 2000, 0.27; 95% CI, 0.18 to 0.37) compared with the period 1987 to 1993 (hazard ratio for HR-positive tumors during the period 1987 to 1993, 0.53; 95% CI, 0.38 to 0.74). Because the HR status was unknown in 19.5% of the patients, we cannot exclude an imbalance in the real HR status between the two periods. If we make the extreme hypothesis that all unknown HR status are negative in the first period and positive in the second, the adjusted period effect remains significant (hazard ratio, 0.77; 95% CI, 0.64 to 0.93). Conversely, if all unknown receptor status are positive in the first period and negative in the second, the adjusted period effect remains significant (hazard ratio, 0.55; 95% CI, 0.46 to 0.67).
Influence of Treatment Period on Survival According to Center and HR Status Survival of breast cancer patients with metastases at diagnosis improved over time without regard to the treatment center. For patients treated in center 1, the 3-year OS rates were 28% for patients treated from 1987 to 1993 and 40% for those treated from 1994 to 2000 (n = 328; P = .01, log-rank test). For patients treated in center 2, the 3-year OS rates were 29% for patients treated from 1987 to 1993 and 53% for those treated from 1994 to 2000 (n = 212; P = .006, log-rank test). For patients treated in center 3, the 3-year OS rates were 23% for patients treated from 1987 to 1993 and 41% for those treated from 1994 to 2000 (n = 183; P = .04, log-rank test). When only patients with HR-positive tumors were considered (n = 389; Fig 2A), median survival was 28 months for patients treated from 1987 to 1993 and 45 months for those treated from 1994 to 2000. In this subset of patients, the 3-year OS rates were 33% for patients treated from 1987 to 1993 and 60% for those treated from 1994 to 2000. In the same subgroup, the 5-year OS rates were 14% for patients treated from 1987 to 1993 and 38% for patients treated from 1994 to 2000. The survival difference between the two groups of patients (1987 to 1993 v 1994 to 2000) was statistically significant (P < .001, log-rank test; Fig 2A).
When only patients with HR-negative tumors were considered (n = 155; Fig 2B), median survival was 12 months both for patients treated from 1987 to 1993 and for those treated from 1994 to 2000. In this subset of patients, the 3-year OS rates were 14% for patients treated from 1987 to 1993 and 16% for those treated from 1994 to 2000. In the same subgroup, the 5-year OS rates were 4% for patients treated between 1987 and 1993 and 8% for patients treated from 1994 to 2000. OS rates were not different between the patients with HR-negative tumors treated in the period from 1987 to 1993 and those treated in the period from 1994 to 2000 (P = .6, log-rank test; Fig 2B).
Although there is a consensus that some active treatments have emerged during the 1990s in metastatic breast cancer, the impact of these advances in daily practice remains to be determined. In this study, we reported that the survival of breast cancer patients who initially present with metastases was improved in the time period from 1994 to 2000 compared with that from 1987 to 1993. Several questions are raised from these data: Is this improvement the result of a bias or treatment advances? If this improvement is related to treatments, which treatments have improved the prognosis of these patients, and in which patients was survival improved? Several factors could mediate a time-related bias in studies focused on temporal improvements in survival of diseases. These include changes in radiologic facilities for detection and diagnosis, changes in diagnostic criteria, and evolution of clinical characteristics over time. In our study, the radiologic facilities used to detect or diagnose metastases of primary breast cancer were similar between the two periods and include bone scan, liver ultrasound, chest x-rays, and CT scan for confirmation. In addition, MRI became available at the end of 1980s. Its use for the diagnosis of metastatic disease was not different in the two periods. No positron emission tomography scan was performed in any patients to detect or diagnose metastasis. Although there is no major difference in the use of technology to diagnose metastatic disease, we can not exclude that some subtle changes in the technologies could have influenced the diagnosis of metastases. For example, the successive generation of ultrasound, CT, and MRI scanners might have detected smaller metastases. Diagnostic criteria of initially metastatic breast cancer also were similar between the two time periods and included the proof of primary breast cancer and a synchronous metastasis. The definition of metastasis did not differ between the two intervals and was based on the 1987 tumor-node-metastasis system classification.17 The only exception exists in patients with ipsilateral isolated supraclavicular lymph nodes. Indeed, these patients were excluded retrospectively from the overall study because their prognosis has been shown to be similar to that of patients with stage III breast cancer.18 Other potential time-related biases include changes in the epidemiology and natural history of breast cancer over the time. Both the screening and the information about populations have influenced the epidemiology of breast cancer.19 This could have influenced the results of our study by facilitating an earlier detection of metastatic breast cancer. Nevertheless, patient characteristics did not change over the time period in our study. It is notable that age, sites of metastasis, number of organs involved, and HR status were similar in the periods from 1987 to 1993 and from 1994 to 2000. The interval between primary tumor and metastatic relapse is one of the most important prognostic factors in metastatic breast cancer.20 This is why only patients presenting with metastases at diagnosis of primary breast cancer were included in our study. Although this inclusion criterion decreases the number of patients included in our study, this excludes a bias that selects patients with a better prognosis in the more recent period. This also avoids a bias related to changes in the adjuvant chemotherapy regimen over the time. It is notable that the subgroup of patients included in our study represents approximately 5% of all breast cancer patients. Although our study reports improvements in the prognosis of initially metastatic breast cancer, the results cannot be generalized to all metastatic breast cancer. Nevertheless, this subgroup of patients is the only one that allows comparison with historical controls with minimal time-related biases. The survival improvement over the time was observed similarly in the three hospitals included in the study. This suggests that this improvement is not due to a center-related bias. One could argue that the improvement is related to poor results in the first cohort. Nevertheless, the survival rates observed during this time period (1987 to 1993) is not different from that reported in other hospital-based cohorts of metastatic breast cancer.20 For example, Chang et al20 reported that median survival time was 21 months for patients with estrogen receptor–positive metastatic breast cancer and 12 months for those presenting with an estrogen receptor–negative metastatic breast cancer. Given that we excluded as much as possible time- and center-related biases, the results of this study suggest that the survival improvement is related to treatment advances that occurred after 1993. This study was not designed to identify what intervention led to survival improvement. Nevertheless, several hypotheses could be put forward to explain the survival improvement observed in our study. The first hypothesis is that advances in anticancer drugs have improved survival. The use of taxanes and new aromatase inhibitors could at least partially explain the evolution of survival over the time. As expected, there are major differences in the use of taxanes and/or new aromatase inhibitors (anastrozole, letrozole, or exemestane) before and after 1993 because 10% of patients treated from 1987 to 1993 and 58% of patients treated from 1994 to 2000 have received at least one of these drugs. It is notable that 76% of patients treated from 1994 to 2000 and who lived at least 3 years have been treated with either a taxane or a new aromatase inhibitor. The hypothesis that these new drugs increase survival of metastatic breast cancer is supported by results of randomized trials.6-8 Our study did not assess which one of these drugs has changed the outcome of patients. Nevertheless, the finding that the survival improved only for patients with HR-positive tumors suggests that the improvement is related to new hormonal therapies or changes in the use of chemotherapy for these patients. The advances in supportive care also could explain the improvement of survival. As previously reported, advances have been made in the field of supportive care during the 1990s. Indeed, bisphosphonates are able to prevent bone fractures14 and treat hypercalcemia, and granulocyte colony-stimulating factor and new antibiotics have improved the management of neutropenia.15 In addition, some advances have been made in the fields of surgery and radiotherapy for metastatic disease. Although there was no major differences between the two periods regarding the locoregional treatments performed, some subtle evolutions in surgery and radiotherapy of the breast could have influenced the prognosis.21 Some changes in the use of imaging technology (including MRI) during the follow-up of patients with metastases also could have allowed a survival improvement. Overall, it is possible to speculate that all of these factors have contributed to the survival improvement. In this study, the 3- and 5-year OS rates were 44% and 28%, respectively, for patients treated from 1994 to 2000. A dramatic survival improvement was noted for patients with HR-positive tumors. Indeed, the 3- and 5-year OS rates were 60% and 38%, respectively, for patients with HR-positive tumors treated from 1994 to 2000. Median survival time was 45 months. These survival rates are similar to those reported in heart failure,22 myeloma,23 and chronic obstructive pulmonary disease with moderate hypoxemia.24 This suggests that HR-positive metastatic breast cancer could be seen as a chronic disease. This finding will have some implications both in the medical, social, and psychological management of these patients. Regarding HR-negative tumors, our study was underpowered to demonstrate a significant survival benefit in this subgroup. In addition, most of the patients did not receive trastuzumab or capecitabine. The finding that no improvement was observed for these patients should therefore be interpreted with caution. In conclusion, our study suggests that new treatments have allowed a survival improvement in breast cancer patients who present with metastasis at diagnosis. This survival improvement is dramatic in patients with HR-positive tumors, for whom median survival reaches 45 months.
The authors indicated no potential conflicts of interest.
We thank L. Bourgoin for technical assistance.
Supported by a Young Investigator Award from the American Society of Clinical Oncology (F.A.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Harris JR, Morrow M, Bonnadonna G: Cancer of the breast, in De Vitta VT Jr, Hellman S, Rosenberg SA (eds). Cancer. Principles and Practice in Oncology (ed 4). Philadelphia, PA, JB Lippincott, 1993, pp 1264-1332 2. Miller KD, Sledge GW Jr: The role of chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am 13:415-434, 1999[CrossRef][Medline] 3. Muss HB, Case D, Richards F, et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med 325:1342-1348, 1991[Abstract] 4. Norton L: Metastatic breast cancer: Length and quality of life. N Engl J Med 325:1370-1371, 1991[Medline] 5. Jones S, Winer E, Vogel C, et al: Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 13:2567-2574, 1995[Abstract]
6. Jassem J, Pienkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001
7. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy: 304 Study Group. J Clin Oncol 17:1413-1424, 1999 8. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16:453-461, 1998[Abstract] 9. Buzdar AU, Jonat W, Howell A, et al: Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: Results of a survival update based on a combined analysis of data from two mature phase III trials: Arimidex Study Group. Cancer 83:1142-1152, 1998[CrossRef][Medline]
10. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial—The Exemestane Study Group. J Clin Oncol 18:1399-1411, 2000
11. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001
12. O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002 13. Crown J, Dieras V, Kaufmann M, et al: Chemotherapy for metastatic breast cancer-report of a European expert panel. Lancet Oncol 3:719-727, 2002[CrossRef][Medline] 14. Mundy GR: Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584-593, 2002[CrossRef][Medline]
15. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines—American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:3558-3585, 2000 16. Manglani HH, Marco RA, Picciolo A, et al: Orthopedic emergencies in cancer patients. Semin Oncol 27:299-310, 2000[Medline] 17. Sobin LH, Hermanek P, Hutter RV: TNM classification of malignant tumors: A comparison between the new (1987) and the old editions. Cancer 61:2310-2314, 1988[CrossRef][Medline]
18. Olivotto IA, Chua B, Allan SJ, et al: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21:851-854, 2003 19. Montella M, Buonanno M, Biondi E, et al: Changing patterns of breast cancer stage at diagnosis in Southern Italy: Hospital data as indicators of progressive changes. Prev Med 30:174-177, 2000[CrossRef][Medline] 20. Chang J, Clark GM, Allred C, et al: Survival of patients with metastatic breast carcinoma: Importance of prognostic markers of the primary tumor. Cancer 97:545-553, 2003[CrossRef][Medline] 21. Carmichael AR, Anderson ED, Chetty U: Does local surgery have a role in the management of stage IV breast cancer? Eur J Surg Oncol 29:17-19, 2003[CrossRef][Medline]
22. Levy D, Kenchaiah S, Larson MG, et al: Long-term trends in the incidence of and survival with heart failure. N Engl J Med 347:1397-1402, 2002
23. Attal M, Harousseau JL, Stoppa AM, et al: Prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996 24. Gorecka D, Gorzelak K, Sliwinski P, et al: Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax 52:674-679, 1997[Abstract] Submitted August 13, 2003; accepted May 12, 2004.
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test, log-rank test, and Cox regression analysis. 
