1 Institute of Medical Oncology, Inselspital, University of Bern, Bern; 2 SAKK Koordinationszentrum, Bern; 3 Kantonsspital, St. Gallen, Switzerland
Received 28 December 2002; revised 12 April 2003; accepted 23 April 2003
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Abstract |
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Adjuvant systemic treatment for patients with isolated locoregional recurrence (ILRR) of breast cancer is based on a single reported randomized trial. The trial, conducted by the Swiss Group for Clinical Cancer Research, compared tamoxifen (TAM) with observation after complete excision of the ILRR and proper radiotherapy. We performed a definitive analysis of treatment outcome at >11 years of follow-up, after the majority of the patients had a subsequent event of interest.
Patient and methods
One hundred and sixty-seven patients with good-risk characteristics of disease were randomized. Good-risk was defined as estrogen receptor expression in the ILRR, or having a disease-free interval of >12 months and a recurrence consisting of three or less tumor nodules, each 3 cm in diameter. Seventy-nine percent of the patients were postmenopausal at randomization.
Results:
The median follow-up time of the surviving patients was 11.6 years. The median post ILRR disease-free survival (DFS) was 6.5 years with TAM and 2.7 years with observation (P = 0.053). The difference was mainly due to reduction of further local relapses (P = 0.011). In postmenopausal patients, TAM led to an increase of DFS from 33% to 61% (P = 0.006). In premenopausal women, 5-year DFS was 60%, independent of TAM medication. For the whole study population, the median post-recurrence overall survival (OS) was 11.2 and 11.5 years in the observation and the TAM group, respectively; premenopausal patients experienced a 5-year OS of 90% for observation compared with 67% for TAM (P = 0.175), while the respective figures for postmenopausal patients were both 75%.
Conclusions:
These definitive results confirmed that TAM significantly improves the post-recurrence DFS of patients after local treatment for ILRR. This beneficial effect does not translate into a detectable OS advantage.
Key words: breast cancer, locoregional recurrence, randomized phase III study, tamoxifen
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Introduction |
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The role of systemic adjuvant treatment is well established in the management of primary breast cancer, but only one randomized phase III study has been performed to examine tamoxifen (TAM) for ILRR. In a first analysis of this trial, conducted from 1982 to 1991, we have demonstrated that TAM significantly prolongs post-ILRR disease-free survival (DFS) at a median observation time of 6.4 years. There was a more pronounced effect on the reduction of further local relapses than on the reduction of distant metastases. Patients eligible for this study had rather favorable disease characteristics, such as positive estrogen-receptors or, in the case of unknown receptor status, not more than three nodules, each 3 cm in diameter, and a disease-free interval (DFI) from primary treatment of at least 1 year [4]. A subsequent analysis indicated that TAM was associated with increased distant failure rates in premenopausal patients, while both distant and local progression rates were reduced in postmenopausal patients [5]. TAM had no significant impact on overall survival (OS). However, the median survival duration of the study population had not been reached at a median follow-up of 6.4 years. This is the only randomized study available on systemic therapy of ILRR to reach its accrual goal. Since even the retrospective series on this subject are generally small in size, it was important to analyze the mature long-term follow-up data of this randomized study. We present here the results of these analyses at a median follow-up of 11.6 years for surviving patients.
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Patients and methods |
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The local treatment consisted of radical excision followed by local radiotherapy of the recurrence site. A total dose of 5000 cGy was given to the involved region at 200 cGy per fraction, 5 days a week. Patients were stratified according to menopausal status, adjuvant chemotherapy and axillary node involvement at diagnosis, and centrally [Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center, Bern] randomized by telephone to either observation or systemic treatment (tamoxifen 20 mg per day orally) until disease progression.
The KaplanMeier method was used to estimate distributions of DFS and OS [6]. Differences in survival distributions were evaluated using the log-rank test [7] and, additionally, for the DFS using the GehanWilcoxon test. The difference between the two tests is that the GehanWilcoxon test places more weight on the beginning of the survival curve and less on the end, whereas the log-rank test places equal weight upon both. A multivariate analysis using the Cox proportional hazards model was performed (SAS v. 8.2, SAS Institute Inc., Carey, NC; S-PLUS v. 6, Insightful Corp., Seattle, WA) [8]. The interaction between treatment and menopausal status was tested as described previously [9]. Cumulative incidence functions totalling the overall event probability were estimated for the competing events and compared between the treatment arms [10, 11]. All P values were derived from a two-sided test for significance.
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Results |
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Discussion |
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The positive impact of TAM on DFS did not translate into a survival benefit. Different factors might have been responsible for this fact, such as small patient numbers and the low number of events. The analyses by menopausal status showed that the beneficial effect of TAM on DFS was confined to postmenopausal patients. This group is also most at risk for death events unrelated to breast cancer, and the positive impact of TAM on DSF might thus not have enough time to influence OS in this age group. Premenopausal patients did not benefit from TAM in terms of DFS. Rather unexpectedly, premenopausal women seemed to be at greater risk of death if treated with TAM compared with observation. These differences, however, were not statistically significant and the patient numbers in the respective subgroups were small. TAM-induced toxicity would be an explanation for this unexpected finding; however, there was no evidence for TAM-associated life-threatening complications or secondary cancers in our patients. Since most deaths occurred due to disease progression, we speculate that TAM might have a trophic effect in a subset of premenopausal breast cancers by elevating circulating estrogens [12].
Premenopausal women with ILRR fulfilling the inclusion criteria of this study had a very good prognosis. In the control arm of the study, the risk of death was only 10% at 3 and 5 years. This occurred despite the fact that 40% and 45% of the patients had already experienced a further relapse at the respective time points. This excellent survival outcome might reflect good treatment options for these patients or the fact that premenopausal control patients mainly experienced further local reappearance of the tumor and not distant metastases. Indeed, six patients suffered from another local relapse, two patients experienced both a local recurrence and distant metastases, and no patients developed distant metastases alone during the observation period of the study. These results are not in accordance with the general observation that young age is a poor prognostic factor in patients with breast cancer [1315]. Rather, they indicate that premenopausal women presenting with ILRR as first relapse site and fulfilling the good prognosis criteria defined in our study represent a favorable prognosis selection of breast cancer patients.
In general, ILRR patients with hormone-sensitive disease represent a favorable subgroup of women relapsing after mastectomy for breast cancer. Our results indicate that 40% of these patients experience long-term disease freedom after receiving local treatment and TAM. Even without systemic treatment, 30% of patients are free from further local and distant relapses. This observation is in accordance with recently published series on ILRR demonstrating long-term relapse-free survival figures in the range of 30%40% [1618]. This is in contrast to the commonly held notion that almost all patients with ILRR eventually develop distant metastases [1]. A possible explanation for this apparent discrepancy is the fact that we, as others, in reporting favorable outcomes [17, 18], were selecting for patients with good prognoses. The selection criteria of our study, such as ER positivity or a DFI of >12 months and small volume disease in case of unknown receptor status, were confirmed in other studies as important prognostic factors for the outcome of ILRR [1720].
The observation that most patients with ILRR develop distant metastases [1] has been taken as evidence that ILRR is rather a marker for metastatic disease than an isolated relapse site and thus should not be approached with a curative intent. However, in contrast to this nihilistic approach, recent data indicate that ILRR itself can serve as a source of distant metastases, which should be eradicated as soon and as radically as possible. Fortin et al. showed, in ILRR patients, that the rate of distant metastases peaked at 56 years compared with a peak incidence at 2 years for patients without local relapse [21]. This observation is conceivable considering the notion that the later incidence peak represents metastases originating from ILRR as their source. Thus, the early and complete eradication of ILRR seems to be an important goal in achieving maximum cure rates.
Nowadays most patients with ILRR fulfilling the good prognosis criteria of our study have already experienced prolonged adjuvant treatment with TAM for primary breast cancer. The results of studies comparing aromatase inhibitors with TAM or megestrol acetate in hormone-responsive metastatic breast cancer have clearly shown that aromatase inhibitors are still effective in TAM-pretreated patients [2225]. For ILRR patients fulfilling the poor-risk criteria defined in our study, the question of the value of combination chemotherapy is still of great relevance. The International Breast Cancer Study Group, in collaboration with the Breast International Group, has initiated a study comparing chemotherapy with local treatment alone in patients with locoregional recurrence of breast cancer (IBCSG Trial 27; http://www.ibcsg.org/pub_trials_open27-02.shtml).
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Appendix |
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Footnotes |
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References |
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