1 Division of Hematology and Oncology, 2 Department of Radiation Oncology, and 4 Division of Biostatistics, Indiana University, Indianapolis, IN; 3 Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Received 18 July 2002; revised 20 January 2003; accepted 14 March 2003
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Abstract |
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As screening central nervous system (CNS) imaging is not routinely performed, the incidence and clinical relevance of occult CNS metastases in advanced breast cancer is unknown.
Patients and methods:
All patients screened for participation in one of four clinical trials were included; each of the trials excluded patients with known CNS involvement and required screening CNS imaging. A cohort of breast cancer patients with symptomatic CNS metastases was identified from the IU Cancer Center Tumor Registry for comparison.
Results:
From November 1998 to August 2001, 155 screening imaging studies were performed. Twenty-three patients (14.8%) had occult CNS metastases. HER-2 overexpression (P = 0.02) and number of metastatic sites (P = 0.03) were predictive of CNS involvement by multivariate analysis. Median survival from time of metastasis (1.78 versus 2.76 years; P <0.0001) and from screening (4.67 versus 10.4 months; P = 0.0013) was shorter in patients with than without occult CNS metastasis. Survival among patients with occult CNS metastasis was similar to patients with symptomatic CNS disease.
Conclusions:
Patients with CNS involvement, whether occult or symptomatic, have an impaired survival. Occult CNS metastasis is relatively common, but impact on survival of treating occult CNS disease in patients with progressive systemic metastases is questionable.
Key words: breast cancer, central nervous system, metastasis, natural history
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Introduction |
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Autopsy series, generally completed before the advent of effective systemic therapies, report a much higher incidence of CNS metastasis (Table 1). As routine CNS imaging is not recommended for asymptomatic patients and autopsy rates have declined dramatically [4], the incidence of clinically occult CNS disease in patients with metastatic breast cancer receiving modern systemic therapy is unknown. Similarly, the clinical relevance of occult CNS metastasis, survival after identification of occult CNS disease and the importance of CNS therapy are unknown.
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Patients and methods |
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Results |
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Discussion |
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Amer first suggested that systemic therapy may alter the natural history of breast cancer, leading to an increase in CNS metastasis [7]. Although adjuvant therapy increased overall survival, patients who relapsed after adjuvant therapy had a higher incidence of CNS metastasis in one series [9]. More recently, Carey et al. reported an excellent disease-free survival but disproportionate CNS relapse after aggressive neoadjuvant therapy [10]. An increase in CNS relapse after initial chemotherapy for metastatic disease has also been suggested. Thirty per cent of patients treated with epirubicin and docetaxel combination therapy subsequently developed symptomatic CNS metastasis [11]. A similar frequency of CNS metastasis was found after initial response to paclitaxel; 12% of patients had isolated CNS relapse with continued control of systemic disease [12].
Two explanations have been offered for the apparent increase in CNS metastasis after chemotherapy: first, the effectiveness of the bloodbrain barrier and secondly, prolonged survival of patients after initial recurrence allows microscopic CNS metastasis to become clinically evident. Our data cannot fully address this question as most patients in our study were heavily pretreated before CNS imaging. Muss et al. used early CT technology to image 116 patients with disseminated breast cancer. CNS lesions were found in 11 of 37 (30%) patients with CNS symptoms but only 1 of 79 (2%) patients without CNS symptoms [13]. The increased prevalence of occult CNS metastasis in our patients likely represents both improvement in imaging technology and patient selection; the impact of differential exposure to systemic therapy is not clear. However, the consistency between the frequency of occult CNS metastasis in our patients and historical autopsy series suggests the impact of chemotherapy may be modest rather than large.
We were able to identify several factors associated with an increased risk of occult CNS metastasis. Performance status and number of extracranial sites of disease likely reflect bulk of systemic disease rather than tumor biology. The association of HER-2 overexpression and CNS metastasis deserves further investigation. Crivellari et al. retrospectively measured HER-2 expression in patients developing symptomatic CNS disease after initial chemotherapy [11]. Although overexpression (3+ by immunohistochemistry) was found in 10 of 16 (62%) patients, HER-2 was not assessed in patients without CNS metastasis, thereby limiting conclusions. An increase in CNS involvement has also been reported in patients receiving trastuzumab [14]. Prior autopsy studies found an inverse correlation between patient age and CNS metastasis [6, 15, 16]. Age was not predictive of occult CNS disease in our analysis, likely due to the young age of patients attracted to early-phase clinical trials. Although other authors have debated the relative sensitivity of contrasted CT and brain MRI for detection of CNS metastasis [17, 18], both appeared equally effective as screening modalities in our patients.
Initial disease-free interval was similar for patients with and without CNS involvement but patients with CNS metastasis had an impaired survival. Somewhat surprisingly, the survival of patients with occult CNS disease was identical to that of patients with symptomatic CNS lesions, whether measured from initial diagnosis, first recurrence or diagnosis of CNS metastasis. The median survival after diagnosis of occult CNS metastasis in our patients is similar to that reported for patients with symptomatic lesions in other series as well [1, 10]. These results imply a unique and aggressive biology of tumors trophic for the CNS with symptoms dependent on the anatomic location of the lesions. Given the disparity in survival, stratification for CNS involvement in phase III trials is warranted if patients with CNS metastasis are enrolled.
The impact of identifying and immediately treating occult CNS metastasis in our patients was questionable at best. End-of-life details are known for 21 of 23 patients with occult CNS lesions; all died of systemic disease progression without intervening CNS symptoms. Occult CNS metastasis appeared to be a marker for, rather than a cause of, limited survival. We cannot exclude the possibility that some patients were spared development of CNS symptoms as nearly all received whole-brain radiation therapy after diagnosis of occult CNS disease. Although some authors have raised the question of prophylactic CNS radiation in high-risk patients as a strategy to improve survival [11], we cannot recommend either routine CNS screening or prophylactic therapy in patients with uncontrolled systemic disease. However, our results cannot be generalized to patients with less advanced disease. Might patients with HER-2-positive breast cancer with prolonged disease control with trastuzumab benefit from CNS screening? This increasingly important clinical question remains unanswered and deserves further study.
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Acknowledgements |
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Footnotes |
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References |
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