J Cancer Res Clin Oncol (1992) 118:542-546

Cancer esearch Clinical 9 ~na

9 Springer-Verlag 1992

Central nervous system metastases in breast cancer I. C. Kiricuta, O. Kiilbl, J. Willner, and W. Bohndorf Clinic and Policlinic for Radiotherapy of the University of Wiirzburg, Federal Republic of Germany Received 20 January 1991 / Accepted 9 March 1992

Summary. Sixty-two breast cancer patients with central nervous system (CNS) metastases were reviewed. The CNS was the first site of metastatic involvement in 38 cases (61%). The median survival from the primary diagnosis was 3.0 years; from the diagnosis of the CNS metastasis, 6 months. The interval between primary diagnosis and CNS metastasis had a median value of 2.0 years; between the initial extra-cranial metastasis and CNS metastasis this was 0.9 years. Prognostic factors for the appearance of CNS metastasis could not be identified. Subsequent to CNS metastasis appearing, the well-known prognostic factors for the survival time and the metastasis-free interval lose their importance. Brain metastases occur, above all, in patients aged between 50 and 55 years, very often in the first 2.5 years after the first distant metastasis and not later than 10 years from the primary diagnosis. Key words: Breast cancer - CNS metastases - Meningeal carcinomatosis - Prognostic factors

ease. Prognostic factors that influence the occurrence of CNS metastasis and survival have not been identified till now. To determine the natural history of breast cancer patients with brain metastases and to identify factors that influence their occurrence and survival, we reviewed our recent experience with the problem. CNS metastases have only been examined as a single morbid process in publications hitherto. The present study does not consider the CNS metastasis as an isolated event, but categorizes it in the dynamic process of the disease seen in toto. For a better overall view, the course of the disease is divided into five succeeding intervals: 1. Recurrence-free interval from the primary diagnosis 2. Metastasis-free interval 3. Interval between the primary diagnosis and CNS metastasis 4. Interval between the first metastasis and CNS metastasis 5. Survival time after the first CNS metastasis.

Materials and methods

Introduction The appearance of a metastasis in the central nervous system (CNS) means the survival probability of female patients is reduced substantially regardless of the status of extracranial metastases. While improved and more effective treatment methods cause the primary turnout to lose its limiting influence on the survival time, there is a comparable increase in the incidence of metastases in the CNS and thus in their importance and influence on the course of dis-

Offprint requests to: I. C. Kiricuta

The retrospective study covers 829 patients with the diagnosis of breast cancer who were treated in the Clinic and Policlinic for Radiotherapy of Wiirzburg University between 1979 und 1988. The radiotherapy was conducted either primarily or adjuvantly within the scope of initial therapy or in the course of the relapsed disease. The median follow-up period for these patients was 63 months. Not included in this assessment were 12 men (1.4%) with breast cancer as well as 22 female patients, who had developed further neoplasms. This study thus covers a total of 795 female patients with breast cancer; 62 patients developed a CNS metastasis. Defined as CNS metastasis are metastasis in the brain, spinal cord (but not perforation of a vertebral metastasis into the vertebral canal) and a meningeal carcinomatosis. The time of CNS metastasis was taken as that time when objective clinical or laboratory or diagnostic evidence was discovered. These results were evaluated at the Computer Centre of Wiirzburg University. Comparison of the various probabilities of survival was conducted according to the Cox method. Survival estimates for the various groups were calculated according to the Kaplan-Meier method.

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Results

Distribution of CNS metastases and combination with other metastases

Patient characteristics Of the 795 patients monitored in the period of observation, 287 developed metastases; 62 of these 287 patients, in turn, had metastases in the CNS. Table 1 shows the most important data of the patient's characteristics. At the time of CNS metastasis diagnosis the median age of these patients was 53.9 years. Of the 62 patients, 20 (32%) were in premenopause at the time of primary diagnosis, 14 (22%) had been in menopause for less than 5 years and 28 (45%) had been in postmenopause more than 5 years. Thirty-one patients had a T status greater than T1; 12 patients had a positive axillary status, i0 of these having more than three lymph nodes involved. Six patients presented as M1 and only 5 patients were in stage I, the remainder being in stage II (17), stage III (12) and stage IV (6).

In the case of 38/62 patients (61%) the CNS was the first site of metastatic involvement, in 15/62 (24%) it was the second site, in 5/62 (8%) the third and in 4 (6%) the fourth site of metastatic involvement (Fig. 1). In 17/62 patients (27%) the CNS metastasis was the one and only metastasis. The CNS metastasis occurred particularly frequently in conjunction with skeletal metastases (24%) or pulmonary metastases (17%). The anatomical distribution of CNS metastases is shown in Table 2 and Fig. 2. The most frequent metastases were in the cerebrum (58%) and meningosis carcinomatosa (21%); in two cases a rare localisation in the nervus opticus was also found. Percent

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Therapy of the CNS metastasis

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Four different treatment methods as well as their concomitant combinations are applied in the therapy of brain metastases, namely the operative method, radiation, chemotherapy and hormonal manipulations. In our sample, 51 patients received radiation therapy and 7 patients were operated on; 4 patients were not subjected to any therapy. The most frequently applied therapy was radiation alone (20 times), followed by radiation and chemotherapy combined (14 times); combined radiation / hormonotherapy or radiation / chemotherapy / hormonotherapy was carried out on 6 patients for each combination. The remaining possible combinations were of subordinate importance as far as the relevant values were concerned. The statistical analysis revealed no significant differences between the therapy forms mentioned.

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Fig. 1. The appearance of metastasis in the CNS as the first, second, third and forth metastatic site CNSwithoutspecifics11/17.1% Cerebrum36/58.0 % ngoslscare. 13/20.9%

Table 1. Patient's characteristics (62 patients) Age at diagnosis of brain metastasis (years) Median 53 Minimum 32 Maximum 80 Menopausal status (no. patients) PremenopausaI I-5 years postmenopause > 5 years postmenopause

20 (32.3%) 14 (22.6%) 28 (45.1%)

T status (no. patients) T1 T2 T3 T4 Not specified

13 (29.6%) 19 (43.2%) 10 (22.7%) 2 (4.5%) 18

N status (no. patients) Negative Positive 1-3 involved > 3 involved Not specified

t3 (28.8%) 32 (71.2%) 12 (26.6%) 10 (22.2%) 17

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Fig. 2. The anatomical distribution of CNS mestastases

544 Sur viral Rate 1E

Table 2. Distribution of the metastases in the CNS Location

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Fig. 4. Survival from the primary diagnosis of patients without metastases, with extracerebral or CNS metastases

T h e age d i s t r i b u t i o n a t the time o f p r i m a r y d i a g n o s i s o f the overall p a t i e n t s was c o m p a r e d to t h a t o f p a t i e n t s w i t h m e t a s t a t i c disease a n d o f p a t i e n t s with C N S metastases. F i g u r e 3 shows a p e a k at age 50-55 y e a r s in the g r o u p w i t h C N S metastases.

F i g u r e 4 shows the survival p r o b a b i l i t y o f the p a t i e n t s w i t h C N S m e t a s t a s e s c o m p a r e d to: (a) the n o r m a l p o p u lation, (b) p a t i e n t s w i t h o u t m e t a s t a t i c disease a n d (c) p a tients w i t h m e t a s t a s i s o t h e r t h a n in the C N S . P a t i e n t s w i t h o u t m e t a s t a t i c disease r e v e a l e d a m e d i a n survival t i m e o f 15 years, n o t differing f r o m the survival p r o b a b i l ity o f the n o r m a l p o p u l a t i o n . T h e m e d i a n survival time o f p a t i e n t s w h o d e v e l o p e d e x t r a - C N S m e t a s t a s e s is 5.5 y e a r s f r o m p r i m a r y diagnosis. F o r p a t i e n t s w h o develo p e d C N S m e t a s t a s e s the m e d i a n survival time was 3 y e a r s f r o m p r i m a r y diagnosis. T h e survival time o f all p a t i e n t s is influenced decisively b y the p r o g n o s t i c f a c t o r s listed in T a b l e 3. Once the m e t a s t a t i c disease was d i a g n o s e d , m a n y o f these factors lost their influence o n the f u r t h e r survival p r o s p e c t s o f the patients. T a b l e 3 p r o v i d e s i n f o r m a t i o n a b o u t the f a c t o r s t h a t c o n t i n u e d to exert influence after a m e t a s t a s i s was d i a g n o s e d . O n c e the C N S is i n v o l v e d b y m e t a s t a t i c disease, even these f a c t o r s lose their p r o g n o s t i c significance, so t h a t

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Fig. 3. Age distribution of patients with CNS metastases Table 3. Prognostic factors for the global

survival time, metastatic free interval for the survival time after metastatic involvement, for the interval between first and second metastasis and for the occurrence of CNS metastasis"

LN, lymph nodes. Statistical significance: - , P>0.08; + / - , P