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© 2002 American Society for Clinical Oncology Epithelial Ovarian Cancer Metastasizing to the Brain: A Late Manifestation of the Disease With an Increasing IncidenceByFrom the Gynaecology Unit, Royal Marsden Hospital, London, United Kingdom. Address reprint requests to Martin E. Gore, PhD, The Royal Marsden Hospital, 203 Fulham Rd, London, SW3 6JJ, United Kingdom; email: Martin.Gore{at}rmh.nthames.nhs.uk
PURPOSE: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site. PATIENTS AND METHODS: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases. RESULTS: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P < .001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P < .001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time. CONCLUSION: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing.
EPITHELIAL OVARIAN carcinoma (EOC) is the fifth most common cancer in women in the industrialized nations; more than 26,000 women are diagnosed annually in the United States.1 The majority of women present with advanced (stage III to IV) disease, and despite debulking surgery and platinum-based chemotherapy, only 20% to 30% of women will be alive at 5 years.2 EOC is a disease that remains locoregionally confined until late in its natural history, and hematogenous metastases are rare at presentation (16%), with the most common sites of metastatic spread being the pleural cavity (33%), liver (26%), and lung (3%).3 CNS metastasis from EOC is rare. Mayer et al,4 in a postmortem study, identified five such patients out of 567 (0.9%) women with EOC. Subsequently a number of other case series have reported an incidence of clinically apparent cerebral metastases in EOC patients of 0.9% to 3.3% in patient populations numbering from 430 to 795.5-8 Some of these reports have suggested that there has been an increase in the incidence of cerebral metastasis from EOC, but this assertion has never been supported by a longitudinal analysis of the data. We present here the Royal Marsden Hospital experience of cerebral metastases from primary EOC over the last 20 years and examine the evidence for an increasing incidence of metastases at this site.
Patients All patients presenting to Gynaecological Cancer Unit, The Royal Marsden Hospital, London, United Kingdom, had their clinical characteristics, surgical details, and pathologic diagnosis entered into a prospective computerized database. The database records patients’ stage at surgery according to the International Federation of Gynecology and Obstetrics classification; the sites of disease; the dates and dosage of any therapy, such as chemotherapy or radiotherapy, given; tumor responses as assessed clinically or radiologically according to World Health Organization criteria; and follow-up information, such as the dates of relapses and death. Surgical interventions are also documented, as are details of any history of cancer or a family history of malignancy. Treatments given to the patients before referral are also entered into the database.
Patient Identification
Data Collected
Patient Characteristics From January 1980 to June 2000, 3,690 women were registered in the Royal Marsden Hospital Gynaecology Unit database as having histologically confirmed EOC; 18 (0.49%) of these women developed CNS metastases (Table 1). The median age of our patients with cerebral metastasis at diagnosis of their ovarian cancer was 52 years (range, 39 to 67 years). The median age at the time of CNS relapse was 57 years (range, 43 to 71 years). Clinical staging at initial diagnosis was as follows: stage I, six (33%) of 18; stage II, three (17%) of 18; stage III, seven (39%) of 18; and stage IV, two (11%) of 18. Six patients (33%) had complete surgery, ie, TAH, BSO, and omentectomy. Twelve patients (67%) underwent TAH and BSO only (six stage I, two stage II, three stage III, and one stage IV). Suboptimal cytoreductive surgery was performed in six patients (33%) with advanced disease. The histologic subtype of the tumors was as follows: 72% (13 of 18) serous, 5.5% (one of 18) mucinous, 5.5% (one of 18) endometrioid, and 17% (three of 18) other types. No patient had a well-differentiated tumor; all tumors were of either moderately (44%) or poorly differentiated (56%) histologic grade. Two patients had histologic confirmation that their cerebral metastases were of ovarian origin: one at surgery and the other at postmortem.
Presentation of CNS Relapse Presenting symptoms of CNS recurrence varied according to the site of disease (not recorded in one patient). The most common symptoms associated with CNS metastases were motor weakness (six patients), confusion (six patients), headaches (five patients), and seizures (three patients). Symptoms of aggression, vomiting, speech disturbance, and visual disturbance also occurred. All CNS recurrences were diagnosed by CT scan (Fig 1). Nine patients had a solitary deposit, and the rest had multiple metastases. The CNS was the only site of disease in eight patients, whereas the other 10 patients had additional sites of involvement. All 10 had parenchymal lung or liver metastases, nine patients also had peritoneal disease in the abdomen or pelvis, and six patients had intra-abdominal lymphadenopathy.
Timing of CNS Relapse The median time from diagnosis of ovarian cancer to the first site of relapse was 25.5 months (range, 10 to 58 months), and the median time from diagnosis to documentation of CNS metastasis was 46 months (range, 12 to 113 months; Table 2). The median time to relapse for patients in the gynecology database with liver (n = 416) or lung (n = 811) metastases was 5 and 7.5 months, respectively (P < .001 v median time to CNS relapse; Fig 2). The median interval from the chemotherapy treatment immediately preceding a diagnosis of CNS relapse to the diagnosis of CNS metastasis was 9 months (range, 14 days to 42 months). This interval was  3 months in four patients (22%) and  12 months in eight patients (44%). Early-stage disease did not affect time to CNS relapse, with a median of 48 months for stage I compared with 44 months for stage II to IV patients.
All patients received at least one line of platinum-based chemotherapy. Eight (44%) of 18 patients received only one line of chemotherapy, three (17%) of 18 received two lines of chemotherapy, two (11%) of 18 received three lines of chemotherapy, and five (28%) of 18 received four lines of chemotherapy (Table 2). One patient developed CNS metastases while receiving first-line treatment, and three patients developed them within a month of completing fourth-line chemotherapy. The median (range) treatment-free intervals between each line of chemotherapy were 12 (2 to 42), 18 (5 to 31), and 4 (1 to 8) months, respectively. The response rates to chemotherapy were as follows: first line, 13 (72%) of 18 (three patients were nonassessable); second line, eight (80%) of 10; third line, three (43%) of seven; and fourth line, two (40%) of five.
Survival
Changing Incidence of CNS Relapse
In common with other reports, we have shown that CNS metastases are rare in patients with EOC; only 18 (0.49%) of 3,690 of our patients with EOC developed clinically apparent disease at this site. A limitation of this study is that histologic confirmation that brain metastases were of ovarian origin occurred in only two cases, raising the possibility that some of the lesions were either primary brain tumors or metastases from other occult primary tumors, eg, breast or lung carcinoma. This is a clear limitation of any study such as this. This lack of histologic confirmation may be because there are often contraindications to brain biopsy in this clinical situation, and subsequent management is rarely significantly altered. Our finding that most patients with EOC and brain metastases have either poorly or moderately differentiated tumors is consistent with the experience of others.9,10 However, six (33%) of our patients originally had stage I disease, and this is rather unusual, because most studies have noted that EOC patients with CNS disease have had stage III or IV tumors at presentation.9,10 We did not find that these six patients had a statistically significant different time to CNS relapse when compared with advanced-stage patients who developed CNS secondary tumors (stage I, median 48 months; stage III to IV, median 44 months), and they had comparable survival, both overall and from the time of CNS recurrence. In this article we have shown that the median time from diagnosis of ovarian cancer to documentation of CNS relapse is 46 months. This is a late time to relapse, particularly when compared with the time taken for hematogenous spread to other sites, such as liver and lung, where median time to relapse was approximately 6 months. This difference was highly statistically significant (P < .001). We have also demonstrated that nearly 40% of our patients received three or more lines of chemotherapy and that in a similar proportion of patients the treatment-free interval from the last treatment before CNS relapse was more than 12 months. Furthermore, nearly half of our patients (eight [44%] of 18) had the CNS as the only site of recurrent disease. These observations suggest that the CNS may be a sanctuary site from chemotherapy in EOC. This is analogous to the situation in the 1960s and 1970s with acute lymphocytic leukemia and, to some extent, Hodgkin’s disease, in which CNS disease became a problem as more effective systemic treatments were developed and complete remissions were obtained.11-13 The small but significant increase in the incidence of CNS metastases from EOC over the last 20 years is shown in our analysis of the literature and confirmed from our own data, which indicate a 10-fold increase in the last 5 years (P < .001). It should be noted that the absolute incidence of brain metastases in our series from 1980 to 1989 (two [0.1%] of 1,878 patients) is lower than that reported in the literature over roughly the same period. This difference is not easy to explain and may simply reflect the nature of our study, ie, database derived, in contrast to the published literature, in which there may be reporting bias. In summary, we describe a large cohort of patients seen over 20 years with EOC, in whom 0.49% had CNS metastases. We have demonstrated that CNS metastases in EOC are a rare and late manifestation of the disease, which occurs in patients with a prolonged survival caused by repeated chemosensitive relapses. Our data suggest that CNS disease is occult in patients with EOC and that the brain may be a sanctuary site from systemic treatment. The incidence of metastasis at this site is still low, but as more effective systemic therapies are developed we can expect the incidence to increase, possibly to levels that may become clinically significant.
1. Li AJ, Karlan BY: Genetic factors in ovarian carcinoma. Curr Oncol Rep 3: 27-32, 2001[Medline] 2. McGuire WP, Ozols RF: Chemotherapy of advanced ovarian cancer. Semin Oncol 25: 340-348, 1998[Medline]
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Bonnefoi H, A’Hern RP, Fisher C, et al: Natural history of stage IV epithelial ovarian cancer. J Clin Oncol 17: 767-775, 1999 4. Mayer RJ, Berkowitz RS, Griffiths CT: Central nervous system involvement by ovarian carcinoma: A complication of prolonged survival with metastatic disease. Cancer 41: 776-783, 1978[CrossRef][Medline] 5. Barker GH, Orledge J, Wiltshaw E: Involvement of the central nervous system in patients with ovarian carcinoma. Br J Cancer 88: 690-694, 1981
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Rodriguez GC, Soper JT, Berchuck A, et al: Improved palliation of cerebral metastases in epithelial ovarian cancer using a combined modality approach including radiation therapy, chemotherapy, and surgery. J Clin Oncol 10: 1553-1560, 1992 7. Geisler JP, Geisler HE: Brain metastases in epithelial ovarian carcinoma. Gynecol Oncol 57: 246-249, 1995[CrossRef][Medline] 8. Kaminsky-Forrett MC, Weber B, Conroy T, et al: Brain metastases from epithelial ovarian carcinoma. Int J Gynecol Cancer 10: 366-371, 2000[CrossRef][Medline]
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Cormio G, Maneo A, Parma G, et al: Central nervous system metastases in patients with ovarian carcinoma. Ann Oncol 6: 571-574, 1995 10. Bruzzone M, Campora E, Chiara S, et al: Cerebral metastases secondary to ovarian cancer: Still an unusual event. Gynecol Oncol 49: 37-40, 1993[CrossRef][Medline] 11. Bunn PA, Schein PS, Banks PM, et al: Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma: Leukaemia revisited. Blood 42: 3-10, 1976 12. Cuttner J, Meyer R, Huang YP: Intracerebral involvement in Hodgkin’s disease. Cancer 43: 1497-1506, 1979[CrossRef][Medline] 13. Ashigbi MY, Venkatraj U, Agarwal V, et al: Intracranial Hodgkin’s disease in two patients with familial Hodgkin’s disease. Med Pediatr Oncol 29: 255-258, 1997 Submitted July 9, 2001; accepted October 18, 2001.
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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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ABSTRACT
INTRODUCTION
