Evaluation of Prognostic Factors and Treatment Modalities in Ovarian Cancer Patients with Brain Metastases

Gynecologic Oncology 85, 487– 492 (2002) doi:10.1006/gyno.2002.6653

Evaluation of Prognostic Factors and Treatment Modalities in Ovarian Cancer Patients with Brain Metastases Noel Anupol,* Sharad Ghamande,† Kunle Odunsi,* Deborah Driscoll,* and Shashikant Lele* ,1 *Division of Gynecologic Oncology, Department of Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263; and †Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912 Received November 28, 2001; published online April 24, 2002

Objective. The objective of this study is to evaluate the impact of different clinical variables and treatment modalities on survival in patients with brain metastases from ovarian carcinoma. Methods. Methods included: (1) retrospective chart review of all patients with ovarian cancer and brain metastases from 1986 to 2000 at Roswell Park Cancer Institute and (2) Medline search was performed to extract data from all published reports with three or more cases of ovarian cancer with brain metastases. Cox regression analysis, Kaplan–Meier test, and log rank test were used to calculate survival and compare the impacts of clinical variables and treatment modalities. Results. Fifteen patients with brain metastases out of 1042 women with ovarian carcinoma were identified from our institution, an incidence of 1.4%. The median time from initial diagnosis to detection of brain metastases was 22 months. Patients who were not treated after brain metastasis had a median survival of 0.5 month versus 6 months with therapy. In the subgroup of patients treated with a combination of radiation, surgery, and chemotherapy, the median survival was 22 months. Literature analysis combined with our data generated 124 patients. The only clinically significant variable impacting survival was the presence or absence of additional distant recurrence with median survivals of 3 and 8 months, respectively (P ⴝ 0.005). Among patients who received treatment, the combination of radiation and surgery with or without chemotherapy appears to be beneficial, with a median survival of 20 months (P < 0.001). Conclusion. Patients with brain metastases from ovarian cancer without any evidence of disease in other sites appear to benefit from aggressive combined treatment with external radiation and surgery with or without chemotherapy with a median survival of 20 months. © 2002 Elsevier Science (USA) Key Words: ovarian carcinoma; brain metastases; brain recurrence; treatment of brain metastases; multimodality treatment.

INTRODUCTION Ovarian cancer is the fifth most common cancer in women and is responsible for 25–26% of all female genital tract cancers in the United States, with 23,400 estimated new cases 1

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annually. It is the leading cause of female genital tract cancerrelated deaths, approximately 13,900 in 2001 [1]. Brain metastases from ovarian carcinoma have traditionally been considered a relatively uncommon site of recurrence. Epithelial carcinoma of the ovary spreads primarily by direct extension, implantation of tumor cells on peritoneal surfaces, by lymphatic spread, and rarely by hematogenous spread [2, 3]. Autopsies of patients with ovarian carcinoma in a collected series of 576 women revealed brain involvement in about 0.9% [4]. Recent reports have shown an apparent increase in the incidence of brain metastases in patients with epithelial ovarian cancer with a range of 2–12% [5–12]. Survival after the diagnosis of brain metastases in patients with ovarian cancer is poor [6 –18]. Without treatment the median survival rate is about 1 month [6, 19]. Previous reports indicate that radiation treatment alone increases survival, with a median survival of 2.5– 4.5 months, and the combination of radiation and chemotherapy increases survival to 10 months [6, 10]. Multimodal treatment including surgery, radiation, and chemotherapy on solitary brain metastasis leads to a median survival of more than 20 months [6]. In an attempt to identify the epidemiological factors, which may predict risk of brain metastasis and evaluate different treatment modalities, we retrospectively reviewed our own institutional experience. Data acquired from our patients were then combined with information extracted from recent published articles that reported three or more cases of patients with brain metastases from ovarian cancer. MATERIALS AND METHODS An institutional review board-approved retrospective chart review of all patients diagnosed with brain metastasis from ovarian carcinoma at Roswell Park Cancer Institute (RPCI) from 1986 to 2000 was performed. Of 1042 patients with ovarian carcinoma 15 who developed brain metastases were identified. Patients were analyzed for age at diagnosis, stage, grade, type of chemotherapy, site of recurrence, CA125 level at the time of brain recurrence, time interval to relapse, and site and number of brain metastases. Different therapeutic modal0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.

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TABLE 1 Summary of Brain Metastases’ Symptoms, Diagnosis, Treatment, and Survival: Roswell Park Cancer Institute Data (n ⴝ 15)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 a

Initial diagnosis to brain metastases (months)

Symptoms

39 18 6 8 35 22 14 0 18 33 36 45 53 41 13

Decreased mental status Headache Left-sided weakness Incoherence Decreased mental status Visual disturbance Memory loss Right-sided weakness Headache Forgetfulness Headache Left-sided facial weakness Foot drop Decreased mental status Decreased mental status, seizure

CA-125

Brain lesions

Other metastases

1765 51 4 125 99 25 571 1396 22 377 33 6.1 76 45 42

M S M S S M S M S S M None M S M

Yes No Yes No No Yes No No No No Yes Yes Yes No Yes

Treatment None RT, CH, RT, CH, RT, CH, RT, CH RT, CH None RT, CH RT, S RT, CH, RT, CH, RT RT, CH RT RT

S S S

S S

Survival from brain metastases (months)

Survival from initial diagnosis (months)

Status

0 20 3 22 2 24 1 11 5 49 9 6 3 15 1

39 38 9 30 37 46 15 11 23 82 45 51 56 56 14

DOD a DOD DOD DOD DOD AWD DOD DOD DOD DOD DOD AWD AWD DOD DOD

S, single; M, multiple; RT, radiotherapy; CH, chemotherapy; S, surgery; DOD, died of disease; AWD, alive with disease.

ities were compared to evaluate their benefit on survival. Medline search of the English literature was done to extract information from all published reports with three or more cases of brain recurrence from ovarian cancer. Examination of data in conjunction with our series of patients with brain metastasis from ovarian carcinoma was performed. The Cox regression analysis and the Kaplan–Meier method were used to calculate survival distributions. The log rank test was used to compare the survival curves. RESULTS Fifteen patients with brain lesions were identified out of 1042 patients with ovarian carcinoma at RPCI from 1986 to 2000, an incidence of 1.4%. The mean age at initial diagnosis was 58 years (range, 39 –74 years). Seven patients (47%) presented with FIGO stage IIIC disease and 8 patients (53%) presented with FIGO stage IV disease. Twelve patients had poorly differentiated (G3) primary tumors, one patient had moderately differentiated (G2), and two patients had no documented grading. Fourteen of the patients had serous histology and one had mixed mullerian mesodermal tumor. Ten patients (67%) had adequate primary cytoreduction (⬍1 cm) at initial diagnosis, 2 patients had ⬎1 cm residual tumor, and 3 patients had no documentation of the extent of cytoreduction. All patients were treated with cisplatin-based chemotherapy. Additionally, taxol was used in 10 patients. Eleven of fifteen patients had complete clinical response. Ten of those eleven patients had second-look surgery; six were negative. One patient with partial response underwent a secondary cytoreductive surgery. The median time from the initial diagnosis of ovarian car-

cinoma to occurrence of brain metastasis was 22 months (Table 1). The most common presenting symptom was decreased mental status (46%) followed by neurological motor deficit (26%), headache (20%), visual disturbance (6%), and seizure (6%). Diagnosis was made by CT scan (6 patients), MRI (4 patients), CT with MRI (4 patients), and spinal tap (1 patient). The patient who had a spinal tap presented with left facial weakness and visual disturbance. MRI showed no lesions, but the spinal fluid was positive for metastatic cells consistent with the primary ovarian cancer. Seven patients had solitary brain lesions and seven had multiple lesions. Size of the brain metastases ranged from 0.5 to 6 cm. The majority (n ⫽ 10) of the patients had an elevated CA125 with a median of 51 and range of 4 to 1765. Survival analysis did not show any favorable advantage based on CA125 level at the time of diagnosis of brain metastases. Interestingly, 7 of 8 (87%) patients with isolated brain metastases had elevated CA125 compared with only 3 of 7 (42%) patients with additional distant metastases. Two patients elected not to receive treatment for brain metastases due to advanced disease. Thirteen patients had external radiation therapy with 30 – 45 Gy to the whole brain in multiple fractions. Five of the patients underwent craniotomy and resection of brain lesions prior to radiation and one patient had stereotactic radiosurgery with an additional 22.25 Gy radiation after an initial 30 Gy whole-brain therapy. The histopathologic findings of those brain tumors from patients who underwent surgical resection were consistent with its corresponding primary ovarian cancer. One patient (patient 10) had a second brain recurrence and had treatment with gamma knife surgery (GKS) and chemotherapy 22 months after the initial brain metastasis treatment. She survived another 27 months.

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TABLE 2 Incidence and Survival of Patients with Brain Metastases from Ovarian Carcinoma

Authors Corn et al. [21] Geisler and Geisler [10] Anupol et al. (this study) Rodriguez et al. [6] LeRoux et al. [13] Larson et al. [14] Bruzzone et al. [9] Ross et al. [7] Hardy [12] Mayer et al. [4] Plaxe [15] Dauplat et al. [8] Stein et al. [11] Ziegler et al. [16] Cooper et al. [17] Deutsch et al. [18]

Median survival Mean from diagnosis of No. of Incidence age at brain metastasis patients (%) diagnosis (months) 32 16 15 15 14 13 9 7 6 6 6 5 5 5 3 3

0.79 3.3 1.4 1.9 1.1 0.29 3.1 1.9 11.6 0.9 1.96 4.5

57 58 55 54 55 59 59 52 47 58 44 52 65 56 52

4 3 6 9 3 4 8 3.5 3.0 5.0 8.0 1 2.0 — 16 5

Systemic chemotherapy was given to 9 patients including those who had craniotomy. The various chemotherapeutic agents used included carboplatin, topotecan, doxil, taxol, gemcitabine, and navelbine. Seven patients had additional distant metastases on or before the diagnosis of brain recurrence. Eight patients had no other distant disease spread aside from the brain. The overall median survival rate from the time of initial diagnosis of ovarian cancer was 38 months (range, 9 – 82 months). From the time of brain metastasis, the median survival was 6 months (range, 0.5– 49 months). All patients who received treatment had survival advantage compared with patients who did not receive any form of therapy, 9 months versus 0.5 month, respectively (P ⫽ 0.0007). The combination of radiotherapy, chemotherapy, and surgery led to a better median survival (22 months) than any other form of therapy or any combination (5 months). Statistical analysis was not performed in this group secondary to the small number of patient (n ⫽ 3) in the radiation, chemotherapy, and surgery group. The Medline search revealed that the reported incidence of brain metastases from ovarian cancer ranges from 0.29 to 11.6% (Table 2). Information from our patients was combined with the data extracted from other clinical series of patients with brain metastasis from ovarian malignancy. A total of 128 patients were identified, but only 124 patients were included in the analysis secondary to incomplete details (Table 3). The median age of patients from the combined series was 56.0 years (range, 13–79). Survival based on age of patients who subsequently develop brain metastasis showed no statistical difference between groups (⬍50, 50 – 60, ⬎60) with a P value of 0.78. Stage of disease at initial diagnosis of ovarian carcinoma showed no statistical difference in survival after diagno-

sis of brain metastases. The majority of patients have histologic grades of 3 (n ⫽ 62) and 2 (n ⫽ 34). Again, there was no improved survival with lower-grade lesions. There were 55 patients in the combined series that had second-look procedures; 38 patients had no evidence (median survival of 8 months) of disease and 27 patients had positive findings (median survival of 5 months). Although, there is a 3-month difference in median survival, the finding was not statistically significant (P ⫽ 0.19). The presence of distant metastases aside from the brain had adverse effects on survival (Fig. 1). Seventy-four patients with no other distant disease involvement had a median survival of 8 months as compared with patients with other distant spread (n ⫽ 50) who had a median survival of 3 months (P ⫽ 0.005). Patients with solitary brain recurrence had a slight advantage over those patients with multiple brain lesions, with median survivals of 7 and 5 months, respectively. However, that finding is not statistically significant (0.07). Survival analyses based on therapeutic information were performed. In the combined group, patients with brain metastasis who received treatment (median survival, 8 months) had a more favorable prognosis than patients who received no therapy (median survival, 2 months) with a P value of ⬍ 0.001. Any combination therapy except chemotherapy and surgery (n ⫽ 1) was advantageous for survival (P ⫽ 0.0001). Among patients receiving combination therapy, raTABLE 3 Survival from Diagnosis of Brain Metastasis Based on Clinical Factors

Age ⬍50 50–60 ⬎60 Stage I II III IV Grade 1 2 3 Second look Negative Positive Other metastases No Yes Number of brain lesions Single Multiple Therapy No Yes

No. of patients

Median survival (months)

Log rank

32 53 39

7 7 4

0.78

10 14 70 30

4 5 6.5 3

0.37

3 34 62

22 5 6

0.23

38 27

8 5

0.19

74 50

8 3

0.005

44 50

7 5

0.07

22 102

2 8

0.001

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TABLE 4 Survival Based on Treatment after Diagnosis of Brain Metastases

FIG. 1. Survival of all patients by other metastases. Yes: patients with other distant metastases aside from the brain lesion. None: patients with brain metastases only.

diation and surgery with chemotherapy appears to be better (P ⬍ 0.001), with a median survival of 22 months (Fig. 2). Radiotherapy with surgery has a median survival of 16 months. When patients who had radiation and surgery with or without chemotherapy were analyzed as a group, a median survival of 20 months (P ⬍ 0.001) was noted. Radiation with chemotherapy showed a median survival of 9 months. Radiotherapy alone had a median survival of 3 months (Table 4). DISCUSSION Ovarian carcinoma remains a leading cause of death from gynecologic malignancy, with 13,900 estimated deaths in 2001 [1]. Cerebral metastases in patients with ovarian cancer are infrequently observed but some recent reports suggest an increasing incidence [6, 9, 11, 12]. Effective chemotherapy for ovarian carcinoma has prolonged survival, allowing metastases

FIG. 2. Survival for all patients by type of treatment. R ⫹ C ⫹ S: radiation therapy with chemotherapy and surgery. C ⫹ S: chemotherapy and surgery. R ⫹ S: radiation and surgery. R ⫹ C: radiation and chemotherapy.

No therapy R C S C⫹S R⫹C R⫹S R⫹S⫹C R⫹S⫾C a

No. of patients

No. of failures

Median survival (months)

22 41 3 2 1 24 21 10 31

22 38 3 2 1 21 19 7 26

2 3 16f, 16f, 30f 0.8f, 33f 11f 9 16 22 20

R, radiotherapy; C, chemotherapy; S, surgery; f, fail; ⫾, with or without.

in distant sites to implant, grow, and become clinically evident disease [2, 8, 10, 13, 14, 18]. The incidence of brain recurrence in our series is 1.4%, and this is comparable to the majority of other reported studies. It is not clear why only a small number of women with ovarian cancer developed brain metastases. It has been suggested that the presence of the blood– brain barrier makes the brain a pharmacological safe haven from chemotherapeutic agents like cisplatin and taxol that cannot cross or have impaired penetration to effectively treat the tumor [10, 13, 14, 20]. Another possible explanation is that the treatment of ovarian cancer with aggressive surgical resection and cytoreduction followed by platinum-based chemotherapy afforded better tumor control. This translates to longer patient survival, hence longer time for the brain lesion to become apparent [4,6,7,16,18,21]. Also, the introduction of better diagnostic tools like CT scan and MRI allows improved imaging and diagnosis. Presently no known biological marker is able to detect brain metastases from ovarian carcinoma. Clinically, CA125 is being used to monitor response to treatment and possibly detect recurrence. Interestingly, 7 of 8 (87%) patients with isolated brain metastases and 3 of 7 (42%) patients with additional distant metastases had elevated CA125. Cooper et al. [22] suggested that metastatic brain lesions from ovarian carcinoma do not always produce CA125 increase or the blood– brain barrier is relatively impervious to the large CA125 molecule in the early stages of metastases. Elevation of CA125 may also relate to undetected local or other distant metastases. In patients with elevated CA125 without any evidence of local or other distant recurrence and those who have any change in neurologic function even without elevation of CA125, evaluation of the central nervous system should be strongly considered. In the study of Bindal et al. [23], 26 patients with multiple brain metastases who underwent resection of all brain lesions were compared with a matched group of 26 patients with solitary lesions that were completely resected. They found that

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the rate of survival was not statistically different. This result is similar to the finding of Geisler and Geisler [10] who compared survival for patients with single brain lesion versus multiple brain lesions from ovarian carcinoma. Similarly, in our study, patients with solitary brain recurrences had no statistically significant survival advantage over patients with multiple brain lesions with a P value of 0.07. Aggressive management of those patients with solitary as well as those with multiple brain lesions can be instituted with a reasonably comparable outcome. In addition, there are no specific clinical and epidemiologic risk factors that affect survival after diagnosis of brain metastases, with the exception of the presence or absence of metastases to other distant sites. The median survival of patients with coexisting metastases to other organs was 3 months compared with that for patients with brain metastasis only, which was 8 months. In the past the survival rate of patients with metastatic brain recurrence from ovarian cancer has been poor, hence some authors have suggested consideration of palliative steroid therapy [8] and radiation therapy [21]. Other authors support a multimodal approach using radiation, surgery, and chemotherapy [6]. Analysis of the combined data showed increase survival with any form of treatment. Combination therapy with radiation and surgery with or without chemotherapy appears to have a significant survival advantage. Addition of chemotherapy to a combination of radiation and surgery is statistically the best combination and may especially benefit those patients who can tolerate further chemotherapy. Although the outcome of our analysis is consistent with those of other authors who suggest combination therapy [6, 10, 14] it should be viewed with caution because of the inherent shortcomings of pooled analyses, as retrospective meta-analysis is subject to selection bias [24, 25]. The patients’ general health and neurological status were not known prior to treatment of brain metastases. Moreover, morbidity and quality of life issues with different treatment methods were not examined. Nonetheless, our findings that patients treated with radiation and surgery with chemotherapy showed a median survival of 22 months suggests that this form of therapy for brain metastasis from ovarian cancer can improve survival, especially for those patients with no other distant disease. Combination therapy and use of gamma knife radiosurgery on patients with surgically inaccessible brain metastases have been reported [26]. One of our patients had gamma knife surgery (GKS) and gemcitabine for a second brain recurrence after 22 months of initial combination treatment with radiation, surgery, and chemotherapy. She survived another 27 months. It is unclear as to whether gamma knife surgery had a major impact on this patient’s survival. A retrospective study to compare the effectiveness of GKS for multiple cerebral metastases from non-small cell lung cancer with that of whole-brain radiation therapy (WBRT) was done by Serizawa et al. [27]. They compared GKS with traditional WBRT with surgery and showed that neurological sur-

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