Key words: brain metastasis, gynecological cancer, ovarian cancer, prognosis, treatment-free interval

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1 JJCO Japanese Journal of Clinical Oncology Japanese Journal of Clinical Oncology, 2017, 47(7) doi: /jjco/hyx047 Advance Access Publication Date: 7 April 2017 Original Article Original Article Prognostic factors for patients with brain metastasis from gynecological cancer: a significance of treatment-free interval of more than 6 months Sho Takeshita 1, Yukiharu Todo 1, *, Yu Furuta 1, Kazuhira Okamoto 1, Shinichiro Minobe 1, Katsushige Yamashiro 2, and Hidenori Kato 1 1 Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, and 2 Division of Pathology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Japan *For reprints and all correspondence: Yukiharu Todo, Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, 4-2, Kikusui, Shiroishi-Ku, Sapporo , Japan. yukiharu@sap-cc.go.jp Received 19 December 2016; Editorial Decision 17 March 2017; Accepted 21 March 2017 Abstract Objective: Treatment-free interval has been confirmed as a significant prognostic factor in recurrent gynecological cancers. However, treatment-free interval has not been evaluated in previous studies investigating brain metastasis from gynecological malignancies. The aim of the study was to establish a predictive model of survival period after brain metastasis from gynecological cancer. Methods: Of a total of 2848 patients with gynecological cancer, patients with brain metastasis were included in the study. Data at the time of brain metastasis diagnosis, which included primary origin, presence of extracranial metastasis, the Eastern Cooperative Oncology Group (ECOG) performance status, the number of brain metastases, brain-metastasis free-interval, treatment-free interval and treatment for brain metastasis were collected. Survival data were analyzed using Kaplan Meier methods and Cox proportional hazards models. Results: Incidences of brain metastasis were 1.7% (47/2848). Median survival period after diagnosis of brain metastasis was 20 weeks (4 5 months). The 6-, 12- and 24-month survival rates after brain metastasis were 44.0%, 22.0% and 16.5%, respectively. Cox regression analysis showed that extracranial metastasis (hazard ratio [HR], 5.2; 95% confidence interval [CI]: ), ECOG performance status of 3 4 (HR, 3.1; 95% CI: ), treatment-free interval of <6 months (HR, 3.8; 95% CI: ), and no anti-cancer treatment for brain metastasis (HR, 3.6; 95% CI: ) were significantly and independently related to poor survival. Conclusion: Treatment-free interval should be assessed in a future study to verify prognostic predictors of brain metastasis from gynecological cancer. Key words: brain metastasis, gynecological cancer, ovarian cancer, prognosis, treatment-free interval Introduction Metastases are the most common type of brain tumors (1) and symptomatic metastatic brain tumors develop in around 9% of cancer patients (2,3). Lung, breast, skin (melanoma), kidney and gastrointestinal tract are the most common sources of metastatic brain tumors (1 3). Brain metastases result in a significant reduction in quality of life, and its prognosis is notoriously poor (4 12). Without intervention, the median survival after diagnosis of brain metastases is 1 month to 2 months (4). According to the literatures in 1980s 1990s, the median survival periods after presentation with The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 604

2 Jpn J Clin Oncol, 2017, Vol. 47, No brain metastases were reported to be 3 6 months (5 10). According to recent large, multi-institutional studies based on data of several thousand cases, the median survival periods were 7 8 months (12,13). Therefore, palliative care is an important part of treatment for patients with brain metastases. However, brain metastases are heterogeneous in terms of type of primary tumor, extent of disease, therapeutic sensitivity and general condition of a patient (10 14). Selected patients with favorable prognostic factors benefit from well-planned treatment strategy (4,14) and nearly 10% of patients with brain metastases survive more than 2 years (15). Therefore, it has been considered that individualized medical care should be promoted in patients with brain metastases. Prognostic prediction models for patients with this intractable disease have been intensively studied during the past two decades (10 13). In 1997, Gaspar et al. conducted recursive partitioning analysis (RPA) to estimate the prognosis of patients with brain metastasis in a retrospective study based on data of 1200 cases from three Radiation Therapy Oncology Group (RTOG) brain metastases trials (10). RPA included performance status, control status of primary disease, age and presence of extracranial metastases. However, the number of metastases or the kind of primary tumor were not assessed in the RPA system. In 2008, Sperduto et al. proposed a scoring system called as graded prognostic assessment (GPA) and the number of metastases was evaluated in the GPA as well as the four factors evaluated in the RPA system (11). In 2012, GPA has been developed into a new prediction model comprising several different systems for each kind of primary tumor through the result of a large, multi-institutional study based on data of 3940 cases (13). For lung cancer, evaluation factors were age, performance status, presence of extracranial metastases and the number of brain metastases. For melanoma and renal cancer, evaluation factors were performance status and the number of brain metastases. For breast cancer, evaluation factors were age, performance status and tumor subtype. For gastrointestinal cancer, the only evaluation factor was performance status. On the other hand, female genital tract is uncommon sources of brain metastases (16) and thus, there has been limited information on prognostic factors (17 20). Nasu et al. conducted a multi-institutional cooperative study with the largest data based on 139 cases of brain metastases from gynecological malignancies and showed that good performance status, absence of extracranial disease, single brain metastasis, ovarian origin, implementation of definitive treatments were independent favorable prognostic factors (17). Some results of their study were inconsistent with corresponding results of other studies (18 20). Especially, discrepancy exists in significance of ovarian origin between previous studies. We evaluated biological aggressiveness of brain metastasis from gynecological cancer and verified each prognostic factor selected in the Nasu et al. study. In the present manuscript, significance of ovarian origin will be discussed and another factor that has not been evaluated ever before, namely treatment-free interval (TFI), will be proposed as a prognostic predictor. Materials and methods Patients In total, 2848 patients were treated for gynecological cancer including carcinoma of the cervix/corpus/ovary/tube/peritoneum cancer at the National Hospital Organization, Hokkaido Cancer Center from January 1995 to December Forty-seven (1.7%) patients with brain metastasis from the gynecological cancers were included in the study. The medical records were reviewed, and data at the time of initial presentation, which included age, International Federation of Gynecology and Obstetrics (FIGO) stage, histological subtype and treatment, were collected. Data at the time of brain metastasis diagnosis, which included age, presence of extracranial metastasis, performance status (evaluated according to the Eastern Cooperative Oncology Group (ECOG) performance status group (21)), number of brain metastases, history of any previous radiation or chemotherapy, onset period and treatment, were collected. Finally, data regarding clinical outcome were obtained. Both data ECOG performance status and number of brain metastasis were not obtained in three patients. Either ECOG performance status or number of brain metastasis was not obtained in two patients. The local institutional review board and the hospital s ethics committee approved the study protocol (IRB number 28-49). Survival analysis The primary outcome measure was the survival period after diagnosis of brain metastasis. Nine variables were used for survival analysis and every variable had a binary classification. (1) age (<65 vs. 65); (2) primary site (cervix/corpus vs. ovary/tube/peritoneum); (3) extracranial metastasis (no vs. yes); (4) ECOG performance status (0 2 vs. 3 4); (5) the number of brain metastasis (single vs. multiple); (6) history of any previous radiation or chemotherapy (no vs. yes); (7) brain metastasis-free interval (<12 months vs. 12 months); (8) TFI (<6 months vs. 6 months) and (9) treatment for brain metastasis (palliative care only vs. surgery/radiotherapy/chemotherapy). The brain metastasis-free interval was defined as the time from initial presentation to diagnosis of brain metastasis. TFI was defined as the time from the last treatment before diagnosis of brain metastasis to diagnosis of brain metastasis. Survival rates were estimated using the Kaplan Meier method and compared between groups using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model. Proportional data were compared using the chi-square test or Fisher s exact test. A P value of <0.05 was considered statistically significant. All analyses were performed using R version 3.2.0: A Language and Environment for Statistical Computing (R Core Team 2015). Results The incidences of brain metastasis were 1.7% (18/1046) in cervical cancer, 1.2% (12/1040) in corpus cancer and 2.2% (17/762) in ovarian/tubal/peritoneal cancer. Clinicopathological characteristics of the 47 patients are shown in Tables 1 and 2. The median age at the time of brain metastasis was 62 years old. Twenty-six patients (55%) had extracranial metastasis at the time of diagnosis of brain metastasis. Twenty-seven patients (63%) had a performance status 3. Twenty-one patients (49%) had multiple brain metastases. Approximately a quarter of brain metastases occurred at the time of initial presentation, and the three quarters occurred at the subsequent progression.the Kaplan Meier curve for the entire cohort is shown in Fig. 1A. The median survival period after diagnosis of brain metastasis was 19.8 weeks (range: weeks). The overall rate of survival after diagnosis of brain metastasis of the entire cohort was 44.0% at 6 months, 22.0% at 1 year, and 16.5% at 2 years. The Kaplan Meier curves by primary origin are shown in Fig. 1B. While the median survival period after diagnosis of brain metastasis from ovarian/tubal/peritoneal cancer was 40 weeks

3 606 Brain metastasis from gynecological cancer Table 1. Profile of the patients at the time of initial presentation (n = 47) Cervix Corpus Ovary/tube/peritoneum No. patients Age at the time of initial presentation: median (years old) 53 yr (range: 37 80) 70 yr (range: 54 78) 58 yr (range: 45 72) FIGO stage I 2 (11%) 4 (33%) 3 (18%) II 6 (33%) 0 (0%) 2 (12%) III 4 (22%) 5 (42%) 8 (47%) IV 6 (33%) 3 (25%) 4 (24%) Histological cell types Seous adenocarcinoma 0 (0%) 3 (25%) 11 (65%) Clear cell carcinoma 0 (0%) 0 (0%) 3 (18%) Endometrioid adenocarcinoma 0 (0%) 6 (50%) 0 (0%) Endocervical/mucinous adenocarcinoma 4 (22%) 0 (0%) 0 (0%) Squamous cell carcinoma 8 (44%) 0 (0%) 0 (0%) Carcinosarcoma 1 (5.6%) 2 (17%) 0 (0%) Neuroendocrine carcinoma 4 (22%) 0 (0%) 0 (0%) Malignant melanoma 1 (5.6%) 0 (0%) 0 (0%) Mixed-epithelial carcinoma 0 (0%) 1 (8.3%) 2 (12%) Undigfferentiated carcinoma 0 (0%) 0 (0%) 1 (5.9%) FIGO, Federation of Gynecology and Obstetrics. Table 2. Clinical characteristics of brain metastasis (n = 47) Cervix Corpus Ovary/tube/peritoneum Total No. patients Age at the time of brain metastasis: 57 yr (range: 41 83) 73 yr (range: 56 80) 62 yr (range: 49 74) 62 yr (range: 41 83) median (years old) Extracranial metastasis 16 (89%) 11 (92%) 9 (53%) 26 (55%) Performance status (ECOG) 3 or 4 a 11 (69%) 9 (82%) 7 (44%) 27 (63%) Multiple brain metastases b 10 (63%) 5 (45%) 6 (38%) 21 (49%) Previous radiation/chemotherapy 14 (78%) 12 (100%) 16 (94%) 42 (89%) Onset of brain metastasis Initial presentation 0 (0%) 0 (0%) 1 (5.9%) 1 (2.1%) Initial progression 0 (0%) 2 (17%) 9 (53%) 11 (23%) Second/subsequent progression 18 (100%) 10 (83%) 7 (41%) 35 (74%) Progression-free interval: median 10 months (range: ) 9 months (range: 2 36) 21 months (range: 0 101) 16 months (range: 0 101) Brain metastasis-free interval: median 20 months (range: ) 22 months (range: 6 148) 28 months (range: 0 194) 26 months (range: 0 194) Treatment-free interval: median 1 months (range: 0 61) 2 months (range: 0 18) 3 months (range: 0 81) 2 months (range: 0 81) Treatment to the metastatic brain tumor Surgery 0 (0%) 0 (0%) 2 (13%) 2 (4.3%) Surgery + radiation 2 (11%) 3 (25%) 3 (19%) 8 (19%) Surgery + chemotherapy 0 (0%) 0 (0%) 0 (0%) 0 (0%) Surgery + radiation + chemotherapy 0 (0%) 0 (0%) 1 (5.6%) 1 (2.1%) Radiation 7 (39%) 4 (33%) 8 (50%) 19 (40%) Radiation + chemotherapy 1 (5.6%) 1 (8.3%) 1 (5.6%) 3 (6.4%) Chemotherapy 0 (0%) 0 (0%) 0 (0%) 0 (0%) Palliative care only 8 (44%) 4 (33%) 1 (5.6%) 13 (28%) ECOG, Eastern Cooperative Oncology Group. a Data on performance status was missing for four women. b Data on number of brain metastasis was missing for four women. (range: weeks), that from cervical cancer was 11 weeks (range: weeks) and that from corpus cancer was 10 weeks (range: weeks) (P = 0.015). Table 3 shows the results of Cox regression analysis of prognostic factors in patients with brain metastasis. When TFI was not incorporated into the multivariate analysis, extracranial metastasis (HR, 9.5; 95% CI: ), ECOG performance status of 3 4 (HR, 3.2; 95% CI: ), brain metastasis-free interval of <12 months (HR, 3.5; 95% CI: ), and no anti-cancer treatment for brain metastasis (HR, 3.7; 95% CI: ) were significantly and independently related to poor survival. Multiple brain metastases (HR, 2.1; 95% CI: ) was marginally related to poor survival. Primary origin was not a predictor of survival. On the other hand, when TFI was incorporated into the multivariate

4 Jpn J Clin Oncol, 2017, Vol. 47, No Figure 1. Kaplan Meier survival curves after diagnosis of brain metastasis in all 47 patients included in this study (A) and primary origin survival curves (B) (P = 0.015). Table 3. Prognostic factors for survival period after diagnosis of brain metastasis selected by Cox proportional hazard model analysis (n = 42) Univariate analysis Multivariate analysis a Multivariate analysis b Unadjusted HR 95% CI P value Adjusted HR a 95% CI a P value Adjusted HR b 95% CI b P value Age < Primary site Cervix/corpus Ovary/tube/peritoneum Extracranial metastasis No Yes Performance status (ECOG) 0 to to Number of brain metastases Single Multiple Previous chemotherapy No Yes Brain metastasis-free interval 12 months <12 months Treatment-free interval 6 months <6 months Treatment for brain metastasis S/RT/CT Palliative care only S, surgery (craniotomy); RT, radiotherapy; CT, chemotherapy. a The multivariate analysis was conducted by incorporating age, primary site, extracranial metastasis, performance status, number of brain metastasis, previous chemotherapy, brain metastasis-free interval and treatment for brain metastasis without incorporating treatment-free interval. b The multivariate analysis was coducted by incorporating all nine variables.

5 608 Brain metastasis from gynecological cancer Table 4. Clinical characteristics of long-term (>1 year) survivors (n = 9) Primary disease Extracarnial metatsasis EOCG PS Number of BM TFI Treatemnt for BM Clinical outcome Survival after BM (months) (months) CX No 3 Multiple 10 RT DOD 36 EM Yes 3 Single 6 RT DOD 22 EM No 3 Single 14 S+RT NED 52 OV No 2 Single 8 RT NED 41 CX Yes 3 Multiple 0 RT DOD 17 TU No 2 Single 15 RT NED 127 OV No 3 Single 6 S+RT DOD 78 OV No 3 Single 17 S+RT DOD 53 OV No 2 Single 11 S DOD 51 EOCG PS, the Eastern Cooperative Oncology Group performance status; BM, brain metastasis; TFI, treatment-free interval; CX, cervical cancer; EM, endometrial cancer; TU: tubal cancer; OV: ovarian cncer; RT: radiation therapy; S: surgery; NED, no evidence of disease; DOD, died of disease. analysis, extracranial metastasis (HR, 5.2; 95% CI: ), ECOG performance status of 3 4 (HR, 3.1; 95% CI: ), TFI of <6 months (HR, 3.8; 95% CI: ), and no anticancer treatment for brain metastasis (HR, 3.6; 95% CI: ) were significantly and independently related to poor survival. Primary origin and the number of brain metastasis were not predictor of survival. Table 4 shows clinical characteristics of a particular group comprising patients who survived for >1 year after brain metastasis. Of the nine long-term survivors, eight patients had 6 months TFI before diagnosis of brain metastasis. Four patients underwent craniotomy ± radiotherapy and five radiotherapy alone. Discussion Previous studies have confirmed that good performance status (17 19), absence of extracranial metastases (17,18,20), single brain metastasis (17), ovarian/tubal/peritoneal origin (17), serous histologic subtype (20) and treatment intervention (17,18,20) were independent favorable prognostic factors for patients with brain metastases from gynecological malignancies. In this study, primary origin was not confirmed as an independent prognostic factor. There are two plausible interpretations of this result. One is that the favorable prognosis of patients with malignancies of ovarian/tubal/peritoneal origins is explained by confounding factors. Indeed, ovarian/tubal/ peritoneal primary and extracranial metastasis were each confounding factors in our study. The rates of extracranial metastasis cases were 53.3% in ovarian/tubal/peritoneal cancer and 90.0% in cervical/corpus cancer (P = 0.011). Primary ovarian/tubal/peritoneal disease had an unadjusted HR of 0.4 (95% CI = , P = ), but an adjusted HR of 0.6 (95% CI = , P = 0.23) after adjusting for extracranial metastasis. In this study, none of the five patients with brain metastases from ovarian/tubal cancer that had long-term (>12 months) survival showed extracranial metastasis. Thus, survival was related to ovarian/tubal/peritoneal primary and TFI in our study. The rates of cases with TFI 6 months were 50.0% for ovarian/tubal/peritoneal cancer and 26.9% for cervical/corpus cancer (P = 0.13). Ovarian/tubal/peritoneal primary had an adjusted HR of 0.64 (95% CI = , P = 0.38) after adjusting for TFI. We admit that the prognosis of ovarian/tubal/ peritoneal primary is better than cervical/corpus origin. However, the real reason is that ovarian/tubal/peritoneal primary is associated with no extracranial lesions and longer TFI. Another interpretation for not finding a significant association between primary origin and prognosis is selection bias. Nasu et al. showed a median survival period after diagnosis of brain metastases from ovarian/tubal/peritoneal cancer of 12.5 months and emphasized the significance of primary site on prognosis (17). Piura et al. reviewed 36 series totaling 513 patients and showed the median survival after diagnosis of brain metastases from ovarian cancer of 6.4 months (22). Of the 36 literatures, 28 (77.8%) reported the short median survival periods (<12 month) in each literature. Of the 28 literatures, 25 (89.3%) showed incidence rates of brain metastases from ovarian cancer. In contrast, of the remaining 8 literatures with the long median survival (>12 months), five (62.5%) did not show original population of ovarian cancer as a background of brain metastases, which led to lack of information on incidence rates of brain metastases from ovarian cancer (23 27). Also in the Nasu et al. study, there was no description on incidence rates of brain metastases. In a nutshell, the ways of sampling in these studies might have been inappropriate for determining an accurate median survival period. Indeed, some studies with the long median survival focused on a particular group, for example, patients with solitary brain metastasis or patients who underwent craniotomy (23 25). According to the results of the largest study, the median survival periods after diagnosis of brain metastases were less than 12 months in every cancer category, namely lung cancer, breast cancer, renal cancer, malignant melanoma, gastrointestinal tract cancer, and other cancer category (12). It would be difficult to consider that prognosis of brain metastases from ovarian cancer is prominent among various kinds of primary sites at present. It is highly possible that ovarian/tubal/peritoneal primary and extracranial metastasis are confounding factors each other. Indeed, the rates of cases of extracranial metastasis were 53.3% in the ovarian/tubal/peritoneal cancer and 90.0% in the cervical/corpus cancer (P = 0.011). All six patients after diagnosis of brain metastases from ovarian/tubal cancer with the long-term survival (>12 months) had no extracranial metastasis in the present study. Ovarian/tubal/peritoneal primary had an unadjusted HR of 0.4 (95% CI = , P = ), but an adjusted HR of 0.6 (95% CI = , P = 0.23) after adjusting for extracranial metastasis. TFI has been confirmed as a significant prognostic factor in recurrent gynecological cancers (28 32). There is a general consensus on this evidence among experts. Although TFI should be assessed in studies investigating prognosis of brain metastasis from gynecological malignancies, this variable has not been evaluated in previous studies (17 20). Performance status, extracranial metastases,

6 Jpn J Clin Oncol, 2017, Vol. 47, No the number of brain metastasis, and treatment-related factors were confirmed as independent prognostic factors in the largest study investigating prognosis of brain metastasis from gynecological malignancies (17). The present study would have supported the greater part of results in that study if TFI was not incorporated into cox regression analysis. However, since TFI was assessed in our study, we resulted in questioning significance of the number of brain metastasis as well as that of primary origin. Multiple brain metastases had an unadjusted HR of 1.8 (95% CI = , P = 0.11) and a HR of 2.1 (95% CI = , P = 0.08) after adjusting for age, primary site, extracranial metastases, performance status, previous chemotherapy, brain metastasis-free interval and treatment for brain metastasis. However, it had a HR of 1.7 (95% CI = , P = 0.27) after adjusting just one factor, i.e. TFI. Our study has some limitations. First, the number of patients included in the study was too small to power statistically conclusive results. Second, there was no consistent follow-up policy for diagnosing metastatic brain tumors and no consistent treatment policy for metastatic brain tumors in our institution. These issues are caused by the fact that ours was a retrospective, observational study conducted at a single institution. However, our study had other strong points; Original population of gynecological cancers were shown as a background of brain metastases, which led to information disclosure regarding incidence rates of brain metastases. TFI well known for one of the most important risk factor in recurrent gynecological cancers were incorporated into survival analyses. There has been no study in which TFI was evaluated in order to select prognostic factors of brain metastasis from gynecological malignancies. 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