Gamma Knife radiosurgery for metastatic brain tumors from ovarian cancer: histopathological analysis of survival and local control. A Japanese multi-institutional cooperative and retrospective cohort study

Shigeo Matsunaga Department of Neurosurgery and
Stereotactic Radiotherapy Center, Yokohama Rosai Hospital, Yokohama, Kanagawa;

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Takashi Shuto Department of Neurosurgery and
Stereotactic Radiotherapy Center, Yokohama Rosai Hospital, Yokohama, Kanagawa;

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Toru Serizawa Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo;

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Kyoko Aoyagi Department of Neurosurgery, Gamma Knife House, Chiba Cerebral and Cardiovascular Center, Ichihara, Chiba;

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Toshinori Hasegawa Department of Neurosurgery, Gamma Knife Center, Komaki City Hospital, Komaki, Aichi;

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Jun Kawagishi Department of Neurosurgery, Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Miyagi;

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Shoji Yomo Division of Radiation Oncology, Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Nagano;

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Hiroyuki Kenai Department of Neurosurgery, Nagatomi Neurosurgical Hospital, Oita;

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Kiyoshi Nakazaki Department of Neurosurgery, Brain Attack Center Ota Memorial Hospital, Fukuyama, Hiroshima;

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Akihito Moriki Department of Neurosurgery, Mominoki Hospital, Kochi;

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Yoshiyasu Iwai Department of Neurosurgery, Osaka City General Hospital, Osaka; and

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Tetsuya Yamamoto Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan

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OBJECTIVE

Brain metastasis is rare in ovarian cancer patients. The results of Gamma Knife radiosurgery (GKRS) for the treatment of patients with brain metastases from ovarian cancer were retrospectively analyzed to derive the efficacy and prognostic factors for survival and local tumor control. Further histopathological analysis was also performed.

METHODS

The authors retrospectively reviewed the medical records of 118 patients with 566 tumors who had undergone GKRS at the 10 GKRS institutions in Japan.

RESULTS

After the initial GKRS, the median overall survival time was 18.1 months. Multivariate analysis showed that uncontrolled primary cancer (p = 0.003) and multiple intracranial metastases (p = 0.034) were significant unfavorable factors. Ten patients died of uncontrolled brain metastases at a median of 17.1 months. The 6-, 12-, and 24-month neurological death rates were 3.2%, 4.6%, and 11.9%, respectively. The 6-, 12-, and 24-month neurological deterioration rates were 7.2%, 13.5%, and 31.4%, respectively. The 6-, 12-, and 24-month distant brain control failure rates were 20.6%, 40.2%, and 42.3%, respectively. Median tumor volume was 1.6 cm3 and marginal dose was 20 Gy. The 6-, 12-, and 24-month local tumor control rates were 97.6%, 95.2%, and 88.0%, respectively. Peritumoral edema (p = 0.043), more than 7-cm3 volume (p = 0.021), and prescription dose less than 18 Gy (p = 0.014) were factors that were significantly correlated in local tumor control failure. Eight patients had symptomatic radiation injury. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 7.8%, and 12.2%, respectively. Primary ovarian cancer was histopathologically diagnosed for 313 tumors in 69 patients. Serous adenocarcinoma was found in 37 patients and other types in 32 patients. Median survival times were 32.3 months for the serous type and 17.4 months for other types after initial GKRS. Patients with serous-type tumors survived significantly longer than patients with other types (p = 0.039). The 6-, 12-, and 24-month local tumor control rates were 100%, 98.8%, and 98.8%, respectively. Serous-type tumors were a significantly good prognosis factor for local tumor control after GKRS (p = 0.005).

CONCLUSIONS

This study established a relationship between the efficacy of GKRS treatment for brain metastases and the histological type of primary ovarian cancer. GKRS for ovarian cancer brain metastasis can provide satisfactory survival and local control, especially in cases of serous adenocarcinoma.

ABBREVIATIONS

CTCAE = Common Terminology Criteria for Adverse Events; GKRS = Gamma Knife radiosurgery; JLGK = Japanese Leksell Gamma Knife; KPS = Karnofsky Performance Status; M-RPA = modified Radiation Therapy Oncology Group recursive partitioning analysis; WBRT = whole-brain radiation therapy.

OBJECTIVE

Brain metastasis is rare in ovarian cancer patients. The results of Gamma Knife radiosurgery (GKRS) for the treatment of patients with brain metastases from ovarian cancer were retrospectively analyzed to derive the efficacy and prognostic factors for survival and local tumor control. Further histopathological analysis was also performed.

METHODS

The authors retrospectively reviewed the medical records of 118 patients with 566 tumors who had undergone GKRS at the 10 GKRS institutions in Japan.

RESULTS

After the initial GKRS, the median overall survival time was 18.1 months. Multivariate analysis showed that uncontrolled primary cancer (p = 0.003) and multiple intracranial metastases (p = 0.034) were significant unfavorable factors. Ten patients died of uncontrolled brain metastases at a median of 17.1 months. The 6-, 12-, and 24-month neurological death rates were 3.2%, 4.6%, and 11.9%, respectively. The 6-, 12-, and 24-month neurological deterioration rates were 7.2%, 13.5%, and 31.4%, respectively. The 6-, 12-, and 24-month distant brain control failure rates were 20.6%, 40.2%, and 42.3%, respectively. Median tumor volume was 1.6 cm3 and marginal dose was 20 Gy. The 6-, 12-, and 24-month local tumor control rates were 97.6%, 95.2%, and 88.0%, respectively. Peritumoral edema (p = 0.043), more than 7-cm3 volume (p = 0.021), and prescription dose less than 18 Gy (p = 0.014) were factors that were significantly correlated in local tumor control failure. Eight patients had symptomatic radiation injury. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 7.8%, and 12.2%, respectively. Primary ovarian cancer was histopathologically diagnosed for 313 tumors in 69 patients. Serous adenocarcinoma was found in 37 patients and other types in 32 patients. Median survival times were 32.3 months for the serous type and 17.4 months for other types after initial GKRS. Patients with serous-type tumors survived significantly longer than patients with other types (p = 0.039). The 6-, 12-, and 24-month local tumor control rates were 100%, 98.8%, and 98.8%, respectively. Serous-type tumors were a significantly good prognosis factor for local tumor control after GKRS (p = 0.005).

CONCLUSIONS

This study established a relationship between the efficacy of GKRS treatment for brain metastases and the histological type of primary ovarian cancer. GKRS for ovarian cancer brain metastasis can provide satisfactory survival and local control, especially in cases of serous adenocarcinoma.

In Brief

The authors conducted a survey of Gamma Knife radiosurgery (GKRS) facilities in Japan to examine the therapeutic efficacy and safety of GKRS for metastatic brain tumors from ovarian cancer and treatment effects associated with different histological types of tumors. The results showed that GKRS is a very effective treatment for brain metastases from ovarian cancer, with few treatment-related complications, and provides more effective tumor control for tumors histologically identified as serous adenocarcinoma than for other tumor types.

Primary ovarian cancer has the highest mortality rate among types of gynecological cancer.1 Generally, most patients with ovarian cancer have tumors localized in the abdominal or pelvic cavities, and distant metastases in the advanced stage.2 Distant metastasis of ovarian cancer mainly occurs in the pleura, liver, and lung through the intraperitoneal route and lymphatic channels. Ovarian cancer metastasis to the central nervous system is rare, occurring in about 0.3%–2.2% of cases, and often occurs after a long period of time has passed since the diagnosis of primary cancer.36 Consequently, brain metastasis is considered to indicate a poor prognosis. Recently, the number of patients diagnosed with brain metastases from ovarian cancer has been on the rise,5,6 probably because of the greater awareness among patients and clinicians as well as the longer survival resulting from improvements in systemic therapies.

Ovarian cancer patients with brain metastases are treated, according to the systemic condition of the patient, with a single therapy or combination of several therapies, including craniotomy, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery or radiotherapy. However, the optimum treatment to produce the most desirable results has not been established.6 Radiosurgery is a minimally invasive and effective treatment for brain metastases from a variety of primary cancers, for the purpose of alleviating neurological symptoms.7 Despite the increasing number of patients with brain metastases from ovarian cancer, the efficacy and safety of this treatment is not very clear.826 Furthermore, the histopathology has not been examined or analyzed.

Therefore, the Japanese Leksell Gamma Knife (JLGK) Society led a survey to assess the retrospective therapeutic effects of Gamma Knife radiosurgery (GKRS) for ovarian cancer brain metastases. This study included a large number of cases of survival after GKRS for brain metastases from ovarian cancer, and focused in particular on neurological death, tumor local control, treatment-related complications, and prognostic factors. In addition, the effect of ovarian cancer histopathology on treatment efficacy was investigated.

Methods

Patient Population

This multi-institutional retrospective study was designed by the JLGK Society (JLGK1801 study). We used a questionnaire to ask the participating institutions to provide clinical and imaging information before, during, and after GKRS treatment. The resulting information was from a population that included a total of 118 Japanese patients with metastatic brain tumors from primary ovarian cancer, who were treated with GKRS at 10 facilities in Japan between November 1991 and December 2017. All GKRS centers that agreed to participate in the current study obtained approval from their local institutional review board to participate in the study. The first author (S.M.) collected and analyzed all treatment data. In all cases, surgical specimens were used to confirm the histopathological diagnosis at facilities where surgery was performed for primary ovarian cancer.

GKRS Techniques

Stereotactic radiosurgery was performed using Leksell Gamma Knife models B, C, and 4C or Perfexion instruments (Elekta Instrument AB). Dose planning for the treatment of GKRS was performed using a Leksell GammaPlan system (Elekta Instrument AB) based primarily on T1-weighted gadolinium-enhanced MR images with 1- or 2-mm slice thickness with no gaps. Only single-dose irradiation was included, and fractionated irradiation was excluded. Prescribed doses were based on target volume, but were basically left to the judgment of the physicians at each institution. Clinical information and imaging studies of the patients after GKRS were obtained from the referring physicians.

Post-GKRS Follow-Up Protocol

All patients who participated in this study underwent periodic clinical symptom checks and neuroradiological follow-up examinations after the initial GKRS. Radiographic changes were evaluated by measuring the change in the maximum diameter of the tumor in post-GKRS MR images. To accurately assess the size of the tumor, the maximum diameter of the target tumor in three directions (axial, coronal, and sagittal) was measured in MR images. The judgment of treatment response based on MRI was classified into four categories: complete response (complete disappearance of tumor), partial response (decrease in the maximum diameter of the tumor by 50% or more), stable disease (increase in the maximum diameter of the tumor by less than 50% and less than 25%), and progressive disease (increase in the maximum diameter of the tumor by 25% or more). Complete response, partial response, and stable disease status, other than progressive disease, were considered to be the three changes that inhibited tumor growth. Progressive disease was differentiated by GKRS surgeons as tumor recurrence or radiation injury. Symptomatic, treatment-related toxicities recorded by adopting the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 developed by the National Cancer Institute’s Cancer Therapy Evaluation Program (http://ctep.cancer.gov) were recorded, and scores of CTCAE grade 3 or higher were determined to be adverse effects of GKRS.

Clinical Outcomes

Endpoints after GKRS were overall survival, neurological death, neurological deterioration, distant brain control failure, local recurrence of the treated tumor, and complications from irradiation. For each endpoint, failure was considered an event, and the rest were censored. The overall survival was defined as the time from GKRS until death from any cause or the date of the last follow-up examination. The modified Radiation Therapy Oncology Group recursive partitioning analysis (M-RPA) system was employed to estimate the survival rate after GKRS for each patient.27 Neurological death was defined as the patient’s death due to uncontrolled brain metastasis, such as tumor recurrence, or meningeal carcinomatosis with leptomeningeal spread at the last follow-up examination. Neurological deterioration was defined as a 20% or greater decrease in Karnofsky Performance Status (KPS) score due to worsening brain metastasis status compared to the time of GKRS. Distant control was defined as the absence of new distant lesions in the brain other than the previously irradiated areas in the post-GKRS neuroimaging. Overall survival, neurological death, neurological deterioration, and distant brain control failure were analyzed on a patient-by-patient basis. Lesion-by-lesion analysis was performed for tumor local control and treatment-related complications.

Statistical Analysis

Summary statistics for baseline variables were analyzed using frequency and proportion for categorical data, and median, interquartile range (IQR), and range for continuous variables. Overall survival and cumulative local tumor control rates were analyzed using the standard Kaplan-Meier method, and their cumulative incidence rates were evaluated by comparing them with the log-rank test. In addition, for the analysis of baseline and clinical variables related to outcome categories other than overall survival and local tumor control, we considered patient death as a competing risk and performed competing risk analysis using Fine-Gray generalization of the proportional hazards model. Analysis with the modified proportional hazards model was performed to show the factors affecting survival and cumulative control rates with hazard ratio (HR) and 95% confidence interval (CI). In addition, differences in characteristics between patients with histopathological diagnosis were analyzed and clarified using Fisher’s exact test. For statistical significance, p < 0.05 in the two-tailed test was judged to be a significant difference. All statistical analyses were calculated using EZR (Y Kanda, Saitama Medical Center, Jichi Medical University, 2012; freely available at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), which is a graphical user interface for R version 2.13.0 (The R Foundation for Statistical Computing).28

Results

Clinical Outcomes of GKRS

This study included 118 patients with 566 tumors treated by GKRS during the study’s investigation period. Patient characteristics are presented in Table 1. The median period between the initial diagnosis of ovarian cancer and the initial GKRS was 28.4 months (range 0–236.9 months, IQR 17.0–58.6 months); 116 patients had been treated with cytotoxic anticancer drugs prior to GKRS, but none of them received novel systemic agents either before or after GKRS.

TABLE 1.

Summary of clinical characteristics of patients with GKRS-treated brain metastases from ovarian cancer

CharacteristicValue
No. of pts118
No. of tumors566
Age, yrs62 (18–86) [53–68]
 No. of pts. aged ≥65/<65 yrs48/70
KPS score90 (50–100) [70–90]
 No. of pts w/ score <70%/≥70%16/102
No. of pts symptomatic/asymptomatic78/40
Primary cancer controlled, no/yes56/62
Extracranial metastases active/controlled76/42
Previous treatment w/ conventional systemic agents, no/yes2/116
No. of tumors at GKRS2 (1–20) [1–4]
 No. of pts w/ <5/≥5 tumors89/29
Tumor vol, cumulative cm35.5 (0.13–39.7) [2.63–10.45]
 No. of pts w/ tumor vol <15/≥15 cm3100/18
Prior craniotomy, yes/no23/95
Prior WBRT, yes/no13/105
Detailed histological diagnosis, yes/no69/49
 Serous37
 Clear cell16
 Other16
M-RPA class
 1+2a31
 2b37
 2c+350

Pts = patients.

Values are expressed as number of patients or median (range) [IQR].

The median overall survival time after the initial GKRS was 18.1 months (range 2–98.1 months, IQR 5.7–21.0 months, 95% CI 14.6–21.4). The overall survival rates at 6, 12, and 24 months after the initial GKRS were 78.2%, 65.6%, and 45.1%, respectively (Fig. 1 left). Post-GKRS median overall survival times determined using the M-RPA system were 26.6 months (95% CI 16.6–37.1) in class 1+2a (31 patients), 21.0 months (95% CI 15.2–45.1) in class 2b (37 patients), and 11.2 months (95% CI 6.3–14.9) in class 2c+3 (50 patients) (stratified p = 0.001). Multivariable analysis showed that uncontrolled primary cancer (HR 2.07, 95% CI 1.28–3.33, p = 0.003) and multiple (5 or more) intracranial metastases (HR 1.79, 95% CI 1.05–3.05, p = 0.034) were significantly correlated with unfavorable overall survival outcomes (Table 2).

FIG. 1.
FIG. 1.

Survival of 118 patients with 566 brain metastases from ovarian cancer following GKRS. Left: Graph showing the Kaplan-Meier survival curve for the overall survival rate. The median overall survival time was 18.1 months. Right: Graph showing the Kaplan-Meier survival curve for the local tumor control rate. Cumulative local tumor control rates at 6, 12, and 24 months after initial GKRS were 97.6%, 95.2%, and 88.0%, respectively.

TABLE 2.

Prognostic variables affecting overall survival after GKRS

Univariate Analysis*Multivariate Analysis
p ValueHR (95% CI)p Value
Age ≥65 yrs0.3181.28 (0.788–2.08)
KPS score <70%0.3251.38 (0.73–2.64)
Primary cancer status, uncontrolled0.0022.14 (1.33–3.45)0.003
Extracranial metastases, uncontrolled0.1421.46 (0.88–2.42)
No previous conventional systemic agents0.9881.01 (0.25–4.17)
Neurological status, symptomatic0.730 1.10 (0.65–1.84)
No. of tumors at GKRS ≥50.0181.91 (1.12–3.26)0.034

Log-rank test.

Cox proportional hazards model.

Significant difference at p < 0.05.

A total of 72 patients died during the follow-up period. Recurrence or worsening of primary ovarian cancer and metastases in other organs after GKRS were the cause of death in 62 patients (86.1%) at a median of 11.3 months (range 2–298.1 months, IQR 4.6–20.2 months, 95% CI 7.4–14.9). The cause of death was neurological disease treatment failure in 10 patients (13.9%) at a median of 17.1 months (range 4.7–29.7 months, IQR 6.6–22.8 months, 95% CI 4.6–23.9) (Table 3), including 9 patients who suffered from meningeal carcinomatosis after GKRS and 1 with tumor recurrence. Cumulative neurological death rates were 3.2%, 4.6%, and 11.9% at 6, 12, and 24 months after initial GKRS, respectively (Table 4).

TABLE 3.

Treatment results after GKRS: crude incidence

Treatment ResultsNo. of Pts (%)
Local tumor recurrence23 (19.5)
Surgery4 (3.4)
Repeat GKRS procedure35 (29.7)
WBRT3 (2.5)
GKRS-related complication8 (6.8)
Neurological death10 (8.5)
Neurological deterioration21 (17.8)
Distant brain control failure41 (34.7)
TABLE 4.

Treatment results after GKRS: cumulative incidences

Treatment ResultsCumulative Incidences After GKRS, %
6 mos12 mos24 mos36 mos48 mos60 mos
Local tumor recurrence2.44.812.019.719.725.4
GKRS-related complication3.37.812.212.212.212.2
Neurological death*3.24.611.925.125.125.1
Neurological deterioration*7.213.531.435.435.435.4
Distant brain control failure*20.640.242.355.362.772.0

Cumulative incidence calculated using a competing risk analysis.

At the time of final confirmation of follow-up, 21 patients had worsening neurological symptoms and a decrease in KPS score compared to the KPS score at the time of the initial GKRS (Table 3). Neurological deterioration occurred at a median of 11.6 months (range 1–28 months, IQR 2.7–17.4 months). Cumulative neurological deterioration rates were 7.2%, 13.5%, and 31.4% at 6, 12, and 24 months after initial GKRS, respectively (Table 4).

Forty-one patients developed new brain metastases in the brain outside the GKRS irradiation site at a median of 4.6 months (range 2.7–50 months, IQR 4.3–10 months) after the first GKRS (Table 3). Cumulative distant brain control failure rates were 20.6%, 40.2%, and 42.3% at 6, 12, and 24 months after initial GKRS, respectively (Table 4). Salvage GKRS was performed for new distant brain metastases in 30 patients (median 4 treatments, range 2–6 treatments), WBRT in 3 other patients, and conservative treatment and follow-up in the others (Table 3).

Local Tumor Control of GKRS

The median volume of the lesions to be irradiated at GKRS was 1.6 cm3 (range 0.01–16.2 cm3, IQR 0.08–1.6 cm3). The locations were supratentorial for 411 brain tumors (72.6%) and infratentorial for 155 (27.4%). The tumor margins were irradiated at a median of 20 Gy (range 12–30 Gy, IQR 18–20 Gy). Peritumoral edema was found in 223 lesions (39.4%) on T2-weighted MR images at GKRS treatment. Cystic components were present at GKRS in 43 lesions (7.6%). The median follow-up imaging period after GKRS was 6.2 months (range 2.1–86.3 months, IQR 3.8–15.7 months). Follow-up neuroimaging showed 138 tumors (24.4%) with complete response, 356 (62.9%) with partial response, 41 (7.2%) with stable disease, and 31 (5.5%) with progressive disease. The cumulative local tumor control rates at 6, 12, and 24 months after GKRS were 97.6%, 95.2%, and 88.0%, respectively (Fig. 1 right). Multivariate analysis showed that peritumoral edema (HR 2.60, 95% CI 1.03–6.56, p = 0.043), more than 7-cm3 tumor volume (HR 2.91, 95% CI 1.17–7.23 cm3, p = 0.021), and less than 18-Gy prescription dose (HR 2.09, 95% CI 1.36–5.08 Gy, p = 0.014) were correlated significantly with poor local control (Table 5). Additional treatments for tumor recurrence were surgical resection in 4 patients, salvage GKRS in 5 patients (median 6 treatments, range 2–6 treatments), and conservative management in another 14 patients (Table 3). In this series, there were no cases of additional WBRT after GKRS.

TABLE 5.

Prognostic variables affecting local tumor control after GKRS

Variable (tested for unfavorable outcome)Univariate Analysis*Multivariate Analysis
p ValueHR (95% CI)p Value
Age ≥65 yrs0.9541.02 (0.49–2.15)
Previous conventional systemic agents (no)0.9061.22 (0.57–2.07)
Tumor location (infratentorial lesion)0.5661.26 (0.57–2.80)
Peritumoral edema (yes)0.0014.52 (2.023–10.12)0.043
Cystic lesion (yes)0.4871.41 (0.54–3.70)
Tumor volume (>7 cm3)<0.00016.41 (3.13–13.09)0.021
Marginal dose (<18 Gy)0.0014.73 (2.12–10.56)0.014

Log-rank test.

Cox proportional hazards model.

Significant difference at p < 0.05.

Eight patients (6.8%) had adverse events related to GKRS at a median of 14.7 months (range 10.5–76 months, IQR 12.1–28.9 months) after GKRS (Table 3). Cumulative GKRS-related complication rates were 3.3%, 7.8%, and 12.2% at 6, 12, and 24 months after initial GKRS, respectively (Table 4). CTCAE late radiation morbidity grade was 3 in all patients with motor weakness. No clinical factor was significantly correlated with complications. All patients received conservative treatment with steroid therapy.

Histopathological Analysis

The histopathological diagnosis of primary ovarian carcinoma was obtained for 313 tumors in 69 patients. For the remaining patients, the histopathological diagnosis of primary ovarian cancer was confirmed by surgery, but detailed histological diagnosis was not available. Patient characteristics and the histopathological diagnosis are shown in Table 6. The most common histopathology was serous adenocarcinoma in 37 patients (53.6%). Other nonserous types were clear cell adenocarcinoma in 16 patients, endometrial adenocarcinoma in 8, mucinous adenocarcinoma in 5, and undifferentiated adenocarcinoma in 3. There were no statistically significant differences between serous and other types of pre-GKRS conditions.

TABLE 6.

Summary of clinical characteristics of 69 patients with GKRS-treated brain metastases from ovarian cancer based on histopathological diagnosis

CharacteristicSerousNonserousp Value*
No. of pts3732
No. of tumors161152
Age, yrs 62 (49–79)65 (31–86)0.712
 No. of pts aged ≥65/<65 yrs13/2415/170.488
KPS score, %90 (20–100)80 (60–100)0.881
 No. of pts w/ score <70%/≥70%4/336/260.812
Neurological status symptomatic/asymptomatic24/1319/130.643
Primary cancer controlled, no/yes16/2115/170.744
Extracranial metastases active/controlled23/1411/210.765
Previous conventional systemic agents, no/yes1/371/310.991
No. of tumors at GKRS3 (1–16) [1–4]3 (1–19) [1–4]0.936
 No. of pts w/ <5/≥5 tumors at GKRS26/1126/60.782
Tumor vol cm34.7 (0.13–39.7) [1.34–9]8.6 (0.5–35) [3.6–11.3]0.214
 No. of pts w/ tumor vol <15/≥15 cm334/326/60.286
Prior craniotomy, yes/no6/317/250.563
Prior WBRT, yes/no3/342/300.778
M-RPA class 0.612
 1+2a116
 2b1112
 2c+31514

Values are expressed as number of patients, median (range), or median (range) [IQR].

Fisher’s exact test.

The median survival times of patients with serous and other tumor types after initial GKRS were 32.3 and 17.4 months, respectively. The cumulative overall survival rates at 6, 12, and 24 months after initial GKRS were 85.7%, 75.4%, and 64.5%, respectively, for the serous type, and 77.2%, 65.9%, and 31.3%, respectively, for the nonserous type. Patients with serous-type tumors survived significantly longer (HR 1.08, 95% CI 1.04–3.93, p = 0.039) (Fig. 2 left). Neurological death occurred after GKRS in 1 patient with the serous type and 2 patients with the nonserous type. No significant difference was found between the two histopathological types in incidence rates of neurological death (HR 2.32, 95% CI 0.21–3.25, p = 0.492). Neurological deterioration appeared in 4 patients at a median time of 12.3 months in the serous type and in 6 patients at 10.6 months in the nonserous type. Post-GKRS distant brain control showed no significant difference between the serous and nonserous types (HR 1.44, 95% CI 0.68–3.04, p = 0.336). Distant brain control failure occurred in 14 patients with the serous tumor type at a median time of 4.8 months and 14 patients with the nonserous type at 4.6 months. Post-GKRS neurological preservation showed no significant difference between the serous and nonserous types of tumors (HR 2.01, 95% CI 0.56–7.15, p = 0.283).

FIG. 2.
FIG. 2.

Survival of 69 patients and 313 tumors with histopathological diagnosis of primary ovarian carcinoma following GKRS. Left: Graph showing the Kaplan-Meier survival curves for the overall survival rate comparing serous adenocarcinoma and other types. The serous type was associated with significantly higher survival after initial GKRS (p = 0.039). Right: Graph showing the Kaplan-Meier survival curves for the local tumor control rate comparing serous adenocarcinoma and other types. The serous type was associated with significantly higher survival after initial GKRS (p = 0.005).

The median radiation dose to the tumor margin was 20 Gy for all histopathological types. The cumulative local tumor control rates at 6, 12, and 24 months after GKRS were 100%, 98.8%, and 98.8%, respectively, for the serous type, and 98.2%, 92.3%, and 75.0%, respectively, for the nonserous type. Serous-type tumors were a significantly favorable factor for local tumor control after GKRS treatment (HR 19.1, 95% CI 2.45–148.2, p = 0.005) (Fig. 2 right). GKRS-related complications occurred in 2 patients with the serous type and 5 with the nonserous type of tumor. Adverse events occurred with no significant difference between the histopathological types (HR 3.41, 95% CI 0.66–17.57, p = 0.143).

Discussion

This study demonstrated the association between clinical and radiological outcomes of GKRS and the histopathology of ovarian cancer. Generally, the main treatment methods for primary ovarian cancer are surgical resection and conventional systemic agents.2,4 Radiation therapy is only used to treat primary ovarian cancer with distant metastases that cannot be treated by regular surgery. Radiation therapy is effective for primary ovarian cancer and intraperitoneal metastasis.29,30 Radiation therapy was effective for 40 patients with ovarian cancer resistant to conventional systemic agents.31 However, no significant difference was found in the efficacy of radiation therapy between histopathological types for primary ovarian cancer and extracranial metastasis.32 Therefore, determination of the efficacy of radiation therapy for ovarian cancer has not yet reached a consensus. In particular, the efficacy of radiation therapy for serous adenocarcinoma is unclear, despite the local control achieved by radiation therapy, based on the histopathology, metastatic pathway, and organ location.

Our study results indicated that brain metastasis of ovarian cancer, especially serous adenocarcinoma, was well controlled by GKRS in terms of overall survival and local tumor control. Such findings might be related to the efficacy of a high irradiation dose to the target volume in GKRS treatment, but we expected that intracranial metastasis from ovarian cancer, especially serous adenocarcinoma, would have good sensitivity for radiation therapy, unlike primary ovarian cancer and intraperitoneal metastasis. The histopathology of the primary cancer was not established in all patients in our series, so we must investigate the sensitivity to radiation therapy of brain metastases from ovarian cancer according to histopathological findings in the future.

The overall survival after initial GKRS was a median of 18.1 months, which was considered to be an excellent outcome compared with the average survival time of patients with brain metastasis from various other primary cancers.7 In our study, the overall survival rate after 24 months from initial GKRS was 45.1%. Patients with serous adenocarcinoma had a survival rate of 63.0%, which was significantly longer than the rate of 31.3% for patients with the nonserous type. In the present study, the neurological death rate at 12 months after initial GKRS was relatively low at only 4.6%. Previously reported neurological death rates at 12 months were 22.2% and 32.0%.24,26 Our series obtained a satisfactorily high prevention of neurological death. The reason for the low number of deaths from neurological causes in this study might be due to the high percentage of patients with serous adenocarcinoma, who were expected to survive for a long time. Therefore, GKRS treatment for brain metastases from ovarian cancer has a lower risk of neurological death than other approaches. Almost one-third of the patients showed various neurological functional deficits after GKRS. In this study, we found that the more often new brain metastases appeared, the more frequently neurological symptoms worsened. This trend might suggest that, at a relatively long time after GKRS, distant brain metastases were not well controlled and neurological dysfunction became progressively impaired. In most cases, salvage GKRS was performed multiple times with the addition of new lesions to be controlled. Therefore, we recommend early detection of distant brain metastases and repeat GKRS for tumor control in order to preserve neurological function and prevent neurological death whenever possible.

Our study obtained acceptable outcomes for local tumor control. The efficacy of radiosurgery for brain metastases has already been largely established by various studies, which generally show good local tumor control rates for metastatic lesions from a variety of primary tumors.7 In our series, as in previously reported studies, more than 80% of patients maintained satisfactory local tumor control in the long term after GKRS.826 When the prognostic factors for local tumor control were analyzed, the significant factors in this study, as in several recent reports, were edema around the tumor, large tumor volume, and low marginal dose during GKRS. Development of radiation therapy for large tumors is required for further improvement of the treatment outcomes. Analysis of histopathology showed that serous ovarian cancer was correlated with favorable local tumor control. Primary serous ovarian cancer generally shows good reaction to chemotherapy but poor sensitivity for radiotherapy. No results were found to support the idea that brain metastases from ovarian cancer (especially serous adenocarcinoma) tend to be less sensitive to radiotherapy and have poorer tumor control. In addition, lower marginal dose was related to failure of local tumor control. Considering the effect of differences in tumor histopathology on GKRS, we should devise some approach for GKRS, such as higher prescription dose, that targets brain metastasis of nonserous ovarian cancer. Only 8 patients in the present study experienced radiation injury that was associated with worsened neurological symptoms, and the severity was relatively low, suggesting that sufficient suppression of side effects is maintained over the long term after GKRS. These results suggest that GKRS is an effective and safe treatment for brain metastasis from ovarian cancer. especially serous adenocarcinoma.

We suggest that this study has a number of limitations. First, this retrospective study was subject to patient selection bias because only patients who had undergone GKRS were included and patients who had not undergone GKRS were excluded at the outset. Second, we could not obtain a histopathological diagnosis in all patients, which might have led to distortions. Third, none of the patients received novel systemic agents, including molecular targeted inhibitors and immune checkpoint inhibitors, because approval for using these agents to treat ovarian cancer patients in Japan was not given until 2013. These drugs are effective for overall survival and local tumor control, especially with regard to the prevention of distant brain metastasis control and meningeal carcinomatosis in patients with brain metastases from ovarian cancer.33 On the other hand, we could discuss the efficacy of only GKRS treatment without the influence of these drugs in this study. In order to further investigate the inhibition of brain metastasis of ovarian cancer, the efficacy of GKRS in combination with novel systemic agents should be tested in the future. Fourth, recent research suggests that extraperitoneal diseases, including brain metastasis, may be more common in patients carrying a BRCA1/2 gene mutation, but we did not obtain any genetic information.34,35 A mutation in the BRCA gene may be a factor in longer survival after the first diagnosis of brain metastasis, so this lack of gene information is a limitation of the current study and previous reports on ovarian cancer that do not include this information. Even if these limitations are fully taken into account, our study established the relationship between histopathological diagnosis and the efficacy of GKRS treatment. Because the sample size in this multicenter retrospective study was much larger than in previous studies, additional information was obtained about the effect of pathological diagnosis of primary ovarian cancer on the effect of GKRS on overall survival and local tumor control.

Conclusions

This JLGK1801 study is the initial analysis to discuss the efficacy of GKRS for brain metastases from primary ovarian cancer and the relationship to histopathology. This multicenter study showed that GKRS was well tolerated and had acceptable long-term efficacy and safety in patients with brain metastases from ovarian cancer, particularly serous ovarian adenocarcinoma. The study is insufficient to establish the optimum treatment for primary ovarian cancer in various aspects, including novel systemic agents and gene mutation, so further study is expected to reveal these relationships with GKRS.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Matsunaga. Acquisition of data: Matsunaga, Serizawa, Aoyagi, Hasegawa, Kawagishi, Yomo, Kenai, Nakazaki, Moriki, Iwai, Yamamoto. Analysis and interpretation of data: Matsunaga. Drafting the article: Matsunaga. Critically revising the article: Shuto, Serizawa, Aoyagi, Hasegawa, Kawagishi, Yomo, Kenai, Nakazaki, Moriki, Iwai, Yamamoto. Reviewed submitted version of manuscript: Shuto, Serizawa, Aoyagi, Hasegawa, Kawagishi, Yomo, Kenai, Nakazaki, Moriki, Iwai, Yamamoto. Statistical analysis: Matsunaga. Study supervision: Shuto.

References

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    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):734.

  • 2

    Deng K, Yang C, Tan Q, et al. Sites of distant metastases and overall survival in ovarian cancer: a study of 1481 patients. Gynecol Oncol. 2018;150(3):460465.

  • 3

    Pietzner K, Oskay-Oezcelik G, El Khalfaoui K, Boehmer D, Lichtenegger W, Sehouli J. Brain metastases from epithelial ovarian cancer: overview and optimal management. Anticancer Res. 2009;29(7):27932798.

    • PubMed
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    Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2017;41:314.

  • 5

    Zhang Y, Grant MS, Stepp WH, Clark LH. Clinical characteristics of CNS metastases from primary gynecologic cancers. Gynecol Oncol Rep. 2019;30:100518.

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    Cagino K, Kahn R, Pannullo S, et al. Treatment patterns and outcomes among women with brain metastases from gynecologic malignancies. Gynecol Oncol Rep. 2020;34:100664.

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    Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387395.

    • Crossref
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    • Search Google Scholar
    • Export Citation
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    Kawana K, Yoshikawa H, Yokota H, et al. Successful treatment of brain metastases from ovarian cancer using gamma-knife radiosurgery. Gynecol Oncol. 1997;65(2):357359.

  • 9

    Corn BW, Mehta MP, Buatti JM, et al. Stereotactic irradiation: potential new treatment method for brain metastases resulting from ovarian cancer. Am J Clin Oncol. 1999;22(2):143146.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Brown JV III, Goldstein BH, Duma CM, Rettenmaier MA, Micha JP. Gamma-knife radiosurgery for the treatment of ovarian cancer metastatic to the brain. Gynecol Oncol. 2005;97(3):858861.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lee YK, Park NH, Kim JW, Song YS, Kang SB, Lee HP. Gamma-knife radiosurgery as an optimal treatment modality for brain metastases from epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):505509.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Monaco E III, Kondziolka D, Mongia S, Niranjan A, Flickinger JC, Lunsford LD. Management of brain metastases from ovarian and endometrial carcinoma with stereotactic radiosurgery. Cancer. 2008;113(9):26102614.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Navarro-Martín A, Maitz A, Manders M, Ducharme E, Chen P, Grills I. Gamma Knife radiosurgery as a primary treatment option for solitary brain metastases from ovarian carcinoma. Clin Transl Oncol. 2009;11(5):326328.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Ratner ES, Toy E, O’Malley DM, et al. Brain metastases in epithelial ovarian and primary peritoneal carcinoma. Int J Gynecol Cancer. 2009;19(5):856859.

  • 15

    Ogino A, Hirai T, Fukushima T, et al. Gamma knife surgery for brain metastases from ovarian cancer. Acta Neurochir (Wien). 2012;154(9):16691677.

  • 16

    Menendez JY, Bauer DF, Shannon CN, Fiveash J, Markert JM. Stereotactic radiosurgical treatment of brain metastasis of primary tumors that rarely metastasize to the central nervous system. J Neurooncol. 2012;109(3):513519.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Niu X, Rajanbabu A, Delisle M, et al. Brain metastases in women with epithelial ovarian cancer: multimodal treatment including surgery or gamma-knife radiation is associated with prolonged survival. J Obstet Gynaecol Can. 2013;35(9):816822.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Shepard MJ, Fezeu F, Lee CC, Sheehan JP. Gamma knife radiosurgery for the treatment of gynecologic malignancies metastasizing to the brain: clinical article. J Neurooncol. 2014;120(3):515522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Nikolaoul M, Stamenković S, Stergiou C, Skarleas C, Torrens M. Management of brain metastasis in a patient with advanced epithelial ovarian carcinoma by gamma-knife radiosurgery. Srp Arh Celok Lek. 2015;143(3-4):205209.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Walter AC, Gunderson CC, Vesely SK, et al. Central nervous system metastasis in gynecologic cancer: symptom management, prognosis and palliative management strategies. Gynecol Oncol. 2015;136(3):472477.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Keller A, Ismail R, Potrebko PS, et al. Role of Gamma Knife radiosurgery for the treatment of brain metastases from gynecological cancers. Cureus. 2016;8(12):e947.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Pillai A. Gamma Knife surgery for metastatic brain tumors from gynecologic cancer: time for what saves time, grants time, and is tested by time? World Neurosurg. 2016;91:597599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Shin HK, Kim JH, Lee H, Cho YH, Kwon H, Roh SW. Clinical outcomes of gamma knife radiosurgery for metastatic brain tumors from gynecologic cancer: prognostic factors in local treatment failure and survival. J Korean Neurosurg Soc. 2016;59(4):392399.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Johnston H, McTyre ER, Cramer CK, et al. Stereotactic radiosurgery in the treatment of brain metastases from gynecologic primary cancer. J Radiosurg SBRT. 2017;5(1):5561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kasper E, Ippen F, Wong E, Uhlmann E, Floyd S, Mahadevan A. Stereotactic radiosurgery for brain metastasis from gynecological malignancies. Oncol Lett. 2017;13(3):15251528.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Ordoñez RML, Amendola BE, Martinez PF, Wolf A, Coy SR, Amendola M. Radiosurgery for brain metastases from ovarian cancer: an analysis of 25 years’ experience with Gamma Knife treatment. Rep Pract Oncol Radiother. 2019;24(6):667671.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Yamamoto M, Kawabe T, Higuchi Y, et al. Validity of prognostic grading indices for brain metastasis patients undergoing repeat radiosurgery. World Neurosurg. 2014;82(6):12421249.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452458.

  • 29

    Patel SC, Frandsen J, Bhatia S, Gaffney D. Impact on survival with adjuvant radiotherapy for clear cell, mucinous, and endometriod ovarian cancer: the SEER experience from 2004 to 2011. J Gynecol Oncol. 2016;27(5):e45.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Brown AP, Jhingran A, Klopp AH, Schmeler KM, Ramirez PT, Eifel PJ. Involved-field radiation therapy for locoregionally recurrent ovarian cancer. Gynecol Oncol. 2013;130(2):300305.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Smart A, Chen YH, Cheng T, King M, Lee L. Salvage radiation therapy for localized recurrent ovarian cancer. Int J Gynecol Cancer. 2019;29(5):916921.

  • 32

    Machida S, Takei Y, Yoshida C, et al. Radiation therapy for chemotherapy-resistant recurrent epithelial ovarian cancer. Oncology. 2014;86(4):232238.

  • 33

    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):24732483.

  • 34

    Ratner E, Bala M, Louie-Gao M, Aydin E, Hazard S, Brastianos PK. Increased risk of brain metastases in ovarian cancer patients with BRCA mutations. Gynecol Oncol. 2019;153(3):568573.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Stasenko M, Cybulska P, Feit N, et al. Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status. Gynecol Oncol. 2019;154(1):144149.

  • Collapse
  • Expand

Illustration from Di Somma et al. (pp 1187–1190). Published with permission from Glia Media | Artist: Martha Headworth, MS.

  • FIG. 1.

    Survival of 118 patients with 566 brain metastases from ovarian cancer following GKRS. Left: Graph showing the Kaplan-Meier survival curve for the overall survival rate. The median overall survival time was 18.1 months. Right: Graph showing the Kaplan-Meier survival curve for the local tumor control rate. Cumulative local tumor control rates at 6, 12, and 24 months after initial GKRS were 97.6%, 95.2%, and 88.0%, respectively.

  • FIG. 2.

    Survival of 69 patients and 313 tumors with histopathological diagnosis of primary ovarian carcinoma following GKRS. Left: Graph showing the Kaplan-Meier survival curves for the overall survival rate comparing serous adenocarcinoma and other types. The serous type was associated with significantly higher survival after initial GKRS (p = 0.039). Right: Graph showing the Kaplan-Meier survival curves for the local tumor control rate comparing serous adenocarcinoma and other types. The serous type was associated with significantly higher survival after initial GKRS (p = 0.005).

  • 1

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):734.

  • 2

    Deng K, Yang C, Tan Q, et al. Sites of distant metastases and overall survival in ovarian cancer: a study of 1481 patients. Gynecol Oncol. 2018;150(3):460465.

  • 3

    Pietzner K, Oskay-Oezcelik G, El Khalfaoui K, Boehmer D, Lichtenegger W, Sehouli J. Brain metastases from epithelial ovarian cancer: overview and optimal management. Anticancer Res. 2009;29(7):27932798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2017;41:314.

  • 5

    Zhang Y, Grant MS, Stepp WH, Clark LH. Clinical characteristics of CNS metastases from primary gynecologic cancers. Gynecol Oncol Rep. 2019;30:100518.

  • 6

    Cagino K, Kahn R, Pannullo S, et al. Treatment patterns and outcomes among women with brain metastases from gynecologic malignancies. Gynecol Oncol Rep. 2020;34:100664.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387395.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Kawana K, Yoshikawa H, Yokota H, et al. Successful treatment of brain metastases from ovarian cancer using gamma-knife radiosurgery. Gynecol Oncol. 1997;65(2):357359.

  • 9

    Corn BW, Mehta MP, Buatti JM, et al. Stereotactic irradiation: potential new treatment method for brain metastases resulting from ovarian cancer. Am J Clin Oncol. 1999;22(2):143146.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Brown JV III, Goldstein BH, Duma CM, Rettenmaier MA, Micha JP. Gamma-knife radiosurgery for the treatment of ovarian cancer metastatic to the brain. Gynecol Oncol. 2005;97(3):858861.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lee YK, Park NH, Kim JW, Song YS, Kang SB, Lee HP. Gamma-knife radiosurgery as an optimal treatment modality for brain metastases from epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):505509.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Monaco E III, Kondziolka D, Mongia S, Niranjan A, Flickinger JC, Lunsford LD. Management of brain metastases from ovarian and endometrial carcinoma with stereotactic radiosurgery. Cancer. 2008;113(9):26102614.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Navarro-Martín A, Maitz A, Manders M, Ducharme E, Chen P, Grills I. Gamma Knife radiosurgery as a primary treatment option for solitary brain metastases from ovarian carcinoma. Clin Transl Oncol. 2009;11(5):326328.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Ratner ES, Toy E, O’Malley DM, et al. Brain metastases in epithelial ovarian and primary peritoneal carcinoma. Int J Gynecol Cancer. 2009;19(5):856859.

  • 15

    Ogino A, Hirai T, Fukushima T, et al. Gamma knife surgery for brain metastases from ovarian cancer. Acta Neurochir (Wien). 2012;154(9):16691677.

  • 16

    Menendez JY, Bauer DF, Shannon CN, Fiveash J, Markert JM. Stereotactic radiosurgical treatment of brain metastasis of primary tumors that rarely metastasize to the central nervous system. J Neurooncol. 2012;109(3):513519.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Niu X, Rajanbabu A, Delisle M, et al. Brain metastases in women with epithelial ovarian cancer: multimodal treatment including surgery or gamma-knife radiation is associated with prolonged survival. J Obstet Gynaecol Can. 2013;35(9):816822.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Shepard MJ, Fezeu F, Lee CC, Sheehan JP. Gamma knife radiosurgery for the treatment of gynecologic malignancies metastasizing to the brain: clinical article. J Neurooncol. 2014;120(3):515522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Nikolaoul M, Stamenković S, Stergiou C, Skarleas C, Torrens M. Management of brain metastasis in a patient with advanced epithelial ovarian carcinoma by gamma-knife radiosurgery. Srp Arh Celok Lek. 2015;143(3-4):205209.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Walter AC, Gunderson CC, Vesely SK, et al. Central nervous system metastasis in gynecologic cancer: symptom management, prognosis and palliative management strategies. Gynecol Oncol. 2015;136(3):472477.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Keller A, Ismail R, Potrebko PS, et al. Role of Gamma Knife radiosurgery for the treatment of brain metastases from gynecological cancers. Cureus. 2016;8(12):e947.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Pillai A. Gamma Knife surgery for metastatic brain tumors from gynecologic cancer: time for what saves time, grants time, and is tested by time? World Neurosurg. 2016;91:597599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Shin HK, Kim JH, Lee H, Cho YH, Kwon H, Roh SW. Clinical outcomes of gamma knife radiosurgery for metastatic brain tumors from gynecologic cancer: prognostic factors in local treatment failure and survival. J Korean Neurosurg Soc. 2016;59(4):392399.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Johnston H, McTyre ER, Cramer CK, et al. Stereotactic radiosurgery in the treatment of brain metastases from gynecologic primary cancer. J Radiosurg SBRT. 2017;5(1):5561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kasper E, Ippen F, Wong E, Uhlmann E, Floyd S, Mahadevan A. Stereotactic radiosurgery for brain metastasis from gynecological malignancies. Oncol Lett. 2017;13(3):15251528.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Ordoñez RML, Amendola BE, Martinez PF, Wolf A, Coy SR, Amendola M. Radiosurgery for brain metastases from ovarian cancer: an analysis of 25 years’ experience with Gamma Knife treatment. Rep Pract Oncol Radiother. 2019;24(6):667671.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Yamamoto M, Kawabe T, Higuchi Y, et al. Validity of prognostic grading indices for brain metastasis patients undergoing repeat radiosurgery. World Neurosurg. 2014;82(6):12421249.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452458.

  • 29

    Patel SC, Frandsen J, Bhatia S, Gaffney D. Impact on survival with adjuvant radiotherapy for clear cell, mucinous, and endometriod ovarian cancer: the SEER experience from 2004 to 2011. J Gynecol Oncol. 2016;27(5):e45.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Brown AP, Jhingran A, Klopp AH, Schmeler KM, Ramirez PT, Eifel PJ. Involved-field radiation therapy for locoregionally recurrent ovarian cancer. Gynecol Oncol. 2013;130(2):300305.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Smart A, Chen YH, Cheng T, King M, Lee L. Salvage radiation therapy for localized recurrent ovarian cancer. Int J Gynecol Cancer. 2019;29(5):916921.

  • 32

    Machida S, Takei Y, Yoshida C, et al. Radiation therapy for chemotherapy-resistant recurrent epithelial ovarian cancer. Oncology. 2014;86(4):232238.

  • 33

    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):24732483.

  • 34

    Ratner E, Bala M, Louie-Gao M, Aydin E, Hazard S, Brastianos PK. Increased risk of brain metastases in ovarian cancer patients with BRCA mutations. Gynecol Oncol. 2019;153(3):568573.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Stasenko M, Cybulska P, Feit N, et al. Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status. Gynecol Oncol. 2019;154(1):144149.

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