Brain metastases in patients with EOC: Clinico-pathological and prognostic factors. A multicentric retrospective analysis from the MITO group (MITO 19)

doi:10.1016/j.ygyno.2016.09.025

Gynecologic Oncology

Volume 143, Issue 3, December 2016, Pages 532-538

https://doi.org/10.1016/j.ygyno.2016.09.025 Get rights and content

Highlights

•
There is no consensus regarding the best management of patients with BM from EOC.
•
BM is a rare manifestation of EOC, typically occurring in platinum sensitive women.
•
Patients receiving multiple treatments for BM achieve a longer OS.
•
BM from EOC is not a unique disease and tailored treatments should be proposed.

Abstract

Background

Brain metastases (BM) from epithelial ovarian cancer (EOC) are considered a rare and unfavourable event. There is no consensus regarding the best management of these patients.

Methods

A multicenter retrospective analysis of patients with BM from EOC treated between 1997 and 2014 in 18 institutions of the MITO (Multicenter Italian Trials in Ovarian cancer) group was conducted. Univariate and multivariate analysis were performed.

Results

A total of 174 women were identified as having BM from EOC. The median time interval between primary diagnosis of EOC and occurrence of BM was 26 months (range 2–129 months). The median overall survival from primary EOC diagnosis was 48 months (95% CI 39.5–56.4 months) and from diagnosis of BM was 12 months (95% CI 9.6–14.3 months). The majority of enrolled women (81.7%) were classified as sensitive to platinum-based chemotherapy. Four variables were significantly associated with poor overall survival in multivariate analysis: multiple BM [HR: 1.86 (95% CI: 1.22–2.84)], presence of extracranial disease [HR: 1.77 (95% CI: 1.11–2.83)] age [HR: 1.74 (95% CI: 1.17–2.59)], and monotherapy [HR: 2.57 (95% CI: 1.64–3.86)]. On the contrary, residual tumor at primary surgery, FIGO stage at primary diagnosis and platinum sensitivity were found to have no significant impact on survival from diagnosis of brain lesions.

Conclusions

Our results suggest that BM is a rare and late manifestation of EOC, with a 12-month life-span expectation. Multiple approach is a positive independent prognostic factor and should be proposed to carefully selected patients.

Section snippets

Background

Brain represents one of the most common sites of metastases in lung, breast, renal and colorectal carcinoma, and malignant melanoma [1], [2]. On the other hand, brain metastases (BM) from epithelial ovarian cancer (EOC) are rare, with an incidence of only 1%–2%, often diagnosed in association with disseminated systemic disease and have a considerably poorer prognosis (median survival 8 months) [3], [4], [5].

Recently, a trend of increased incidence of brain metastases in EOC has been noted [5],

Methods

The present study was designated as a multi-institutional retrospective study conducted among MITO (Multicenter Italian Trials in Ovarian cancer) affiliate centers (MITO 19 study). Between January 1997 and December 2014 174 patients enrolled were diagnosed as having BM from EOC. Further inclusion criteria were pathological diagnosis of primary EOC, diagnosis of metastases by CT, MRI, and/or PET-CT and no prior therapy to the brain. Exclusion criteria were: history of treatment for malignancies

Results

From 1997 to 2014, 174 patients having BM were identified in 18 Italian Centres; there was a trend towards more patients being identified in the last third of the screened time period: between 1997 and 2002 15 patients were identified (8.6%), between 2003 and 2008 40 patients were identified (23%) and between 2009 and 2014 119 patients were identified (68.4%). The median age at diagnosis of EOC was 57 years (range 34–87 years), the median age at occurrence of brain lesions was 60 years (range 35–88

Discussion

In this retrospective multicentre study we found that BM is a rare and late manifestation of EOC, typically occurring in platinum sensitive patients and presenting with multiple brain lesions, with a 12-month life-span expectation. We also found that younger patients, with single and isolated BM, and those who received multiple treatments for BM achieved a longer OS after BM diagnosis (Table 5).

During the last two decades, the survival of EOC patients has improved due to the improvement of

Conflict of interests

Domenica Lorusso has attended advisory boards for Astrazeneca and Roche.

Acknowledgement

We would like to thank Sandro Pignata for his endless support and encouragement.

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Management of central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) is an unmet need. We analyzed data on 41 such patients to evaluate predictors of outcome. Between January, 2010 and December 2020, among 1028 patients with EOC treated at our institute 41 (3.98%) developed CNS metastasis. Median age of patients was 48 years, ranging from 22 to 75 years. Primary outcome measure was progression free survival (PFS). Overall survival (OS), and analysis of prognostic factors were secondary outcome measures. An intention to treat analysis was done. We also performed review the literature (n=2253) as regards to clinicopathological and radiological features, treatment received, survival outcomes and prognostic factors. Median time from diagnosis of EOC to CNS metastasis was 27 months (range: 0 to 101 months). 33(80.5%) patients had FIGO stage III-IV at baseline and serous carcinoma (75.6%) was common pathology subtype. Thirteen (31.7%) patients had isolated CNS metastasis and 28 (68.3%) had intra-abdominal disease in addition. Nineteen (46.3%) patients achieved complete response post treatment with surgery, radiation and chemotherapy. Median PFS and OS from the time of CNS metastasis is 12 (range:1 to 51) months and 33 (range: 1 to 71) months, respectively. Absence of extracranial disease and lower serum CA-125 at diagnosis of CNS metastasis were predictive of superior PFS and OS on multivariate analysis. CNS metastasis is a late event in EOC, post multiple lines of treatment. Patients with disease limited to brain and treated with surgical resection and chemoradiation have best outcome.
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Patients with brain metastases from gynecologic malignancies were identified between 2004 and 2019 at two institutions. Descriptive statistics were performed using N (%) and median (interquartile range). Univariate cox proportional hazards regression was performed to evaluate the effect of different factors on overall survival.
32 patients presented with brain metastasis from gynecologic primaries (ovarian/fallopian tube/primary peritoneal n = 14, uterine n = 11, cervical n = 7). Median age of initial cancer diagnosis was 61 (34–79). At initial cancer diagnosis 83% of patients were Stage III/IV and underwent surgery (66%), chemotherapy (100%), and/or pelvic radiation (33%). Median time from initial cancer diagnosis to brain metastasis was 18 months. Treatment of brain metastasis with surgery and radiation compared to stereotactic radiosurgery or whole brain radiation therapy alone revealed a trend toward longer overall survival (p = 0.07). Time from initial cancer diagnosis to brain metastasis was associated with longer overall survival with each one-month increase from initial cancer diagnosis associated with a 7% reduction in risk of death (HR 0.93, 95% CI = 0.89–0.97, p = 0.01). Initial cancer treatment, stage, histology, and number of brain lesions did not affect overall survival.
Patients with brain metastasis secondary to gynecologic malignancies with the longest overall survival had the greatest lag time between initial cancer diagnosis and brain metastasis. Brain metastasis treated with surgery and radiation was associated with longer overall survival.
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Several other studies have attempted to identify prognostic factors in gynaecological brain metastases. In the biggest cohort, from the MITO 19 study, 174 women with BMs from epithelial ovarian cancer were included [19]. After multivariable analysis, the following variables were significantly associated with survival: multiple BMs, extracranial metastases, age, and monotherapy.
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Median overall survival in our cohort was 14.4 months, with a one-year survival of 56.4% and a two-year survival of 39.1%. Thirty-eight patients (52.1%) had ovarian carcinoma as the primary malignancy. The following factors were significantly associated with survival: age (HR 1.05 per year), CA-125 (HR 1.02 par 50 U/ml), and uterine and vulvar primary tumours (when compared to ovarian carcinoma, with HRs 3.07 and 8.70). A post-hoc analysis with primary tumour site reclassified into ovary versus non-ovary showed a HR of 0.50 for ovarian primary tumour type.
We have found that age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours. Our findings may provide a foundation for future development of prediction models, for the benefit of both patients and physicians.
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Ovarian brain metastases represent a very rare occurrence and without treatment, prognosis is very poor, with a median survival of one month. We present a unique case of a patient affected by a giant cystic intracerebral metastasis (>7 cm) secondary to an ovarian papillary serous adenocarcinoma, along with a review of the literature regarding large cystic ovarian metastases and their management.
A 49-years-old female patient was admitted to our institution because she presented progressive headache and altered consciousness. Brain computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed the presence of a giant left frontal intracerebral cystic lesion. The patient underwent a surgical removal of an ovarian high-grade papillary serous adenocarcinoma three years before. We performed a left frontal craniotomy and microsurgical removal of the brain lesion, achieving a safe macroscopic total resection, thanks to intraoperative neurophysiological monitoring (IONM). The post-operative period was uneventful with a complete recovery. Post-operative brain MRI showed a complete removal of the lesion.
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The protein of the gene is responsible for the development of metastases through several mechanisms, including the anchorage of metastatic cells, activity of matrix metalloproteinases as well as function of protein kinase C. Thus, the process of metastatic development is extremely complex [27,32,33]. Brain metastases in the course of ovarian cancer are rare, which has also been confirmed by the European MITO analysis [34]. From the literature, the percentage of germline mutations in BRCA1 in a general population of ovarian cancer patients is 15%, and somatic mutations are detected in around 3% [35,36].
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In most patients (65.5% of BC patients and 68.2% of patients with OC tumors) BRCA1 protein loss was found. No correlation was disclosed between the levels of ERα, PR receptors, HER2, SDF1, CXCR4, AEG1, BRMS1 and BRCA1 status, patient age, stage of disease advancement, grade of histological maturity of the cells, presence of metastases to lymph nodes. A statistically significant correlation was disclosed between the negative expression of PR receptors and a high expression of CXCR4 in patients with BC. High values of the AEG1 protein (linked to metastases) were detected alongside a high expression of BRMS1 (a suppressor of metastases).
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Research PaperBrain metastases in patients with EOC: Clinico-pathological and prognostic factors. A multicentric retrospective analysis from the MITO group (MITO 19)

Highlights

Abstract

Background

Methods

Results

Conclusions

Section snippets

Background

Methods

Results

Discussion

Conflict of interests

Acknowledgement

Crit. Rev. Oncol. Hematol.

Gynecol. Oncol.

Cancer Treat. Rev.

Ann. Oncol.

Ann. Oncol.

Int. J. Gynaecol. Obstet.

Gynecol. Oncol.

Gynecol. Oncol.

Eur. J. Obstet. Gynecol. Reprod. Biol.

Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma

Cancer

Prognostic factors associated with brain metastases from epithelial ovarian carcinoma

Int. J. Gynecol. Cancer

Epithelial ovarian cancer metastasizing to the brain: a late manifestation of the disease with an increasing incidence

J. Clin. Oncol.

Brain metastasis from ovarian cancer: a systematic review

J. Neuro-Oncol.

Research Paper
Brain metastases in patients with EOC: Clinico-pathological and prognostic factors. A multicentric retrospective analysis from the MITO group (MITO 19)