Abstract
Central nervous system involvement is a rare finding in the management of epithelial ovarian cancer with an incidence between 1-2%. A sharp rise in the incidence has been widely and repeatedly proclaimed for nearly two decades now, but has to be treated with scepticism after a careful review of the current literature. Brain metastases from ovarian cancer are known to be related to a very poor prognosis. Since brain imaging is not part of the routine follow-up care for ovarian cancer patients, and since CA-125 - one of the standard tools - cannot be relied upon to detect central nervous system relapse, brain lesions are mostly traced by unspecific neurological symptoms only. Several prognostic factors are still being discussed today. But only a high performance status and the absence of an extra cranial disease at the time of CNS relapse have been accepted throughout the current literature as having a highly significant positive impact on survival. In the past, therapeutic efforts have focused on symptom palliation with corticosteroids and whole-brain radiation therapy (WBRT). During the last years several other therapy options have evolved from encouraging efforts made by several study groups, including chemotherapy, neurosurgery and radiosurgery. It has been shown that a multi-modal approach, combining these strategies, promises the best prolongation of survival and in some cases even resulted in long-term remissions. The present article gives an overview of brain metastases in epithelial ovarian cancer and discusses the current treatment options.
Brain metastases are a common but severe complication in the field of oncology. Approximately 20-40% of all cancer patients will develop brain metastases during their course of disease, with breast cancer, lung cancer and melanoma representing the most common primary malignancy (1). The occurrence of brain lesions is usually associated with a grim prognosis in these diseases and an overall survival rate of 1-2 months only (1). The standard treatment consists of whole-brain radiotherapy (WBRT), which was shown to improve the quality of life by a reduction of neurological symptoms and seems to result in a prolongation of survival to 3-6 months (2, 3). Patients with a good performance status, a controlled extracranial disease and a single brain lesion are those generally considered for more aggressive unimodal or multimodal therapy strategies, including surgical resection, stereotactic radiosurgery (SRS), postoperative radiation, various radiotherapy dose fraction schedules and chemotherapy. These therapy options are mostly incorporated into established guidelines, due to the common occurrence of central lesions in these malignancies. Brain metastases from epithelial ovarian cancer (EOC) on the other hand are a very rare finding in the gynaecological-oncological setting. Because of the likewise poor prognosis and limited experience with this complication in the management of EOC, the question has been raised in the past whether or not these patients should be submitted to any form of therapy apart from the administration of corticosteroids. Studies which have been conducted in response were able to demonstrate that patients with CNS relapse from EOC do benefit from any kind of interventional therapy (radiation, surgery, chemotherapy) when compared to treatment with corticosteroids only (4). In the last years, more and more therapy options have evolved from the experience with brain metastases in other malignancies and have been put into effect to challenge this complication in the management of ovarian cancer. Different meta-analyses of larger patient collectives have reported that a multimodal approach yields the best results in terms of reduction of neurological symptoms and prolongation of survival (3, 4). This review is intended to present the different therapeutic options and their individual values to patients with brain metastases from EOC, as well as to provide an overview of this uncommon condition.
Incidence
Brain metastases from ovarian cancer have traditionally been considered to be a very rare form of relapse since its first description in 1978 by Mayer et al. (5). In their autopsy report of 567 cases between 1973 and 1979, they found an incidence of 0.9%. After this first report, subsequent investigators reported a higher incidence of 1-2.5% (6-8). This rise in incidence has been contributed to several factors. The most plausible one reflects the advances and increased availability of imaging techniques, leading to an earlier and more sensitive diagnosis of brain lesions. Another factor is stated to be the prolonged survival achieved by better therapy regimens including more aggressive cytoreductive surgery and systemic chemotherapy. This results in brain metastases being a variation of the basic disease, a finding that was not possible 20 years ago because of the short time interval between first diagnosis and death. Other theories claim a connection to modern chemotherapy and the blood-brain barrier (BBB), stating either that cancer cells can implant more easily through an impaired BBB after chemotherapy, or that the BBB acts as a safe haven from chemotherapeutic agents.
There are several authors who state that the incidence of CNS relapse in ovarian cancer is rising even more rapidly during the last years and is approaching 12%. However, after a careful review of the current literature, reports of an incidence over 2.5% are the exception and limited only to a few articles which are now mostly outdated. Even though these reports are often cited in current articles as proof of an ongoing sharp rise in incidence, most of the authors who studied larger collectives in the last years reported a stable incidence between 1-2.5% (Table I). Despite the fact that the incidence reported has not changed rapidly in the last decades, 1-2.5% is most certainly still a strong underestimate of the true figure. This is due to the fact that nearly all articles published on this subject are clinical studies rather than autopsy studies. Because brain imaging is not part of the routine follow-up care of ovarian cancer patients, the reported incidence of 1-2.5% is more likely a figure just below the rate of symptomatic brain lesions in ovarian cancer, given that the often unspecific symptoms will not always result in further diagnostic steps.
Site and Appearance of Metastatic Manifestation
Metastases from EOC can present themselves in a variety of phenotypic manifestations (Figure 1). The tumour lesions can be solid, cystic and mixed, whereas mixed solid-cystic seems to be the most common form. At the time of CNS relapse from ovarian cancer, the number of patients with a single brain lesion and multiple lesions is balanced in most reports (2, 8). However, there seems to be a trend towards multiple lesions being the more common form of presentation, as currently reported by several authors (Table II) (7, 9). This observation is in concordance with experience from other malignancies such as lung cancer and melanoma. In these carcinomas, which regularly cause brain metastases, multiple brain lesions occur more frequently than they do in ovarian cancer (10). In terms of regional distribution, the frontal lobe was reported to be the most frequent localisation of metastatic manifestation, followed by the parietal lobe, the temporal lobe and the cerebellum (11). At time of diagnosis of brain metastases, proof of extra cranial disease is found in over half of the patients.
Clinical Criteria of Patients with Brain Metastases from EOC
The mean age at diagnosis of brain metastases from ovarian cancer ranges from 54-56 years (6, 17, 18). This seems to be lower than the classical mean age of ovarian cancer patients which is between 59 and 62 years. About 80% of the patients had a FIGO stage III or IV when first diagnosed as having EOC, whereas only the remaining 20% had FIGO stage I and II (3). The most common histology is the serous type, which is found in over half of the cases. This is followed by mixed epithelial, endometrioid, adenocarcinoma, mucinous, undifferentiated and clear cell histology, all in decreasing frequency (3). This sequence is not surprising, because investigators could not identify any histological type that increases the risk to develop brain lesion and because of the fact that the serous type is the most common histological type in ovarian cancer. Undifferentiated primary tumours are reported far more often in EOC patients than differentiated ones are, with undifferentiated malignancies being found in 68% (grades III and IV), and differentiated tumours in only 32% (grades I and II) (3). Cohen et al. reported a median time from primary diagnosis to development of cerebral lesions of 4.7 years in patients with tumour grades I and II versus 1.5 years in patients with tumour grade III (7). LeRoux et al. on the other hand reported that the interval between primary diagnosis and occurrence of brain relapse is five times shorter in patients with stages III and IV, than it is for stages I and II (17). These findings add to the assumption that patients with undifferentiated primary tumours and advanced disease at the time of first diagnosis of EOC have a higher risk of developing brain lesions.
Prognostic Factors
In the last few decades many investigations have been performed in order to gain a better understanding of ovarian cancer metastatic to the brain. One of the main perspectives of these efforts has been to identify prognostic factors for the survival of these patients. Many different factors have been investigated but partly with conflicting results. Only two factors were able to achieve acceptance by most authors of the current literature. One factor is the presence of extracranial disease at the time of brain relapse, which was shown to have a significantly negative impact on survival. Anupol et al. reported a median survival of 8 months for the occurrence of brain lesions for patients without any evidence of extracranial disease, in comparison to 3 months for cases which did yield that evidence (p=0.005) (2). Cohen et al. affirmed these findings and reported a median survival of 12.2 versus 3.5 months (p=0.001) (7). The other independent factor is the performance status of the patients at the time of recurrent disease. It was shown that a high performance status is likewise related to a higher median survival from the time of central metastatic relapse (31).
For the factors “single” versus “multiple” metastases and the time interval between primary diagnosis and metastatic manifestation, no consistent conclusion can be drawn from the recent literature because the results are not significant in multivariate analysis. A solitary lesion most likely promises a slight advantage over presentation with multiple lesions, as reported by Anupol et al. with a median survival of 7 versus 5 months (p=0.07), but this factor does not withstand multivariate analysis in most reports (2). A short time interval between primary diagnosis and brain relapse was reported to have a negative impact on survival. Cormio et al. for instance found a median survival of 9 months for patients with an interval shorter than 40 months versus a median survival of 16 months for patients with a longer interval (p=0.03) (12). But again, this factor did not pass multivariate analysis. On the other hand, for most of the other factors which have been investigated in the past, like tumour stage, grade, histotype, age at diagnosis of CNS relapse, and site of lesion, it is widely agreed upon in the current literature that these are not related to survival (12).
Therapeutic Options
Therapeutic options for patients with brain metastases from EOC include best supportive care with or without corticosteroids, surgery, radiation (including SRS) and chemotherapy. Death in these patients often results from cranial herniation in the wake of highly increased intracranial pressure. This can be due to large, mostly cystic lesions causing a mass effect, or due to a cerebral oedema surrounding the lesions. A therapeutic approach to this problem is the treatment with corticosteroids, which often results in a satisfactory symptom reduction. However, it was shown by McMeekin et al. that this treatment is of strictly palliative nature and is equivalent to no treatment in terms of mortality, whereas any other form of therapy (radiation, surgery, gamma-knife, chemotherapy), not focusing on the treatment modality, does translate to a prolongation of median survival from 2 to 7 months (4). When compared with each other individually, the conventional neurosurgical approach promises the best results. Even though success of surgical therapy options is often boosted by selection bias, there is evidence that surgery is the most promising individual technique when applicable in the individual patient. Despite that fact, the most commonly used individual therapy strategy is WBRT. This is mostly due to contraindications to surgery, inaccessibility of lesions and the presence of multiple metastases. WBRT applied individually has the potential to decrease neurological symptoms and prolong median survival up to 3-6 months (7, 21). The technique is easily applicable to most patients, even with multiple and otherwise inaccessible lesions, but can cause severe dementia and brain atrophy (in case the patient lives long enough to experience late sequelae).
Even though chemotherapy is an inherent part of standard treatment for ovarian cancer and even extracranial recurrence, its role in the treatment of brain metastases still remains somewhat controversial with regards to the management of EOC. Case reports have shown good results and even complete remission with platinum-based agents such as carboplatin and cisplatin (32, 33). There are very few reports on any experience with chemotherapy as an individual therapeutic strategy. Melichar et al. reported a median survival of 16 months after chemotherapy alone, while other studies observed a median survival of 11-15 months only, even when combined with surgery or radiation (3, 6, 31). Up to this point there is not enough evidence on individually applied chemotherapy, and further trials are needed to support promising results. Also, the focus in future studies should shift towards agents with the potential of reaching a high concentration in the cerebrospinal fluid, because of their ability to cross the BBB. Most agents of platinum-based chemotherapy - the standard choice for ovarian cancer - do not possess this potential (34). Cisplatin for example reaches only a mere concentration of 0-2% compared to the blood level, while agents like topotecan can achieve a concentration of up to 40% (34, 35). Even although it is known that the BBB is already impaired in the metastatic lesion itself, there is experience, from other malignancies frequently causing brain metastases, which favours agents with that potential (36). Although an individual therapy strategy has benefits because of simple application and limited side-effects, many investigators have proven that the therapeutic potential can be greatly increased by the combination of different modalities into a multimodal approach. Cohen and colleagues report a median survival of 5.6 months for surgery or WBRT when these are employed individually, but they also observed a multiplication of the median survival to 23.1 months after a combination of both strategies (7). Great efforts have been undertaken to identify the optimal combination of modalities, but the results remain to a certain extent a matter of dispute. Two strategies have evolved as most promising from studies with large collectives and meta-analysis. One is the combination of surgery and radiation, the other a threefold approach with additional chemotherapy. Pectasides et al. reported a median survival of 21 months after treatment with surgery plus radiotherapy versus 20 months with additional chemotherapy (16). Melichar et al. on the other hand observed a median survival of 17 months after surgery and radiotherapy compared to 20 months after a triple therapy with added chemotherapy (31). Anupol et al. found a median survival of 16 months after radiation plus surgery versus 22 months after added chemotherapy (2). However, this benefit achieved through additional chemotherapy has to be weighed against the potential side effects of this option. Even though chemotherapeutical agents are usually well tolerated, a number of frequent side effects are known to exist. These effects might not pose a great threat, but most chemotherapy-related side-effects result in a decrease of quality of life for the patient. Considering that brain relapse in ovarian cancer is generally a palliative situation, quality of life should be one of the main objectives that has to be taken into account in the decision on the optimal therapy strategy. In the last few years SRS (for instance linear accelerator- or gamma-knife-based) has come into focus as another promising therapy option in brain metastases from ovarian cancer. SRS is mostly applied in patients with no more than 3 cerebral lesions, which are treated with one single high-dose radiation fraction. Lee et al. even observed a remarkable median survival of 29 months after treatment with SRS compared to 6 months after WBRT (37). Few investigators have combined this option with other strategies, despite its promising properties. Even though the findings of Lee et al. might be subject to selection bias, SRS is a very promising option that should be further investigated in future trials and integrated into a multimodal approach.
Conclusion
The outcome of patients with brain metastases from EOC is very poor, having an overall survival from diagnosis of CNS-lesions of about 7 months only (4). A multimodal therapy approach may achieve an improved outcome for the patients and should therefore be utilized whenever applicable. The evidence available to date is pointing towards a combination of surgery and radiotherapy as the treatment modality with the best benefit to drawback ratio (3). An additional chemotherapy can potentially improve clinical outcome in some patients, but this benefit has to be measured against possible side-effects. Further research is needed to clarify the value of chemotherapeutic agents having a potential of reaching high concentrations in the cerebrospinal fluid in patients with brain relapse from EOC. Even though it is known that the BBB is already impaired in metastatic lesions, there is some evidence that agents with that potential have a higher impact on tumour reduction (36). A promising strategy for the future might be an increased employment of the stereotactic radiosurgery, with its capability to remove lesions inaccessible to neurosurgery with an efficiency equivalent to surgical resection (37). Future studies should focus on the integration of stereotactic radiosurgery into the multimodal approach, in order to obtain optimal surgical tumour removal even in patients with multiple lesions prior to any application of chemotherapy.
Footnotes
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↵* Presented at the 8th International Conference of Anticancer Research, 17-22 October 2008, Kos, Greece.
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This work was presented in part at the VII International Symposium of the North-Eastern German Society of Gynecologic Oncology (NOGGO) at the 8th International Conference of Anticancer Research 2008.
- Received January 6, 2009.
- Revision received March 5, 2009.
- Accepted April 2, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved