Brain Metastases from Epithelial Ovarian Cancer: A Review of
作者：Dimitrios Pectasides, Melina Pectasides, Theofanis Economopoulos
【关键词】 Brain,metastases,•,Surgery,•,Stereotactic,radiosurgery,•,Whole-brain,radiotherapy,•,Chemotherapy
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
Select the appropriate treatment strategies for ovarian cancer patients with solitary brain metastases and extracranial disease.
Describe the most important prognostic factors for ovarian cancer patients with brain metastases.
List the diagnostic steps needed to establish the diagnosis of brain metastases in ovarian cancer patients.
ABSTRACT
Background. Brain metastases from epithelial ovarian cancer (EOC) are rare. This report is based on a review of the literature.
Methods and Results. This review summarizes the incidence, clinical features, pathophysiology, and diagnostic evaluation of EOC. The section on current treatment includes a thorough evaluation of the literature, highlights controversies over treatment options, and provides insight into novel approaches. Current treatment options include surgical resection, whole-brain radiation therapy (WBRT), stereotactic radiosurgery, and chemotherapy. Corticosteroids and anticonvulsant medications are commonly used for the palliation of mass effects and seizures, respectively. In the reviewed series, a better outcome was seen following surgical resection and WBRT with or without chemotherapy for solitary and resectable brain metastases.
Conclusion. The prognosis for patients with brain metastases from EOC is poor. A better outcome might be obtained using multimodality therapy. Because of the small number of patients included in the reported studies, multicenter clinical trials are needed for further investigation in order to critically evaluate the clear benefit of these treatment options in selected patients.
INTRODUCTION
Ovarian cancer is a major cause of morbidity and mortality among gynecological malignancies [1]. The current standard treatment of epithelial ovarian cancer (EOC) of all histological subtypes involves primary optimal debulking surgery followed by cisplatin-based chemotherapy. However, despite the significant advances in surgery and chemotherapy achieved over the past decades, the resulting overall 5-year survival rate in patients presenting with advanced-stage disease remains quite low, approximately 40%, probably because of the lack of effective therapies [25]. Brain metastases from EOC are rare and a late manifestation of the disease that occurs in patients with prolonged survival as a result of platinum-based chemotherapy. The incidence of brain metastases from EOC ranges from 0.29% to 5% [68]. Some reports have indicated that the rate is >5% and approaching 12% [911].
Several meta-analyses of up to 194 patients have been conducted in an effort to formulate therapeutic guidelines [8, 1214]. A review of the English literature dealing with the relatively large series of patients with brain metastases from EOC is presented in order to assist the management of this interesting yet rare clinical entity.
INCIDENCE
In the reviewed series of 22,240 women with EOC, 219 cases with brain metastases were reported. The incidence of brain metastases from EOC is estimated to be 1.01%, ranging from 0.49% to 2.2% (Table 1). In a large series with brain metastases, the incidence was 6 out of 916 (0.7%) [15] or 13 out of 740 patients (1.8%) [16]. The estimates of the incidence of brain metastases in EOC patients may be considered reliable only in large centers based on records of hundreds of treated patients. In a large series that included 4,456 EOC patients over a period of 40 years (19441984), no central nervous system (CNS) metastases were observed before 1968 [17]. Mayer et al. [18] reported on five cases from 567 autopsies performed on patients with EOC, an incidence of 0.9%. In other autopsy series, the incidence of CNS metastases ranged from 1% (1 out of 86 cases) [19] to 6% (6 out of 100 cases) [20]. However, these figures could be underestimates of the true incidence. Many patients, regardless of disease stage at presentation or at follow-up, do not routinely undergo brain imaging as part of the metastatic workup, given that some lesions remain asymptomatic. Several authors recently have called attention to the rising incidence of EOC metastatic to the brain [7, 8]. Other recent studies have reported that the incidence of brain metastases has increased over time to 2%4% [21]. In a series of 42, 110, and 52 EOC patients, the incidences of brain metastases were reported to be 7.1% [8], 4.5% [9], and 11.6% [10], respectively. However, those studies only included a small number of patients. Some reports have indicated that the rate is >5% and is approaching 12 % [10, 11]. A possible explanation for the increased incidence of brain metastases that has been reported during the past three decades is that there has been a change in the natural course of EOC as a result of better primary control of intra-abdominal disease with platinum-based chemotherapy, resulting in longer survival. This allows metastases at distant sites to implant and grow. Another explanation is the availability of better imaging techniques for the diagnosis of brain metastases [11, 2124]. In addition, chemotherapy may cross the bloodbrain barrier (BBB) poorly, yet it increases the propensity for CNS metastases. Metastasis to the CNS from EOC has been postulated to occur via direct hematogenous seeding through Virchow-Robin perivascular spaces, through retrograde lymphatic spread in the case of meningeal involvement, or by direct invasion into the CNS after bony involvement [25]. The median age at presentation is 54.8 years (range, 3179 years). The median interval from diagnosis of EOC to CNS involvement is 21.5 months (range, 0126 months). In approximately 4% of patients, brain metastases either precede or occur simultaneously with the diagnosis of ovarian carcinoma [1113, 17, 22, 26, 27].
STAGE, HISTOPATHOLOGY, AND GRADE OF PRIMARY TUMOR
The Federation of Gynecology and Obstetrics (FIGO) stage was shown to be correlated with the incidence of brain metastases. The majority of patients (>80%) with brain metastases had stage III and stage IV disease at the time of initial diagnosis (Table 2). The most common histological grade was III, which is consistent with the experience of most reports [6, 14, 21, 25, 28], while a minority of patients had grade I tumors (4%5%) (Table 2). However, in the series of Kolomainen et al. [29], an unusually large proportion (one third) of the patients with CNS involvement had stage I disease. LeRoux et al. [30] reported that the time between primary diagnosis and brain metastasis was five times shorter in stage III and stage IV disease than in stage I and stage II disease. It has been argued, however, that this finding could be related to the advanced stage of EOC at diagnosis [13]. In the series by Cohen et al. [6], patients with grade I and grade II tumors had a median interval of 4.73 years from the diagnosis of primary cancer to the development of CNS involvement, as opposed to a median interval of 1.5 years in patients with grade III tumors (p = .03). This is in agreement with the belief that advanced disease and poorly differentiated tumors at the time of initial diagnosis place a patient at greater risk for CNS metastasis [6, 23, 30]. In contrast, other investigators reported that the degree of histological differentiation does not seem to be clearly correlated with brain metastasis [24, 28]. The most common type of EOC is the serous type [6, 13, 14, 24, 30], which is also the most common histological variant of EOC. Cohen et al. [6] reported that most of the patients in their study had either mixed histology (46%) or serous type (24%). This is consistent with previous reports [28, 31].
BRAIN METASTASES
The majority of patients with EOC have synchronous brain metastases and extracranial disease (65%), while one third of cases have isolated CNS relapse. Most patients have meta-chronous brain metastases, typically developing 23 years after their EOC diagnosis. However, cases of synchronous brain metastases [27, 32] or CNS involvement preceding the diagnosis of EOC by several months [26] have been reported. In the reviewed series, the brain metastases were single in 43% of patients and multiple in 50.1%, while 6.3% of patients had meningeal involvement (Table 3). In the study by Kaminsky-Forrett et al. [13], 54% of the patients had multiple metastases, and in the series by Cohen et al. [6], 35% of the patients had single and 65% had multiple metastases. In our series, 13 of 17 patients had multiple metastases [14]. The cerebral hemisphere was the most common site of metastasis, followed by the cerebellum. The falx cerebri and spinal cord were only occasional sites of metastasis [33]. The distribution of cerebral metastases included the parietal lobe, the frontal lobe, and the temporal lobe, in order of decreasing frequency. In the reviewed series, at the time of CNS metastasis, the EOC was disseminated to other organs in 52% of the patients. In our series, a high rate of isolated CNS involvement was found (76.5%) [14], while Kaminsky-Forrett et al. [13] reported a high rate of other sites of metastasis (87% of patients). Sanderson et al. [34] reported a higher proportion of patients as having extraperitoneal disease at the time of diagnosis, while Kolomainen et al. [29] demonstrated that approximately 50% of patients had the CNS as their only site of recurrent disease. In addition, some of the relapsing patients were complete responders after first-line chemotherapy. The presence of distant metastases aside from brain metastases seems also to have an adverse effect on survival. Because of the relative lack of effective salvage chemotherapy, most patients share a similar course of progressive intra-abdominal disease irrespective of intracranial disease state. Therefore, the cause of death in the majority of patients is related both to the brain metastases and to the abdominal spread of the disease. Cohen et al. [6] reported that extraperitoneal metastasis at the time of diagnosis of the brain metastasis was adversely correlated with survival in a univariate analysis (median survival time of 3.5 months vs. 12.23 months in patients with isolated brain metastases; p = .0001). However, this factor did not hold as an independent prognostic variable on multivariate analysis (p = .153). These results agree with those reported by Cormio et al. [28], who found a shorter median survival time (4.5 months) in patients with synchronous extracranial disease than in patients with the CNS as their only site of detectable disease (10 months), and with LeRoux et al. [30], but not with Rodriguez et al. [12]. The median time between the initial diagnosis of EOC and brain metastasis ranged in the literature from 15 to 70 months. In our series [14], the median interval from diagnosis of EOC to documentation of brain metastases was 15.9 months (range, 1.470.8 months).
CLINICAL MANIFESTATIONS
Brain metastases can present with focal or generalized symptoms, while headache is the most common symptom. Headache occurs in 40%50% of patients with brain metastases. They are most common in patients with multiple metastases or metastases located in the posterior fossa. Headache is probably a result of the increased intracranial pressure caused by edema or hydrocephalus. It is associated with visual disturbances, vomiting, confusion, and syncopal episodes and most commonly resembles a tension-type headache. Funduscopic examination is important to rule out papilledema. Headache is often dull in nature and bifrontal in location. For a minority of patients, the headache is reported to be ipsilateral to the location of the tumor. Patients with brain metastases tend to have a subacute progressive syndrome that may present occasionally, suddenly, or episodically. The clinical manifestations of cerebral metastases are also highly variable depending on the location of the lesions. Hemiparesis is the most common sign, followed by altered mental status. Papilledema is found infrequently, and many other focal dysfunctions that help localize the lesion may be present. Bladder/bowel dysfunction was most common with meningeal involvement. All of the patients presenting with coma died within 2 days to 2 weeks of diagnosis. Among patients with concurrent extracranial disease at the time diagnosis of brain metastases, the most common sites of recurrence were in the pelvis, abdominoperitoneum, liver, lungs, and lymph nodes.
DIAGNOSIS
One should suspect brain metastases in any EOC patient who develops a neurologic deficit. Magnetic resonance imaging (MRI) is the imaging modality of choice. It provides superior resolution over computed tomography (CT) scanning and is especially useful in evaluating the posterior fossa for metastatic lesions. MRI using a greater dose of gadolinium contrast may detect a lesion as small as 1.9 mm in size. MRI should be performed if a solitary lesion is found on a CT scan before surgical treatment is planned. Routine CT scanning of the brain is not recommended because follow-up procedures focus on the documentation of intra-abdominal relapse and do not usually include an evaluation of the CNS with imaging techniques. However, in the case of neurological symptoms, diagnosis of CNS metastases becomes obvious on CT or MRI scans in most cases. Cerebrospinal fluid examination for malignant cells confirms the presence of meningeal spread, although leptomeningeal spread is very rare. None of the patients in our series developed leptomeningeal disease [14], and previous reviews of the literature have shown 19 cases of leptomeningeal carcinomatosis secondary to EOC [6, 3537]. Contrast-enhanced CT is often negative for leptomeningeal carcinomatosis, with hydrocephalus or brain parenchyma lesions being the most common abnormalities found [35]. Noncontrast enhanced MRI is as insensitive as CT [38]. The sensitivity of contrast-enhanced MRI is much better with contrast enhancement occurring in a micronodular or linear pattern [38].
Characteristic findings of brain metastases include multiple lesions, lesions at the greywhite junction, relatively smooth margins, and a small tumor focus with abundant vasogenic edema. Not all lesions have significant surrounding edema. Lesions measuring <5 mm often have less surrounding edema. New imaging techniques using a greater gadolinium dose with delayed imaging, MR spectroscopy, positron emission tomography, and single photon emission computed tomography technology may offer better diagnostic utility, but further studies are needed to identify whether these modalities will provide an appropriate and cost-effective advantage over the current imaging techniques. The differential diagnosis for single lesions includes primary brain tumors, infarcts, cerebral abscess, and hemorrhages. When patients with known generalized cancer and single lesions on MRI were biopsied, it was found that 11% of the patients had lesions other than metastases. Half of these lesions were primary brain tumors, and the other half were infections [39]. In many cases, a brain biopsy is necessary for definitive diagnosis. It is important to accurately diagnose single CNS metastases because the management and prognosis are different than in patients with multiple metastases.
TREATMENT
The main role of treatment in patients with brain metastases is to control the neurologic symptoms and improve quality of life. Although treatment of brain metastases does not result in cure, the proper therapy can increase life expectancy and quality of life. Treatment is not always indicated if the patient’s age, performance status, and progressive widespread systemic disease preclude more aggressive therapies. Therapeutic options include: no treatment in patients with extensive, progressive widespread metastatic disease; rapid treatment to correct life-threatening complications of metastases, including obstructing hydrocephalus and increased intracranial pressure; and various other treatment strategies, including corticosteroids, whole-brain radiotherapy (WBRT), surgery, radiosurgery, and chemotherapy (Table 4). Death results from edema surrounding the brain lesion, creating increased intracranial pressure and resulting in cerebral herniation.
Because of the rarity of these patients, the optimal treatment for brain metastases is currently ill-defined. Treatment modalities have differed for patients with brain metastases. The therapeutic approach toward EOC with brain metastases must take into account the number and location of the metastases, the presence or absence of extracranial disease, previous treatment, performance status, and neurosurgery possibilities. The goal of treatment is to alleviate the neurologic symptoms. However, treatment management is different for isolated solitary metastases than for multiple metastases. Patients with isolated solitary brain metastases generally undergo craniotomy with resection of metastases followed by WBRT. For patients with multiple CNS metastases, the treatment is often palliative. Thus, patients with multiple brain metastases with or without extracranial disease receive WBRT with or without chemotherapy.
Corticosteroids
The mechanism of action of corticosteroids is not completely clear. Corticosteroids are known to enhance extracellular fluid absorption and decrease capillary permeability. Edema is markedly reduced by corticosteroids, while headache is usually improved more than focal deficits. The preferred corticosteroid is dexamethasone because of its minimal mineralocorticoid effect and lower rates of psychosis. In patients who require antiepileptic agents, those most often used are phenytoin, carbamazepine, phenobarbital, and valproate. The prophylactic use of anticonvulsant agents in patients with brain metastases is not indicated. Some patients with poor performance status received only corticosteroids, mannitol, and anticonvulsant agents. Corticosteroids result in a rapid improvement in symptoms. Although the effect of corticosteroids appears to begin within the first 624 hours, >70% of patients report a significant improvement in symptoms by the second day of treatment. The maximum effect of corticosteroids is often seen after 37 days. However, the benefit of corticosteroids is temporary. The median survival time of patients with CNS metastases on corticosteroids alone is 2 months, similar to that expected in response to palliative treatment in patients with all types of brain metastases [6, 13, 14, 40, 41].
WBRT
WBRT with or without chemotherapy remains the treatment of choice for patients with multiple brain metastases with or without extracranial disease. Palliative radiotherapy alone was administered in 30%50% of patients with multiple brain metastases in all the reviewed series [6,13,25,31]. Corn et al. [42] reported the results of radiotherapy in 32 patients treated at five centers. The median survival time of these patients was only 4 months, similar to that of patients treated with radiotherapy alone in the pooled analysis reported by Melichar et al. [43]. The median survival time with WBRT alone was 36 months (range, 1.527 months) [6, 13, 25, 31]. Studies conducted by Radiation Therapy Oncology Group (RTOG) showed no significant difference in response using 20 Gy of radiation over 1 week compared with 50 Gy over 4 weeks. Thus, for nonoperable multiple metastases, the preferred dose of WBRT is 30 Gy in 10 fractions over 2 weeks [4446]. Patients may require accelerated therapy or larger doses if clinical deterioration is rapid. However, a large randomized trial conducted by the RTOG showed no difference in survival using hyperfractionated treatments compared with the standard 30 Gy in 10 fractions doses [47].
Surgery with or Without WBRT
Traditionally, for patients with isolated CNS relapse with single and/or resectable metastases, surgical resection followed by WBRT and systemic chemotherapy has been a realistic option. Single metastases occurs in 43% of patients with EOC. Approximately 50% of these patients are not surgical candidates because of extracranial disease or tumor inaccessibility. However, for those patients who are good candidates, surgical excision may control neurological symptoms, improve quality of life, and prolong survival [48]. A surgical series of 583 patients reported a median survival time of 9.4 months [49]. A recent prospective randomized study showed that patients with solitary brain metastases of any histological type treated with surgical excision plus WBRT had a longer time to relapse, longer overall survival, and longer duration of functional independence when WBRT was added to surgery, compared with those patients treated with WBRT alone [50]. Pothuri et al. [51] at Memorial Sloan-Kettering Cancer Center conducted a retrospective review of all patients who underwent craniotomy between 1989 and 2001 for pathologically recurrent EOC metastatic to the CNS. They concluded that craniotomy with adjuvant WBRT can provide control of brain metastases in the majority of these patients and may result in longer survival than with WBRT alone in selected patients [51]. These results are in line with those reported by other investigators [6, 13, 14, 25, 30, 31]. Cohen et al. [6] reported that the combination of surgery and WBRT was significantly better than surgery or WBRT alone (p < .01). In the reported series, only a few patients were treated with surgery alone [6, 13, 25]. Pothuri et al. [51] reported a median survival time of 18 months in 14 patients treated with surgery. Similarly, Cormio et al. [28], in a series of 22 patients treated with surgery, reported a median survival time of 16 months, compared with 4 months observed in 34 patients who did not have surgery. The median survival time of patients treated with surgery alone was comparable with that achieved with WBRT alone (6.9 months vs. 5.3 months) in the reviewed series [6, 13, 25].
The role of surgery in patients with multiple metastases is controversial because there are limitations for surgery in these patients. In a retrospective review, the median survival times were 6 months for the 30 patients who did not have all brain metastases surgically resected and 14 months for the 26 patients who had resection of all brain metastases [52]. That study demonstrated that resection of all lesions in selected patients with multiple brain metastases is feasible and results in significantly longer survival, with an outcome similar to that of patients undergoing surgery for a single metastasis. Cohen et al. [6] reported that metastases to other organs was not a significant predictor of the length of survival on univariate analysis in patients undergoing surgery alone or WBRT alone, nor was it a significant predictor of survival when adjusting for the other treatment modalities in the multivariate analysis.
Radiosurgery
Stereotactic radiosurgery (SRS) offers an alternative approach in which high doses of focused radiation are delivered by a linear accelerator or by a gamma-knife to the brain metastases [53, 54]. Gamma-knife SRS treats CNS lesions without a surgical incision [55]. Many of the lesions slowly decrease in size and dissolve following treatment with gamma-knife SRS [56]. Combs et al. [57] studied the impact of WBRT and focal boost SRS versus SRS alone in patients with brain metastases from primary breast cancer. They reported that survival was longer in patients receiving SRS only than in those receiving WBRT plus SRS as a focal boost. In the largest randomized trial, conducted by the RTOG, 333 patients were treated with WBRT or WBRT plus SRS [58]. That study showed no significant difference in survival (median survival time, 5.7 months vs. 6.3 months; p = .13). In that study, the radiosurgery technique (linear accelerator vs. gamma-knife) had no impact on outcome. There is no prospective study comparing surgery with SRS for the treatment of patients with single brain metastases. Two studies retrospectively compared these treatment modalities and demonstrated contradictory results [52, 59]. In a retrospective review of 569 patients, median survival did not differ for patients treated with SRS alone or with SRS followed by WBRT (8.2 months vs. 8.6 months) [60]. In the group of patients treated with SRS plus WBRT, fewer brain recurrences occurred. In addition, 37% of the patients treated with only SRS needed salvage therapy, compared with only 7% of the patients treated with SRS plus WBRT. Thus, there is strong evidence for the use of SRS in patients with single brain metastases but no evidence from randomized trials that SRS is beneficial in patients with multiple metastases. SRS is especially useful for patients with a single lesion who are unable to tolerate surgery and for those with surgically inaccessible lesions [61].
Chemotherapy
It is well known that almost all patients with EOC receive chemotherapy after initial diagnosis. Some investigators have suggested that the increased incidence of brain metastases from EOC is related to more effective chemotherapy [7] or that cisplatin-based chemotherapy may contribute to the increased incidence of CNS metastases [21, 53, 62]. The integrity of the BBB is thought to limit delivery of large hydrophilic drugs to the site of brain metastases, thus presenting problems in choosing which agents and doses to use [53]. However, with progressive growth of metastases, the integrity of the BBB may be violated. This explains the possible response of brain metastases to systemic chemotherapy. In addition, the inherent chemotherapy resistance of brain metastases was regarded as another limitation. However, in patients who have not been heavily pretreated with chemotherapy, response of brain metastases to chemotherapy generally has been similar to that of tumors of similar histology located extracranially [62].
The significance of chemotherapy in managing brain metastases remains somewhat controversial. Chemotherapy is frequently administered when there are other sites of recurrence. Chemotherapy has several benefits, such as simple administration on an outpatient basis and potential effectiveness against occult recurrent disease at other sites. Furthermore, chemotherapy does not induce brain damage, such as brain atrophy or dementia. Because brain metastases are part of disseminated recurrent disease in about two thirds of patients with brain metastases from EOC, systemic chemotherapy may help to control not only the brain metastases but also those outside the CNS. Recent studies with systemic chemotherapy have shown objective responses and longer survival for patients with CNS metastases from breast cancer and germ cell tumors [63]. Objective responses and survival benefits have also been reported, even in patients with EOC [12, 28, 37, 64, 65]. It may be possible to use cisplatin, particularly in patients who have had a previously documented response to platinum-based chemotherapy, or for chemotherapy-naive patients. Complete response of brain metastases after carboplatin has been reported in the literature [28, 56, 65, 66]. Paclitaxel has demonstrated activity in EOC. However, no reports in the literature were found using paclitaxel for the treatment of brain metastases. Melichar et al. [43] reported a response in a patient with brain metastases treated with cisplatin and gemcitabine, and Watanabe et al. [37] reported a response in a patient treated with carboplatin and docetaxel.
In conclusion, CNS metastases in EOC are rare and most likely late manifestations of the disease. Patients with isolated solitary CNS metastases usually undergo craniotomy and metastasectomy followed by WBRT. Patients with multiple CNS metastases with or without systemic disease have a poor prognosis and can benefit from WBRT and/or systemic chemotherapy. The role of chemotherapy in the treatment of brain metastases is unclear.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors indicate no potential conflicts of interest.
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