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Keywords:

  • ovarian carcinoma;
  • endometrial carcinoma;
  • brain metastases;
  • stereotactic radiosurgery;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Metastases to the brain from ovarian and endometrial carcinoma are uncommon and to the authors' knowledge consensus regarding optimal management is lacking. Stereotactic radiosurgery (SRS) has proven useful for the treatment of many benign and malignant brain tumors. In the current study, the authors evaluated outcomes after SRS in patients with ovarian and endometrial carcinoma.

METHODS

Twenty-seven patients with brain metastases underwent gamma–knife SRS. Six patients had endometrial carcinoma, whereas 21 patients had ovarian carcinoma. Eighteen patients also received whole–brain radiotherapy. A total of 68 tumors were treated with gamma–knife SRS.

RESULTS

At the time of last follow–up, 1 patient was still alive and 26 had died. The median survival was 7 months after the initial diagnosis of brain metastasis and 5 months after SRS. The 1-year survival rate after radiosurgery was 15% and that from the diagnosis of brain metastases was 22%. On final imaging, all tumors were controlled without further growth. Two patients (7.4%) developed new or progressive neurologic deficits after SRS.

CONCLUSIONS

SRS is an acceptable choice for the treatment of brain metastases resulting from ovarian and endometrial carcinoma, and provides local tumor control with limited morbidity. Careful patient selection is warranted in the setting of patients with uncontrolled systemic disease in whom a limited survival benefit is expected. Cancer 2008. © 2008 American Cancer Society.

Although endometrial carcinoma is the most common gynecologic malignancy. brain metastases from this disease are rare. The incidence of brain metastases from endometrial carcinoma ranges from 0.3% to 1.4%.1, 2 To our knowledge, there are only a few case reports and small series that describe patients with brain metastases from endometrial carcinoma, and the treatments and outcomes vary widely.1, 3–8

Brain metastases from ovarian cancer are rare and a late manifestation of the disease that occurs in patients with prolonged survival.9–16 The incidence of brain metastases from ovarian cancer ranges from 0.29% to 5%.17, 18 To our knowledge, only a few case series analyzing outcome and prognostic factors have been published to date in an effort to formulate therapeutic guidelines.19, 20

Stereotactic radiosurgery (SRS) has been used as a primary or adjunct therapy in the management of brain metastases. In the current study, we reviewed our experience with 27 patients who underwent gamma-knife SRS for brain metastases resulting from endometrial or ovarian carcinoma. We assessed tumor control, patient survival, and adverse radiation effects in these patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Twenty-seven patients with endometrial or ovarian carcinoma and brain metastases underwent SRS. Six patients (22%) had endometrial carcinoma as their primary malignancy and 21 patients (78%) had ovarian carcinoma. The mean age at of the patients at the time of presentation was 60.4 years and the median Karnofsky performance score was 90. One patient (3.7%) had previously undergone a brain biopsy, 4 patients (14.8%) had undergone a previous macroscopic total resection, 18 patients (66.7%) received whole–brain radiotherapy (WBRT), and 24 patients (88.9%) had received systemic chemotherapy. The data regarding initial American Joint Committee on Cancer (AJCC) stage of disease was available for 7 patients. Five patients had stage IIIC disease and 2 had stage IIB disease. Levels of tumor marker CA 125 were high in 4 of the patients with ovarian cancer.

Radiosurgery Technique

Our radiosurgical technique has been described in detail in previous reports.21, 22 In brief, patients underwent application of an imaging–compatible stereotactic head frame under local anesthesia supplemented by intravenous sedation. High–resolution magnetic resonance imaging (MRI) was then performed. Patients underwent either a sagittal scout MRI scan or a 3-dimensional localizer sequence that included axial, coronal, and sagittal images. The entire brain was then imaged using contrast–enhanced images with spoiled gradient recalled acquisition in steady state (SPGR) sequence. The entire brain was covered with 2-mm thick images without any gap. SPGR images were occasionally supplemented with T2–weighted MRI scans using the fast spin echo technique to assess the infiltrative tumor volume. The target volume included enhancing tumor regions. In all patients, the radiosurgery dose was prescribed to the entire tumor volume.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Survival

At the time of last follow-up, 1 patient (3.7%) was alive and 26 patients (96.3%) had died. The mean follow-up after SRS was 5.8 months. The overall median survival from the time of SRS was 5 months (range, 0.2 months–25 months) and that from the time of the initial diagnosis of brain metastasis was 7 months. The 6-month and 1-year survival rates from the time of diagnosis were 63% and 22%, respectively. The 6-month and 1-year survival rates from the time of SRS were 44% and 15%, respectively.

Tumor Control

Follow-up imaging was available for 18 patients. This imaging revealed that 1 patient (3.7%) achieved a complete response (ie, the tumor disappeared), 15 patients (55.6%) had tumors that decreased in size (partial response), 2 patients (7.4%) had tumors that demonstrated no change, and no patients developed progressive disease. Imaging data were not available for 9 patients (33.3%). No tumors hemorrhaged after SRS. During follow-up, 1 patient (3.7%) was found to have new brain metastases. Also during follow-up, 11 of 17 evaluable patients (64.7%) had a demonstrable loss of contrast uptake in the tumor center as interpreted by imaging studies.

Clinical Symptoms

Seventeen patients (62.9%) had neurologic deficits at the time of SRS. These included ataxia, gait disturbance, limb weakness, hemiplegia, memory, sensory disturbance, diplopia, hearing deficit, and visual deficit. After SRS, 7 of these patients improved, 8 remained without change, and 2 had worsening of their deficit. No patients developed a new deficit after SRS: preradiosurgery symptoms (A): 17 patients; postradiosurgery symptoms (B): 10 patients; A not B: 7 patients; A and B: 8 patients; A and worse B: 2 patients; not A and B: 0 patients; and not A and not B: 9 patients.

Two of 16 patients (12.5%) developed increased peritumoral edema. One patient received systemic chemotherapy for ovarian carcinoma after SRS, and a second received pentoxifylline and vitamin E for the management of an adverse radiation effect.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Endometrial Carcinoma

Endometrial carcinoma is the most frequent gynecologic malignancy diagnosed in the US. Despite this, metastasis to the brain from endometrial carcinoma is a rare phenomenon, with a reported incidence of 0.3% to 1.4%.1, 2 In large series, endometrial carcinoma comprises approximately 1% of all central nervous system (CNS) metastases, and it is only the third most common female genitourinary malignancy to involve the brain, behind ovarian carcinoma and choriocarcinoma. However, its incidence may be increasing secondary to improved diagnosis, more effective management of the primary disease, and overall increased survival.

Brain metastases from endometrial carcinoma tend to occur in the context of widely disseminated disease. Three factors–high tumor grade, advanced stage of disease, and the presence of lymphovascular space invasion–have been reported to be correlated with the future development of brain metastases. Correspondingly, the prognosis of patients with brain metastases is historically poor, with a median survival of 1 to 2 months. Given the rarity of brain metastases from endometrial carcinoma, studies aimed at determining the most efficacious approaches to treating these patients are few and are largely limited to case reports and small retrospective case series. Often, larger solitary brain metastases in resectable locations and in the presence of controlled systemic disease are surgically removed and subsequently treated with WBRT.23 Mahmoud-Ahmed et al retrospectively reviewed 10 cases of endometrial carcinoma that were metastatic to the brain to investigate the role of radiotherapy in treatment.24 They observed that patients treated with a combination of surgery and radiotherapy experienced a longer median survival (15 months) than patients treated with either radiotherapy or surgery alone (approximately 2 months for each). Most often, WBRT is used as the sole management of brain disease. More recently, SRS has been performed as a less invasive option compared with surgical resection.

The cerebrum is the most frequent site of metastases from endometrial carcinoma, which is consistent with the observed localization of metastatic lesions in general. A substantial proportion of patients reported to date have had multiple brain metastases, and these patients had shorter average median survivals compared with those with isolated lesions. The reason for this finding is not completely clear, but it may reflect a bias toward the more aggressive treatment of patients with solitary lesions. The treatment of multiple brain metastases remains controversial. However, it has been suggested that when all lesions are resectable, survival rates are equal for patients harboring solitary versus those with multiple brain metastases. SRS was used by Shiohara et al in their report of the successful treatment of 1 patient with multiple brain metastases from endometrial carcinoma.25 This limited experience is supported by multiple lines of evidence suggesting that SRS is beneficial for the treatment of multiple or unresectable brain metastases, regardless of the tumor histology.

Finally, to our knowledge, the role of systemic and intrathecal chemotherapy is as yet unknown. The treatment of brain metastases with systemic chemotherapy has been repeatedly disappointing. This is believed to be attributable to the difficulty of chemotherapeutic agents in crossing the blood-brain barrier. To our knowledge, there are no modern reports specifically addressing the use of chemotherapy for brain metastases resulting from endometrial carcinoma. Therefore, despite limited data, current recommendations support the use of aggressive multimodality treatment, including a combination of surgical resection or SRS with WBRT for brain metastases from endometrial carcinoma. Systemic chemotherapy for the management of local and distant disease is appropriate for patients in whom it can be tolerated.

Ovarian Carcinoma

Ovarian carcinoma is the leading cause of cancer deaths from female genitourinary malignancies. The biology of ovarian carcinoma shares features with endometrial carcinoma. The majority of cases are discovered late, and thus the disease is often at an advanced stage at the time of diagnosis. Dissemination is primarily via local spread in the peritoneal cavity and via lymphatic channels. Brain metastases from ovarian carcinoma are relatively rare, with an incidence ranging from 0.29% to 5%.17, 18 Secondary to better management of the primary disease, the incidence of brain metastases may be increasing. Approximately half of the reported cases to date involve solitary metastases. Most metastases are localized to the cerebrum followed by the cerebellum, and only rarely are leptomeningeal.

Surgical resection, WBRT, systemic chemotherapy, and SRS alone and in combination have been explored for the treatment of brain metastases resulting from ovarian carcinoma. In a retrospective case series, Cohen et al demonstrated that surgical resection of solitary ovarian cancer metastases followed by WBRT resulted in better survival compared with WBRT alone (median survival of 23 months vs 5 months).17 To our knowledge, the use of systemic chemotherapy for the treatment of brain metastases resulting from ovarian carcinoma is not well defined. McMeekin et al conducted an analysis of 15 studies to determine features associated with survival and optimal management.26 They concluded that aside from surgical intervention, the use of systemic chemotherapy was the only other modality associated with improved survival. Because many of the patients reported to have brain metastases also had active disease elsewhere, it is not clear whether chemotherapy extends survival by treating systemic or CNS disease. Importantly, Chen et al, in a small retrospective study, demonstrated that the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) may be useful for predicting survival in patients with brain metastases resulting from ovarian carcinoma.27

To our knowledge SRS has been used as part of a multimodality approach in only a limited number of patients, and therefore little more can be said regarding its efficacy in brain metastases from ovarian carcinoma versus tumors of other histologies. To our knowledge to date, it has proven useful in treating deep-seated and metastatic ovarian tumors not amenable to resection and refractory to WBRT. In a report by Corn et al, SRS produced more frequent complete radiographic responses in brain metastases from ovarian carcinoma (40% vs 29%) and higher 2-year survival rates (60% vs 15%) compared with WBRT.28

Given the limited number of patients reported to date, the variability in treatment approaches, the lack of prospective data, and the varied outcomes observed, certainty regarding the optimal approach for the treatment of brain metastases from endometrial and ovarian carcinoma is lacking. Available retrospective data support the combined use of surgical resection followed by WBRT for the treatment of larger solitary metastases in select patients. SRS has proven to be an effective therapeutic modality for the treatment of smaller solitary and multiple brain metastases because of its reduced invasiveness, ability to target surgically inaccessible lesions, and ability to exact local tumor control. However, to our knowledge, experience with the use of SRS in the treatment of brain metastases from endometrial and ovarian carcinoma has been limited to date. Careful patient selection and goal-defined therapy are essential to optimize the care of patients with endometrial and ovarian carcinoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES