The main objective of treating brain metastases is to improve survival and to reduce symptom burden, preserve function, and enhance quality of life. As such, concurrent local control of existing brain metastases, prevention of future metastasis elsewhere in the brain, and control of the systemic cancer are required. The treatment modalities used to achieve these aims include surgery, radiation, and medical therapy. This article is devoted to the medical management of brain metastases, namely the role of medical treatments and chemotherapy. Radiation therapy and surgery are discussed in detail elsewhere; however, a brief discussion of all of these modalities is included for the sake of thoroughness.
Metastases to the brain are 5 to 10 times more common than primary brain tumors and commonly originate from the lung, breast, skin, kidney, and colon. According to the 2008 American Cancer Society Registry, roughly 1.5 million Americans are diagnosed with cancer every year, and up to 40% of these patients, over a half million people annually, will develop one or more brain metastases. Brain metastases may be identified in asymptomatic patients or present as headaches, seizures, mental status changes, and motor or sensory deficits. Additionally, the incidence of brain metastasis appears to be increasing likely due to the number of systemic cancer patients living long enough to develop metastases as a result of improved primary cancer therapies. Treatment for patients with brain metastases should be individualized and balanced with regard to patient-specific and cancer-specific characteristics. The main objective of treating brain metastases is to improve survival and to reduce symptom burden, preserve function, and enhance quality of life. As such, concurrent local control of existing brain metastases, prevention of future metastasis elsewhere in the brain, and control of the systemic cancer are required. The treatment modalities used to achieve these aims, either alone or in combination, include surgery, radiation, and medical therapy. This article is devoted to the medical management of brain metastases, namely the role of medical treatments and chemotherapy. Radiation therapy and surgery are discussed in detail elsewhere; however, a brief discussion of all of these modalities is included for the sake of thoroughness, and further information is available in several recent review articles.
Patient prognostic factors
Prognostic factors maximize therapy for a patient and help avoid unnecessary and harmful treatment. The prognosis of patients with symptomatic brain metastases is poor, with a median survival in untreated patients of 4 weeks. Supportive care with corticosteroids increases survival to about 8 weeks, while more recognized treatments, like radiotherapy, lengthen the median survival time to roughly 4 months. Several studies have attempted to identify factors that predict better survival. In 1999, Lagerwaard and colleagues published a retrospective review of 1292 patients with metastatic brain disease and identified prognostic factors. Eighty-four percent of the patients reviewed were treated with whole-brain radiation therapy (WBRT). Nine percent were treated with steroids only, and 7% were treated with surgery and radiotherapy. Data acquired included age, gender, Karnofsky performance status (KPS), number and distribution of brain metastases, site of primary tumor, histology, interval between primary tumor and brain metastases, systemic tumor activity, response to steroid treatment, and treatment modality. The overall median survival was 3.4 months, with 6-month, 1-year, and 2-year survival percentages of 36%, 12%, and 4%, respectively. Median survival was 1.3 months in patients treated with steroids alone, 3.6 months in patients treated with radiotherapy, and 8.9 months in patients treated with surgical resection followed by radiation. Multivariate analysis revealed that treatment modality was the most significant factor in predicting survival. Response to steroid treatment, performance status, systemic tumor activity, age, and number of metastases were also independent prognostic factors on survival, but secondary to treatment modality in level of significance.
More recent studies have confirmed these findings on prognostic factors. Further analysis of the factors influencing the survival of patients with brain metastases resulted in the development of prognostic indexes. The Recursive Partitioning Analysis (RPA), developed by the Radiation Therapy Oncology Group (RTOG), categorized patients who received WBRT into one of three prognostic groups. RPA class 1 represented patients younger than 65 years with a KPS of at least 70 and a controlled primary tumor with the brain the only site of metastases, resulting in a median survival of 7.1 months. RPA class 3 represented patients with a KPS less than 70, resulting in a median survival of 2.3 months. RPA class 2 represented all other patients, resulting in a median survival of 4.5 months. The RPA, however, is limited by its subjective estimation of systemic tumor control and total brain metastases, two factors that influence survival. Such factors are incorporated into the more recent Graded Prognostic Assessment (GPA), which has four factors (age, KPS, number of brain metastases, and the status of disease outside the central nervous system [CNS]) that partition patients into one of four categories, with median overall survival ranging from 2.6 to 11 months. An even more recent study attempted to identify significant diagnosis-specific prognostic factors (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). This was done by retrospective analysis of 4259 patients with newly diagnosed brain metastases using univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment. Results showed that significant prognostic factors varied by histologic diagnosis. For example, for nonsmall cell lung cancer and small cell lung cancer, the significant prognostic factors were KPS, age, presence of extracranial metastases, and number of brain metastases. For melanoma and renal cell cancer, the significant prognostic factors were KPS and the number of metastases. For breast and gastrointestinal (GI) cancer, the only significant prognostic factor was KPS. These data should be considered in the design of future randomized trials and in clinical decision making.
Treatment guidelines
The modalities used to treat brain metastases include surgery, radiation, and systemic therapy, used alone or in combination. The choice of which of these modalities to use is influenced by patient preference, provider preference, cost, availability, and continuing research. Clinical practice parameter guidelines for the treatment of patients with metastatic brain tumors have been published with the aim of limiting variation in care without affecting clinical judgment. For example, in 2010, the American Association of Neurologic Surgeons (AANS), the Congress of Neurologic Surgeons (CNS), and the Joint Tumor Section (AANS/CNS) produced multidisciplinary, evidence-linked clinical practice guidelines for the treatment of patients with metastatic brain tumors. Additionally, guidelines on metastatic brain tumors have been produced by the American College of Radiology (ACR) Appropriateness Criteria and the National Cancer Institute (NCI), National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. With general regard to all of these guidelines, patients considered to have a poor prognosis are likely to receive symptom management alone or WBRT. In contrast, patients considered to have a good prognosis are more likely to receive multimodality therapy, typically a combination of therapies aimed at local brain control, distant brain control, and systemic control.
Treatment guidelines
The modalities used to treat brain metastases include surgery, radiation, and systemic therapy, used alone or in combination. The choice of which of these modalities to use is influenced by patient preference, provider preference, cost, availability, and continuing research. Clinical practice parameter guidelines for the treatment of patients with metastatic brain tumors have been published with the aim of limiting variation in care without affecting clinical judgment. For example, in 2010, the American Association of Neurologic Surgeons (AANS), the Congress of Neurologic Surgeons (CNS), and the Joint Tumor Section (AANS/CNS) produced multidisciplinary, evidence-linked clinical practice guidelines for the treatment of patients with metastatic brain tumors. Additionally, guidelines on metastatic brain tumors have been produced by the American College of Radiology (ACR) Appropriateness Criteria and the National Cancer Institute (NCI), National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. With general regard to all of these guidelines, patients considered to have a poor prognosis are likely to receive symptom management alone or WBRT. In contrast, patients considered to have a good prognosis are more likely to receive multimodality therapy, typically a combination of therapies aimed at local brain control, distant brain control, and systemic control.
WBRT
WBRT was the mainstay of metastatic brain tumor therapy for decades through the mid-1990s. The goals of WBRT include treatment of the known metastases and prevention of future ones. The most common regimen used in North America uses parallel-opposed external beams to deliver a dose of 30 Gy, divided in a 10-dose fraction for 2 weeks. Evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control, or neurocognitive outcomes when compared with standard WBRT dose/fractionation. (ie, 30 Gy in 10 fractions).
Acute complications of WBRT include cerebral edema, nausea/vomiting, alopecia, skin reactions, and mucositis. Later complications include radiation necrosis, dementia, endocrinopathies, and diminished neurocognitive function. WBRT is often used alone in RPA class 3 patients whose alternative is best supportive care. In this setting, both overall response rate and neurologic improvement range from 50% to 60%, and survival improves from between 1 and 2 to 4 months. WBRT is often used in conjunction with local treatment (surgery or stereotactic radiosurgery [SRS]) in RPA class 1/2 patients whose alternative is local treatment alone or local treatment combined with systemic treatment.
Surgical resection
The objectives of surgery include establishment of a diagnosis, local control, and rapid relief of symptoms caused by mass effect, hemorrhage, or hydrocephalus. Surgery often is used in patients with RPA class 1/2, a single metastasis, and a minimal or controlled systemic tumor. Prospective surgical studies report an excellent ability to establish a diagnosis and partially improve symptoms, yet little influence on distant brain control and survival. Surgical resection followed by WBRT represents a superior treatment regimen, in terms of improving tumor control at the original site of the metastasis and in the total brain, when compared with surgical resection alone. Additionally, evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection plus WBRT for patients with single-brain metastases, so long as ready detection of distant site failure and salvage radiotherapy are feasible.
SRS
The common objective of SRS, a convenient single outpatient procedure, is to treat single or multiple metastases and nonsurgical candidates. Tumors amenable to SRS normally measure less than 3 cm in maximum diameter and produce minimal mass effect. SRS uses head immobilization, computer planning, and convergent beams to deliver a single dose of radiation with high intensity at the target and rapid dose fall-off at the margins. SRS usually is reserved for patients with a known diagnosis. According to AANS/CNS guidelines, single-dose SRS along with WBRT leads to significantly longer patient survival compared with WBRT alone for patients with single metastatic brain tumors who have a KPS greater than or equal to 70. Also, single-dose SRS along with WBRT is superior in terms of local tumor control and maintaining functional status when compared with WBRT alone for patients with one to four metastatic brain tumors who have a KPS greater than or equal to 70. Retrospective and prospective studies report local control rates of 60% to 75% at 2 years, distant brain control rates of about 46% at 2 years, survival of about 10 months, decrease in the need of steroids, and trend toward survival in RPA class 1/2 patients. Across retrospective studies, factors predicting distant brain control and improved outcome after SRS alone include female gender, youth, higher KPS, fewer than three lesions, smaller total metastasis volume, surgery before SRS, nonmelanoma histology, and minimal or controlled systemic disease. Otherwise and similar to surgery, there is limited impact on distant brain control and overall survival.
Chemotherapy
The primary therapeutic modality for disseminated systemic cancer remains chemotherapy. Chemotherapy is used to improve local control, distant brain control, and systemic control. Chemotherapy can be used at initial diagnosis of metastatic disease or at progression. It also may be used alone or in combination with radiation and can be selected either for its capacity to penetrate the blood–brain barrier (BBB) or its efficacy in specific cancer types. General toxicities associated with cytotoxic chemotherapy include myelosuppression, immunosuppression, GI dysfunction, fatigue, and drug-specific toxicities.
The utility of chemotherapy in the treatment of brain metastases is limited by the BBB and by the tumor. The BBB limits the passage of large, hydrophilic molecules. Many chemotherapeutic agents are thus relatively excluded from the brain, and ones that do cross the BBB may do so in inadequate concentrations. Supporting this difficulty of crossing the BBB is the observation that intracranial radiographic response rates to chemotherapy are typically lower than extracranial radiographic response rates. An alternative hypothesis for this finding is that patients are exposed to cytotoxic therapies for their systemic disease, and it is therefore chemoresistant tumors that spread to the brain. However, data in newly diagnosed, previously untreated patients with small cell lung cancer (SCLC) suggest that intracranial response rates remain significantly lower than extracranial response rates, thereby suggesting that chemoresistant tumors do not explain this issue in full. Furthermore, agents that affect peritumoral edema or CNS vasculature, including steroids and vascular endothelial growth factor (VEGF) inhibitors, may partially and temporarily affect the BBB and affect the ability to appropriately interpret imaging. Tumor-related factors also limit the usefulness of chemotherapy, including their relative size, number, chemosensitivity, and heterogeneity within the tumor itself.
Taking these factors into account, the influence or direct role of chemotherapy in patients with brain metastases is difficult to determine. Defining chemotherapy’s role is further made challenging by the limited number of studies conducted, most of which are in patients with NSCLC and thus cannot be extrapolated to other histologies with confidence. Also, many studies include patients with various tumor types, uncontrolled systemic disease, undefined numbers of prior recurrences or treatments, and subjectivity in the assessment of progression and imaging response. Confounding the conclusions further is the fact that some of these patients were pretreated with chemotherapy, whereas others were chemotherapy-naïve. End points also vary between studies, with some unable to reach a statistically significant conclusion with regard to a primary end point, such as survival, while reporting significant differences in other secondary end points, such as tumor radiographic response.
Many studies have looked at administering chemotherapy concurrently, before or after radiotherapy or sometimes alone. The optimal role and timing of combination therapy remain undefined. What follows is a succinct review of chemotherapy studies done to date in the context of the four most common designs in which chemotherapy has been studied in patients with brain metastases:
- 1.
WBRT plus chemotherapy versus WBRT alone
- 2.
Chemotherapy plus WBRT versus chemotherapy
- 3.
Chemotherapy with concomitant WBRT versus chemotherapy with delayed WBRT
- 4.
Chemotherapy first followed by WBRT versus WBRT first followed by chemotherapy.
Again, the role of chemotherapy in patients with brain metastases remains ill-defined, and the following review will allow the reader to better understand why.
WBRT Plus Chemotherapy versus WBRT Alone
Several chemotherapy agents have been evaluated for combination with radiation, including nitrosoureas, platinums, 5-fluorouracil agents, etoposide, topotecan, and temozolomide. To date, temozolomide has been one of the most extensively studied because of its penetration through the BBB. For example, in 2002, Antonadou and colleagues conducted a phase 2 trial in which patients with brain metastases were randomized to WBRT alone or WBRT plus temozolomide. Adult patients aged 18 or older, with brain metastases from cancer of the lung, breast, or unknown primary, were included. Patients either received 40 Gy of WBRT in 20 fractions of 2 Gy each or received the same dose of WBRT with 75 mg/m 2 /d of temozolomide orally during WBRT and continued temozolomide therapy (200 mg/m 2 /d for 5 days every 28 days) for an additional 6 cycles after WBRT. The two groups were similar with respect to gender, age, KPS, neurologic functional level, and tumor type. The study end points were radiographic response, neurologic symptom evaluation, and survival. The median survival was 7 months in the WBRT alone group and 8.6 months for the combination group, which was not statistically significant. The overall response rate was 67% versus 96% for WBRT alone versus combination, which was statistically significant. There was neurologic improvement in the group receiving temozolomide, with fewer patients needing corticosteroids in this same group.
In 2003, Verger and colleagues conducted a phase 2 trial in patients with brain metastases randomized to WBRT alone or WBRT plus temozolomide. Adult patients aged 18 or older with a KPS greater than or equal to 50 were included. Exclusion factors included previous chemotherapy within the previous 3 weeks, prior cranial radiotherapy, and leptomeningeal involvement. Patients either received 30 Gy WBRT in 10 fractions of 3 Gy or received the same dose of WBRT with 75 mg/m 2 /d of temozolomide orally during WBRT and continued temozolomide therapy (150–200 mg/m 2 /d for 5 days every 28 days) for an additional 2 cycles after WBRT. The primary outcome was an analysis of neurologic toxicity, but radiologic response and progression-free survival were analyzed. The trial was stopped prematurely because of low patient accrual. The median survival was 3.1 months versus 4.5 months for WBRT alone versus combination and was not statistically significant. The overall response at day 30 was 32% for both groups. There was a statistically significant difference in cause of death between the two groups, with neurologic death occurring in 69% of patients in the WBRT alone cohort compared with 41% of patients in the WBRT plus temozolomide group.
In 2008, a single-institution phase 2 clinical trial examined the efficacy of a dose-intensified, protracted course of temozolomide (TMZ) after WBRT. Patients were eligible if they had at least one bidimensionally measurable brain metastasis from breast cancer or NSCLC. Twenty-seven patients were treated with 30 Gy of WBRT with concomitant TMZ (75 mg/m 2 /d) for 10 days, and subsequent TMZ at a dose of 75 mg/m 2 /d for 21 days every 4 weeks, for up to 12 cycles. Two complete responses (7.4%) and 11 partial responses (40.7%) were achieved. The overall median survival was 8.8 months, and the median progression-free survival was 6 months. Authors concluded that the concomitant use of WBRT and protracted low-dose TMZ appeared to be an active, well-tolerated regimen.
In this context, other chemotherapies have been studied also. In 2004, Guerrieri and colleagues published a multi-institutional, randomized controlled trial of palliative radiation with concomitant carboplatin for patients with brain metastases from NSCLC. Overall survival was the primary end point. Prior chemotherapy and prior brain radiotherapy were exclusion criteria. Forty-two patients were randomized to two groups: WBRT or WBRT plus carboplatin. The radiotherapy dose was 20 Gy in 5 fractions in both arms, and the carboplatin dose was 70 mg/m 2 /d intravenously for 5 days. Unfortunately, the trial was terminated early because of low patient accrual, thus limiting the ability to draw statistically significant conclusions. The median survival was comparable, 4.4 months for WBRT versus 3.7 months for WBRT plus carboplatin, which was not statistically significant. In 2005, Kim and colleagues published a retrospective cohort study that included NSCLC patients with brain metastases who received WBRT for intracranial lesions or WBRT plus platinum-based chemotherapy. The exclusion criteria were patients who did not receive WBRT. The WBRT dose was 30 to 40 Gy, and several platinum doublets were employed. There was a marked difference in median survival, WBRT alone: 19.0 weeks versus WBRT plus chemotherapy: 58.1 weeks ( P <.001).
WBRT Plus Chemotherapy versus Chemotherapy
Under this design category, in 2000 a phase 3 randomized study compared teniposide versus teniposide with WBRT in patients with brain metastases from SCLC. The primary end point was survival. Teniposide was administered intravenously at 120 mg/m 2 on days 1, 3, and 5 every 3 weeks up to a maximum of 12 courses or until disease progression either inside or outside the brain. WBRT, dosed at 30 Gy in 10 fractions over 2 weeks, had to be started within 3 weeks of the start of treatment with teniposide. Although the response rate in the combined modality group was significantly higher (57%) than in the teniposide alone group (22%), this did not result in a prolongation of survival, thought to be due to progression of disease outside the brain.
In 2003, Mornex and colleagues performed a prospective randomized phase 3 trial of fotemustine plus WBRT versus fotemustine alone in patients with cerebral metastases from malignant melanoma. The main end points were objective response and time to cerebral progression. Patients were required to have received no chemotherapy in the prior 4 weeks, no previous nitrosourea-based chemotherapy, and no previous cerebral radiotherapy. The dose of WBRT was 37.5 Gy in 15 fractions over 3 weeks. Fotemustine was given intravenously at 100 mg/m 2 on days 1, 8, and 15, followed by a 5-week rest period and then every 3 weeks in nonprogressing patients. Although the fotemustine-alone patients had somewhat worse prognostic factors, there was no difference in cerebral response or control or in overall survival. There was a statistically significant difference in time to cerebral progression favoring the WBRT plus fotemustine group, with that group having a median time to objective cerebral progression of 56 days compared with 49 days in the chemotherapy-alone group.
Chemotherapy with Concomitant WBRT versus Chemotherapy with Delayed WBRT
Robinet and colleagues conducted a randomized trial in 1998 evaluating the use of systemic chemotherapy for the treatment of inoperable brain metastases from NSCLC with early WBRT versus WBRT delayed until progression. They treated 85 patients with cisplatin and vinorelbine concurrently with WBRT and 86 with the same chemotherapy, but with WBRT delayed for at least two cycles. Patients had histologically verified NSCLC and at least one brain metastasis greater than10 mm in diameter. Patients were treated with cisplatin 100 mg/m 2 on day 1, vinorelbine 30 mg/m 2 on days 1, 8, 15, and 22, with cycles repeated every 4 weeks. In one group, chemotherapy was started concurrent with WBRT, administered as 30 Gy in 10 fractions of 3 Gy given over 2 weeks. In the other group, radiation was deferred. The primary outcome reported was survival, for which there was no significant difference between the groups. The secondary endpoint of radiographic response was also similar, at 20% in both groups. Neurologic cause of death was reported as 88% in the group with delayed WBRT as opposed to 81% in the group treated with concurrent WBRT and chemotherapy. This study remains the only study to have attempted to answer the question of concurrent versus delayed WBRT with chemotherapy.
Chemotherapy Followed by WBRT versus WBRT Followed by Chemotherapy
Lee and colleagues performed a randomized trial in 2008 examining the use of chemotherapy followed by WBRT versus WBRT followed by chemotherapy for the treatment of advanced NSCLC with brain metastases. They treated 25 patients with gemcitabine and vinorelbine before WBRT; 23 patients were treated with WBRT followed by the same chemotherapy. Eligible patients were 18 to 75 years of age and had measurable disease in both intracranial and extracranial sites. The dose of gemcitabine was 900 mg/m 2 on day 1, and vinorelbine was 25 mg/m 2 on days 1 and 8, every 3 weeks, with a maximum of 6 cycles or disease progression. WBRT was administered as 30 Gy in 10 fractions of 3 Gy given over 10 days. In the WBRT-first arm, chemotherapy was initiated after at least a 2-week rest period. In the primary chemotherapy arm, all patients received WBRT after systemic disease progression or six cycles. There was no difference in overall response rates between the two arms (39% vs 28%, WBRT-first vs chemotherapy first). With a median follow-up of 40 months, there was no difference in progression-free survival or overall survival.
Chemotherapy Synopsis
There are other small and heterogeneous studies evaluating chemotherapy in patients with brain metastases other than what has been discussed. However, even including these other studies, there remains insufficient evidence to make definitive chemotherapy recommendations in patients with newly diagnosed or recurrent/progressive brain metastases. Chemotherapy should be individualized based on a patient’s functional status, extent of disease, volume and number of metastases, recurrence or progression at original versus nonoriginal site, previous treatment, and type of primary cancer. Enrollment in clinical trials is encouraged. Chemotherapy has been demonstrated to improve response rates when used as an adjunct to radiation therapy; however, these improvements in response rates have not been correlated with an improvement in median survival.
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