Contrary to the incidence of primary cancers, the incidence of brain metastasis has been increasing. This increase is likely because of the effects of an aging population, improved neuroimaging surveillance, and better control of systemic cancer, allowing time for brain metastasis to occur. Unlike systemic cancers, for which chemotherapy is the mainstay of treatment, the therapeutic strategies available to treat brain metastasis have traditionally been limited to surgical resection, whole brain radiation therapy, or stereotactic radiosurgery, either individually or in combination. It is important to put the treatment in the context of the prognosis for patients with brain metastases.
Approximately 1 million Americans are diagnosed with cancer every year, and approximately 1 out of every 2 men and 1 out of every 3 women have some type of cancer during their lifetime ( www.cancer.org ). The true incidence of brain metastasis is difficult to accurately ascertain because many patients who are neurologically asymptomatic do not undergo routine neuroimaging. A modest estimate of the true incidence of brain metastasis from cancer suggests that one-third of patients with systemic cancer or approximately 200,000 patients every year in the United States have metastasis of the brain. When compared with primary brain tumors, with an incidence estimated to be 20,000 persons in the United States, metastatic brain tumors are much more common. Contrary to the incidence of primary cancers, the incidence of brain metastasis has been increasing. This increase is likely because of the effects of an aging population, improved neuroimaging surveillance, and better control of systemic cancer, allowing time for brain metastasis to occur. Metastatic brain tumors have the capacity to bypass the blood-brain barrier, which provides them a harbor for unmitigated growth; once in the brain, they are generally protected from the cytotoxic effects of chemotherapy. The mechanism of metastatic growth involves genetic transformation of normal or, perhaps, cancer stem cells into a proliferative mass of tumor, which then gains access to the brain through angiogenesis and to the blood stream ( Fig. 1 ).
Unlike systemic cancers, for which chemotherapy is the mainstay of treatment, the therapeutic strategies available to treat brain metastasis have traditionally been limited to surgical resection, whole brain radiation therapy (WBRT), or stereotactic radiosurgery (SRS), either individually or in combination. Each of these treatments has their advantages and disadvantages. It is important to put the treatment in the context of the prognosis for patients with brain metastases. At the beginning of the twentieth century, diagnosis of a brain metastasis was a sign of terminal cancer and meant a survival limited to weeks. With the advent of WBRT and glucocorticoids for symptomatic improvement, survival was increased dramatically to 4 to 6 months. Later, in the 1990s, the combination of surgical resection and WBRT was shown to be superior to WBRT alone or surgery alone in high-functioning patients. The median survival was increased to 6 months in patients treated with WBRT alone and 10 months to those treated with surgical resection followed by WBRT. Surgery provides local disease control, especially for large-volume metastatic lesions, and can correct the potentially life-threatening consequences of mass effect and herniation. However, surgery does not protect against progression of disease at a local site or recurrence at distant sites. Furthermore, some patients may not be suitable surgical candidates because of their systemic disease and/or comorbidities or the location of the metastatic lesions.
With the advent of the Gamma Knife and modifications to the linear accelerator, SRS was introduced as another therapeutic option for patients with brain metastases. SRS with WBRT was found to be equivalent to surgical resection followed by WBRT for smaller lesions (<3 cm) without major mass effect. When WBRT is combined with surgical resection or SRS, it has been shown to help decrease local and distant recurrences. However, WBRT has been shown to cause various neurocognitive side effects and is indiscriminate in its neurotoxic effects. Still, with the individualized use of these treatment methods, survival with brain metastases has been extended to more than 1 year, and most patients now succumb to systemic effects of their cancer rather than their brain metastases.
It is in the context of the advantages and disadvantages of current therapies that experimental therapies must be judged. In general, the new or experimental treatments are divided into 5 major categories, as proposed by a recent summary of existing treatment options for patients with metastatic brain disease : (1) radiation sensitizers, (2) local irradiation to a resection or biopsy bed, (3) local chemotherapy to the resection or biopsy bed, (4) new chemotherapeutic agents, and (5) therapies that have shown promise in vitro and/or in animal experiments.
Radiation sensitizers
Because of the indiscriminate neurotoxic effects of WBRT and the associated cognitive side effects, radiation sensitizers are used to make tumor cells more susceptible to radiation while minimizing the exposure of surrounding normal tissue to radiation. Several of these sensitizers have been studied, albeit with mixed results.
Lonidamine, an indazole carboxylic acid derivative, showed promise in in vitro experiments and animals studies as a potent sensitizer of tumor cells to radiation but failed to show any difference in response rate or survival when compared with standard WBRT doses.
Thalidomide, although a potent teratogen, has recently been approved as part of a treatment paradigm for newly diagnosed multiple myeloma. However, it failed to show survival benefit when combined with conventional WBRT as compared with WBRT alone, although these patients had multiple, large, or midbrain metastases.
The 2 most recent sensitizers motexafin gadolinium (MGd) and efaproxiral (RSR13) similarly showed promise in early studies, but their efficacy in randomized controlled trials has been disappointing. However, there are some positive aspects to the agents worth noting.
MGd is a metalloporphyrin with its exact mechanism of action not entirely understood but is thought to increase intracellular levels of reactive oxygen species and hence induce apoptosis in the cells that have taken up MGd. It has been shown to have selective reuptake in tumor cells, is able to cross the blood-brain barrier, and because it contains the ferromagnetic material gadolinium, it can be imaged with magnetic resonance imaging. Early phase 1b/2 studies showed that MGd was well tolerated and had very favorable radiological response exceeding 70%. However, a subsequent randomized controlled study comparing MGd and WBRT to WBRT alone failed to show any difference in median survival. Subset analysis revealed that neurologic progression of disease was delayed in the MGd and WBRT combination versus WBRT alone for those patients with lung cancer, but other cancer types did not demonstrate this effect ( Fig. 2 ). A subsequent phase 3 study of patients with non–small cell lung carcinoma (NSCLC) failed to show significant differences in time to neurologic progression between patients treated with MGd and WBRT versus WBRT, although it was shown that in those patients treated with MGd and WBRT promptly, there was a significant delay in neurologic progression. Thus, in select patients, namely those with NSCLC that has metastasized to the brain, there may be benefit to administer MGd with WBRT in a prompt manner.
RSR13 is a synthetic substance that causes a conformational change in hemoglobin, decreasing its oxygen-binding affinity resulting in greater oxygen tension and hence greater radiation sensitization. A phase 2 trial of WBRT plus RSR13 resulted in a median survival time of 6.4 months, which was significantly longer than the survival of 4.1 months with WBRT alone from the Radiation Therapy Oncology Group database. A subsequent phase 3 trial failed to show significant differences in survival between RSR13 and WBRT and WBRT alone, although subset analysis showed that there was a significant survival benefit for women with metastatic breast cancer. However, a confirmatory phase 3 trial of women with metastatic breast cancer failed to show significant differences between those treated with RSR13 and WBRT and WBRT alone. Thus, it would seem that although the premise is promising, the use of RSR13 may not be warranted at present.
Local irradiation
Brachytherapy, which is the placement of radiation sources close to the area being treated, has been used successfully in treating cancers, including prostate, cervical, and breast cancers. The most common brachytherapy source is iodine 125 ( 125 I). The first cohort study comparing 125 I seeds and WBRT with 125 I seeds alone showed median survival time of 17 and 15 months, respectively, which was not statistically different. Two other case series showed efficacy of 125 I seeds, but no randomized controlled study has been completed. Other studies have combined surgery and delivery of 125 I through the GliaSite Radiation Therapy System (Cytyc Surgical Products II, Mountain View, CA, USA), with mixed results ( Fig. 3 ). A phase 2 study showed a median survival of approximately 40 weeks, with local control rate at approximately 80% and distant brain control rate at 50% that are comparable to previous studies of surgery followed by WBRT or SRS. The major concern in this study was the occurrence of radiation necrosis, which was estimated to be 17%. The investigators suggested that such a therapeutic strategy may be effective in delaying WBRT after resection, thus minimizing toxic effects to the rest of the brain. Other case series have shown some positive results, but no randomized controlled study has been completed comparing surgery and local brachytherapy to current standard treatments, including surgery, WBRT, or SRS. Thus, there does seem to be some advantage to local brachytherapy, especially regarding local tumor control and possibly delaying WBRT. However, this advantage may be offset by the increased risk for radiation necrosis.
Local irradiation
Brachytherapy, which is the placement of radiation sources close to the area being treated, has been used successfully in treating cancers, including prostate, cervical, and breast cancers. The most common brachytherapy source is iodine 125 ( 125 I). The first cohort study comparing 125 I seeds and WBRT with 125 I seeds alone showed median survival time of 17 and 15 months, respectively, which was not statistically different. Two other case series showed efficacy of 125 I seeds, but no randomized controlled study has been completed. Other studies have combined surgery and delivery of 125 I through the GliaSite Radiation Therapy System (Cytyc Surgical Products II, Mountain View, CA, USA), with mixed results ( Fig. 3 ). A phase 2 study showed a median survival of approximately 40 weeks, with local control rate at approximately 80% and distant brain control rate at 50% that are comparable to previous studies of surgery followed by WBRT or SRS. The major concern in this study was the occurrence of radiation necrosis, which was estimated to be 17%. The investigators suggested that such a therapeutic strategy may be effective in delaying WBRT after resection, thus minimizing toxic effects to the rest of the brain. Other case series have shown some positive results, but no randomized controlled study has been completed comparing surgery and local brachytherapy to current standard treatments, including surgery, WBRT, or SRS. Thus, there does seem to be some advantage to local brachytherapy, especially regarding local tumor control and possibly delaying WBRT. However, this advantage may be offset by the increased risk for radiation necrosis.
Local chemotherapy
There have been a few studies evaluating the use and efficacy of local chemotherapy to increase local control of brain metastases. A biodegradable biopolymer wafer containing BCNU (carmustine) (marketed as Gliadel in the United States) has shown promising results in the treatment of primary brain tumors. This wafer has recently been used in the treatment of metastatic brain tumors. In one study, 25 patients with solitary brain metastases were enrolled in a single-arm study of surgical resection, with the use of BCNU wafers and WBRT. Median survival was 33 weeks, and with a median follow-up of 36 weeks, there was no local recurrence of tumor, although distant metastases occurred. Other groups have shown some success with other substances such as 5-fluoro-2′-deoxyuridine administered with the use of an Ommaya reservoir. To date, no randomized study of local chemotherapy has been published, although the clinical and preclinical data are promising.
Other local treatments
There has been a renewed interest in other local therapies such as photodynamic therapy (PDT) and interstitial radiosurgery. PDT consists of injecting a photosensitizer, a chemical compound that can be excited by application of light of a certain wavelength. Once the photosensitizer is excited, it has the capability of acting as a killer substance. In a prospective trial, 14 patients were treated with PDT and followed up for 70 weeks, with a mean survival of 40 weeks. Again, without a comparable control group, it is difficult to ascertain the true effectiveness of this therapy, although it seems promising. One disadvantage of this treatment paradigm is that patients must stay out of direct sunlight for an extended period. There have also been numerous reports of local radiosurgery in which a small x-ray generator is placed within difficult-to-reach tumors. These treatments seem to increase local control, but distant metastases are not inhibited.
The use of interstitial laser ablation for treatment of brain metastasis was reported as far back as 1992. This technology uses the heat generated by a laser to treat an intracranial brain metastasis. A fiberoptic cable is stereotactically inserted into the tumor to deliver the treatment. Advantages of this treatment include the ability to control the amount of energy delivered and conform the treatment to the specific volume of the lesion. More recently, this treatment has evolved to incorporate the use of nanoparticles to augment the effect of the laser (increasing the amount of heat delivered to the tumor). Nanoshells delivered intravenously diffuse passively into an orthotopic xenograft, and an optical fiber is implanted within the tumor. This process not only augments the amount of thermal energy delivered to the tumor but also minimizes the amount of damage to adjacent normal brain tissues.
Systemic chemotherapy
Apart from local control, as well as control of distant metastases, a third and critical component of treating brain metastasis is securing systemic control of cancer. Although surgical resection of primary site of cancer is a mainstay of treatment, additional treatment often entails the use of chemotherapy. This section does not review chemotherapy aimed at systemic control but concentrates on chemotherapy aimed specifically at brain metastases. The 2 important compounds that have some success in the treatment of brain metastases are temozolomide (TMZ) and fotemustine.
TMZ is an oral alkylating agent that has shown considerable efficacy in treating primary brain tumors, especially glioblastoma multiforme (GBM). However, numerous studies have shown that TMZ is promising as a treatment of metastatic brain tumors. Although TMZ is administered orally, it has demonstrated reasonable penetration of the blood-brain barrier. Two randomized phase 2 studies showed benefit in patients who were administered TMZ and WBRT compared with those who received only WBRT, with those who received TMZ demonstrating a greater local response rate and time to progression, although the overall survival times were not significantly different. Similar to the fact that the expression of O 6-methylguanine-DNA methyltransferase (MGMT) has been shown to correlate with a greater response to TMZ in patients with GBM, a recent study showed that MGMT expression was more likely in metastatic lung cancer than in primary lesions. Positive MGMT expression correlated significantly with longer survival times ( Fig. 4 ).
Related posts:
Review of Imaging Techniques in the Diagnosis and Management of Brain Metastases
Radiotherapy for Brain Metastases
Management of Skull Base Metastases
Radiosurgical Management of Brain Metastases
Neurocognitive and Quality of Life Measures in Patients with Metastatic Brain Disease
Evidence-Based Guidelines for the Management of Brain Metastases
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