Prognosis for patients with brain metastasis remains poor. Whole brain radiation therapy is the conventional treatment option; it can improve neurological symptoms, prevent and improve tumor associated neurocognitive decline, and prevents death from neurologic causes. In addition to whole brain radiation therapy, stereotactic radiosurgery, neurosurgery and chemotherapy also are used in the management of brain metastases. Radiosensitizers are now currently being investigated as potential treatment options. All of these treatment modalities carry a risk of central nervous system (CNS) toxicity that can lead to neurocognitive impairment in long term survivors. Neuropsychological testing and biomarkers are potential ways of measuring and better understanding CNS toxicity. These tools may help optimize current therapies and develop new treatments for these patients.

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This article will review the current management of brain metastases, summarize the data on the CNS effects associated with brain metastases and whole brain radiation therapy in these patients, discuss the use of neuropsychological tests as outcome measures in clinical trials evaluating treatments for brain metastases, and give an overview of the potential of biomarker development in brain metastases research. Brain metastases, the most common intracranial tumor occurring in approximately 10–30% of adult cancer patients and 6–10% of children with cancer, are a major cause of morbidity and mortality [ ]. The majority of these tumors metastasize from lung carcinoma, breast carcinoma and melanoma. Patients often present with headaches, nausea and/or vomiting and seizures. Many patients also suffer from some form of neurological and/or neurocognitive impairment which can cause emotional difficulties and affect quality of life. The prognosis for these patients is poor and without therapeutic intervention the natural course is one of progressive neurological deterioration with a median survival time of one month [ ]. Patients treated with whole brain radiation therapy (WBRT) have a median survival of 3–6 months [ – ].

The addition of WBRT can relieve neurologic symptoms and prevent death from neurological causes [ ]. Abbreviations: KPS = Karnofsky Performance Status; CNS = central nervous system.

Methods to increase the efficacy of treatment but limit CNS toxicity are currently being investigated. To measure the effectiveness of these emerging treatment modalities various tools will need to be incorporated into clinical trials. Neuropsychological testing and biomarkers are two such useful tools that will assist in optimizing radiation delivery methods and in evaluating agents that modify the effects of radiation. Biomarkers and neuropsychological testing also may aid in making earlier diagnoses, monitoring disease progression, and determining prognosis. This review will briefly summarize the current treatment options available for brain metastases and will review the literature on neuropsychological outcome measures and biomarkers in this patient population. Treatment options. WBRT is considered the standard treatment option for patients who present with multiple brain metastases.

It results in a median survival of 3–6 months [ – ], reduces the recurrence rate of metastases, and prevents death from neurological causes [ ]. By controlling and improving neurological symptoms, it improves quality of life in 75 to 85% of patients [ ].

In addition, WBRT is used in patients with metastases that impinge on important brain structures or are too numerous for either surgery or SRS to be effective. WBRT is used in conjunction with surgery and SRS and its combination has been shown to improve local control [ ]. WBRT is effective and, unlike surgery and SRS, it treats both gross and microscopic disease. Fahn Tolosa Marin Tremor Rating Scale Pdf To Autocad.

Table lists the randomized trials that have been performed to determine doses and fractionation schedules of radiation for patients with brain metastases [, – ]. The results from these studies showed that the differences in dose, timing, and fractionation do not have a statistically significant difference in median survival. Currently the most common radiation dose in the United States for brain metastases is 30 Gy in ten 3 Gy fractions over two weeks.

Surgical resection is used as a treatment option for patients with a favorable prognosis, surgically assessable metastases and who have minimal extracranial disease [ ]. In patients with tumor(s) elsewhere in the body under control, the resection of one or more closely situated metastases can increase survival significantly. Four randomized trials that have been completed to address the role of surgical resection of brain metastases are summarized in Table. Three of the trials demonstrated that combining surgery and WBRT for patients with a single metastasis significantly extends survival and improves quality of life when compared to WBRT alone [ – ]. One of the randomized trials failed to show an increase in survival or a benefit in quality of life [ ]. However, in this study the patients had lower KPS and a higher incidence of extracranial disease which may have affected the outcome. Overall these results support the position that surgical treatment should be utilized in patients with limited extracranial disease and in those patients with good performance status.

Abbreviatio n: S = Surgery Stereotactic radiosurgery SRS is an alternative to neurosurgery, in which multiple convergent beams of high energy x-rays, gamma rays, or protons are delivered to a discrete radiographically defined treatment volume. SRS can be used to treat single lesions or multiple lesions (usually up to 3) and can be used to treat deep-seated surgically inaccessible lesions. It has been shown in several large retrospective analyses to be equivalent to surgery [, ]. Results from one randomized trial and several retrospective studies have shown that when SRS is used after WBRT there is a survival benefit as well as stabilization or improvement in KPS [, ]. There is no clear consensus on the survival advantage of using SRS followed by adjunct WBRT. A randomized trial by Aoyama et al [ ], comparing SRS alone to WBRT plus SRS, did not demonstrate a survival difference in patients with 1 to 4 brain metastases. In this study intracranial relapse occurred more frequently in those who did not receive WBRT [ ].

In a phase II trial looking at patients treated with SRS for renal cell carcinoma, melanoma, or sarcoma found that there was a high degree of failures within the brain (approximately 50% of patients by 6 months) with the omission of WBRT [ ]. The role of WBRT after SRS remains unclear. Some investigators advocate the omission of WBRT after SRS because SRS has excellent local tumor control for single metastasis and withholding WBRT will spare the patient from the neurocognitive deficits associated with WBRT.

Others argue that many patients initially treated with SRS either have micrometastases or will develop recurrent brain metastasis and thus should receive WBRT for local and distant tumor control. Radiosensitizers and WBRT. Radiosensitizers are chemicals or biological agents that increase the lethal effects of radiation on the tumor without causing additional damage to normal tissue. Efaproxiral (RSR13) is one example of a radiosensitizer that has shown some promise [ ]. It is an allosteric modifier of hemoglobin that works by decreasing the binding affinity of hemoglobin to oxygen thus permitting greater oxygenation of hypoxic tumor cells and enhancing the effect of radiation. In addition to this example, other agents have been investigated in clinical trials (Table ) [ – ]. Overall these studies have produced mixed results, some have shown a slight survival benefit, while the majority of studies have not shown a difference in survival.

These results have not been strong enough to bring any of these agents into routine clinical care. At this time there are several clinical trials underway involving other potential radiosensitizers. Study (ref) Year n Radioenhancer (Gy)/number of fractions Median Survival (months) WBRT + RS vs WBRT Eyre et al.

[ ] 1984 111 metronidazole 30/10 3.0 vs 3.5 DeAngelis et al. [ ] 1989 58 lonidamine 30/10 3.9 vs 5.4 Komarnicky et al.

[ ] 1991 779 misonidazole 30/6-10 3.9 Phillips et al. [ ] 1995 72 BUdR 37.5/15 4.3 vs 6.1 Mehta et al. [ ] 2003 401 motexafin gadolinium 30/20 5.2 vs 4.9 Shaw et al. [ ] 2003 57 efaproxiral 30/10 7.3 vs 3.4 Suh et al. [ ] 2006 515 efaproxiral 30/10 5.4 vs 4.4 Knisely et al.

[ ] 2008 183 thalidomide 37.5/15 3.9 vs 3.9. Abbreviations: RS = Radiation Sensitizer, BUdR = bromodeoxyuridine Chemotherapy for brain metastases The role of conventional chemotherapy has traditionally been limited by the presence of the blood brain barrier and by the potential resistance to chemotherapeutic agents. Conventional chemotherapeutic agents include topotecan, cisplatin, paclitaxel and temozolomide. Temozolomide, a second-generation alkylating agent, has 100% bioavailability and readily crosses the blood-brain barrier.

Phase II results show that temozolomide is well tolerated and gives an improvement in response rate [ ]. Preclinical data has also shown that temozolomide could be combined with radiation to enhance its effect [ ]. Agents that are being currently investigated include gefitinib, lapatinib, valproic acid and thalidomide. Future success of chemotherapy will hinge on the development of new agents that have improved penetration into CNS. CNS effects of radiation therapy for brain metastases. WBRT, the standard of care for brain metastases, decreases the tumor burden, which delays neurocognitive decline and maintains quality of life.

However, WBRT also can cause brain injury and neurologic complications. There is risk of dementia in long term survivors of brain metastases treated with WBRT [, ], which is thought to be dependent on the total dose of radiation, the size of the irradiated field, and the fraction size. Understanding and measuring the neurotoxicity associated with WBRT as well as SRS is important for evaluating different treatment regimens beyond the effects on survival and time to disease progression. Pathophysiology of radiation induced CNS toxicity Radiation predominantly causes vascular endothelial damage and demyelination of white matter leading to white matter necrosis [ ]. Clinically, radiation injury of the brain can be divided into three categories: acute, subacute and late. Acute effects occur within the first few weeks of radiation treatment and are likely caused by cerebral edema and disruption of the blood brain barrier. Symptoms include drowsiness, headache, nausea and vomiting.

Subacute encephalopathy occurs at one to six months after the completion of radiation and its mechanism of damage is believed to be due to diffuse demyelination. Symptoms, which resolve in several months, include headache, somnolence, fatigability, and a transient impairment in cognitive functioning.

Late effects are seen six months after radiation and are usually due to damage of the white matter tracts caused by injury to vascular endothelial cells, axonal demyelination, and coagulation necrosis. These late effects usually cause permanent and progressive memory loss and can lead to severe dementia [ ]. The incidence of radiation induced dementia is not well studied. The most commonly cited study is from a retrospective review of 47 patients who survived more than one year treated with WBRT [ ]. Five (11%) of those patients were reported to develop severe radiation-induced dementia at one year.

However, four of these five patients were treated with high radiation fractions (5 or 6 Gy) that are not routinely used. Another study by the same authors reports an incidences of 1.9 to 5.1%, but once again this retrospective review included patients treated with unconventional fractions (4 – 5 Gy) [ ]. Rengou Vs Zaft 2 Plus Isometric Exercises. Contrast enhancing CT findings in these patients reveal cortical atrophy and hypodense white matter. Autopsies on patients with severe radiation induced dementia reveal diffuse chronic edema of hemispheric white matter in the absence of tumor recurrence [ ].

The pathophysiology of late radiation injury is a complex process involving damage to oligodendrocytes, endothelial cells, neurons, microglia and astrocytes and the depletion of stem and progenitor cells. It also is a dynamic process that involves recovery/repair responses with release of various cytokines and the involvement of secondary reactive processes that result in persistent oxidative stress [ ]. Vascular damage leading to ischemia and consequently white matter necrosis is thought to be a major mechanism for late delayed neurocognitive impairment caused by WBRT. This mechanism is supported by animal experiments designed specifically to study the long-term cognitive effects of rats treated with whole brain radiation.

Using this model, investigators found that loss of vessel density appeared before cognitive impairment with no other gross brain pathology being present, suggesting cognitive impairment arose after brain capillary loss [ ]. Damage to the subgranular zone of the hippocampal dentate gyrus also has been suggested as a mechanism of long term radiation induced cognitive impairment. Recent animal experiments have shown that this area is extremely sensitive to whole brain radiation [ ]. Dosimetric planning for WBRT to spare the hippocampal region is already underway [ ]. Neuropsychological functioning of patients treated with radiation for brain metastases For many patients with brain metastases, controlling neurological symptoms, preventing cognitive dysfunction, and maintaining functional independence are just as important as prolonging survival. Multiple factors, however, may negatively impact the neurocognitive functioning of these patients including the presence of the tumor, WBRT, SRS, neurosurgical procedures, chemotherapy, and other drugs that have neurotoxic effects such as steroids and anticonvulsants [, ]. Research investigating the effects of treatment, including WBRT, on the neurocognitive functioning of patients with brain metastases is limited.

While many studies have evaluated the neurocognitive outcome of patients treated with radiation, particularly children [, ] and long term survivors of gliomas [, ], the data from these populations are not directly comparable to patients undergoing WBRT and/or SRS for brain metastases. To examine the neurocognitive functioning of patients with brain metastases treated with radiation, some studies used the Folstein Mini-Mental State Examination (MMSE) [ ] while more recent trials administered a battery of neuropsychological tests. Neurocognitive impairments prior to radiation Neurocognitive impairment in patients with brain metastases is common prior to receiving radiation treatment. In studies using the MMSE to assess neurocognitive status, 8 to 16% of patients were classified as having dementia [ – ] prior to receiving radiotherapy. Lower MMSE scores at baseline were associated with greater tumor volume [, ] and death [ ]. Neuropsychological testing was used in a phase III randomized trial to evaluate whether motexafin gadolinium administered with WBRT could improve neurologic and neurocognitive outcome and survival in patients with brain metastases [, ].

This trial administered a brief battery of standardized neurocognitive tests as.