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Anaplastic Oligodendroglioma
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The AODs comprise between 20% and 50% of all oligodendroglial tumors and approximately 5% of anaplastic tumors. The peak incidence is between ages 40 and 50. The clinical presentation of these tumors is similar to that of other anaplastic tumors, with focal neurologic signs, seizures, or symptoms of increased intracranial pressure. These lesions, which are usually contrast enhancing, can show calcification on CT scans as well as cystic structures, necrosis, and hemorrhage.
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The initial standard therapy for an AOD is surgery, with the goal of gross total resection. In RTOG 9402, random assignment of 291 eligible patients with AO/AOA was made for the patients to receive PCV plus RT versus RT alone. There was no difference in median survival by treatment between the 148 patients randomized to PCV plus RT and the 143 patients randomized to RT (66). However, the significance of codeletion of 1p/19q was supported by the results of EORTC 26951 with increased survival of both AOD and AOA with 1p/19q codeletion noted regardless of the treatment given: radiation alone versus radiation with chemotherapy (67). The prognostic significance of 1p/19q was validated in the long-term results of RTOG 9402. Patients with co-deleted tumors lived longer than those with non–co-deleted tumors with the median survival of those patients with co-deleted tumors treated with PCV plus RT being twice that of patients who received RT alone. Neither timing (before, during, or following radiation treatment) nor dose intensity of PCV was found to be significant. No difference in median survival by treatment arm was appreciated in patients with non–co-deleted tumors (66). A phase III study (CATNON) is under way to examine the appropriate treatment of anaplastic gliomas without 1p/19q codeletion.
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Although PCV is the most studied regimen, in clinical practice temozolomide is typically favored for its more tolerable toxicity profile. Further study is ongoing from the RTOG/NCCTG/EORTC trial to determine if chemotherapy (PCV or temozolomide) can replace radiation and maintain the survival benefit. Despite initially high response rates, these tumors usually recur. Median survival for AOD treated with surgery, irradiation, and chemotherapy ranges from 3 to 5 years, although some patients survive past 10 years (55). Recurrent disease is often treated with salvage regimens similar to those used for AA and GBM (Tables 40-5 and 40-6).
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Anaplastic Astrocytoma
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Anaplastic astrocytomas are diffusely infiltrating with nuclear atypia and anaplasia as well as marked proliferation, features that distinguish them from low-grade astrocytomas. A lack of vascular proliferation or necrosis distinguishes these tumors histologically from GBM. The highest incidence of AA is in the fourth decade, followed by the third decade, with nearly equal incidence rates in the second, fifth, and sixth decades. These tumors account for 7.5% of all glial tumors (9). Some patients may have a history of prior low-grade astrocytoma. Brain imaging shows diffuse hypointense tumor on CT scans and T1-weighted MRI. There is usually more mass effect and edema compared with low-grade astrocytomas, and contrast enhancement is typical. Because these tumors can occasionally be nonenhancing, neuroimaging alone is not sufficient to distinguish these lesions from low-grade astrocytomas. The median survival for patients with AA ranges from 5 to 7 years.
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Optimal initial management begins with surgery with the goal of maximal, safe resection, both to provide adequate tissue for accurate analysis of pathology and to improve survival. Following surgery, limited-field radiation therapy to a target dose of 60 Gy is commonly recommended. The target radiation field typically includes the contrast-enhancing region of the tumor as well as the surrounding edema or nonenhancing tumor plus a 2-cm margin. The size of this field is often reduced after a 46-Gy dose has been applied to the contrast-enhancing lesion alone plus a 2-cm margin. Clinical trials using alternate radiation schemes of hyperfractionation or accelerated fractionation have not demonstrated an increased survival benefit over conventional fractionated conformal radiation therapy (68). Adjuvant chemotherapy following radiation therapy increases time to progression and survival. Standard agents include combination therapy composed of PCV or (see Table 40-6) temozolomide (69).
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Patients with recurrent AA should be considered for clinical trials. Surgical resection should also be considered to provide a palliative benefit, relieve mass effect, allow dose reduction of steroids, and confirm histology. The recurrent tumor may actually have progressed to GBM from AA, and such patients are often eligible for a wider array of clinical trials than are available for recurrent AA. Trials have used temolozomide in combination with agents such as interferon alfa (IFN-α), cis-retinoic acid, metalloproteinase inhibitors, carmustine, irinotecan, and thalidomide (70,71,72). Other agents that have been used for recurrent AA include tamoxifen, carboplatin, etoposide, irinotecan, and combination chemotherapy. To date, no single trial has proven to be superior (Fig. 40-25). Reirradiation can be considered for patients who are over 2 years beyond their original radiation treatment and for patients whose site of recurrent disease lies outside the initial radiation treatment field.
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Glioblastoma is the most common and most malignant glial tumor of the brain. It comprises 50% of all glial tumors, with an incidence of approximately two to three per 100,000 per year (9). Glioblastomas are characterized by poorly differentiated astrocytes with cellular polymorphism, nuclear atypia, microvascular proliferation, and necrosis. The peak incidence is in the fifth decade, followed by the sixth and fourth decades. Glioblastoma is rare in children and young adults (9). Clinically, these tumors often present with signs of increased intracranial pressure, such as headache. They can also present with seizures or focal neurologic symptoms such as hemiparesis and aphasia, often with a short history of symptoms.
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Imaging with CT or MRI usually reveals a contrast-enhancing lesion with irregular borders, frequently with a necrotic center. Vasogenic edema and nonenhancing tumor often surround the area of contrast enhancement and are best seen on T2-weighted or FLAIR imaging on MRI. Glioblastomas commonly spread through white matter tracts across the corpus callosum, internal capsule, and optic radiations. Multifocal lesions are seen. If these multiple lesions truly arise independently as opposed to spreading diffusely through tracts that are not visualized by imaging or pathology, they may have a polyclonal origin.
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Glioblastomas are highly lethal. Despite extensive clinical research, survival has not changed greatly during the last 20 years. Prognostic factors include age and Karnofsky performance status (KPS). Surgical resection has shown some benefit, especially gross total resection, described when 90% or more of the enhancing tumor is removed (73) (Fig. 40-26).
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The addition of chemotherapy to radiation emerged as the standard of care for GBM based on the seminal large prospective, randomized, phase III trial from the EORTC. This trial randomized 573 patients to receive either standard RT (60 Gy in 30 daily fractions) or concurrent temozolomide (75 mg/m2/d) with RT followed by adjuvant temozolomide for 6 months (150 to 200 mg/m2/d for 5 days every 28 days). The group receiving concurrent and adjuvant temozolomide had a significant improvement in PFS (median 7.2 vs 5.0 months), survival (median 14.6 vs 12 months), and 2-year survival rate (median 26% vs 8%). Both groups had similar age, KPS, and surgical resection rates.
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Our center strongly recommends patient participation in clinical trials, which enroll patients from initial resection to radiation therapy and salvage therapy at relapse. Patients are eligible for entry into a clinical protocol for recurrent disease if it has been greater than 12 weeks since completion of concurrent chemoradiation to avoid enrolling patients with pseudoprogression (radiographic change that can mimic tumor progression but is actually due to radiation-induced changes). If a patient is not enrolled in an “up-front” trial, we recommend evaluation by our neurosurgery service to explore the prospect of gross total resection. It is not unusual for our patients to have repeat resection of tumor following biopsy or subtotal resection at an outside institution. Following resection, we treat patients with concurrent temozolomide (75 mg/m2/d throughout radiation therapy) and standard conformal radiation therapy (59.4 Gy in 1.8-Gy fractions). Following radiation therapy, we use adjuvant temozolomide or temozolomide combination therapy. Although the EORTC study only used adjuvant temozolomide for 6 months, we typically continue treatment for at least 1 year, given the lethal natural history of GBM.
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Dose-dense scheduling of temozolomide was evaluated in a large randomized, phase III trial based on the premise that prolonged exposure to temozolomide would result in prolonged depletion of MGMT, possibly translating into an improved survival in patients with newly diagnosed GBM. Standard adjuvant temozolomide (days 1-5 every 28 days) was compared to a dose-dense schedule (days 1-21 every 28 days). No statistically significant difference in either median OS or median PFS was observed between the two treatment arms. Treatment toxicity was higher with the dose-dense schedule (3).
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Patients with GBM and progressive disease are offered salvage therapy if their KPS is adequate. We consider options including resection of tumor, chemotherapy, and stereotactic radiation therapy. Some novel neurosurgical clinical trials have offered local therapy with gene therapy using p53, although this was limited by lack of dispersion of the therapy into surrounding tissues (74). An interleukin 13–conjugated Pseudomonas exotoxin has been studied using convection-enhanced delivery to lead to higher tissue concentration with larger volumes of distribution in phase I (75,76). Another ongoing trial uses a conditionally replication-competent adenovirus (Delta-24-RGD) injected into the resection cavity for recurrent malignant gliomas.
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One advantage of re-resection of progressive disease is to confirm pathology and specifically to determine whether the progressive enhancement on MRI represents tumor or radiation necrosis. Magnetic resonance imaging dynamic contrast and MR spectroscopy imaging, FDG-PET scanning, and brain SPECT thallium imaging sometimes help to distinguish between these two possibilities. However, all of these modalities have limited sensitivity and specificity, and sometimes the pathology reveals both treatment-related necrosis and foci of active tumor. Patients with pathology-confirmed radiation necrosis are often treated with steroids. More recently, bevacizumab, a monoclonal antibody targeted against the VEGF, has been utilized to treat radiation necrosis (77).
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Chemotherapy for recurrent disease typically produces response rates less than 10% and a 6-month PFS of 15% (4). Response rates that include stable disease and complete or PRs are 40% at best, but as the 6-month PFS value indicates, these responses are not durable. It is hypothesized that the multiple mutations and alterations in GBM and the heterogeneity of the tumor cell population may partially explain the striking resistance of these tumors to therapy. Younger patients respond best to chemotherapy, although responses to alkylating agents can be seen in patients older than 60 years of age. Long-term survivors of GBM (over 5 years) have typically had gross total resection, radiation therapy to a dose of 60 Gy, and chemotherapy, generally with temozolomide or a nitrosourea or other alkylating agent.
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Salvage agents used for malignant glioma are identical to those used for recurrent AA (see Table 40-6). Rechallenging with continuous dose-intense temozlomide 50 mg/m2/d is a valuable therapeutic option as evidenced by the RESCUE study. The overall 6-month PFS for recurrent progressive GBM was 23.9% (78) in contrast to 15% based on a pooled analysis of eight consecutive phase II trials of cytostatic and cytotoxic agents. In this study, the greatest therapeutic benefit was observed in patients with progressive disease during the first six cycles of conventional adjuvant temozolomide therapy (150-200 mg/m2 × 5 days every 28 days) or after a treatment-free interval (4).
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Bevacizumab has been approved by the Food and Drug Administration (FDA) for progressive disease following prior therapy, based on two trials. One study showed a 6-month PFS of 42% and overall survival of 8.7 months in patients receiving bevacizumab alone (79). Another study showed a response rate of 19.6% with median duration of 3.9 months. The 6-month PFS was 29%, and 6-month survival was 57%. In addition, 50% of patients experienced decreased cerebral edema, 58% were able to decrease corticosteroid dependency, and 52% had improvement in neurologic symptoms (80).
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Bevacizumab was subsequently evaluated in phase III clinical trials for newly diagnosed GBM. Unfortunately, no effect was seen on overall patient survival. Two recent large randomized, phase III trials, AVAglio and RTOG 0825, demonstrated that the addition of bevacizumab to up-front treatment with radiation and temozolomide conferred no benefit in terms of overall survival. Progression-free survival was prolonged in both studies by approximately 3 to 4 months, reaching statistical significance in the AVAglio study but not in the RTOG 0825 study based on predefined criteria (81,82).
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Other active agents include irinotecan and carboplatin, which have been investigated as single agents in the salvage setting and in combination with bevacizumab in bevacizumab-naïve recurrent GBM (83). The optimal schedule and combination of bevacizumab with alternative drugs has not been identified. Agents targeting angiogenesis have also been studied, although the use of interferon, thalidomide, EGF-RTK antagonists, and integrin receptor antagonists is not standard. Many of these targeted therapies demonstrated only limited activity as single agents, and efforts are under way to combine them with cytotoxic therapy (84). Other cellular pathways being investigated with small-molecule inhibitors include the ras pathway with farnesyl-transferase inhibitors and the PI3Kinase pathway with mTOR inhibitors. Other novel approaches to malignant brain tumor therapy include use of oncolytic adenovirus, vaccine and dendritic cell immunotherapy, and histone deacetylase inhibitors. An important reaction has been discovered from the interaction between anticonvulsants that induce the hepatic cytochrome P-450 3A4 enzyme and other chemotherapy agents also metabolized by this same enzyme. Pharmacokinetic studies of patients with malignant glioma on single-agent irinotecan and sirolimus found significantly lower levels of active drug in patients on enzyme-inducing anticonvulsant drugs (85). We recommend that patients on chemotherapy avoid the use of anticonvulsants that induce the expression of the P-450 3A4 enzyme whenever possible (Table 40-7).
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The management of seizures in patients with brain tumor is important to improve patient functioning and quality of life. A decline in seizure control may indicate tumor progression or worsening edema. It may also indicate a systemic infection or a drug interaction leading to decreased anticonvulsant drug effectiveness. In the case of tumor progression, a reduction in the amount of brain edema with high-potency corticosteroids (dexamethasone) may be sufficient to prevent further seizures. A second anticonvulsant is often necessary. Dexamethasone is a hepatic cytochrome P-450 3A4–inducing agent and often causes a reduction in serum levels of antiepileptic medications such as phenytoin and carbamazepine (also enzyme inducers) when the dose is increased. Similarly, patients can become symptomatic with toxic levels of anticonvulsants in the midst of a dexamethasone taper. It is important to follow serum anticonvulsant levels when using agents metabolized by the cytochrome P-450 system. Anticonvulsants that are highly protein bound can demonstrate significant changes in levels of circulating free drug without significantly changing the total serum level. It is useful to check serum-free phenytoin or valproic acid levels when patients taking these agents have seizures or show signs of toxicity.
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Despite the numerous choices of anticonvulsants, it can be difficult to control seizures. Of the newer generation of anticonvulsants, we have had success using levetiracetam and lacosamide, which are easily titrated without significant drug interactions. Phenobarbital and clonazepam can be useful in resistant cases of seizures. Short-term use of lorazepam can help bridge changes in anticonvulsant regimens.
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Quality-of-Life Considerations
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It is critical to provide effective supportive care to patients with brain tumors to improve their functional status and quality of life for themselves and their caregivers. This care is typically labor intensive and often beyond the means of patients and their families to provide. We involve social work and case management early in the treatment of patients. They can provide interventions that may prevent a later breakdown in care.
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The incidence of depression is high among this population and should be treated early. The causes of depression are typically multifactorial and may include direct effects of the tumor, side effects of chemotherapy and radiation therapy, and side effects of steroids in addition to issues associated with a loss of independence and a diagnosis of cancer. We suggest referral to psychiatry to optimally address these issues. A related concern is the impact of fatigue and somnolence, common side effects of brain radiation. We advocate the use of psychostimulants such as methylphenidate to treat both fatigue and cognitive side effects (59). Although there are theoretical concerns that the use of stimulants may exacerbate seizures, we have not observed this in practice.
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Patients often require high doses of steroids to manage edema and experience both acute and chronic toxicities from their administration. Acutely, the steroids may induce hyperglycemia requiring an insulin sliding scale. Patients often become agitated and irritable, suffer extreme mood swings, and even become psychotic when taking steroids. Low-dose neuroleptics can be effective in treating these side effects. Clinicians should aim to taper steroid use to the lowest doses necessary. Patients typically tolerate initial steroid weaning but often experience fatigue or worsening of neurologic function as dexamethasone doses are reduced to below 4 mg daily. This can be ameliorated with an extremely slow steroid taper and only lowering doses every 1 to 2 weeks by decrements of 1 mg or even 0.5 mg. Psychostimulants can help treat the inevitable fatigue experienced with the steroid taper. There is no effective treatment for steroid myopathy other than tapering off steroids and initiating physical therapy and rehabilitation as early as possible.
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Meningiomas comprise 32% of primary brain tumors, with a rate of 5.35 per 100,000 person-years. The incidence of meningioma increases with age; the median age at diagnosis is 64 years (9). The tumor is often discovered incidentally without any symptoms. Clinically, these tumors typically present with headache, cognitive or personality changes, persistent focal neurologic deficits, and sometimes seizure. The main treatment is surgical resection, with the goal of complete resection when possible, accounting for relative risks and benefits depending on the patient’s age and condition (86). Options for residual tumor include observation and radiation therapy, which can incorporate stereotactic delivery to minimize effects to local tissue (87).
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Chemotherapy for meningioma has been used for patients who have progressive disease after resection and RT; it is sometimes used adjuvantly following RT when pathology indicates malignant meningioma. Response rates have been disappointing in small case series. Agents that have been used include hydroxyurea (88), IFN-α (89), and liposomal doxorubicin (90). Results using temozolomide have been discouraging, with no responders (91). As there are no established treatments after surgery and radiation have been exhausted and response to chemotherapy has been disappointing, the use of molecularly targeted therapy is being explored in aggressive meningioma. Frequently, EGF, PDGF, and VEGF receptors are overexpressed in meningiomas. Clinical trials using small-molecule signal transduction inhibitors such as erlotinib, gefitinib, and imatinib are being explored but have not yet shown significant efficacy (92,93). In a recent phase II trial, sunitinib, a small-molecule tyrosine kinase inhibitor that targets VEGF and PDGF receptors, was found to have activity in patients with recurrent atypical/malignant meningiomas and warrants investigation in a randomized trial (94). A novel genomic-driven clinical trial currently in development will examine the efficacy of SMO and AKT inhibitors in patients with surgery-confirmed mutations in these oncogenes.
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Primary Central Nervous System Lymphoma
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In contrast to most other brain tumors, chemotherapy is the initial treatment of choice for CNS lymphoma. Efforts at surgical resection have largely been discouraged as PCNSL has a tendency to involve deep brain structures and a multifocal pattern of growth. The traditional view has been that gross total resection conferred no survival benefit over biopsy, but this view has been challenged recently. In a phase III trial of 526 patients, PFS was found to be significantly shorter in patients who were biopsied compared to patients who had undergone subtotal or gross total resections, with no difference in outcome attributable to KPS or age, suggesting that surgical resection could be considered for patients with single lesions for which resection is deemed safe (95).
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Methotrexate-based, multiagent chemotherapy has been viewed as the treatment of choice in PCNSL. The incorporation of high-dose methotrexate (greater than 1 g/m2) has resulted in a significantly greater response and improved survival compared with previous regimens using a CHOP regimen prior to whole-brain radiation therapy (WBRT). A report by DeAngelis, incorporating methotrexate (1 g/m2), followed by whole-brain irradiation and two cycles of high-dose cytarabine (ara-C) (3 g/m2), demonstrated a median survival of 42.5 months (96). This strategy is the basis for current CNS lymphoma protocols that have increased the dose of methotrexate and incorporated agents that more easily cross the BBB, such as procarbazine. A follow-up clinical trial incorporating methotrexate at 3.5 g/m2 with procarbazine and vincristine, followed by whole-brain irradiation and cytarabine demonstrated a median survival of 60 months (97). The improvement in patient survival has also brought to attention significant rates of cognitive decline and radiation-induced dementia, especially in patients older than 60 years (98).
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Current approaches to therapy of CNS lymphoma are investigating whether radiation therapy can be avoided or delayed to reduce cognitive decline and dementia without adversely affecting survival. Preliminary results from a trial using single-agent methotrexate at 8 g/m2 every 2 weeks demonstrated a PFS of 12.8 months. Median survival had not been reached at more than 22.8 months (99). Many clinicians at our center are cautiously delaying radiation therapy until relapse and continuing to use high-dose–based methotrexate regimens. In hoping to improve the results of single-agent methotrexate (99), some regimens continue to incorporate procarbazine. Other agents that may be active in this setting include temozolomide and rituximab.
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Patients with recurrent disease may respond again to methotrexate. Other regimens used include PCV (100), high-dose cytarabine (101), temozolomide (102), rituximab (103), and the combination of temozolomide and rituximab (104). High-dose chemotherapy with autologous stem cell rescue may also be effective (105).
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The treatment of brain metastasis involves optimal interactions between oncology, neurosurgery, and radiation therapy. Depending on the setting of relapse, patient survival may depend more on local tumor control in the brain or on systemic control for progressive metastasis. Advances in local brain tumor control with surgery and radiosurgery will not improve patient survival if the patient ultimately succumbs to progressive systemic disease or continues to develop new brain metastases. The median survival of patients with brain metastases is 3 to 6 months (106).
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The options for therapy include surgical resection, WBRT, stereotactic radiosurgery (SRS), and systemic chemotherapy. Surgical resection is the treatment option considered primarily in patients with single large tumors. Resection of brain metastases has emerged as a standard treatment option for patients with surgically accessible single lesions, good performance status, and controlled or absent extracranial disease. The advantages of surgical resection is that the mass effect can be immediately ameliorated and removal of the tumor decreases edema. Surgical resection also provides pathologic confirmation of the diagnosis. Stereotactic radiosurgery utilizes multiple convergent beams to deliver a single high dose of radiation to a discrete target volume and is usually reserved for lesions whose maximum diameter is 3 cm or less. The ability to treat locations that were otherwise considered surgically inaccessible is a distinct advantage of SRS. Whole-brain radiation therapy via 30 to 40 Gy (in daily fractions of 2 to 3 Gy) is the standard therapy for brain metastasis, with an established body of literature supporting its use for multiple metastases. This therapy has the ability to eradicate micrometastatic disease to delay recurrence (106,107) and is often used in conjunction with surgical resection or radiosurgery. It is well tolerated and can be effective for radiosensitive tumors such as metastases from small cell lung cancer or germ cell tumors. The greatest concern about WBRT has been the risk of neurocognitive effects, which can range from mild impairment to dementia. Hippocampal-sparing WBRT has been under active investigation in a large multicenter clinical trial (clinicaltrials.gov, identifier NCT01227954) as a technique to reduce neurotoxicity. Overall, the neurocognitive impact of WBRT in patients with brain metastases has not been well studied, and future research efforts will focus on the identification of risk factors predicting vulnerability. Neurocognitive end points should also be integrated into clinical trial designs.
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We frequently treat patients at our institution with surgery if the lesions are greater than 3 cm and the patients are symptomatic. If the patient’s medical condition makes a surgical procedure risky, the patient may receive WBRT. Patients who have lesions smaller than 3 cm can receive radiosurgery if they are asymptomatic or if the lesion is in a deep region not amenable to resection. However, patients with symptoms resulting from the lesions more frequently receive surgery to remove mass effect as long as their medical condition permits. There is also debate over the role of whole-brain irradiation following surgery or radiosurgery to single lesions.
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Chemotherapy for Brain Metastasis
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Several small clinical trials and case reports support the concept that systemic chemotherapy demonstrates activity in treating brain metastases. Chemosensitive tumor types include breast cancer, small cell lung cancer, and germ cell tumors. The primary consideration in choosing a given regimen of chemotherapy is to use agents with known activity in a given tumor type. In many trials, response rates of brain metastases have been comparable to response rates of systemic disease. Patients who have had prior chemotherapy usually respond at lower rates.
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Most clinical trials of investigational agents for solid tumors explicitly exclude patients with brain metastases. Compounding this omission is their common inclusion in studies of a heterogeneous group of patients with mixed tumor types and differing prior exposures to chemotherapy. Patients might also be expected to be more resistant to treatment with chemotherapeutic agents if they had failed RT. If chemotherapy is given during and after RT, it may be difficult to separate the efficacy due to RT versus chemotherapy. These factors make it difficult to compare treatment regimens and interpret studies (108).
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Newer drugs targeting specific extracellular receptors or blocking intracellular signal transduction systems are under investigation. Owing to their specificity, they often lack the side effects commonly associated with standard cytotoxic chemotherapy. If the therapeutic target is crucial for the cancer cell’s continued viability, the drug can be especially effective. The identification of BRAF mutations in 50% to 60% of advanced melanomas resulted in the development of potent and selective inhibitors. Vemurafenib and dabrafenib are FDA approved for the treatment of advanced melanoma and have transformed melanoma therapy, with high response rates seen in patients even with advanced, symptomatic, metastatic disease (109).
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Immune checkpoint blockade is emerging as a highly effective immunotherapeutic strategy in metastatic melanoma and other solid tumors. Ipilimumab, a human immunoglobulin (Ig) G1 monoclonal antibody to cytotoxic T-lymphocyte antigen 4 (CTLA-4), has been demonstrated to result in a durable response and improved overall survival when compared to non–ipilimumab-containing treatment arms in randomized trials (110). Ipilimumab has also been shown to be efficacious in the treatment of patients with melanoma with brain metastases, as evidenced by the measurable tumor reduction seen with ipilimumab used as monotherapy (111).
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The use of chemotherapy for brain metastases is faced with great challenges. The most important imperative is to discover new agents that can overcome tumor resistance to standard chemotherapy, whether through selection by prior pretreatment or inherent chemoresistance of tumor cell clones that metastasize from a primary site. Because most patients with brain metastases succumb to progressive systemic disease, improvement of local brain control will likely have a limited effect on survival. Conversely, the development of agents that are effective in establishing durable tumor control, both systemically and in the brain, will improve survival, as in the unique case of germ cell tumors.
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Clinical variables associated with survival in the setting of brain metastases have been studied. The most well-known prognostic scoring system is the recursive partitioning analysis classification developed from 1,200 patients who received WBRT in the RTOG database. Patients were categorized into one of three classes based on age, KPS, status of primary tumor, and extent of extracranial disease (106). Recently, the Graded Prognostic Assessment scale was developed based on the analysis of 1,960 patients in the RTOG database; it also incorporates the number of metastatic lesions in the scoring system (112) These prognostic scoring systems may help identify patients who might benefit from chemotherapy and help design clinical trials that account for specific tumor histology and prior exposure to chemotherapy. Improvement in patient survival will result from improved local control of CNS disease if the primary disease site remains dormant, illustrating the need for a multimodality approach to the treatment of the patient with brain metastases.
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Commentary: The Role of Radiation Therapy for Brain Tumors
Radiation therapy is used to enhance local control and overall survival as a sole modality or in combination with surgery or chemotherapy for many benign and malignant CNS tumors.
Radiotherapy is prescribed in the unit of Gray, which measures the energy absorbed in a material (J/kg). Typically, radiation treatments are fractionated as 1.8 to 2 Gy per day. The prescribed dose of radiation depends on the inherent radiosensitivity of the lesion and the risk to the normal tissues that are in or close to the RT volumes. For example, CNS leukemia is treated with 18 to 24 Gy in 10 to 12 fractions, whereas, GBM requires 60 Gy delivered in 30 fractions. The risk of cataract formation increases after a total dose of only 2 Gy, but brain necrosis typically will not occur below a dose of 60 Gy.
A variety of different RT techniques and modalities are available for the treatment of CNS tumors. All current treatment techniques—three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), SRS, proton therapy, and intensity-modulated proton therapy (IMPT)—use three-dimensional algorithms that calculate dose distributions in all planes and display dose in the axial, coronal, and sagittal views. The tumor and normal tissues are delineated using the planning CT scan and other imaging modalities, such as MRI or PET, that may facilitate this process. The tumor delineation involves determination of the gross tumor volume (GTV), which represents the macroscopic visible tumor; the clinical target volume, which is GTV with a margin that incorporates areas of possible microscopic extension; and planning target volume, which gives an additional margin for day-to-day setup differences.
The basic form of three-dimensional planning is 3DCRT. These plans use conformal fields from different angles optimized to the individual patient’s needs. Any RT modality, that is, photons, electrons, or protons, can be used for 3DCRT.
Stereotactic radiosurgery and fractionated stereotactic radiotherapy (FSRT) are techniques that use stereotactic positioning by using an external fiducial system to immobilize and position patients allowing submillimeter precision for RT treatments. A large single fraction of radiation is given with SRS, whereas FSRT uses multiple fractions of repeated doses of radiation with a noninvasive stereotactic frame. Stereotactic radiosurgery is typically used for noninfiltrating tumors that are less than 3 cm and away from critical structures such as the optic chiasm. Fractionated stereotactic radiotherapy may be used for a tumor that is close to a critical structure where the highest precision for delivery is required.
Intensity-modulated radiotherapy is typically used with photon beams with a few centers now using it with proton beams (IMPT). Intensity modulation can also be implemented with the stereotactic approach, which may allow an increase in precision of delivery and conformality. The IMRT plans use multiple beams optimized for the tumor location and patient. For each beam, the multileaf collimation varies during the dose delivery to modulate the dose from that beam to “paint” a dose to allow improved conformality and reduction in normal tissue doses.
Proton RT is a modality that is becoming more available worldwide and allows treatment of larger, deeper tumors without an exit dose, thereby reducing the volume of normal tissue receiving low-to-moderate doses, which could result in a reduction in acute and late toxicities. Proton RT may be a useful technology in young patients with curable tumors.
The results of RT vary according to the type of tumor being treated. Benign tumors such as meningiomas or acoustic schwannomas have control rates as high as 90%; malignant tumors such as GBM have lower durable control rates.
Anita Mahajan
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Commentary: Surgical Management of Primary Brain Tumors
The primary goal in the surgical management of primary brain tumors, like gliomas, is maximum safe resection. The decision to resect or not to resect should be made after close collaboration between the neurosurgeons, neuro-oncologists, and radiation oncologists. The surgeon must consider a number of critical factors prior to making the decision to operate: age, neurologic status, location and size of the tumor, number and extent of recurrences, and whether the patient would be suitable for adjuvant treatments, including radiation and chemotherapy. In both low-grade gliomas and high-grade gliomas, compared with patients having lesser degrees of resection, those undergoing gross total resections have a better neurologic outcome on long-term follow-up without added perioperative morbidity or mortality. Recent surgical series in low-grade gliomas have shown maximum safe resection if the tumor is an independent predictor of both PFS and OS. Lacroix et al described 416 consecutive patients with GBM and demonstrated that radical resection of the main tumor mass (≥98% by volumetric analysis) was an independent variable that significantly prolonged survival (73). The median survival for these patients was 13.4 months compared with 8.8 months for patients who had lesser resections (P < .0001). The study relied on a prospective computerized measurement of the volume of tumors, with the extent of resection expressed as a percentage of the preoperative volume. A 90% resection did not result in a statistically significant survival prolongation; the greatest benefit was noted when the extent of resection was 98% or greater. These data are particularly important because of their precision of volumetric assessments and their avoidance of subjective terms such as “gross total” or “subtotal” to describe the degree of resection.
Beyond extending survival, several other benefits can result from more radical resections of gliomas in our experience. These include: (1) a diagnostic advantage in terms of better sampling of tumors and better tissue quality acquired for IHC and molecular diagnosis; (2) a symptomatic advantage through relief of mass effect, leading to improved performance status and enhanced tolerance to RT; (3) an oncologic advantage by reducing the number of neoplastic cells by almost two logs; and (4) a research advantage by harvesting ample tissue material for molecular analysis and fingerprinting, with the eventual identification of novel and specific molecular targets that will form the basis of future therapies.
Several technological adjuncts to surgery are available to aid in localizing the brain mass, in identifying zones of brain function, and in aiding the surgeon to maintain proper orientation in reference to the mass and to its surrounding anatomic structures. Of these, intraoperative ultrasound is an inexpensive, readily accessible surgical tool that allows localization of the mass in real time and aids in the assessment of the completeness of tumor resection. Most gliomas and metastases are hyperechoic with respect to normal brain and thus can be localized easily with the ultrasound probe. It is almost inconceivable to perform such procedures without intraoperative ultrasound.
Frameless stereotactic systems have provided significant assistance on many levels, including adequate placement and sizing of the bone flap, identification of the surface margins, and localization of the mass and the navigational direction for the dissection around or into the mass. The obvious drawback of these systems is their inability to provide a true assessment of residual tumor because of brain shifts that occur necessarily during surgery. Experience with these systems and correlation of the image-derived data with the ultrasound data and with what is visible in the operative field are necessary for the safe use of these techniques in obtaining maximum tumor resection. Recently, intraoperative MRI has been introduced in a few centers, including ours. This technique identifies residual tumor more accurately than other methods. Its main drawback is that it is expensive to install and can prolong operation times. Early systems had low field magnetic strength and as such were less sensitive and provided more indistinct images than the current generation of high-field (1.5-T and higher) magnets.
Neurophysiologic techniques are employed primarily when the tumor is in or adjacent to eloquent brain (those parts of the brain that control language, motor, or sensory function). The most commonly used techniques for cortical mapping include somatosensory evoked potentials, continuous motor evoked potentials, and direct cortical and subcortical stimulation. For motor and sensory localization, the patient is usually (although not invariably) under general anesthesia; for speech localization, however, an awake craniotomy is necessary. The introduction of these techniques has made it possible to perform larger resections with an increased margin of safety in both high- and low-grade gliomas.
Existing data concerning the benefits of surgical resection suggest a survival advantage in patients with gliomas who undergo complete tumor mass resection. Careful preoperative planning should allow for the gross total resection of most gliomas. Until convincing data to the contrary, the goal of a neuro-oncologic operation should be a complete resection of the tumor mass.
Sujit S. Prabhu