- TABLE OF CONTENTS
- Etiology and Risk Factors
- Signs and Symptoms
- Screening for Metastatic Brain Tumors
- Staging and Prognosis
- Supportive Therapy
- Definitive Therapy: Primary Brain Tumors
- Radiation therapy
- Alternatives to conventional radiotherapy
- Definitive Therapy: Brain Metastasis
- Suggested Reading
Treatment of primary brain tumors and brain metastases consists of both supportive and definitive therapies.
Supportive treatment focuses on relieving symptoms and improving the patient's neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.
Anticonvulsants are administered to the 25% of patients who have a seizure at presentation. Traditionally, phenytoin(Drug information on phenytoin) was the most commonly used medication, but carbamazepine(Drug information on carbamazepine) and valproic acid are equally effective. Doses of all these anticonvulsants can be titrated to the appropriate serum levels to provide maximal protection.
Newer anticonvulsants, such as levetiracetam(Drug information on levetiracetam) (Keppra), gabapentin(Drug information on gabapentin), lamotrigine(Drug information on lamotrigine) (Lamictal), and topiramate(Drug information on topiramate) (Topamax), are preferred and have become the first choice in many patients. Most of these agents have the advantages of causing fewer cognitive adverse effects and less induction or inhibition of the hepatic microsomal system, so they are less likely to alter the metabolism of chemotherapeutic agents. Serum levels of these agents are less reliable than those of older drugs. These agents should replace the older drugs as first-line antiepileptic therapy in most patients.
Prophylaxis. Prospective studies have failed to show the efficacy of prophylactic anticonvulsants for patients with brain tumors who have not had a seizure. Consequently, prophylactic anticonvulsants should not be administered, except during the perioperative period, when their use may reduce the incidence of postoperative seizures; the drugs can be tapered off within 2 weeks of surgery. Increasingly, the new agents are being used for prophylaxis.
Corticosteroids reduce peritumoral edema, diminishing mass effect and lowering intracranial pressure. This effect produces prompt relief of headache and improvement of lateralizing signs. Dexamethasone(Drug information on dexamethasone) is the corticosteroid of choice because of its minimal mineralocorticoid activity. The starting dose is approximately 16 mg/d, but this dose is adjusted upward or downward to reach the minimum dose necessary to control neurologic symptoms. In patients whose MRI is suggestive of CNS lymphoma, urgent biopsy should precede the initiation of corticosteroid therapy.
Long-term corticosteroid use is associated with hypertension, diabetes mellitus, a nonketotic hyperosmolar state, myopathy, weight gain, insomnia, and osteoporosis. Thus, the corticosteroid dose in patients with a brain tumor should be tapered as rapidly as possible once definitive treatment has begun. Most patients can stop taking corticosteroids by the time they have completed cranial irradiation. All patients who take corticosteroids for more than 6 weeks should receive antibiotic prophylaxis for Pneumocystis jiroveci (formerly carinii) pneumonia. Prophylaxis should continue for 1 month after the corticosteroids have been discontinued. This practice is without supporting evidence (as shown in a large Cochrane review), although it is routinely used.
Definitive treatment of brain tumors includes surgery, radiation therapy, and chemotherapy. The first step is to devise an overall therapeutic plan that should outline the sequence and elements of multidisciplinary therapy.
Various surgical options are available, and the surgical approach should be carefully chosen to maximize tumor resection while preserving vital brain structures and minimizing the risk of postoperative neurologic deficits. The goals of surgery include (1) obtaining an accurate histologic diagnosis, which in the modern era involves obtaining sufficient tissue for molecular diagnostics; (2) reducing tumor burden and associated mass effect caused by the tumor and/or peritumoral edema; (3) maintaining or re-establishing pathways for CSF flow; (4) achieving a potential "cure" by gross total removal; and (5) reducing tumor burden before adjuvant irradiation or chemotherapy. Surgery for a primary brain tumor rarely achieves cure but can reduce tumor burden so that the tumor becomes more amenable to adjuvant irradiation or chemotherapy. In glioblastomas, resection of greater than 98% of tumor, as measured by postoperative MRI, is associated with improved survival. Similarly, improved survival has also been demonstrated for low-grade gliomas when gross total resection is achieved. Limitations of stereotactic biopsy are that small volumes of tissue are obtained and that tissue sampling errors may result in a failure to reach a correct diagnosis. Stereotactic biopsy may be nondiagnostic in 3% to 8% of cases and has a surgical morbidity of approximately 5%.
Surgical tools. A variety of tools are available to help the neurosurgeon achieve these goals, including stereotactic and image-based guidance systems and electrophysiologic brain mapping.
Stereotactic frames provide a rigid, three-dimensional (3D) coordinate system for accurate targeting of brain lesions identified on CT or MRI scans and are particularly well suited for obtaining tissue for biopsy from tumors located in sites where aggressive tissue removal would produce unacceptable neurologic deficits.
Image-based guidance system. "Frameless" or "image-guided" stereotactic systems use computer technology to coregister preoperative imaging studies with intraoperative head position, thereby establishing stereotactic accuracy without the need for a frame. These systems are useful for stereotactic biopsy or achieving maximal resections of predefined tumor volumes and minimizing surgical morbidity. Intraoperative MRI accomplishes similar goals but is limited by a requirement for specialized operating suites.
Intraoperative brain mapping, also termed "cortical mapping," uses electrical stimulation of the cortical surface to define the primary motor, sensory, or speech cortex. By identifying the exact location of these areas before tumor resection, the surgeon can avoid these structures, thereby preserving neurologic function. These tools enable the neurosurgeon to perform more complete removal of tumors with less morbidity. Intraoperative MRI is being used in a number of centers to facilitate the complete removal of a tumor. Images are obtained before the operation is completed to ensure removal of all visible tumor.
Pathology-based surgical approach for primary brain tumors. The surgical approach to an intracranial lesion is strongly influenced by the suspected or previously confirmed pathology. Guidelines for the management of the most common tumors are discussed.
• Meningiomas and other extra-axial tumors—Benign extra-axial tumors, such as meningiomas, usually have a well-defined plane separating them from the surrounding brain parenchyma. In general, total extirpation can be achieved by open craniotomy, particularly when the tumor is located over the convexity. Firm attachment of the tumor to the dura, cranial nerves, vascular structures, or skull base may make this impossible. Subtotal resections that preserve neural or vascular structures while reducing mass effect are often favored for extensive skull base tumors.
The surgical management of other benign extra-axial tumors, such as acoustic neuroma, pineocytoma, choroid plexus papilloma, and pituitary adenoma, closely parallels that of meningiomas. Gross total resection is generally curative and should be attempted whenever it is safe.
• Low-grade gliomas—Gross total resection, whenever possible, is the goal of surgery for low-grade gliomas and mixed neuronal-glial tumors (eg, astrocytoma, oligodendroglioma, pilocytic astrocytoma, and ganglioglioma). Long-term survival is better in patients who have undergone gross total resection than in those who have had subtotal resection (5-year survival rates > 80% for gross total resection vs approximately 50% for subtotal resection).
If radiographically proven gross total resection is attained, postoperative irradiation or chemotherapy can often be withheld until there is evidence of tumor progression (see section on "Radiation therapy"). If a postoperative scan reveals a small but surgically accessible residual lesion, immediate reoperation should be considered, particularly in children or in those with pilocytic astrocytomas (WHO grade I).
When low-grade tumors are found in patients with medically refractory chronic epilepsy, surgical management should be oriented toward curing the epilepsy as well as achieving total tumor removal.
• Ependymomas—Gross total resection is the goal of surgery whenever possible for ependymomas. Because ependymomas arise in the ventricular system, they can disseminate in the CSF. Therefore, all patients should be assessed for subarachnoid metastases with complete cranial and spinal MRI performed with gadolinium.
• High-grade gliomas—More extensive resections improve the quality of life and neurologic function of patients with high-grade gliomas (glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma) by reducing mass effect, edema, and corticosteroid dependence. Resection of more than 98% of the tumor volume prolongs survival relative to subtotal or partial resections, but extensive subtotal resections do not appear to confer any survival advantage over biopsy. For this reason, most neurosurgeons attempt to achieve maximal resection while minimizing the risk to critical areas of the brain.
• Recurrent or progressive tumors—When a brain tumor recurs or enlarges, reoperation is often necessary to reduce mass effect. Although rarely curative, these procedures can improve quality of life and modestly extend survival. In general, reoperation is not considered in patients with a Karnofsky performance status (KPS) score of 60 or less or in those patients who are not candidates for additional therapy following surgery.
• Pseudoprogression—describes an increase in contrast enhancement independent of tumor growth in patients who have recently received radiation therapy. It occurs most frequently (58%) within the first 3 months following radiation therapy and is more commonly seen after concurrent chemoradiation therapy. It is estimated that up to 50% of patients with an increase in enhancement have true tumor progression. However, in practice, the patient's current treatment regimen of temozolomide(Drug information on temozolomide) is usually continued for at least 3 months to avoid discontinuing an effective therapy. Pseudoprogression may represent a more robust response to therapy and may correlate with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation and a better therapeutic outcome. A recurrent tumor cannot be distinguished from radiation necrosis on routine MRI. Both disorders may cause severe mass effect and edema, and resection is the optimal treatment for both if the patient is symptomatic. Occasionally, PET or MRS can distinguish tumor from treatment effect, but these imaging modalities are unreliable.
Initial resection or reoperation followed by intracavitary or intraparenchymal administration of chemotherapy, immunotherapy, or liquid I-125 radiotherapy (GliaSite) is being explored but is still investigational. Carmustine(Drug information on carmustine)-impregnated wafers (Gliadel) are the only form of intracavitary chemotherapy currently approved by the FDA for glioblastoma.
Radiation therapy plays a central role in the treatment of brain tumors in adults. It is the most effective nonsurgical therapy for patients with malignant gliomas and also has an important role in the treatment of patients with low-grade gliomas and metastatic brain tumors.
Whole-brain vs partial-brain irradiation. Whole-brain irradiation is reserved for multifocal lesions, lesions with significant subependymal or leptomeningeal involvement, and metastatic brain tumors. For the majority of patients with unifocal disease, limited-field treatment results in less morbidity and appears to produce equal, albeit poor, overall survival.
Intensity-modulated radiotherapy is an advanced technique to deliver high-precision radiotherapy to a tumor. Treatment is planned using 3D CT images to design a dose that will conform to the 3D shape of the tumor. Using multiple beams, a uniform dose of radiotherapy is delivered to the whole tumor while sparing normal tissues.
Radiation therapy for low-grade gliomas. Retrospective studies suggest a limited radiation dose response in low-grade gliomas. However, selection bias may play a role in these studies.
Several randomized studies addressed the question of optimal timing and dose of radiotherapy in patients with low-grade gliomas. An American intergroup randomized trial compared 50.4 vs 64.8 Gy of radiation in patients with low-grade glioma. An EORTC trial compared 45 vs 59.4 Gy of radiation in patients with low-grade astrocytoma. Both studies confirmed the superiority or equivalent efficacy of the lower radiation dose with less toxicity.
A second EORTC trial tested immediate vs delayed radiotherapy in individuals with low-grade glioma. Although immediate radiotherapy significantly improved 5-year progression-free survival, overall survival was identical in the two treatment arms. Furthermore, quality of life was better in patients whose radiotherapy was deferred until clinical or radiographic disease progression was evident.
Recommended treatment approach for low-grade astrocytomas. The role of postoperative radiotherapy in the management of incompletely resected low-grade astrocytomas has not been firmly established. However, on the basis of the available data, the following principles appear reasonable:
• Complete surgical resection of hemispheric astrocytomas should be attempted.
• If complete surgical resection has been attained, radiation therapy can be withheld until MRI or CT studies clearly indicate a recurrence that cannot be approached surgically.
• When complete surgical resection is not performed, postoperative irradiation may be recommended, depending on the patients' clinical condition.
• Radiation therapy should be delivered, using a megavoltage machine, in 1.7- to 2-Gy daily fractions, to a total dose of about 50 Gy. The treatment fields should include the primary tumor volume only, as defined by MRI, and should not encompass the whole brain.
• In low-grade astrocytomas, radiation therapy can be expected to produce a 5-year survival rate of 50% and a 10-year survival rate of 20%. Patients with low-grade oligodendrogliomas survive even longer.
• Cognitive impairment may develop in long-term survivors of low-grade gliomas. This may be due to the disease itself, surgical resection, antiepileptic drug use, and radiotherapy if used.
Radiation therapy for high-grade gliomas. An analysis of three studies of high-grade gliomas performed by the Brain Tumor Study Group showed that postoperative radiotherapy doses greater than 50 Gy were significantly better in improving survival than no postoperative treatment and that 60 Gy resulted in significantly prolonged survival compared with 50 Gy. Doses greater than 60 Gy used in the American intergroup protocol resulted in competing morbidity.
On the basis of these data, involved-field radiotherapy to 60 Gy in 30 to 33 fractions is standard treatment for high-grade histologies; this amount corresponds to a dose just above the threshold for radionecrosis. About half of patients with anaplastic astrocytomas exhibit radiographic evidence of response following 60 Gy of radiation, compared with 25% of patients with glioblastoma. Complete radiographic response is rare in either case. Elderly patients with glioblastoma have a particularly poor prognosis, with a median survival of 4 to 6 months in most series. Some of these patients are not treated at all, but a randomized controlled study demonstrated that 50 Gy yields a significantly longer survival than supportive care alone (median of 29.1 weeks vs 16.9 weeks; P = .002) without compromising quality of life. Such an abbreviated course of radiotherapy should be considered in patients older than 70 years.
The results of standard radiation treatment in patients with malignant gliomas are poor. Patients with glioblastoma have a median survival of 15 months, whereas patients with anaplastic astrocytomas survive a median of 3 to 5 years. To improve these poor results, a number of new approaches have been tried, including hyperfractionated radiotherapy (HFRT), focal dose escalation with interstitial brachytherapy, and radiosurgery, but none has demonstrated improved survival in randomized controlled trials. Brachytherapy and HFRT have been abandoned. Radiosurgery is still considered in the recurrent setting; however, the evidence for this practice has not yet reached the strength of other treatment recommendations.
Radionecrosis. Both brachytherapy and stereotactic radiosurgery can induce focal radionecrosis. This complication produces symptoms of mass effect in about 50% of patients with malignant glioma, requiring resection to remove the necrotic debris. Occasionally, treatment with corticosteroids can control the edema around the radionecrotic area, but often the patient becomes corticosteroid-dependent, with all of the attendant complications of long-term corticosteroid use. Radionecrosis can be a significant limitation of the focal radiotherapy techniques.
Recommended approach for extra-axial tumors. Surgery alone is curative in the vast majority of patients with benign tumors. However, in certain subsets of patients, postoperative radiotherapy may control further growth of these lesions.
• Pituitary adenomas—For hormonally inactive pituitary adenomas that persist or recur after surgery, 45 to 50 Gy is delivered in 25 to 28 fractions to the radiographic boundaries of the tumor. For Cushing disease and acromegaly, higher doses are required for biochemical remission. Coronal-enhanced MRI is critical for treatment planning, because CT often does not visualize the skull base and the entire extent of disease.
The most common indications for radiotherapy are invasion of the cavernous sinus or the suprasellar space and incomplete resection of macroadenomas (> 1.5 cm). Most pituitary lesions do not grow following radiotherapy, and hormonally active tumors usually demonstrate a hormonal response, with a reduction in hormone hypersecretion in 1 to 3 years. Following radiation therapy, 20% to 50% of patients develop panhypopituitarism, requiring hormone replacement therapy. Other significant complications (ie, damage to the visual apparatus) are rare today.
• Meningiomas—are readily curable with complete surgical resection. However, base of skull lesions and lesions involving a patent venous sinus often cannot be resected completely. For some patients with these lesions, a course of postoperative radiotherapy is indicated. In general, 54 Gy is delivered in 30 fractions to the radiographic tumor region using 3D treatment planning. Malignant meningiomas always require postoperative radiotherapy, even after gross total resection. Radiosurgery may also be useful in treating meningiomas, and doses of 13 to 18 Gy are associated with a high rate of control 10 years following therapy.
• Acoustic neuroma—has classically been considered a surgical disease. Following total resection, recurrence rates are less than 5%. When only subtotal resection is possible, disease recurs in at least 60% of patients.
Radiosurgery has been used as an alternative to surgery for acoustic neuroma. Tumor control rates of of greater than 80% at 20 years have been reported. For patients with useful hearing before radiosurgery, that function is preserved in fewer than 50%. After radiosurgery, 10% of patients experience facial weakness, and 25% have trigeminal neuropathy. The risk of cranial neuropathies is related to the size of the lesion treated.
Malignant gliomas. Chemotherapy has a limited but measurable benefit in the treatment of patients with malignant gliomas, and temozolomide and PCV (procarbazine, CCNU, and vincristine) are the most active agents.
In a large phase III trial, patients with newly diagnosed glioblastoma were randomized to receive radiotherapy alone or radiotherapy with concurrently administered temozolomide followed by adjuvant temozolomide. A total of 573 patients were studied, and median survival was significantly prolonged from 12.1 months to 14.6 months with the addition of temozolomide to radiotherapy. The 2-year survival rate was only 10% in those treated with radiotherapy alone compared with 27% in those who received radiotherapy plus temozolomide. The combined-modality regimen was well tolerated and was associated with minimal additional toxicity. The benefit of adding temozolomide to radiotherapy in newly diagnosed glioblastoma persists throughout 5 years of follow-up. This regimen has now become the standard for all patients with newly diagnosed glioblastoma and combines the potential radiosensitizing effect of concurrent temozolomide with the benefit of adjuvant chemotherapy.
This study demonstrates clear benefit in patients with glioblastoma, and many investigators have extrapolated this regimen for use in patients with gliomas of all grades. Current practice varies from treating anaplastic astrocytoma with radiation therapy alone, to sequential radiotherapy and chemotherapy, to concurrent chemoradiation therapy. Two ongoing phase III trials are addressing this question.
In a nonrandomized phase II trial, 70 patients 70 years and older with glioblastoma and a KPS score of less than 70 were given temozolomide alone (150 to 200 mg/m2 daily for 5 days every 4 weeks) until progression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median progression-free survival was 16 weeks and median overall survival was 25 weeks, significantly greater than with supportive care alone, compared with historical controls. Eighteen patients (26%) increased their KPS score to 70 or greater.
The Radiation Therapy Oncology Group (RTOG) 0525 randomized 833 patients with glioblastoma to standard temozolomide (150 to 200 mg/m2 for 5 days) or dose-dense temozolomide (75 to 100 mg/m2 for 21 days) every 4 weeks for 6 to 12 cycles and found no difference for median overall survival, median progression-free survival, or methylation status. MGMT methylation was associated with improved overall survival (21.2 months vs 14 months; P < .0001) and progression-free survival (8.7 months vs 5.7 months; P < .0001), suggesting that standard-dose temozolomide should continue to be used outside a clinical trial. Those who received dose-dense temozolomide had increased grade (≥ 3) toxicity primarily with lymphopenia and fatigue (19% vs 27%; P = .008).
Sidebar: The NOA-08 trial demonstrated both the noninferiority of temozolomide compared with radiation therapy in the treatment of elderly patients with high-grade glioma and the potential predictive utility of MGMT promoter methylation. Patients older than 65 years with a KPS greater than 60 with newly diagnosed anaplastic astrocytoma or glioblastoma were randomized to radiation therapy or temozolomide. Median overall survival and event-free survival did not differ between arms. Patients with MGMT methylation had longer event-free survival when treated with temozolomide (8.4 months vs 4.6 months) and those without promoter methylation had superior results with radiation therapy compared with temozolomide (4.6 months vs 3.3 months). This effect was also seen for overall survival (Wick W et al: J Clin Oncol 30[suppl]:abstract 2000, 2012).
Despite initial treatment, all malignant gliomas eventually recur. At relapse, patients may benefit from re-resection or different chemotherapeutic agents such as procarbazine(Drug information on procarbazine) or lomustine(Drug information on lomustine) (CCNU). However, re-challenging with temozolomide at higher doses and using an alternate schedule may improve outcome in the setting of recurrence. Patients with progressive grade III or IV glioma after standard temozolomide (150 to 200 mg/m2, days 1 to 5) were given metronomic temozolomide at 50 mg/m2 daily for up to 1 year or until disease progression. Six-month progression-free survival was 24%, and 1-year survival was 27% for glioblastoma and 36% and 61%, respectively, for anaplastic glioma. Those deriving the greatest benefit from temozolomide re-challenge were patients whose disease progressed in the first 6 months of therapy and those whose disease progressed after initial treatment discontinuation.
Sidebar: The conditional probability of survival for patients with newly diagnosed glioblastoma was analyzed. Survival data from seven phase II protocols from 1975 to 2007 were compiled. The probability of surviving another year after surviving for 1, 2, 3, and 4 years was 35%, 49%, 69%, and 93%, respectively, supporting a nonconstant hazard for death (Polley MY et al: J Clin Oncol 29:4175-4180, 2011).
Molecularly targeted agents have been a major focus of glioblastoma treatment in recent years. Randomized phase II trials have generated attention for their ability to expedite clinical testing of new agents. Unfortunately, targeted therapy has not been shown to be effective as single-agent therapy.
In a randomized phase II trial, cilengitide, an integrin receptor inhibitor, was given to patients with recurrent glioblastoma. Those receiving a dose of 2,000 mg twice weekly had an overall survival of 9.9 months. In another randomized phase II trial, patients with progressive glioblastoma were given either erlotinib (Tarceva) or cytotoxic chemotherapy with temozolomide or carmustine. Erlotinib compared unfavorably, with progression-free survival at 6 months of only 11% vs 24% in the control group. EGFRvIII mutation did not correlate with efficacy.
Recently, a phase III trial randomized patients to receive enzastaurin, a protein kinase C beta inhibitor, or lomustine for progressive glioblastoma. The 6-month progression-free survival rate was 11% for enzastaurin and 19% for lomustine.
Targeting angiogenesis has proved to be an effective approach to prolong progression-free survival at recurrence. Bevacizumab(Drug information on bevacizumab) (Avastin), a monoclonal antibody that targets vascular endothelial growth factor, received accelerated FDA approval for recurrent glioblastoma on the basis of two studies. In one study, patients with recurrent glioblastoma were given either bevacizumab alone or with irinotecan(Drug information on irinotecan). Six-month progression-free and overall survival rates were 43% and 9.2 months, respectively, in the bevacizumab-alone group and 50% and 8.7 months in the combination group. Although bevacizumab frequently is combined with irinotecan, it is not clear how much benefit chemotherapy adds to bevacizumab alone.
Disease progression after vascular-targeted agents may occur at the primary tumor site or a distant site in the brain. It may have an atypical imaging pattern with diffuse infiltration that is nonenhancing and seen only on MRI FLAIR sequences or more recently described on diffusion-weighted sequences. There has been no increase in intratumoral hemorrhage with the antiangiogenic agents, which makes them safe for use in patients with malignant gliomas. Current studies are using multitargeted approaches to enhance efficacy.
Astrocytomas. Chemotherapy has no role in the initial treatment of low-grade astrocytomas, and often they have progressed to malignant tumors at the time of recurrence.
Oligodendroglioma. In contrast, oligodendroglioma is now recognized as a particularly chemosensitive primary brain tumor. This finding was first observed with the anaplastic oligodendroglioma but has recently been seen with the more common low-grade oligodendroglioma. Chemosensitivity of anaplastic and low-grade tumors is associated with loss of chromosomes 1p and 19q.
Several alkylating agents are active, but the best-studied regimen is PCV, which produces response rates of 75% and 90% in malignant and low-grade oligodendrogliomas, respectively. PCV is an active regimen but has largely been supplanted by temozolomide because of the significant myelosuppression, neuropathy, and asthenia associated with PCV. Consequently, chemotherapy is an important therapeutic modality and may be used as initial treatment in patients with low-grade tumors who require therapeutic intervention. This approach defers or eliminates the late cognitive toxicity associated with cranial irradiation in patients with low-grade tumors who can have relatively prolonged survival. Patients with malignant oligodendrogliomas require radiotherapy with or without chemotherapy for initial treatment.
Sidebar: Results from RTOG 9402 and European Organization for Research and Treatment of Cancer (EORTC) 26951 demonstrate the significant impact of chemotherapy for newly diagnosed anaplastic oligodendroglioma. The RTOG study randomized patients with anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOA) to either chemotherapy with PCV followed by radiation therapy or to radiation therapy alone. Survival time did not differ overall; however, patients with 1p/19q co-deleted tumors given both chemotherapy and radiation therapy had a median survival of 14.7 years vs 7.3 years. EORTC 26951 randomized patients with AO and AOA to radiation therapy followed by PCV or to radiation therapy alone. They found that survival for the entire cohort was greater in the chemotherapy-containing arm, at 42.3 months vs 30.6 months, and patients with 1p/19q co-deletion had a greater benefit of combined therapy with survival that was not reached after 140 months of follow-up vs 113 months. There was no survival difference for patients whose tumors were intact for 1p/19q. The disagreement in overall survival for the entire cohort in these two studies may have been affected by the relative differences in tumor histology between the studies as reflected by a larger number of patients whose co-deletion status was not known in the EORTC study (9.6% RTOG and 18.5% EORTC) (Cairncross JG et al: J Clin Oncol 30[suppl]:abstract 2008b, 2012; Van Den Bent MJ et al: J Clin Oncol 30[suppl]:abstract 2, 2012).