Central Nervous System Malignancies
- Infiltrating Glioma
- What every physician needs to know:
Are you sure your patient has infiltrating glioma? What should you expect to find?
Beware of other conditions that can mimic infiltrating glioma:
- Which individuals are most at risk for developing infiltrating glioma:
- What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
- What therapies should you initiate immediately i.e. emergently?
- What should the initial definitive therapy for the cancer be?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- Follow-up surveillance and therapy/management of recurrences.
What's the evidence?
What every physician needs to know:
Over 60,000 people are diagnosed with a primary brain tumor each year. The most common are infiltrating gliomas. Infiltrating gliomas vary in aggressiveness from World Health Organization (WHO) grade II tumors, which can be associated with prolonged survival, to WHO grade IV astrocytoma, also known as glioblastoma, with median survival of less than two years.
All varieties of infiltrating glioma share several common characteristics. Patients typically present with seizure, headaches or focal neurological deficits. The natural history of untreated glioma is to progressively invade normal brain tissue, with WHO grade II and III tumors progressing to grade IV pathology and behavior over time. Infiltrating gliomas are not surgically curable tumors, even when all apparent areas of abnormality on imaging are resected. After surgery, further treatment options depend on tumor grade, and range from observation alone to treatment with radiation and chemotherapy.
Glioblastoma (WHO grade IV Astrocytoma)
Glioblastoma is the most frequent, and most aggressive, infiltrating glioma. Glioblastoma may arise de novo as a grade IV tumor, or it may result from progression of a lower-grade glioma. The former situation, referred to as “primary glioblastoma” is far more common than the latter situation - "secondary glioblastoma.”
In either case, treatment begins with maximum safe resection, which is followed by radiation therapy and chemotherapy. The current standard-of-care regimen involves six weeks of radiation therapy with concurrent oral temozolomide chemotherapy, followed by monthly cycles of oral temozolomide chemotherapy. Despite aggressive treatment, tumor recurrence is universal, and a variety of treatments may be employed for recurrent disease. Median survival time has increased in recent years due to new treatment options, but remains under two years.
Anaplastic Glioma (WHO grade III)
WHO grade III astrocytomas, oligodendrogliomas, and oligoastrocytomas (also referred to as anaplastic gliomas) share many clinical features with glioblastoma, but are less aggressive tumors with more variability in survival. Oligodendrogliomas and oligoastrocytomas have a better prognosis than “pure” astrocytomas. A variety of tumor markers, such as 1p/19q codeletion and IDH1 mutation status, offer additional prognostic information.
Treatment of WHO grade III gliomas is an area of controversy, with some clinicians favoring aggressive treatment similar to the standard glioblastoma regimen and others using radiation alone or chemotherapy alone.
Low-Grade Glioma (WHO grade II)
Although the term “malignant glioma” is typically reserved for WHO grade III and IV tumors, low-grade gliomas are not clinically benign. Median survival after diagnosis is approximately a decade, although some patients live significantly longer. As with high-grade gliomas, treatment begins with maximal safe surgical resection. In patients in whom the entire area of tumor visible on MRI can be resected, initial observation after surgery is reasonable. In patients with residual tumor after surgery, radiation and chemotherapy is typically recommended.
Are you sure your patient has infiltrating glioma? What should you expect to find?
The typical MRI appearance of a glioblastoma is a solitary ring-enhancing lesion on T1 post-contrast imaging. Additionally T2 and FLAIR (fluid attenuation and inversion recovery) imaging demonstrates signal abnormality surrounding the enhancing portion of the tumor (
WHO grade III astrocytoma is similar in appearance, though it typically shows patchy or indistinct enhancement on T1 post-contrast imaging rather than ring-enhancement. WHO grade III oligodendroglioma or oligoastrocytoma are more frequently cystic and heterogenous in appearance.
WHO grade II gliomas are visible on MRI as hyperintense abnormalities on T2-weighted or FLAIR images that are hypointense on T1-weighted images. Degree of contrast enhancement is imperfectly correlated to tumor grade. Some WHO grade II gliomas contain areas of enhancement, and occasionally entirely non-enhancing tumors suspected to be low-grade on imaging meet pathological criteria for glioblastoma.
Advanced MRI techniques, such as spectroscopy, perfusion, and diffusion imaging do not yet offer sufficient discriminatory power to be useful in routine diagnostic imaging of a brain mass of unknown etiology. However, these imaging techniques may assist in clinical decision-making once a diagnosis is established. Computerized tomography (CT) of the brain has been largely replaced by MRI in routine practice (
Ultimately, glioma is a pathological diagnosis, and tissue confirmation is needed prior to treatment (except when obtaining tissue is considered to present unacceptably high risk). Guidelines for central nervous system tumor classification are published periodically by the WHO, and were last updated in 2007.
Whenever possible, tumor tissue should be examined by an expert neuropathologist, as there is a significant rate of discordance between neuropathologists and general pathologists, particularly in the diagnosis of WHO grade II and grade III tumors. Physicians must also be aware of potential tumor sampling issues at biopsy.
Gliomas are heterogenous in nature with the tumor grade of the entire tumor defined by the region meeting criteria for the highest WHO grade. This is not simply a classification issue; tumor behavior is driven by the most aggressive portion. Thus, if a biopsy results in the diagnosis of a glioma that is lower in grade than expected based on imaging (e.g. a patient with a ring-enhancing lesion in whom biopsy yields WHO grade II astrocytoma), the possibility of a non-representative biopsy must be considered.
Beware of other conditions that can mimic infiltrating glioma:
As noted, both the symptomatic presentation and imaging appearance of glioma are nonspecific. Both non-malignant conditions and other malignancies may share these characteristics.
Mimics of high-grade glioma include:
Demyelinating disease (i.e. tumefactive multiple sclerosis)
Bacterial or fungal infection/abscess
Primary CNS lymphoma
Mimics of low-grade glioma include:
Which individuals are most at risk for developing infiltrating glioma:
Infiltrating gliomas are tumors found in adults, with incidence rates of glioblastoma ranging from a low of 0.13 per 100,000 person years in children age 0-14 years to a high of 14.49 per 100,000 person years in adults age 75-84 years. Lower-grade gliomas are more frequently diagnosed in young adults, with the incidence of WHO grade II oligodendroglioma peaking at 0.43 per 100,000 person years in adults age 45-53.
Approximately 60% of gliomas occur in men and 40% in women. Reasons for this male predominance remain unclear.
The only well-established risk factor for glioblastoma is exposure to ionizing radiation, most frequently in the form of prior therapeutic radiation. Overall, this is an infrequent cause of glioma, and in the vast majority of cases there is no recognized cause. In recent years, there has been a great deal of interest in the potential role of cellular phone exposure, but no conclusive link between cellular phones and glioma has been discovered to date.
Genetic predisposition to infiltrating gliomas appears to be relatively uncommon, although gliomas may be inherited as a part of several familial diseases. Specifically, type 1 neurofibromatosis, Turcot's syndrome, and Li-Fraumeni syndrome are associated with the greatest risk of brain tumors. Recently, a number of common genetic polymorphisms associated with glioma have been discovered via genome-wide association studies. The mechanisms by which these polymorphisms influence glioma risk remain to be elucidated.
What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
The primary purpose of laboratory studies after diagnosis of glioma is to assess a patient's ability to tolerate chemotherapy or monitor the effects of concurrent medications.
Metastasis of infiltrating glioma outside of the central nervous system is exceedingly rare; thus, systemic staging procedures are not warranted.
Patients should undergo a contrast-enhanced MRI of the brain as soon as possible following resective surgery to establish extent of resection. This should ideally be performed within 48 hours of surgery, prior to the development of most post-surgical changes.
A variety of molecular markers associated with prognosis have been reported for glioma. The most important of these are O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, 1p/19q codeletion, and isocitrate dehydrogenase (IDH) mutation.
The presence of MGMT methylation, the presence of 1p/19q codeletion, and the presence of IDH1 mutation (or less frequently IDH2 mutation) are all associated with favorable prognosis.
Recently, 1p/19q codeletion and the presence of IDH mutation have also been found to predict benefit from treatment with chemotherapy in patients with either anaplastic oligodendroglioma or anaplastic oligoastrocytoma.
What therapies should you initiate immediately i.e. emergently?
Management of patients with seizure
Antiepileptic therapy is indicated in patients who present with seizure activity. No single agent has been shown to be superior to alternative treatments for this purpose, so agents can be selected on the basis of side effect profile, cost, and convenience. Phenytoin is often used as a first-line antiepileptic drug (AED) with a starting dose of 300mg by mouth every evening. More recently, levetiracetam has become widely used in patients with intracranial tumors.
The initial goal dose of levetiracetam is 500 to 750mg by mouth twice daily. Levetiracetam is generally well tolerated, and has a lower risk of long-term side effects such as osteoporosis than first generation AEDs. Of note, enzyme-inducing antiepileptic drugs(EIAEDs) such as carbamazepine, phenytoin, and oxcarbazepine do not need to be avoided in patients who will be receiving temozolomide chemotherapy, but EIAEDs do interact with many other antineoplastic agents and are contra-indicated in some clinical trials.
Non enzyme-inducing antiepileptic drugs include levetiracetam, valproic acid, lamotrigine, topiramate, and zonisamide. Monitoring of medication levels is possible for some AEDs, such as phenytoin. Medication levels should be used with caution. In particular, decreasing the AED dose of a seizure-free patient with a minimally or moderately “high” AED level but no signs of toxicity may precipitate breakthrough seizure.
There is no proven role for long-term prophylactic AED therapy in patients with a brain tumor who have not experienced a seizure. Prophylactic AEDs may be used for a limited period of time after surgery, at the discretion of the operating neurosurgeon, but should be discontinued as soon as appropriate - usually - after the first postoperative week.
Management of cerebral edema
Asymptomatic edema seen on imaging does not require steroid treatment, except in the rare circumstance that it is causing significant midline shift or placing the patient at risk for herniation. In patients with significant symptoms, dexamethasone 4 mg by mouth four times daily is a reasonable starting dose, and can be tapered downward over time.
Cerebral edema may transiently worsen during radiation therapy, particularly in patients who have not undergone debulking surgery, and increasing steroid requirements are not uncommon during this time. Long-term steroid therapy may be associated with significant side effects, and the lowest effective dose should be used.
Corticosteroids should be used with caution if CNS lymphoma is in the radiographic differential diagnosis, as steroids may cause transient tumor shrinkage and diminish the yield of pathology. Tumefactive multiple sclerosis, a radiographic mimic of glioblastoma, may also improve with steroid therapy.
What should the initial definitive therapy for the cancer be?
The current standard-of-care therapy for newly diagnosed glioblastoma is multimodality treatment involving surgery, radiation therapy, and temozolomide chemotherapy.
Definitive therapy for glioma begins with surgery. There are three primary rationales for surgery in patients with infiltrating glioma; to establish a diagnosis, to debulk tumors causing significant mass effect, and to potentially improve outcome if extensive resection can be safely performed.
Infiltrating glioma is not surgically curable, owing to the extension of microscopic disease well beyond the region of imaging abnormality. Nevertheless, significant retrospective and prospective data suggest that gross total resection (GTR) is associated with improved survival when it can be performed without negatively impacting patient functional status. In situations where the tumor is located in a known eloquent brain region, such as the motor strip or Broca's area, resection is usually not possible.
Biopsy is most often chosen when gross total resection cannot be safely performed and no debulking surgery is necessary. Biopsy has the advantage of low morbidity and mortality. The primary disadvantage of biopsy is the risk of obtaining non-diagnostic tissue or non-representative tumor samples (e.g. yielding tumor meeting criteria for WHO grade II astrocytoma in a tumor that has focally progressed to high-grade glioma in another region).
Radiation therapy (RT)
Involved-field radiation using multiple field techniques is the cornerstone of post-surgical treatment of high-grade glioma. Prior to the routine use of radiation therapy, median survival after glioblastoma diagnosis was several months, and median survival increased to approximately one a year in patients receiving radiation.
Radiation therapy is typically delivered to a total dose of approximately 54-60Gy in 30 fractions, with the highest dose targeted to the area of contrast-enhancing tumor and a lesser dose to the surrounding T2/FLAIR abnormality. In patients with poor prognosis, such as the elderly and those with poor Karnofsky Performance Status (KPS), shortened courses of radiation (e.g. 40 Gy in 15 fractions or 34 Gy in 10 fractions) have been evaluated and suggested to be as effective as standard radiation in this patient group. Furthermore, in some patients with poor prognosis, radiation can even be omitted in favor of temozolomide chemotherapy alone.
Complications of RT are categorized as acute, sub-acute, or late. Acute complications occur during treatment or shortly thereafter and are both predictable and transient. Common acute radiation-related toxicities include alopecia, scalp irritation, serous otitis, and fatigue. Fatigue may be significant, and may worsen in the first week after the conclusion of radiation before beginning to resolve.
As noted previously, radiation may transiently increase peri-tumoral cerebral edema, and this may be especially problematic in patients with large lesions or pre-radiation symptoms of elevated intracranial pressure. Sub-acute complications appear after RT within a few weeks to months. The most frequent sub-acute complication of radiation therapy for glioma is “pseudoprogression,” in which treatment-related changes on MRI mimic tumor growth. Although this phenomenon may be asymptomatic, in some cases there is sufficient edema to require symptomatic management with steroids and even bevacizumab. Pseudoprogression appears to be more common in the current era of combined treatment with radiation and temozolomide chemotherapy.
Brain tissue necrosis is an important late toxicity of radiation for glioblastoma. The latency of necrosis varies from 3 months to years after RT. After treatment for glioma, the 3-year actuarial risk of developing necrosis has been reported to be as high as 13.3%. The only treatment for radiation necrosis that is clearly supported by randomized trial data is the use of bevacizumab. When used for this purpose, bevacizumab is given as 7.5 mg/kg intravenously every 21 days for up to four cycles.
Other treatments that have been evaluated for the treatment of radiation necrosis include hyperbaric oxygen therapy and theophylline, neither of which has been shown unambiguously to be useful. Surgery may be useful for decompression as well as definitive diagnosis of radiation necrosis.
Stereotactic radiosurgery (SRS) systems, such as Gamma Knife or CyberKnife™, deliver large doses of radiation to well-defined targets, with little radiation to surrounding structures. This makes SRS useful in well-circumscribed tumors with little or no infiltration of surrounding brain tissue, such as brain metastases and certain types of primary brain tumors, but it has no proven role in the treatment of infiltrative tumors such as glioma. A prospective randomized trial of standard radiation with or without SRS boost to the core of the glioblastoma showed no survival benefit of SRS boost relative to standard therapy, and a higher rate of symptomatic radiation necrosis was seen.
Temozolomide chemotherapy has been part of the standard-of-care treatment of glioblastoma since 2005, when a pivotal phase III clinical trial showed that temozolomide plus radiation was more effective than radiation alone. This trial also confirmed the prognostic importance of MGMT methylation. The presence of MGMT methylation is prognostic of increased survival, regardless of chemotherapy treatment, rather than predictive of response to chemotherapy. As such, temozolomide treatment should be part of standard treatment for glioblastoma, regardless of methylation status.
Temozolomide is an orally administered alkylating agent that is FDA approved for use in combination with radiation therapy for patients with newly diagnosed glioblastoma.
The most commonly used regimen is six weeks of concurrent oral temozolomide with radiation therapy followed by monthly cycles of adjuvant temozolomide: Temozolomide 75 mg/m2/day along with radiation therapy.
During this time, temozolomide is administered 7 days per week.
Then, starting 4 weeks after radiation therapy: Temozolomide 150 mg/m2 daily for 5 days every 28 days.
If the first cycle is well-tolerated the dose of subsequent cycles is increased to 200mg/m2 daily for 5 days every 28 days.
A total of six cycles of temozolomide were used in the clinical trial that demonstrated the efficacy of temozolomide in newly diagnosed glioblastoma, but some clinicians prefer to continue treatment for longer periods of time if it is well-tolerated and no signs of tumor progression are seen. The authors typically treat with six cycles of temozolomide in their clinical practices, but acknowledge this as an area of controversy within neuro-oncology.
Alternative “dose dense” adjuvant temozolomide regimens have been evaluated in an effort to improve the efficacy of treatment. The Radiation Therapy Oncology Group (RTOG) 0525 trial did not demonstrate any statistically significant difference in survival between the control group treated with standard therapy and the experimental arm treated with a “dose-dense” regimen of temozolomide at a lower daily dose but given 21 days out of every 28-day cycle, for a significantly higher cumulative monthly dose.
With temozolomide, hematologic issues are the most common side effects, with 4% of patients experiencing severe or life-threatening neutropenia, and 3% of patients experiencing severe or life-threatening thrombocytopenia during the 6-week daily dosing radiation-concurrent phase of treatment. 14% of patients experience grade 3 or 4 hematologic toxicity, with thrombocytopenia occurring more frequently than neutropenia. Due to profound lymphopenia during concurrent radiation therapy and daily temozolomide (which can be exacerbated by corticosteroid administration), prophylaxis with trimethoprim-sulfamethoxazole is recommended.
With respect to non-hematologic toxicity, nausea can be significantly reduced by pre-treatment with an oral anti-emetic. As a whole, temozolomide is generally well-tolerated; in the EORTC/NCIC trial no decrease in health-related quality of life resulted from the addition of temozolomide to standard radiotherapy.
While acute side effects occur relatively frequently, their severity and clinical significance can be minimized through vigilant monitoring and prophylaxis. During the concurrent phase of TMZ chemotherapy, weekly complete blood count (CBC) is recommended, along with monthly serum electrolyte panel and liver function tests. If significant hematologic toxicity is seen, transfusion, growth factor administration, or TMZ dose reduction can be considered as appropriate. During the adjuvant cycles of TMZ chemotherapy, a CBC should be checked before the beginning of each cycle. Treatment can be delayed or dose-reduced as needed if significant hematological toxicity occurs.
Recurrent disease/alternative therapy
Bevacizumab 10 mg/kg IV every 2 weeks.
Monitoring includes blood pressure assessments and urinalysis to evaluate for proteinuria.
Bevacizumab 10 mg/kg IV every 2 weeks.
Irinotecan 125 mg/m2 IV every 2 weeks (if not on enzyme-inducing anticonvulsant) or 340 mg/m2 IV every 2 weeks (if on an enzyme-inducing anticonvulsant).
Examples of enzyme-inducing anticonvulsants include phenytoin (Dilantin), cabamazapine (Tegretol), and phenobarbital. Valproic acid (Depakote), levetiracetam (Keppra), and lamotrigine (Lamictal) are
See WHO grade III glioma section.
See WHO grade III glioma section.
Other chemotherapy regimens
The U.S. Food Drug Administration (FDA) has approved the use of carmustine-impregnated degradable polymers for the treatment of newly diagnosed gliomas and recurrent glioblastoma. However, the median survival associated with that treatment is only slightly better than with placebo. A large number of molecularly targeted agents have been or are being evaluated in the clinical trial setting, but the current data are insufficient to recommend routine use of any of these therapies for newly diagnosed glioblastoma. Two large phase III clinical trials have recently demonstrated that the addition of bevacizumab to standard chemoradiation with temozolomide in patients with newly diagnosed glioblastoma does not improve overall survival.
WHO grade III glioma
WHO grade III gliomas are both less common and more heterogeneous in behavior than glioblastomas. Treatment decisions are influenced by tumor morphology (i.e. anaplastic astrocytoma versus anaplastic oligodendroglioma) and by molecular markers such as 1p/19q codeletion and IDH mutations. There is substantially more variability in the initial treatment of WHO grade III glioma than in glioblastoma, even among centers with expertise in neuro-oncology.
As in glioblastoma, the treatment of WHO grade III glioma begins with maximum safe resection. The distinction between grade III glioma and glioblastoma is often not apparent prior to surgery, so preoperative assessment and intraoperative management are essentially identical.
In the U.S., the most common standard treatment includes radiation therapy immediately following recovery from surgery.
As patients with grade III tumors have longer expected survival than patients with glioblastoma, they are at higher risk of developing late complications of radiation. In addition to the complications of radiation discussed in reference to glioblastoma, patients with lower-grade tumors are at increased risk of developing cognitive sequelae of treatment, which typically begin years after treatment.
Clinical trials (RTOG 9402) have clearly demonstrated that patients with either anaplastic oligodendrogliomas (AOD) or anaplastic oligoastrocytomas (AOA) that are either 1p/19q codeleted or IDH mutated have longer survival when treated with chemotherapy along with upfront radiation. Although radiation therapy upfront followed by chemotherapy at progression is not recommended in this patient population, such a strategy may be considered in patients without the aforementioned molecular markers.
Treatment with chemotherapy up front with radiation only at progression has also been explored due to an interest in delaying radiation therapy. A phase III clinical trial has demonstrated that an upfront chemotherapy approach has a similar overall survival to an upfront radiation approach, provided the alternative therapy is provided at progression. While there are concerns regarding long term cognitive decline with radiation therapy, there are also concerns that delaying radiation therapy may result in inferior survival. Phase III trials have not yet explored the outcomes of early versus delayed radiation in patients with 1p/19q codeleted or IDH mutated AOD/AOA.
No large trials comparing either initial radiation or chemotherapy alone versus a strategy of combined upfront temozolomide chemotherapy and radiation, akin to that used in glioblastoma, have been completed to date.
Decision to treat
In clinical practice, the initial treatment of WHO grade III glioma depends heavily on tumor morphology and molecular markers, which are associated with tumor aggressiveness. Patients with anaplastic astrocytoma, the grade III glioma with the worst prognosis, are typically treated with either radiation alone or radiation in combination with temozolomide chemotherapy.
On the other hand, as mentioned earlier, up front radiation followed by chemotherapy is recommended in patients with either 1p/19q codeleted or IDH mutated AOD/AOA as this combination prolongs survival when compared with radiation alone. This treatment combination does not improve survival in the absence of both of these markers.
The standard radiation regimen for WHO grade III glioma, 54-60 Gy in 30 fractions, is identical to that used in glioblastoma.
Chemotherapy may be used alone or in combination with radiation therapy for newly diagnosed WHO grade III glioma.
Decision to treat
The role of adjuvant chemotherapy in anaplastic astrocytoma remains controversial. Some phase III trials have demonstrated no benefit of adjuvant chemotherapy compared with radiation alone, whereas others have demonstrated benefit.
In light of its proven efficacy against glioblastoma and generally acceptable side effect profile, some neuro-oncologists routinely recommend temozolomide treatment along with radiation for anaplastic astrocytoma, while other neuro-oncologists recommend radiation alone and prefer to reserve temozolomide for recurrent anaplastic astrocytoma, where its efficacy has been proven. Initial chemotherapy without radiation is infrequently used in the U.S., although randomized data suggests this approach may be reasonable.
Anaplastic oligodendroglioma and oligoastocytoma are more responsive to chemotherapy than are anaplastic astrocytomas. Prospective trials have demonstrated that approximately 50% to 70% of patients with anaplastic oligodendrogliomas that recur after radiotherapy respond to chemotherapy with either temozolomide or the combination of procarbazine, CCNU (lomustine) and vincristine, collectively known as PCV.
As mentioned previously, long-term results of the RTOG 9402 trial demonstrate that the survival of patients with either 1p/19q codeleted or IDH mutated anaplastic oligodendroglial tumors is significantly prolonged by initial treatment with chemoradiotherapy rather than radiation alone. In the absence of either of these molecular markers, chemoradiotherapy was no better than radiation alone. The RTOG trial employed PCV as it was conducted prior to the use of temozolomide. A phase III trial comparing adjuvant temozolomide to PCV is ongoing.
(see regimen under Glioblastoma section above)
CCNU (Lomustine) 110-130 mg/m2 orally on day 1
Procarbazine 75 mg/m2 orally daily days 8-21
Vincristine 1.4 mg/m2 IV on days 8 and 29.
Repeat every 6 weeks for up to 6 cycles or until the occurrence of dose-limiting toxicity. The CCNU dose is the same when given as monotherapy as when used as part of PCV.
BCNU (Carmustine) 150-200 mg/m2 in one dose or 2-3 divided consecutive daily doses every 6 weeks.
Temozolomide related toxicity is similar to that experienced when temozolomide is used to treat glioblastoma. The most common serious systemic toxicity of PCV chemotherapy is myelosuppression.
Characteristically, PCV-associated myelosuppression is delayed by at least three to four weeks after the first day of each cycle. In addition, myelosuppression is cumulative. As the risk of myelosuppression increases with each subsequent dose, most patients will be unable to receive more than a limited number of cycles before myelosuppression limits further therapy. Moreover, the myelosuppression may be permanent, limiting the possibility of treatment with other myelosuppressive agents in the future.
Other potentially serious side effects of nitrosourea therapy include hepatic and pulmonary toxicity. Pulmonary toxicity is more common with use of intravenous BCNU (carmustine) than it is with oral CCNU (lomustine). Patients should undergo pulmonary function testing (PFT) prior to treatment with the first cycle of BCNU, then, at a minimum, before the third and fifth cycles.
If the diffusing capacity of the lung for carbon monoxide (DLCO) at baseline is less than 60% of predicted, BCNU should not be given. If DLCO drops below 55% of predicted during treatment, BCNU should be discontinued. As pulmonary toxicity is much less frequent with oral CCNU (lomustine), PFT evaluation can be omitted at the discretion of the treating physician unless there is underlying pulmonary disease. Nausea, vomiting, fatigue, and sensory neuropathy are often seen, but are frequently mild or responsive to medical management.
WHO Grade II Glioma
WHO grade II gliomas, also known as low-grade gliomas, are slow-growing primary brain tumors that typically affect young adults. Although the term "malignant glioma" is typically reserved for WHO grade III and IV tumors, low-grade gliomas are not clinically benign, and most patients eventually succumb to tumor-related complications. Treatment of low-grade glioma is controversial, and varying strategies for initial management are employed, including observation, resection, radiation, and/or chemotherapy.
Currently, there is no non-invasive way to definitively diagnose low-grade glioma, so surgery is necessary for diagnostic purposes. Only rarely is biopsy deferred in favor of treatment without tissue diagnosis. Initial observation of asymptomatic suspected low-grade glioma is sometimes recommended, typically in patients with coexistent health issues that would complicate resection. This approach is not preferred as tumor growth during observation may limit surgical options when surgery is needed.
An initial strategy of post-surgical observation (“watchful waiting”) following diagnosis has been proposed by some clinicians. The rationale for watchful waiting is that, while radiation therapy has been shown to improve overall survival in subtotally-resected tumors, the optimum timing of radiation is an ongoing controversy in neuro-oncology. In clinical practice, observation after initial surgery is reserved for patients thought to have a high likelihood of prolonged progression-free survival even in absence of radiation therapy. This group is typically limited to patients lacking substantive symptoms or signs who have undergone a gross total resection of their tumor.
Radiation therapy is often used as the initial post-surgery treatment of low-grade glioma. This is especially true in patients with residual tumor after surgery, as they are at high risk of early progression, and it is clear that tumor progression is associated with cognitive and functional decline as well as mortality. Recent data demonstrate prolonged survival with the addition of PCV following radiation therapy as compared with radiation therapy alone in patients who were either over the age of 40 years or who had less than a gross total tumor resection. In patients less than age of 40 years with a gross total tumor resection, we do not know the effects of chemoradiation as initial therapy. Furthermore, there are no studies to date that have compared patients with low grade glioma who receive initial chemoradiotherapy with those who receive chemotherapy alone followed by radiation at recurrence.
Decision to treat
Since there is now convincing evidence that chemoradiation prolongs survival compared with radiation alone in patients with less than gross total resection and in those older than age 40, the decision to delay radiation therapy has become more problematic. We do not know if radiation therapy given as salvage treatment at the time of progression after initial chemotherapy is as effective as initial chemoradiotherapy. On the other hand, late cognitive impairment related to radiation therapy is clearly a potential risk, and delaying the risk is reasonable, albeit at the risk of a shortened life expectancy. Disclosure of the risks to the patient and joint decision-making concerning early versus delayed radiation therapy is important.
Randomized trials have established that low-dose radiation (50-54 Gy) is as effective as higher doses.
Complications of treatment
A potential long-term complication of radiation of special concern in this patient population is cognitive decline. A longitudinal study of patients with low-grade glioma suggests that in the first several years after diagnosis the primary predictor of cognitive decline is the presence or absence of tumor progression rather than radiation history.
In the longer term, patients without tumor progression who received radiation are more likely to show a progressive cognitive decline than patients without tumor progression who did not receive radiation. At a mean follow-up time of 12 years after initial diagnosis, patients treated with radiation displayed deficits in attentional functioning, executive functioning, and information processing speed.
Ongoing randomized trials that examine cognitive function and quality of life from time of diagnosis to death as well as duration of survival will provide a more nuanced understanding of the relative pros and cons of different treatment strategies.
Previously, chemotherapy was typically reserved for treatment of progression after radiation therapy, but more recently up-front chemotherapy strategies have gained prominence. As mentioned previously, recent data from R9802 have demonstrated significant benefit with the use of six cycles of PCV chemotherapy immediately following radiation therapy.
Decision to treat
Of the low-grade gliomas, tumors with a significant oligodendroglial component are thought to be both less aggressive and more responsive to chemotherapy than pure astrocytomas. Initial treatment with chemotherapy may be used in these patients to delay radiation and thus delay any potential radiation-related side effects, although the duration of disease control and survival with this strategy is unknown. Alternatively, chemotherapy may be used in combination with radiation. The value of temozolomide compared with PCV as initial chemotherapy is currently under investigation in an ongoing phase III clinical trial.
Once the decision to administer radiation has been made for a patient with a low-grade glioma, chemotherapy should be administered after the completion of radiation therapy.
PCV is given as 6-week cycles as follows:
CCNU 110 mg/m2 orally on day 1.
Procarbazine 75 mg/m2 orally on days 8 through 21.
Vincristine 1.4 mg/m2 intravenously on days 8 and 29.
Treatment continues for a total of six cycles, or until the occurrence of dose-limiting toxicity.
Nitrosourea regimens have activity against low-grade glioma as demonstrated by a significant rate of radiographic response.
The duration of nitrosourea therapy is limited by cumulative toxicity, but ongoing decreases in tumor size can be seen for years following discontinuation of chemotherapy.
In the past decade, temozolomide chemotherapy had largely displaced nitrosourea-based regimens in the treatment of low-grade glioma. Temozolomide dosing regimens for low-grade glioma mirror those for glioblastoma. While there has not been a published head-to-head trial of temozolomide versus nitrosourea therapy, many clinicians favor temozolomide due to perceived similar efficacy and superior tolerability. However with the recent findings from RTOG 9802, chemotherapy with PCV is likely to resume its significance.
Chemotherapy-related toxicities associated with WHO grade II tumors mirror those previously discussed for higher-grade tumors.
What other therapies are helpful for reducing complications?
Antiemetic therapy is necessary in all patients receiving temozolomide chemotherapy. The serotonin 5-HT3 receptor antagonists are frequently used for this purpose. Granisetron 1 mg or ondansetron 4mg by mouth one hour before each dose of chemotherapy are commonly used regimens. Additional anti-emetics can be used on an as-needed basis.
Pneumocystis pneumonia (PCP) is an opportunistic infection caused by the yeast-like fungus Pneumocystis jirovecii (formerly known as Pneumocystis carinii). PCP most frequently occurs in immunosuppressed patients, including those receiving chemotherapy. Prophylaxis with trimethoprim and sulfamethoxazole should be considered; one single-strength tablet by mouth daily is a common regimen. PCP prophylaxis is typically initiated along with radiation and concurrent temozolomide and is continued through the full duration of adjuvant chemotherapy. In sulfa-allergic patients, other agents such as dapsone or inhaled pentamidine may be employed.
Constipation is a frequent symptomatic issue in patients receiving temozolomide chemotherapy and anti-emetic prophylaxis. This can often be managed with dietary changes and fiber supplementation. Alternatively, stool softeners such as docusate sodium may be employed.
What should you tell the patient and the family about prognosis?
The median survival time associated with glioblastoma has increased in the past decade, likely due to the widespread use of temozolomide. In the EORTC/NCIC trial that proved the efficacy of this treatment, the patient group treated with radiation alone had a median survival time of 12.1 months, while the patient group treated with radiation and temozolomide had a median survival of 14.6 months.
Furthermore, the temozolomide therapy group contained a higher proportion of long-term survivors than the radiotherapy only group, 27.2% versus 10.9% at two years and 9.8% versus 1.9% at five years, respectively. Data from clinical trials also suggest that further improvements in mortality have occurred more recently, perhaps due to the availability of better salvage therapies such as bevacizumab at the time of tumor progression, with median survival ranging 18-23 months.
The three most important predictors of survival time after glioblastoma diagnosis are patient age, performance status, and tumor MGMT methylation. Data from the Surveillance, Epidemiology, and End Results (SEER) program shows that between 2005 and 2008, median survival times of patients treated with surgery and a radiation-containing regimen (presumably also including chemotherapy in most cases) ranged from a high of 31.9 months in patients age 20-29 to a low of 5.6 months in patients age 80 and older.
The presence of MGMT promoter methylation in glioblastoma is indicative of a prolonged survival with patients surviving a median of 18.2 months in contrast to a median survival of 12.2 months in those without MGMT promoter methylation. Similarly, IDH mutations in glioblastoma also portend a favourable prognosis; however, these are uncommon in primary glioblastoma. Patients with IDH mutated glioblastoma have a median survival of 31 months, while those without IDH mutation have a median survival of 15 months.
WHO grade III glioma
Survival after diagnosis of WHO grade III glioma depends heavily on tumor morphology, 1p/19q codeletion, and IDH mutations. In patients with anaplastic astrocytoma, the 2011 Statistical Report of the Central Brain Tumor Registry of the United States reports that 2-year, 5-year, and 10-year relative survival rates are 43%, 27%, and 19%, respectively. In contrast, patient with anaplastic oligodendroglioma have 2-year, 5-year, and 10-year relative survival rates of 69%, 52%, and 39%. Mixed tumors (i.e. anaplastic oligoastrocytoma) have an intermediate prognosis.
However, molecular alterations appear to have greater influence upon survival than histologic diagnosis. For example, patients with IDH mutated anaplastic astrocytoma have a median survival of 65 months, while those without IDH mutation have a median survival of 20 months. Similarly, 1p/19q codeletion is also associated with a favorable prognosis.
WHO grade II glioma
Most patients diagnosed with low-grade glioma will eventually succumb to the tumor, although long-term survival is much more common in low-grade glioma than in higher grade tumors. The 2014 Statistical Report of the Central Brain Tumor Registry of the United States reports that 2-year, 5-year, and 10-year relative survival rates for low-grade astrocytoma are 61%, 47%, and 37%, respectively. The 2-year, 5-year, and 10-year relative survival rates for low-grade oligodendroglioma are 90%, 80%, and 63%, respectively. As with grade III gliomas, 1p/19q codeletion and IDH mutations are associated with much longer survival in patients with identical histologic diagnoses.
What if scenarios.
Management of radiographic progression soon after completion of radiation therapy
Treatment-related changes on MRI, termed pseudoprogression, are seen in 20% to 30% of patients with glioblastoma who receive treatment with radiation and temozolomide. Pseudoprogression is typically seen within the first three months after completion of radiation.
If early radiographic signs of progression are seen in a clinically stable patient, most clinicians continue with the current therapy for one or two additional months before repeating imaging. If the patient is symptomatic, then consideration should be given to surgical intervention, which may be both therapeutic and diagnostic.
Follow-up surveillance and therapy/management of recurrences.
Patients with glioblastoma typically undergo their first surveillance MRI 1-2 months after the completion of radiation therapy. The purpose of this MRI is to establish a post-radiation baseline, rather than to assess for early signs of tumor progression, as “pseudoprogression” (discussed previously) is a significant issue at this timepoint. Follow-up MRIs are often performed every two to three months while a patient is actively receiving therapy, or more often as clinically indicated. The follow-up interval may be lengthened following the completion of adjuvant therapy, at the discretion of the treating physicians.
Management of recurrence
Surgical resection of recurrent glioblastoma may be considered if the diagnosis of recurrence is in doubt (i.e. if radiation-related changes are suspected) or if relief of mass effect is needed. There is significantly less consensus amongst neuro-oncologists regarding optimum salvage treatment of recurrent glioblastoma than for newly diagnosed disease.
Chemotherapy is generally the first line of therapy, with additional alkylator chemotherapy or the use of the targeted anti-angiogenic agent bevacizumab being two common approaches. Patients should be assessed for participation in clinical trials as well.
If chemotherapeutic approaches have been exhausted or if there is a contraindication to chemotherapy, an additional course of fractionated radiation therapy is reasonable. Other salvage radiation approaches, such as stereotactic radiosurgery (e.g. Gamma Knife, Cyberknife) and brachytherapy (e.g. GliaSite) have been evaluated, but these are associated with higher rates of symptomatic radiation necrosis than is fractionated therapy.
WHO grade III glioma
Like glioblastoma, recurrence of WHO grade III glioma is nearly universal. However, it may not occur for a number of years after initial diagnosis, particularly in patients with 1p/19q codeleted oligodendroglial tumors. Surveillance and management of recurrence are identical to that for glioblastoma patients.
WHO grade II glioma
Patients should be imaged approximately every 3 months following initial diagnosis and treatment. In patients with early MRI changes following radiation therapy, treating clinicians should strongly consider the possibility that this represents treatment effect rather than rapid tumor progression. After 1-2 years of clinical and radiographic stability, the imaging interval can be lengthened to 6 months. Further increases in imaging intervals can be considered in patients who remain stable on this schedule. Lifelong follow-up is required, as late recurrence is not unusual.
Management of recurrence
As in grade III glioma, in patients initially treated with radiation alone, chemotherapy at recurrence is the standard treatment, and vice versa. In patients who were initially treated with chemotherapy and developed recurrence only after the termination of chemotherapy, a second course of chemotherapy in order to forestall radiation may also be considered.
The risk of “sporadic” glioma may be influenced by the presence of one or more common genetic polymorphisms, each associated with only a modest relative risk. In 2009, two groups independently published work identifying single nucleotide polymorphisms (SNPs) associated with glioma risk via genome-wide association studies. Follow-up studies have demonstrated that individual SNPs are associated with tumors of specific grades and morphologies, rather than glioma in general. The mechanisms by which these common polymorphisms influence glioma risk are not yet known.
Glioma stem cells
The presence of a small population of cells within human gliomas that possess stem cell-like features was first recognized in 2004. The glycoprotein CD133 has been proposed as a marker of glioma stem cells. The extent to which these cells are truly stem cells remains an area of significant discussion, and some authors prefer to use more general terms such as tumor-initiating cells when discussing this concept. This cell population appears to be especially resistant to radiation and chemotherapy, and may partially explain the high rate of tumor recurrence following initial treatment.
Isocitrate dehydrogenase gene mutation
In 2008, Parsons and colleagues were the first to report mutations in the isocitrate dehydrogenase gene in patients with glioma. Follow-up investigations have demonstrated that this is a common mutation in WHO grade II and grade III glioma, as well as secondary glioblastoma (i.e. glioblastoma which has arisen from lower-grade glioma), but relatively uncommon in primary glioblastoma.
Molecular classification of glioblastoma
Recent advances in understanding regarding the genetic underpinnings of glioma, provided by such efforts as the Cancer Genome Atlas, have allowed the elucidation of glioblastoma subtypes with distinctly different behaviors and prognoses. With respect to glioblastoma, patterns of alteration in IDH, PTEN, EGFR, p53, and other genes can be used to classify glioblastoma into subtypes via a number of classification systems such as that of Verhaak et al, which groups tumors as Proneural, Neural, Classical, and Mesenchymal.
What's the evidence?
Armstrong, GT, Conklin, HM, Huang, S. "Survival and long-term health and cognitive outcomes after low-grade glioma". Neuro Oncol. vol. 13. 2011. pp. 223-34.
Attenello, FJ, Mukherjee, D, Datoo, G. "Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: a 10-year institutional experience". Ann Surg Oncol. vol. 15. 2008. pp. 2887-93.
Bauman, G, Fisher, B, Watling, C. "Adult supratentorial low-grade glioma: long-term experience at a single institution". Int J Radiat Oncol Biol Phys. vol. 75. 2009. pp. 1401-7.
Bay, JO, Linassier, C, Biron, P. "Does high-dose carmustine increase overall survival in supratentorial high-grade malignant glioma? An EBMT retrospective study". Int J Cancer. vol. 120. 2007. pp. 1782-6.
Berger, MS, Deliganis, AV, Dobbins, J. "The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas". Cancer. vol. 74. 1994. pp. 1784-91.
Brandes, AA, Franceschi, E, Tosoni, A. "Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status". Cancer. vol. 115. 2009. pp. 3512-8.
Brandes, AA, Franceschi, E, Tosoni, A. "MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients". J Clin Oncol. vol. 26. 2008. pp. 2192-7.
Brandes, AA, Tosoni, A, Amista, P. "How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial". Neurology. vol. 63. 2004. pp. 1281-4.
Brandsma, D, Stalpers, L, Taal, W. "Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas". Lancet Oncol. vol. 9. 2008. pp. 453-61.
Brandsma, D, van den Bent, MJ. "Pseudoprogression and pseudoresponse in the treatment of gliomas". Curr Opin Neurol. vol. 22. 2009. pp. 633-8.
Buckner, JC, Pugh, SL, Shaw, EG. "Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG and SWOG". J Clin Oncol. vol. 32. 2014.
Cairncross, G, Berkey, B, Shaw, E. "Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402". J Clin Oncol. vol. 24. 2006. pp. 2707-14.
Cairncross, JG, Wang, M, Jenkins, RB. "Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH". J Clin Oncol. vol. 32. 2014. pp. 783-790.
Chaichana, KL, McGirt, MJ, Niranjan, A. "Prognostic significance of contrast-enhancing low-grade gliomas in adults and a review of the literature". Neurol Res. vol. 31. 2009. pp. 931-9.
Chamberlain, MC, Raizer, J. "Extended exposure to alkylator chemotherapy: delayed appearance of myelodysplasia". J Neurooncol. vol. 93. 2009. pp. 229-32.
Chang, EF, Clark, A, Jensen, RL. "Multiinstitutional validation of the University of California at San Francisco Low-Grade Glioma Prognostic Scoring System. Clinical article". J Neurosurg. vol. 111. 2009. pp. 203-10.
Chang, EF, Potts, MB, Keles, GE. "Seizure characteristics and control following resection in 332 patients with low-grade gliomas". J Neurosurg. vol. 108. 2008. pp. 227-35.
Chinot, OL, Honore, S, Dufour, H. "Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy". J Clin Oncol. vol. 19. 2001. pp. 2449-55.
Chinot, OL, Wick, W, Mason, W. "Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma". New Engl J Med. vol. 370. 2014. pp. 709-722.
Clarke, JL, Iwamoto, FM, Sul, J. "Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma". J Clin Oncol. vol. 27. 2009. pp. 3861-7.
Claus, EB, Black, PM. "Survival rates and patterns of care for patients diagnosed with supratentorial low-grade gliomas: data from the SEER program, 1973-2001". Cancer. vol. 106. 2006. pp. 1358-63.
De Santis, A, Villani, R, Sinisi, M. "Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study". Epilepsia. vol. 43. 2002. pp. 175-82.
Deorah, S, Lynch, CF, Sibenaller, ZA. "Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001". Neurosurg Focus. vol. 20. 2006. pp. E1.
Dietrich, J, Norden, AD, Wen, PY. "Emerging antiangiogenic treatments for gliomas - efficacy and safety issues". Curr Opin Neurol. vol. 21. 2008. pp. 736-44.
Douw, L, Klein, M, Fagel, SS. "Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up". Lancet Neurol. vol. 8. 2009. pp. 810-8.
Fink, J, Born, D, Chamberlain, MC. "Pseudoprogression: relevance with respect to treatment of high-grade gliomas". Curr Treat Options Oncol. vol. 12. 2011. pp. 240-52.
Fogh, SE, Andrews, DW, Glass, J. "Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas". J Clin Oncol. vol. 28. 2010. pp. 3048-53.
Friedman, HS, Prados, MD, Wen, PY. "Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma". J Clin Oncol. vol. 27. 2009. pp. 4733-40.
Gilbert, MR, Dignam, JJ, Armstrong, TS. "A randomized trial of bevacizumab for newly diagnosed glioblastoma". New Engl J Med. vol. 370. 2014. pp. 699-708.
Gilbert, MR, Wang, M, Aldape, KD. "Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial". J Clin Oncol. vol. 31. 2013. pp. 4085-91.
Glantz, MJ, Cole, BF, Forsyth, PA. "Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. vol. 54. 2000. pp. 1886-93.
Glantz, MJ, Cole, BF, Friedberg, MH. "A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors". Neurology. vol. 46. 1996. pp. 985-91.
Gutin, PH, Iwamoto, FM, Beal, K. "Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas". Int J Radiat Oncol Biol Phys. vol. 75. 2009. pp. 156-63.
Hartmann, C, Hentschel, B, Wick, W. "Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas". Acta Neuropathol. vol. 120. 2010. pp. 707-18.
Hegi, ME, Diserens, AC, Gorlia, T. "MGMT gene silencing and benefit from temozolomide in glioblastoma". N Engl J Med. vol. 352. 2005. pp. 997-1003.
Hess, KR, Broglio, KR, Bondy, ML. "Adult glioma incidence trends in the United States, 1977-2000". Cancer. vol. 101. 2004. pp. 2293-9.
Houillier, C, Wang, X, Kaloshi, G. "IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas". Neurology. vol. 75. 2010. pp. 1560-6.
Iwamoto, FM, Abrey, LE, Beal, K. "Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma". Neurology. vol. 73. 2009. pp. 1200-6.
Jackson, RJ, Fuller, GN, Abi-Said, D. "Limitations of stereotactic biopsy in the initial management of gliomas". Neuro Oncol. vol. 3. 2001. pp. 193-200.
Jenkins, RB, Wrensch, MR, Johnson, D. "Distinct germ line polymorphisms underlie glioma morphologic heterogeneity". Cancer Genet. vol. 204. 2011. pp. 13-8.
Kappelle, AC, Postma, TJ, Taphoorn, MJ. "PCV chemotherapy for recurrent glioblastoma multiforme". Neurology. vol. 56. 2001. pp. 118-20.
Keles, GE, Lamborn, KR, Berger, MS. "Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome". J Neurosurg. vol. 95. 2001. pp. 735-45.
Khasraw, M, Bell, D, Wheeler, H. "Long-term use of temozolomide: could you use temozolomide safely for life in gliomas?". J Clin Neurosci. vol. 16. 2009. pp. 854-5.
Kreisl, TN, Kim, L, Moore, K. "Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma". J Clin Oncol. vol. 27. 2009. pp. 740-5.
Kuijlen, JM, Teernstra, OP, Kessels, AG. "Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis". Seizure. vol. 5. 1996. pp. 291-8.
Lacroix, M, Abi-Said, D, Fourney, DR. "A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival". J Neurosurg. vol. 95. 2001. pp. 190-8.
Lai, A, Tran, A, Nghiemphu, PL. "Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme". J Clin Oncol. vol. 29. 2011. pp. 142-8.
Levin, VA, Bidaut, L, Hou, P. "Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system". Int J Radiat Oncol Biol Phys. vol. 79. 2011. pp. 1487-95.
Li, J, Wang, M, Won, M. "Validation and Simplification of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification for Glioblastoma". Int J Radiat Oncol Biol Phys In Press. 2010.
Louis, DN, Ohgaki, H, Wiestler, OD, Cavenee, WK. "WHO Classification of Tumours of the Central Nervous System". IARD Press. 2007.
McGirt, MJ, Chaichana, KL, Attenello, FJ. "Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas". Neurosurgery. vol. 63. 2008. pp. 707-8.
McGirt, MJ, Chaichana, KL, Gathinji, M. "Independent association of extent of resection with survival in patients with malignant brain astrocytoma". J Neurosurg. vol. 110. 2009. pp. 156-62.
McGirt, MJ, Than, KD, Weingart, JD. "Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme". J Neurosurg. vol. 110. 2009. pp. 583-8.
Meyers, CA, Hess, KR, Yung, WK. "Cognitive function as a predictor of survival in patients with recurrent malignant glioma". J Clin Oncol. vol. 18. 2000. pp. 646-50.
Newlands, ES, Blackledge, GR, Slack, JA. "Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856)". Br J Cancer. vol. 65. 1992. pp. 287-91.
Neyns, B, Chaskis, C, Joosens, E. "A multicenter cohort study of dose-dense temozolomide (21 of 28 days) for the treatment of recurrent anaplastic astrocytoma or oligoastrocytoma". Cancer Invest. vol. 26. 2008. pp. 269-77.
Nghiemphu, PL, Green, RM, Pope, WB. "Safety of anticoagulation use and bevacizumab in patients with glioma". Neuro Oncol. vol. 10. 2008. pp. 355-60.
Norden, AD, Drappatz, J, Wen, PY. "Antiangiogenic therapy in malignant gliomas". Curr Opin Oncol. vol. 20. 2008. pp. 652-61.
Norden, AD, Young, GS, Setayesh, K. "Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence". Neurology. vol. 70. 2008. pp. 779-87.
Ostrom, QT, Gittleman, H, Liao, P. "CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011". Neuro Oncol 16. 2014. pp. iv1-iv63.
Park, JK, Hodges, T, Arko, L. "Scale to predict survival after surgery for recurrent glioblastoma multiforme". J Clin Oncol. vol. 28. 2010. pp. 3838-43.
Perry, JR, Belanger, K, Mason, WP. "Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study". J Clin Oncol. vol. 28. 2010. pp. 2051-7.
Pignatti, F, van den Bent, M, Curran, D. "Prognostic factors for survival in adult patients with cerebral low-grade glioma". J Clin Oncol. vol. 20. 2002. pp. 2076-84.
Prasad, G, Haas-Kogan, DA. "Radiation-induced gliomas". Expert Rev Neurother. vol. 9. 2009. pp. 1511-7.
Recht, LD, Lew, R, Smith, TW. "Suspected low-grade glioma: is deferring treatment safe?". Ann Neurol. vol. 31. 1992. pp. 431-6.
Roa, W, Brasher, PM, Bauman, G. "Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial". J Clin Oncol. vol. 22. 2004. pp. 1583-8.
Sanai, N, Alvarez-Buylla, A, Berger, MS. "Neural stem cells and the origin of gliomas". N Engl J Med. vol. 353. 2005. pp. 811-22.
Sanai, N, Berger, MS. "Glioma extent of resection and its impact on patient outcome". Neurosurgery. vol. 62. 2008. pp. 753-64.
Sanai, N, Berger, MS. "Operative techniques for gliomas and the value of extent of resection". Neurotherapeutics. vol. 6. 2009. pp. 478-86.
Schiffer, CA, Anderson, KC, Bennett, CL. "Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology". J Clin Oncol. vol. 19. 2001. pp. 1519-38.
Shete, S, Hosking, FJ, Robertson, LB. "Genome-wide association study identifies five susceptibility loci for glioma". Nat Genet. vol. 41. 2009. pp. 899-904.
Souhami, L, Seiferheld, W, Brachman, D. "Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol". Int J Radiat Oncol Biol Phys. vol. 60. 2004. pp. 853-60.
Stewart, LA. "Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials". Lancet. vol. 359. 2002. pp. 1011-8.
Stupp, R, Hegi, ME, Gilbert, MR. "Chemoradiotherapy in malignant glioma: standard of care and future directions". J Clin Oncol. vol. 25. 2007. pp. 4127-36.
Stupp, R, Hegi, ME, Mason, WP. "Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial". Lancet Oncol. vol. 10. 2009. pp. 459-66.
Stupp, R, Mason, WP, van den Bent, MJ. "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma". N Engl J Med. vol. 352. 2005. pp. 987-96.
Taphoorn, MJ, van den Bent, MJ, Mauer, ME. "Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial". J Clin Oncol. vol. 25. 2007. pp. 5723-30.
Tsao, MN, Mehta, MP, Whelan, TJ. "The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma". Int J Radiat Oncol Biol Phys. vol. 63. 2005. pp. 47-55.
van den Bent, MJ, Afra, D, de Witte, O. "Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial". Lancet. vol. 366. 2005. pp. 985-90.
van den Bent, MJ, Chinot, O, Boogerd, W. "Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972". Ann Oncol. vol. 14. 2003. pp. 599-602.
van den Bent, MJ, Dubbink, HJ, Sanson, M. "MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951". J Clin Oncol. vol. 27. 2009. pp. 5881-6.
van den Bent, MJ, Taphoorn, MJ, Brandes, AA. "Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971". J Clin Oncol. vol. 21. 2003. pp. 2525-8.
Verhaak, RG, Hoadley, KA, Purdom, E. "Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1". Cancer Cell. vol. 17. 2010. pp. 98-110.
Vredenburgh, JJ, Desjardins, A, Herndon, JE 2nd. "Bevacizumab plus irinotecan in recurrent glioblastoma multiforme". J Clin Oncol. vol. 25. 2007. pp. 4722-9.
Wang, M, Cairncross, G, Shaw, E. "Cognition and quality of life after chemotherapy plus radiotherapy (RT) vs. RT for pure and mixed anaplastic oligodendrogliomas: radiation therapy oncology group trial 9402". Int J Radiat Oncol Biol Phys. vol. 77. 2010. pp. 662-9.
Watanabe, T, Nobusawa, S, Kleihues, P. "IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas". Am J Pathol. vol. 174. 2009. pp. 1149-53.
Weller, M, Felsberg, J, Hartmann, C. "Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network". J Clin Oncol. vol. 27. 2009. pp. 5743-50.
Wen, PY, Macdonald, DR, Reardon, DA. "Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group". J Clin Oncol. vol. 28. 2010. pp. 1963-72.
Westphal, M, Hilt, DC, Bortey, E. "A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma". Neuro Oncol. vol. 5. 2003. pp. 79-88.
Wick, A, Felsberg, J, Steinbach, JP. "Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma". J Clin Oncol. vol. 25. 2007. pp. 3357-61.
Wick, W, Hartmann, C, Engel, C. "NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide". J Clin Oncol. vol. 27. 2009. pp. 5874-80.
Wick, W, Wick, A, Weiler, M. "Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence". Curr Neurol Neurosci Rep. vol. 11. 2011. pp. 305-12.
Wick, W, Platten, M, Meisner, C. "Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial". Lancet Oncol. vol. 13. 2012. pp. 707-715.
Wrensch, M, Jenkins, RB, Chang, JS. "Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility". Nat Genet. vol. 41. 2009. pp. 905-8.
Yan, H, Bigner, DD, Velculescu, V. "Mutant metabolic enzymes are at the origin of gliomas". Cancer Res. vol. 69. 2009. pp. 9157-9.
Yan, H, Parsons, DW, Jin, G. "IDH1 and IDH2 mutations in gliomas". N Engl J Med. vol. 360. 2009. pp. 765-73.
Yung, WK, Albright, RE, Olson, J. "A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse". Br J Cancer. vol. 83. 2000. pp. 588-93.
Yung, WK, Prados, MD, Yaya-Tur, R. "Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group". J Clin Oncol. vol. 17. 1999. pp. 2762-71.
Zuniga, RM, Torcuator, R, Jain, R. "Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan". J Neurooncol. vol. 91. 2009. pp. 329-36.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- Novel Blood Test Detects Cancer, Locates Tumor Without Invasive Procedures
- Cabozantinib Activates Innate Immune Response, Eliminating Prostate Cancer
- Shorter Treatment of Breast Cancer with Trastuzumab May Lead to Improved Results
- Neurofeedback Reduces Symptoms of Chemotherapy-induced Peripheral Neuropathy
- Directly Informing Patients of Breast Cancer Risk, Options Improves Follow-Up Screening
- Early Palliative Care Reduced ICU Use in Patients With Advanced Cancer
- Ginger Extract Raises Antioxidant Levels in Patients Undergoing Chemotherapy
- Nurse Navigators Improve Physician Engagement in Pretreatment Discussions
- Novel Blood Test Detects Cancer, Locates Tumor Without Invasive Procedures
- Screening Increases Early Palliative Care, Reduces Aggressive EOL Measures
- Risk of Second Cancers Increased in Hodgkin Lymphoma Survivors
- ONS Partners with ASCO CancerLinQ to Launch CancerLinQ® Ambassadors Program
- Characteristics of Clinical Trials and Barriers to Patient Enrollment Identified
- Exercise Improves Coping While Undergoing Chemotherapy for Advanced GI Cancer
- Genetic Similarity to BRCA1/BRCA2 Mutations May Impact Treatment Options
Sign Up for Free e-newsletters
Regimen and Drug Listings
GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION
|Head and Neck Cancer||Regimens||Drugs|