Over 75,000 people are diagnosed with a primary brain tumor each year in the United States. The most common are ‘diffuse gliomas’. These vary in aggressiveness from oligodendrogliomas, which can be associated with prolonged survival, to glioblastomas, with a median survival of less than two years.

All varieties of diffuse glioma share several common characteristics. Patients typically present with seizure, headaches or focal neurological deficits. The natural history of untreated diffuse glioma is to progressively invade normal brain tissue, with WHO grade II and III tumors progressing to grade IV pathology and behavior over time. Diffuse 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.

Recent advances in understanding regarding the genetic underpinnings of glioma, provided by such efforts as the Cancer Genome Atlas, have revolutionized the classification of diffuse gliomas. A combined histological and genetic diagnosis is now recommended, incorporating key molecular traits such as ‘IDH mutation’ and ‘1p/19q codeletion’ because of their influence on glioma development, prognosis and their ability to predict response to chemotherapy.

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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.

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 ongoing 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.

In 2008, Parsons and colleagues were the first to report mutations in the isocitrate dehydrogenase gene in patients with diffuse 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.

1p/19q codeletion is a hallmark finding in oligodendrogliomas and anaplastic oligodendrogliomas, distinguishing these tumors from other IDH-mutated gliomas such as diffuse astrocytoma and anaplastic astrocytoma. 1p/19q codeletion is very rare in glioblastomas.

H3F3A and HIST1H3B/C are DNA histone coding genes and play an important role in nucleosome structure. K27M mutations in these genes are a hallmark feature of diffuse midline gliomas.

Glioblastoma is the most frequent, and most aggressive diffuse glioma. Glioblastoma may arise de novo as a grade IV tumor, or it may result from progression of an IDH-mutated lower-grade glioma. The former situation, referred to as “primary glioblastoma, IDH-wildtype” is far more common than the latter situation – “secondary glioblastoma, IDH-mutant.”

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 for IDH-wildtype glioblastomas. IDH-mutant glioblastoma has a slightly better prognosis with a median survival between 2-3 years.

WHO grade III ‘anaplastic diffuse gliomas’ mainly consist of ‘anaplastic astrocytoma, IDH mutant’ and ‘anaplastic oligodendrogliomas, IDH-mutant and 1p/19q-codeleted’. These tumors share many clinical features with glioblastoma, but are less aggressive tumors with more variability in survival. Anaplastic oligodendrogliomas have a better prognosis than “pure” anaplastic astrocytomas. Both of these tumors typically harbor IDH-mutations while they differ in the presence of 1p/19q-codeletion, a hallmark feature of oligodendrogliomas.

The treatment of WHO grade III IDH-mutated diffuse gliomas begins with safe maximal resection, which is followed by radiation. Although the use of chemotherapy was historically controversial, recent clinical trial data supports the use of chemotherapy for the treatment of these tumors.

WHO grade II diffuse gliomas have historically been described as ‘low-grade gliomas’; however, this term is now discouraged because these tumors 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.

WHO grade IV diffuse midline glioma, H3 K27M-mutant, is a more recently identified aggressive groups of tumors which are typically located in the brainstem, thalamus and spinal cord. Diffuse midline gliomas can be challenging to biopsy and are frequently diagnosed clinically. Treatment consists of radiation therapy alone and prognosis is very poor, with most patients surviving less than one year.

  • 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 (Figure 1, Figure 2).

  • WHO grade III diffuse glioma is similar in appearance, though it typically shows patchy or indistinct enhancement on T1 post-contrast imaging rather than ring-enhancement. WHO grade III oligodendrogliomas are more frequently cystic and heterogenous in appearance.

  • WHO grade II diffuse 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 diffuse gliomas contain areas of enhancement, and occasionally entirely non-enhancing tumors suspected to be low-grade on imaging meet pathological criteria for glioblastoma.

  • Diffuse midline gliomas are typically large brainstem masses which appear T1-hypointense and T2-hyperintense on MRI. Partial contrast enhancement may be present.

Figure 1.

MRI FLAIR Image of Glioblastoma.

Figure 2.

MRI Post-Contrast Image of 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 (Figure 3, Figure 4).

Figure 3.

MRI FLAIR Image of WHO Grade II Oligodendroglioma.

Figure 4.

MRI Post-Contrast Image of WHO Grade II Oligodendroglioma.

Ultimately, diffuse 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 2016.

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.

Diffuse 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 diffuse 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 diffuse astrocytoma), the possibility of a non-representative biopsy must be considered.

As noted, both the symptomatic presentation and imaging appearance of diffuse glioma are nonspecific. Both non-malignant conditions and other malignancies may share these characteristics.

Mimics of WHO grade III/IV diffuse gliomas include:

  • Non-malignant

    Demyelinating disease (i.e., tumefactive multiple sclerosis)

    Subacute stroke

    Bacterial or fungal infection/abscess

    Sarcoidosis

  • Other Malignancy

    Metastatic disease

    Primary CNS lymphoma

    Hemangioblastoma

Mimics of WHO grade II gliomas include:

  • Non-Malignant

    Congenital malformation

    Demyelinating disease

    Viral encephalitis

    Auto-immune encephalitis

    Leukoencephalopathies

Which individuals are most at risk for developing diffuse glioma?

Diffuse gliomas are mostly tumors found in adults. The incidence rates of glioblastoma range from a low of 0.16 per 100,000 person years in children of age 0-19 years to a high of 15.24 per 100,000 person years in adults of age 75-84 years. The median ages of diagnosis for IDH-wildtype and IDH-mutant glioblastoma are 62 and 44 years, respectively. Lower grade diffuse gliomas (WHO grade II/II) usually present in the mid-thirties. Diffuse midline gliomas predominate in children with a median age of 5-11 years.

Approximately 60% of diffuse 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 respective 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 anaplastic oligodendrogliomas.

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 300 mg 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 750 mg 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.

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 pathologic analysis. Tumefactive multiple sclerosis, a radiographic mimic of glioblastoma, may also improve with steroid therapy.

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).

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. Median survival increases to approximately one year in patients receiving radiation.

Radiation therapy is typically delivered to a total dose of approximately 54-60 Gy 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 these groups. 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%. 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

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 200 mg/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.

Temozolomide toxicity

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.

Monitoring

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.

Bevacizumab

  • Bevacizumab 10 mg/kg IV every 2 weeks.

Monitoring includes blood pressure assessments and urinalysis to evaluate for proteinuria.

Lomustine (CCNU)

  • Lomustine 110-130 mg/m2 PO every 6 weeks.

Monitoring includes weekly CBCs to monitor for hematologic toxicity.

The U.S. Food Drug Administration (FDA) has approved the use of carmustine (BCNU)-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.

Tumor treating fields (TTF) is a new treatment strategy in which alternating electrical fields are delivered to the glioblastoma using electrodes applied to a shaved scalp. The true value of this treatment remains controversial.

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 United States, 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.

Most patients should be treated with radiation therapy after recovery from surgery, except in unusual circumstances where up-front chemotherapy may be considered.

The standard radiation regimen for WHO grade III glioma, 54-60 Gy in 30-33 fractions, is similar to that used in glioblastoma.

Several clinical trials have confirmed that chemotherapy improves survival in most newly diagnosed grade III diffuse gliomas when used after radiation therapy. Certain molecular subtypes (IDH-wildtype and 1p/19q non-codeleted) seem to be more resistant to chemotherapy.

Treatment with chemotherapy upfront with radiation only at progression has also been explored due to an interest in delaying radiation therapy to prevent long-term radiation-induced cognitive decline. However, any benefit from this strategy is similar to upfront radiation therapy alone at best, and is probably inferior to an upfront combination of radiation and chemotherapy.

In clinical practice, the initial treatment of WHO grade III diffuse glioma depends heavily on tumor morphology and molecular markers.

Patients with IDH-mutant and/or 1p/19q codeleted anaplastic oligodendrogliomas should be treated with radiation followed by chemotherapy. Clinical trials (RTOG 9402, EORTC 26951) have clearly demonstrated that patients with anaplastic oligodendrogliomas (AOD) that are either 1p/19q codeleted or IDH mutated have longer survival when treated with chemotherapy along with upfront radiation.

These trials used a combination of procarbazine, CCNU (lomustine) and vincristine, collectively known as PCV. Some neuro-oncologists replace PCV with temozolomide therapy as the latter is a better tolerated regimen. However there is no definitive evidence that these regimens are equally effective when combined with radiation. A phase III clinical trial is currently ongoing to answer this question.

IDH-wildtype and 1p/19q non-codeleted anaplastic oligodendrogliomas are unusual. These tumors do not benefit from PCV chemotherapy and may be treated with radiation up front followed by chemotherapy at progression.

Patients with anaplastic astrocytoma (without 1p/19 codeletion) should be treated with radiation and chemotherapy. Early reports from the CATNON clinical trial have confirmed that anaplastic diffuse gliomas which do not harbor the 1p/19q codeletion benefit from the addition of temozolomide after radiation therapy. Although the additional benefit of adding temozolomide during radiation therapy is still unclear, this is generally well-tolerated and has proven efficacy against glioblastoma. Therefore, treatment with a regimen similar to that for glioblastoma is reasonable.

Temozolomide

(see regimen under Glioblastoma section above)

PCV

  • 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 lomustine dose is the same when given as monotherapy as when used as part of PCV.

BCNU

  • BCNU (Carmustine) 150-200 mg/m2 IV in one dose or 2-3 divided consecutive daily doses every 6 weeks.

Toxicity

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 precludes 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 diffuse gliomas have historically been described as ‘low-grade gliomas.’ However, this term is now discouraged. These tumors are not clinically benign, and most patients eventually succumb to tumor-related complications. Although the timing of radiation is controversial, the value of combination radiation and chemotherapy has recently been confirmed definitively.

Surgery

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.

Post-surgical observation

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

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 the 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.

Treatment regimen

Randomized trials have established that low-dose radiation (50-54 Gy) is as effective as higher doses.

Radiation complications

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. Recent data from RTOG 9802 have demonstrated significant benefit with the use of six cycles of PCV chemotherapy immediately following radiation therapy.

Decision to treat

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. Oligodendrogliomas respond better to this addition of chemotherapy than diffuse astrocytomas.

The trial establishing this benefit used a combination of procarbazine, CCNU (lomustine) and vincristine, collectively known as PCV. Some neuro-oncologists replace PCV with temozolomide therapy as the latter is a better-tolerated regimen; however, there is no definitive evidence that these regimens are equally effective when combined with radiation. A phase III clinical trial is currently ongoing to answer this question.

Oligodendrogliomas are both less aggressive and more responsive to chemotherapy than pure astrocytomas. Initial treatment with chemotherapy may be considered in patients with these tumors 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.

Treatment regimen

PCV

PCV is given as 6-week cycles as follows:

  • CCNU 110-130 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 grade II diffuse 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.

Temozolomide

(see regimen under Glioblastoma section above)

Toxicity

Chemotherapy-related toxicities associated with WHO grade II tumors mirror those previously discussed for higher-grade tumors.

Diffuse midline gliomas are challenging tumors with poor prognoses and very limited treatment options. Most patients survive less than one year regardless of treatment, and there is a dire need to develop new therapies for these patients.

Surgery

Diffuse midline gliomas typically develop in eloquent areas of the central nervous system such as the brainstem, thalamus and spinal cord. Surgical resection and even biopsy can be challenging, and these patients are frequently diagnosed clinically without obtaining tissue for pathology.

Radiation

Radiation therapy is the only treatment strategy that has demonstrated any benefit in patients with diffuse midline glioma. Alternative radiation strategies have been attempted; however, none have proven to be better than conventional radiation. Although responses to radiation can be dramatic, these are generally transient.

Treatment regimen

Patients are typically treated with 54-59 Gy of radiation administered over several weeks.

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 4 mg 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-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.

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.

Molecular characteristics including MGMT promoter hypermethylation and IDH mutation are critical predictors of survival time after glioblastoma diagnosis. The presence of MGMT promoter methylation in glioblastoma is associated with longer median survival of 18.2 months compared with 12.2 months in those without MGMT promoter methylation. Similarly, IDH mutations in glioblastoma also portend a favorable prognosis; however, these are uncommon in 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.

Clinical factors including patient age and performance status also play important roles in prognosis. 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.

Survival after diagnosis of WHO grade III diffuse glioma depends heavily on tumor morphology, IDH mutation and 1p/19q codeletion. In patients with anaplastic astrocytoma, the 2015 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 44%, 28%, and 20%, respectively. In contrast, patients with anaplastic oligodendroglioma have 2-year, 5-year, and 10-year relative survival rates of 69%, 52%, and 39%.

However, molecular alterations have a 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. For example, in anaplastic oligodendroglial tumors, the median survival of IDH mutant, 1p/19q codeleted tumors is 14.7 years while the median survival of IDH mutant, 1p/19q non-codeleted tumors is 5.5 years. The median survival of IDH wildtype anaplastic oligodendroglial tumors is only 1 year.

Most patients diagnosed with grade II diffuse glioma will eventually succumb to the tumor, although long-term survival is much more common in grade II diffuse glioma than in higher grade tumors. The 2015 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 diffuse astrocytoma are 61%, 48%, and 38%, respectively. The 2-year, 5-year, and 10-year relative survival rates for oligodendroglioma are 90%, 80%, and 64%, respectively. The recent recommendation for upfront PCV chemotherapy in these tumors is expected to lead to further improvements in long-term survival. As with grade III diffuse gliomas, 1p/19q codeletion and IDH mutations are associated with much longer survival in patients with identical histologic diagnoses.

Diffuse midline gliomas have not been studied in large registry studies as yet. That being said, the median survival for these patients is less than one year, and less than 10% of patients survive more than two years after diagnosis.

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.

Glioblastoma

Surveillance

Patients with glioblastoma typically undergo their first surveillance MRI one month 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 time-point. 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 diffuse glioma

Similar to glioblastoma, recurrence of WHO grade III diffuse 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 diffuse glioma

Surveillance

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

In patients initially treated with observation alone, radiation and chemotherapy should be administered at recurrence. In patients who were initially treated with radiation and chemotherapy, an alternative course of chemotherapy may be considered. Similar to glioblastoma, another surgical resection may also be reasonable.

Diffuse midline glioma

Surveillance

Patients should be monitored closely after completion of radiation therapy with MRI every 1-2 months because of the aggressive nature of these tumors.

Management of recurrence

Currently available chemotherapy agents are ineffective in these tumors, and these patients should universally be considered for clinical trials.

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