Introduction
The understanding of low-grade gliomas has significantly changed over the past 10 years. Genomic and epigenetic discoveries have revolutionized our understanding of these cancers. For the first time, the 2016 WHO classification of central nervous system tumors integrated molecular information with histologic classification to more precisely differentiate types of brain and spinal cord tumors. Previous histologic systems classified low-grade gliomas as astrocytomas, oligodendrogliomas, or mixed oligoastrocytomas based on their histologic appearance. Now, molecular classification has allowed for a more precise characterization of tumor biology (see Chapter 1 for further discussion of molecularly defined classification of gliomas).
Most diffuse low-grade gliomas can be separated into three molecularly, prognostically, and clinically distinct groups: (1) Isocitrate dehydrogenase (IDH)- gene mutated tumors with co-deletion of chromosomes 1p and 19q (e.g., IDH -mutated, co-deleted low-grade gliomas), (2) IDH -mutant non–co-deleted diffuse gliomas, and (3) IDH wild-type diffuse gliomas. This first group of IDH -mutant, co-deleted tumors are molecularly the pure oligodendrogliomas that are associated with a prolonged survival and an excellent response to chemotherapy. IDH -mutant, non–co-deleted tumors do not possess loss of chromosomes 1p and 19q (e.g., non–co-deleted) and are molecularly astrocytomas. They have an intermediate prognosis; compared to the IDH -wild-type gliomas, they have better survival rates and response to chemotherapy. IDH wild-type gliomas have the worst prognosis of the three groups and behave similarly to glioblastoma despite their lower grade.
Molecular characterization now not only influences our classification of gliomas but also guides molecularly driven clinical management decisions. Compared to treatment of high-grade gliomas, the decision for treatment of low-grade gliomas is more complex. Available data do not address all clinical questions that confront treating clinicians. One of the common challenges in clinical management of patients with low-grade gliomas is whether to initiate treatment at the time of first diagnosis or to wait until tumor growth is evident (e.g., timing of therapy). Another challenge is choosing which chemotherapeutic regimen is most optimal. Common regimens include temozolomide or lomustine, procarbazine, and vincristine (PCV) (see Chapter 4 for an evidence-based review of chemotherapy for glioma).
In this chapter, we present a single clinical case of a patient presenting with a low-grade glioma and walk through key data that guides the increasingly complex algorithms for managing patients with low-grade gliomas.
Clinical case
Case . A 51-year-old woman without contributory medical history acutely developed word-finding difficulties. A few minutes later she lost consciousness, collapsed to the ground, and had generalized involuntary jerking movements consistent with a generalized tonic-clonic seizure. The episode lasted for approximately 2 minutes before she regained consciousness. She was evaluated in the emergency room where her physical examination was significant for lethargy and disorientation to place and situation. Her Karnofsky performance status (KPS) was 90%. A CT scan of the head revealed an area of hypodensity in the right parietal lobe; there were no signs concerning for intracranial hemorrhage.
Brain magnetic resonance imaging (MRI) with and without contrast was requested to better characterize the lesion ( Fig. 11.1 ). The images showed an infiltrative lesion that involved the cortex and the subcortical white matter. The mass had a significant amount of perilesional T2/fluid attenuated inversion recovery (FLAIR) hyperintensity with minimal punctate contrast enhancement. The patient gradually recovered over the next 4 hours and was back to her baseline status without residual deficits on examination. She was started on levetiracetam 500 mg orally twice daily and dexamethasone 4 mg every 6 hours.
The patient was evaluated by a neurosurgeon who recommended performing an open biopsy through an awake craniotomy. The surgeon achieved a subtotal resection a few days after her initial presentation, while preserving eloquent brain regions. Histologic appearance was consistent with a low-grade oligodendroglioma, WHO grade II. The Ki-67 proliferation index was low and molecular studies revealed deletions of the entire short arm of chromosome 1 and the entire long arm of chromosome 19 (e.g., 1p/19q co-deletion), as well as an IDH1 R132H gene mutation. Her seizures were controlled medically and she was tapered off corticosteroids quickly after surgery. Once the pathology results were available, neuro-oncology and radiation oncology consults were requested.
Key clinical questions for consideration by consultants:
- 1.
What final diagnosis integrates the histopathologic analysis with molecular characterization?
- 2.
Is this patient at high or low risk of early tumor progression?
- 3.
Should active therapy be recommended now or is initial observation an option?
- 4.
If treatment is recommended, which treatment should the patient receive?
Key points
Teaching point #1: How to determine an integrated histologic and molecular diagnosis of low-grade glioma
The tumor in this case was found to be a WHO grade II diffuse glioma with an IDH1 gene mutation and whole arm loss of chromosomes 1p and 19q, which is consistent with a diagnosis of IDH -mutated, co-deleted low-grade glioma. Historically, the diagnosis of low-grade gliomas was based on histopathologic analysis showing a glial-based tumor that infiltrated brain tissue and was low-grade with no or low mitotic activity, no endothelial proliferation, and no pseudopallisading necrosis (representative examples shown in Fig. 11.2 ). Over the past decade, landmark discoveries, including genome-wide studies, have shown that profiling molecular characteristics of cancer provides a more accurate way to predict treatment response and risk of recurrence. Molecular features are now a major component in the diagnosis and subgrouping of tumors and trump histopathologic interpretation and provide a more precise description of the tumor’s biology, as well as prognostic and treatment implications ( Fig. 11.3 ). Occasionally, histopathologic findings in low-grade gliomas can be difficult to distinguish from a reactive process or other brain tumors. Pilocytic astrocytomas can have a morphology that resembles oligodendrogliomas. Some tumors have features of both oligodendrogliomas and astrocytomas, historically described as oligoastrocytomas or “mixed” gliomas. In these instances, molecular characterization can guide the diagnosis. In fact, in the most recent WHO classification of gliomas, this entity of “mixed” gliomas virtually ceases to exist and these tumors are classified as oligodendrogliomas (e.g., IDH -mutant, 1p19q co-deleted) or astrocytomas (e.g., IDH -mutant, non–co-deleted) based on molecular characteristics.
Integrated glioma diagnoses
Oligodendrogliomas are characterized by the presence of an IDH1 or IDH2 mutation and synchronous whole arm deletions of chromosomes 1p and 19q. Partial deletions of 1p and 19q do occur and are not associated with the oligodendroglial phenotype; they are frequently associated with tumors of astrocytic lineage, which carry a worse prognosis. , Oligodendrogliomas frequently have an activating mutation of the TERT promoter region and mutations of the CIC and FUBP1 genes. , Astrocytic tumors may also demonstrate IDH1 or IDH2 mutation but lack co-deletion of 1p/19q and TERT promoter mutations, and instead are characterized by a loss of ATRX and mutations in the TP53 gene.
Gliomas have a similar histologic appearance in adult and pediatric populations; however, the molecular signatures of low-grade gliomas differ by age. Approximately 80–90% of low-grade tumors in adult patients harbor a mutation in the IDH1 or IDH2 genes. By contrast, low-grade gliomas in children rarely have these mutations. Adult patients with IDH wild-type diffuse astrocytomas carry a worse prognosis, especially those with a TERT promoter mutation, EGFR amplification, or a concurrent whole chromosome 10 loss and whole chromosome 7 gain. Due to the more aggressive nature of these tumors, it has been suggested that they be classified as grade IV neoplasms, irrespective of their histologic appearance.
In addition to low-grade diffuse oligodendrogliomas and diffuse astrocytomas, both of which are classified as WHO grade II tumors, there are a myriad of other low-grade gliomas. These include several histologic subtypes of tumors with an astrocytic lineage such as pilocytic astrocytoma (WHO grade I), pilomyxoid astrocytoma, gemistocytic astrocytoma, subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma, and astroblastoma among others. Some of these tumors are exclusively seen in young adults and in the pediatric population. Other low-grade tumors arise from ependymal surfaces; these include subependymomas and ependymomas of different subtypes (myxopapillary, clear cell, tanacytic, and papillary).
Teaching point #2: How to differentiate high-risk from low-risk low-grade glioma
The patient in this case had both favorable and concerning clinical prognostic features at presentation. On the one hand, the patient was considered to be at high risk for early disease progression due to her age (i.e., >40 years), subtotal resection (instead of complete resection of the tumor), and the proximity of the tumor to eloquent brain areas. On the other hand, several favorable prognostic factors were also identified, including her good performance status, and favorable molecular features including the presence of 1p/19q co-deletion and IDH –gene mutation.
Clinical presentation and prognostic risk factors
The clinical presentation of a low-grade glioma varies depending on the tumor location. Signs and symptoms may include seizures, headaches, changes in mental status, and other symptoms associated with intracranial hypertension. Imaging findings can suggest the etiology, but in most cases, pathologic examination of a tissue sample from a biopsy or resection is needed to confirm the diagnosis. A lumbar puncture for analysis of cerebrospinal fluid has low diagnostic yield and could lead to severe complications in cases where there is risk of herniation. Patients who present with seizures are managed with antiepileptics and, when focal neurologic deficits or symptoms of increased intracranial pressure are evidenced, corticosteroids are initiated.
The natural history and prognosis of low-grade gliomas is highly variable, and assessment of risk in newly diagnosed patients is complex. There are currently no uniformly agreed-upon validated criteria to assess risk factors for early progression and poor prognosis. However, several clinical risk factors have been identified that can be used in clinical decision-making. These include tumor-related symptoms, poor performance status, preoperative tumor size (worse if ≥5 cm), incomplete resection, age (high-risk is >40 years of age), astrocytic histology, and high proliferative index (poor if MIB-1 is >3%). In addition, the absence of IDH mutation and co-deletion of 1p/19q are adverse risk factors. Many of these factors represent a continuum (for example, age), and the interplay of the different factors needs to be carefully considered on an individual basis. The best possible risk assessment relies on a personalized evaluation of clinical, molecular, and treatment factors to determine those patients who may benefit from early postoperative treatment and those for whom initial observation may be appropriate.
Teaching point #3: How to determine whether to observe the tumor or initiate treatment at diagnosis
The treatment options in this case included (1) close observation and initiation of treatment at first evidence of tumor progression or (2) initiation of treatment now. Careful consideration of these options is best conducted by a multidisciplinary team that engages the patient and caregiver in shared decision-making. After careful deliberation, the patient and her multidisciplinary team opted to proceed with treatment.
Treatment of low-grade gliomas
When treated, low-grade gliomas are managed with maximal safe resection. Radiation therapy is recommended when residual tumor is present after surgical treatment or when patients are considered to be high-risk. The randomized European Organization for Research and Treatment of Cancer (EORTC) trial 22845 compared treatment with radiation at initial diagnosis versus deferring radiation to the time of progression in patients with low-grade gliomas. This trial showed that early treatment did not affect overall survival. Median survival was 7.4 years in patients treated with immediate radiotherapy of 54 Gy in 6 weeks and 7.2 years in patients who were treated at progression. However, early treatment was associated with prolonged progression-free survival (median 5.4 versus 3.7 years) and reduced seizure burden at 1 year. The lack of an overall survival benefit from early treatment with radiation has served as a rationale for postponing adjuvant radiation in patients with low-grade gliomas who are appropriate for initial observation, thereby delaying radiation-related toxicity. This must be weighed against the potential benefit of delaying tumor progression and controlling seizures.
A select group of low-grade gliomas may be treated with targeted therapies. That is the case for the subependymal giant cell astrocytomas (SEGAs) that occur in tuberous sclerosis complex (see Chapter 17 , Case 17.4 for the approach to SEGA in tuberous sclerosis) for which treatment with an inhibitor of the mammalian target of rapamycin (mTOR) pathway (e.g., everolimus or sirolimus) has been shown to be effective. Patients with pleomorphic xanthoastrocytomas, and to a lesser extent those with pilocytic astrocytomas, commonly harbor a BRAF V600E gene mutation and have shown responses to treatment with the combination of BRAF and MEK inhibitors. To minimize the risk of adverse effects, these therapies require specific screening studies before their administration and patients should be monitored closely while on treatment for signs of complications and tumor progression.
Teaching point #4: How to determine a patient-specific treatment plan
The patient in this case was treated with radiation therapy followed by six cycles of adjuvant chemotherapy with PCV. The patient required dose reductions of her chemotherapy due to myelosuppression, and vincristine was discontinued after two cycles due to early signs of neuropathy that later resolved. After treatment, she was closely monitored with MRI images every 3 months for 2 years and then every 6 months. She continues to be observed with serial MR scans 7 years after her initial diagnosis, with no evidence of tumor recurrence.
The role of surgery
Diffuse low-grade gliomas (with the exception of IDH wild-type gliomas) typically grow slower than the high-grade malignant gliomas (e.g., WHO grade III and grade IV gliomas). They follow a more indolent disease course. Nonetheless, these tumors are not considered curable, and the majority of patients eventually die from their disease or disease-related complications. The goal of treating these cancers is to not only prolong survival and time to tumor recurrence but to also carefully consider treatment-related morbidity, as patients often live for several years and sometimes decades with their disease. Treatment decisions are best made with a multidisciplinary team including neurosurgeons, medical or neuro-oncologists, and radiation oncologists. Surgery is usually the first step in management of low-grade gliomas (see Chapter 2 for further discussion of surgical approaches to glioma). Surgery helps to establish the diagnosis and provides cytoreduction through debulking of the tumor. The extent of surgery is location-dependent, and some patients are candidates for biopsy only. In rare situations, such as in some brainstem locations, even a biopsy is not feasible.
The benefit of greater extents of resection has been a controversial topic. Immediate best possible surgical resection is most commonly pursued. In select cases of small, asymptomatic, or minimally symptomatic tumors (including in patients with controlled seizures), initial observation can be considered, with more aggressive resection reserved for time of progression or worsening symptoms. Arguments for early diagnosis and best possible resection include (1) maximizing reduction of tumor burden; (2) allowing for accurate risk assessment based on histological features, tumor grade, and molecular markers at the time of diagnosis; and (3) improved assessment of prognosis, treatment choice, and timing of postoperative therapy.
The role of chemotherapy
To date, the largest clinical trial that has addressed the question of a potential benefit from adding chemotherapy to radiation is the Radiation Therapy in Oncology Group study RTOG 9802 17 (also see Chapter 4 for review of evidence-based approaches to chemotherapy for glioma). In this study, 251 adult patients with supratentorial low-grade gliomas were randomized to receive either radiation alone or radiation followed by chemotherapy with lomustine, procarbazine, and vincristine (PCV, planned six cycles). Patients with oligodendrogliomas, astrocytomas, and oligoastrocytomas were included. As this study was designed prior to the discovery of the role of IDH mutations and co-deletion of 1p/19q, these molecular markers could not be factored into the analysis. Also, this study started prior to the introduction of temozolomide as a treatment option for patients with gliomas. RTOG 9802 showed an overall survival benefit from the addition of PCV chemotherapy to radiation compared to radiation alone of 13.3 versus 7.8 years, which was statistically significant. Separated by histology, there were clear differences in magnitude of benefit from chemotherapy in association with histology. Patients with oligodendrogliomas derived the most overall benefit, followed by oligoastrocytomas, followed by astrocytomas; although there was a separation in survival curves also in patients with astrocytomas, the benefit from the addition of PCV was not statistically significant in this subgroup ( Fig. 11.4 ) . In tumors for which IDH mutation data were available, a clear overall benefit from the addition of chemotherapy was observed. As this study did not include information on 1p/19q co-deletion, and only incomplete IDH mutation data, these data need to be interpreted with great caution. In patients with low-grade astrocytomas, the benefit of the addition of chemotherapy to radiation has not yet fully been elucidated and remains controversial.
Teaching point #5: How to select a patient-specific chemotherapy regimen
The patient in this case was treated with PCV—procarbazine, CCNU or lomustine, and vincristine. The choice of chemotherapy for low-grade gliomas remains controversial and many clinicians consider either temozolomide or PCV (see Chapter 4 for evidence-based approach to chemotherapy for glioma); however, head-to-head data are not available, and it is not currently known whether these regimens are interchangeable or whether one is more effective.
In 1p/19q co-deleted oligodendrogliomas with IDH mutation, the highest level of evidence exists for the use of radiation and PCV based on data extrapolated from several clinical trials in patients with anaplastic oligodendroglioma (i.e., EORTC 26951 and RTOG 9402) and in low-grade gliomas (i.e., RTOG 9802). Temozolomide is the standard chemotherapy used in the treatment of glioblastoma and other malignant gliomas (i.e., WHO grade III and grade IV gliomas). Importantly, PCV was not shown to have comparable benefit to temozolomide in treating glioblastoma or anaplastic astrocytoma, and these two chemotherapy regimens cannot be considered interchangeable. Chemoradiation with temozolomide followed by adjuvant temozolomide is the standard of care for treatment of glioblastoma and tends to be tolerated better than PCV with lower adverse event rates. Temozolomide may also have the advantage of functioning as a radiation sensitizer when administered during the concurrent radiation treatment phase. However, these two regimens have not been prospectively compared in patients with low-grade gliomas, and controversy remains.
Low-grade gliomas with co-deletion of 1p/19q are markedly more sensitive to chemotherapy than gliomas without co-deletion. In select patients with co-deleted oligodendrogliomas for whom treatment is needed but there is concern for radiation-related side effects (e.g., due to tumor size, age, and frailty), treatment with chemotherapy alone with deferred radiation may be considered. Data on long-term outcomes with this approach are limited. This approach should therefore only be considered with great caution. A multidisciplinary evaluation may be helpful to carefully weigh the short- and long-term risks and benefits and select a patient-specific approach to treatment.
Patient-specific treatment using molecularly defined algorithm for low-grade gliomas
Approach to IDH -mutant low-grade gliomas
In general, newly diagnosed IDH -mutant low-grade gliomas can be divided into co-deleted and non–co-deleted tumors. The prognosis for tumors that are IDH -mutant and 1p/19q co-deleted (“true” oligodendrogliomas) is more favorable than for patients without co-deletion (i.e., mostly astrocytomas). Some patients may have had prior brain imaging, which can be helpful in assessing tumor aggressiveness based on growth over time. In patients who do not have prior imaging data available, risk assessment is based on clinical, histopathologic, and molecular factors alone.
Observation with deferred treatment
Based on data from the study EORTC 22845, observation of low-risk asymptomatic patients, including patients with controlled seizures, is reasonable and typically includes magnetic resonance imaging every 3 months, which is gradually lengthened in patients whose gliomas show stability. If rapid tumor growth is detected, new symptoms occur, or if there is concern for malignant degeneration to a higher grade (e.g., new contrast enhancement), treatment is initiated. In select cases, if there is concern for progression to a higher grade or more aggressive biology, repeat neurosurgical biopsy or resection may be considered.
Treatment approach
Once a patient is considered appropriate for postoperative therapy (either immediately, or after observation), a decision should be made regarding a treatment regimen. Options include radiation followed by PCV or concurrent chemoradiation with temozolomide followed by adjuvant temozolomide. In select cases, chemotherapy alone with deferred radiation may be carefully considered.
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For 1p/19q co-deleted oligodendrogliomas, randomized phase 3 data from RTOG 9802 indicates that the most evidence-based treatment is radiation plus PCV. Many clinicians also consider chemoradiation with temozolomide followed by temozolomide an effective therapy for these patients. To date, these two regimens have never been prospectively compared in this population. A large ongoing clinical trial (i.e., CODEL study, NCT00887146), is comparing the two regimens in 1p/19q co-deleted gliomas and will eventually answer this question.
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For IDH -mutant non–co-deleted astrocytomas, the optimal treatment regimen is not as clear. The benefit from chemotherapy with PCV in these tumors has remained controversial (see Fig. 11.3 ). Data from the randomized phase 3 RTOG 9802 study provides the highest level of published evidence and shows a modest benefit from adding PCV to radiation therapy in patients with histologically defined astrocytomas. This study was not designed to prospectively compare outcomes by molecular subgroup and did not compare chemotherapy regimens. Low-grade astrocytomas will eventually progress to become anaplastic astrocytomas (WHO grade III) and/or glioblastomas (WHO grade IV), for which the most evidence-based therapy is temozolomide. Thus, some clinicians will extrapolate data from WHO grade III and grade IV gliomas, which favor the use of temozolomide over PCV in IDH -mutant non–co-deleted tumors. Further prospective data are needed to more definitively address this question.
Approach to IDH wild-type low-grade gliomas
A fraction of tumors with morphologic characteristics suggestive of a low-grade glioma carry molecular signatures that more resemble higher-grade neoplasms. The biology of these tumors is frequently more aggressive and patients tend to have worse outcomes. , , , This group is heterogeneous but, in general, these gliomas do not harbor mutations in the IDH1 or IDH2 genes and are IDH wild-type. Some IDH wild-type diffuse gliomas will develop in midline structures including the pons, thalamus, spinal cord, and parasagittal cortex. These tumors are considered diffuse midline gliomas and may harbor mutations in histone coding genes. Mutation of the H3F3A gene at the K27 position (i.e., H3 K27M mutation) is the most common of these alterations and confers a high-grade WHO grade IV classification even when routine pathologic criteria such as proliferation index may suggest lower-grade histology. Diffuse midline gliomas and the H3 K27M-mutant glioma are more frequently diagnosed in children and adolescents, but can present at any age and carry a dismal prognosis.
Additional molecular findings can aid in prognosticating patients with IDH wild-type low-grade gliomas. The presence of an EGFR amplification, TERT promoter mutation, or combined gain of chromosome 7 and loss of chromosome 10 (+7/−10) have been associated with an aggressive clinical course. , Patients with IDH wild-type diffuse gliomas are monitored closely with serial physical examinations and MRI studies. The optimal approach to treatment for these patients is not well established and should be individualized. Early treatment including radiation and chemotherapy may be offered. Participation in a clinical trial should be encouraged when possible; however, classification of these tumors as high-grade gliomas has not yet been widely adopted, and most clinical trials currently exclude patients with tumors that have a low-grade diagnosis by histology.
Approach to seizure management in low-grade gliomas
Seizures are common at initial presentation in patients with low-grade gliomas. This patient population has a higher incidence of seizures when compared to patients with higher-grade neoplasms or metastatic central nervous system (CNS) disease. The overall frequency has been reported between 53% and 90%. The majority of seizures are focal, but secondary generalization can occur. As with other forms of focal epilepsy, the semiology of the events depends on the location of the lesion. Tumors involving the frontal, temporal, and parietal cortex have a higher frequency of epileptic activity, especially if they are located in eloquent areas. , Other factors associated with the development of seizures include tumor burden and cortical involvement. Interestingly, tumor progression, rate of growth, or mass effect have not been strongly associated with a higher frequency of seizures. , , Conversely, gross total resection of the tumor correlates with improved seizure freedom.
In patients with primary brain tumors, including low-grade gliomas, who have never experienced a seizure, the use of prophylactic anticonvulsants is not recommended. Randomized studies evaluating seizure prophylaxis have failed to show a significant improvement in seizure-free survival. If used, perioperative prophylactic anticonvulsants may be tapered 1 week after craniotomy to avoid the potential deleterious effects of these medications and their interactions with other drugs. , ,
Well-established treatment options for tumor-related epilepsy primarily include anticonvulsant medications and resection of the epileptic focus. The basic tenets of treatment for epilepsy in patients with brain tumors is not significantly different from those with other types of symptomatic focal seizures. Although no evidence-based guidelines are available for this patient population, a few considerations are important when choosing an anticonvulsant regimen. When possible, monotherapy is preferable to decrease the risk of adverse effects and to avoid interactions with other medications. Unfortunately, refractory seizures are common, and a combination of drugs might be necessary. Several anticonvulsants have been studied ( Table 11.1 ). Levetiracetam is commonly prescribed as a first-line therapy due to its favorable efficacy, tolerability, and few interactions with other medications. The efficacy of lacosamide as an adjunctive agent has been evaluated in patients with gliomas and metastatic tumors with focal seizures with or without secondary generalization. A 50% reduction in seizure frequency was reported in 40–50% of patients, and seizure-freedom was reported to be as high as 43%. Lacosamide is generally well tolerated and does not have significant drug-to-drug interactions.
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