© Springer International Publishing AG 2017
Jennifer Moliterno Gunel, Joseph M Piepmeier and Joachim M. Baehring (eds.)Malignant Brain Tumors 10.1007/978-3-319-49864-5_1717. Tumor-Specific Approach: Oligodendroglioma (IDH1 Mutated, 1p/19q Deleted)
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9500 Euclid Ave./T-28, Cleveland, OH 44195, USA
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Keywords
OligodendrogliomaRadiationTemozolomideTMZPCV1p/19q1p19qIDHD-2-hydroxyglutarateIntroduction
Oligodendroglioma (OD) is a histologic subtype of gliomas representing approximately ~5% of CNS gliomas. Of the 77,670 CNS tumors estimated for 2016, ODs are estimated to comprise 490 of them [1]. The majority of these tumors are World Health Organization (WHO) grade II; however, >10% are grade III disease requiring nuclear atypia, brisk mitotic activity, endothelial proliferation, and/or necrosis [2]. Oligodendrogliomas tend to develop in younger patients in the 4th to 5th decade of life and have a long natural history given their slower progression than other malignant gliomas. However, regardless of treatment, the risk of recurrence is high and ~70% will undergo anaplastic transformation in their lifetime [3]. These histologic changes are thought to occur gradually over time which can make it difficult to determine when treatment is required. The current treatment paradigm involves a combination of maximum safe resection followed by observation or further treatment with radiation therapy and/or chemotherapy.
The choice and timing of the most appropriate adjuvant therapy is currently changing to strike a balance between optimal survival and minimizing toxicities. Previously, decisions were based mostly on clinical factors; however, there is a myriad of new molecular factors that aid in our decision making [4, 5]. These factors will likely help select patients who may, or may not, require more intensive therapy [6].
Overview
Origin/History
There is very little data on the exact etiology of ODs with no significant inheritance pattern. These tumors typically arise within the cerebral hemispheres, and specifically the frontal lobe, with a higher incidence in African Americans and males in the 5th and 6th decades of life [1, 7]. These tumors are rarely associated with genetic syndromes (i.e., Lynch syndrome, Li–Fraumeni syndrome, neurofibromatosis type 1) and even rarer to be the hallmark of these syndromes [8]. Oligodendrogliomas are thought to have improved outcomes compared to other similar glial tumors, such as astrocytoma, and are increasingly identified as requiring a thoughtful treatment approach [8]. The diagnosis of ODs requires a combination of neuroimaging, histopathology, and molecular characterization.
Neuroimaging
Gliomas are typically initially identified on magnetic resonance imaging (MRI), usually after a symptomatic presentation. They are classically hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences with little mass effect or vasogenic edema [9]. Contrast enhancement on CT and MRI was initially thought to be a hallmark of high-grade disease and regarded as a sampling error if a low-grade tumor was identified. Newer evaluations are showing it is possible that contrast enhancement may be present in roughly half of low-grade ODs and was not significant for low- versus high-grade disease [10, 11]. Oligodendrogliomas with contrast enhancement have worse outcomes when compared to their non-enhancing counterparts [12–14].
Oligodendrogliomas can be distinguished from other gliomas by their tendency to present with seizures on initial diagnosis as it can be seen in over 80% of cases [15]. While gliomas tend to originate from the frontal/temporal lobes and grow along white matter tracts, the type of seizure can indicate the location of the greatest lesion load with generalized tonic–clonic seizures showing in the mesial frontal regions and partial seizures located more caudolaterally in the orbitofrontal and temporal lobes [16, 17]. Seizures were initially thought to be a favorable prognostic factor for ODs; however, this has not been replicated in larger trials by EORTC [18]. The reason is complicated by the fact that patients with seizures tend to be without neurological deficits possibly due to the location of the lesion or it could be the association with seizures and 1p/19q codeleted tumors which is one of the most significant recent advancements in molecular genetics and tumor evaluation [19].
Newer imaging techniques may aid in further determining higher risk disease. Amino acid uptake of [F-18] fluoroethyltyrosine ([17] F-FET) PET with a diffuse pattern on MRI correlated with a higher risk of transformation and death in low-grade glioma compared to a circumscribed pattern [20]. MR spectroscopy is being utilized to aid in identification of isocitrate dehydrogenase (IDH)-mutated tumors based on elevated protein levels and may be able to aid in distinguishing ODs from astrocytomas [21, 22]. While these newer imaging techniques may inform our management decisions, pathologic examination remains critical in the diagnosis.
Histology
The classification is still largely based on histopathologic features which centers on the 2007 World Health Organization classification [2]. These cells resemble oligodendroglia and are called anaplastic if they have focal or diffuse features which infer a worse prognosis. According to the WHO 2007 classification, the type of tumor must first be differentiated as astrocytic, oligodendroglial, or mixed. These tumors are then classified as grade II (low-grade), grade III (anaplastic), or grade IV (glioblastoma). Features used to make this differentiation include mitotic activity, microvascular proliferation, nuclear atypia, and necrosis [7]. Accurate diagnosis can be hampered by the fact that a biopsy alone may result in sampling error and the innate heterogeneity of gliomas [23, 24].
Oligodendroglioma cells are characteristically round and uniform with clear nuclear membranes. Occasionally seen is a clear perinuclear halo which is due to how the tumor is fixed with formalin. The perinuclear halo in combination with the round membrane appears similar to a fried egg and is classically associated with ODs. Oligodendrogliomas are usually evenly spaced in a honeycomb- or ‘chicken wire’-like pattern with various branching capillaries. Calcifications are common in ~20% of low-grade gliomas and can be suggestive of ODs [25].
Oligodendroglioma Versus Astrocytoma
Even with histologic characterization, it can be difficult to identify ODs as we are limited in immunohistochemical identifiers specific to ODs [26]. Glial fibrillary acidic protein (GFAP) is occasionally expressed by these cells which can aid in diagnosis; however, it has not been associated with a significant prognostic value [27]. Olig2 and neuronal intermediate filament alpha-internexin (INA) expression were thought to be helpful in distinguishing ODs given their association in development. Yet recent publications have shown they do not provide the accuracy necessary to classify ODs from its astrocytoma counterparts [28–31]. INA expression has been associated with 1p/19q codeletion along with the absence of phosphorylated cyclic-AMP responsive element binding protein (p-CREB) expression as it is associated with astrocytoma histology [30–32]. These markers will require further study to fully assess their value as they are still very early in evaluation.
Molecular Characterization
The advancement of molecular genetics has allowed for further classification of gliomas and is playing a larger role given its prognostic value. The exact clinical prognostic significance for ODs is limited as the majority of data available are from research encompassing ODs, mixed oligoastrocytomas, and astrocytomas [18, 33]. The most commonly used prognostic models are the EORTC model and RPA for low-grade gliomas developed by Bauman et al. [18, 34]. The EORTC prognostic model was based on analysis of EORTC 22844 and 22845 which identified a number of prognostic factors including age ≥40 years, tumor diameter >6 cm, tumor crossing midline, neurologic deficits at diagnosis, and astrocytoma histology. The RPA classification categorizes tumors to four different risk groups based on KPS, age at diagnosis, and presence/absence of contrast enhancement.
The association of OD and loss of heterozygosity for chromosome arms 1p and 19q was initially reported in 1994 and has since shown to have a significant prognostic significance [35, 36]. Patients with 1p/19q codeletion have significantly longer median and progression-free survival compared to their counterparts with preserved 1p and 19q. The majority of tumors showing 1p/19q codeletion are thought to be due to a single unbalanced translocation event between arms 1 and 19 at centromere (q10;p10) rather than smaller deletions [37]. This may explain why tumors require both 1p and 19q loss for a better predictive outcome rather than 1p or 19q alone [38, 39]. In further evaluation, 1p/19q codeletion has since been shown to be predictive of treatment response in large prospective randomized studies and associated with improved overall survival and improved response to PCV chemotherapy [35, 40–42].
A second major discovery was the association of IDH mutation with 1p/19q and can correlate with tumor type as IDH1 mutations are mostly found at codon 132 in astrocytic tumors and IDH2 mutations at codon 172 in oligodendroglial tumors [43]. Newer studies now believe that IDH mutations may be one of the initial events of early tumor mutations and are created prior to 1p/19q deletion. These mutations can drive gliomas toward OD subtype unlike tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome, X-linked (ATRX) mutations which are associated with the astrocytoma histology [44]. Both IDH1 and IDH2 are associated with improved outcomes in oligodendroglial tumors [45]. However, attempts to associate IDH-mutated astrocytomas with improved PFS and OS have not held for IDH1-mutated tumors [46, 47].
Of recent interest are two mutations which are rarely found together: telomerase reverse transcriptase (TERT) and alpha–thalassemia/mental retardation syndrome, X-linked (ATRX) [48]. ATRX is associated with telomere maintenance, and a mutation is typically associated with astrocytoma histology where IDH is mutated and 1p/19q is intact [49–51]. Recent molecular analysis of the NOA-04 clinical trial showed improved survival in anaplastic astrocytomas tumors which were ATRX mutated [49]. TERT is required to maintain telomere length, and mutations result in increased telomerase activity. It is most commonly found in high-grade disease, but it can present in oligodendrogliomas with 1p/19q codeletion. When absent in 1p/19q codeleted tumors or the mutation is present in 1p/19q non-codeleted or IDH wild-type tumors, it carries a poor prognosis which some compare to glioblastomas [52–54].
The investigation and sequencing of 1p/19q deleted tumors led to the discovery of two inactivating mutations in a homologue of Dropsophilia Capicua (CIC) on 19q and far-upstream binding protein 1 (FUBP1) on 1p [55]. Both CIC and FUBP1 are associated with tumor suppressor activity and are present in 46 and 24% of grade II/III oligodendrogliomas, respectively, but rarely in mixed oligoastrocytomas or astrocytomas [55, 56]. The impact of these mutations on prognosis is indeterminate at this time; however, they may play a role, in conjunction with ATRX, in better defining astrocytic versus oligodendroglial tumors [57].
Another factor to consider is O6-methylguanine-DNA-methyltransferase (MGMT), which is an important DNA repair enzyme which acts to prevent errors during DNA replication. In higher grade tumors, MGMT promotor methylation has been associated with improved prognosis and with increased sensitivity to alkylating chemotherapies such as temozolomide [58]. MGMT methylation is closely associated with IDH mutation status and whether it is the former or the latter that is important in prognosis is difficult to determine. It may play a larger role is in IDH wild-type tumors where patients with MGMT methylation were shown to have a more favorable prognosis [53, 59, 60].
Current Management
Our treatment approaches in the past have been based on grade of tumor and classic prognostic factors. However, with new molecular prognostic information of these tumors, the treatment approaches will likely change in near future. Historically, approach to treatment for grade III tumors was a combination of maximal safe resection followed by radiation and/or chemotherapy, which has yielded median survival times of 12–14 years in patients with WHO grade III 1p/19q codeletion [61]. Similarly, treatment approaches for grade II tumors start with maximal safe resection followed by observation or adjuvant therapies based on the classic prognostic factors. Although the outcomes may be better in WHO grade II patients, the risk of recurrence is still high [8]. Initial management is generally focused on symptom control including antiepileptic drugs for seizures, steroids for vasogenic edema, and occasionally surgical drainage or decompression if there is significant obstruction or intracranial pressure [62]. With improved imaging and prognostic factors, physicians are increasingly considering delayed treatment given the long and indolent history of these tumors with good prognostic factors once the initial symptoms are controlled. However we await randomized data to help guide treatment such as the ongoing CATNON and CODEL trials. CODEL [NCT00887146] will attempt to evaluate TMZ versus PCV concurrent with radiation and if radiation can be delayed with TMZ alone. In patients who are 1p/19q codeleted, CATNON [NCT00626990] has recently closed and is focused the role of concurrent and/or adjuvant TMZ with radiation.
Surgery
First-line management generally utilizes surgery at diagnosis as it has many additional benefits above tumor debulking as it can be utilized to improve symptom control and provide tissue which can better predict outcomes and aid in treatment management. Given the long natural history of these tumors and high risk of recurrence, even with GTR, some have considered up-front observation with the idea that this may improve a patient’s quality of life without an impact on overall survival if they are followed closely [63, 64]. While this may be an option with a more carefully selected patient population, recent studies are showing improved survival in patients with earlier surgical intervention [5, 65]. A recent evaluation in Norway of two centers, one which favored biopsy and another favoring early resection of LGGs, showed improved OS in patients at the center with earlier surgical intervention. Also of concern is evidence that these tumors will continue to grow over time and can complicate future treatments given the increase in size [66]. In patients presenting with seizures, surgery is important not only as a means of symptom control, but also has been shown to impact overall survival [65].
Surgery can range anywhere from biopsy to complete resection with aggressiveness of surgery dependent on a multitude of factors including patient age/performance status, tumor involvement of eloquent brain areas, amount and feasibility of tumor reduction with aggressive surgery, and time since last intervention [67]. While there are no randomized trials evaluating extent of resection, there is increasing evidence that correlates a more aggressive surgical intervention with improved outcomes among low-grade tumors [68–71]. This is especially true in larger tumors or patients presenting with seizure as GTR can improve seizure control over STR by almost double (43–79%) [72]. When compared to GTR, patients with a STR have up to 1.4 and 4.9 times the risk of recurrence and death, respectively [68]. However, there is an inverse correlation between the increasing size of a lesion and the decrease in extent of resection [18].
The data involving extent of resection are limited in ODs as the majority of previous studies included low- and high-grade tumors or mixed oligoastrocytomas/astrocytomas. The more protracted course and increased chemosensitivity of ODs may allow for less aggressive early surgical intervention. El-Hateer et al. [19] had previously shown an OS and PFS benefit with > 90% resection, but when evaluating solely tumors with OD subtype, they were unable to show a benefit with increased extent of resection at presentation which has been supported in other evaluations [14, 73, 74].
As we attempt to better determine which patients require more extensive resection, molecular genetics are becoming important even in surgical evaluation. Patients with IDH wild-type tumors tend to be more infiltrative on MRI compared to their counterpart IDH-mutated tumors which tend to be more localized and often presenting with seizures [75, 76]. Conversely, IDH-mutated tumors are associated with a more complete surgical resection, even in enhancing disease [77]. With the aid of utilizing improved imaging techniques such as awake craniotomy, functional MRI mapping, and intraoperative MRI (as outlined in previous chapters), we may be able to obtain a safer and more extensive resection. There may be a subset of OD patients who would not benefit with significant surgical resection at presentation; however, this population is difficult to define without a prospective evaluation.
Radiation Therapy
Historically, radiotherapy followed surgery either within weeks from completion or delayed and utilized at time of recurrence/progression. Radiation acts by causing DNA damage and subsequent apoptosis of active tumors cells but is non-discriminatory and also damages normal surrounding brain tissue. The acute side effects such as fatigue, headaches, dizziness, nausea, vomiting, and seizure can resolve; however, the concern comes with long-term clinical side effects such as neurocognitive changes, reduced quality of life, and radiation necrosis [78, 79]. Careful consideration is given to the timing of radiotherapy especially given the longer life span associated with these tumors.
Treatment of gliomas, specifically ODs, is usually a dose to 45–54 Gy in 1.8–2.0 Gy/fractions. Attempts at escalating beyond these doses were performed in prospective randomized trials. EORTC 22844 showed there was no benefit to dose escalation of 59.4 Gy over 45 Gy at 1.8 Gy/fraction with similar 5-year OS (59% with high doses vs. 58% with lower doses) and PFS (50% vs. 47%) [70]. Given that the majority of recurrences occur within the radiation field, further dose escalation was evaluated by the combined efforts of NCCTG, RTOG, and EORTC. They compared radiation doses of 50.4 and 64.8 Gy at 1.8 Gy/fraction [11]. Again, there was no significant improvement in OS (65% vs. 72% in the low-dose group) while also showing a significant increase in risk of grade 3–5 radiation necrosis from 2.5 to 5%.
Given the slow progression of ODs, some have questioned the role of radiation therapy immediately following surgery as radiation can be an effective salvage therapy. EORTC 22845 was a large phase 3 trial which attempted to evaluate this question of radiation alone after surgery or delayed until progression [3]. After 7 years of follow-up, there was a benefit in 5-year PFS of 55% with early RT and 35% with delayed RT but no benefit in 5-year overall survival (68.4% vs. 65.7%) as most patients in the observation arm received salvage radiotherapy. Quality of life and cognitive toxicity were not evaluated in this trial, but there was a benefit in seizure control if RT was received after surgical intervention.
With the introduction of stereotactic radiosurgery (SRS), some institutions have utilized SRS in select cases of both initial and recurrent treatment. The benefit of SRS is the theoretical ability to decrease radiation dose to normal tissues surrounding the tumor. In the up-front setting, current reviews show that these treatments are well tolerated; however, they have been unable to show a clear advantage over standard treatment outcomes [80]. While patients did have favorable short-term and long-term outcomes, the patients selected can be biased by tumor location, size, and patient performance [81–83]. SRS may be advantageous in recurrent tumors who have previously received radiation as these patients can sometimes be limited in further treatment options. Reirradiation has been shown to be well tolerated in a small subset of patients with recurrent low- and high-grade disease, but the exact fractionation and timing is unclear [84, 85].
There is still concern for the long-term impact of radiation with some retrospective series showing evidence that RT can be associated with increased late neurotoxicity [86–88]. It may be more appropriate to identify patients at high risk with poor prognostic factors who may better benefit from early intervention with RT. One of these subsets may be subtotally resected tumors as they are at higher risk for earlier progression, 1p/19q intact patients as they are less susceptible to chemotherapy, and possibly IDH wild-type tumors [69, 89].
Chemotherapy
In the few years with increasing recognition of the chemosensitivity associated with ODs and 1p/19q, chemotherapy has played a significant role in the management of this disease. The association of 1p/19q with chemosensitivity was shown to be significant in anaplastic ODs and oligoastrocytomas after the long-term results of RTOG 9402 was published [61]. While chemotherapy did not influence median survival in combination with radiation in non-deleted tumors (2.6 vs. 2.7 years), there was a significant improvement if procarbazine, lomustine, and vincristine (PCV) were given concurrently with RT (14.7 vs. 7.3 years). Given the increasing role of IDH status in gliomas, this was retrospectively validated in RTOG 9402 and, again, there was an overall survival benefit to combined chemotherapy and radiotherapy in IDH-mutated tumors but not in IDH wild-type tumors [90].
In low-grade gliomas specifically, the results of the phase III study RTOG 9802 did show a significant benefit in PFS and initially no OS benefit with the addition of concurrent PCV chemotherapy to RT in high-risk patients (age >40 or STR) [91]. However, with longer follow-up, there was a significant OS benefit (p = 0.002) with a 10-year overall survival of 40% with RT alone versus 60% with addition of PCV chemotherapy [92]. These results, unfortunately, did not include molecular analysis which was shown to be such an important factor in RTOG 9402. While the role of 1p/19q and IDH status is a known prognostic marker, its role in chemosensitivity is not as clearly defined as in anaplastic gliomas. Still, recent data are promising.
Reviews have shown longer PFS and improved response to chemotherapy in tumors with 1p/19q codeletion [93–95]. In a study of 132 patients with a known IDH status, there was an association with IDH mutation with improved overall survival and chemosensitivity with temozolomide [96]. The methylation status of MGMT has also been shown to be a predictor of response to chemotherapy in low-grade disease [97]. The majority of this data are limited in size, population, and extent of analysis and as such questions still remain if these markers can predict response to chemotherapy on their own or, instead, predicting response to treatment. Hopefully, upcoming prospective trials by RTOG, EORTC, and ECOG will shed light on this question as they are also hoping to answer the other important question of the use of temozolomide.
PCV Versus Temozolomide
While PCV was used in the earlier large published prospective trials, temozolomide is gaining increased use over the historically proven PCV. When undergoing treatment with temozolomide, patients with low-grade gliomas are able to maintain their quality of life in all realms [98]. It can be given safely and has been shown to have an improved response in 1p/19q codeleted tumors with favorable outcomes [99–102]. While the role for treatment in higher grade disease is more certain, the role in low-grade gliomas is still under active investigation and will hopefully be answered in the coming years given the already early results.
RTOG 0424 evaluated high-risk patients undergoing RT with concurrent and adjuvant temozolomide which has shown an improved three-year overall survival of 73.1% compared to historical controls in EORTC 22844 and 22845 [103]. While limited by the comparison to historical controls, EORTC 22033–26033 will attempt to answer the difficult question of radiation versus temozolomide after surgical resection with 1p status included in the stratification. Still early in analysis, patients with 1p intact who received temozolomide trended toward a worse PFS, while those with 1p deleted had an improved OS [104]. While long-term follow-up is required, early results show that 1p/19q status may allow for stratification into different treatment algorithms. The ECOG-E3F05 will further attempt to define the role of temozolomide as it investigates concurrent and adjuvant treatment with RT versus radiation alone in low-grade glioma patients with tumor progression or uncontrolled symptoms.
Even if results prove to have better outcomes, there may be those who advocate for temozolomide. The reasoning is due to the toxicity and complexity of administration of PCV chemotherapy. Recent studies have shown up to 38% of patients are forced to discontinue PCV versus 8% for TMZ and 9% refused to continue PCV versus 4% for TMZ [105]. This does not account for patients who required dose reduction, treatment interruptions (both impairing treatment outcomes) or had more severe toxicities such as debilitating fatigue, neuropathy, and even death. PCV chemotherapy also requires three agents given over 6–8 weeks of varying dose and intensity. This can be further complicated by non-compliant patients, given the complexity of the schedule, who already have difficulty with the cognitive effects of their disease, surgery, and/or radiation. TMZ is an oral agent which is given at a relatively simpler dosing schedule at more regular intervals. There has already been a large shift by a number of large institutions away from PCV to TMZ chemotherapy given the belief that TMZ will be similar to PCV in terms of outcomes and it may be difficult for some to shift back if PCV has improved outcomes [106].
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