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Diagnosis and management of oligodendroglioma
Diagnosis and Management of Oligodendroglioma M.J. van den Bent The discovery of the sensitivity to chemotherapy of oligodendroglial tumors has greatly increased the interest in this tumor type. After the first studies showing the activity of chemotherapy with procarbazine, lomustine (CCNU), and vincristine (PCV), it is now clear that temozolomide is also effective in this tumor type. Fifty percent to 70% of patients with recurrent oligodendroglial tumors may respond to chemotherapy. The histological diagnosis of oligodendroglial tumors is still subject to a significant observer bias. This variation appears to be one of the causes of the recent relative increase in incidence of oligodendroglial tumors. Genetically, 60% to 70% of oligodendroglial tumors are characterized by the loss of the short arm of chromosome 1 (1p) and the loss of the long arm of chromosome 19 (19q). Virtually all tumors with the combined loss of 1p/19q respond to chemotherapy, which has been the first demonstration of the clinical usefulness of the genotyping of brain tumors. These tumors also more often have a classical oligodendroglial histology and have a much better prognosis than oligodendrogliomas without 1p/19q loss. Although the belief is widely held that in the near future the genotype of oligodendroglial tumors may help in selecting patients for treatment, this assumption has not been proven. Prospective trials on oligodendroglial tumors with analyses of the genotype are needed before such conclusions can be drawn. In the meantime it is clear that ultimately all patients with oligodendroglial tumors die of their disease, and that novel treatments are required to improve prognosis. For an improved prognosis, a better understanding of the aberrant pathways and the driving force behind these tumors is required. Semin Oncol 31:645-652 © 2004 Elsevier Inc. All rights reserved.
O
ligodendrogliomas (ODs) constitute 5% to 20% of all glial tumors. They are predominantly a tumor of adulthood, with a peak incidence between the fourth and sixth decade of life. Low-grade ODs tend to arise in slightly younger patients. Although patients with low-grade ODs in particular may have a median survival time of more than 10 years, the outcome is almost invariably fatal. Until some 15 years ago, the diagnosis of an OD merely described a pathological entity. The only clinically relevant meaning of this diagnosis was the observation that the prognosis of OD was better than that of astrocytic tumors of similar grade. This changed with the recognition of the marked sensitivity to procarbazine, lomustine (CCNU), and vincristine (PCV regimen) chemotherapy of these tumors.1,2 It is now generally recognized that the histological diagnosis of OD has clear clinical implications and chemotherapy has become part of the standard treatment either at first diagnosis Neuro-oncology Unit, Daniel den Hoed Cancer Clinic/Erasmus University Medical Center, Rotterdam, The Netherlands. Address reprint requests to Daniel ven den Bent, MD, Neuro-oncology Unit, Daniel den Hoed Cancer Clinic/Erasmus University Medical Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands. E-mail: m.vandenbent@ erasmusmc.nl
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.07.006
or at recurrence. Two developments have had an important impact on the treatment of OD tumors in the past 5 years: the recognition that chemotherapy-sensitive ODs are characterized by specific chromosomal losses, and the introduction of temozolomide, a novel cytotoxic agent. The clinical need to distinguish OD from astrocytoma appears to have resulted in a widening of the histological criteria for OD and an increase in frequency of ODs.3 An important step forward in the diagnosis of these tumors was the identification of loss of 1p/19q as a characteristic genetic lesion of OD, a genotype that was subsequently found associated with an excellent response to chemotherapy.4,5 Virtually all ODs with combined loss of 1p/19q respond to chemotherapy, suggesting that these tumors are a different clinical entity.6,7 This is the first example in the field of neuro-oncology of clinical usefulness of the genotyping of glial tumors. Temozolomide is a new alkylating agent, the efficacy of which was first proven in anaplastic astrocytoma.8 It has also been shown to be very effective in recurrent OD.9 This raises the question whether PCV chemotherapy should be replaced by temozolomide. The pathogenesis and the driving genetic alteration of OD are still unknown, and an explanation of the sensitivity to 645
646 chemotherapy is also lacking. It may well be that the loss of 1p and 19q is an epiphenomenonon, by itself not explaining the sensitivity to chemotherapy. These questions are the focus of ongoing research.
Clinical Presentation The presenting signs and symptoms of OD are nonspecific, and depend on the localization and rate of progression of the tumor. Patients may present with partial or complex seizures, increased intracranial pressure, cognitive deficits, or focal deficits. Low-grade OD patients tend to present with seizures, whereas those with high-grade tumors often present with focal deficits, increased intracranial pressure, or cognitive deficits early in the course of their disease.
Radiological Presentation On magnetic resonance imaging (MRI), low-grade ODs show increased signal intensity on T2-weighted images without enhancement.10 On computed tomography (CT) scans, these tumors appear as low-density masses with no enhancement and may exhibit calcifications. The presence of calcification is suggestive but not specific for OD. Lowgrade ODs may or may not show mass effect. On MRI or CT, most anaplastic ODs are characterized by enhancement, which is presumed to be the macroscopic equivalent of microvascular proliferation. However, the absence of enhancement does not rule out the possibility of an anaplastic tumor.11,12 The final diagnosis can only be made with microscopic examination of tumor tissue, as none of the imaging findings are specific. Similarly to other gliomas, ODs tend to remain localized to the central nervous system (CNS). Extra-CNS metastases (especially bone metastases) have been described, but these are rare and occur in occasional patients at later stages of the disease. Leptomeningeal spread is far from rare, but it usually does not develop until the time of recurrence. A staging procedure (like craniospinal axis imaging or cerebrospinal fluid sampling) is only indicated in the presence of clinical signs and symptoms suggestive of leptomeningeal involvement. The presence of leptomeningeal spread may alter treatment options and should be taken into account. In the majority of these cases, leptomeningeal spread is readily recognized by the presence of distant tumor nodules along the ventricles or subarachnoid space. For the occasional nonenhancing tumor, T2-weighted images may be more sensitive.
Pathology Most ODs arise in the white matter of cerebral hemispheres, predominantly in the frontal lobes. However, these tumors can arise throughout the CNS, including infratentorial sites and the spinal cord. They diffusely infiltrate brain tissue but, in contrast to astrocytoma, areas of remarkable sharp borders with surrounding brain tissue can often be found. The current World Health Organization (WHO) definition of oligo-
M.J. van den Bent dendroglioma is “a well-differentiated, diffusely infiltrating tumor of adults, typically located in the cerebral hemispheres and composed predominantly of cells morphologically resembling oligodendroglia.”13 Histologically, low-grade OD is characterized by uniformly round to oval cells with round nuclei and bland chromatin. The cell density is usually low to moderate. The morphology of these cells is often referred to as the “fried egg appearance” because of a perinuclear halo. A delicate network of branching blood vessels (chicken-wire pattern) is also indicative of low-grade OD. The WHO definition for anaplastic oligodendroglioma is “an oligodendroglioma with focal or diffuse histological features of malignancy and a less favorable prognosis.” Over time, ODs gradually become more anaplastic and evolve from lowgrade, “well-differentiated” gliomas into high-grade gliomas with anaplastic features (high cell density, mitosis, nuclear atypia, microvascular proliferation, and necrosis). Since these morphologic changes, characteristic of high-grade glioma, appear gradually within a glioma, the exact delineation of low- and high-grade (or anaplastic) oligodendroglioma (AOD) is unclear. ODs may also present as anaplastic tumors, without a clinically manifest low-grade precursor lesion. Unfortunately, neither clear diagnostic criteria nor specific markers for OD exist, and in part the diagnosis rests on subjective criteria. ODs may exhibit sparse glial fibrillary acidic protein (GFAP) staining, which is usually due to the presence of reactive astrocytes. Therefore, the presence of GFAP staining does not rule out OD. The value of newer markers like OLIG remains to be established; in particular their relation with combined loss of 1p/19q and their ability to predict sensitivity to chemotherapy needs further investigation.14 Mixed oligoastrocytoma (OA) tumors have morphologic characteristics of both astrocytic tumors and pure ODs. These tumors are graded either according to their astrocytic or their oligodendroglial component. These tumors are generally associated with tumoral oligodendroglial foci and gemistocytic astrocytic components mixed within the same region of the tumor. Unlike pure ODs, OAs typically have areas that are GFAP-positive. This staining pattern may be due to the astrocytic component of the tumor, but it may also be due to reactive astrocytes. There are no widely accepted histological criteria how much oligodendroglial elements need to be present in a predominant astrocytic lesion before a tumor may be called oligoastrocytoma. Recent European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) trials used as arbitrary cut-off points the presence of more than 25% oligodendroglial elements, but these scores are subject to interobserver variation.15 Genotyping of OAs suggest these tumors are either of oligodendroglial or of astrocytic origin (see below).16 In the past about 5% of all glial tumors were considered oligodendroglial, a number that increased to 20% in recent publications.3 Histological criteria for distinguishing OD from astrocytoma are subjective, with a significant interobserver variability.17 Coons et al suggested that the classic histological features described above are not sufficient for the
Diagnosis and management of oligodendroglioma diagnosis of OD and, therefore, OD may often be misdiagnosed as anablastic astrocytoma (AA) or glioblastoma multiforme (GBM).3 They suggested that when using histological features to diagnose OD, special emphasis should be given to identifying other signs, such as microgemistocytes, gliofibrillary oligodendrocytes, and protoplasmic astrocytes, which all may suggest the tumor to be of oligodendroglial origin. The changes and widening of criteria proposed by these and other authors has greatly increased the percentage of tumors that are considered oligodendroglial. Nevertheless, a loosening of the histological criteria for an OD diagnosis will result in a more heterogeneous tumor population in terms of genetic lesions and—more importantly—their sensitivity to treatment.
Genetic Lesions in OD The most frequent chromosomal lesions in OD are allelic loss of the 1p and 19q loci.4,18 The incidence of either 1p or 19q chromosomal deletions in OD is approximately 75%, and that of combined loss of 1p and 19q is 60% to 70%.5,17 AODs usually have additional chromosomal deletions; in particular loss of heterozygosity for 9p and/or deletion of the CDKN2A gene occurs in 33% to 42% of AODs, and deletions on chromosome 10 occur in 19% to 25% of cases.18 Studies combining morphology and genetic analysis found that oligodendroglial tumors with a classical histological appearance (perinuclear halo, chicken-wire vascular pattern) are associated with the loss of 1p/19q, whereas in tumors with an atypical appearance, often other chromosomal abnormalities are found (eg, TP53 mutations).7,19 However, some atypical ODs have 1p/19q loss of heterozygosity and some typical OD tumors do not show these lesions. Maintz et al have provided evidence that OAs are not mixed tumors at all, but rather tumors of either oligodendroglial or astrocytic origin.16 In this study, OA fell into two categories: those that had 1p and 19q deletions, typical of ODs, and those that had TP53 mutations, typical of astrocytoma. In AOD both the loss of 10q and the amplification of the epidermal growth factor receptor (EGFR) were found inversely related to 1p/19q loss, and were associated with poor chemosensitivity and short survival.20 The mutually exclusive occurrence of 1p/19q loss in one set of tumors and TP(53) mutations, EGFR amplification, 10q loss, or PTEN mutations in other tumors suggests that these neoplasms are derived from different precursor cells with a different genetic mechanism of disease. Analysis of the localization of the tumor and its relation with the genotype further support this assumption. ODs with loss of 1p/19q rarely arise in the temporal lobe. Similarly, oligoastrocytoma located solely within the temporal lobe have significantly more frequent TP53 mutations without 1p/19q loss.21 The marked differences in the response to treatment and the prognosis of these genetically diverse tumors gives further support for this assumption.
647
Prognosis in the “Pre-genetic” Era Pure oligodendroglial tumors have a better prognosis than astrocytic tumors of the same grade; the prognosis of mixed oligoastrocytoma is in between these histologies.15,22-24 One study (albeit with small numbers of ODs) reported that in 285 patients with supratentorial anaplastic glioma, patients with AOD had the longest median survival time (5.3 years) compared with patients with GBM, AA, and AOA.25 Before results of chromosomal analysis of OD became available, the single most important prognostic factor for progression-free and overall survival in patients with OD was the pathologic tumor grade. Patients with low-grade ODs (WHO grades I and II) have a median survival of 10 to 17 years and a 5-year survival rate of approximately 75%.26,27 In addition, patients with low-grade ODs or OAs experience longer overall survival compared with patients with low-grade astrocytoma (13 v 7.5 years, P ⫽ .003). Patients with AODs have a substantially worse prognosis, with reported median survivals of 4 to 5 years and a 5-year survival rate of only about 40%.28 The prognosis of mixed OA lies between the prognosis of OD and pure astrocytic tumors, perhaps because these tumors are in fact either astrocytic or oligodendroglial (see below). Various anaplastic histological features, including cell density, the number of mitoses (including Ki-67 labeling index), and the presence of endothelial hyperplasia, necrosis, or pleomorphism have been identified as important prognostic factors for AOD.29,30 In tumors that carry all anaplastic elements, the prognosis is almost as poor as for GBM, with a median survival time of about 18 months.31 Known clinical prognostic factors are the age of the patient, the performance status, and the type of presentation. The presence of enhancement on neuro-imaging has also been found to be of prognostic significance, and probably reflects endothelial proliferation.30
Prognosis in the “Genetic” Era Recent studies have shown that the presence of loss of 1p and 19q is a more relevant prognostic factor than either histology or clinical characteristics. The evidence is becoming increasingly convincing that OD with 1p/19q loss constitutes a different biologic entity with a more favorable clinical course and better response to treatment than OD or OA without these genetic lesions.17 One study found that loss of 1p and 19q were both independent predictors of survival.32 Virtually all ODs with combined loss of 1p and 19q respond to PCV chemotherapy, and the presence of 1p deletions in oligodendroglial tumors is associated with longer progression-free survival after radiotherapy or chemotherapy.7,33,34 Furthermore, ODs with 1p/19q loss tend to have a more indolent behavior before initiation of treatment compared to tumors without 1p/19q loss; they are rarely located in the temporal lobe and they have a more homogeneous enhancing pattern.6,7,21 In contrast, the presence of EGFR amplification, loss of
M.J. van den Bent
648 10q, PTEN mutations, and CDKN2A are associated with a worse prognosis.6,33,35 These findings appear to be related to either the presence of anaplastic histological features or to an astrocytic lineage.18,20 Taken together, these findings show that the genotyping of OD has resulted in the emergence of a specific group of tumors with OD morphology, a more favorable prognosis, and a better response to treatment. Since all the evidence indicates that the genotype characterizes these tumors better than conventional histology, genotyping of tumors with oligodendroglial elements is likely to become a standard diagnostic procedure.36 A first example and proof of principle is the recently published study by Nutt et al, which showed that gene expression profiling of a set of histologically nonclassic glioma proved superior in predicting prognosis than classical pathology.37 The role of the above-described clinical and histological factors needs to be reinvestigated, taking the genotype of the tumor into account.
Treatment: When to Initiate? Most randomized phase III trials on the treatment of glial tumors included both astrocytic and oligodendroglial tumors. No results are available from trials that limited accrual to oligodendroglial tumors, and most data on the treatment of OD are derived from retrospective surveys with known inherent pitfalls. An exception is the many chemotherapy studies devoted to oligodendroglial tumors, but these are uncontrolled single-arm studies. The best treatment policy for young patients with presumed low-grade glioma on neuro-radiological imaging presenting with seizures only constitutes an ongoing controversy. As many of these patients may remain stable for protracted periods without any treatment, many physicians tend to defer treatment until clinical or radiological progression. An important rationale for the deferral of radiotherapy is the concern that early treatment including radiotherapy may in fact contribute to the cognitive deficits in patients with low-grade glioma.38,39 This assumption was recently questioned by a large Dutch study, which showed that only a large radiotherapy fraction size (⬎2 Gy) and the use antiepileptic drugs were associated with cognitive deficits in lowgrade glioma patients.40 Whether limited-field radiotherapy in fractions of 1.5 to 1.8 Gy increases long-term cognitive deficits in low-grade glioma patients is at present unclear. Advocates of early intervention in patients with presumed low-grade glioma (including histological verification of the nature of the process) also point to the fact that up to 30% of patients with nonenhancing low-grade glioma-like lesions have an anaplastic tumor. They recommend always obtaining histological proof in cases of a presumed low-grade glioma.11,12,41 There is general agreement that in patients with enhancing lesions, evidence of mass effect, focal neurologic signs or symptoms, or signs of increased intracranial pressure, treatment should be initiated without delay.
Surgery Surgery for glioma serves three goals: verification of the nature of the lesion, relief of signs and symptoms in patients suffering from a lesion with mass effect, and improvement of the prognosis. The relevance of the first two are generally acknowledged, but so far no trial has given evidence beyond reasonable doubt that extensive surgery improves survival compared to less extensive resections. All available data both for low-grade glioma and high-grade glioma come from retrospective or post hoc analyses; no randomized controlled trial has evaluated the effect of resection on survival in glioma as the primary endpoint. A drawback of these retrospective studies is that superficial and small tumors are more likely candidates for extensive resections. In contrast, deep-seated lesions, large tumors, or tumors with growth into midline structures may confer a worse prognosis regardless of the extent of resection. Such patients will never undergo nearcomplete resections.23 One uncontrolled study found that complete resection in low-grade OD is associated with long disease-free intervals.42 In another study, patients who underwent subtotal resection had improved survival, although many of these patients were young and had low-grade tumors (which are favorable prognostic factors).24,43,44 In contrast, other studies have shown that gross total resection in patients with OD provided no survival benefit.30,45 Nonetheless, given the potential clinical benefits it is considered standard treatment to resect glioma regardless of histology and tumor grade as extensively as safely possible.
Radiotherapy Randomized trials in high-grade glioma have demonstrated that adjuvant radiotherapy provides significant yet modest improvements in survival.46 In low-grade glioma, the benefit of early radiation therapy as compared to radiotherapy at the time of progression resulted in a modest improvement of time to progression without affecting overall survival.47 However, no trial has specifically addressed anaplastic OD. Some retrospective studies support postoperative radiation therapy in patients with OD.48,49 Others found survival benefit of radiotherapy in patients with OD, mainly in the subgroup of patients with neurological deficit or for whom surgery was limited to biopsy or partial surgery. Other studies have reported no benefit of postoperative radiation in the treatment of OD at all.27,43,50,51 In the absence of randomized trials, one may withhold radiotherapy until tumor progression in younger patients in good clinical condition with a low-grade OD who have undergone a complete or almost complete resection. In contrast, patients with large, unresectable, or incompletely resected tumors, focal deficits, anaplastic tumors, or enhancing lesions should be treated including radiotherapy without delay. Following the randomized dose-finding EORTC and North Central Cancer Treatment Group (NCCTG) trials, in low-grade OD a cumulative dose of 50 to 54 Gy should be given in fractions of 1.8 Gy to limit long-term cognitive se-
Diagnosis and management of oligodendroglioma
649
Table 1 PCV and PCV-I (intensified) Chemotherapy Drug CCNU Day 1 Vincristine Day 8, 29 Procarbazine Day 8-21
Standard-Intensity PCV
Intensified PCV
110 mg/m2 orally 1.4 mg/m2 IV 60 mg/m2 orally
130 mg/m2 orally 1.4 mg/m2 IV 75 mg/m2 orally
may be less responsive are most likely due to the low frequency of combined 1p/19q loss in OA. Following the documentation of significant activity of temozolomide in recurrent glioma, this alkylating agent was investigated in several trials on recurrent OD (Table 3). So far, only one trial investigated first-line temozolomide in recurrent OD.9 This trial reported a 54% response rate with 40% of patients free from progression at 12 months, which is in the range of the 65% to 70% response rate and 50% progression-free survival at 12 months obtained with the PCV regimen. In second-line therapy after prior PCV (either given adjuvant or at first recurrence), 20% to 30% of patients responded to temozolomide with 30% to 50% and 10% to 30% of patients free from progression at 6 and 12 months, respectively.57-59 A fourth trial involved predominantly patients who had responded favorably to PCV (response rate to firstline PCV, 83%).60 The objective response rate to temozolomide in this trial was 44%, with 50% and 25% of patients free from progression at 6 and 12 months. Clearly these results indicate that better patient selection results in a more favorable outcome. These results have raised the question which treatment is to be preferred as first-line therapy, temozolomide or PCV? So far no results of a head-to-head comparison are available. A major advantage of temozolomide is the good tolerability, with generally modest myelosuppression and easily controllable nausea/vomiting being its major side effects. In this respect, temozolomide compares favorably to the PCV regimen.
NOTE. Cycles to be repeated every 6 to 8 weeks, for a maximum of six cycles. Abbreviation: IV, intravenous.
qualae.52,53 In high-grade OD, 60 to 65 Gy in 30 to 35 fractions should be given. More and more clinicians tend to replace radiotherapy by upfront chemotherapy, but clinical data to support this change are absent (see below).
Chemotherapy for Recurrent OD Most data on chemotherapy in OD were obtained from studies in recurrent tumors. Initially, most studies investigated PCV chemotherapy (Table 1), while recent publications have focused on the new alkylating agent temozolomide. No clear explanation is yet available for the favorable response to chemotherapy of oligodendroglial tumors as compared to astrocytic tumors. There are indications that the nuclear enzyme alkyltransferase, which mediates at least a part of the cell resistance to alkylating agents, is less expressed in OD.54 However, it is unlikely that this explanation accounts for the entire difference in sensitivity to chemotherapy between astrocytic tumors and ODs. It also does not explain why ODs with combined loss of 1p and 19q are in particular sensitive to chemotherapy. Approximately two thirds of patients respond favorably to PCV chemotherapy (Table 2). The time to progression in these patients is generally 12 to 18 months, but occasionally much longer than 24 months.1,2,55 This benefit has made the PCV schedule standard treatment for patients with recurrent OD and OA following radiotherapy, regardless of the grade of the tumor. However, the cumulative hematological toxicity and gastrointestinal side effects associated with standard PCV often limit the duration of its administration. Some of these studies also explored the Intensified PCV regimen (see Table 1), which was found to be considerably more toxic (especially hematological and general side effects, including malaise and weight loss) without evidence of superior results.2,56 In the absence of superior results, this regimen cannot be recommended. Several of these reports that suggested OA
Other Agents Paclitaxel, irinotecan, carboplatin, and etoposide plus cisplatin have been investigated as second-line chemotherapy in patients with AOD.61-64 Except for the small numbers investigated with cisplatin and etoposide (with four of 10 patients responding), the response rates are low (in the 10% to 15% range) with one third of patients free from progression at 6 months and virtually all patients progressing by 12 months. A drawback of some of these agents (paclitaxel, irinotecan) is that they are metabolized through the CYP 3A4 cytochrome, which implies that their metabolism may have been induced by enzyme-inducing anti-epileptic agents. This metabolic route limits the role of these cytotoxic agents in glial tumors (but may also have affected the observed activity in the above-mentioned trials).
Table 2 Response Rates and Median Time to Progression in Three Studies of PCV Chemotherapy in Recurrent or Newly Diagnosed Oligodendroglial Tumors Response Rate (%) Reference van den Bent et al2 Soffietti et al55 Cairncross et al1 Total (n)
n
CR
PR
SD
PD
52 26 24 102
17% 12% 38% 21
46% 50% 38% 46
19% 31% 17% 22
17% 8% 8% 13
MTP for CR/PR/SD (mo) 25/12/7 45/16/24 25/16/7
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; MTP, median time to progression.
M.J. van den Bent
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Table 3 Results of First- and Second-Line Chemotherapy With Temozolomide in Recurrent Oligodendroglioma
Study EORTC 269719 van den Bent et al57 EORTC 2697258 Constanza et al59 Chinot et al60
n
1st/ 2nd line
Response to PCV (%)
n
(%)
n
38 27 28 34 48
1st 2nd 2nd 2nd 2nd
NA 38 50 50 83
20 7 7 9 21
(53) (26) (28) (26) (44)
12 8 9 15 19
OR
(%)
Median PFS (mo)
6-mo PFS (%)
12-mo PFS (%)
(32) (30) (30) (44) (40)
10.1 4 3.7 6 6.7
71 44 29 48 50
40 27 11 30 25
SD
Abbreviations: 1st, 2nd line, first- or second-line chemotherapy; OR, objective response (complete or partial response); SD, stable disease; PFS, progression-free survival.
In 24 patients treated with second-line PCV for recurrent OD after first-line temozolomide, 17% of patients achieved an objective response and 50% of patients remained free from progression for at least 6 months.65 The median time to progression in the 15 responding and stabilized patients was 10 months, which implies that PCV is an option for treatment failures after first-line temozolomide. This study and the studies on second-line temozolomide show that whatever sequence of chemotherapy regimen is used, the response rate is lower to either temozolomide or PCV given as second-line therapy after prior therapy with the other regimen.
High-Dose Chemotherapy With Autologous Bone Marrow Rescue Both in newly diagnosed OD and in recurrent disease, highdose thiotepa chemotherapy with autologous stem cell support has been investigated in patients responding to PCV chemotherapy. In patients with recurrences after prior radiotherapy this approach was believed to be too toxic. Although some durable responses were observed (20 of 38 patients were treated with the high-dose regimen, and six of them remained free from progression at 2 years), the authors concluded that this was a disappointing strategy with a median overall progression-free survival of only 20 months.66 In newly diagnosed patients this approach appears better tolerated, with an estimated median progression-free survival of 69 months.67 Out of a total of 69 patients, 37 received the high-dose chemotherapy part of the study; in these patients, radiotherapy was deferred until progression. The obvious limitation to this study design is its uncontrolled nature. In the absence of a comparator, no conclusions can be drawn except for the expected feasibility of the approach. In view of generally limited role of myeloablative chemotherapy in solid tumors, it is unlikely that small phase II studies with their inherent selection bias will determine the value of this approach.
Adjuvant Chemotherapy The value of adjuvant chemotherapy in high-grade glioma was finally shown in a large meta-analysis which demonstrated that this therapy increases the 1- and 2-year survival rates by approximately 5% from 40% to 46% and
from 15% to 20%, respectively.68 As this benefit is rather small and no data exist on the influence on the quality of life of adjuvant chemotherapy, the real value of adjuvant chemotherapy in high-grade glioma remains a matter of debate. The sensitivity to chemotherapy of recurrent OD has renewed interest in the role of adjuvant chemotherapy for this subset of glial tumors. In a chemotherapy-sensitive tumor one would expect a larger benefit from adjuvant chemotherapy, but this does not have to be the case if a good salvage treatment exists. Attempts to evaluate whether patients with AOD in particular benefited from adjuvant chemotherapy failed to provide support for this assumption.69 This may well be more a matter of best timing of the chemotherapy, in the adjuvant setting or at the time of recurrence. An often forgotten advantage of chemotherapy at the time of recurrence and in the presence of measurable disease is that this strategy allows the discontinuation of treatment if the tumor proves to be chemotherapy-resistant, thus avoiding an inactive treatment. At present two ongoing trials (in the EORTC and RTOG) are investigating the value of adjuvant or early chemotherapy in OD.
Up-front Chemotherapy in Newly Diagnosed AOD A new development is the treatment of newly diagnosed OD with up-front chemotherapy strategies, with or without subsequent radiotherapy.70 Although this approach may seem appealing, in the absence of randomized trials no conclusions can be drawn from the limited data so far published. The key issue here may well be the involved toxicities, and one should ask for the rationale why a local treatment delivered with modern radiotherapy techniques should be abandoned for a treatment with systemic toxicity. It is clear that with up-front PCV or temozolomide chemotherapy good responses are obtained, but whether the overall outcome is as good as that following radiotherapy is unknown. It is also unclear whether in the presence of a favorable response to chemotherapy, radiation therapy can be withheld. In view of the expected long overall survival in OD, these questions may be more a matter of side effects and active salvage regimens, rather than of progression-free survival. Phase III trials are obviously needed to answer these questions.
Diagnosis and management of oligodendroglioma
Up-front Chemotherapy in LowGrade OD The clinical data regarding chemotherapy for low-grade OD are limited but suggest these tumors are as sensitive as their anaplastic counterparts.56,71-73 Both the PCV schedule and temozolomide have been investigated. Even tumors without loss of 1p/19q and mixed oligoastrocytoma may respond, and responses may last for a considerable interval of time. In the absence of comparative trials, this may be an appropriate choice for patients with large OD lesions (oligodendroglial “gliomatosis cerebri”) in order to avoid whole-brain radiotherapy in patients with a favorable prognosis for long-term disease-free survival. Whether this approach is also useful in patients with smaller lesions who are candidates for radiation therapy with limited fields may again be more a matter of the side effects. As noted earlier, it is questionable whether it is rational to try to avoid limited-fields radiation therapy of a small brain lesion, delivered by modern irradiation techniques, by replacement with prolonged systemic chemotherapy.
Conclusion Some 15 years after the initial observation of the sensitivity of OD to PCV chemotherapy, it is now clear that the chemotherapy-sensitive OD is characterized by a specific genotype showing combined loss of 1p and 19q. Although this genotype identifies the more treatment-sensitive tumors, no real treatment improvement has been achieved since the initial discovery of the sensitivity to the PCV regimen, and all patients still die of recurrent disease. The introduction of temozolomide does not improve treatment efficacy, with its real advantage being the better tolerability. The obvious conclusion is that with a superior identification of treatment-sensitive tumors we still lack more active therapies and a more fundamental knowledge of the driving force behind the oligodendroglial tumor. The drawback of a better identification of treatment sensitive OD is the fact that we are dealing again with a rather rare disease that requires multi-institutional trials to achieve further progress.
References 1. Cairncross G, Macdonald D, Ludwin S. et al: Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12:2013-2021, 1994 2. van den Bent MJ, Kros JM, Heimans JJ, et al: Response rate and prognostic factors of recurrent oligodendroglioma treated with PCV chemotherapy. Neurology 51:1140-1145, 1998 3. Coons SW, Johnson PC, Scheithauer BW, et al: Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 79:1381-1391, 1997 4. Reifenberger J, Reifenberger G, Liu L, et al: Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175-1190, 1994 5. Smith JS, Alderete B, Minn Y, et al: Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene 18:4144-4152, 1999 6. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473-1479, 1998
651 7. van den Bent MJ, Looijenga LHJ, Langenberg K, et al: Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features. Cancer 97:1276-1284, 2003 8. Yung WKA, Prados M, Yaya-Tur R, et al: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762-2771, 1999 9. van den Bent MJ, Taphoorn MJ, Brandes AA, et al: EORTC brain tumor group study 26971: First line chemotherapy with temozolomide in recurrent oligodendroglioma. A phase II study. J Clin Oncol 21:25252528, 2003 10. Lee Y, van Tassel P: Intracranial oligodendrogliomas: Imaging findings in 35 untreated cases. AJR 152:361-369, 1989 11. Ginsberg LE, Fuller GN, Hashmi M, et al: The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: Histopathological evaluation of a series. Surg Neurol 49:436-440, 1998 12. Kondziolka D, Lunsford LD, Martinez AJ: Unreliability of contemporary neurodiagnostic imaging in evaluating suspected adult supratentorial (low-grade) astrocytoma. J Neurosurg 79:533-536, 1993 13. Reifenberger G, Kros JM, Burger P, et al: Oligodendroglioma, in Kleihues P, Cavenee WK (eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Nervous System. Lyon, France, IARC Press, 2000, pp 55-70 14. Marie Y, Sanson M, Mokhtari K, et al: Olig2 as a specific marker of oligodendroglial tumour cells. Lancet 358:298-300, 2001 15. Krouwer HGJ, van Duinen SG, Kamphorst W, et al: Oligoastrocytomas: A clinicopathological study of 52 cases. J Neuroonncol 33:223-238, 1997 16. Maintz D, Fiedler K, Koopmann J, et al: Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 56:10981104, 1997 17. Smith JS, Perry A, Borell TJ, et al: Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytoma, and mixed oligoastrocytomas. J Clin Oncol 18:636-645, 2000 18. Bigner SH, Matthews MR, Rasheed BKA, et al: Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 155:375-386, 1999 19. Sasaki H, Zlatescu MC, Betensky RA, et al: Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade “oligodendroglioma.” J Neuropathol Exp Neurol 61:58-63, 2002 20. Hoang-Xuan K, Huguet S, Mokhtari K, et al: Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression. Neurology 57:1278-1281, 2002 21. Mueller W, Hartmann C, Hoffmann A, et al: Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets. Am J Pathol 161:313-319, 2002 22. Donahue B, Scott CB, Nelson JS, et al: Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: A report of Radiation Therapy Oncology Group 83-02. Int J Radiat Oncol Biol Phys 38:911-914, 1997 23. Pignatti F, van den Bent MJ, Curran D, et al: Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076-2084, 2002 24. Shaw EG, Scheithauer BW, O’Fallon JR, et al: Mixed oligoastrocytomas: A survival and prognostic factor analysis. Neurosurgery 34:577-582, 1994 25. Winger MJ, Macdonald DR, Cairncross JG: Supratentorial anaplastic gliomas in adults. J Neurosurg 71:487-493, 1989 26. Leighton C, Fisher B, Bauman G, et al: Supratentorial low-grade glioma in adults: An analysis of prognostic factors and the timing of radiation. J Clin Oncol 15:1294-1301, 1997 27. Shaw EG, Scheithauer BW, O’Fallon JR, et al: Oligodendrogliomas: The Mayo Clinic experience. J Neurosurg 76:428-434, 1992 28. Shaw EG, Scheithauer BW, O’Fallon JR: Supratentorial gliomas: A comparative study by grade and histologic type. J Neurooncol 31:273-278, 1997 29. Giannini C, Scheithauer BW, Weaver A, et al: Oligodendrogliomas: Reproducibility and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol 60:248-262, 2001 30. Daumas-Duport C, Tucker ML, Kolles H, et al: Oligodendrogliomas. Part II: A new grading system based on morphological and imaging criteria. J Neurooncol 34:61-78, 1997
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652 31. Kros JM, Troost D, Van Eden CG, et al: Oligodendroglioma: A comparison of two grading systems. Cancer 61:2251-2259, 1988 32. Matthew J, Fuller G, Goodman JC, et al: The impact of histology and 1p/19q status on the outcome of patients with anaplastic oligodendroglioma. Neurooncology 4:344, 2002 (abstr) 33. Ino Y, Betensky RA, Zlatescu MC, et al: Molecular subtypes of anaplastic oligodendroglioma: Implications for patient management at diagnosis. Clin Cancer Res 7:839-845, 2001 34. Bauman GS, Ino Y, Yeki K, et al: Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendroglioma. Int J Radiat Oncol Biol Phys 48:825-830, 2000 35. Sasaki H, Zlatescu MC, Betensky RA, et al: PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am J Pathol 159:359-367, 2001 36. Reifenberger G, Louis DN: Oligodendroglioma: Toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 62: 111-126, 2003 37. Nutt CL, Mani DR, Betensky RA, et al: Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 63:1602-1607, 2003 38. Surma-aho O, Niemelä M, Vilkki J, et al: Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 56: 1285-1290, 2001 39. Reijneveld JC, Sitskoorn MM, Klein M, et al: Cognitive status and quality of life in suspected versus proven low-grade gliomas. Neurology 56:618-623, 2001 40. Klein M, Heimans JJ, Aaronson NK, et al: Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low grade gliomas: A comparative study. Lancet 360:13611368, 2002 41. Barker FG, Chang CH, Huhn SL, et al: Age and the risk of anaplasia in magnetic resonance-nonenhancing supratentorial cerebral tumors. Cancer 80:936-941, 1997 42. Berger MS, Deliganis AV, Dobbins J, et al: The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. Cancer 74:1784-1791, 1994 43. Celli P, Nofrone I, Palma L, et al: Cerebral oligodendroglioma: Prognostic factors and life history. Neurosurgery 35:1018-1035, 1994 44. Schiffer D, Dutto A, Cavalla P, et al: Prognostic factors in oligodendroglioma. Can J Neurol Sci 24:313-319, 1997 45. Kros JM, Pieterman H, Van Eden CG, et al: Oligodendroglioma: The Rotterdam-Dijkzigt experience. Neurosurgery 34:959-966, 1994 46. Walker MD, Alexander E, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333-343, 1978 47. Karim ABMF, Afra D, Bleehen NM, et al: Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer study 22845 with the Medical Research Council study BRO4: An interim analysis. Int J Radiat Oncol Biol Phys 52:316-324, 2002 48. Gannett DE, Wisbeck WM, Silbergeld DL, et al: The role of postoperative irradiation in the treatment of oligodendroglioma. Int J Radiat Oncol Biol Phys 30:567-573, 1994 49. Wallner KE, Gonzales M, Sheline GE: Treatment of oligodendrogliomas with or without postoperative irradiation. J Neurosurg 68:684688, 1988 50. Bullard DE, Rawlings CE, III Philllips B, et al: Oligodendroglioma. An analysis of the value of radiation therapy. Cancer 60:2179-2188, 1987 51. Nijjar TS, Simpson WJ, Gadalla T, et al: Oligodendroglioma. The Princess Margaret Hospital Experience (1958-1984). Cancer 71:40024006, 1993 52. Karim ABMF, Maat B, Hatlevoll R, et al: A randomized trial on doseresponse in radiation therapy of low grade cerebral glioma: European
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O
ligodendrogliomas (ODs) constitute 5% to 20% of all glial tumors. They are predominantly a tumor of adulthood, with a peak incidence between the fourth and sixth decade of life. Low-grade ODs tend to arise in slightly younger patients. Although patients with low-grade ODs in particular may have a median survival time of more than 10 years, the outcome is almost invariably fatal. Until some 15 years ago, the diagnosis of an OD merely described a pathological entity. The only clinically relevant meaning of this diagnosis was the observation that the prognosis of OD was better than that of astrocytic tumors of similar grade. This changed with the recognition of the marked sensitivity to procarbazine, lomustine (CCNU), and vincristine (PCV regimen) chemotherapy of these tumors.1,2 It is now generally recognized that the histological diagnosis of OD has clear clinical implications and chemotherapy has become part of the standard treatment either at first diagnosis Neuro-oncology Unit, Daniel den Hoed Cancer Clinic/Erasmus University Medical Center, Rotterdam, The Netherlands. Address reprint requests to Daniel ven den Bent, MD, Neuro-oncology Unit, Daniel den Hoed Cancer Clinic/Erasmus University Medical Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands. E-mail: m.vandenbent@ erasmusmc.nl
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.07.006
or at recurrence. Two developments have had an important impact on the treatment of OD tumors in the past 5 years: the recognition that chemotherapy-sensitive ODs are characterized by specific chromosomal losses, and the introduction of temozolomide, a novel cytotoxic agent. The clinical need to distinguish OD from astrocytoma appears to have resulted in a widening of the histological criteria for OD and an increase in frequency of ODs.3 An important step forward in the diagnosis of these tumors was the identification of loss of 1p/19q as a characteristic genetic lesion of OD, a genotype that was subsequently found associated with an excellent response to chemotherapy.4,5 Virtually all ODs with combined loss of 1p/19q respond to chemotherapy, suggesting that these tumors are a different clinical entity.6,7 This is the first example in the field of neuro-oncology of clinical usefulness of the genotyping of glial tumors. Temozolomide is a new alkylating agent, the efficacy of which was first proven in anaplastic astrocytoma.8 It has also been shown to be very effective in recurrent OD.9 This raises the question whether PCV chemotherapy should be replaced by temozolomide. The pathogenesis and the driving genetic alteration of OD are still unknown, and an explanation of the sensitivity to 645
646 chemotherapy is also lacking. It may well be that the loss of 1p and 19q is an epiphenomenonon, by itself not explaining the sensitivity to chemotherapy. These questions are the focus of ongoing research.
Clinical Presentation The presenting signs and symptoms of OD are nonspecific, and depend on the localization and rate of progression of the tumor. Patients may present with partial or complex seizures, increased intracranial pressure, cognitive deficits, or focal deficits. Low-grade OD patients tend to present with seizures, whereas those with high-grade tumors often present with focal deficits, increased intracranial pressure, or cognitive deficits early in the course of their disease.
Radiological Presentation On magnetic resonance imaging (MRI), low-grade ODs show increased signal intensity on T2-weighted images without enhancement.10 On computed tomography (CT) scans, these tumors appear as low-density masses with no enhancement and may exhibit calcifications. The presence of calcification is suggestive but not specific for OD. Lowgrade ODs may or may not show mass effect. On MRI or CT, most anaplastic ODs are characterized by enhancement, which is presumed to be the macroscopic equivalent of microvascular proliferation. However, the absence of enhancement does not rule out the possibility of an anaplastic tumor.11,12 The final diagnosis can only be made with microscopic examination of tumor tissue, as none of the imaging findings are specific. Similarly to other gliomas, ODs tend to remain localized to the central nervous system (CNS). Extra-CNS metastases (especially bone metastases) have been described, but these are rare and occur in occasional patients at later stages of the disease. Leptomeningeal spread is far from rare, but it usually does not develop until the time of recurrence. A staging procedure (like craniospinal axis imaging or cerebrospinal fluid sampling) is only indicated in the presence of clinical signs and symptoms suggestive of leptomeningeal involvement. The presence of leptomeningeal spread may alter treatment options and should be taken into account. In the majority of these cases, leptomeningeal spread is readily recognized by the presence of distant tumor nodules along the ventricles or subarachnoid space. For the occasional nonenhancing tumor, T2-weighted images may be more sensitive.
Pathology Most ODs arise in the white matter of cerebral hemispheres, predominantly in the frontal lobes. However, these tumors can arise throughout the CNS, including infratentorial sites and the spinal cord. They diffusely infiltrate brain tissue but, in contrast to astrocytoma, areas of remarkable sharp borders with surrounding brain tissue can often be found. The current World Health Organization (WHO) definition of oligo-
M.J. van den Bent dendroglioma is “a well-differentiated, diffusely infiltrating tumor of adults, typically located in the cerebral hemispheres and composed predominantly of cells morphologically resembling oligodendroglia.”13 Histologically, low-grade OD is characterized by uniformly round to oval cells with round nuclei and bland chromatin. The cell density is usually low to moderate. The morphology of these cells is often referred to as the “fried egg appearance” because of a perinuclear halo. A delicate network of branching blood vessels (chicken-wire pattern) is also indicative of low-grade OD. The WHO definition for anaplastic oligodendroglioma is “an oligodendroglioma with focal or diffuse histological features of malignancy and a less favorable prognosis.” Over time, ODs gradually become more anaplastic and evolve from lowgrade, “well-differentiated” gliomas into high-grade gliomas with anaplastic features (high cell density, mitosis, nuclear atypia, microvascular proliferation, and necrosis). Since these morphologic changes, characteristic of high-grade glioma, appear gradually within a glioma, the exact delineation of low- and high-grade (or anaplastic) oligodendroglioma (AOD) is unclear. ODs may also present as anaplastic tumors, without a clinically manifest low-grade precursor lesion. Unfortunately, neither clear diagnostic criteria nor specific markers for OD exist, and in part the diagnosis rests on subjective criteria. ODs may exhibit sparse glial fibrillary acidic protein (GFAP) staining, which is usually due to the presence of reactive astrocytes. Therefore, the presence of GFAP staining does not rule out OD. The value of newer markers like OLIG remains to be established; in particular their relation with combined loss of 1p/19q and their ability to predict sensitivity to chemotherapy needs further investigation.14 Mixed oligoastrocytoma (OA) tumors have morphologic characteristics of both astrocytic tumors and pure ODs. These tumors are graded either according to their astrocytic or their oligodendroglial component. These tumors are generally associated with tumoral oligodendroglial foci and gemistocytic astrocytic components mixed within the same region of the tumor. Unlike pure ODs, OAs typically have areas that are GFAP-positive. This staining pattern may be due to the astrocytic component of the tumor, but it may also be due to reactive astrocytes. There are no widely accepted histological criteria how much oligodendroglial elements need to be present in a predominant astrocytic lesion before a tumor may be called oligoastrocytoma. Recent European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) trials used as arbitrary cut-off points the presence of more than 25% oligodendroglial elements, but these scores are subject to interobserver variation.15 Genotyping of OAs suggest these tumors are either of oligodendroglial or of astrocytic origin (see below).16 In the past about 5% of all glial tumors were considered oligodendroglial, a number that increased to 20% in recent publications.3 Histological criteria for distinguishing OD from astrocytoma are subjective, with a significant interobserver variability.17 Coons et al suggested that the classic histological features described above are not sufficient for the
Diagnosis and management of oligodendroglioma diagnosis of OD and, therefore, OD may often be misdiagnosed as anablastic astrocytoma (AA) or glioblastoma multiforme (GBM).3 They suggested that when using histological features to diagnose OD, special emphasis should be given to identifying other signs, such as microgemistocytes, gliofibrillary oligodendrocytes, and protoplasmic astrocytes, which all may suggest the tumor to be of oligodendroglial origin. The changes and widening of criteria proposed by these and other authors has greatly increased the percentage of tumors that are considered oligodendroglial. Nevertheless, a loosening of the histological criteria for an OD diagnosis will result in a more heterogeneous tumor population in terms of genetic lesions and—more importantly—their sensitivity to treatment.
Genetic Lesions in OD The most frequent chromosomal lesions in OD are allelic loss of the 1p and 19q loci.4,18 The incidence of either 1p or 19q chromosomal deletions in OD is approximately 75%, and that of combined loss of 1p and 19q is 60% to 70%.5,17 AODs usually have additional chromosomal deletions; in particular loss of heterozygosity for 9p and/or deletion of the CDKN2A gene occurs in 33% to 42% of AODs, and deletions on chromosome 10 occur in 19% to 25% of cases.18 Studies combining morphology and genetic analysis found that oligodendroglial tumors with a classical histological appearance (perinuclear halo, chicken-wire vascular pattern) are associated with the loss of 1p/19q, whereas in tumors with an atypical appearance, often other chromosomal abnormalities are found (eg, TP53 mutations).7,19 However, some atypical ODs have 1p/19q loss of heterozygosity and some typical OD tumors do not show these lesions. Maintz et al have provided evidence that OAs are not mixed tumors at all, but rather tumors of either oligodendroglial or astrocytic origin.16 In this study, OA fell into two categories: those that had 1p and 19q deletions, typical of ODs, and those that had TP53 mutations, typical of astrocytoma. In AOD both the loss of 10q and the amplification of the epidermal growth factor receptor (EGFR) were found inversely related to 1p/19q loss, and were associated with poor chemosensitivity and short survival.20 The mutually exclusive occurrence of 1p/19q loss in one set of tumors and TP(53) mutations, EGFR amplification, 10q loss, or PTEN mutations in other tumors suggests that these neoplasms are derived from different precursor cells with a different genetic mechanism of disease. Analysis of the localization of the tumor and its relation with the genotype further support this assumption. ODs with loss of 1p/19q rarely arise in the temporal lobe. Similarly, oligoastrocytoma located solely within the temporal lobe have significantly more frequent TP53 mutations without 1p/19q loss.21 The marked differences in the response to treatment and the prognosis of these genetically diverse tumors gives further support for this assumption.
647
Prognosis in the “Pre-genetic” Era Pure oligodendroglial tumors have a better prognosis than astrocytic tumors of the same grade; the prognosis of mixed oligoastrocytoma is in between these histologies.15,22-24 One study (albeit with small numbers of ODs) reported that in 285 patients with supratentorial anaplastic glioma, patients with AOD had the longest median survival time (5.3 years) compared with patients with GBM, AA, and AOA.25 Before results of chromosomal analysis of OD became available, the single most important prognostic factor for progression-free and overall survival in patients with OD was the pathologic tumor grade. Patients with low-grade ODs (WHO grades I and II) have a median survival of 10 to 17 years and a 5-year survival rate of approximately 75%.26,27 In addition, patients with low-grade ODs or OAs experience longer overall survival compared with patients with low-grade astrocytoma (13 v 7.5 years, P ⫽ .003). Patients with AODs have a substantially worse prognosis, with reported median survivals of 4 to 5 years and a 5-year survival rate of only about 40%.28 The prognosis of mixed OA lies between the prognosis of OD and pure astrocytic tumors, perhaps because these tumors are in fact either astrocytic or oligodendroglial (see below). Various anaplastic histological features, including cell density, the number of mitoses (including Ki-67 labeling index), and the presence of endothelial hyperplasia, necrosis, or pleomorphism have been identified as important prognostic factors for AOD.29,30 In tumors that carry all anaplastic elements, the prognosis is almost as poor as for GBM, with a median survival time of about 18 months.31 Known clinical prognostic factors are the age of the patient, the performance status, and the type of presentation. The presence of enhancement on neuro-imaging has also been found to be of prognostic significance, and probably reflects endothelial proliferation.30
Prognosis in the “Genetic” Era Recent studies have shown that the presence of loss of 1p and 19q is a more relevant prognostic factor than either histology or clinical characteristics. The evidence is becoming increasingly convincing that OD with 1p/19q loss constitutes a different biologic entity with a more favorable clinical course and better response to treatment than OD or OA without these genetic lesions.17 One study found that loss of 1p and 19q were both independent predictors of survival.32 Virtually all ODs with combined loss of 1p and 19q respond to PCV chemotherapy, and the presence of 1p deletions in oligodendroglial tumors is associated with longer progression-free survival after radiotherapy or chemotherapy.7,33,34 Furthermore, ODs with 1p/19q loss tend to have a more indolent behavior before initiation of treatment compared to tumors without 1p/19q loss; they are rarely located in the temporal lobe and they have a more homogeneous enhancing pattern.6,7,21 In contrast, the presence of EGFR amplification, loss of
M.J. van den Bent
648 10q, PTEN mutations, and CDKN2A are associated with a worse prognosis.6,33,35 These findings appear to be related to either the presence of anaplastic histological features or to an astrocytic lineage.18,20 Taken together, these findings show that the genotyping of OD has resulted in the emergence of a specific group of tumors with OD morphology, a more favorable prognosis, and a better response to treatment. Since all the evidence indicates that the genotype characterizes these tumors better than conventional histology, genotyping of tumors with oligodendroglial elements is likely to become a standard diagnostic procedure.36 A first example and proof of principle is the recently published study by Nutt et al, which showed that gene expression profiling of a set of histologically nonclassic glioma proved superior in predicting prognosis than classical pathology.37 The role of the above-described clinical and histological factors needs to be reinvestigated, taking the genotype of the tumor into account.
Treatment: When to Initiate? Most randomized phase III trials on the treatment of glial tumors included both astrocytic and oligodendroglial tumors. No results are available from trials that limited accrual to oligodendroglial tumors, and most data on the treatment of OD are derived from retrospective surveys with known inherent pitfalls. An exception is the many chemotherapy studies devoted to oligodendroglial tumors, but these are uncontrolled single-arm studies. The best treatment policy for young patients with presumed low-grade glioma on neuro-radiological imaging presenting with seizures only constitutes an ongoing controversy. As many of these patients may remain stable for protracted periods without any treatment, many physicians tend to defer treatment until clinical or radiological progression. An important rationale for the deferral of radiotherapy is the concern that early treatment including radiotherapy may in fact contribute to the cognitive deficits in patients with low-grade glioma.38,39 This assumption was recently questioned by a large Dutch study, which showed that only a large radiotherapy fraction size (⬎2 Gy) and the use antiepileptic drugs were associated with cognitive deficits in lowgrade glioma patients.40 Whether limited-field radiotherapy in fractions of 1.5 to 1.8 Gy increases long-term cognitive deficits in low-grade glioma patients is at present unclear. Advocates of early intervention in patients with presumed low-grade glioma (including histological verification of the nature of the process) also point to the fact that up to 30% of patients with nonenhancing low-grade glioma-like lesions have an anaplastic tumor. They recommend always obtaining histological proof in cases of a presumed low-grade glioma.11,12,41 There is general agreement that in patients with enhancing lesions, evidence of mass effect, focal neurologic signs or symptoms, or signs of increased intracranial pressure, treatment should be initiated without delay.
Surgery Surgery for glioma serves three goals: verification of the nature of the lesion, relief of signs and symptoms in patients suffering from a lesion with mass effect, and improvement of the prognosis. The relevance of the first two are generally acknowledged, but so far no trial has given evidence beyond reasonable doubt that extensive surgery improves survival compared to less extensive resections. All available data both for low-grade glioma and high-grade glioma come from retrospective or post hoc analyses; no randomized controlled trial has evaluated the effect of resection on survival in glioma as the primary endpoint. A drawback of these retrospective studies is that superficial and small tumors are more likely candidates for extensive resections. In contrast, deep-seated lesions, large tumors, or tumors with growth into midline structures may confer a worse prognosis regardless of the extent of resection. Such patients will never undergo nearcomplete resections.23 One uncontrolled study found that complete resection in low-grade OD is associated with long disease-free intervals.42 In another study, patients who underwent subtotal resection had improved survival, although many of these patients were young and had low-grade tumors (which are favorable prognostic factors).24,43,44 In contrast, other studies have shown that gross total resection in patients with OD provided no survival benefit.30,45 Nonetheless, given the potential clinical benefits it is considered standard treatment to resect glioma regardless of histology and tumor grade as extensively as safely possible.
Radiotherapy Randomized trials in high-grade glioma have demonstrated that adjuvant radiotherapy provides significant yet modest improvements in survival.46 In low-grade glioma, the benefit of early radiation therapy as compared to radiotherapy at the time of progression resulted in a modest improvement of time to progression without affecting overall survival.47 However, no trial has specifically addressed anaplastic OD. Some retrospective studies support postoperative radiation therapy in patients with OD.48,49 Others found survival benefit of radiotherapy in patients with OD, mainly in the subgroup of patients with neurological deficit or for whom surgery was limited to biopsy or partial surgery. Other studies have reported no benefit of postoperative radiation in the treatment of OD at all.27,43,50,51 In the absence of randomized trials, one may withhold radiotherapy until tumor progression in younger patients in good clinical condition with a low-grade OD who have undergone a complete or almost complete resection. In contrast, patients with large, unresectable, or incompletely resected tumors, focal deficits, anaplastic tumors, or enhancing lesions should be treated including radiotherapy without delay. Following the randomized dose-finding EORTC and North Central Cancer Treatment Group (NCCTG) trials, in low-grade OD a cumulative dose of 50 to 54 Gy should be given in fractions of 1.8 Gy to limit long-term cognitive se-
Diagnosis and management of oligodendroglioma
649
Table 1 PCV and PCV-I (intensified) Chemotherapy Drug CCNU Day 1 Vincristine Day 8, 29 Procarbazine Day 8-21
Standard-Intensity PCV
Intensified PCV
110 mg/m2 orally 1.4 mg/m2 IV 60 mg/m2 orally
130 mg/m2 orally 1.4 mg/m2 IV 75 mg/m2 orally
may be less responsive are most likely due to the low frequency of combined 1p/19q loss in OA. Following the documentation of significant activity of temozolomide in recurrent glioma, this alkylating agent was investigated in several trials on recurrent OD (Table 3). So far, only one trial investigated first-line temozolomide in recurrent OD.9 This trial reported a 54% response rate with 40% of patients free from progression at 12 months, which is in the range of the 65% to 70% response rate and 50% progression-free survival at 12 months obtained with the PCV regimen. In second-line therapy after prior PCV (either given adjuvant or at first recurrence), 20% to 30% of patients responded to temozolomide with 30% to 50% and 10% to 30% of patients free from progression at 6 and 12 months, respectively.57-59 A fourth trial involved predominantly patients who had responded favorably to PCV (response rate to firstline PCV, 83%).60 The objective response rate to temozolomide in this trial was 44%, with 50% and 25% of patients free from progression at 6 and 12 months. Clearly these results indicate that better patient selection results in a more favorable outcome. These results have raised the question which treatment is to be preferred as first-line therapy, temozolomide or PCV? So far no results of a head-to-head comparison are available. A major advantage of temozolomide is the good tolerability, with generally modest myelosuppression and easily controllable nausea/vomiting being its major side effects. In this respect, temozolomide compares favorably to the PCV regimen.
NOTE. Cycles to be repeated every 6 to 8 weeks, for a maximum of six cycles. Abbreviation: IV, intravenous.
qualae.52,53 In high-grade OD, 60 to 65 Gy in 30 to 35 fractions should be given. More and more clinicians tend to replace radiotherapy by upfront chemotherapy, but clinical data to support this change are absent (see below).
Chemotherapy for Recurrent OD Most data on chemotherapy in OD were obtained from studies in recurrent tumors. Initially, most studies investigated PCV chemotherapy (Table 1), while recent publications have focused on the new alkylating agent temozolomide. No clear explanation is yet available for the favorable response to chemotherapy of oligodendroglial tumors as compared to astrocytic tumors. There are indications that the nuclear enzyme alkyltransferase, which mediates at least a part of the cell resistance to alkylating agents, is less expressed in OD.54 However, it is unlikely that this explanation accounts for the entire difference in sensitivity to chemotherapy between astrocytic tumors and ODs. It also does not explain why ODs with combined loss of 1p and 19q are in particular sensitive to chemotherapy. Approximately two thirds of patients respond favorably to PCV chemotherapy (Table 2). The time to progression in these patients is generally 12 to 18 months, but occasionally much longer than 24 months.1,2,55 This benefit has made the PCV schedule standard treatment for patients with recurrent OD and OA following radiotherapy, regardless of the grade of the tumor. However, the cumulative hematological toxicity and gastrointestinal side effects associated with standard PCV often limit the duration of its administration. Some of these studies also explored the Intensified PCV regimen (see Table 1), which was found to be considerably more toxic (especially hematological and general side effects, including malaise and weight loss) without evidence of superior results.2,56 In the absence of superior results, this regimen cannot be recommended. Several of these reports that suggested OA
Other Agents Paclitaxel, irinotecan, carboplatin, and etoposide plus cisplatin have been investigated as second-line chemotherapy in patients with AOD.61-64 Except for the small numbers investigated with cisplatin and etoposide (with four of 10 patients responding), the response rates are low (in the 10% to 15% range) with one third of patients free from progression at 6 months and virtually all patients progressing by 12 months. A drawback of some of these agents (paclitaxel, irinotecan) is that they are metabolized through the CYP 3A4 cytochrome, which implies that their metabolism may have been induced by enzyme-inducing anti-epileptic agents. This metabolic route limits the role of these cytotoxic agents in glial tumors (but may also have affected the observed activity in the above-mentioned trials).
Table 2 Response Rates and Median Time to Progression in Three Studies of PCV Chemotherapy in Recurrent or Newly Diagnosed Oligodendroglial Tumors Response Rate (%) Reference van den Bent et al2 Soffietti et al55 Cairncross et al1 Total (n)
n
CR
PR
SD
PD
52 26 24 102
17% 12% 38% 21
46% 50% 38% 46
19% 31% 17% 22
17% 8% 8% 13
MTP for CR/PR/SD (mo) 25/12/7 45/16/24 25/16/7
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; MTP, median time to progression.
M.J. van den Bent
650
Table 3 Results of First- and Second-Line Chemotherapy With Temozolomide in Recurrent Oligodendroglioma
Study EORTC 269719 van den Bent et al57 EORTC 2697258 Constanza et al59 Chinot et al60
n
1st/ 2nd line
Response to PCV (%)
n
(%)
n
38 27 28 34 48
1st 2nd 2nd 2nd 2nd
NA 38 50 50 83
20 7 7 9 21
(53) (26) (28) (26) (44)
12 8 9 15 19
OR
(%)
Median PFS (mo)
6-mo PFS (%)
12-mo PFS (%)
(32) (30) (30) (44) (40)
10.1 4 3.7 6 6.7
71 44 29 48 50
40 27 11 30 25
SD
Abbreviations: 1st, 2nd line, first- or second-line chemotherapy; OR, objective response (complete or partial response); SD, stable disease; PFS, progression-free survival.
In 24 patients treated with second-line PCV for recurrent OD after first-line temozolomide, 17% of patients achieved an objective response and 50% of patients remained free from progression for at least 6 months.65 The median time to progression in the 15 responding and stabilized patients was 10 months, which implies that PCV is an option for treatment failures after first-line temozolomide. This study and the studies on second-line temozolomide show that whatever sequence of chemotherapy regimen is used, the response rate is lower to either temozolomide or PCV given as second-line therapy after prior therapy with the other regimen.
High-Dose Chemotherapy With Autologous Bone Marrow Rescue Both in newly diagnosed OD and in recurrent disease, highdose thiotepa chemotherapy with autologous stem cell support has been investigated in patients responding to PCV chemotherapy. In patients with recurrences after prior radiotherapy this approach was believed to be too toxic. Although some durable responses were observed (20 of 38 patients were treated with the high-dose regimen, and six of them remained free from progression at 2 years), the authors concluded that this was a disappointing strategy with a median overall progression-free survival of only 20 months.66 In newly diagnosed patients this approach appears better tolerated, with an estimated median progression-free survival of 69 months.67 Out of a total of 69 patients, 37 received the high-dose chemotherapy part of the study; in these patients, radiotherapy was deferred until progression. The obvious limitation to this study design is its uncontrolled nature. In the absence of a comparator, no conclusions can be drawn except for the expected feasibility of the approach. In view of generally limited role of myeloablative chemotherapy in solid tumors, it is unlikely that small phase II studies with their inherent selection bias will determine the value of this approach.
Adjuvant Chemotherapy The value of adjuvant chemotherapy in high-grade glioma was finally shown in a large meta-analysis which demonstrated that this therapy increases the 1- and 2-year survival rates by approximately 5% from 40% to 46% and
from 15% to 20%, respectively.68 As this benefit is rather small and no data exist on the influence on the quality of life of adjuvant chemotherapy, the real value of adjuvant chemotherapy in high-grade glioma remains a matter of debate. The sensitivity to chemotherapy of recurrent OD has renewed interest in the role of adjuvant chemotherapy for this subset of glial tumors. In a chemotherapy-sensitive tumor one would expect a larger benefit from adjuvant chemotherapy, but this does not have to be the case if a good salvage treatment exists. Attempts to evaluate whether patients with AOD in particular benefited from adjuvant chemotherapy failed to provide support for this assumption.69 This may well be more a matter of best timing of the chemotherapy, in the adjuvant setting or at the time of recurrence. An often forgotten advantage of chemotherapy at the time of recurrence and in the presence of measurable disease is that this strategy allows the discontinuation of treatment if the tumor proves to be chemotherapy-resistant, thus avoiding an inactive treatment. At present two ongoing trials (in the EORTC and RTOG) are investigating the value of adjuvant or early chemotherapy in OD.
Up-front Chemotherapy in Newly Diagnosed AOD A new development is the treatment of newly diagnosed OD with up-front chemotherapy strategies, with or without subsequent radiotherapy.70 Although this approach may seem appealing, in the absence of randomized trials no conclusions can be drawn from the limited data so far published. The key issue here may well be the involved toxicities, and one should ask for the rationale why a local treatment delivered with modern radiotherapy techniques should be abandoned for a treatment with systemic toxicity. It is clear that with up-front PCV or temozolomide chemotherapy good responses are obtained, but whether the overall outcome is as good as that following radiotherapy is unknown. It is also unclear whether in the presence of a favorable response to chemotherapy, radiation therapy can be withheld. In view of the expected long overall survival in OD, these questions may be more a matter of side effects and active salvage regimens, rather than of progression-free survival. Phase III trials are obviously needed to answer these questions.
Diagnosis and management of oligodendroglioma
Up-front Chemotherapy in LowGrade OD The clinical data regarding chemotherapy for low-grade OD are limited but suggest these tumors are as sensitive as their anaplastic counterparts.56,71-73 Both the PCV schedule and temozolomide have been investigated. Even tumors without loss of 1p/19q and mixed oligoastrocytoma may respond, and responses may last for a considerable interval of time. In the absence of comparative trials, this may be an appropriate choice for patients with large OD lesions (oligodendroglial “gliomatosis cerebri”) in order to avoid whole-brain radiotherapy in patients with a favorable prognosis for long-term disease-free survival. Whether this approach is also useful in patients with smaller lesions who are candidates for radiation therapy with limited fields may again be more a matter of the side effects. As noted earlier, it is questionable whether it is rational to try to avoid limited-fields radiation therapy of a small brain lesion, delivered by modern irradiation techniques, by replacement with prolonged systemic chemotherapy.
Conclusion Some 15 years after the initial observation of the sensitivity of OD to PCV chemotherapy, it is now clear that the chemotherapy-sensitive OD is characterized by a specific genotype showing combined loss of 1p and 19q. Although this genotype identifies the more treatment-sensitive tumors, no real treatment improvement has been achieved since the initial discovery of the sensitivity to the PCV regimen, and all patients still die of recurrent disease. The introduction of temozolomide does not improve treatment efficacy, with its real advantage being the better tolerability. The obvious conclusion is that with a superior identification of treatment-sensitive tumors we still lack more active therapies and a more fundamental knowledge of the driving force behind the oligodendroglial tumor. The drawback of a better identification of treatment sensitive OD is the fact that we are dealing again with a rather rare disease that requires multi-institutional trials to achieve further progress.
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