Multidisciplinary management of adult anaplastic oligodendrogliomas and anaplastic mixed oligo-astrocytomas

Multidisciplinary Management of Adult Anaplast!c Oligodendrogliomas and Anaplastlc Mixed Oligo-Astrocytomas Glenn S. Bauman and J. Gregory Cairncross Once thought to be rare, oligodendroglial tumors might actually represent up to 25% of primary glial neoplasms. In recent years, the histologic criteria for the diagnosis of oligodendroglioma have been broadened to include most small cell, monomorphic glial neoplasms. These refinements have led to an increased recognition of oligodendroglial neoplasms, but uniform definitions of pure versus mixed oligodendroglioma as well as the criteria for high-grade (anaplastic) versus low-grade tumors remain elusive. From a prognostic standpoint, the presence of an oligodendroglial component in a malignant glioma predicts longer survivals

times for patients treated with surgery, and radiation therapy with or without chemotherapy. High rates of response to PCV (procarbazine, CCNU and Vincristine) chemotherapy also have been noted among patients with anaplastic oligodendroglial neoplasms. Ongoing prospective trials seek to clarify the role of PCV chemotherapy when added to radiation therapy and surgery. In addition, the role of molecular markers as diagnostic aides and guides to therapy and prognosis are being explored for patients with pure and mixed anaplastic oligodendroglial tumors. Copyright 9 2001 by W.B. Saunders Company

ow-grade oligodendroglial neoplasms frequently present with seizures in the younger adult. Occasionally, patients might present with symptoms of mass effect or with nonconvuls.ive symptoms of long duration. Typically, supratentorial and frontal in location, these slow growing neoplasms present (on computed tomography [CT]) as a low-density mass, sometimes with calcification and minimal or no enhancement. On magnetic resonance imaging (MRI), the appearance might vary, but a honeycomb or stippled pattern is considered characteristic, and, unlike CT, calcification might be difficult to appreciate5 Enhancement is usually absent. High-grade or anaplastic oligodendroglial tumors might appear in a middle-aged adult and are more likely than low-grade oligodendrogliomas to present with a short duration of symptoms and either focal neurologic deficits or symptoms of mass effect. 2-4 Patients with known low-grade oligodendroglial neoplasms can present with malignant transformation of their tumor while under surveillance. Such malignant transformation can be signaled by clinical deterioration, new enhance-

ment, or progressive growth on serial imaging. E n h a n c e m e n t on C T or MRI, either punctate, patchy uniform, or ring, is indicative of a more aggressive tumor (Fig 1). In the grading system proposed by Daumas-Duport, enhancement on imaging is regarded as the macroscopic equivalent of microvascular proliferation, and defines a malignant subset of oligodendroglial tumors. 5. Clinical factors, such as older age and poor performance status, also are associated with a more aggressive histology or behaviour. Barker et al 6 noted an increasing incidence of anaplasia on biopsy with increasing age in a group of patients with a preoperative MRI consistent with a lowgrade glioma. In a recursive partitioning analysis, Bauman et al 7 noted particularly poor survival among those patients with low-grade gliomas with older age and poor performance status or older age and contrast enhancement.

L

From the Departments of Oncology (GSB, JGC) and Neurological Sciences ~[GC), Unviersity of Western Ontario, and the London Regional Cancer Center (GSB, JGC), London, Ontario, Canada. Address reprint requests to Glenn Bauman, MD, London Regional Cancer Centre, 719 CommissionersRoad East, London, Ontario, Canada, N6A 4L6. Copyright @ 2001 by W.B. Saunders Company 1053-4296/01/1102-0010535.00/0 doi:l O.l O53/srao.2001.21429

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Histopathology and Grading The classic oliogodendroglial tumor is characterized by a moderately cellular collection of cells with round nuclei and perinuclear halos (socalled fried egg appearance) accompanied by a delicate branching (chicken wire) vasculature and calcification, Secondary structures ot" Scherer (perineuronal satellitosis, spread along white m a t t e r tracts, subpial spread, and perivascular spread) are commonly seen. 8 Using this classic definition, Mork et al, 9 in a study of the Cancer Registry of Norway, f o u n d oliogodendrogliomas represented 4.2% of all primary brain tumors.

Seminars in Radiation Oncology, Vol 11, No 2 (April), 2001: pp 170-180

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However, it is becoming recognized that oligodendroglial tumors might in fact represent a much larger percentage of diffuse gliomas. Coons et al 1~ and Daumas-Duport et al 2,5 noted that a significant number of diffuse fibrillary astrocytomas are actually composed of neoplastic oligodendroglial cells entrapped in a background of axons and fibrillary reactive gliosis. Daumas-Duport, 2,5 in a review of 153 pure oligodendrogliomas, noted two patterns of growth: type III, composed of isolated infiltrating tumor cells, and type II, comprised of a solid t u m o r tissue component surrounded by isolated infiltrating tumor cells. Type III tumors were more likely to be misdiagnosed as diffuse fibrillary astrocytomas and also were associated with more indolent growth and longer survival. Type II tumors were more likely to show focal neurologic deficits, contrast enhancement, and neovascularization and were associated with shorter survivals. Coons et aP ~ studied the interobserver concordance of the classification and grading of primary gliomas and noted difficulty in distinguishing diffuse astrocytomas from oligodendrogliomas and oligo-astrocytomas.' They found that a classical oligodendroglial cytology or vasculature was not required for the diagnosis of oligodendroglial tumors and emphasized the importance of recognizing microgemistocytes, gliofibrillary oligodendrocytes, or protoplasmic astrocytes as clues to an oligodendroglial component. They noted a tendency to misclassify oligodendroglial tumors as anaplastic astrocytomas or glioblastoma multiforme. With the revised criteria, they estimated that up to 25% of gliomas might be, in fact, oligo-dendrogliomas or mixed oligoastrocytomas, t~ The distinction between pure oligodendroglioma and mixed oligo-astrocytoma presents another diagnostic dilemma. Coons et aP ~ found difficulties with interobserver concordance in the definition of mixed oligodendrog!ial-astrocytoma tumors. Dit~ficulties were especially evident with

Figure 1. (A) MRI T1 gadolinium-enhanced coronal view of a right temporal-parietal anaplastic oligodendroglioma showing patchy enhancement. (B) MRI T1 gadolinium-enhanced coronal view of" tumor post subtotal resection. Residual contrast enhancing tumor in the deep superior and medial resection cavity. (C) MRI T2 axial view of tumor post subtotal resection. Residual tumor and edema surrounding the surgical cavity.

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high-grade tumors in which pleomorphism obscured typical cytologic features of the oligodendroglial component. Such tumors were often labeled anaplastic astrocytomas or glioblastomas. Furthermore, in tumors with obvious and predominantly oligodendroglial elements, there was difficulty in defining the amount of fibrillary or gemistocytic astrocytic elements necessary to assign a diagnosis of mixed oligo-astrocytoma. They settled on an operational definition of oligo-astrocytoma "as tumors with well-developed fibrillary and/or gemistocytic components association with an obvious oligodendroglial component." Although there is general agreement that cytologic atypia, mitotic activity, microvascular or endothelial proliferation, and tumor necrosis are features of high-grade tumors, the importance of other markers of malignancy are unclear. Higher indices of proliferation such increased MIB-1, Ki67, and proliforating cell nuclear antigen PCNA have been associated with worse outcome in patients with oligodendroglial tumors. 4,11,12 Other markers, such as vimentin positivity or P53 protein over-expression also have been associated with worse outcome in anaplastic oligodendrogliomas.4,11 These additional features of malignancy are not included in official grading systems for oligodendrogliomas, of which there are several (Table 1). Four-tier grading systems include those of Kernohan, ~3 Smith ~4 and the Ste-Anne/ Mayo scheme. ~5 Within the 4-tier schemes, poor resolution within the intermediate grades has been reported. Kros, ~G in a comparison of the Kernohan and Smith grading schemes, suggested that the Kernohan grade IIflII and Smith B/C grades could be collapsed (Modified Smith, Table 1) to yield a simpler 3-tier scheme with better prognostic capacity. Likewise, the Ste-Anne/ Mayo scheme is often collapsed into a 2-tier scheme (grades I/II versus III/IV) to achieve prognostic significance, t7,1a The current World Health Organization (WHO) system uses a 3-tier grading scheme. 19 Recently, Daumas-Duport 5 reported a 2-tier scheme based on the presence of microvascular proliferation or contrast enhancement. The grading schemes also differ in the assignment of grade, with the Smith and StAnne/Mayo using a point system to assign grade, whereas the Kernohan and WHO systems relying more on qualitative descriptions of malignancy. Currently, the W H O system is the most commonly used scheme for grading pure oligodendro-

gliomas or mixed oligo-astrocytomas. Typically, tumors with features of anaplasia (mitoses, pleomorphism, atypia) and a predominantly oligodendrogIial component are termed anaplastic oligodendrogliomas. Within the WHO system, tumors with pseudopalisading and necrosis are termed W H O grade IV/glioblastoma multiforme. In the grading of mixed tumors, anaplasia within either the astrocytic or oligodendroglioma components might result in the diagnosis of anaplastic mixed glioma. It is not clear what minimum oligodendroglial component is required to diagnose an anaplastic mixed glioma. Donahue et aF ~ noted an improvement in survival when any oligodendroglial component was present compared with patients with pure anaplastic astrocytic tumors. Although the presence of an oligodendroglial component might be a favorable prognostic factor, the proportion of otigodendroglial components also might be important. Improved survival between patients with pure anaplastic oligodendrogliomas versus anaplastic mixed oligo-astrocytomas 21,99 as well as oligodendroglioma-predominant tumors has been noted, la The current North American phase III trial comparing radiation alone with induction PCV. followed by radiation for anaplastic oligodendrogliomas (Radiation Therapy Oncologdz Group [RTOG] 9402; Intergroup lINT] 0149) uses the following criteria for eligibility: at least 25% oligodendroglial component and 2 or more anaplastic features (one of which must be frequent mitoses or endothelial proliferation). Tumors are further stratified as moderately anaplastic (2 to 3 features of malignancy present: high cellularity, nuclear pleomorphism, frequent mitoses, vascular proliferation, or necrosis) or highly anaplastic (4 to 5 features present).

Spectrum and Significance of Molecular Alterations in Oligodendroglioma and Mixed Glioma Recently, molecular characterization of oligodendroglial tumors has been reported. Smith noted a highly significant correlation be_tween lp loss of heterozygosity; 19q loss of heterozygosity and combined loss of lp and 19q with an oligodendroglial phenotype in an analysis of t62 patients with diffuse gliomas. 23 Within the oligodendroglial population, they noted a prolongation in overall survival among those patients with combined loss

Adult Anaplastic Oligodendrogliomas

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of lp and 19q even after adjusting for effects of patient age and tumor grade. Likewise, Cairncross 24 noted an association between radiographically-defined response to chemotherapy and longer survivals for those patients with anaplastic oligodendroglial tumors exhibiting specific molecular changes. Loss of lp heterozygosity was strongly associated with response to chemotherapy and improved survival. Loss of 19q heterozygosity was associated with improved survival but not improved response to chemotherapy. Combined loss of heterozygosity on lp and 19q was associated with a high response rate to chemotherapy and improved survival compared with patients with preserved lp or 19q. Finally, CDKN2A gene deletion was associated with significantly shorter survival. Allelic loss of chromosomes 10q and TP53 gene mutation were not associated with survival or response rate in this series. Molecular markers such as lp and 19q loss might improve the ability to diagnose oligodendroglial tumors objectively, to select therapies for patients based on anticipated response, and to predict prognosis.

Role of Surgery Surgery has several roles in the management of patients with anaplastic oligodendroglial tumors. Biopsy or resection will provide tissue for classification, grading, and, increasingly, for molecular characterization of the tumor. In symptomatic patients, surgical debulking can relieve symptoms of mass effect or neurologic deficits and can improve seizure control. 95 In patients with lowgrade oligodendroglial tumors, complete surgical removal can be associated with long disease-free intervals and might permit safe deferral of adjuvant radiotherapy. Berger et al, 26 in a review of the literature, noted a trend towards improvement in survival for patients with low-grade tumors and near-total or gross total resections. Karim et al, 27 in a prospective trial of 2 different adjuvant radiation doses for patients with lowgrade gliomas, noted improved survivals for patients undergoing more extensive resections. For patients with high-grade malignant glioma, larger surgical resections have been associated with improved survival, especially in the presence of mass effect. 25,28,29 The data examining the benefit of surgery among patients with anaplastic oligodendroglial tumors is less robust. Dehghani 4

noted an improved survival for patients treated with total (73% 1-year survival) versus subtotal (25% 1-year survival) resection among patients with anaplastic oligodendrogliomas treated with surgery and/or radiation. Other retrospective series 4,12,1a,~~176 found extent of resection to be an independent prognostic factor on multivariate analysis of patients treated for oligodendroglioma or oligo-astrocytoma. In view of the possible clinical benefits and improved characterization possible with larger tumor samples, a maximum safe surgical resection would seem advisable for patients with suspected or biopsy-proven anaplastic oligodendroglial tumors.

Role of Radiation Therapy Surgery followed by radiation therapy is the standard of care for patients with malignant gliomas. 3t Randomized trials comparing radiation with best supportive care after surgery and radiation plus chemotherapy to chemotherapy alone have confirmed a modest (6 to 8 month) improvement in median survival with adjuvant radiation and a small (approximately 10%) number of longerterm survivors. 32,33 A dose-response analysis of the early Brain Tumor Cooperative Group trials, as well as randomized trials by the MRC and Scandinavian Brain Tumor Cooperative Group, confirmed that a dose fractionation scheme of approximately 60 Gy in 1.8 to 2.0 Gy/d fractions was associated with improved survival compared with lower-dose schemes. 31 Trials of altered fractionation schemes (accelerated fractionation or hyperfractionation) have not shown an improvement in survival over conventionally fractionated radiotherapy. 34-$6 Dose escalation with conventional radiotherapy techniques in high-grade or low-grade gliomas have shown increased toxicity and no improvement in survival. 27,37 Dose escalation using 3-dimensional (3D) conformal external beam radiotherapy or radiosurgery are the subject of ongoing RTOG trials. Previous randomized trials of interstitial brachytherapy in malignant glioma have not shown imp~roved survival with cumulative doses approaching 120 Gy, -~a so it remains to be seen if escalation with these strategies will be more successful for patients with anaplastic oligodendroglial tumors. The value of radiation adjuvant to surgical resection for patients with anaplastic oligoden-

Adult Anaplastic Oligoden~rogliomas

drogliomas has not been the subject of randomized controlled trials. Retrospective reviews of patients with anaplastic oligodendrogliomas have tended to suggest improved survival with the addition of radiation to surgery versus surgery alone; however, these findings did not always reach statistical significance.4, 30 Retrospective reviews of R T O G trials in malignant glioma have identified a substantial number of patients with oligodendroglial tumors treated with surgery and radiation. Median survival times of these patients were noted to be substantially better than those with pure astrocytic tumors. In a review of the R T O G 83-02 trial, Donahue 2~ noted a median survival of patients with anaplastic pure or mixed oligodendrogliomas of 7.3 years compared with the median survival of 3.4 years for pure anaplastic astrocytomas. In multivariate analysis, an oligodendroglial component was an independent prognostic factor for survival as was age and extent of surgery. In a similar analysis of the same trial, 7% of patients included with a diagnosis of glioblastoma had oligodendroglial elements; 3-year survival for these patients was significantly longer (34% versus 4%) than those patients with glioblastoma and no oligodendroglial elementsY ~ Similar findings have been noted by Winger, 21 who noted patients with anaplastic oligodendroglioma had a m e d i a n survival of 278 weeks compared with 63 and 32 weeks for patients with anaplastic astrocytoma (AA) or glioblastoma (GBM), retrospectivelyY 1 O f interest, they also noted the survival of patients with anaplastic mixed oligo-astrocytoma to be similar to that of the pure anaplastic astrocytoma (median survival 57 weeks). Likewise, in a population of/patients treated with surgery, radiation, and chemotherapy, patients with pure (> 99%) anaplastic oligodendroglioma had an improved median survival (five-year survival, 65%) compared with patients with smaller components of oligodendroglial cells (five-year survival, 25%). ~2 However, others have noted the survival of anaplastic mixed oligo-astrocytomas to be similar to that of pure anaplastic oligodendrogliomas (Table 2).39,4o Genetic analysis of mixed anaplastic oligodendrogliomas sometimes shows a genetic signature more consistent with a tumor of the astrocytic lineage. Genetic heterogeneity in the setting of a histologically mixed tumor might account for the variability,.in outcome between series.

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Little retrospective data exists regarding radiation dose or volume effects for anaplastic oligodendrogliomas or mixed oligo-astrocytomas. Treatment for patients with anaplastic oligodendroglial tumors is typically planned with doses and volumes similar to those for glioblastoma or anaplastic astrocytomas. Malignant gliomas might infiltrate large distances into the brain, and serial biopsies through the edematous region surrounding the contrast-enhancing volume on CT or MRI have revealed a gradient of tumor cells infiltrating into the normal brain. 4~ This infiltrative capacity must be balanced against the potential morbidity of large-volume irradiation within the central nervous system (CNS) and the failure patterns noted clinically. 42 Analysis of failure patterns in patients with malignant gliomas have shown that the epicenter of recurrence is most frequently within 1 to 2 cm of the original contrast-enhancing t u m o r . 43,44 For patients with malignant glioma, the gross tumor volume (GTV) usually is delineated by the preoperative contrast-enhancing volume on the CT/MRI, and the clinical target volume (CTV) is usually delineated by the edematous volume on CT/MRI with a 2-cm margin or the GTV with a 3- to 4-cm margin. In trials for malignant astrocytomas (AA or GBM), the R T O G specifies a 2-stage technique with the initial volume (CTV1) being defined as the edematous volume + 2 cm (treated to 46 Gy) and boost volume (CTV2) as the GTV + 2.5 cm (treated for an additional 14 Gy for a total dose of 60 Gy). Within the current Intergroup study (RTOG 9402), patients with anaplastic oligodendroglioma are treated in a 2-stage fashion, but based on the postoperative tumor volume. CTV1 is defined as the edematous volume on the postoperative T2-weighted MRI with a 2-cm margin to block edge. This volume is treated to 5,040 cGy in 28 fractions. The boost volume (CTV2) is the postoperative contrast enhancing tumor on the gadolinium-enhanced Tl-weighted MRI with a 1-cm margin. This volume receives an additional 900 cGy in 5 fractions, for a total dose of 5,940 cGy in 33 fractions (Fig 2). This treatment scheme represents a departure from usual treatment plan~ ning practices for malignant gliomas in which the preoperative edema volume and contrast enhancement is typically targeted. An analysis of patterns of failure of patients treated on the R T O G 9402 will delineate whether tumor recur-

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Table 2. Selected Series Anaplastic Oligodendroglial Tumors

Reference

Year

N

Smith 14

1983

Mork 9 Winger21

1985 1980

25 23 26 10

Kros 1G

1988

Shaw 17

1992

Kryitsis39

1993

11 23 45 44 55 20

Schimizu52 Celli3~ Kros 3

1993 1994 1994

Nijjar5~ Shaw 18

1993 1992

14 30 48 14 14 33

Kim 22

1996

32

Kirby49 Allison54 Boiardi4~

1996 1997 1997

Daumas-Duport 5

1997

Donahue 2~

1997

Schiffer 12

1997

Dehghani 4

1998

7 9 14 16 20 59 24 133 109 25 23 24

Turgot 55 HageP 1

1998 1999

22 34

Jeremic 5~

1999

Paleoglogos 56

1999

18 5 36

Survival (Median) Surgery

Histology~Grade St. Anne/Mayo III St. Anne/Mayo IV AO (WHO IV) AO AOA Smith D/Kernohan IV Smith B/C Kernohan II/III St. Anne/Mayo III/IV Kernohan III/IV AO (Smith B, C, D) AOA (Smith B, C, D) AO & AOA AW (WHO) Smith B/C AO/AOA Smith D AO/AOA AO St. Anne Mayo III/IV Kernohan III/IV AO AOA AO AO or AOA AO + AOA WHO III Grade B Grade A AOA AOA + AA AA St. Anne/Mayo III St. Anne/Mayo IV AO/AOA WHO II AO + AOA WHO III AO/AOA WHO II AOA WHO IV AO WHO III AOA WHO III AO

Survival (Median) Surgery + Radiation

Survival (Median) Surgery + Radiation + Chemotherapy

4.3 y 1.4 y 1.41 y 5.3 y 1.1y 1.3 y/1 y 5y/3y 4.6 y 3.2 y

75% (5 y)

60% (5 y) 2.3y

4.2 y 3.2 y 2y 0.83 y 4.2 y 4.3 y 2.8 y 4.1y 1.25 y 58% (2 y) 5/9 controlled 6.1y 6.0 y 3.5 y lly 7.3 y 3.4 y 3.0 y 3.0 y 2.0 y ly

ly

O.67 y 2 y 15 mo 5y 2.25 y

Legend: AO, anaplastic oligodendroglioma;AOA, anaplastic mixed oligoastrocytoma; AA, anaplastic astrocytoma

fences are in field or out of field or m a r g i n a l . As long as these redu
Role of Chemotherapy O n e of the u n i q u e f e a t u r e s of anaplastic oligod e n d r o g l i o m a s or m i x e d oligoastrocytomas is

t h e i r sensitivity to c h e m o t h e r a p e u t i c agents, particularly the c o m b i n a t i o n of procarbazine, lomustine ( C C N U ) a n d vincristine (PCV) first described by Levin et al. 45 Early reports of d u r a b l e complete or p a r t i a l responses t o_PCV4Uhave res u l t e d in considerable i n t e r e s t in the use of this c o m b i n a t i o n in the a d j u v a n t s e t t i n g after surgery a n d r a d i a t i o n or as a salvage t r e a t m e n t for rec u r r e n t oligodendrogliomas. P e t e r s o n et a147 reported on a retrospective series of p a t i e n t s t r e a t e d with salvage chemo-

Adult Anaplastic Oligodendrogliomas

Figure 2. T2-weighted axial view of the radiation plan to treat the tumor displayed in Figure 1. GTV is gross residual tumor on postoperative MRI. PTV1 is the T2-weighted abnormality (tumor plus edema) with a 2-cm expansion. PTV2 is the gross residual tumor with a 1-cm expansion. PTV1 received 50.4 Gy; PTV2 received 59.4 Gy. therapy for recurrent anaplastic oligodendroglioma. They noted high (7/7) response rates to PCV when prior chemotherapy was a non-PCV regimen and the ability of a combination of etoposide and cisplatin to salvage some patient s who had responded to PCV previously and then relapsed. In a prospective trial by the National Cancer Institute of Canada (NCIC), 33 patients were enrolled on a trial of PCV in patients with newly diagnosed or recurrent pure anaplastic oligodendroglioma who had never received chemotherapy. Strict criteria for radiograph!c response were used, and a central pathology :review was performed. Nine of the 33 patients were found to be ineligible on the basis of pathology review, emphasizing the potential for misclassification of these tumors. Eighteen of 24 eligible patients (75%) showed a response to PCV c h e m o t h e r a p y with 9/24 (38%) showing a complete response. Response rates were high among those patients who had received (11/15) or not received (7/9) prior radiotherapy as well as among patients whose tumors had necrosis (10/15) or no necrosis (8/9) on pathology. The study concluded that the effectiveness of PCV in the setting of recurrent

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anaplastic oligodendroglioma justified examining the use of PCV adjuvant to surgery and radiation for patients with newly diagnosed anaplastic oligodendroglioma. 48 Kirby et a149 described the use of PCV neoadjuvant to radiation in a group of patients with malignant glioma. In a subset of patients with anaplastic oligodendroglioma or oligo-astrocytomas, 3 out of the 7 patients responded to the chemotherapy and 2-year survival was 58%. Kryitsis et aP 9 reported on 20 patients treated with a combination of surgery, radiation and chemot h e r a p y for anaplastic oligodendroglioma or anaplastic mixed glioma (Smith Grade, B-D). Two-year survival rates were 75% and 65%, respectively (difference not statistically different), with a variety of chemotherapy regimens and radiation schedules. Boiardi et al 4~ reported on a group of 71 patients with anaplastic gliomas (WHO grade III) treated with neoadjuvant C C N U and cisplatin. The 30 patients with anaplastic oligodendroglioma or oligo-astrocytoma had a median survival time of 6 years, significantly better than the patients with anaplastic astrocytoma (median survival time, 3.2 years). No survival difference between patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas was noted.Jeremic et al 5~ treated 23 patients with anaplastic mixed gliomas (WHO grade III) with PCV c h e m o t h e r a p y adjuvant to surgery and radiation. High response rates (83%) and a five-year survival rate of 52% were seen in this group of patients as was a trend towards better survival among the patients with pure anaplastic oligodendrogliomas versus the anaplastic mixed tumors. Finally, K i m et a122 reported on a group of 32 patients treated with a combination of surgery, radiation and PCV chemotherapy. Their median survival times were 50 months, 16 months, and more than 76 months for patients with W H O grade III oligoastrocytoma, W H O grade IV oligoastroctyoma, and anaplastic oligodendroglioma, respectively. The difference in median survival time between the 3 classes was statistically significant, as was survival compared according to the percentage of oligodendroglial elements in the tumor. Those patients with more' than 99% oligodendroglial component (ie, pure anaplastic oligodendroglioma) survived significantly longer than those patients with a significant astrocytic component.

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Comparison of the results of surgery alone, surgery plus radiation, and surgery plus radiation plus chemotherapy in the treatment of oligodendroglioma are summarized in Table 2. Review of these data suggests an incremental benefit in survival with the addition of radiation to surgery and chemotherapy to surgery plus radiation in patients with anaplastic oligodendroglioma or mixed glioma. These data also suggest that patients with pure anaplastic oligodendroglioma do somewhat better with the combination of surgery plus radiation plus chemotherapy than those patients with anaplastic mixed gliomas, but both groups do significantly better than those patients with pure anaplastic astrocytoma; However, the available data have serious limitations that prohibit definitive conclusions regarding the utility of combination surgery plus radiation plus chemotherapy in the treatment of these tumors. Patients treated with combined modality therapies have been treated in more recent times; improvements in diagnostic imaging, surgical, and radiotherapy technique and availability of salvage regimens might have contributed to the improved survival noted. Case numbers among the available series is small, and a lack of a uniform histologic classification a n d grading system for oligodendroglial tumors precludes direct comparisons between series. Finally, PCV chemotherapy might have significant side effects including nausea, vomiting, asthenia, rash, neuropathy, and myelosuppression. Available series, although reporting on toxicity, including toxic deaths in some instances, have not compared toxicity or quality of life among patients treated with combination therapy versus surgery plus radiation alone. The toxicity of PCV notwithstanding, neoadjuvant chemotherapy might reduce the potential toxicity of radiotherapy by allowing treatment volumes to be reduced if significant chemotherapy induced regression of the tumor is achieved. In some cases, dramatic response to neoadjuvant chemotherapy might be seen, and durable tumor control without radiotherapy has been possible. Thus, reduction of treatment volumes or deferral of radiation might actually improve quality of life for patients receiving neoadjuvant chemotherapy. Use of molecular markers to predict response to chemotherapy would be useful to select patients for this strategy.

Randomized Trials Given the apparent improvement in survival with the combination of surgery, radiation, and chemotherapy over surgery plus radiation alone, both the European Organization for the Research and T r e a t m e n t of Cancer (EORTC) and the R T O G have activated their own randomized controlled trials of PCV chemotherapy combined with radiation versus radiation alone, both adjuvant to surgery. As previously mentioned, within the R T O G 9402 (INT 0149) trial, patients with pure or mixed anaplastic oligodendroglial tumors are eligible for inclusion. Histologic criteria (on central pathology review) necessary for inclusion include at least 25% oligodendroglial component, and 2 or more anaplastic features, one of which must be endothelial proliferation or increased mitotic count. Eligible patients are stratified by age (less than 50 versus 50 or older), Karnofsky performance status (KPS 60 to 70 versus --> 80) and tumor grade (moderately anaplastic versus highly anaplastic) and randomized to either 4 cycles of PCV followed by radiation or radiation therapy alone (ie, PCV deferred until the time of. tumor recurrence). The primary endpoint is overall survival with secondary endpoints of time to tumor progression, frequency of severe (>-- grade 3) complications, quality of life, and neurologic function. A sample size of 292 patients is planned to detect an improvement in median survival of 50% or better. An important component of this trial is the central pathology review and banking of patients' tumor tissue and peripheral blood samples. Evaluation of the diagnostic and prognostic importance of histologic tumor grade as well as other markers (chromosomal alterations, ploidy, S-phase fraction, tumor suppressor genes, oncogenes, and other novel immunohistochemical markers) will be possible with the combination of the clinical database and tumor tissue bank. To date, 230 patients have been accrued to the trial with an estimated completion date of June 30, 2001. Within the EORTC trial, patients are randomized to postoperative radiation alone or radiation followed by 6 cycles of PCV chemotherapy. Again, the primary endpoint is overall survival with secondary endpoints of time to tumor progression, complications, and quality of life.

Adult Anaplastic Oligodendrogliomas

Conclusions Improvements in the histologic criteria and molecular characterization of oligodendroglial tumors are increasing the frequency of diagnosis of these tumors, Current multimodality approaches ( s u r g e r y p l u s r a d i a t i o n p l u s c h e m o t h e r a p y ) is associated with more durable tumor control and l o n g s u r v i v a l t i m e s , p a r t i c u l a r l y for t h o s e p a tients with pure anaplastic oligodendrogliomas. O n g o i n g p r o s p e c t i v e t r i a l s s e e k to c l a r i f y t h e r o l e of chemotherapy when added to radiation and surgery. In addition, the role of molecular marke r s as d i a g n o s t i c a i d s a n d g u i d e s to t h e r a p y a n d p r o g n o s i s a r e b e i n g e x p l o r e d for p a t i e n t s w i t h pure and mixed oligodendroglial tumors.

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