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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2715-2722 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.6078 Adjuvant Procarbazine, Lomustine, and Vincristine Improves Progression-Free Survival but Not Overall Survival in Newly Diagnosed Anaplastic Oligodendrogliomas and Oligoastrocytomas: A Randomized European Organisation for Research and Treatment of Cancer Phase III Trial
From the Departments of Neurology and Pathology, Daniel den Hoed Cancer Center/Erasmus University Hospital, Rotterdam; Department of Neurology, Medical Center Haaglanden/Westeinde Ziekenhuis, the Hague; Canisius Wilhemina Ziekenhuis, Nijmegen; Department of Neurology, Elisabeth Gasthuis, Tilburg; Department of Neurology, Academisch Ziekenhuis Groningen, the Netherlands; Department of Neurology, Centre Hospitalier Universitaire Pitié-Salpétrière, Paris; Department of Neurology, Centre Antoine Lacassagne, Nice, France; Medical Oncology Department-Neurooncology Unit, Azienda Ospedale-Università-Istituto Oncologico Veneto, Padova, Italy; Ludwig Boltzmann Institute Neurooncology and Kaiser Franz Josef Spital, Vienna, Austria; National Institute of Neurosurgery, Budapest, Hungary; and European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium on behalf of the European Organisation for Research and Treatment of Cancer Brain Tumor Group and the Medical Research Council Clinical Trials Group Address reprint requests to Martin J. van den Bent, MD, Neuro-Oncology Unit, Daniel den Hoed Oncology Center, PO Box 5201, 3008AE Rotterdam, the Netherlands; e-mail: m.vandenbent{at}erasmusmc.nl
PURPOSE: Anaplastic oligodendrogliomas are more responsive to chemotherapy than high-grade astrocytomas. We investigated, in a multicenter randomized controlled trial, whether adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy improves overall survival (OS) in newly diagnosed patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas. PATIENTS AND METHODS: The primary end point of the study was OS; secondary end points were progression-free survival (PFS) and toxicity. Patients were randomly assigned to either 59.4 Gy of radiotherapy (RT) in 33 fractions only or to the same RT followed by six cycles of standard PCV chemotherapy (RT/PCV). 1p and 19q deletions were assessed with fluorescent in situ hybridization. RESULTS: A total of 368 patients were included. The median follow-up time was 60 months, and 59% of patients have died. In the RT arm, 82% of patients with tumor progression received chemotherapy. In 38% of patients in the RT/PCV arm, adjuvant PCV was discontinued for toxicity. OS time after RT/PCV was 40.3 months compared with 30.6 months after RT only (P = .23). RT/PCV increased PFS time compared with RT only (23 v 13.2 months, respectively; P = .0018). Twenty-five percent of patients were diagnosed with combined 1p/19q loss; 74% of this subgroup was still alive after 60 months. RT/PCV did not improve survival in the subgroup of patients with 1p/19q loss. CONCLUSION: Adjuvant PCV chemotherapy does not prolong OS but does increase PFS in anaplastic oligodendroglioma. Combined loss of 1p/19q identifies a favorable subgroup of oligodendroglial tumors. No genetic subgroup could be identified that benefited with respect to OS from adjuvant PCV.
Phase II studies in the mid-1990s on recurrent anaplastic oligodendrogliomas and anaplastic mixed oligoastrocytomas showed that 60% to 70% of these tumors respond to chemotherapy consisting of procarbazine, lomustine, and vincristine (PCV).1,2 One of the questions that these studies raised was whether adjuvant PCV chemotherapy would increase survival in anaplastic oligodendroglial tumors. Although classical adjuvant nitrosourea-based chemotherapy in high-grade glioma results in only a modest increase of 5% in 24-month survival, the high response rates in recurrent oligodendroglioma suggest that patients with newly diagnosed oligodendroglial tumors might have a more substantial benefit from adjuvant chemotherapy.3 To answer this question, in 1995, the European Organisation of Research and Treatment of Cancer (EORTC) initiated a randomized study (EORTC 26951) that investigated the value of six cycles of adjuvant PCV chemotherapy after 59.4 Gy of radiotherapy (RT) in anaplastic oligodendroglioma. The control arm received only RT, with the recommendation to administer chemotherapy at the time of tumor progression. Because the first chemotherapy reports on recurrent oligodendroglial tumors noted similar response rates in anaplastic oligodendrogliomas and anaplastic mixed oligoastrocytomas, the study design included both tumor types. This study was supported by the Medical Research Council Clinical Trials Group. After the initiation of the study, it became clear that a specific subgroup of patients with oligodendroglial tumors, those with combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), is particularly sensitive to chemotherapy. In several studies, oligodendroglial tumors with combined 1p/19q loss were shown to have an almost 100% response rate to chemotherapy, in contrast to a 25% response rate in tumors without 1p/19q loss.4,5 In view of this observation, loss of 1p and 19q was analyzed with fluorescent in situ hybridization (FISH) using locus-specific probes, which allows assessment of chromosomal losses and gains in paraffin-embedded tissue samples. The current report describes the overall outcome of the study on the intent-to-treat population and in relation to 1p/19q status.
Patients were eligible for this study if they had been diagnosed by the local pathologist with an anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma with at least 25% oligodendroglial elements; had at least three of five anaplastic characteristics (high cellularity, mitosis, nuclear abnormalities, endothelial proliferation, and necrosis); were between 16 and 70 years old; had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; had provided written informed consent; had not undergone prior chemotherapy or RT to the skull; had no diseases interfering with follow-up; and had adequate hematologic, renal, and hepatic function (WBC count  3.0 x 109/L, platelets 100 x 109/L, serum creatinine < 120 µmol/L, and serum bilirubin < 25 µmol/L). All centers had to obtain approval of the study design from their local ethical board before study activation.
Treatment PCV chemotherapy consisted of six cycles of standard PCV chemotherapy and had to start within 4 weeks after the end of RT. Each cycle consisted of lomustine 110 mg/m2 orally on day 1 with antiemetics (domperidone or metoclopramide, and if necessary, ondansetron or a similar agent), procarbazine 60 mg/m2 orally on days 8 to 21, and vincristine 1.4 mg/m2 intravenous on days 8 and 29 (with a maximum dose of 2 mg). Cycles were to be repeated every 6 weeks, with dose reductions as previously described.2 During the entire treatment period, corticosteroids were to be kept at the lowest possible dose. Treatment at the time of progression was left to the discretion of the local investigators, but the protocol advised the treating physicians to consider PCV chemotherapy.
Follow-Up
Pathology Review
Assessment of 1p and 19q Status
Statistical Design
Random Assignment Procedure
This report is based on the data as of March 30, 2005. Between August 13, 1996 and March 3, 2002, 368 patients were randomly assigned by 40 institutions; 183 patients were assigned to the control arm (RT only), and 185 were assigned to RT plus PCV (RT/PCV; Fig 1). The median follow-up time was 62.6 months in the RT/PCV arm and 59 months in RT arm. Table 1 lists the patient characteristics of the two treatment groups; no significant baseline differences were observed.
Treatment Ninety-five percent of patients received at least 59 Gy of RT. The calculated dose-intensity was more than 90% in 88.5% of patients, without differences between the two treatment groups. From the 185 patients randomly assigned to RT/PCV, 161 patients started PCV. Reasons for not starting PCV were progression during or before RT (n = 6), patient refusal (n = 8), other (n = 4), and unknown (n = 4). The total number of administered PCV cycles was 601 cycles; the median number of cycles administered was three. Of the 161 patients who started PCV, 37% completed at least five cycles, and 30% completed six cycles (Table 2). Reasons for premature discontinuation of PCV were hematologic toxicity in 33% of patients, nonhematologic toxicity in 5%, tumor progression in 24%, patient refusal in 5%, and other reasons in 4%. Table 3 lists the observed grade 3 and 4 toxicities during PCV chemotherapy, which were mainly hematologic.
Salvage Treatment At the time of this report, 107 patients in the RT/PCV arm and 131 patients in the RT arm were diagnosed with disease progression. In 95% of patients, the diagnosis of progression was based on findings at neuroimaging. Table 4 lists further treatment in these patients at the time of progression. In the RT arm, 82% of the patients with disease progression received some kind of chemotherapy, and 65% received PCV chemotherapy. Temozolomide was slightly more often used in the RT/PCV arm compared with the RT arm (43% v 37% of patients, respectively).
Outcome At the time of analysis, 103 patients in the RT/PCV arm (55.7%) and 114 patients in the RT arm (62.3%) had died; 70.7% of patients had either died or experienced progression. Table 5 lists the OS and PFS in both treatment groups. Median OS time in the RT arm was 30.6 months; in the RT/PCV arm, median OS time was 40.3 months (hazard ratio = 0.85; 95% CI, 0.65 to 1.11; P = .23; Fig 2). PFS time in the RT/PCV arm was significantly better compared with the RT arm (median PFS time, 23.0 v 13.2 months, respectively; hazard ratio = 0.68; 95% CI, 0.53 to 0.87; P = .0018; Fig 3).
1p/19q Analysis For 311 patients (85%), sufficient tissue was available to assess 1p and 19q status. Survival in patients in whom 1p/19q status was assessed was similar to the survival in patients without 1p/19q assessment (data not shown). Combined 1p and 19q loss was observed in 78 patients (25.1%); 1p loss without 19q loss was observed in 48 patients (15.4%); and 19q loss without 1p loss was observed in 12%. The presence of chromosomal losses was balanced between the two treatment groups. Table 6 lists median and 5-year OS and PFS. Both were significantly better in patients with combined 1p/19q loss, but in none of the subgroups did RT/PCV provide a better outcome compared with RT only (Figs 4 and 5).
Predictive Factor Analysis The results from a predictive factor analysis including the stratification factors, the presence of the five anaplastic features according to the review pathology, 1p/19q loss, treatment, and treatment in relation to 1p/19q loss are listed in Table 7. Age, extent of surgery, previous surgery for a low-grade tumor, 1p/19q loss, PS, endothelial proliferation, and necrosis were found to be related to survival. The presence of 1p/19q loss was found to be the most important factor, with a hazard ratio of 0.27.
This trial on 368 patients with anaplastic oligodendroglioma compared adjuvant PCV chemotherapy with PCV chemotherapy at the time of recurrence. More than 80% of the patients who experienced progression and who were randomly assigned to the RT only arm indeed received chemotherapy at the time of progression. The outcome shows that, although adjuvant PCV chemotherapy improves PFS, it does not affect OS. Most likely, the absence of a benefit in OS is a result of the efficacy of chemotherapy at the time of recurrence. Therefore, the primary conclusion that can be drawn from the present data is that, provided chemotherapy is administered, the timing of chemotherapy is less relevant with regard to OS. PCV chemotherapy was only moderately well tolerated; more than one third of patients who started PCV discontinued treatment because of (usually asymptomatic) cumulative myelosuppression before reaching the intended six cycles of adjuvant treatment. As a consequence, the achieved dose-intensity was much less than what was intended by the protocol. In this respect, PCV differs from temozolomide, which is increasingly being used for both recurrent and newly diagnosed glioma. As a rule, this drug is better tolerated, with most patients receiving more than 90% of the intended dose-intensity.8 Several reports published during the past decade have shown a considerable interobserver variation in the histologic diagnosis of oligodendroglial tumors and an increasing tendency among pathologists to diagnose oligodendroglial tumors.9,10 This shift is at least partly a result of the absence of objective diagnostic criteria for oligodendroglioma and the presence of mixed oligoastrocytomas, which, by definition, contain elements of both astrocytomas and oligodendrogliomas.11 The presence of 25% oligodendroglial elements, which both we and others have used as a criterion for inclusion onto trials on oligodendroglioma, is also subjective and prone to interobserver variation.12 Well after the initiation of the study, it became clear that the subset of patients with oligodendroglial tumors with combined loss of 1p and 19q is particularly sensitive to PCV chemotherapy, with almost 100% of patients responding.4,5 Today, genotyping allows much more reliable diagnosis of patients with chemotherapy-sensitive oligodendroglial tumors compared with classical histology. In this study, only 25% of the samples available for analysis had combined 1p and 19q loss. Thus, only a minority of our patients carried the chemotherapy-sensitive 1p/19q loss oligodendroglial tumor subtype, which represents the subgroup of tumors that this trial was originally aiming to study. Still, even in this subgroup, the survival curves of the two treatment groups are overlapping, without any suggestion of OS benefit of early chemotherapy for the patients with chemotherapy-sensitive tumors. Obviously, the small number of patients with 1p/19q loss limits the power to detect clinical differences in this subset of patients, but from the present data, no benefit of early adjuvant chemotherapy in the 1p/19q loss patients can be concluded. In this study, 1p and 19q loss was the most important predictive factor for outcome. Although it is usually assumed that 1p/19q loss predicts, in particular, a better outcome to chemotherapy, the present study shows that PFS after RT only in patients harboring 1p/19q loss tumors is also much better. After a median follow-up time of 60 months, median survival time in patients with tumors without 1p/19q loss is less than 2 years, whereas it was not reached in patients with 1p/19q loss. This improved outcome has also been observed in retrospective studies on heterogeneously treated patients with 1p/19q loss.9,13 Clearly, tumors with 1p/19q loss are a completely different biologic entity and should be kept apart in future studies on glioma. Vice versa, trials on anaplastic glioma can include tumors with oligodendroglial morphology having no 1p/19q loss. These tumors have a similar prognosis as anaplastic astrocytoma, and until new molecular markers are identified, there is no reason to keep them apart based on rather subjective histologic criteria. Simultaneously with our study, the North American Radiation Therapy Oncology Group (RTOG) has carried out a similar study (RTOG 94-02), which differed in only the following few aspects: chemotherapy was administered before RT, patients received intensified PCV, and patients with two of five anaplastic characteristics were allowed as long as frequent mitosis or endothelial proliferation were present.14 The conclusions of that study are similar to ours; an increased PFS after neoadjuvant PCV was observed, but there was no difference in OS. Interestingly, in contrast to our study, the RTOG study observed an increase in PFS only in patients with 1p/19q loss but not in patients with intact 1p/19q. It is tempting to speculate that this is a result of the different sequence of treatments; 1p/19q-intact tumors are less sensitive to chemotherapy, and historical trials on high-grade glioma have shown that RT is more effective for this disease than chemotherapy.15 Another striking difference is the higher rate of patients with 1p/19q loss (46%) in the RTOG study and the better OS (median OS time was almost 5 years). The longer survival may be explained by the higher percentage of patients with 1p/19q loss in the RTOG trial and by the inclusion of tumors with only two anaplastic features. The considerable difference in the percentage of tumors with 1p/19q loss between the European and the North American trials points to differences among pathologists and further stresses the need to classify these tumors according to their genetic profile. It is rather confusing to see that two trials on adjuvant chemotherapy in oligodendroglioma, which is a chemotherapy-sensitive subset of tumors, failed to demonstrate improved OS, whereas the recent EORTC trial on concurrent and adjuvant temozolomide demonstrated an improved survival in glioblastoma multiforme, which is a chemotherapy-resistant disease.8 One explanation for this surprising finding could be that, in the trial on glioblastoma, temozolomide chemotherapy was administered daily during RT, which is an approach that has not been tried before in glioma and which is not feasible with nitrosourea-based chemotherapy like PCV. The study on concurrent chemoirradiation with temozolomide in glioblastoma multiforme also identified a subset of patients with tumors showing methylation of the promoter gene MGMT to be the patients who profited most from combined-modality treatment.16 Determination of MGMT status in a subset of patients from this study is ongoing. Several studies on glioma and on brain metastases have now shown that early chemotherapeutic or radiotherapeutic treatment postpones progression without affecting OS.17,18 These studies show that, by postponing adjuvant treatment, OS is not jeopardized if effective salvage treatment is available. However, none of these studies have determined whether patients deteriorate at the time of progression. If that is the case, postponing progression becomes a target because it will help to maintain the patients in a better condition. Instruments must be developed that allow the objective assessment of neurologic deterioration–free survival in trials. What conclusions should be drawn from this trial? First, the trial shows that the timing of chemotherapy is of little relevance with regard to survival if it is administered sequentially with RT and using a classical adjuvant approach. Second, future studies on anaplastic oligodendroglioma should keep the patients with 1p/19q loss tumors apart. Third, the high attrition rate in patients treated with PCV suggests that this is not an optimal regimen for adjuvant treatment.
The following centers participated in this study (in order of accrual): Centre Hospitalier Universitaire Pitie-Salpetriere, Paris, France; Erasmus University Hospital/Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Azienda Ospedale-Università-Istituto Oncologico Veneto, Padova, Italy; University Hospital Utrecht, Utrecht, the Netherlands; University Hospital St Radboud, Nijmegen, the Netherlands; Centre A. Lacassagne, Nice, France; Verbeeten Institute, Tilburg, the Netherlands; Kaiser F. Joseph Spital, Vienna, Austria; National Institute for Neurosurgery, Budapest, Hungary; University Hospital Groningen, Groningen, the Netherlands; Free University Hospital, Brussels, Belgium; Weston Park Hospital, Sheffield, United Kingdom; Medisch Centrum Haaglanden, the Hague, the Netherlands; Helsinki University Hospital, Helsinki, Finland; Royal Marsden Hospital, London, United Kingdom; Umea University Hospital, Umea, Sweden; Centre R. Gauducheau, Nantes, France; Linkoping University, Linkoping, Sweden; Klinikum F. Schiller, Jena, Germany; University Hospital Bordet, Brussels, Belgium; Free University Medical Center, Amsterdam, the Netherlands; Academic Medical Center, Amsterdam, the Netherlands; Royal Devon and Exeter, Exeter, United Kingdom; Hopital St Julien, Nancy, France; Universiteits Ziekenhuis, Leuven, Belgium; Institute Gustave Roussy, Villejuif, France; Cookridge Hospital, Leeds, United Kingdom; Velindre Hospital, Cardiff, United Kingdom; Western General Hospital, Edinburgh, United Kingdom; Western Infirmary, Glasgow, United Kingdom; Bristol Oncology Centre, Bristol, United Kingdom; Ospedale Regionale Treviso, Treviso, Italy; Oldchurch Hospital, Romford, United Kingdom; Centre Francois Baclesse, Caen, France; Centre Hospitalier Universitaire Hopital Caremeau, Nimes, France; Turku University Hospital, Turku, Finland; Henriettenstiftung Hannover, Hannover, Germany; Southend Hospital, Southend, United Kingdom; Northamptonshire Oncology, Northampton, United Kingdom; and Royal Preston Hospital, Preston, United Kingdom.
The authors indicated no potential conflicts of interest.
Supported by the European Organisation for Research and Treatment of Cancer (EORTC) Translational Research Fund Grant No. TRF 01/02, by AstraZeneca EORTC Translational Research Grant No. AZ/01/02, and by Dutch Cancer Society Grant No. DDHK 2005-3416. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando FL, May 13-17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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 procarbazine, CCNU and vincristine chemotherapy. Neurology 51:1140-1145, 1998 3. Glioma Meta-Analysis Group: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011-1018, 2002[CrossRef][Medline] 4. 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 5. 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[CrossRef][Medline] 6. International Commission on Radiation Units and Measurements: International Commission on Radiation Units and Measurements Report 50: Prescribing, Recording and Reporting Photon Beam Therapy. International Commission on Radiation Units and Measurements, Bethesda, MD, 1993, pp 1-72 7. Macdonald DR, Cascino TL, Schold SC, et al: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277-1280, 1990[Abstract] 8. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 9. 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 10. 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[CrossRef][Medline] 11. van den Bent MJ, Chinot O-L, Cairncross JG: Recent developments in the molecular characterization and treatment of oligodendroglial tumors. Neuro-oncol 5:128-138, 2003[Abstract] 12. Krouwer HGJ, van Duinen SG, Kamphorst W, et al: Oligoastrocytomas: A clinicopathological study of 52 cases. J Neurooncol 33:223-238, 1997[CrossRef][Medline] 13. 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[CrossRef][Medline] 14. Cairncross JG, Seiferheld W, Shaw E, et al: An intergroup randomized controlled clinical trial (RCT) of chemotherapy plus radiation (RT) versus RT alone for pure and mixed anaplastic oligodendrogliomas: Initial report of RTOG 94-02. J Clin Oncol 23:107, 2004 (suppl, abstr 1500) 15. 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[Medline] 16. Hegi ME, Diserens A-C, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 17. Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 280:1485-1489, 1998 18. van den Bent MJ, Afra D, De Witte O, et al: Long term results of EORTC study 22845: A randomized trial on the efficacy of early versus delayed radiation therapy of low-grade astrocytoma and oligodendroglioma in the adult. Lancet 366:985-990, 2005[CrossRef][Medline] Submitted October 17, 2005; accepted December 14, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
40 v > 40 years), extent of resection (biopsy v resection), WHO ECOG PS (0 or 1 v 2), and possible prior surgery for a low-grade oligodendroglioma (yes v no). Treatment was assigned using the minimization technique of Simon and Pocock to ensure balance with respect to the stratification factors. 
