Phase III Trial of Chemotherapy Plus Radiotherapy Compared With Radiotherapy Alone for Pure and Mixed Anaplastic Oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402

University of Toronto, Toronto, Ontario, Canada
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2006; 24(18):2707-14. DOI: 10.1200/JCO.2005.04.3414
Source: PubMed


Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery and radiotherapy (RT) at diagnosis, but they also respond to procarbazine, lomustine, and vincristine (PCV), raising the possibility that early chemotherapy will improve survival. Furthermore, better outcomes in AO have been associated with 1p and 19q allelic loss.
Patients with AO and AOA were randomly assigned to PCV chemotherapy followed by RT versus postoperative RT alone. The primary end point was overall survival. The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization.
Two hundred eighty-nine eligible patients were randomly assigned to either PCV plus RT (n = 147) or RT alone (n = 142). At progression, 80% of patients randomly assigned to RT had chemotherapy. With 3-year follow-up on most patients, the median survival times were similar (4.9 years after PCV plus RT v 4.7 years after RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26). Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of patients experienced grade 3 or 4 toxicity, and one patient died. Patients with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and 19q had longer median survival times (> 7 v 2.8 years, respectively; P < or = .001); longer progression-free survival was most apparent in this subset.
For patients with AO and AOA, PCV plus RT does not prolong survival. Longer progression-free survival after PCV plus RT is associated with significant toxicity. Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both.

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Available from: Minesh P Mehta, Oct 06, 2015
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    • "AO/AOA is expected to show a high response rate to chemotherapy among malignant gliomas, especially in subgroup with 1p-19q co-deletion. Reported results of PCV chemotherapy for newly diagnosed AO/AOA are fairly high, up to 75% although with significant occurrence of hematologic toxicity5,6,19). Thus, availability of salvage chemotherapy for recurrent AO/AOA has been limited by clinical parameters such as chemo-experience and old age, and reports of response rates are rare and vary by regimen in a range of 23-77%1,3,4,9-11,28,32). "
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    ABSTRACT: To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA). A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m(2)/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed. TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (≥grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient's histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01). For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.
    Journal of Korean Neurosurgical Society 12/2013; 54(6):489-95. DOI:10.3340/jkns.2013.54.6.489 · 0.64 Impact Factor
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    • "In 1998, Cairncross and colleagues reported that loss of 1p (and 1p/19q co-deletion) predicts a better response to procarbazine-lomustine-vincristine chemotherapy and a longer survival in patients with AO [13]. These findings have been reproduced in many subsequent studies, including prospective and randomized phase III trials [14, 15]. Moreover, oligodendroglial tumors with loss of 1p/19q showed a response to treatment with the alkylating drug TMZ and radiotherapy, indicating its predictive value for a broader spectrum of therapeutic regimens [16–18]. "
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    ABSTRACT: This study was designed to display the molecular genetic features of short-term survivors in glioblastomas with oligodendroglioma component (GBMO). A total of 186 patients with histological diagnosis of primary gliomas, including 11 GBMO-STS (short-term survivors, survival ≤12 months), 29 GBMO-LTS (relatively long-term survivors, survival >12 months), 36 anaplastic oligoastrocytoma (AOA) and 110 glioblastoma multiforme (GBM), enrolled in the study. An evaluation form was developed and used to document molecular pathological, clinical and treatment-associated parameters between subgroups. Kaplan–Meier plots for survival showed that the median progression-free survival (PFS) and overall survival (OS) of GBMO-STS were 5.0 and 10.0 months, respectively. Intergroup comparison revealed that the GBMO-STS harbored the most dismal prognosis than those with AOA, GBMO-LTS or GBM (P < 0.001 for PFS, P < 0.001 for OS, respectively). Cox regression analyses revealed that 1p/19q co-deletion and 19p polysomy were independent prognostic factors (P < 0.05). Pearson’s Chi square test demonstrated GBMO-STS exhibited lower 1p/19q co-deletion, IDH1 mutation rates than AOA or GBMO-LTS (P = 0.032, P = 0.045 for 1p/19q co-deletion; P = 0.034, P = 0.005 for IDH1 mutation, respectively) but higher chromosome 1q, 19p polysomy rates compared with AOA or GBM (P = 0.037, P = 0.030 for 1q polysomy; P = 0.017, P = 0.011 for 19p polysomy, respectively). Patients with glioblastomas with oligodendroglioma component concurrent with polysomy for chromosomes 1 and 19 always confers an unfavorable prognosis which needs our extra attention in clinic. Electronic supplementary material The online version of this article (doi:10.1007/s11060-013-1311-3) contains supplementary material, which is available to authorized users.
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    • "The 1p/19q deletions were incorporated into three major therapeutic trials in patients with AO. All the trials confirmed the prognostic and possible predictive role of this biomarker at initial therapy [4-6]. "
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    ABSTRACT: To determine the prognostic value of isocitrate dehydrogenase 1 (IDH1) mutation, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion in Japanese patients with malignant gliomas. We studied 267 malignant gliomas, which included 171 glioblastomas (GBMs), 40 anaplastic astrocytomas (AAs), 30 anaplastic oligodendrogliomas (AOs), and 26 anaplastic oligoastrocytomas (AOAs). These malignant gliomas were divided into 2 groups (Group 1: GBM + AA, Group 2: AO + AOA) according to the presence of the oligodendroglioma component. We examined IDH1 mutation and MGMT promoter methylation in each group by direct sequencing and methylation-specific PCR, respectively. We further examined 1p/19q co-deletion in Group 2 by fluorescence in situ hybridization. Survival between groups was compared by Kaplan--Meier analysis. In Group 1, patients with IDH1 mutations exhibited a significantly longer survival time than patients with wild-type IDH1. However, no significant difference was observed in Group 2, although patients with IDH mutations tended to show prolonged survival. For both Group 1 and Group 2, patients with MGMT methylation survived longer than those without this methylation. Further, patients with 1p/19q co-deletion showed significantly better outcome in Group 2. Our study confirms the utility of IDH1 mutations and MGMT methylation in predicting the prognosis of Group 1 patients (GBM + AA) and demonstrated that IDH1 mutations may serve as a more reliable prognostic factor for such patients. We also showed that MGMT methylation and 1p/19q co-deletion rather than IDH1 mutations were prognostic factors for Group 2 patients (AOA + AO). Our study suggests that patients survive longer if they have IDH1 mutations and undergo total resection. Further, irrespective of MGMT promoter methylation status, the prognosis of glioma patients can be improved if total resection is performed. Moreover, our study includes the largest number of Japanese patients with malignant gliomas that has been analyzed for these three markers. We believe that our findings will increase the awareness of oncologists in Japan of the value of these markers for predicting prognosis and designing appropriate therapeutic strategies for treating this highly fatal disease.
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