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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3133-3138 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.169 Temozolomide As Initial Treatment for Adults With Low-Grade Oligodendrogliomas or Oligoastrocytomas and Correlation With Chromosome 1p DeletionsFrom the Fédération Neurologique Mazarin, Service de Neurochirurgie, Laboratoire de Neuropathologie, and Service de Radiothérapie, Groupe Hospitalier Pitié-Salpêtrière; Institut National de la Santé et de la Recherche Médicale U495; Université P. et M. Curie; Service d'Anatomopathologie, Hôpital Lariboisière, Paris; and Unité de Biostatistique, INSERM U472, Villejuif, France Address reprint requests to K. Hoang-Xuan, MD, Fédération Neurologique Mazarin and INSERM U495, Groupe Hospitalier Pitié-Salpêtrière, 47 Blvd de l'Hôpital, 75651 Paris Cedex 13, France; e-mail: khe.hoang-xuan{at}psl.ap-hop-paris.fr
PURPOSE: To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS: Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS: Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION: TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.
Oligodendroglial tumors include pure oligodendrogliomas or mixed gliomas (oligoastrocytomas) and represent approximately 25% of all gliomas.1-3 Low-grade oligodendroglial tumors (LGOT) mainly affect young adults, and their most common clinical presentation is partial or generalized seizures. These tumors usually grow slowly, but their natural history is to infiltrate the brain progressively and to acquire anaplastic features over time.4 Whenever possible, gross total resection is recommended at diagnosis by a majority of researchers.5 Postoperative radiotherapy (RT) is a therapeutic option for low-grade gliomas, but the optimal dose and timing remains a matter of controversy. In randomized clinical trials, neither immediate postoperative irradiation (v delayed RT) nor increasing dose (from 45 to 65 Gy) improved survival.6-8 The only benefit of early RT was a small but significant improvement of time to tumor progression, but this should be balanced with the risk of disabling delayed neurotoxicity.9 Based on these data, the current recommendation is to postpone treatment in asymptomatic patients, whereas focal irradiation is proposed when the patient develops symptoms that substantially affect his quality of life or when tumor progression on magnetic resonance imaging (MRI) indicates the imminence of clinical manifestations.10 Anaplastic oligodendrogliomas and oligoastrocytomas are chemosensitive tumors that respond to combined treatment with procarbazine, lomustine, and vincristine (PCV) in 60% to 70% of patients.11-13 More recently, chromosome 1p deletion (alone or combined with chromosome 19q loss) has been associated with high radiographic response rates and with prolonged survival times in patients with anaplastic oligodendrogliomas receiving PCV chemotherapy.14,15 Much less is known about the potential chemosensitivity of LGOTs. Several studies have suggested that these tumors may also respond well to PCV chemotherapy but at the price of significant myelosuppression.9,16 Recently, temozolomide (TMZ), which is an oral alkylating agent, has been shown to be active and particularly well tolerated in patients suffering from anaplastic oligodendroglial tumors,17,18 in addition to patients with various subtypes of progressive low-grade gliomas.19-21 In the present study, we evaluated the activity of TMZ delivered specifically to patients with LGOTs and as first-line therapy. In addition, we investigated the predictive value of chromosome 1p loss on the radiographic tumor response.
Patients The study was conducted in our institution between January 1999 and May 2003, with a final evaluation in October 2003. The following inclusion criteria were required: histologic diagnosis of LGOT or oligoastrocytoma (WHO grade 2) after central review (M.K., K.M.); age  18 years; Karnofsky performance score 40; measurable disease on MRI; evidence of progressive disease, either clinically (pharmacoresistant epilepsy, progressive deficits, or cognitive dysfunction) and/or radiologically; no previous specific treatment of the tumor except surgery; and informed consent systematically obtained.
Treatment
Tumor Response Criteria
Molecular Genetic Methods
Statistical Analyses
Patient Characteristics Sixty consecutive patients who fulfilled the inclusion criteria were enrolled onto the study. The main clinical characteristics of the patients are listed in Table 1. The median age was 43 years (range, 24 to 72 years). The median Karnofsky score at the onset of treatment was 90. According to the WHO classification (2000),23 49 patients had pure grade 2 oligodendroglioma (82%) and 11 patients had grade 2 mixed oligoastrocytomas (18%). The median delays between the first symptoms or histologic confirmation and the onset of treatment were 23 months (range, 1.5 to 214 months) and 3 months (range, 0.1 to 108 months), respectively. Scant contrast enhancement at the MRI was present in seven cases (11%).
Response Rate to TMZ and PFS The median follow-up was 14 months (range, 6 to 46 months). The median number of TMZ cycles was 11 (range, one to 20 cycles). Response was assessable in 59 patients. One patient could not be assessed because he received early radiotherapy after grade 4 thrombocytopenia after the first TMZ cycle. At the time of analysis, 10 patients (17%) achieved a PR, eight patients (14%) achieved an MR, 36 patients (61%) were stable, and five patients had PD (8%). Hence the objective response rate was 31%. The median time to the onset of radiographic response was 4 months, but responses were sometimes delayed, becoming apparent only after up to 10 cycles (range, 2 to 10 months). The median time to maximum radiographic response was 12 months (range, 5 to 20 months; Fig 1). It should be emphasized that clinical improvement, particularly a clear reduction in seizure frequency, was more frequent than objective radiologic response. Indeed, 30 patients (51%) improved neurologically, including 12 (33%) of 36 patients who were radiologically stable. The 1-year rate of patients free of progression was 73.4% (95% CI, 61% to 88%).
Tolerance The treatment was generally well tolerated, with hematologic toxicity as the main side effect. Five patients (8%) developed a grade 3 (one thrombocytopenia, one neutropenia) or 4 (one thrombocytopenia, two neutropenia) toxicity. In all but one case, the treatment could be continued with a 25% dose reduction. As mentioned earlier, TMZ was discontinued after the first cycle in one patient who developed grade 4 thrombocytopenia and received radiotherapy.
Molecular Genetic Analysis
This study indicates that initial treatment of LGOT with TMZ induces a substantial rate of clinical and radiologic response. In addition, deletion of chromosome 1p seems to be a favorable predictor of response in LGOT. The radiologic response rate was 31% (17% PR, 14% MR), but tumors often responded slowly, as the median time to best response after treatment onset was 12 months (range, 5 to 20 months). This long delay differs from anaplastic oligodendroglial tumors, where the median time to maximum response after TMZ is shorter at approximately 2 months.17 The fact that 33% of patients who were stable on MRI improved clinically, particularly in terms of seizure frequency, suggests that chemotherapy may affect the tumor burden without MRI counterpart, either because the tumor reduction does not reach the threshold at which it is detectable on MRI or because a longer follow-up/duration of treatment may be needed in some patients to detect objective changes on MRI. Considering the delayed response and the good tolerance to TMZ, it seems appropriate to recommend a protracted treatment in LGOT (12 to 18 months). More prolonged treatment should be discussed individually, taking into account the clinical benefit and the radiologic response already achieved, as well as the tolerance of the treatment. Although encouraging, our results are less impressive than those of two recent studies by Quinn et al19 and Pace et al,20 who have reported a 61% and 47% response rate (CR + PR), respectively, in series of patients suffering from progressive low-grade gliomas. However, the rate of contrast enhancement of the tumors was much higher than in our series (up to 70% v 11%), and many patients had experienced treatment failure with prior radiotherapy and/or chemotherapy (Table 2). Thus the patients reported by these two latter studies probably had higher-grade tumors than ours, and it is therefore not surprising that their pattern of response was similar to the one reported in anaplastic or recurrent oligodendrogliomas treated by TMZ.17,18 Consistently, Brada et al21 have recently reported a lower rate of response to TMZ (delivered for a maximum of 12 cycles) in a series of radio- and chemotherapy-naïve low-grade gliomas without imaging evidence of high-grade transformation (20% PR and 30% MR in the small oligodendroglioma subgroup).
Studies evaluating PCV chemotherapy in LGOT are also scarce. Mason et al24 first reported positive results in a small series of six patients. More recently, the efficacy of PCV was confirmed by Buckner et al,16 who treated prospectively a series of 25 LGOT with one to six cycles of PCV immediately before radiotherapy. A 52% response rate and a 32% SD rate after radiologic review were reported. However, comparison with our results is also difficult, because the rate of enhancing lesions was higher in the Buckner et al series (46%) and because the response criteria were not based on reproducible measurable radiologic criteria. More pertinent for comparison is the retrospective study of Soffietti et al,25 which was specifically devoted to nonenhancing LGOT treated with PCV and used MRI criteria for response assessment. A PR rate of 25% and an additional MR rate of 25% were reported in this series of 20 patients. A possible superiority of PCV over TMZ in this setting should be evaluated by prospective studies that also take the toxicity issue into account. Indeed, the rate of grade 3 to 4 hematotoxicity in the present study was 8%, and only one (< 2%) of 60 patients had to stop chemotherapy prematurely, as compared with a 46% to 75% rate of grade 3 to 4 hematologic toxicity requiring discontinuation of chemotherapy in up to 32% of cases previously reported with the PCV regimen.9,16 In addition to its safely profile, one theoretical advantage of TMZ over PCV is the absence of cumulative toxicity, allowing chemotherapy to be delivered for a prolonged time, which might be a crucial point for the treatment of low-grade tumors. Loss of chromosome 1p is found in 50% to 80% of oligodendroglial tumors.22,26 The presence of this deletion has been found to be a powerful predictor of longer survival14,15,22,27,28 and of greater likelihood of response to chemotherapy in anaplastic oligodendroglioma.14,15,29 In the present study, we report for the first time a significant correlation between the presence of chromosome 1p loss and the radiographic response rate to TMZ in LGOT. To our knowledge, only two studies have specifically investigated the predictive value of 1p loss on chemotherapy response in LGOT. Both involved the PCV regimen. Among 13 patients with LGOT treated with PCV "at conversion to more aggressive lesions," Sasaki et al30 found loss of chromosome 1p in 10 of 11 responding as compared with zero of two non-responding tumors. However, Buckner et al16 could not find this correlation in a series of patients with newly diagnosed LGOT treated with neoadjuvant PCV chemotherapy. As suggested by Buckner et al, this apparently contradictory result is probably due to the lack of statistical power related to small sample size in these infrequent tumors. Altogether, there is growing evidence that one or several yet unknown important tumor suppressor gene(s) located on chromosome 1p are involved in the tumorigenesis and the chemosensitivity of oligodendroglial tumors, whatever the grade. In summary, this study suggests that initial treatment with TMZ is an interesting option among the therapeutic armamentarium of LGOT, particularly if the clinician's choice is guided by the analysis of the chromosome 1p status. Nevertheless, although the activity/toxicity ratio of this strategy seems favorable on a short-term basis, it should be emphasized that its long-term effects remain unknown. From this perspective, our data would support a randomized phase III study comparing chemotherapy and radiotherapy in progressive LGOT with stratification for chromosome 1p loss, as planned by the European Organization for Research and Treatment of Cancer Brain Tumor Group.
The authors indicated no potential conflicts of interest.
We thank Anne-Marie Lekieffre, Josiane Valero, and Murielle Brandel from the ARTC for their precious technical assistance.
Supported by a grant from the Fondation de France (grant No. 2002008957). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
2 tests were used to examine the relationship between radiologic response and LOH on 1p, age, Karnofsky performance status, histology, and contrast enhancement. Kaplan-Meier estimates were used to describe the distribution of progression-free survival (PFS). PFS was defined as the time between the start of chemotherapy and progression. Patients who had no evidence of disease progression were treated as censored for the analysis of PFS. 
70 v > 70), and contrast enhancement, were not correlated with response to chemotherapy. 
