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© 2001 American Society for Clinical Oncology Safety and Efficacy of Temozolomide in Patients With Recurrent Anaplastic Oligodendrogliomas After Standard Radiotherapy and ChemotherapyFrom the Services de Neurochirurgie, Pharmacie, Neuropathologie, and Radiothérapie, Hôpital de la Timone, and Faculté de Médecine, Laboratoire de Cancérologie Expérimentale, Marseille, France. Address reprint requests to O. Chinot, MD, Hôpital de la Timone, Service de Neurochirurgie, Boulevard Jean Moulin, 13385 Marseille, Cedex, France; email: OCHINOT{at}mail.ap-hm.fr
PURPOSE: Most primary oligodendrogliomas and mixed gliomas (oligoastrocytoma) respond to treatment with procarbazine, lomustine, and vincristine (PCV), with response rates of approximately 80%. However, limited data on second-line treatments are available in patients with recurrent tumors. A novel second-generation alkylating agent, temozolomide, has recently demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme and anaplastic astrocytoma. This study describes the effects of temozolomide in patients with recurrent anaplastic oligodendroglioma (AO) and anaplastic mixed oligoastrocytoma (AOA). PATIENTS AND METHODS: Forty-eight patients with histologically confirmed AO or AOA who had received previous PCV chemotherapy were treated with temozolomide (150 to 200 mg/m2/d for 5 days per 28-day cycle). The primary end point was objective response. Secondary end points included progression-free survival (PFS), time to progression, overall survival (OS), safety, and tolerability. RESULTS: Eight patients (16.7%) experienced a complete response, 13 patients (27.1%) experienced a partial response (objective response rate, 43.8%), and 19 patients (39.6%) experienced stable disease. For the entire treatment group, median PFS was 6.7 months and median OS was 10 months. For objective responders, median PFS was 13.1 months and median OS was 16 months. For complete responders, PFS was more than 11. 8 months and OS was more than 26 months. Response correlated with improved survival. Temozolomide was safe and well tolerated. Twelve patients developed grade 1/2 thrombocytopenia and three patients developed grade 3/4 thrombocytopenia. CONCLUSION: Temozolomide is safe and effective in the treatment of recurrent AO and AOA.
APPROXIMATELY 127,000 new cases of cancer of the brain and the CNS are seen worldwide each year.1 Among the estimated 17,000 new cases of high-grade brain tumors in the United States in 1999,2 5% to 30% were oligodendrogliomas. Clinically, oligodendrogliomas present in a manner similar to astrocytomas,3 but they tend to develop over a longer period of time with a higher incidence of associated seizures.4 These tumors vary from low-grade, slow-growing forms to more aggressive, high-grade forms that have an increased incidence of invasion of the leptomeninges (gliomatosis meningitis) and metastases, and such tumors are associated with poor survival.5-7 In addition, oligodendrogliomas may demonstrate a mixed histology that displays features of both oligodendroglioma and astrocytoma. Approximately two thirds of patients with anaplastic oligodendrogliomas (AO) or anaplastic oligoastrocytomas (AOA) respond to a combination of surgery, radiation, and procarbazine, lomustine, and vincristine (PCV) chemotherapy used in the adjuvant setting or at the time of recurrence after surgery and radiotherapy,3,5,8-13 with some studies suggesting that tumors with a mixed histology (AOA) may be less sensitive to chemotherapy than are "pure" tumors (AO).14 However, despite the success of front-line therapy, most patients experience tumor recurrence.4 For AO, limited data are available on second-line therapy after PCV failure, primarily on the basis of retrospective studies with a small number of patients,15,16 and clearly a need exists for more effective secondary therapy. Temozolomide, a novel alkylating agent with demonstrated antitumor activity in recurrent gliomas,17-19 is rapidly absorbed and highly bioavailable after oral administration,20 crossing the blood-brain barrier and achieving effective concentrations in the CNS. Thrombocytopenia and neutropenia are the most common dose-limiting toxicities,21 with grade 3 or 4 myelosuppression occurring in less than 10% of treated patients. Of particular interest for the treatment of patients with previous exposure to nitrosoureas is that temozolomide-induced myelosuppression is reversible and does not seem to be cumulative.22 In recently reported multicenter phase II trials, temozolomide demonstrated efficacy in both recurrent anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). In patients with AA or AOA, temozolomide treatment after first relapse resulted in objective responses in 35% of patients.23 Median overall survival (OS) was 13.6 months, with 6- and 12-month survival rates of 75% and 56%, respectively. In the second phase II study, which compared temozolomide with procarbazine in recurrent GBM, both median overall progression-free survival (PFS) (12.4 v 8.32 weeks; P = .0063) and 6-month OS (60% v 44%; P = .019) were improved in patients treated with temozolomide.24 The demonstrated efficacy and favorable side-effect profile prompted the evaluation of temozolomide in other high-grade gliomas. The objective of this study was to assess the efficacy and safety of temozolomide in patients with AO or AOA after relapse after first-line chemotherapy with PCV.
Patient Characteristics Patients presenting with histologically confirmed recurrent pure AO or AOA after previous standard therapy (PCV after standard external radiotherapy) were recruited from a single clinical center between April 1995 and July 1999. Written informed consent was obtained from all patients according to the institutional review board guidelines. Histology was reviewed by the same pathologist by the Daumas-Duport criteria6,7 and was based on the most recent histologic diagnosis before study enrollment. Eligible patients were required to be at least 18 years old, at least 12 weeks postradiation therapy, and have a Karnofsky performance status (KPS) score of 60 or more. In addition, patients were required to have at least one contrast-enhancing lesion measurable by magnetic resonance imaging (MRI). Adequate laboratory values were required, including an absolute neutrophil count of 1,500/mm3 or more, a platelet count of 100,000/mm3 or more, AST and ALT levels of less than three times the upper limit of laboratory normal, and urea, serum creatinine, and total bilirubin less than 1.5 times the upper limit of laboratory normal. Patients were also required to have been on a stable corticosteroid therapy for at least 2 weeks before baseline MRI evaluation, to have a life expectancy of more than 12 weeks, and to provide written informed consent. Patients who had previously undergone more than one course of chemotherapy or who had received chemotherapy or radiotherapy within 12 weeks before the start of treatment were excluded. In addition, patients with human immunodeficiency virus, who had disease related to AIDS, or who had not fully recovered from toxicities from previous treatments were excluded. Once patients were in the study, treatment was discontinued after disease progression or any clinically significant adverse event.
Study Design
Treatment
Statistical Methods The primary end point was the objective response rate, as assessed by successive MRI scans 1 month or more apart, with responses defined according to the criteria of MacDonald et al.25 The size of the enhancing part of the tumor was defined as the product of the largest perpendicular diameters of enhancement on the MRI scan. A complete response (CR) was defined as the disappearance of all enhancing tumor on consecutive MRI scans 1 month or more apart with no corticosteroid use. A partial response (PR) was defined as 50% or more and less than 100% reduction in the enhancing tumor volume on consecutive MRI scans with stable corticosteroid use and stable or improved neurologic status. Progressive disease was defined 25% or more increase in the enhancing tumor on consecutive MRI scans or the appearance of new tumor or neurologic degradation or necessity of increasing corticosteroids. Stable disease described all other situations. All responses were confirmed by another MRI scan performed 1 to 2 months later. Response rates were analyzed for the intent-to-treat population by the  2 test according to demographic characteristics, time from initial diagnosis, histologic type and grade, and previous response to PCV. The secondary end points were PFS at 12 months, OS, and the safety and tolerability of treatment. The Kaplan-Meier method was used in the analysis of PFS at 12 months and of OS.
Patient Characteristics Patient demographics and baseline disease characteristics of treated patients are outlined in Table 2. A total of 48 patients with a median age of 41 years entered the study. The patient population was evenly divided between male and female subjects. Most patients (70.8%) had a KPS score of 70 to 80 v 29.2% with a KPS score of 60 or less. Histologic diagnosis was AO in 39 patients (81.3%) and AOA in nine patients (18.8%). Seventeen patients (35.4%) had a history of low-grade glioma, and 64.6% had de novo anaplastic tumors. Thirty-one patients had undergone surgical resection at the time of initial diagnosis (partial, n = 10; complete, n = 21); the other 17 patients had undergone biopsy only.
Forty-seven patients had received previous treatment with radiation therapy, then chemotherapy with either PCV (93.6%) or carmustine (6.4%). Limited-field conventional radiation therapy was performed either at the time of low-grade diagnosis (11 of 17 patients) or anaplastic diagnosis (37 patients) by means of 1.82- to 2-Gy fractions up to a total median dose of 58 Gy (range, 50 to 60 Gy). The standard PCV regimen was always administered at the time of anaplastic diagnosis, either as adjuvant therapy after complete removal (n = 13), after biopsy (n = 18), after partial removal (n = 8), or at the time of recurrence (n = 5). Because 13 patients were treated at an adjuvant setting after complete removal of their tumors, we were only able to assess 35 patients for response to initial PCV therapy. Of these, 16 (45.7%) had a CR to first-line PCV therapy, with 13 (37.1%) demonstrating PR and four (11.4%) with stable disease. Median time to response to PCV was 4.7 months (range, 1 to 16 months), and the median time to tumor progression was 17.7 months (range, 2 to 54 months). Median time from initial diagnosis to recurrence was 31.4 months. One patient underwent surgery (partial removal of the tumor on the basis of the findings of the postoperative MRI) at the time of initial recurrence, without receiving PCV chemotherapy, before the initiation of temozolomide therapy.
Efficacy of Temozolomide
The responses to temozolomide therapy were examined according to clinical and pathologic variables. Age and KPS had a prognostic impact on response and survival rates ( Table 4). Patients more than 40 years of age (n = 24) displayed significantly improved responses to temozolomide, including objective response rate (54.2% v 33.3%), median PFS (10.0 months v 4.6 months; P = .01), and median OS (13.4 months v 7.6 months; P = .023) compared with those patients 40 years of age or less (n = 24). A KPS score of more than 60 was also correlated with improved responses to temozolomide. Patients with a KPS score of more than 60 (n = 34) demonstrated a similar response rate (44.1% v 42.9%), but an increased rate of stable disease (47.1% v 21.4%), an increased median PFS (7.4 months v 4.7 months), and a significantly improved median OS (10.9 months v 4.9 months; P = .016) compared with patients with a KPS score of 60 or less (n = 14).
In patients with a previous CR to PCV therapy, 43.7% experienced an objective tumor response to temozolomide (Table 4). In addition, objective responses were observed in 46.2% of patients after a PR to PCV. Importantly, a significant improvement (P = .011) in median PFS with temozolomide treatment in those patients with a previous response to PCV was seen. Patients with no history of low-grade glioma (de novo diagnosis) experienced an objective response rate of 48.4%, a median PFS of 7.4 months, and a median OS of 10.8 months after temozolomide therapy. In comparison, patients with a previous low-grade glioma demonstrated a response rate of 35.3%, with a median PFS of 4.7 months and a median OS of 8.1 months. Compared with patients with AOA, patients with confirmed AO had an objective response rate of 48.7% (v 22.2%), a median PFS of 7.3 months (v 5.6 months), and a median OS of 9.9 months (v 8.7 months) after temozolomide therapy.
Safety of Temozolomide
Although oligodendrogliomas are recognized as chemosensitive tumors,3,8-11,13 most patients will relapse, and the prognosis for patients with recurrent AO or AOA is poor. Although the retrospective study of Peterson et al15 emphasized the potential of patients with AO to respond to salvage chemotherapy as second-, third-, and even fourth-line treatment, the PCV regimen seems to be an effective second-line treatment only in those patients who relapsed after non-PCV chemotherapy regimens.15,26,27 This suggests that previous treatment with PCV may result in resistance to this regimen. In addition, the usefulness of repeated PCV therapy is often limited by cumulative hematologic toxicity.4,26,28-30 In an attempt to identify an effective second-line treatment, several drugs have been examined in a number of small clinical studies. In recurrent AO after first-line PCV therapy, response rates of 40% (four of 10 patients) with etoposide and cisplatin15 and 15% (three of 20 patients) with paclitaxel16 have been reported, although in few patients. The success of temozolomide in patients with recurrent GBM and AA23,31 has indicated that this drug should be investigated for efficacy in other recurrent malignant glioma populations. In the current study, single-agent temozolomide demonstrated efficacy in patients with relapsed AO or AOA who failed to respond to PCV therapy, with an overall response rate of 43.8% (Table 3). In responding patients, PFS and OS were significantly improved (P < .0001) compared with nonresponding patients. A correlation between response and PFS in AO patients has been previously reported,26,27,32 and this does suggest that in AO, assessments of efficacy should be restricted to CR and PR. Although this represents the largest study of salvage chemotherapy in recurrent AO patients performed to date, importantly, these data demonstrate that patients who have failed to respond to PCV therapy can benefit from treatment with temozolomide. In the present study, temozolomide was efficacious despite the fact that a significant proportion of these patients (29.2%) were not functioning well, as indicated by a KPS score of 60 or less (Table 2). In contrast, only 1.8% of the recurrent AA and AOA patients had a KPS score of 60 or less in the pivotal phase II trial,23 in which an objective response rate of 35% was reported with temozolomide. In those patients, a decreased PFS was associated with previous PCV therapy (4.8 months v 6.2 months in nonpretreated patients). Approximately 94% of the patients in the present study had received previous PCV therapy treatment, and the PFS in the entire treatment group was 6.7 months. In addition, temozolomide induced a CR for 12 months or more in two of four patients with symptomatic meningeal gliomatosis. Subanalyses have revealed a number of factors that correlate with a response to temozolomide therapy. Age (> 40 years of age) was associated with significantly improved median PFS (P = .01) and OS (P = .023) (Table 4). This is in contrast to previous studies that demonstrated either no correlation between age and survival26,27 or a correlation between lower age and increased survival.33-35 The correlation observed in the present study may be explained by the significant proportion (P = .034) of patients with a history of low-grade disease who were less than 40 years of age (12 of 17 patients; 70.6%), compared with patients with de novo disease who were less than 40 years of age (12 of 31 patients; 38.7%). Patients with a history of low-grade disease displayed lower objective response rates (35.3% v 48.4%), decreased PFS (4.7 months v 7.4 months), and decreased OS (8.1 months v 10.8 months) compared with patients with de novo disease. Response rates were improved relative to the overall patient population in patients with AO, confirming the reported chemosensitivity of this tumor subtype. In the subset of histologically confirmed AOA patients in the multicenter phase II trial,23 the objective response rate to temozolomide was 42.9% (six of 14 patients), with a median PFS of 5.8 months. This compares with an objective response rate of 22.2% and a median PFS of 5.6 months for the AOA patients within this study, a lesser but still clinically relevant response, and one consistent with previous reports of temozolomide efficacy in this tumor.23,31 The efficacy of temozolomide in both pure AO and mixed AOA is important because these tumor subtypes are difficult to distinguish from each other and are often clinically grouped together.36 In an earlier study of recurrent AA and AOA,23 baseline KPS was the only prognostic factor that correlated meaningfully with survival. The present study has indicated the presence of a number of factors that seem to influence the response to temozolomide, perhaps suggestive of important biologic differences between AA and tumors with an oligodendroglial component. The heterogeneous responses of AO and AOA to chemotherapy may be the result of genetic alterations in these tumors.10 The combined loss of chromosome arms 1p and 19q known to occur in 50% to 70% of AO could represent a significant predictor of chemotherapeutic response and survival in patients with AO.10,36 This is part of ongoing investigations in our laboratory. Further, given the heterogeneity of this tumor type, careful patient management is important in terms of correct tumor diagnosis, previous therapies, and timing the treatment regimen. Indeed, the time to response to temozolomide treatment was as long as 12 months (median, 2.0 months; range, 1 to 12 months), and in our experience, we have observed patients with progressive tumors after one cycle who achieve a CR after two to four further cycles. Therefore, it is important that patients are maintained on a high number of treatment cycles and carefully evaluated. Temozolomide therapy was safe and well tolerated in this patient population (Table 5), which allowed treatment with few dose reductions in the majority of patients. Myelosuppression, the predominant side effect of therapy with alkylating agents, was reversible and noncumulative, allowing nearly continuous therapy and increased numbers of cycles. Nonhematologic adverse effects occurred with low frequency and were easily managed with antiemetics. In conclusion, temozolomide was effective in the treatment of recurrent AO and AOA after previous surgery, radiation, and PCV therapy. The response rates obtained with temozolomide, which were comparable to those reported for other second-line therapies such as etoposide or paclitaxel, were also associated with a prolonged PFS and OS. In addition, temozolomide was safe and well tolerated, and patients are able to sustain intense, continuous therapy cycles. The data clearly support additional studies of temozolomide in the treatment of recurrent gliomas and indicate the need for studies to be conducted comparing temozolomide and PCV in the front-line setting. Given the excellent tolerability profile and the clear correlation between response and survival, the use of temozolomide in combination regimens in the front-line setting, particularly with nitrosoureas, could lead to significant improvements in objective response rates and, consequently, patient survival.
Supported in part by the Lionel Perrier Foundation. We thank the study nurses, Elise Dekker, Jean Cougnard, the patients, and their families for their support and encouragement.
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Landis SH, Murray T, Bolden S, et al: Cancer statistics 1999 (erratum appears in CA Cancer J Clin 49: 1, 1999). CA Cancer J Clin 49: 8-31, 1999 3. Kyritsis AP, Yung WK, Bruner J, et al: The treatment of anaplastic oligodendrogliomas and mixed gliomas. Neurosurgery 32: 365-370, 1993[Medline] 4. Levin VA, Leibel SA, Gutin PH: Neoplasms of the central nervous system, in De Vita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia PA, Lippincott-Raven, 1997, pp 2022-2082 5. Allison RR, Schulsinger A, Vongtama V, et al: Radiation and chemotherapy improve outcome in oligodendroglioma. Int J Radiat Oncol Biol Phys 37: 399-403, 1997[Medline] 6. Daumas-Duport C, Varlet P, Tucker ML, et al: Oligodendrogliomas: Part I. Patterns of growth, histological diagnosis, clinical and imaging correlations: A study of 153 cases. J Neurooncol 34: 37-59, 1997[Medline] 7. 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[Medline] 8. Cairncross JG, Macdonald DR, Ramsay DA: Aggressive oligodendroglioma: A chemosensitive tumor. Neurosurgery 31: 78-82, 1992[Medline] 9. Cairncross JG, Macdonald DR: Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23: 360-364, 1988[Medline]
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Reid JM, Stevens DC, Rubin J, et al: Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. Clin Cancer Res 3: 2393-2398, 1997 21. Brada M, Judson I, Beale P, et al: Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 81: 1022-1030, 1999[Medline] 22. Dhodapkar M, Rubin J, Reid JM, et al: Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Clin Cancer Res 3: 1093-1100, 1997[Abstract]
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Paleologos NA, Macdonald DR, Vick NA, et al: Neoadjuvant procarbazine, CCNU, and vincristine for anaplastic and aggressive oligodendroglioma. Neurology 53: 1141-1143, 1999 29. Shaw EG, Scheithauer BW, O’Fallon JR, et al: Mixed oligoastrocytomas: A survival and prognostic factor analysis. Neurosurgery 34: 577-582, 1994[Medline] 30. Shaw EG, Scheithauer BW, O’Fallon JR, et al: Oligodendrogliomas: The Mayo Clinic experience. J Neurosurg 76: 428-434, 1992[Medline] 31. Bower M, Newlands ES, Bleehen NM, et al: Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 40: 484-488, 1997[Medline]
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Smith JS, Perry A, Borell TJ, et al: Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18: 636-645, 2000 Submitted September 18, 2000; accepted February 7, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
