Journal of Clinical Oncology, Vol 17, Issue 9
(September), 1999: 2762
© 1999 American Society for Clinical Oncology
Multicenter Phase II Trial of Temozolomide in Patients With Anaplastic Astrocytoma or Anaplastic Oligoastrocytoma at First Relapse
W.K. Alfred Yung,
Michael D. Prados,
Ricardo Yaya-Tur,
Steven S. Rosenfeld,
Michael Brada,
Henry S. Friedman,
Robert Albright,
Jeffrey Olson,
Susan M. Chang,
Alison M. O'Neill,
Allan H. Friedman,
Janet Bruner,
Nancy Yue,
Margaret Dugan,
Sara Zaknoen,
Victor A. Levin,
for the Temodal Brain Tumor Group
From the University of Texas M.D. Anderson Cancer Center, Houston, TX; University of California, San Francisco, San Francisco, CA; University of Alabama, Birmingham, AL; Duke University, Durham, NC; University of Cincinnati, Cincinnati, OH; Emory Clinic, Atlanta, GA; Johns Hopkins University, Baltimore, MD; Schering-Plough Pharmaceuticals, Kenilworth, NJ; Hôpital de la Pitié-Salpetrière, Paris, France; and Royal Marsden Hospital, Surrey, United Kingdom.
Address reprint requests to W.K. Alfred Yung, MD, University of Texas M.D. Anderson Cancer Center, Department of Neuro-oncology, Box 100, 1515 Holcombe Blvd, Houston, TX 77030; emailyung@ manderson.org.
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ABSTRACT
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PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse.
PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m2/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m2/d; the dose could be increased to 200 mg/m2/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle.
RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients.
CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.
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INTRODUCTION
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MALIGNANT ASTROCYTOMAS account for approximately 60% of all primary brain tumors in adults. They are associated with a high rate of recurrence after primary therapy and a high mortality rate. Median survival does not exceed 3 to 4 years from initial diagnosis. Malignant astrocytomas can be further separated into two grades, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), based on histology.1,2 GBMs tend to occur in a slightly older population and carry a worse prognosis than AAs. Historically, the neuro-oncology community has not separated the treatment of patients with recurrent malignant astrocytomas into the two histologic subtypes. The standard of care for primary disease in both histologic groups has been surgery and radiation therapy; adjuvant chemotherapy is still controversial. The studies by Levin et al3 have suggested a benefit from postradiotherapy adjuvant chemotherapy with procarbazine, lomustine, and vincristine (PCV) in patients with AA. No standard of care exists for recurrent disease. A recent systematic review of the literature on recurrent high-grade glioma identified only the nitrosoureas as active agents, but their usefulness at recurrence is limited by the presence of toxicities resulting from previous administration (reviewed by Rodriguez and Levin4). Therefore, new agents with a favorable toxicity profile are needed for patients with recurrent AA.
Temozolomide is an alkylating agent that has demonstrated clinical antitumor activity5-9 and a relatively well-tolerated safety profile in phase I and phase II trials in patients with various advanced cancers, including malignant gliomas.9,10 Temozolomide is rapidly absorbed after oral administration and undergoes spontaneous hydrolysis at physiologic pH to its active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC).5,11 The mechanism of action of MTIC is thought to be alkylation at the O6 position of guanine, with additional alkylation at the N7 position.12,13 Both in nonhuman primate models and in one human melanoma patient, the concentration of temozolomide measured in CSF is approximately 35% to 39% of that measured in plasma. Additionally, temozolomide achieves higher levels in human astrocytoma compared with contralateral normal brain.14 The antitumor activity and favorable side effect profile of temozolomide have prompted the evaluation of this chemotherapeutic agent in the present multicenter trial of patients with AA at first relapse.
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PATIENTS AND METHODS
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Study Design
The present study was an open-label, single-arm, multicenter phase II trial designed to evaluate the antitumor efficacy and safety profile of temozolomide in patients with AA at first relapse. Thirty-two centers (15 in the United States and 17 internationally) participated in the study. The primary objective of this trial was to evaluate progression-free survival (PFS) at 6 months and the safety of temozolomide in treated patients. This short primary end point was selected because a companion GBM trial was performed at the same time. All investigators concurred that a 6-month end point was appropriate in the GBM setting because, at that time, most patients failed to respond to the drug. It was also agreed to use a similar end point in the present trial for the purpose of comparison and to ensure uniformity of trial design. The secondary objectives were the evaluation of overall survival and the determination of health-related quality of life (HQL) and population pharmacokinetics. The original enrollment goal was 100 patients with central review-confirmed eligible histology. However, as enrollment continued during histology evaluation, the final number of patients with eligible histologies was 111, with 162 potential candidates enrolled in the intent-to-treat population.
Patient Eligibility
In this trial, patients were required to demonstrate histologically proven, supratentorial anaplastic glioma at first relapse, as assessed by independent central pathology review of all pathology slides (J.B.) based on the three-tiered system of Nelson et al and Burger et al.1,2 Histologic criteria included the presence of mitotic activity and/or microvascular proliferation and the absence of necrosis in the initial diagnostic specimen or the absence of necrosis with neoplastic pseudopalisading in the posttreatment specimen. Eligible histologies included AA and anaplastic mixed oligoastrocytoma (AOA) and were based on the most recent histologic diagnosis before study enrollment. Tumors with a significant presence of the oligodendroglia component (20% or more) were considered mixed glioma and classified as AOA. Tumors with 80% to 90% oligodendroglia component were classified as oligodendrogliomas or anaplastic oligodendroglioma. Patients had to show unequivocal evidence of tumor recurrence or progression at first relapse by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) or a contrast-enhanced computed tomography scan after failing a conventional course of radiation therapy for initial disease. The presence of assessable (measurable or nonmeasurable) enhancing residual disease documented on a baseline Gd-enhanced MRI scan was required. Multifocal disease was allowed. Only chemotherapy-naïve patients or patients previously treated with a nitrosourea in an adjuvant setting were eligible for this study. All patients were  18 years of age with a Karnofsky performance status (KPS) 70. Adequate laboratory values were required as follows: absolute neutrophil count 1,500/µL, platelet count 100,000/µL, hemoglobin greater than 10 g/dL or 100 g/L, blood urea nitrogen and serum creatinine less than 1.5 times the upper limit of laboratory normal, total and direct serum bilirubin less than 1.5 times the upper limit of laboratory normal, AST or ALT less than three times the upper limit of laboratory normal, and alkaline phosphatase less than two times the upper limit of laboratory normal. Patients were required to have been on a nonincreasing corticosteroid dose for 72 hours before baseline neuroimaging and study drug administration, to have a life expectancy greater than 12 weeks, and to have provided written informed consent.
Treatment
Temozolomide was administered for a maximum of 2 years or until unacceptable toxicity or tumor progression occurred. Chemotherapy-naive patients received temozolomide 200 mg/m2/d in a fasting state for 5 consecutive days (1,000 mg/m2 per 28-day cycle). Patients who were previously treated with any chemotherapy initially received temozolomide 150 mg/m2/d for 5 days (750 mg/m2 per cycle). In the absence of grade 3 or 4 hematologic toxicity, dosing for the following cycle could be increased to 200 mg/m2/d. Repeat cycles were administered on schedule only if the absolute neutrophil count 72 hours before the first day of the next cycle was 1,500/µL and the platelet count was 100,000/µL. Any discontinuation of treatment resulting from hospitalization, grade 4 thrombocytopenia, or low blood counts requiring administration of growth factors or transfusion was recorded as a major adverse event. Any nonhematologic or hematologic toxicity of grade 3 or 4 recorded in the previous cycle could result in dose adjustment in the following cycle at the discretion of the investigator.
Prophylactic antiemetics were permitted as needed. Neurologic stability was provided with the lowest corticosteroid dose when required. Colony-stimulating factors were permitted only for rescue from grade 4 neutropenia.
Patient Evaluation
Gd-enhanced MRI scans were performed at the principal investigators' institutions or at designated radiology facilities. Copies of all scans were centrally reviewed by a committee from Johns Hopkins University (Baltimore, MD; headed by N.Y.) The size of the enhancing tumor was defined as the product of the largest perpendicular diameters of enhancement. Nonmeasurable lesions were approximated to provide means of comparison compatible with those used for measurable lesions.
A comprehensive neurologic examination was performed at each study visit. Evaluation was based on changes in signs and symptoms from the previous examination deemed unrelated to postictal state or to such other unrelated events as infection. Relative changes were graded as definitely better (+2), possibly better (+1), unchanged (0), possibly worse (-1), or definitely worse (-2).
Objective assessments of overall response were based on tumor assessments from MRI scans interpreted in the light of corticosteroid use, as suggested by Macdonald et al,15 with appropriate support from the neurologic status tests. Briefly, complete response (CR) implies disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart and no corticosteroid use except for physiologic doses, with stable or improved neurologic condition. Partial response (PR) implies a 50% reduction in contrast enhancement for all measurable lesions or a definite improvement for all nonmeasurable lesions on consecutive MRI scans at least 1 month apart and stable corticosteroid use for 7 days before each scan at the same dose administered at the time of the previous scan or at a reduced dose, with stable or improved neurologic condition. Progressive disease implies a 25% increase in contrast enhancement for any measurable lesions or definite worsening for any nonmeasurable lesions or any new tumor on MRI scans and stable corticosteroid use for 7 days before each scan at the same dose administered at the time of the previous scan or at an increased dose, with or without neurologic progression. Stable disease (SD) applies to all other situations.
Weekly hematologic evaluation was performed. Complete blood counts were obtained during each cycle of therapy to evaluate potential hematologic toxicity and to determine the appropriate timing and dosage for each subsequent course of therapy. Other treatment-emergent adverse events were recorded and graded using the common toxicity criteria scale.
The impact of therapy on the patients' well-being was assessed by self-administration of the validated European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ-C30),16,17 termed herein QLQ-C30 (+3) because it contained three additional questions, and the recently validated malignant brain cancer module (BCM-20).18 The QLQ-C30 (+3) encompasses six HQL domains, including physical functioning, role functioning, cognitive functioning, emotional status, social functioning, and a global assessment. The BCM-20 addresses concepts of visual disorder, motor dysfunction, communication deficit, headaches, seizure, drowsiness, weakness in both legs, bladder control, uneasiness about hair loss, itchy skin, and the future. Data were collected on day 1 and at every visit throughout the study.
Statistical Analysis
PFS and overall survival were assessed by the product-limit method of Kaplan-Meier for both the ITT population and the eligible histology subgroup. The proportion of progression-free patients at 6 months was provided with a 95% confidence interval (CI) based on Kaplan-Meier estimates. Large sample CIs, based on the normal distribution, were used when the number of patients was greater than 30 and the binomial CIs were calculated when there were 30 or fewer patients.
The potential influence of baseline characteristics on PFS and overall survival was assessed using the Cox regression model. The variables included in the model were center (domestic or international), histology (AA or AOA confirmed subgroup), age, sex, prior chemotherapy, surgery at initial diagnosis, time from initial diagnosis to first relapse, time from end of radiation therapy at initial diagnosis to first relapse, and baseline KPS. Subgroup analyses were performed for both PFS and overall survival based on the prognostic variables used in the Cox model.
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RESULTS
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Patient Characteristics
One hundred sixty-two patients were entered onto this multicenter, single-arm, phase II trial. These patients constituted the ITT population. After central pathologic review, 111 (69%) of the patients had confirmed AA or AOA. Patients with a nonAA or nonAOA histology had a variety of other histologic diagnoses (Table 1). At enrollment, patients had a median age of 42 years (range, 19 to 76 years), and 57% (93 of 162) were men. Sixty-seven percent of patients (108 of 162) had a KPS 80. Sixty-eight percent of patients (110 of 162) had undergone surgical resection at the time of initial diagnosis, and the rest of the patients were diagnosed on the basis of stereotactic biopsy. All patients received radiation therapy. Nitrosourea-based chemotherapy had also been administered to 60% (97 of 162) of patients. The median time from initial diagnosis to first relapse was 15.2 months, and, at first relapse, 18% (30 of 162) of patients had had surgical resection.
Efficacy Evaluation
All efficacy analyses were performed on the ITT population. The results of the analyses performed on the eligible histology subgroup (AA plus AOA) and the ITT population were similar. PFS at 6 months, the primary protocol end point, was 46% (95% Cl, 38% to 54%) for the ITT population and 48% (95% CI, 39% to 58%) for the eligible histology subgroup. Within the eligible histology group, PFS at 6 months was 49% (95% CI, 39% to 59%) for patients with AA and 46% (95% CI, 19% to 73%) for patients with AOA. Median PFS was 5.4 months for patients in the ITT population and 5.5 months for eligible histology patients. Within the eligible histology group, the median PFS was 5.5 months for patients with AA and 5.8 months for patients with AOA. Twenty-four percent of ITT patients were progression-free at 12 months based on Kaplan-Meier estimates (Fig 1). The median overall survival was 13.6 months in the ITT population and 14.5 months in the eligible histology subgroup. Within the subgroup, median overall survival was 14.2 months for patients with AA and 14.8 months for patients with AOA. In the ITT population, the 6-month and 12-month survival rates based on Kaplan-Meier estimates were 75% (95% CI, 68% to 82%) and 56% (95% CI, 48% to 64%), respectively (Fig 1). In the eligible histology subgroup, the 6-month survival rate was 78% (95% CI, 70% to 86%) for patients with AA and 79% (95% CI, 57% to 100%) for patients with AOA.
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Fig 1. Kaplan-Meier estimates of PFS and overall survival in patients with malignant glioma treated with temozolomide (intent-to-treat population).
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A Cox regression analysis was performed to identify possible prognostic factors for PFS and overall survival. Only baseline KPS was shown to be a significant prognostic factor (P .03) for PFS and overall survival (Table 2). In addition, a subgroup analysis performed on each of the prognostic factors demonstrated the consistency of the results (Table 2). No factor, except baseline KPS, influenced either PFS or overall survival.
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Table 2. PFS and Overall Survival in Various Subgroups of Patients With Malignant Astrocytoma Treated with Temozolomide
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One of the most notable findings of the study was the high number of objective responses achieved with temozolomide. Based on the central reviewer's assessment of objective response, 8% (13 of 162) of the ITT population achieved CR; 35% (57 of 162) achieved CR or PR; and 62% (101 of 162) achieved CR, PR, or SD (Table 3). For the 13 complete responders, the PFS range was 11 months to more than 2 years, with seven patients remaining in CR beyond 16 months. For the 44 partial responders, the median PFS was 11 months and the median overall survival was 21 months. Patients with SD had a median PFS of 4.4 months. The objective response rates achieved by the eligible histology subgroup were similar, and it is important to note that patients with AA (the majority of the eligible histology population) responded to therapy (Table 3). The objective response rate observed did not depend on the history of prior chemotherapy. Sixty-nine percent of patients (45 of 65) who were chemotherapy-naive achieved an objective response, whereas only 58% of patients (56 of 97) who had received prior chemotherapy achieved an objective response (Table 4).
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Table 3. Central Reviewer's Assessment of Response to Temozolomide Administration in Patients With Malignant Astrocytoma at First Relapse
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Table 4. Central Reviewer's Assessment of Objective Response to Temozolomide Based on Prior Chemotherapy Administration in ITT Patients With Malignant Astrocytoma
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Drug Exposure
Of the 162 patients in the ITT population, 158 received at least one cycle of temozolomide. Ninety-nine percent (156 of 158) of patients received the correct starting dose based on previous chemotherapy. The majority of patients, 93% (147 of 158), received more than one cycle of temozolomide, with a median number of five cycles. Of the patients who received more than one cycle of treatment, 88% (129 of 147) were receiving either their initial dose or a higher dose at the time of their last cycle. Dose reductions occurred in only 4% of cycles (42 of 1,168). The primary reason for dose reductions was hematologic toxicity (86%, 36 of 42). After cycle 1, 40% of the cycles (404 of 1,010) were delayed; 39% of the delays were because of scheduling conflicts and 28% were caused by hematologic toxicity.
Adverse Events
The most common, probably treatment-related, adverse events were nausea (53%), vomiting (42%), headache (41%), fatigue (34%), and constipation (33%). Hematologic adverse events were minimal and included thrombocytopenia (7%), leukopenia (2%), neutropenia (2%), and anemia (1%). The majority of reports of nausea and vomiting were mild to moderate in severity and were readily controlled with standard antiemetics. The most common treatment-emergent adverse events reported during all cycles of therapy are listed in Table 5. Nine patients discontinued treatment because of adverse events. Of these, only six were deemed possibly or probably related to the study drug.
Quality of Life
Seventeen of the 162 patients in the ITT population had no baseline HQL data and were excluded from the HQL analysis population. The HQL analysis included 63 patients who were progression-free at 6 months. Baseline HQL profiles, including the QLQ-C30 (+3) functioning and symptoms scores and the BCM-20 symptoms scale scores, were similar for patients who were 6-month progression-free survivors and for those whose disease had progressed by 6 months. To assess the HQL benefit of maintaining progression-free status with temozolomide, a change from baseline analysis was carried out for the 63 temozolomide patients who were progression-free survivors at 6 months and had HQL data. The mean change from baseline values for the QLQ-C30 (+3) functioning and symptoms and BCM-20 symptoms scores (Fig 2A, B, and C, respectively) showed maintenance, if not notable improvement, in the majority of HQL domain scores. This analysis highlights the clinical benefit in terms of HQL improvement associated with achieving 6-month PFS.
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Fig 2. Mean change in QLQ-C30 (+3) functioning scores (A) and symptoms scores (B) and BCM-20 symptoms scores (C) from baseline in progression-free survivors at 6 months.
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In addition, the HQL benefit of achieving an objective response of CR or PR or of being maintained in SD was evaluated. Quality-of-life improvements and responses were tabulated for these patients and compared with those who did not achieve an objective response, as assessed by the central reviewer. Among those who achieved a CR or PR or were maintained in SD, HQL responses were consistently seen across all seven domains (Fig 3A). Additionally, HQL responses in these same domains were seen in 25% to 40% of patients with a best objective response of SD. When the analysis was restricted to patients who could show improvement (ie, those with baseline functioning scores < 90 or symptoms scores > 10), the percentage of patients achieving HQL responses increased (Fig 3B). Ninety-two percent of patients with a CR or PR achieved an HQL response in one or more domains, and 82% had an HQL response in three or more domains. With temozolomide therapy, as many as 59% of patients with SD achieved an HQL response (Table 6).
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Fig 3. Proportion of patients with improved HQL responses as a function of clinical response to temozolomide treatment; entire population (A), patients with baseline QLQ-C30 (+3) functioning scores < 90 or symptoms scores > 10 (B).
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Table 6. Number of Responses in Selected QLQ-C30 (+3) Functioning Domains and BCM-20 Symptoms Domains as a Function of Quality of Response to Temozolomide Therapy in Patients With Malignant Astrocytoma
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DISCUSSION
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The prognosis for relapsing patients with malignant astrocytoma remains poor, even when nitrosoureas are still an option.19 Recent combination therapy with carmustine (BCNU) plus interferon alfa,20,21 intra-arterial administration of BCNU with vincristine plus procarbazine,22 and other associations of BCNU or lomustine (CCNU) with various agents23-26 have not improved outcome significantly. However, recent results with combination PCV chemotherapy administered before or after radiation therapy have shown encouraging response rates and improved PFS and overall survival.27,28 Despite these encouraging results, in most cases median survival times rarely exceed 1 year, and the toxicity associated with the therapy is, on occasion, detrimental to the well-being of the patient, thus adding to disease burden. These considerations prompted us to design the present multicenter phase II trial to demonstrate the antitumor efficacy of temozolomide in a setting in which few drugs are effective and to assess the PFS and safety profile of this agent in a large population of patients with poor prognosis. To ensure consistency of findings among the different centers participating in the trial, both the assessment of eligible histologic diagnoses and the evaluation of response by Gd-enhanced MRI were conducted by independent central review, the former at the University of Texas M.D. Anderson Cancer Center and the latter at Johns Hopkins University. The lack of a standard, well-accepted, effective single-agent regimen made the choice of a control group difficult because rechallenge of a relapsing tumor with nitrosoureas, the only agents approved for initial therapy, is limited by the cumulative toxicity. Of the 162 patients entered onto the trial, 60% and 9% were confirmed to have AA and AOA, respectively, by histologic central review. Among this eligible histology population, 35% of patients demonstrated a clinically meaningful objective response, with an additional 26% showing disease stabilization. This response rate compares favorably with that observed with other agents used as monotherapy, including procarbazine, with response rates (CR + PR) of 15% to 26%,29,30 and carboplatin, with response rates of 20%.31,32 Additionally, temozolomide provided a complete response rate of 8%, comparable to that observed with either procarbazine or carboplatin.29-32 PFS at 6 months, the primary end point for the study, was 46% compared with a 10% threshold of effectiveness for agents active in this population of patients. The median overall survival of 14.5 months in the eligible histology subgroup and 13.6 months in the ITT population improves hope for patients with recurrent disease. Notably, there was no difference in efficacy in patients with AA or AOA, which demonstrated that the drug is effective in the more difficult to treat and traditionally less chemosensitive AA histologic diagnosis.
These data corroborate previously reported studies with temozolomide9 and compare favorably with the more traditional nitrosourea-based therapies.20-22 Many combination cytotoxic therapies, including CCNU, BCNU, and other agents, have produced objective response rates from 25% to 80%. Many of these trials, however, included as few as six patients33,34 and rarely exceeded 45 individuals,35-38 adding to uncertainty in the evaluation of response. The median duration of response observed in these trials ranged from 3 months33 to 13 months,39 and median survival rates averaged 6 months to 7 months20,34,36 and rarely exceeded 1 year with the most recent combinations.21,24 Additionally, some of the earlier trials relied on diagnostic techniques less precise than those currently available for the evaluation of response and disease progression. The validity of MRI scanning used in this trial was also strengthened by using an independent central reviewer to preclude variability in the interpretation of the scans from the 28 centers involved in the trial. In addition, to minimize the possibility of an inappropriate determination of response from MRI scans because of such inherent methodologic uncertainties as extrapolation of volumetric estimates from composite scans, the determination of a response as either complete or partial required the simultaneous demonstration of neurologic improvement or symptom stabilization according to corticosteroid use and neurologic status. The subjective nature of neurologic evaluation was minimized by conducting a patient self-evaluation of HQL status at baseline and during the trial. Preliminary evaluation of these data suggests that responses (as determined by MRI and corticosteroid use criteria) to therapy and maintenance of progression-free status were both associated with an improved HQL; the majority of responders did not use corticosteroids, and few patients with an improved HQL required an increase in corticosteroid use (in preparation). These data strengthen the correlation of a response, as determined by MRI scans, with neurologic status and overall well-being as experienced by the patients.
Subanalyses performed to determine the existence of prognostic factors in the patient population under evaluation revealed that baseline KPS was the only prognostic factor that correlated meaningfully with median survival. Patient age had little relationship to either median PFS or overall survival. Although many other studies have shown that chemotherapy seems to provide better overall survival rates in patients younger than 60 years of age compared with older patients, the lack of age effect in this study was not entirely unexpected because the majority of patients were younger than usual. This situation caused the selection of an age split at 45 years of age to provide a meaningful analysis.
Myelosuppression, a well-documented side effect of therapy with alkylating agents, was noncumulative with temozolomide and typically resolved with a one-dose level reduction. Consequently, therapy could be administered continuously, and although the median number of administered cycles was five, 36 patients (23%) received 12 cycles and one patient received as many as 22 cycles. Similarly, the majority of reported side effects were mild to moderate in severity. Nausea and vomiting, the most frequently reported adverse events, were also mild to moderate and could be readily controlled with the administration of standard antiemetics. The noncumulative toxicity and favorable adverse events profile of temozolomide make this agent a logical choice against recurrent malignant astrocytomas and suggest that, unlike nitrosoureas, it could be used effectively at relapse.
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APPENDIX Participants in the Temodal Brain Tumor Group Study
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The following investigators participated in the study: M. Brada, The Royal Marsden Hospital, Sutton, Surrey, United Kingdom; M. Findlay, Royal Prince Alfred Hospital, Camperdown, Australia; J. Villemure, Institut Neurologique de Montreal, Quebec, Canada; D. Stewart, Ottawa Regional Cancer Center, Ontario, Canada; D.R. MacDonald, The London Regional Cancer Center, Ontario, Canada; H.S. Poulsen, Rigshospitalet, Copenhagen, Denmark; O. Chinot, Hopital de la Timone, Marseille, France; J.-Y. Delattre, Hopital Pitie-Salpetriere, Paris, France; E. Bouffet, Centre Regional Leon Berard, Lyon, France; B. Zonnenberg, University Hospital Utrecht, Utrecht, The Netherland; M. Santos Ortega, Sanatorio San Francisco de Asis, Madrid, Spain; F. Lejeune, Kantonsspitals Basel, Basel, Switzerland; C. Zielinski, University Clinic Vienna, Vienna, Austria; L. Davila Maldonado, Hospital Angeles, Mexico City, Mexico; V. Levin, W.K.A. Yung, University of Texas M.D. Anderson Cancer Center, Houston, TX; M. Prados, University of California, San Francisco, San Francisco, CA; H. Friedman, Duke University Medical Center, Durham, NC; W. Shapiro, Barrow Neurological Institute, Phoenix, AZ; R.E. Albright, Barrett Cancer Center, Cincinnati, OH; M. Glantz, Memorial Hospital of Rhode Island, Pawtucket, RI; K. Fink, University of Texas, Southwestern Medical School, Dallas, TX; H. Greenberg, University of Michigan Medical Center, Ann Arbor, MI; N.A. Vick, N. Paleologos, Evanston Hospital, Evanston, IL; R.G. Selker, West Penn Hospital, Pittsburgh, PA; S. Rosenfeld, University of Alabama at Birmingham, Birmingham, AL; J. Olson, The Emory Clinic, Atlanta, GA; A. Spence, University of Washington, Seattle, WA; P. Phillips, University of Pennsylvania Medical Center, Hospital of the University of Pennsylvania, Philadelphia, PA; L. Dirix, Universitair Ziekenhuis Antwerpen, Edegem, Belgium; R. Engenhart-Cabillic, F.K. Albert, Klinikum der Ruprecht-Karls Universität Heidelberg, Heidelberg, Germany; B. Marques, D. Salgado, Instituto Portugues de Oncologia, Lisbon, Portugal.
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ACKNOWLEDGMENTS
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Supported in part by grants from Schering-Plough Research Institute (SPRI), Kenilworth, NJ. A.Y., M.P., M.B., H.F., N.Y., and V.L. are consultants to SPRI and have received honoraria from speaking engagements sponsored by SPRI.
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accepted April 22, 1999.
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S. L. Chua, M. A. Rosenthal, S. S. Wong, D. M. Ashley, A.-m. Woods, A. Dowling, and L. M. Cher
Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme
Neuro-oncol,
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6(1):
38 - 43.
[Abstract]
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K. Vera, L. Djafari, S. Faivre, J.-S. Guillamo, K. Djazouli, M. Osorio, F. Parker, C. Cioloca, B. Abdulkarim, J.-P. Armand, et al.
Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors
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[Abstract]
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M. Brada, L. Viviers, C. Abson, F. Hines, J. Britton, S. Ashley, S. Sardell, D. Traish, A. Gonsalves, P. Wilkins, et al.
Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas
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M. J. van den Bent, W. Grisold, D. Frappaz, R. Stupp, J. P. Desir, T. Lesimple, C. Dittrich, M. J. A. de Jonge, A. Brandes, M. Frenay, et al.
European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme
Ann. Onc.,
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[Abstract]
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L. Tentori, C. Leonetti, M. Scarsella, G. d'Amati, M. Vergati, I. Portarena, W. Xu, V. Kalish, G. Zupi, J. Zhang, et al.
Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma
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[Abstract]
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The Neuro-Oncology Working Group of the German Can
Neuro-Oncology Working Group 01 Trial of Nimustine Plus Teniposide Versus Nimustine Plus Cytarabine Chemotherapy in Addition to Involved-Field Radiotherapy in the First-Line Treatment of Malignant Glioma
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I. F. Pollack, J. M. Boyett, A. J. Yates, P. C. Burger, F. H. Gilles, R. L. Davis, J. L. Finlay, and for the Children's Cancer Group
The influence of central review on outcome associations in childhood malignant gliomas: Results from the CCG-945 experience
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[Abstract]
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M.J. van den Bent, M.J.B. Taphoorn, A.A. Brandes, J. Menten, R. Stupp, M. Frenay, O. Chinot, J.M. Kros, C.C.D. van der Rijt, Ch.J. Vecht, et al.
Phase II Study of First-Line Chemotherapy With Temozolomide in Recurrent Oligodendroglial Tumors: The European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971
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H. A. Fine, P. Y. Wen, E. A. Maher, E. Viscosi, T. Batchelor, N. Lakhani, W. D. Figg, B. W. Purow, and C. B. Borkowf
Phase II Trial of Thalidomide and Carmustine for Patients With Recurrent High-Grade Gliomas
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K. A. Jaeckle, K. R. Hess, W.K. A. Yung, H. Greenberg, H. Fine, D. Schiff, I. F. Pollack, J. Kuhn, K. Fink, M. Mehta, et al.
Phase II Evaluation of Temozolomide and 13-cis-Retinoic Acid for the Treatment of Recurrent and Progressive Malignant Glioma: A North American Brain Tumor Consortium Study
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[Abstract]
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W. J. Bodell, N. W. Gaikwad, D. Miller, and M. S. Berger
Formation of DNA Adducts and Induction of lacI Mutations in Big Blue Rat-2 Cells Treated with Temozolomide: Implications for the Treatment of Low-Grade Adult and Pediatric Brain Tumors
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[Abstract]
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M. van den Bent, O.-L. Chinot, and J. G. Cairncross
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[Abstract]
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M. J. van den Bent, O. Chinot, W. Boogerd, J. Bravo Marques, M. J. B. Taphoorn, J. M. Kros, C. C. D. van der Rijt, C. J. Vecht, N. De Beule, and B. Baron
Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972
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E. Raymond, M. Fabbro, V. Boige, O. Rixe, M. Frenay, G. Vassal, S. Faivre, E. Sicard, C. Germa, J. M. Rodier, et al.
Multicentre phase II study and pharmacokinetic analysis of irinotecan in chemotherapy-naive patients with glioblastoma
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J. A. Quinn, D. A. Reardon, A. H. Friedman, J. N. Rich, J. H. Sampson, J. M. Provenzale, R. E. McLendon, S. Gururangan, D. D. Bigner, J. E. Herndon II, et al.
Phase II Trial of Temozolomide in Patients With Progressive Low-Grade Glioma
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J. C. Buckner, D. Gesme Jr, J. R. O'Fallon, J. E. Hammack, S. Stafford, P. D. Brown, R. Hawkins, B. W. Scheithauer, B. J. Erickson, R. Levitt, et al.
Phase II Trial of Procarbazine, Lomustine, and Vincristine as Initial Therapy for Patients With Low-Grade Oligodendroglioma or Oligoastrocytoma: Efficacy and Associations With Chromosomal Abnormalities
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L. S. Lashford, P. Thiesse, A. Jouvet, T. Jaspan, D. Couanet, P. D. Griffiths, F. Doz, J. Ironside, K. Robson, R. Hobson, et al.
Temozolomide in Malignant Gliomas of Childhood: A United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study
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M. R. Gilbert, H. S. Friedman, J. F. Kuttesch, M. D. Prados, J. J. Olson, G. H. Reaman, and S. L. Zaknoen
A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy
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[Abstract]
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D. Antonadou, M. Paraskevaidis, G. Sarris, N. Coliarakis, I. Economou, P. Karageorgis, and N. Throuvalas
Phase II Randomized Trial of Temozolomide and Concurrent Radiotherapy in Patients With Brain Metastases
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K. Seiter, D. Liu, T. Loughran, A. Siddiqui, P. Baskind, and T. Ahmed
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D. B. Bocangel, S. Finkelstein, S. C. Schold, K. K. Bhakat, S. Mitra, and D. M. Kokkinakis
Multifaceted Resistance of Gliomas to Temozolomide
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W.-J. Hwu, S. E. Krown, K. S. Panageas, J. H. Menell, P. B. Chapman, P. O. Livingston, L. J. Williams, C. J. Quinn, and A. N. Houghton
Temozolomide Plus Thalidomide in Patients With Advanced Melanoma: Results of a Dose-Finding Trial
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L. Tentori, C. Leonetti, M. Scarsella, G. d'Amati, I. Portarena, G. Zupi, E. Bonmassar, and G. Graziani
Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site
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[Abstract]
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R. Stupp, P.-Y. Dietrich, S. O. Kraljevic, A. Pica, I. Maillard, P. Maeder, R. Meuli, R. Janzer, G. Pizzolato, R. Miralbell, et al.
Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide
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W. Wick, A. Wick, J. B. Schulz, J. Dichgans, H. P. Rodemann, and M. Weller
Prevention of Irradiation-induced Glioma Cell Invasion by Temozolomide Involves Caspase 3 Activity and Cleavage of Focal Adhesion Kinase
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C. R. Miller, C. R. Williams, D. J. Buchsbaum, and G. Y. Gillespie
Intratumoral 5-Fluorouracil Produced by Cytosine Deaminase/5-Fluorocytosine Gene Therapy Is Effective for Experimental Human Glioblastomas
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D. Bafaloukos, H. Gogas, V. Georgoulias, E. Briassoulis, G. Fountzilas, E. Samantas, Ch. Kalofonos, D. Skarlos, A. Karabelis, and P. Kosmidis
Temozolomide in Combination With Docetaxel in Patients With Advanced Melanoma: A Phase II Study of the Hellenic Cooperative Oncology Group
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R. B. Khan, J. J. Raizer, M. G. Malkin, K. A. Bazylewicz, and L. E. Abrey
A phase II study of extended low-dose temozolomide in recurrent malignant gliomas
Neuro-oncol,
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39 - 43.
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S. Gururangan, I. Cokgor, J. N. Rich, S. Edwards, M. L. Affronti, J. A. Quinn, J. E. Herndon II, J. M. Provenzale, R. E. McLendon, S. Tourt-Uhlig, et al.
Phase I study of GliadelTM wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas
Neuro-oncol,
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[Abstract]
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M.J. van den Bent, F. Keime-Guibert, A.A. Brandes, M.J.B. Taphoorn, J.M. Kros, F.A.L.M. Eskens, and A.F. Carpentier
Temozolomide chemotherapy in recurrent oligodendroglioma
Neurology,
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O.-L. Chinot, S. Honore, H. Dufour, M. Barrie, D. Figarella-Branger, X. Muracciole, D. Braguer, P.-M. Martin, and F. Grisoli
Safety and Efficacy of Temozolomide in Patients With Recurrent Anaplastic Oligodendrogliomas After Standard Radiotherapy and Chemotherapy
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D. M. Kokkinakis, R. M. Hoffman, E. P. Frenkel, J. B. Wick, Q. Han, M. Xu, Y. Tan, and S. C. Schold
Synergy between Methionine Stress and Chemotherapy in the Treatment of Brain Tumor Xenografts in Athymic Mice
Cancer Res.,
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Y. Ino, R. A. Betensky, M. C. Zlatescu, H. Sasaki, D. R. Macdonald, A. O. Stemmer-Rachamimov, D. A. Ramsay, J. G. Cairncross, and D. N. Louis
Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis
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N. D. Doolittle, C. P. Anderson, W. A. Bleyer, J. G. Cairncross, T. Cloughesy, S. L. Eck, P. Guastadisegni, W. A. Hall, L. L. Muldoon, S. J. Patel, et al.
Importance of dose intensity in neurooncology clinical trials: Summary Report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium
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D. Osoba, M. Brada, M. D. Prados, and W.K. A. Yung
Effect of disease burden on health-related quality of life in patients with malignant gliomas
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V. J. Patel, G. B. Elion, P. J. Houghton, S. Keir, A. E. Pegg, S. P. Johnson, M. E. Dolan, D. D. Bigner, and H. S. Friedman
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H. S. Friedman, T. Kerby, and H. Calvert
Temozolomide and Treatment of Malignant Glioma
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J. G. Cairncross
Understanding low-grade glioma: A decade of progress
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S. S. Agarwala and J. M. Kirkwood
Temozolomide, a Novel Alkylating Agent with Activity in the Central Nervous System, May Improve the Treatment of Advanced Metastatic Melanoma
Oncologist,
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION
