LOW-GRADE gliomas include astrocytomas, oligodendrogliomas,

Transcription

1 Phase II Trial of Temozolomide in Patients With Progressive Low-Grade Glioma By Jennifer A. Quinn, David A. Reardon, Allan H. Friedman, Jeremy N. Rich, John H. Sampson, James M. Provenzale, Roger E. McLendon, Sridharan Gururangan, Darell D. Bigner, James E. Herndon II, Nicholas Avgeropoulos, Jonathan Finlay, Sandra Tourt-Uhlig, Mary Lou Affronti, Brandon Evans, Valerie Stafford-Fox, Sara Zaknoen, and Henry S. Friedman Purpose: Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3- methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma. Patients and Methods: Temodar was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg/m 2 /d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar. Response criteria used a combination of magnetic resonance imaging and physical examination to evaluate activity. Results: Forty-six patients with low-grade glioma have been treated to date. The objective response rate was 61% LOW-GRADE gliomas include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. 1 Despite the designation of these tumors as low grade and the implicit pathologic assumption that they are benign, it is important to recognize that they can display an aggressive biologic course, with infiltration and destruction of normal brain. 2 Surgical resection is the treatment of choice for localized disease, and survival has been shown to correlate with the degree of resection. 3 Rarely completely respectable, with the possible exception of pilocytic astrocytomas, these tumors slowly grow over months to years with progressive neurologic dysfunction and are ultimately the cause of death in the majority of cases. Although the need for effective adjuvant therapy is obvious in this setting, the choice of which modalities and when to employ them remains problematic. Radiotherapy (RT) has traditionally been administered to patients with incompletely resected new tumors or to patients at the time of tumor recurrence if prior RT was not initially From the Departments of Surgery, Radiology, Pathology, Biostatistics and Bioinformatics (JH), Duke University Medical Center, Durham, NC; Hassenfeld Cancer Center, and Beth Israel Medical Center, New York, NY; Walt Disney Memorial Cancer Institute, Orlando, FL; and Schering-Plough Research Institute, Kenilworth, NJ. Submitted January 2, 2002; accepted October 22, Address reprint requests to Jennifer A. Quinn, MD, The Brain Tumor Center at Duke, Box 3624 Duke University Medical Center, Durham, NC 27710; quinn008@mc.duke.edu by American Society of Clinical Oncology X/03/ /$20.00 (24% complete response and 37% partial response), with an additional 35% of patients having stable disease. Median progression-free survival (PFS) was 22 months (95% confidence interval [CI], 15 to months) with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%). Toxicity observed during the study was limited to only six patients. Three patients experienced grade 3 neutropenia, with a duration greater than 3 weeks in one patient, and two patients experienced grade 3 thrombocytopenia. One patient experienced > grade 4 toxicity, with intracerebral hemorrhage, neutropenia, thrombocytopenia, sepsis, and death. Conclusion: Initial results indicate that Temodar may be active in the treatment of low-grade glioma, and thus, further evaluation of this agent in the treatment of these tumors is warranted. J Clin Oncol 21: by American Society of Clinical Oncology. employed. 4,5 However, the toxicity of RT 6,7 has provided the rationale for the use of chemotherapy to defer, or to completely avoid, RT. Chemotherapeutic agents that have been used to treat low-grade glioma include dactinomycin, vincristine, carboplatin, and etoposide (VP-16), as well as combinations of drugs, including carboplatin/vincristine, procarbazine/lomustine/vincristine, and the five-drug combination regimen incorporating vincristine, procarbazine, 6-thioguanine, dibromodulcitol, and lomustine We report a single-agent phase II trial of Temodar for patients with progressive or recurrent low-grade glioma, demonstrating substantial activity of this methylating agent against this group of tumors. Objectives PATIENTS AND METHODS The objectives of the study were twofold: to determine the antitumor activity of Temodar, including response and progression-free survival (PFS) in the treatment of adults and children with progressive low-grade glioma, including astrocytoma, oliogodendroglioma, mixed glioma, and pilocytic astrocytoma; and to evaluate the toxicity of Temodar in this patient population. Eligibility Criteria For entry into the study, patients were required to have a histologically confirmed diagnosis of primary intracranial, infratentorial, or supratentorial low-grade glioma (eg, astrocytoma, oligodendroglioma, or mixed glioma). However, biopsy was not required for patients with an intrinsic chiasmatic mass or tumor infiltration along the posterior optic tracts. All patients were required to have measurable disease on magnetic resonance imaging (MRI) or computed tomography (CT) scan. All patients, whether newly diagnosed or previously treated, were required to exhibit evidence of progressive 646 Journal of Clinical Oncology, Vol 21, No 4 (February 15), 2003: pp DOI: /JCO

2 PHASE II TRIAL OF TEMODAR IN LOW-GRADE GLIOMA primary CNS neoplasm while on a nondecreasing dose of corticosteroids. Radiographic progression was defined as a greater than 25% enlargement on sequential neuroimaging studies. Neurologic progression was defined as new and/or worsening neurologic deficits (excluding seizures), which could be localized to the area of brain tumor involvement on neuroimaging studies. Progressive disease had to have been evident after all prior interventions with chemotherapy, RT, and/or surgical resection. However, if the sole intervention included biopsy or partial resection, where less than 50% of the tumor was debulked, then progressive disease had to have been evident before or after the intervention. For patients with optic pathway gliomas, additional eligibility criteria included one or more of the following: progressive loss of vision as documented by neurological exam, increase in proptosis (the forward displacement of the eye) less than 3 mm, increase in diameter of the optic nerve of 2 mm or more on neuroimaging, and increase in the distributions of the tumor involving the optic tracts or optic radiations measured by CT or MRI using T1 (with and without contrast) and T2 imaging. The patients were required to be at least 4 years of age, have a Karnofsky performance status 70%, and have a life expectancy of greater than 12 weeks. Additional enrollment criteria included adequate pretreatment bone marrow function (hemoglobin 10 g/dl, absolute neutrophil count 1,500 cells/mm 3, platelet count 100,000 cells/mm 3 ), renal function (blood urea nitrogen and serum creatinine 1.5 times the upper limits of normal), and hepatic function (serum glutamic oxalacetic transaminase and serum glutamic pyruvate transaminase 2.5 times the upper limits of normal, and total serum bilirubin 1.5 times the upper limit of normal). For patients on corticosteroids, a stable dose for 1 week before entry into the study was required. Women of reproductive potential were required to take contraceptive measures for the duration of the therapy with Temodar. All patients were informed of the investigational nature of the study and were required to provide signed informed consent as approved by the institutional review board. The following patients were excluded from the study: pregnant women, nursing women, potentially fertile women or men who were not using an effective contraception method, and patients recovering from surgery. Patients with the following conditions were also excluded: frequent vomiting or a medical condition that could interfere with oral medication intake; known HIV positivity or AIDS-related illness; previous or concurrent malignancies at other sites, with the exception of surgically cured carcinoma-in-situ of the cervix and basal or squamous cell carcinoma of the skin; neurologic instability; poor medical risk because of nonmalignant systemic disease; and concurrent acute infection requiring treatment with intravenous antibiotics. Drug Administration and Dose Modification Temodar was commercially available from Schering-Plough Research Institute (Kenilworth, NJ) as a machine-filled, white, opaque, preservativefree, two-piece, hard gelatin capsule available in 250-mg, 100-mg, 20-mg, and 5-mg strengths. The dose was rounded to the nearest 5 mg. Patients in a fasting state received Temodar orally once a day for five consecutive days (days 1 through 5) at a starting dose of 200 mg/m 2 /d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar from the previous cycle (Table 1). Water was allowed during the fasting period, which began a minimum of 1 hour before the administration of each dose of Temodar. Patients continued fasting for 2 hours after the administration of each dose. Temodar was given to the patient with approximately 8 ounces of water over as short a time period as possible. Patients were instructed to swallow (without chewing) whole capsules in rapid succession. If vomiting occurred during the course of treatment, no redosing of the patient was allowed before the next scheduled dose. In the absence of disease progression or unacceptable toxicity, patients continued to receive Temodar for up to a maximum of 12 cycles. Growth factors were not used to induce elevations in absolute neutrophil count (ANC) for the purposes of administration of Temodar on the scheduled dosing interval or to allow treatment with Temodar at a higher dose. If Temodar was not administered to the patient on the scheduled day of dosing, the complete blood count (CBC) was repeated weekly for up to, and including, 3 weeks, until the ANC was more than 1,500 cells/mm 3 and the platelet count was more than 100,000 cells/mm 3. If these hematological criteria were met, chemotherapy was administered according to dose adjustments as follows: no dose modification for an ANC nadir 1,000 cells/mm 3 or platelet nadir 50,000 cells/mm 3 ; dose modification of 50 mg/m 2 for an ANC nadir less than 1,000 cells/mm 3 or platelet nadir less than 50,000 cells/mm 3. If the ANC remained less than 1,500 cells/mm 3 or the platelet count remained less than 100,000 cells/mm 3 at 3 weeks after the scheduled day of Temodar administration, the patient no longer received Temodar. In addition, if the patient required dose reductions to a dosage of less than 100 mg/m 2 /d, they also no longer received Temodar. For Common Toxicity Criteria (Version 2.0; National Cancer Institute, 1998), grades 3 and 4 nonhematologic toxicity dosage for the subsequent cycle was reduced by two dose levels, but the patient received no less than 100 mg/m 2 /d of Temodar. If these toxicity grades recurred at the subsequent repeat dosing, the patient was withdrawn from the study. If no further grade 3 or 4 nonhematologic toxicity occurred on subsequent repeat dosing, then the total dose of Temodar used for the next cycle was the same as the dose used during the previous cycle. Supportive Care Table 1. Characteristic Prophylactic antiemetics were permitted as needed. Patients who were taking anticonvulsants on enrollment into the study continued those medications as prescribed. Chronic oral administration of corticosteroids was used as needed to minimize effects produced by the tumor; the doses were increased to combat worsening symptoms or decreased according to the result of antitumor therapy. Evaluation During Therapy Baseline Patient Characteristics 647 Patients (n 46) % Age (yrs) Median 41 Range 7 to 61 Sex Male Female Histology Astrocytoma Oligodendroglioma Mixed 5 11 Pilocytic astrocytoma 5 11 Nonbiopsied optic pathway glioma 0 0 Prior treatment Surgery Biopsy Subtotal resection Gross total resection 5 11 Radiotherapy External beam 7 15 None Chemotherapy Carboplatin Cyclophosphamide 1 2 PCV 1 2 None MRI/CT Enhancing lesion Nonenhancing lesion Entry criteria MRI progression Neurologic progression 8 17 Abbreviations: PCV, procarbazine, lomustine, vincristine; MRI/CT, magnetic resonance imaging/computed tomography. Patients underwent physical and neurologic examinations and hematologic tests and chemistries before every 4-week cycle. Hematologic parameters

3 648 QUINN ET AL were also evaluated on day 21 of each cycle. MRI scans were performed before every odd cycle at 8-week intervals. All MRI scans were made available for central review by a neuroradiologist to determine overall radiographic response. Response to treatment was verified by the principal investigator. In cases in which there was disagreement between the neuroradiologist and the principal investigator concerning the level of radiographic response, the response that minimized the radiographic change was recorded. Neurologic performance was monitored by grading both the symptoms and the signs. A comprehensive, standardized neurologic examination was performed at each study visit. Evaluation was based on any changes in the neurologic exam from the previous examination. Changes in this exam were unrelated to postictal state or other unrelated events, such as infection. The following scale was used to designate relative changes: 2 definitely better, 1 possibly better, 0 unchanged, 1 possibly worse, 2 definitely worse. Toxicity was graded according to the National Cancer Institute s Common Toxicity Criteria. Tumor Response Criteria Response determination was based on measurable changes in tumor size as determined by CT or MRI, taking into consideration the corticosteroid requirement and the results of the neurologic examination. Complete response (CR) was defined as the complete disappearance of all enhancing or nonenhancing tumor from baseline on consecutive scans at least 8 weeks apart, with the patient not receiving corticosteroids and being neurologically stable or improved (ie, a neurologic exam score of 0, 1, or 2). Partial response (PR) was defined as 50% reduction in the size (measured as the product of the largest perpendicular diameters) of enhancing or nonenhancing tumor from baseline and maintained for at least 8 weeks, with use of a stable or reduced corticosteroid dose, and the patient being neurologically stable or improved (ie, a neurologic exam score of 0, 1, or 2). Progressive disease (PD) was defined as more than 25% increase in size of enhancing or nonenhancing tumor or any new tumor on MRI scan after 4 weeks of therapy or neurological worsening (ie, a neurologic exam score of 2) of the patient without a documented nonneurologic etiology while on a stable or increased corticosteroid dose. Stable disease (SD) was defined as any other clinical status not meeting the criteria for CR, PR, and PD that was observable for more than one course of therapy. Off-Study Criteria Patients were removed from the study if one of the following was noted: PD or recurrent disease at any time after the completion of at least one cycle of therapy as documented by MRI, recurrence of grade 3 or 4 nonhematologic toxicity, dose reduction of Temodar to less than 100 mg/m 2 /d, delay in dosing beyond 3 weeks, use of growth factor to induce elevation in ANC, and no disease progression for 12 cycles. Statistical Analysis A two-stage phase II design was used for this trial. Within each of five histologic strata astrocytoma, pilocytic astrocytoma, well-differentiated oligodendroglioma, mixed glioma, and nonbiopsied optic pathway glioma the response rate of Temodar was assessed after every two cycles of therapy. If disease control (ie, defined by CR, PR, or SD) was not attained in any of the first nine patients, we could infer with 95% confidence that the disease control rate was less than 30% and that the study should be closed. Otherwise, the study was to continue until 25 evaluable patients were accrued. With this number of patients, the disease control rate could be estimated with a standard error 10% or less. Kaplan-Meier 25 estimates were used to describe the distribution of progression-free survival (PFS) overall and within patient subgroups defined by age, histologic diagnosis, initial MRI/CT enhancement, study entry criteria (neuroimaging v neurologic progression), response, and prior therapy. PFS was defined as the time between initiation of treatment and disease progression or death from disease progression. The log-rank test was used to compare patient subgroups relative to PFS. Exact binomial confidence intervals were calculated for response rates. Exact 2 tests were used to examine the relationship between response and tumor location, prior chemotherapy, and prior RT. Statistical analyses were performed using software packages manufactured by SAS (Cary, NC), including JMP. RESULTS Enrollment of patients began in June 18, 1998, and is still ongoing. Interim analysis was performed on all patients enrolled before May 31, As summarized in Table 1, 46 patients with recurrent or progressive low-grade gliomas consented to participate in the phase II study before May 31, The median period of follow-up for patients remaining progression free was 11.2 months (range, 0.85 to 31.7 months). All patients had a Karnofsky performance status of 70%. The median age was 41 years (range, 7 to 61 years), and there was a slight male predominance (59%). Consistent with the epidemiology of CNS neoplasms in adults, the majority of patients had either an astrocytoma (35%) or oligodendroglioma (43%), whereas mixed glioma (11%), pilocytic astrocytoma (11%), and nonbiopsied optic chiasm glioma (0%) were rare. Both of the optic chiasm gliomas were biopsied and found to be pilocytic astrocytomas. At the time of enrollment, 70% of the neuroimaging studies revealed an enhancing lesion. On entry into the study, most patients (83%) showed evidence of disease progression on neuroimaging studies, except for eight (17%) patients who showed only neurologic progression. Although a small majority (52%) of patients underwent tumor resection, only a minority of patients underwent prior treatment with RT (15%) or chemotherapy (22%). Twenty-nine patients (63%) received at least one prior treatment modality including resection, RT, or chemotherapy. Five of seven patients who received prior RT underwent repeat biopsy to rule out necrosis. Of the two patients who did not have a biopsy, one patient had progression of disease on MRI outside of the radiation field, and the other had a positron emission tomography (PET) scan with [ 18 F]fluorodeoxyglucose (FDG) uptake of intermediate intensity. Both of these patients were biopsied on completion of this trial at disease progression, confirming that they had low-grade tumor and not necrosis. Tumor Histology Table 2. Patients Tumor Response Data by Histologic Diagnosis Complete Response (CR) Partial Response (PR) Stable Disease (SD) Total (CR PR SD) No. % No. % No. % No. % Astrocytoma Oligodendroglioma Mixed Pilocytic astrocytoma Overall

4 PHASE II TRIAL OF TEMODAR IN LOW-GRADE GLIOMA 649 Table 4. Median Progression-Free Survival in Various Subgroups of Patients Variable Patients Median PFS (months) P Fig 1. Progression-free survival. All efficacy analyses were performed on the total study population. Tumor response could not be determined in one patient who died after an intracerebral hemorrhage and sepsis before she completed a full cycle of Temodar. This patient was censored in the analyses for PFS at the time of death. Confirmed objective responses (ie, CR or PR) were observed in 28 of the 46 patients, resulting in a response rate of 61% (95% CI, 43% to 77%). Sixteen (35%) of the 46 patients achieved a best response of stable disease, resulting in a disease control rate (ie, CR, PR, or SD) of 96% (95% CI, 83% to 99.6%). One patient had a best response of progressive disease. Patients with stable disease, or those who showed CR or PR, all had a median PFS of 22 months. The response rates stratified by histologic diagnosis were similar and are listed in Table 2. No association was found between response and tumor location (P.586), prior chemotherapy (P.717), or prior RT (P.999). Median PFS was 22 months, with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%), as illustrated by the PFS curve in Fig 1. The median PFS, 6-month PFS, and 12-month PFS within each histologic group are summarized in Table 3. There was no significant difference in PFS between the histologic groups. PFS in relation to clinical characteristics is reported in Table 4. Age, histology, initial MRI/CT enhancement, response, and study entry criteria (ie, neuroimaging v neurologic progression) did not prove to be statistically significant determinants of PFS according to the log-rank test (P.05). However, prior chemotherapy, RT, or both proved to be statistically significant determinants of PFS according to the log-rank test (P.05). This analysis, however, should be regarded as exploratory because the low number of progressions (n 16) limits the power to detect any clinically meaningful difference in PFS. Age 45 years years Histology Astrocytoma 16 NE.462 Oligodendroglioma Mixed Pilocytic MRI/CT enhancement No 14 NE.149 Yes Entry criteria MRI progression Neurologic progression 8 NE Response SD PR CR Prior chemotherapy No Yes Prior radiotherapy No Yes Prior chemotherapy and/ or radiotherapy No 32 NE.002 Yes Abbreviations: PFS, progression-free survival; NE, nonevaluable; MRI/CT, magnetic resonance imaging/computed tomography; SD, stable disease; PR, partial response; CR, complete response. Toxicity The toxicities of Temodar treatment in these patients were limited to myelosuppression. There were two episodes of grade 3 thrombocytopenia and three episodes of grade 3 neutropenia, with one episode lasting more than 3 weeks. Tragically, one patient did not seek medical attention for grade 4 neutropenia and thrombocytopenia associated with gram-negative sepsis and died of an intracerebral hemorrhage. Because medical attention was delayed in this case, the sequence of events remains unclear. DISCUSSION The optimal management of low-grade gliomas remains unclear. Complete surgical resection is universally recommended, but the diffuse infiltrative nature of these tumors and the risk of major surgery in important areas of the brain frequently result in tumors that are incompletely resected or merely biopsied. Table 3. Progression-Free Survival Overall and by Histologic Diagnosis Tumor Histology Patients Progressions Median PFS, Months (range) 6-Month PFS Rate (range) 12-Month PFS Rate (range) Astrocytoma 16 4 NE (0.52 to 1.00) Oligodendroglioma (21.9 to ) (0.61 to 1.00) Mixed (14.1 to ) 0.80 (0.52 to 1.00) 0.80 (0.52 to 1.00) Pilocytic astrocytoma (11.8 to ) (0.30 to 1.00) Overall (15.2 to ) 0.98 (0.94 to 1.00) 0.76 (0.63 to 0.92) Abbreviations: PFS, progression-free survival; MRI/CT, magnetic resonance imaging/computed tomography; NE, nonevaluable.

5 650 QUINN ET AL Postoperative RT has been frequently used for patients with biopsies or incomplete resections of newly diagnosed, low-grade gliomas. 4,5,26-28 Many retrospective analyses have concluded that postoperative RT significantly prolongs overall survival and PFS when compared with no postoperative RT. 26,29-31 The toxicities of RT, including intellectual deterioration, endocrine dysfunction, radiation-induced necrosis, vasculopathy, and cortical atrophy, 6,7 have led to attempts to reduce the use of RT for these patients. Leighton et al 4 have shown that RT of incompletely resected tumors can be withheld until evidence of progressive disease without adversely affecting overall survival. It is important to realize that the patients in that study were rigorously followed with surveillance radiographic imaging, which presumably allows earlier intervention with RT for progressive disease. Many academic centers, including The Brain Tumor Center at Duke, will not offer additional therapy to patients with low-grade glioma who have undergone a major (75% or greater) tumor resection. These patients are closely followed, with intervention only offered if progressive disease is noted. Unfortunately, patients with clinically evident, newly diagnosed, low-grade gliomas who only receive more modest resections or biopsies require additional intervention. The toxicities of RT 6,7 have fueled efforts to design alternative strategies for treatment of these patients. Not surprisingly, the initial efforts to use chemotherapy for the treatment of low-grade glioma were initiated in pediatric patients, particularly for patients less than 5 years of age, for whom RT may be not only damaging but also neurologically devastating. Trials using dactinomycin, vincristine, VP-16, carboplatin, carboplatin/vincristine, and even five-drug combination regimens have all demonstrated unequivocal antitumor activity. The largest study to date, recently updated by Packer et al, 9 indicates that carboplatin and vincristine produced a PFS rate of 75% 6% at 2 years and 68% 7% at 3 years in 78 children ranging from 3 months to 16 years of age with newly diagnosed, progressive low-grade gliomas. Thirty-three percent of the patients demonstrated PR or CR. These results are encouraging and indicate that chemotherapy may be effective in delaying RT for the majority of children with low-grade gliomas. The Pediatric Oncology Group recently reported similar results using single-agent carboplatin for young children (ie, 6 years of age) with progressive optic pathway tumors, with the majority of children demonstrating SD or better. 13 RT seems to have equally devastating effects in adults as it does in children. In the hope of delaying RT or avoiding it altogether, efforts to use chemotherapy to treat adults with low-grade gliomas were initiated. These studies were initiated with the awareness that the most common type of low-grade glioma in children treated with chemotherapy, pilocytic astrocytoma, was unlikely to be the target tumor in adults. Indeed, all chemotherapeutic trials of adults with low-grade glioma have included, almost exclusively, grade 2 astrocytomas, oligodendrogliomas, or mixed tumors, reflecting the prevalence of these tumors in adults. Nevertheless, previous studies have confirmed the benefit of carboplatin and a combination of procarbazine, lomustine, and vincristine (PCV) for adults with low-grade glioma These regimens, unlike Temodar, require intravenous administration and, in the case of PCV, may produce substantial and progressive hematopoeitic toxicity. The activity of Temodar in high-grade glioma led us to initiate a trial in 1998 of this agent in adults with progressive or recurrent low-grade gliomas. 35 Our results demonstrated activity and minimal toxicity for this agent in this group of low-grade tumors. Although the current trial s response rate of 61% is high, similar trials, in which progressive, low-grade gliomas were treated with combination chemotherapy, have reported equally high response rates. Response rates of 62%, 69%, and 63% were recorded in two prospective and one retrospective clinical trial, respectively, in which adults with recurrent or progressive oligodendrogliomas or mixed oligoastrocytomas received PCV. 19,23,36 Children with progressive low-grade gliomas have shown similar response rates of 62% and 56% when treated with carboplatin and vincristine, respectively, 9,37 and 67% when treated with carboplatin plus VP Although the percentage of patients in our study with enhancing abnormalities (ie, enhancing lesions) on MRI or CT seems high, a plausible explanation can be found. Prior retrospective studies on low-grade gliomas have determined the presence of enhancement on neuroimaging studies at initial diagnosis, not at disease progression as ascertained in this study. This finding would suggest that as the disease progresses, an accumulation of enhancement abnormalities on neuroimaging studies ensue. This idea is supported by the prospective study published by Soffietti et al, 23 in which patients with recurrent low-grade glioma were treated with PCV. Although on initial diagnosis, only 38% of patients showed enhancement on MRI or CT scans, once disease progression was evident, another 35% of patients scans showed enhancement. In other words, 73% of patients showed enhancement on disease progression, which is twice as many as those who had enhancement at initial diagnosis. Although the discernment of contrast enhancement on neuroimaging studies on initial diagnosis was not determined in this trial, 70% of patients had contrast enhancement on disease progression, which now may seem plausible. The results in our trial are supported by two other trials using a similar regimen and dose of Temodar in adults with low-grade glioma. 39,40 Although follow-up is still relatively short in all three trials, the documented activity and modest toxicity of this agent strongly support further evaluation of Temodar as a treatment for adults and children with low-grade glioma. ACKNOWLEDGMENT We thank the following health care professionals for providing clinical care to these patients: Susanne Jackson, Deborah Allen, Karen Ziegler, Waynette Buchanan, Kara Penne, Christy Lentz, Cindy Bohlin, Steve Silver, Elaine Martel, Joan Cahill, and Susan Boulton.

6 PHASE II TRIAL OF TEMODAR IN LOW-GRADE GLIOMA Bigner DD, McLendon RE, Bruner JM (eds): Russell and Rubenstein s Pathology of Tumors of the Nervous System (ed 6). London, Edward Arnold, 1998, pp Davis FG, Freels S, Grutsch J, et al: Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: An analysis based on Surveillance, Epidemiology, and End Results (SEER) data, J Neurosurg 88:1-10, Wallner KE, Gonzales M, Sheline GE: Treatment of oligodendrogliomas with or without postoperative irradiation. J Neurosurg 68: , Leighton C, Fisher B, Bauman G, et al: Supratentorial low-grade glioma in adults: An analysis of prognostic factors and timing of radiation. J Clin Oncol 15: , Karim AB, Maat B, Hatlevoll R, et al: A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study Int J Radiat Oncol Biol Phys 36: , Cohen L, Schultheiss TE, Kennaugh RC: A radiation overdose incident: Initial data. Int J Radiat Oncol Bio Phys 33: , Olson JD, Riedel E, DeAngelis LM: Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurol 54: , Packer RJ, Sutton LN, Bilaniuk LT, et al: Treatment of chiasmatic, hypothalamic gliomas of childhood with chemotherapy: An update. Ann Neurol 23:79-85, Packer RJ, Ater J, Allen J, et al: Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86: , Friedman HS, Krischer JP, Burger P, et al: Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: A pediatric oncology group randomized phase II study. J Clin Oncol 10: , Moghrabi A, Friedman HS, Burger PC, et al: Carboplatin treatment of progressive optic pathway gliomas to delay radiotherapy. J Neurosurg 79: , Prados MD, Edwards MSB, Rabbitt J, et al: Treatment of pediatric low-grade gliomas with nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 32: , Mahoney DH, Cohen ME, Friedman HS, et al: Carboplatin is effective therapy for young children with progressive optic pathway tumors: A pediatric oncology group phase II study. Neuro-Oncol 2: , Friedman HS, Lovell S, Rasheed K, et al: Treatment of adults with progressive oligodendroglioma with carboplatin (CBDCA): Preliminary results. Med Pediatr Oncol 31:16-18, Cairncross JG, Macdonald DR: Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23: , Macdonald DR, Gaspar LE, Cairncross JG: Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neuro 27: , Paleologos NA, Vick NA, Kachoris JP: Chemotherapy for low-grade oligodendrogliomas? Ann Neurol 36: , Cairncross JG, Macdonald DR, Ramsay DA: Aggressive oligodendroglioma: A chemosensitive tumor. Neurosurg 31:78-82, Glass J, Hochberg FH, Gruber ML, et al: The treatment of oligodendroglioma and mixed oligodendroglioma-astrocytomas with PCV chemotherapy. J Neurosurg 76: , Cairncross G, Macdonald DR, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 12: , 1994 REFERENCES 21. Mason WP, Krol GS, DeAngelis LM: Low-grade oligodendroglioma responds to chemotherapy. Neurol 46: , Soffietti R, Chio A, Moccellini C, et al: Response of oligodendroglial tumors to PCV chemotherapy. Neurol 44: , Soffietti R, Ruda R, Bradac GB, et al: PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurg 43: , Soffietti R, Ruda RR, Borgognone M, et al: Chemotherapy with PCV for low-grade nonenhancing oligodendrogliomas and oligoastrocytomas. Neurol 52:A423-A424, 1999 (abstr) 25. Kleinbaum DG: Survival Analysis: A Self-Learning Text. Springer, New York, 1996, pp Shaw EG, Scheithauer BW, Gilbertson DT, et al: Post-operative radiotherapy of supratentorial low-grade gliomas. Int J Radiat Oncol Biol Phys 16: , Shaw EG, Scheithauer BW, O Fallon JR, et al: Oligodendrogliomas: The Mayo Clinic experience. J Neurosurg 76: , Levin VA: Controversies in the treatment of low-grade astrocytomas and oligodendrogliomas. Curr Opin Oncol 8: , Laws ER, Taylor WF, Clifton MB, et al: Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg 61: , Shibamoto Y, Kitakabu Y, Takahashi M, et al: Supratentorial lowgrade astrocytoma. Correlation of computed tomography findings with effect of radiation therapy and prognostic variables Cancer 72: , Garcia DM, Fulling KH, Marks JE: The value of radiation therapy in addition to surgery for astrocytomas of the adult cerebrum. Cancer 55: , Friedman HS, McLendon RE, Kerby T, et al: DNA mismatch repair and O 6 -alkylguanine-dna alkytransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 16: , Yung A, Prados M, Poisson M, et al: Multicenter Phase II trial of temozolomide in patients with malignant astrocytoma at first relapse. J Clin Oncol 17: , Yung A, Levin VA, Brada M, et al: Randomized, multicenter, open-label, phase II, comparative study of temozolomide and procarbazine in the treatment of patients with glioblastoma multiforme at first relapse. Br J Cancer 83: , Quinn JA, Rich JN, Cokgor I, et al: Phase II trial of temodar for progressive low-grade glioma. Presentation: Society of Neuro-Oncology, November 9-12, 2000, Chicago, Illinois. Neuro-Oncol 2:173, van den Bent MJ, Kros JM, Heimans JJ, et al: Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU and vincristine chemotherapy Neurol 51:1140, Packer RJ, Lange B, Ater J, et al: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol 11:850, Castello MA, Schiavetti A, Varrasso G, et al: Chemotherapy in low-grade astrocytoma management. Child s Nerv Syst 14:6, van den Bent MJ, Eskes FALM, Keime-Guibert F, et al: Temozolomide chemotherapy in recurrent oligodendroglioma. Neuro-Oncol 2:217, Brada M, Viviers L, Murphy P, et al: Phase II trial of primary chemotherapy with temozolomide in patients with low-grade cerebral gliomas. Neuro-Oncol 2:27, 2000