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Neuro Oncol. 2009 April; 11(2): 167–175.
PMCID: PMC2718988

Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131

Abstract

The primary objectives of this phase II study were to evaluate the use of preirradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma (MOA). Preirradiation temozolomide (150 mg/m2/day) was given on a 7-day-on/7-day-off schedule for up to six cycles. The primary end point was the response rate during the 6-month, pre-RT chemotherapy. Tumor tissue was analyzed for the presence of chromosomal deletions on 1p and 19q and for MGMT-promoter methylation. Forty-two patients were enrolled; 39 were eligible. The objective response rate was 32% (6% [complete response, CR], 26% [partial response PR]), and the rate of progression during pre-RT chemotherapy was 10%. The worst nonhematological toxicity was grade 4 in three patients (8%). Twenty-two patients completed concurrent chemotherapy and RT. There were no grade 4 nonhematological toxicities during the concurrent chemotherapy and RT. Seventeen of 28 (60.7%) evaluable cases had codeletion of 1p/19q; all 17 were free from progression at 6 months. Sixteen of 20 (80%) evaluable cases had MGMT-promoter methylation; all 16 were free from progression at 6 months. In conclusion, the rate of progression of 10% during pre-RT temozolomide chemotherapy for newly diagnosed AO and MAO compared favorably with prior experience with pre-RT PCV chemotherapy (20% in RTOG 9402). The toxicity of the dose-intense pre-RT regimen used in this study may warrant evaluation of other, less intense dosing strategies. Future studies will need to prospectively stratify patients according to the presence of deletions of chromosomes 1p and 19q.

Keywords: 1p/19q loss of heterozygosity, MGMT, oligo-dendroglioma, RTOG, temozolomide

Anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma (MOA) represent about 5% of primary brain tumors.1 While standard treatment for these tumors has included maximally feasible resection and radiotherapy (RT), there has been long-standing interest in the use of chemotherapy as well. Prior to FDA approval of temozolomide, most gliomas had been treated with resection followed by radiotherapy alone or additional carmustine or a combination regimen that included procarbazine, lomustine, and vincristine (PCV).2,3 Interest in the use of chemotherapy for these tumors was further driven by the discovery of an identifiable subset of tumors that harbor loss of heterozygosity (LOH) of chromosomes 1p and 19q, which render them highly responsive to adjuvant therapies.4,5 The presence of 1p/19q LOH, which is likely the result of a chromosomal translocation,6 has been shown to be associated with radiosensitivity, chemosensitivity, and prolonged survival.4,5,710 Those patients who had tumors with deletion of the 1p chromosome had a 100% response rate to adjuvant therapy and a median survival in excess of 10 years.5

The addition of PCV chemotherapy, either before or after RT, has been investigated in two large phase III randomized trials (RTOG 9402 and EORTC 26951).11,12 While neither trial showed an overall survival (OS) advantage with the addition of chemotherapy to RT, subset analysis of patients whose tumors harbored combined 1p and 19q LOH (1p/19q codeletion) showed that these patients had a longer progression-free survival (PFS) with the up-front use of chemotherapy. In addition, patients with 1p/19q codeletion had longer OS and PFS, regardless of treatment arm than did the patients whose tumors had LOH of either one or neither chromosome. However, the use of PCV in these trials was associated with significant levels of toxicity, which limits enthusiasm for the broad application of this regimen, particularly for those patients who are predicted to have lengthened survival.

Temozolomide is a cytotoxic alkylating agent that has a less toxic profile than PCV and that has demonstrated clinical antitumor activity against high-grade gliomas, including oligodendrogliomas, both at initial diagnosis and relapse.1318

Preirradiation or neoadjuvant chemotherapy has several potential advantages. First, in the absence of radiation-induced vascular changes, drug delivery to the tumor is maximized. Second, neoadjuvant chemotherapy allows early treatment of infiltrating tumor cells that may be at or beyond the border of the radiation port. Further, preirradiation chemotherapy allows a true assessment of the efficacy of chemotherapy. Combined chemotherapy with RT with the use of low-dose, daily temozolomide has been used with acceptable levels of toxicity and enhanced clinical benefit in patients with glioblastoma.19 The primary objectives of this phase II study were to evaluate response rate, time to progression, and toxicity of preirradiation chemotherapy with temozolomide followed by concurrent temozolomide and RT in patients with AO and MOA.

Patients and Methods

Patients aged ≥ 18 years with a newly diagnosed, supra-tentorial AO or MOA were eligible. Anaplasia was based on an evaluation of the following five microscopic features: tumor cellularity, nuclear pleomorphism, mitotic activity, vascular proliferation, and necrosis. To be classified as an anaplastic glioma, the tumor had to include two anaplastic features, one of which was frequent mitoses or endothelial proliferation. A 25% or greater oligodendroglial component was required for the diagnosis of MOA. Pathology was confirmed by central pathology review. Patients with prior suspected or proven low-grade glioma were eligible provided they had a currently biopsy-proven pure or mixed anaplastic oligodendroglioma and had not been treated with either RT or chemotherapy. Eligible patients also had a Zubrod 0 or 1; absolute granulocyte count ≥ 1,500/mm3; platelet count ≥ 100,000/mm3; hemoglobin ≥ 10 g/dl; serum creatinine ≤ 1.5 × normal; bilirubin and alkaline phosphatase ≤ 2 × normal; aspartate aminotransferase (AST) ≤ 3 × normal; life expectancy > 12 weeks; and no medical problems unrelated to the malignancy that would pose an undue risk or that would limit full compliance with the study.

Patients were excluded if they had tumor predominantly located in the posterior fossa (i.e., brain stem or cerebellum) or in the spinal cord, evidence of spinal drop metastasis or spread to noncontiguous meninges (MRI of the spine was not required in asymptomatic patients, and patients were not excluded based on pathologic evidence of local meningeal infiltration by underlying tumor); prior malignancy (excluding carcinoma in situ of the cervix or nonmelanomatous skin cancer) unless disease free for at least 3 years; prior radiotherapy to the brain, head, or neck; prior chemotherapy for this malignancy; active infectious process; surgery requiring general anesthesia ≤ 14 days before the start of treatment; or if they were pregnant or nursing (as it is unknown what effects temozolomide has on a developing fetus). Women of childbearing potential and sexually active men were required to agree to use a reliable form of birth control. All study centers had institutional review board approval, and all patients signed a study-specific informed consent prior to study entry.

Study Design and Treatment

Patients were registered only after pretreatment evaluation was completed and eligibility criteria, including central pathology review, were met. Within 6 weeks following completion of pre-RT chemotherapy and evaluation of responses, all patients were reregistered for the second phase of the study (RT plus temozolomide or observation). All patients were to receive the same therapeutic regimen.

Pre-RT temozolomide chemotherapy was administered orally at 150 mg/m2/day on days 1–7 and days 15–21 of a 28-day cycle (7 days on/7 days off). The planned duration of preirradiation therapy was six cycles, and CT/MRI scans were obtained every 8 weeks. Nonprogressing patients (i.e., responders, or those who had stable disease or absence of evaluable disease) continued to receive treatment until two cycles after maximum response (up to six cycles). Temozolomide was discontinued (and RT started) for treatment delays in excess of 8 weeks between cycles, unacceptable toxicity, CT- or MRI-documented tumor progression, clinical deterioration (which in the judgment of the treating physician was due to disease progression), or patient withdrawal from the study. Dose reductions but not escalations were permitted for toxicity.

The dose of temozolomide during RT was 75 mg/m2/ day for 42 days. During concurrent radiation-temozolomide therapy, patients were provided with prophylaxis against Pneumocystis pneumonia with trimethoprim sulfamethoxazole double-strength tablets three times per week. Acceptable alternatives to trimethoprim sulfamethoxazole included either dapsone 50 mg twice daily or aerosolized pentamidine 300 mg by nebulizer every 4 weeks (i.e., two doses during radiation). This prophylactic therapy was discontinued at the end of RT, which was given in 1.8 Gy per fraction (to isocenter), 1 fraction per day, 5 days per week, to a total of 59.4 Gy in 33 fractions. No further adjuvant therapy after completion of the RT was specified by the clinical protocol.

The target volumes were based on an MRI scan (T2 and T1 gadolinium-enhanced images) obtained within 2 weeks of the start of RT, that is, at the end of pre-RT chemotherapy and not upon the MRI at the time of study entry. The initial 50.4 Gy in 28 fractions included an initial target volume (T2-MRI plus a 2-cm margin). The final 9 Gy in five fractions included a boost volume (T1-enhanced MRI plus 1-cm margin). The target volumes received 95%–105% of the prescribed dose. Mega-voltage machines of energy ≥ 4 MV were required for treatment delivery. RT was required to begin no later than 6 weeks after completing the final cycle of temozolomide (i.e., within 6 weeks of day 28 of the final cycle of temozolomide), blood counts permitting.

If there was no measurable disease on MRI (including FLAIR/T2 sequences) following the completion of six cycles of temozolomide (complete response [CR]), then RT was not given, and the patient was observed until the study end point (postchemotherapy, pre-RT therapy progression) was reached. Verification of CR was performed by central review.

Corticosteroid therapy was permitted for cerebral edema, anticonvulsants were permitted for seizures, and antiemetics were permitted for nausea or vomiting. All patients received granisetron 1 mg or dolasetron 100 mg 1 hour before each dose of temozolomide. Deletions of chromosomes 1p and 19q were determined by fluorescent in situ hybridization (FISH) analysis of paraffin-embedded, fixed tumor tissue samples. The primary end point of this trial was the rate of postchemotherapy, pre-RT therapy progression. The study also assessed the toxicity of concurrent administration of temozolomide and RT in this patient population and OS.

Surveillance and Follow-up

Baseline assessments included a CBC with differential, electrolytes, glucose, creatinine, bilirubin, AST/alanine aminotransferase (ALT), alkaline phosphatase, chest x-ray, CT or MRI, and a complete physical and neurological examination including a mini-mental–status examination. During the pre-RT temozolomide therapy, CBC and blood chemistries were checked, and toxicity was assessed before the start of each new cycle. These assessments also included steroid-dosing assessment and mini-mental status. Biweekly assessments of CBC, blood chemistries, and toxicity were assessed during the combined chemoradiotherapy. Mini-mental status was reassessed at the end of RT. CT or MRI was performed every 8 weeks during pre-RT therapy and within 4 months after completion of RT. Follow-up assessments, including mini-mental status and corticosteroid requirements, were performed at 9 and 12 months in year 1, every 4 months in year 2, every 6 months in years 3–5, and then annually until progression or death. Tumor progression was modified from Macdonald et al.,20 and it included assessment of residual enhancing, nonenhancing, or minimally enhancing tumor; progression was defined as a > 25% increase in tumor area (two diameters) provided that the patient had not had his or her dose of steroids decreased since the last evaluation period. CR required a confirmatory imaging examination at a minimum of 4 weeks after the first determination of CR. The National Cancer Institute Common Toxicity Criteria version 2.0 and RTOG/EORTC Late Radiation Morbidity Scoring Scheme Criteria were employed to grade observed toxicity.

FISH Analysis

FISH was performed as previously described.8 Briefly, locus-specific FISH probes mapping to 1p36, 1q24, 19p13.1, and 19q13.3 were purchased from Abbott, Inc. (Downers Grove, IL, USA). The bacterial artificial chromosome clones composing the locus-specific probes mapping to 1p36 and 19q13.3 were selected based on previous reports that the clones map to regions of common allelic loss in gliomas. All FISH probes used for these analyses were previously developed by the Mayo Clinic group,8 and the capacities of these probes to detect alterations of chromosomes 1p and 19q have been validated by comparison with LOH and comparative genomic hybridization (CGH) analyses.21

For each case, a paraffin-embedded tumor block was selected based on tumor content, including the highest grade component and representation of the predominant morphology of the individual case. Approximately 20 5-μm sections were prepared for various studies from each selected tumor block. The first and last sections were hematoxylin-and-eosin stained, regions representing tumor and normal tissue were delineated, and the first section was examined to ensure that it met the standards by which the block was selected. Importantly, for the present study, FISH analyses were performed using the sections immediately adjacent to the first hematoxylin-and-eosin–stained slide to minimize the effects of tumor heterogeneity. Ranges for normal FISH probe copy number were established by hybridizing and enumerating gliosis specimens and through extensive comparisons of FISH, LOH, and CGH data.21 A Zeiss Axioplan microscope (Thornwood, NY, USA) equipped with a triple-pass filter (DAPI/Green/Orange; Abbott, Downers Grove, IL, USA) was used to assess the number of FISH signals for each locus-specific FISH probe. Approximately 60 nonoverlapping nuclei were enumerated per hybridization.

Methylation-Specific PCR Analysis of MGMT

DNA methylation patterns in the CpG island of the MGMT gene were determined by chemical modification of unmethylated, but not the methylated, cytosines to uracil and subsequent PCR using primers specific for either methylated or the modified unmethylated DNA.22 Primer sequences of MGMT were for the unmethylated reaction 5'-TTTGTGTTTTGATGTTTGTAG-GTTTTTGT-3' (upper primer) and 5'-AACTCCA-CACTCTTCCAAAAACAAAACA-3' (lower primer) and for the methylated reaction 5'-TTTCGACGTTCG-TAGGTTTTCGC-3' (upper primer) and 5'-GCACTCT-TCCGAAAACGAAACG-3' (lower primer). The annealing temperature was 59°C. Placental DNA treated in vitro with Sss I methyltransferase (New England Bio-labs, Ipswich, MA, USA) was used as a positive control for methylated alleles of MGMT, and DNA from normal lymphocytes was used as a negative control for methylated alleles of MGMT.

Briefly, 1 μg of DNA was denatured by NaOH and modified by sodium bisulfite. DNA samples were then purified using Wizard DNA purification resin (Promega Corp, Madison, WI, USA), again treated with NaOH, precipitated with ethanol, and resuspended in water. Controls without DNA were performed for each set of PCRs. Preamplification with flanking bisulfite-specific primers was used prior to methylation-specific PCR analysis. Each PCR reaction (10 μl) was directly loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and visualized under UV illumination.

Statistical Analysis

This phase II study was designed to have 80% power to determine if pre-RT chemotherapy with temozolomide achieves a 6-month progression rate of 5% for newly diagnosed anaplastic oligodendroglioma and mixed anaplastic oligoastrocytoma patients. The null hypothesis was a rate of progression of 20%, based on the results of RTOG 9402, which included a similar patient population.11 Based on this design, it was concluded that if ≤ 4 of the first 35 evaluable patients had progressed within 6 months, then the null hypothesis would be rejected in favor of the alternative, and we would conclude that pre-RT temozolomide merited further investigation in a phase III setting.

Frequency tables with counts and percentages were used to describe pretreatment characteristics, adverse events, and compliance-review results. OS and PFS were estimated using the Kaplan-Meier method.23 An event in OS was death due to any cause. An event in PFS was death due to any cause or progression (determined by CT or MRI scans). OS and PFS were estimated from the date of registration. The log-rank test24 was used to compare the survival curves of 1p/19q deleted versus one or neither deleted. Two-sided Fisher exact tests were used to compare the distributions of survival status (alive vs. dead) by 1p/19q deletion status (1p/19q deleted vs. one or neither deleted) and by MGMT status (unmethylated vs. methylated). The same analysis was done for progression status (progression vs. no progression).

Results

Patients

From July 30, 2002, to April 30, 2004, 42 patients from 18 institutions were enrolled. Three patients were deemed ineligible: one site that had enrolled one patient did not submit data and resigned from the study; one patient refused protocol treatment prior to the start of therapy; and one patient did not meet eligibility criteria (ineligible Zubrod score). For the remaining 39 patients, the median age was 45 years (range, 18–71 years); 21 (54%) were male; 35 (90%) had at least a partial resection; 20 (51%) had minor, 4 (10%) had moderate, and 15 (38%) had no neurological symptoms; 32 (82%) had a normal mental status; and 26 (67%) had an oligodendroglioma or an oligo-dominant mixed glioma (see Table 1). FISH analysis for 1p/19q deletion could be performed in 36 (92.3%) of 39 cases. The median duration of follow-up for all patients was 29.4 months (range, 2.8–50.4 months).

Table 1
Pretreatment characteristics (n = 39 patients)

Patient Disposition and Treatment Delivery

Chemotherapy was delivered per protocol to all 39 patients. Twenty-five patients (64.1%) received all six cycles of pre-RT temozolomide. Ten patients (25.6%) received fewer than six cycles secondary to tumor progression (5.1%), withdrawal from the protocol (10.2%), or unacceptable toxicity or concurrent illness (10.2%). An additional three patients (8.7%) were reported as having completed six cycles, but documentation of the date or dose of the final cycle was incomplete. One patient received eight cycles of pre-RT chemotherapy. There were no grade 5 toxicities. The worst nonhematological toxicity was less than grade 3 in 29 patients (74.4%), and it consisted most frequently of nausea or vomiting, fatigue, or changes in AST/ALT. Nine patients reported a total of 15 grade 3 or 4 nonhematological toxicities: deep venous thrombosis (1), fatigue (1), nausea or vomiting (1), blurred vision (1), headache (1), other pain (one case each of arthralgia and myalgia), pulmonary disorders (one case of pneumonitis, one acute respiratory distress syndrome [ARDS], and one dyspnea), second malignancy (1), skin reaction to phenytoin (1), infection (1), and irregular menses (2). Fifteen patients (38.5%) developed grade 3 bone marrow suppression. A summary of the toxicities associated with pre-RT chemotherapy is shown in Table 2.

Table 2
Pre-radiotherapy temozolomide toxicity (n = 39 patients)

Primary end point evaluation is shown in Table 3. Evaluation of the primary end point required that there be 6-month scans (MRI or CT) available for review; however, there were 8 (21%) patients who did not have their CT or MRI centrally reviewed, thereby leaving 31 (79%) available for evaluation. Since the targeted accrual for the primary end point of this study was 35 and only 31 patients had 6-month progression data, the parameters for the rejection criteria of the primary end point hypothesis test needed to be adjusted. The revised rejection criterion stipulated that if ≤ 3 of all 31 patients progressed within 6 months, then the null hypothesis would be rejected, and the primary end point would be met. Of these 31 patients, 3 (10%) had progression within the first 6 months; hence, the null hypothesis rate of 20% progression was rejected in favor of the alternative hypothesis rate of 5%. Induction temozolomide appears to have decreased the progression rate for patients with anaplastic oligodendrogliomas compared to the RTOG 9402 historical control, which used PCV chemotherapy. A complete summary of the response characteristics of the patients to pre-RT temozolomide is shown in Table 3.

Table 3
Primary end point results from the 6-month scan (MRI or CT) review

Twenty-two patients completed concurrent chemotherapy and RT per protocol. Of the original 39 patients, 8 withdrew due to patient refusal to continue therapy or toxicity; 3 had tumor progression and underwent further therapy off-protocol; 1 had stable disease (SD) and did not receive RT due to physician preference; 1 had SD and did not receive RT due to incarceration in prison; and 4 had CR or absence of evaluable disease and therefore did not receive RT as specified in the protocol. All 22 patients completed combined chemoradiotherapy as specified. This therapy was well tolerated; there were no grade 4 or 5 toxicities. The worst nonhematological toxicity was grade 3 in four patients (one each of nausea or vomiting, irregular menses, tremor, and motor neuropathy or speech impairment), and four patients had grade 3 bone marrow suppression. A summary of the toxicities observed during concurrent chemoradiotherapy is shown in Table 4.

Table 4
Concurrent radiotherapy and temozolomide toxicity (n = 22 patients)

The median follow-up time for patients still alive was 30.3 months (range, 2.8–50.4 months); 8 patients died. The OS and PFS at 30 months for all patients, including those without 6-month scans, were 81% and 64%, respectively (Fig. 1). There were 13 failures for progressive disease (PD), and the salvage treatment given for these progressions included surgery (62%), chemotherapy (54%), and RT or radiosurgery (46%).

Fig. 1
Kaplan-Meier curves showing overall survival (top) and progression-free survival (bottom) of all patients.

Analysis of 1p/19q Chromosome Losses

FISH analysis for 1p/19q deletion could be performed in 36 (92.3%) of 39 cases; 23 tumors (63.9%) had LOH of chromosome 1p, 24 tumors (66.7%) had LOH of chromosome 19q, and 22 tumors (61.1%) had 1p/19q codeletion. Of the 13 tumors described as pure oligodendrogliomas, 10 (76.9%) had a codeletion of 1p/19q. Of the remaining 12 tumors with a codeletion, 7 (58.3%) were oligo-dominant, 5 (41.7%) were equally oligo and astro, and none were astro-dominant.

Twenty-eight cases had informative 1p/19q data and were evaluable for progression at 6 months. Of these 28 cases, 17 (60.7%) had codeletion of 1p/19q. Three of the four patients with CR or absence of evaluable disease had codeletion of 1p/19q. Six of eight cases with PR were evaluated by FISH; five of these had codeletion of 1p/19q. Nine of the 16 patients with SD also had codeletion of 1p/19q. Two of the three patients who progressed on therapy had analysis of their tumors, and both tumors were intact at both loci. Hence, all 17 of the patients with a combined 1p/19q deletion were free from progression at 6 months (Table 5). However, the relationship between 1p/19q codeletion and 6-month progression was not statistically significant (p = 0.15; two-sided Fisher exact test), likely due to the small number of cases. When progression at any time was taken into consideration, there was a total of 36 cases with informative 1p/19q data. There were 11 cases of progression, of which 8 (72.7%) had one or neither deletion; 25 cases showed no progression, of which only 6 (24%) had one or neither deletion (Table 6). In this case, the presence of a 1p/19q codeletion was associated with a reduced risk of progression (p = 0.01; two-sided Fisher exact test) and an improved PFS (Fig. 2).

Fig. 2
Kaplan-Meier curves showing progression-free survival of patients based on tumor 1p/19q status.
Table 5
1p/19q deletion status versus 6-month scan
Table 6
1p/19q deletion status versus progression at any time for all patients

Eight of the 36 patients with 1p/19q data died; two had a 1p/19q codeletion. The presence of a 1p/19q code-letion predicted improved survival (p = 0.04; two-sided Fisher exact test).

MGMT analysis was performed on a total of 25 patients. Of these, 20 also had evaluable scans at 6 months. Sixteen (80%) of the 20 patients had tumors with MGMT-promoter methylation; none of these 20 patients showed progression at 6 months, so the relationship between MGMT promoter methylation and progression during pre-RT temozolomide could not be evaluated. However, 13 (81%) of the 16 tumors with MGMT promoter methylation also had 1p/19q codeletion (p = 0.06; two-sided Fisher exact test). The presence of MGMT promoter methylation was not associated with prolonged survival (p = 0.99; two-sided Fisher exact test).

Discussion

Prior evaluation in phase III trials of the role and timing of PCV in the treatment of AO and MAO showed a favorable impact on PFS, particularly in tumors with a 1p/19q codeletion but no impact on survival compared to initial therapy with RT alone.11,12 However, the improvement in PFS came at a cost of significant toxicity associated with the PCV regimen. Other clinical trials in a variety of grades of glioma have suggested that temozolomide produces an improved response rate with less toxicity than does PCV chemotherapy.9,17,18,25 In addition, temozolomide given together with RT has shown significant activity in grade IV glioma.16 The primary goal of the current study was to generate preliminary prospective data to evaluate whether neoadjuvant temozolomide would provide an improved response rate with less toxicity relative to PCV and also whether the addition of combined chemoradiotherapy would be associated with an acceptable rate of toxicity.

We found that only 3 of 31 evaluable patients had radiographic progression during the 6-month neoadjuvant phase. This result met our statistical criterion for showing an improved freedom from progression compared to what had been observed in RTOG 9402 when PCV chemotherapy had been provided as neoadjuvant therapy.11 However, we are aware that this is a relatively small cohort of patients, and that eight patients (20.5%) who met entry criteria and received protocol therapy did not continue therapy for a variety of reasons, most likely related to investigator or to subject intolerance of the chemotherapy regimen. None of these patients had documented tumor progression at the time of withdrawal. Surprisingly, we observed only two (6%) CRs, and the best response was SD in over 50% of evaluable patients at the 6-month time point. However, the criteria for a CR in this study were more stringent than in prior studies in that we required resolution of T2/FLAIR and not just lack of enhancing disease. The addition of the T2/FLAIR criterion to our definition of CR went beyond the more conventionally used imaging criterion of T1-enhancing disease.20 The overall response rate (CR + PR) was 32%. Among patients with a 1p/19q codeletion, the response rate was still only 35.3%. The results for our entire series, including those patients who did not have 6-month scans available for central review, are similar to other retrospective series. Patients with AO or MAO for whom previous RT and PCV chemotherapy had failed and who were then challenged with temozolomide showed response rates (CR + PR) ranging from 25% to 63%.17,25 However, the response rate among patients with a 1p/19q codeletion in our study was less than that reported in another small series where 9 of 10 patients with at least a 1p deletion showed responses to temozolomide.9

Data for all 39 protocol-eligible patients were available to assess the toxicity of the 7-day-5-on/7-day-5-off temozolomide regimen. Slightly more than half the patients reported a grade 3 or 4 toxicity, and there were no grade 5 toxicities. Three of the eight patients who withdrew from the study reported the reason to be side effects from the preirradiation temozolomide. Four others did not specify a reason, and one is left to speculate that their withdrawal was due to either investigator or patient concerns about side effects. Despite these withdrawals, the toxicity results for the preirradiation chemotherapy regimen compare favorably with RTOG 9402, where 66% of patients on the RT + PCV arm reported grade 3 or 4 toxicity and there was one toxicity-related death.

The concurrent chemoradiotherapy regimen was well tolerated by the 22 patients who went on to this therapy. Only 36% reported a grade 3 toxicity, and there were no grade 4 or 5 toxicities. These results, however, are limited to a group of patients who tolerated the earlier regimen of dose-dense temozolomide therapy, and prior phase III experience has shown that RT is well tolerated in patients with AO or MAO.11,12

Consistent with prior retrospective analyses of the relationship between 1p/19q codeletion and PFS or OS, our results to date demonstrate that patients in this molecular genetic subgroup had a longer OS and time to progression. These results need to be interpreted with caution as they represent a subgroup of the study, and the data are still maturing. Similarly, the lack of association between MGMT promoter methylation and response rate is likely due to the fact that there was a very high percentage of tumors with MGMT promoter methylation in the subgroup that had tissue available for analysis.

In summary, this prospective phase II study provides evidence that temozolomide may be a reasonable chemotherapy regimen for patients with AO or MAO because it likely provides tumor control that is as good as or better than PCV, with less toxicity. It remains to be determined whether a less dose-dense neoadjuvant chemotherapy strategy would be better tolerated without sacrificing tumor control or whether the use of concurrent chemo-radiation as primary therapy would be as well tolerated as it was in the group of patients in this study who completed their initial temozolomide therapy. Furthermore, it remains unclear whether a chemotherapy-only regimen is sufficient to provide long-term control of 1p/19q codeleted AO or MAO without the use of concurrent or separate RT. Our trial design provided for only 6 months of pre-RT chemotherapy, and we are encouraged that we found no cases of progression in patients with 1p/19q codeleted tumors during the dose-dense chemotherapy regimen we used. The neurooncology community lacks consensus as to the optimal therapy of AO and MAO, with or without 1p/19q codeletion.26 Participation in phase III studies will be essential to better define optimal therapy for these groups of patients with AO or MAO.

References

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