Ali K. Choucair

Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial

BACKGROUND To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT). METHODS Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed. RESULTS Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62-0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks. CONCLUSIONS Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852.

Net Clinical Benefit Analysis of Radiation Therapy Oncology Group 0525: A Phase III Trial Comparing Conventional Adjuvant Temozolomide With Dose-Intensive Temozolomide in Patients With Newly Diagnosed Glioblastoma

PURPOSE Radiation Therapy Oncology Group trial 0525 tested whether dose-intensifying temozolomide versus standard chemoradiotherapy improves overall survival (OS) or progression-free survival (PFS) in newly diagnosed glioblastoma. Tests of neurocognitive function (NCF) and symptoms (using the MD Anderson Symptom Inventory-Brain Tumor module; MDASI-BT) and of quality of life (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ] -C30/BN20) examined the net clinical benefit (NCB) of therapy. PATIENTS AND METHODS NCF tests (Hopkins Verbal Learning Test-Revised, Trail Making Test, and Controlled Oral Word Association), MDASI-BT, and EORTC QLQ-C30/BN20 were completed in a subset of patients. Multivariate Cox proportional hazard regression modeling determined the prognostic value of baseline and early change from baseline to cycle 1 for OS and PFS. Two-sample proportional test statistic was used to evaluate differences between treatments (dose-dense v standard-dose) on NCB measures from baseline to cycle 4 in stable patients. RESULTS Overall, 182 patients participated in the study. Baseline NCF tests and the physical functioning quality of life scale were associated with OS and PFS. Baseline to cycle 1 in all NCB components were associated with OS and PFS. There was greater deterioration in the dose-dense arm from baseline to cycle 4 in the Global Health and Motor Function subscales (EORTC QLQ-C30/BN20) as well as in overall symptom burden, overall symptom interference, and activity-related symptom interference subscales (MDASI-BT). There were no between-arm differences in NCF. CONCLUSION Longitudinal collection of NCB measures is feasible in cooperative group studies and provides an added dimension to standard outcome measures. Greater adverse symptom burden and functional interference, as well as decreased global health and motor function were observed in patients randomly assigned to the dose-dense arm. Baseline and early change in NCB measures were associated with decreased rates of survival.

RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients.

PURPOSE To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients. METHODS AND MATERIALS Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression. RESULTS The maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients. CONCLUSIONS The addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.

Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021.

Preclinical studies support the concept that inhibition of protein kinase C (PKC) by tamoxifen (TAM) should provide both antineoplastic effects and radiosensitization. High-dose TAM (80 mg/m2 p.o. daily in divided doses) was given with and after conventional radiotherapy (XRT) to inhibit PKC-mediated signaling, which is known to be enhanced in glioblastoma (GBM). Seventy-seven patients were accrued between December 2000 and December 2001; two were ineligible and not included in the efficacy results. Pretreatment characteristics of the patients included the following: 52% were less than 60 years of age, 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms, and 65% were Radiation Therapy Oncology Group-recursive partition analysis (RPA) class III and IV. Eighty-six percent of patients achieved acceptable dosing of TAM. Notable toxicity included late radiation grade 3 in two patients and thromboembolic events in 16 patients (two grade 2, 10 grade 3, three grade 4, and one grade 5), for an incidence of 20.8% (which is lower than expected, based on the literature for deep vein thrombophlebitis in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months as compared (by three different statistical methodologies) to the historical GBM control database of 1457 RPA class III, IV, and V drug/XRT-treated patients. After controlling for RPA class IV, the MST was 11.3 months, which compares to the historical RPA control of 11.3 months (P = 0.37). The results obtained do not exhibit a substantial advance over those of previous studies with various XRT/drug doublets, including BCNU. However, as TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trials. Historically, the incidence of thromboembolic events in GBM patients is approximately 30%. The lower-than-expected incidence seen here has also been observed in other high-dose TAM GBM studies. We speculate that TAM inhibited the PKC-mediated phosphorylation of coagulation factors.

Management of Low-Grade Gliomas: A Review of Patient-Perceived Quality of Life and Neurocognitive Outcome

Low-grade glioma (LGG) comprises nearly 20% of all central nervous system glial tumors, with approximately 2000-3000 patients diagnosed annually in the United States. Because of their infiltrative ability and aggressive nature, the average 10-year survival is 30% when <90% of the tumor is resected. Since the 1970s, prognosis for LGGs has improved significantly. This improvement is primarily attributable to earlier diagnoses via magnetic resonance imaging scanning, increased awareness of the more favorable oligo component, technical advances in intraoperative neurosurgery, and stratification for young age. Using a number of prognostic factors, LGGs have been classified into low-risk and high-risk subgroups. Optimal therapy for patients with low-risk, supratentorial grade II glioma remains a highly controversial issue in the neuro-oncology community. The concerns regarding the toxicity of therapy often outweigh the benefits of delaying tumor progression. The recommendation for observation is made without full prospective understanding of the impact of radiologic tumor progression on the quality of life (QOL), neurocognitive function (NCF), seizure control, and functional status of these patients. We present a review of the current knowledge of the management of LGG with emphasis upon patient-reported outcomes of QOL, NCF, and seizure control. We also discuss current clinical trials with proposals to evaluate QOL, NCF, and seizure control in patients undergoing observation alone after newly diagnosed low-risk LGG or treatment options for those patients in the high-risk group.

An update of phase I data from RTOG 0211: A phase I/II clinical study of gefitinib+ radiation for newly-diagnosed glioblastoma (GBM) patients

1571 Background: The Radiation Therapy Oncology Group (RTOG) initiated a Phase I/II clinical study of the EGFR tyrosine kinase inhibitor, Gefitinib, in combination with radiation for newly diagnosed GBM patients. This report is an update of Phase I toxicity data. METHODS Patients entered on RTOG 0211 were stratified into two groups based on whether they were on enzyme-inducing anticonvulsant drugs (EIACDs:Group I) or not (non-EIACDs: Group II). The planned Gefitinib dose escalation during radiation was from 250 to 750mg in Group I and 250 to 500mg in Group II in 250 mg increments. A standard 3+3 design was used to evaluate dose-limiting toxicities (DLTs), which were defined as designated acute (<90 days) toxicity events. RESULTS A total of 18 patients in Group I (16 eligible and analyzable) and 13 patients in Group II (12 eligible and analyzable) were included in this update. In Group I, no DLTs were observed up to 750 mg. One subject in Group I had late (>90 days) Grade 3 elevation of SGOT. In Group II, one subject experienced a Grade 3 elevation of SGOT at the 250 mg dose level within 90 days. At the 500 mg dose level in Group II, one patient had late Grade 3 elevation of SGOT and one patient had acute Grade 4 elevation of SGOT. Other observed side-effects (e.g. fatigue, skin rash, headaches, seizures) did not fit the definition of DLTs or were deemed to be unrelated to Iressa. CONCLUSIONS Gefitinib in combination with radiation appears to be well-tolerated in GBM patients at the dose levels examined. Further dose escalation is being planned for Group I, given the favorable side-effect profile in EIACD patients in this, as well as previously reported studies in the setting of recurrent disease. For non-EIACD patients, the Phase II component of the study has been initiated at the 500 mg dose level. No significant financial relationships to disclose.

Quality of life measures as a preliminary clinical indicator in patients with primary brain tumors

Background: The health-related quality of life (HRQOL) measures serve as valuable indicators of survival in patients with newly diagnosed primary brain tumors (PBTs). HRQOL outcomes may benefit clinical decision-making by individualizing patient treatment and improving communications between the doctor, patient, and families. Exploring the individual items of the European Organization and Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QOL) measures may be predictive of prognosis. Methods: We prospectively collected the validated HRQOL and standard clinical and radiological measures from 48 patients with newly diagnosed PBT. The patients were followed every 3 months over 2 years. No proxies were allowed. Questionnaire responses were compared between two groups: Patients with recurrence and/or death (n = 26) and patients without a recurrence (n = 22). A total of 17 patients succumbed to a tumor-related death. Statistical analysis utilizing nonparametric t-tests and Wilcoxon sign tests assessed QOL responses. Results: Significant group differences were noted in the QOL measures with more negative responses in the recurrence group. EORTC QLQ-C30 questions revealed a poor global HRQOL scale (P < 0.005) and pain interfering with daily activities (P < 0.05). EORTC QLQ-BN20 questions revealed weakness of the legs (P < 0.05), coordination difficulties (P < 0.005), and unsteady gait (P < 0.05). Hospital Anxiety and Depression Scale (HADS) questions reflected a patient who is slowed down (P < 0.01) and “frightened” (P < 0.05). Conclusion: Our analysis of longitudinal HRQOL measures may shed light on the prognostic significance of HRQOL measures in patients with newly diagnosed PBT. Further research is warranted to determine which selected individual measures of the EORTC QOL measures may be predictive of a patients progression-free and overall survival and to test their validity and reliability in clinical trials.

Long term survivors with glioblastoma multiforme (GBM) treated on RTOG protocols with irradiation and nitrosurea have higher initial expression of Ki-67

9661 Background: Ki-67 is a nuclear antigen that is upregulated during cellular proliferation. Ki-67 expression has been both positively and negatively associated with survival in a number of tumor primaries. Similarly, in patients with GBM, prior studies of the prognostic value of initial Ki-67 expression for overall survival have reported conflicting results with some suggesting a positive, others a negative, and others no correlation. METHODS In this study we compared the nuclear expression of Ki-67 using Mib-1 antibody between 28 long term (>18 months) and 35 short term (< 6 months) GBM survivors receiving irradiation and BCNU who were selected from RTOG Tissue Bank and who met the following criteria: eligibility requirements for the RTOG study on which they were enrolled, received the BCNU arm, and had survival 18 months. Tumor cell expression was quantitated by performing immunohistochemistry on tumor array slides with determination of positively staining cells by use of the Chromovision automated cell imaging system. [Figure: see text] Results: *Multivariate logistic regression with Ki-67, age, KPS and extent of resection. CONCLUSIONS In this patient population, long term GBM survivors have a higher percentage of tumor cells expressing Ki-67. This suggests that further investigation of factors that are altered during the cell cycle may be of value in identifying prognostic factors for long term GBM survivors. No significant financial relationships to disclose.

A phase II trial of conventional radiation therapy (XRT) plus high dose tamoxifen (TAM) for the treatment of supratentorial glioblastoma multiforme (GBM): RTOG protocol BR-0021

1529 Background: Preclinical studies support the concept that inhibition of protein kinase C (PKC) by TAM should provide both anti-neoplastic effects and radiosensitization. METHODS High dose TAM (80 mg/m2PO daily in divided doses) was given with and after conventional XRT to inhibit PKC mediated signaling, which is known to be enhanced in GBM. Patients (n=77) were accrued between 12/00-12/01; 75 patients were analyzable. Pretreatment characteristics included: 52%<60 years of age; 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms; 65% were RTOG -recursive partition analysis (RPA) class III & IV. RESULTS A sample of 46 patients was reviewed for TAM delivery; 78% achieved acceptable dosing. Notable toxicity included: Late radiation Grade (G) G3 =2; Thrombo-embolic disease G2=2, G3=8, G4=3, G5=1 for an incidence of 18.7%, (which is lower than expected, based on the literature for DVT in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months (M). This result was compared (using 3 different statistical methodologies) to the historical GBM control database of 1443 drug / XRT treated patients RPA class III, IV, & V. After controlling for RPA class IV, the MST was 11.3M, which compares to the historical RPA control of 11.2 M (p=0.38). CONCLUSIONS 1) The results obtained do not exhibit a substantial advance over previous studies with various XRT/drug doublets including BCNU. As TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trails. 2) Historically the incidence of thrombo-embolic events in GBM patients is ∼30%. The lower than expected incidence seen here has also been observed in other high dose TAM GBM studies. We speculate that TAM inhibited the PKC mediated phosphorylation of coagulation factors. No significant financial relationships to disclose.