Brachman, David

LBA2010 Background: RTOG 0825 evaluated the addition of BEV to standard CRT in the treatment of GBM and included molecular stratification that assessed the degree of mesenchymal (MES) gene enrichment. We investigated the ability of the MES signature to predict response to BEV. Methods: Sufficient FFPE tissue for molecular analysis was available for 650 registered, eligible patients. TaqMan PCR was performed prospectively using the molecular stratifier on all patients and an expanded 43 member MES set on 234 cases. A subset of specimens was subjected to whole genome expression profiling (GEP). Predictive models were evaluated for their ability to predict survival (overall, OS, and progression-free, PFS) in the training cohort of the BEV arm after adjusting for prognostic factors and treatment arm. Unsupervised clustering of GEP data was used to identify molecular subsets and gene set enrichment analysis (GSEA) performed to evaluate for MES enrichment. Results: We observed a significant association between increasing MES signature and worse PFS and OS in the BEV arm (p=0.036 and p=0.032, respectively). Based on the association between high MES expression and poor outcome in the BEV arm, we sought to optimize a predictor using an expanded set of MES genes. Unbiased gene selection from a total of 43 genes followed by radial basis machine modeling identified a 10-gene predictor of outcome in the BEV arm (p<0.001/HR 4.04 for OS and p<0.001/HR 2.21 for PFS). To further support the association of MES enrichment and poor outcome in the BEV arm, we performed GEP. Unsupervised clustering identified a subtype of tumors with MES enrichment associated with the 10-gene predictor survival probability (p=0.0124, t-test). Ongoing studies will determine the extent to which this represents a predictive marker for BEV. Conclusions: We developed a 10-gene predictor specific to BEV treatment and suitable for FFPE that may serve to identify subsets of patients with newly diagnosed GBM who benefit from BEV. Supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and Brain SPORE P50 CA127001 from the NCI and Genentech. Clinical trial information: NCT00884741.

1 Background: Chemoradiation (CRT) with temozolomide (TMZ/RT→TMZ) is the standard of care for newly diagnosed GBM. This trial determined if the addition of Bev to standard CRT improves survival (OS) or progression-free survival (PFS) in newly diagnosed GBM. Methods: This phase III trial was conducted by the RTOG, NCCTG, and ECOG. Neurologically stable pts > 18 yrs with KPS ≥ 60, and > 1cm3 tumor tissue block, were randomized to Arm 1: standard CRT + placebo or Arm 2: standard CRT plus Bev (10 mg/kg iv q 2wks). Experimental treatment began at wk 4 of radiation then thru 6-12 cycles of maintenance chemotherapy. Protocol specified co-primary endpoints were OS and PFS, with significance levels of .023 and .002, respectively. At progression, treatment was unblinded and pts allowed to crossover or continue Bev. Symptom, QOL and neurocognitive (NCF) testing was performed in the majority of pts. Secondary analyses evaluated impact of MGMT methylation (meth) and prognostic 9 gene signature status. Results: From 978 registered pts, 637 were randomized. Inadequate tissue (n=105) and blood on imaging (n=40) were key reasons for non-randomization. No difference was found between arms for OS (median 16.1 vs. 15.7 mo, p = 0.11). PFS was extended for Arm 2 (7.3 vs. 10.7 mo, p = 0.004). Pts with MGMT meth had superior OS (23.2 vs. 14.3 mo, p < 0.001) and PFS (14.1 vs. 8.2 mo, p < 0.001). Neither the 9 gene signature nor MGMT predicted selective benefit for Bev treatment, but best prognosis pts (MGMT meth, favorable 9-gene), had a worse survival trend with Bev (15.7 vs 25 mo p = 0.08). To date, 128 pts were unblinded on Arm 1 (salvage Bev in 86) and 87 pts on Arm 2 (continued Bev in 39). Increased grade ≥ 3 toxicity was seen with Bev, mostly neutropenia, hypertension, and DVT/PE. Conclusions: The addition of Bev for newly diagnosed GBM did not improve OS, did improve PFS but did not reach the significance criterion. MGMT and 9 gene profile did not identify selective benefit, but risk subset results suggested strongly against the upfront use of Bev in the best prognosis pts. Full interpretation of the PFS results incorporating symptom burden, QOL, and NCF is ongoing. Support: NCI U10 CA 21661, U10 CA37422, and Genentech. Clinical trial information: NCT00884741.

Purpose Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT. Patients and Methods Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT. Results IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT. Conclusion IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.

Purpose The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. Patients and Methods A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini–Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. Results Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. Conclusion The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.

Purpose Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live longer after chemoradiotherapy is unknown. Patients and Methods Eligible patients with AO/AOA were randomly assigned to procarbazine, lomustine, and vincristine (PCV) plus radiotherapy (RT) versus RT alone. The primary end point was overall survival (OS). Results Two hundred ninety-one eligible patients were randomly assigned: 148 to PCV plus RT and 143 to RT. For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT v 4.7 years for RT; hazard ratio [HR] = 0.79; 95% CI, 0.60 to 1.04; P = .1). Patients with codeleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 v 2.6 years, HR = 0.36, 95% CI, 0.23 to 0.57, P < .001; RT: 7.3 v 2.7 years, HR = 0.40, 95% CI, 0.27 to 0.60, P < .001), and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03). For those with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 v 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = .39). In Cox models that included codeletion status, the adjusted OS for all patients was prolonged by PCV plus RT (HR = 0.67; 95% CI, 0.50 to 0.91; P = .01). Conclusion For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis.

Purpose A prior Radiation Therapy Oncology Group (RTOG) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine, lomustine, and vincristine (PCV) chemotherapy in addition to radiation therapy (RT), as have smaller trials in low-grade glioma (LGG). Patients and Methods Eligibility criteria included supratentorial WHO grade 2 LGG, age 18 to 39 years with subtotal resection/biopsy, or age ≥ 40 years with any extent resection. Patients were randomly assigned to RT alone or RT followed by six cycles of PCV. Survival was compared by using the modified Wilcoxon and log-rank tests. Results In all, 251 patients were accrued from 1998 to 2002. Median overall survival (OS) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63% versus 72%, respectively (hazard ratio [HR]; 0.72; 95% CI, 0.47 to 1.10; P = .33; log-rank P = .13). Median progression-free survival (PFS) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46% versus 63%, respectively (HR, 0.6; 95% CI, 0.41 to 0.86; P = .06; log-rank P = .005). OS and PFS were similar for all patients between years 0 and 2. After 2 years, OS and PFS curves separated significantly, favoring RT + PCV. For 2-year survivors (n = 211), the probability of OS for an additional 5 years was 74% with RT + PCV versus 59% with RT alone (HR, 0.52; 95% CI, 0.30 to 0.90; log-rank P = .02). Conclusion PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.

Object In 1998, the Radiation Therapy Oncology Group initiated a Phase II study of observation for adults < 40 years old with cerebral low-grade glioma who underwent a neurosurgeon-determined gross-total resection (GTR). Methods Patient eligibility criteria included the presence of a World Health Organization Grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma confirmed histologically; age 18–39 years; Karnofsky Performance Scale score ≥ 60; Neurologic Function Scale score ≤ 3; supratentorial tumor location; neurosurgeon-determined GTR; and pre- and postoperative MR imaging with contrast enhancement available for central review by the principal investigator. Patients were observed following GTR and underwent MR imaging every 6 months. Prognostic factors analyzed for their contribution to patient overall survival, progression-free survival (PFS), and tumor recurrence included age, sex, Karnofsky Performance Scale score, Neurologic Function Scale score, histological type, contrast enhancement on preoperative MR imaging, preoperative tumor diameter, residual disease based on postoperative MR imaging, and baseline Mini-Mental State Examination score. Results Between 1998 and 2002, 111 eligible patients were entered into the study. In these 111 patients, the overall survival rates at 2 and 5 years were 99 and 93%, respectively. The PFS rates in these 111 patients at 2 and 5 years were 82 and 48%, respectively. Three prognostic factors predicted significantly poorer PFS in univariate and multivariate analyses: 1) preoperative tumor diameter ≥ 4 cm; 2) astrocytoma/oligoastrocytoma histological type; and 3) residual tumor ≥ 1 cm according to MR imaging. Review of the postoperative MR imaging results revealed that 59% of patients had < 1 cm residual disease (with a subsequent 26% recurrence rate), 32% had 1–2 cm residual disease (with a subsequent 68% recurrence rate), and 9% had > 2 cm residual disease (with a subsequent 89% recurrence rate). Conclusions These data suggest that young adult patients with low-grade glioma who undergo a neurosurgeondetermined GTR have a > 50% risk of tumor progression 5-years postoperatively, warranting close follow-up and consideration for adjuvant treatment.

Purpose Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery and radiotherapy (RT) at diagnosis, but they also respond to procarbazine, lomustine, and vincristine (PCV), raising the possibility that early chemotherapy will improve survival. Furthermore, better outcomes in AO have been associated with 1p and 19q allelic loss. Patients and Methods Patients with AO and AOA were randomly assigned to PCV chemotherapy followed by RT versus postoperative RT alone. The primary end point was overall survival. The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization. Results Two hundred eighty-nine eligible patients were randomly assigned to either PCV plus RT (n = 147) or RT alone (n = 142). At progression, 80% of patients randomly assigned to RT had chemotherapy. With 3-year follow-up on most patients, the median survival times were similar (4.9 years after PCV plus RT v 4.7 years after RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26). Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of patients experienced grade 3 or 4 toxicity, and one patient died. Patients with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and 19q had longer median survival times (> 7 v 2.8 years, respectively; P ≤ .001); longer progression-free survival was most apparent in this subset. Conclusion For patients with AO and AOA, PCV plus RT does not prolong survival. Longer progression-free survival after PCV plus RT is associated with significant toxicity. Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both.