Mehta, Minesh P.

LBA2010 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

1 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

2008b Background: Anaplastic oligodendrogliomas, pure (AO) and mixed (AOA), are chemosensitive tumors, especially if co-deleted for chromosomes 1p and 19q, but whether addition of CT to RT prolongs overall survival (OS), is unknown. Methods: In the RTOG 9402 Phase III trial, patients (pts) with AO/AOA were randomly assigned to PCV [procarbazine, CCNU (lomustine) and vincristine] followed by immediate RT vs. immediate RT alone. Early analysis showed no OS benefit for the PCV+RT group but combined therapy was associated with a longer progression-free survival (PFS). It also showed that the finding of 1p/19q co-deletion was associated with a longer OS independent of treatment. The current analysis has a median follow up of 11.3 years (yrs). Results: Two hundred ninety-one patients were randomized, 148 to PCV+RT and 143 to RT. PCV+RT was associated with longer PFS [2.5 vs. 1.7 yrs, hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.53, 0.88), P = 0.003] and the 1p/19q co-deletion with a longer Median Survival Time (MST) [8.7 vs. 2.7 yrs, HR 0.41, 95% CI (0.30, 0.55), P < 0.001]. For the entire cohort, there was no difference in MST by treatment [4.6 yrs for PCV+RT vs. 4.7 yrs for RT, HR 0.79, 95% CI (0.60, 1.04), P = 0.1]. However, patients with 1p/19q co-deleted tumors lived much longer after PCV+RT (n = 59) than after RT (n = 67) [14.7 vs. 7.3 yrs, HR 0.59, 95% CI (0.37, 0.95), P = 0.03]. There was no difference in MST by treatment in pts without the 1p/19q co-deletion [n=137; 2.6 vs. 2.7 yrs, HR 0.85, 95% CI (0.58, 1.23), P = 0.39]. Re-operation rates upon progression were similar between treatment arms in co-deleted pts (43%, PCV+RT vs. 54%, RT) but salvage CT rates were higher in the RT arm [57% vs. 81% (P = 0.04)]. Conclusions: PCV followed by immediate RT was a highly effective therapy for patients with 1p/19q co-deleted AO/AOA. In this setting, 1p/19q co-deletion was both prognostic and predictive, and the early PFS benefit in co-deleted cases was a harbinger of their longer OS. [This work was supported by RTOG grants U10 CA21661 and U10 CA32115, NCCTG grant U10 CA25224, ECOG grants CA17145 and CA21115, SWOG grant CA32102, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI)]

9014 Background: MGd, a radiosensitizer that selectively accumulates in tumors, generates reactive oxygen species intracellularly. In preclinical experiments, MGd enhances RT-induced apoptosis. Methods: A multi-institutional Phase I dose escalation and pharmacokinetic (PK) study was performed in children with newly diagnosed BSG to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of MGd administered i.v. 2 to 5 hours prior to involved field radiotherapy (RT) (1.8 Gy/day, total 54 Gy). Cohort 1 received MGd, 1.7 mg/kg/dose M-F × 3 wks and cohort 2 received the same dose M, W and F × 6 wks. The 6 subsequent cohorts of 3 to 6 pts received MGd M-F × 6 weeks at doses of 1.9, 3.4, 4.4, 5.5, 7.1 and 9.2 mg/kg/dose. Serum for PK analysis, and MRI scans (MGd is detectable by MR), were obtained for analysis of drug accumulation and responses. Results: 44 pts (42 fully evaluable for toxicity) with a median age of 6 years (range 2–20) were enrolled. At the 9.2 mg/kg/dose, 2/2 pts experienced DLT. During subsequent expansion of the 7.1 and 5.5 mg/kg/dose cohorts, DLTs, including transaminitis, hypertension and urticaria, were observed in 2/5 and 2/6 pts. At the MTD of 4.4 mg/kg/dose, 1/6 pts had reversible grade 3 serum transaminase elevations. PK analysis showed biphasic elimination with a terminal t 1/2 of 6.4 h. At the MTD, serum MGd concentrations were >250 ng/ml for 24 h. Serum clearance and steady-state volume of distribution were 0.0243 L/h/kg and 0.162 L/kg. MRI for intra-tumoral MGd distribution is ongoing. One patient had a CR and 4 had a PR. The estimated median survival is 10.3 months (95% confidence interval: 8.1 months-11.5 months). Conclusions: The recommended phase II dose of MGd for children with BSG is 4.4 mg/kg/d administered M-F × 6 weeks with involved field RT. A COG phase II trial is planned. [Table: see text]

1517 Background: In a previous report, we showed in patients with newly diagnosed anaplastic oligodendrogliomas (AOs) and mixed anaplastic oligoastrocytomas (MAOs) that temozolomide (TMZ) can be given concurrently with radiation therapy (RT) with acceptable toxicity. We have now evaluated the efficacy of this regimen and correlated durability of response with tumor 1p/19q genotype. Methods: A phase II study was performed to evaluate the use of pre-RT TMZ followed by concurrent RT and TMZ in patients with newly diagnosed AO or MAO. The primary endpoint was to determine the pre-RT TMZ six-month progression rate, and secondary endpoints included progression-free survival and overall survival. Results: 40 eligible patients were entered into the trial. Thirty-two patients completed 6 months of pre-RT TMZ and concurrent RT and TMZ. Of the remaining eight patients, 4 withdrew due to toxicity and 4 other patients withdrew from study without evidence of toxicity or pre-RT progression. 1p/19q data are available in 37 cases; 23 tumors had loss of heterozygosity (LOH) of both 1p and 19q (double-deleted) while 14 tumors had LOH of either 1p or 19q (n = 3), or no LOH (n = 11). To date, 11 patients have experienced tumor progression; 1p/19q data are available for 10 of these cases (2 are double-deleted (2/23 = 9%), 8 have at least one intact chromosome (8/14 = 57%). Kaplan-Meier analysis demonstrates that progression free survival is significantly better for the double-deleted group (median time to progression not reached) than for the intact group (median time to progression = 15.2 months, p = 0.001). Overall survival is 98% (39/40) with a median follow-up of 17.5 months (2.8 - 31.1 months). Conclusions: LOH of both 1p and 19q is strongly correlated with a durable response of AO and MAO to a combined regimen of chemotherapy and radiation therapy. Tumors that are intact at 1p and/or 19q progress early despite an aggressive therapeutic regimen. These results suggest that future clinical trials should be prospectively stratified by tumor 1p/19q genotype. [Table: see text]

1500 Background: Treatment of adult LGG is controversial. Favorable patients (pts) (age <40 years [yrs] who undergo gross total resection [GTR]) are typically observed. Unfavorable pts (age ≥40 who have subtotal resection [STR] or biopsy [B]) are usually given initial radiation therapy (RT), reserving chemotherapy (historically procarbazine, CCNU and vincristine [PCV]) for recurrence. In 1998, the RTOG, in conjunction with SWOG, NCCTG, and ECOG initiated prospective studies of adult LGG, the results of which are reported herein. Methods: Favorable pts were observed postoperatively in a single arm Phase II study (Arm 1). Unfavorable pts were stratified by age, histology, KPS, and presence/absence of contrast enhancement on preoperative magnetic resonance imaging and randomized to either RT alone (54Gy in 30 fractions to a local treatment field) (Arm 2) or RT followed by 6 cycles of standard dose PCV (Arm 3). Reported results include overall survival (OS) rate, median overall survival time (MOST), progression-free survival (PFS) rate, and median progression-free survival time (MPFST). Survival data are compared using Wilcoxon p-values. Results: A total of 362 eligible/analyzable pts were accrued between 1998 and 2002. Median follow-up time is 4 years. For the 111 favorable pts observed on Arm 1, OS at 2- and 5-yrs is 99% and 94%. PFS at 2- and 5-yrs is 82% and 50%. For the 251 unfavorable pts on Arms 2 (RT alone) and 3 (RT+PCV), there was no difference in OS or PFS. OS at 2- and 5-yrs was 87% and 61% with RT alone versus (vs) 86% and 70% with RT+PCV (p=0.72). MOST was not reached in RT alone pts and was 6.0 yrs in RT+PCV pts. PFS at 2- and 5-yrs was 73% and 39% with RT alone vs 72% and 61% with RT+PCV (p=0.38). MPFST was 4.0 yrs with RT alone vs 6.0 yrs with RT+PCV. Acute grade 3–4 toxicity occurred in 9% of pts who received RT alone, 67% who received RT+PCV (mostly hematologic). There were no treatment deaths on either arm. Conclusions: 5-yr PFS was poor in all three arms ranging from 39% to 61%. Only half of favorable pts were disease-free at 5 yrs. In unfavorable pts, there was no OS advantage with the addition of PCV to RT. Both PFS and MPFST were better with the addition of PCV, but not significantly. Analysis of outcome by 1p19q status is pending. No significant financial relationships to disclose.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Abstract Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

AbstractBuilding on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.

Abstract BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.