Groot, John de

Abstract Background To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). Methods Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). Results A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). Conclusions In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

Abstract Background We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM). Methods Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis. Results Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79–0.94) for the final G3+L prediction model. Conclusions Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.

Abstract Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.

PURPOSE Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.