Rifaquat Rahman

The Impact of T2/FLAIR Evaluation per RANO Criteria on Response Assessment of Recurrent Glioblastoma Patients Treated with Bevacizumab

Purpose: The RANO criteria have not been assessed using outcome data from prospective trials. We examined the radiologic data of patients with recurrent glioblastoma from the randomized phase II trial (AVF3708g) to determine the effect of including T2/FLAIR evaluation as per RANO criteria on measurements of objective response rates (ORRs) and progression-free survival (PFS) compared with assessment based on contrast enhancement (Macdonald criteria). Experimental Design: The ORRs and median PFS were determined using the RANO criteria and compared with those obtained using the Macdonald criteria. Landmark analyses were performed at 2, 4, and 6 months, and Cox proportional hazard models were used to determine the associations between OR and progression with subsequent survival. Results: The ORRs were 0.331 [95% confidence interval (CI), 0.260–0.409] and 0.393 (95% CI, 0.317–0.472) by RANO and Macdonald criteria, respectively (P < 0.0001). The median PFS was 4.6 months (95% CI, 4.1–5.5) using RANO criteria, compared with 6.4 months (95% CI, 5.5–7.1) as determined by Macdonald criteria (P = 0.01). At 2-, 4-, and 6-month landmarks, both OR status and PFS determined by either RANO or Macdonald criteria were predictive of overall survival [OS; hazard ratios for 4-month landmark (OR HR = 1.93, P = 0.0012; PFS HR, 4.23, P < 0.0001)]. Conclusions: The inclusion of T2/FLAIR assessment resulted in statistically significant differences in median PFS and ORRs compared with assessment of solely enhancing tumor (Macdonald criteria), although OR and PFS determined by both RANO and Macdonald criteria correlated with OS. Clin Cancer Res; 22(3); 575–81. ©2015 AACR.

Recurrent glioblastoma: Volumetric assessment and stratification of patient survival with early posttreatment magnetic resonance imaging in patients treated with bevacizumab

Despite a high radiographic response rate in patients with recurrent glioblastoma following bevacizumab therapy, survival benefit has been relatively modest. We assess whether tumor volume measurements based on baseline and early posttreatment MRI can stratify patients in terms of progression‐free survival (PFS) and overall survival (OS).

Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab

BACKGROUND Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen. METHODS In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment. RESULTS Forty-two patients were identified (28 males) with a median age of 49 years (range, 24-78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3-4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen. CONCLUSION The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.

Quantitative imaging biomarkers for risk stratification of patients with recurrent glioblastoma treated with bevacizumab

Background Anti-angiogenic therapy with bevacizumab is the most widely used treatment option for recurrent glioblastoma, but therapeutic response varies substantially and effective biomarkers for patient selection are not available. To this end, we determine whether novel quantitative radiomic strategies on the basis of MRI have the potential to noninvasively stratify survival and progression in this patient population. Methods In an initial cohort of 126 patients, we identified a distinct set of features representative of the radiographic phenotype on baseline (pretreatment) MRI. These selected features were evaluated on a second cohort of 165 patients from the multicenter BRAIN trial with prospectively acquired clinical and imaging data. Features were evaluated in terms of prognostic value for overall survival (OS), progression-free survival (PFS), and progression within 3, 6, and 9 months using baseline imaging and first follow-up imaging at 6 weeks posttreatment initiation. Results Multivariable analysis of features derived at baseline imaging resulted in significant stratification of OS (hazard ratio [HR] = 2.5; log-rank P = 0.001) and PFS (HR = 4.5; log-rank P = 2.1 × 10-5) in validation data. These stratifications were stronger compared with clinical or volumetric covariates (permutation test false discovery rate [FDR] <0.05). Univariable analysis of a prognostic textural heterogeneity feature (information correlation) derived from postcontrast T1-weighted imaging revealed significantly higher scores for patients who progressed within 3 months (Wilcoxon test P = 8.8 × 10-8). Generally, features derived from postcontrast T1-weighted imaging yielded higher prognostic power compared with precontrast enhancing T2-weighted imaging. Conclusion Radiomics provides prognostic value for survival and progression in patients with recurrent glioblastoma receiving bevacizumab treatment. These results could lead to the development of quantitative pretreatment biomarkers to predict benefit from bevacizumab using standard of care imaging.

Residual low ADC and high FA at the resection margin correlate with poor chemoradiation response and overall survival in high-grade glioma patients

PURPOSE We hypothesized that ADC and FA of enhancing tumor (ET) and/or non-enhancing tumor (NT) adjacent to the operative resection margin before and during temozolomide and/or chemoradiation may allow prediction of chemoradiation response and patient survival. MATERIAL AND METHODS DTI was acquired in 37 patients with newly diagnosed HGG at two time points: after resection at the time of pre-RT planning MRI (Baseline) and after 30Gy of radiation therapy (mid-RT). ADC and FA at each time point and change in ADC and FA between the two time points were assessed by hot spot method in both residual ET and NT within 2cm of the resection margin and correlated with overall survival (OS) using receiver operating characteristics (ROC) area under curve (AUC) analysis and log-rank testing. RESULTS At baseline NT ADC<104×10(-5)mm(2)/s was strongly correlated with shorter 15 month OS (95% CI: 227-412 days vs 492-695 days) compared to patients with higher ADC (AUC 0.82). There was good separation between the groups and significance at log-rank testing (p=0.0002). Baseline NT FA>0.257 also correlated with shorter OS (95% CI: 300-515 days vs 438-686 days), compared with patients with lower FA (AUC 0.74), but there was considerable overlap between the groups and non-significance at log-rank testing (p=0.089). Residual ET ADC increased significantly (p=0.0004) and FA decreased significantly (p=0.03) for all patients during early RT but the change in ADC and FA was less strongly correlated with OS than baseline NT metrics. CONCLUSION Post-operative pre-radiation baseline low ADC in non-enhancing tumor at the resection margin correlates strongly with worse treatment response and decreased overall survival in a heterogeneous sample of high grade glioma patients treated with radiation and/or temozolamide chemoradiation.

fMRI BOLD Response of High-risk College Students (Part 2): During Memory Priming of Alcohol, Marijuana and Polydrug Picture Cues

AIMS This study examined brain activity using functional magnetic resonance imaging (fMRI) and reaction time (RT) during an implicit repetition priming memory task involving alcohol, polydrug, marijuana and emotional picture cues. METHODS Participants were 5 male and 5 female high-risk college students who had just participated in a cue exposure study (Ray et al., this issue). fMRI and RT data were collected while participants made decisions about previously seen and new picture cues. RESULTS Both behavioral RT and brain imaging data revealed strong memory priming for drug and alcohol cues. Neurologically, a repetition priming effect (suppression in neural activity for repeated cues) was observed in response to alcohol cues in the left prefrontal, bilateral occipital, and bilateral occipitotemporal regions, as well as right insula and right precuneus (Z ranged from 3.03 to 3.31 P < 0.05). Polydrug cues elicited priming in the occipital and temporal areas, and marijuana cues in the occipital area. CONCLUSIONS Prefrontal and insular cortex involvement both in reactivity to alcohol cues (Ray et al., this issue) and subsequent implicit memory processing of these cues, as found in this study, suggests their potential role in the maintenance of high-risk alcohol use behaviors.

The clinical trials landscape for glioblastoma: is it adequate to develop new treatments?

Background There have been few treatment advances for patients with glioblastoma (GBM) despite increasing scientific understanding of the disease. While factors such as intrinsic tumor biology and drug delivery are challenges to developing efficacious therapies, it is unclear whether the current clinical trial landscape is optimally evaluating new therapies and biomarkers. Methods We queried ClinicalTrials.gov for interventional clinical trials for patients with GBM initiated between January 2005 and December 2016 and abstracted data regarding phase, status, start and end dates, testing locations, endpoints, experimental interventions, sample size, clinical presentation/indication, and design to better understand the clinical trials landscape. Results Only approximately 8%-11% of patients with newly diagnosed GBM enroll on clinical trials with a similar estimate for all patients with GBM. Trial duration was similar across phases with median time to completion between 3 and 4 years. While 93% of clinical trials were in phases I-II, 26% of the overall clinical trial patient population was enrolled on phase III studies. Of the 8 completed phase III trials, only 1 reported positive results. Although 58% of the phase III trials were supported by phase II data with a similar endpoint, only 25% of these phase II trials were randomized. Conclusions The clinical trials landscape for GBM is characterized by long development times, inadequate dissemination of information, suboptimal go/no-go decision making, and low patient participation.

Radiologic predictors of immune checkpoint inhibitor response in advanced head and neck squamous cell carcinoma

Radiologic predictors of response to immune checkpoint blockade (ICPi) in advanced head and neck squamous cell carcinoma (HNSCC) patients could help guide patient selection and management. We analyzed a large institutional cohort of 100 consecutive HNSCC patients treated with ICPi to investigate associations between molecular and radiologic phenotype and assess radiologic predictors of response and survival. Of particular interest was the impact of increased total tumor burden (TB), calculated as the sum of the largest diameter of all measurable lesions according to RECIST 1.1, and early radiologic indicators of response versus progression. Within our cohort, 42% of patients had HPV+ associated disease, 64% had persistent/recurrent head and neck lesions, and 77% had distant metastases. Median TB was 5.4 cm. HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (p < 0.01 and p = 0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5 months. A lower tumor burden at baseline was associated with clinical benefit (p = 0.03) and improved OS (p < 0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (p = 0.02, HR 2.39). These data suggest that HNSCC patients who benefit from ICPi are more likely to have lower tumor burden at the onset of treatment and minimal increase in tumor burden while on treatment.