INTRODUCTION: Central radiology review may change both response rates and progression free survival (PFS). Bevacizumab treatment of recurrent glioblastoma has been associated with increased progression on T2/FLAIR images only and a different pattern of progression. We centrally reviewed the responses obtained within the prospective randomized BELOB trial and examined the pattern of progression. METHODS: Patients treated within the BELOB trial underwent MR disease assessment every 6 weeks within the first 6 months, thereafter every 12 weeks. Response was assessed using the RANO criteria, the protocol did not require response confirmation after 4 weeks. Two independent reviewers re-assessed all responses (ORR) and dates of progression; in case of disagreement a third reviewer served as the adjudicator. To define the pattern of progression we distinguished between local/distant/diffuse/multifocal progression according to Pope et al (Neurology 2011;76:432-7). RESULTS: For 137 patients central review of response was possible. Agreement between the two central reviewers and between the definitive central and local response was modest (kappa 0.60 and 0.54 respectively). The 6mo PFS rate at central review was similar to the local analysis. In 115 patients the pattern of progression could be assessed. Of 76 patients treated with bevacizumab (with or without lomustine) 13 had T2 progression only, as opposed to only 1 out of 39 lomustine monotherapy patients (p = 0.032). T2 mass progression only was observed in 8:76 bevacizumab treated patients vs 0:39 lomustine monotherapy patients ( p = 0.0497). Treatment with bevacizumab did not result in more multifocal or diffuse relapses. CONCLUSION: Despite interobserver variation at the patient level, at the trial level both ORR and 6 mo PFS outcome of the BELOB remained the same after central review. In the BELOB trial bevacizumab was associated with progression limited to increased T2/FLAIR abnormalities, but not with a different pattern of progression.
Supplementary Figure from Convection Enhanced Delivery of the Oncolytic Adenovirus Delta24-RGD in Patients with Recurrent GBM: A Phase I Clinical Trial Including Correlative Studies
<div>AbstractPurpose:<p>Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.</p>Patients and Methods:<p>Dose-escalation phase I study with 3+3 cohorts, dosing 10<sup>7</sup> to 1 × 10<sup>11</sup> viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.</p>Results:<p>Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. Four patients demonstrated tumor response on MRI, one with complete regression and still alive after 8 years. Most serious adverse events were attributed to increased intracranial pressure caused by either an inflammatory reaction responding to steroid treatment or viral meningitis being transient and self-limiting. Often viral DNA concentrations in CSF increased over time, peaking after 2 to 4 weeks and remaining up to 3 months. Concomitantly Th1- and Th2-associated cytokine levels and numbers of CD3<sup>+</sup> T and natural killer cells increased. Posttreatment tumor specimens revealed increased numbers of macrophages and CD4<sup>+</sup> and CD8<sup>+</sup> T cells. No evidence of viral shedding in excreta was observed.</p>Conclusions:<p>CED of Delta24-RGD not only in the tumor but also in surrounding brain is safe, induces a local inflammatory reaction, and shows promising clinical responses.</p></div>
Background Patients with medically unexplained physical symptoms (MUPS) are prevalent 25–50% in general and specialist care. Medical specialists and residents often find patients without underlying pathology difficult to deal with, whereas patients sometimes don’t feel understood. We developed an evidence-based communication training, aimed to improve specialists’ interviewing, information-giving and planning skills in MUPS consultations, and tested its effectiveness. Methods The intervention group in this multi-center randomized controlled trial received a 14-hour training program to which experiential learning and feedback were essential. Using techniques from Cognitive Behavioral Therapy, they were stimulated to seek interrelating factors (symptoms, cognitions, emotions, behavior, and social environment) that reinforced a patient’s symptoms. They were taught to explain MUPS understandably, reassure patients effectively and avoid unnecessary diagnostic testing. Before and after the intervention training, specialists videotaped a total of six consultations with different MUPS patients. These were evaluated to assess doctors’ MUPS-focused communicating skills using an adapted version of the Four Habit Coding Scheme on five-point Likert scales. Participants evaluated the training by self-report on three-point Likert scales. Doctors in the control group received training after completion of the study. Results 123 doctors (40% specialists, 60% residents) and 478 MUPS patients from 11 specialties were included; 98 doctors completed the study (80%) and 449 videotaped consultations were assessed. Trained doctors interviewed patients more effectively than untrained ones (p < 0.001), summarized information in a more patient-centered way (p = 0.001), and better explained MUPS and the role of perpetuating factors (p < 0.05). No effects on planning skills were found. On a 3-point scale the training was evaluated with 2.79. Conclusion MUPS-focused communication training increases the interviewing and information-giving skills of medical specialists. We recommend that the training is incorporated in postgraduate education for medical specialists and residents who frequently encounter patients with MUPS. Trial Registration Dutch Trial Registration NTR2612
Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log₁₀CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log₁₀CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS.CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.
