Concurrent Olaparib and Radiation Therapy in Older Patients With Newly Diagnosed Glioblastoma: The Phase 1 Dose-Escalation PARADIGM Trial.

PURPOSE: Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. METHODS AND MATERIALS: Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination. RESULTS: Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib-radiation therapy combination. CONCLUSIONS: Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy for patients with brain tumors.

Diversity in radiation therapist/therapeutic radiographer (RTT) advanced practice (AP) roles delivering on the four domains.

INTRODUCTION: Advanced practice roles are well documented, and continue to respond to the changing landscape in radiotherapy and oncology. In the UK the highest level of AP for the therapeutic radiographer/radiation therapist (RTT) is the consultant radiographer. These posts should meet the four domains of practice, as set out in national guidance. Here we aim to describe well established roles that meet this criteria, and provide subgroups of examples. METHODOLOGY: Three AP post holders with over 10 years AP experience completed a questionnaire adapted from the consultant radiographer toolkit. These were completed in conjunction with guidance and framework documents. The examples were to demonstrate how they achieve a high level of practice in clinical and expert practice; professional leadership and consultancy; education, training and development; and practice and service development, research and evaluation. Participants then categorised results to add subgroups to each domain. RESULTS: The questionnaire was completed by three RTTs specialising as a lung consultant radiographer (LCR), a neuro-oncology consultant radiographer (NCR) and a lead research radiographer (RR). Each post holder described how they meet the criteria by discussing the benefit they make to their profession, department and patients. All posts had examples for all criteria, achieving consultant practice. Clinical and expert practice was the dominant domain for the clinical specialist posts, and professional leadership and research evaluation was the strongest domains for the RR. CONCLUSION: All three consultant RTTs have demonstrated expert practice with clear and transparent examples of their professional practice which evidence the four domains of consultant practice. Following two decades of AP practice for RTTs there is a need to be strategic in the development of future posts with a prospective view on succession planning that safeguards their longevity.

PARADIGM-2: Two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status.

Glioblastoma has a dismal prognosis and molecular targeted agents have failed to improve outcomes to date. PARADIGM-2 is a phase I dose escalation study evaluating olaparib plus radiotherapy ±â€¯temozolomide in newly diagnosed glioblastoma, using MGMT methylation status to stratify patients and inform treatment schedules.