ESTRO38 Congress Report

Clinical

5. CRANIAL Phase III randomized trial of Prophylactic Cranial Irradiation with or without Hippocampus Avoidance in SCLC: primary endpoint on neurocognition (E38-2563) J. Belderbos 1 , D. De Ruysscher 2 , K. De Jaeger 3 , F. Koppe 4 , M. Lambrecht 5 , Y. Lievens 6 , E. Dieleman 7 , j. Jaspers 8 , J. Van meerbeeck 9 , J. Ubbels 10 , M. Kwint1, M. Kuenen 11 , S. Deprez 12 , M.B. De Ruiter 11 , K. Sikorska 13 , H. Van Tinteren 13 , S.B. Schagen 11 . 1 The Netherlands Cancer Institute, Radiation Oncology, Amsterdam, The Netherlands, 2 Maastricht University Medical Center- School For Oncology And Developmental Biology Grow, Radiation Oncology, Maastricht, The Netherlands, 3 Catharina Hospital, Radiation Oncology, Eindhoven, The Netherlands, 4 Institute Verbeeten, Radiation Oncology, Tilburg, The Netherlands, 5 UZ Gasthuisberg, Radiation Oncology, Leuven, Belgium, 6 Ghent University Hospital and Ghent University, Radiation Oncology, Gent, Belgium. 7 Amsterdam UMC- Location AMC, Radiation Oncology, Amsterdam, The Netherlands, 8 Erasmus MC Cancer Institute- Erasmus MC University Medical Center, Radiation Oncology, Rotterdam, The Netherlands, 9 Antwerp University Hospital, Department of Pulmonology & Thoracic Oncology, Antwerp, Belgium, 10 University of Groningen- University Medical Center Groningen, Radiation Oncology, Groningen, The Netherlands, 11 The Netherlands Cancer Institute, Division of Psychosocial Research And Epidemiology, Amsterdam, The Netherlands, 12 University Hospitals Leuven- KUL, Imaging and Pathology, Leuven, Belgium, 13 The Netherlands Cancer Institute, Department Of Biometrics, Amsterdam, The Netherlands.

Context of the study Prophylactic cranial irradiation (PCI) is standard treatment in patients with Small Cell Lung cancer (SCLC) and remission following treatment of the primary tumour, to prevent brain metastases. PCI results in a significant decrease in the incidence of brain metastases and improves survival. Adverse effects of PCI include fatigue, nausea, neurocognitive deterioration (such as learning and memory), and ataxia. These side effects may bemild and transient, but can also be progressive and persistent. Memory dysfunction is a major complaint following PCI, and previous studies demonstrated a significant decline in hippocampus related memory function following PCI. We hypothesized that sparing the hippocampus would improve neurocognitive decline after PCI. We therefore initiated amulticentre randomized phase III trial (NCT01780675) to investigate memory functioning after PCI with or without Hippocampus Avoidance (HA) in SCLC patients with a response to chemotherapy, or after chemo-radiation of the lung. Overview of abstract Memory functioning of patients included in the trial was assessed by a neuropsychological test battery at baseline, 4, 8, 12, 18 and 24 months after the brain irradiation with or without HA. The primary endpoint was a decline in the total recall score of the Hopkins Verbal Learning Test– Revised (HVLT–R), assessed at 4 months and a decline of ≥ 5 points was considered a failure. Secondary objectives were other cognitive outcomes/quality of life, radiological brain abnormalities on MRI (baseline, 4 and 12 months) and evaluation of the incidence and location of brain metastases following standard PCI (25 Gy in 10 fractions) compared to HA-PCI with a mean biological hippocampus dose ≤ 6.1 Gy (α/β=2Gy). What were the three main findings of your research 1. In both treatment arms the total recall score of the HVLT-R dropped at 4 months at least 5 points compared to baseline in 28% of the patients. 2. Based on the total recall score of HVLT-R (where a 5 point decline or greater was considered a failure) this prospective phase III trial did not show a significant

difference in memory decline between patients who received HA PCI and patients who were treated with conventional PCI at 4, and also not at 8 months 3. The incidence of brain recurrences was not increased

in the hippocampus avoidance region. What impact could your research have?

Having improved knowledge on the neurocognitive effects of PCI in SCLC helps to better inform patients about side effects, as it may also help us to identify those at particular risk for cognitive decline. The translational research part in this trial, including extensive fMRI and biomarkers, may give thus far unknown insights in the effects of radiation to the brain and on brain functioning in general. This knowledge will be used to design new trials aiming at decreasing side- effects of PCI. Is this research indicative of a bigger trend in oncology? There is increasing awareness about the impact of cancer treatments on neuro-cognitive functioning of patients. Our trial is the first worldwide to investigate the role of hippocampus sparing in PCI. It shows that we still lack fundamental knowledge in brain functioning to optimize the balance between the delivery of an effective cancer treatment such as PCI and the prevention of side effects. Other groups are investigating pharmacological interventions like memantine to reduce neuro-cognitive decline or try to avoid PCI by MRI surveillance of the brain.

Congress report | CLINICAL

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