Hippocampal-avoidance whole-brain radiotherapy with dose escalation on metastases: A prospective randomized trial (HIPPORAD).
Abstract
2038 Background: The HIPPORAD trial aimed to evaluate a new method of whole brain radiation therapy (WBRT) with simultaneous integrated boost (SIB) to the metastases, with versus without hippocampal avoidance in patients with brain metastases. Methods: We conducted a prospective, multicentre, randomised, double-blind trial (DRKS00004598). Patients with 4-10 brain metastases > = 5mm were randomised at 13 centres in Germany 1:1 between WBRT+SIB with hippocampus avoidance (HA-WBRT+SIB) (arm A) and WBRT+SIB (arm B). Patients and assessors of outcome were blinded to the randomised arm. All patients received WBRT with 30 Gy and SIB with 51 Gy or 42 Gy in 12 fractions, 5x/week. The primary endpoint was the change in neurocognitive function (assessed by the Verbal Learning and Memory Test [VLMT]) 3 months after treatment. Secondary endpoints included neurocognitive changes at 9 and 18 months, development of anxiety and depression, quality of life and measures of oncological outcome. Results: Between August 2 nd , 2016 and September 7 th , 2021, 170 patients were recruited and 136 were randomised between HA-WBRT+SIB (n = 67) and WBRT+SIB (n = 69). Of these, 38 patients in arm A and 42 in arm B were known to be alive 3 months after treatment and were included in the primary endpoint analysis. The change in overall learning performance at 3 months was not significantly different between arms (p = 0.83). VLMT-scores decreased after 3 months, but improved at 9 and 18 months, with HA-WBRT+SIB showing an overall superior trend over WBRT+SIB. At 18 months, VLMT-scores improved to values above baseline in both arms. Patients treated with HA-WBRT+SIB had significantly less depression compared to patients treated with WBRT+SIB at 3 (p = 0.047) and 18 months (p = 0.048). The 12-month-tumor control for boosted metastases was 96% in Arm A and 88% in Arm B, while for the WBRT area it was 78% in both arms. Time to hippocampal tumour progression was comparable between arms (p = 0.98). After 12 months, 4% of patients in arm A and 12% in arm B had suffered neurological death. Conclusions: To our knowledge, this is the first prospective trial to show that hippocampal avoidance during WBRT leads to significantly lower rates of depression. The development of VLMT values after HA-WBRT+SIB and WBRT+SIB with 30 Gy in 2.5 Gy-fractions was comparable and a good recovery was observed at 18 months in both arms. The method showed a considerably higher intracerebral tumour control with lower neurological mortality rates compared to historical cohorts. Clinical trial information: DRKS00004598 .
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Anca-Ligia Grosu
Claudia Schmoor
From Bielefeld University, Medical School and University Medical Center Ostwestfalen-Lippe, Campus Hospital Lippe, Detmold, Germany (J.H.); the Department of Radiation Oncology, Medical University of Graz, Graz, Austria (T.B.); the Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany (C.S.); the Institute of Surgical Pathology, University Medical Center Freiburg, Germany (P.B.); the Department of Surgery, University Medical Center Schleswig-Holstein–Campus Lübeck, Lübeck, Germany (B.K., T.K.); Comprehensive Cancer Center Augsburg, Faculty of Medicine, University of Augsburg, Augsburg, Germany (R.C.); the Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany (S.U.); the Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg–Eppendorf, Hamburg, Germany (J.R.I.); the Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute and San Raffaele Vita-Salute Universi...
Erika Graf
Institute of Medical Biometry and Statistics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
Lars Frings
Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
Thomas Rothe
Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
Sabine Schneider-Fuchs
Clinical Trials Unit, University Medical Center Freiburg, Freiburg, Germany
Oliver Oehlke
Department of Radiation Oncology, Kliniken Maria Hilf Gmb, Mönchengladbach, Germany
Ursula Nestle
Department of Radiotherapy and Radiation Oncology, Kliniken Maria Hilf, Moenchengladbach, Germany
Florian Würschmidt
Radiologische Allianz, Strahlentherapie, Hamburg, Germany
Maximilian Niyazi
Department of Radiation Oncology University Hospital Tubingen Tubingen Germany
Raphael Bodensohn
Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
Frank Paulsen
Department of Radiation Oncology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
Victor Lewitzki
Department of Radiation Oncology, University Hospital Wuerzburg, Würzburg, Germany
Jürgen Dunst
22Department of Radiation Oncology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Emmanouil Fokas
Sophie Wetzel
Department of Radiation Oncology, Krankenhaus Nordwest, Frankfurt, Germany
Ilja Ciernik
Department of Radiation Oncology, City Hospital Dessau, Dessau, Germany
Christian T. Dietzel
Department of Radiation Oncology, University Hospital Halle (Salle), Halle, Germany
Marcel Ott
Department of Radiation Oncology, Klinikum Wolfsburg, Wolfsburg, Germany
Ilinca Popp
Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany