Calculating the net clinical benefit in neuro-oncology clinical trials using two methods: quality-adjusted survival effect sizes and joint modeling

Marijke B Coomans; Linda Dirven; Neil K Aaronson; Brigitta G Baumert; Martin van den Bent; Andrew Bottomley; Alba A Brandes; Olivier Chinot; Corneel Coens; Thierry Gorlia; Ulrich Herrlinger; Florence Keime-Guibert; Annika Malmström; Francesca Martinelli; Jeff A Sloan; Roger Stupp; Andrea Talacchi; Michael Weller; Wolfgang Wick; Jaap C Reijneveld; Martin J B Taphoorn

doi:10.1093/noajnl/vdaa147

Calculating the net clinical benefit in neuro-oncology clinical trials using two methods: quality-adjusted survival effect sizes and joint modeling

Neurooncol Adv. 2020 Oct 29;2(1):vdaa147. doi: 10.1093/noajnl/vdaa147. eCollection 2020 Jan-Dec.

Authors

Marijke B Coomans¹, Linda Dirven^{1

2}, Neil K Aaronson³, Brigitta G Baumert^{4

5}, Martin van den Bent⁶, Andrew Bottomley⁷, Alba A Brandes⁸, Olivier Chinot⁹, Corneel Coens⁷, Thierry Gorlia¹⁰, Ulrich Herrlinger¹¹, Florence Keime-Guibert¹², Annika Malmström¹³, Francesca Martinelli⁷, Jeff A Sloan¹⁴, Roger Stupp¹⁵, Andrea Talacchi¹⁶, Michael Weller¹⁷, Wolfgang Wick¹⁸, Jaap C Reijneveld^{19

20}, Martin J B Taphoorn^{1

2}

Affiliations

¹ Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
² Department of Neurology, Haaglanden Medical Center, Den Haag, the Netherlands.
³ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁴ Institute of Radiation-Oncology, Kantonsspital Graubünden, Chur, Switzerland.
⁵ Department of Radiation Oncology (MAASTRO clinic), and GROW (School for Oncology and Developmental Biology), Maastricht University Medical Center, Maastricht, the Netherlands.
⁶ The Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁷ Quality of Life Department, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
⁸ Department of Medical Oncology, Azienda USL-IRCCS Institute of Neurological Sciences, Bologna, Italy.
⁹ Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service de Neuro-Oncologie, Marseille, France.
¹⁰ European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
¹¹ Division of Clinical Neurooncology, Department of Neurology, University of Bonn Medical Center, Bonn, Germany.
¹² Groupe Hôpital Pitié-Salpetrière, Paris, France.
¹³ Division of Cell biology and Department of Biomedicine and Clinical Sciences, Linköping University, Linköping, Sweden.
¹⁴ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁶ Department of Neurosciences, Azienda Ospedaliera San Giovanni Addolorata, Roma, Italia.
¹⁷ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
¹⁸ Neurology Clinic and National Centre for Tumour Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany.
¹⁹ Department of Neurology and Brain Tumour Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands.
²⁰ Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.

Abstract

Background: Two methods combining survival and health-related quality of life (HRQoL) data in glioma trials to calculate the "net clinical benefit" were evaluated: Quality-adjusted effect sizes (QASES) and joint modeling (JM).

Methods: The net clinical benefit in two trials was calculated as proof of concept for other trials. With the QASES method, effect sizes for differences in progression-free survival (PFS) or overall survival (OS) and HRQoL between the experimental arm and standard treatment arm were calculated, while the relative emphasis placed on survival/HRQoL varied. JM allows simultaneous modeling of HRQoL and OS/PFS.

Results: In the EORTC 26951 trial, combined radiochemotherapy significantly prolonged OS (difference 11.7 months), but also resulted in more patients experiencing clinically relevant worsening (≥10 points) in appetite loss and nausea/vomiting shortly after treatment. Using QASES, the survival benefit of additional procarbazine, lomustine, and vincristine (PCV) decreased from 42.3 months to 29.5 and 28.2 months when accounting for appetite loss and nausea/vomiting, respectively. JM analyses resulted in a loss of the beneficial effect of additional PCV between 13% and 24% when adjusting for different HRQoL parameters. The EORTC 22033 trial showed no significant PFS difference between radiotherapy or temozolomide alone (46 vs 39 months), nor clinically relevant differences in HRQoL. JM analyses also showed no significant association between PFS and HRQoL scales/items, whereas QASES showed that temozolomide alone was more favorable when considering symptom burden (47-49 instead of 39 months).

Conclusions: Both methods resulted in different outcomes, but adjusting for the impact of treatment on HRQoL resulted in theoretically reduced survival benefits.

Keywords: glioma; joint model; net clinical benefit; quality of life; survival.