title: Which dogs with appendicular osteosarcoma benefit most from chemotherapy after surgery? Results from an individual patient data meta-analysis.
abstract: Osteosarcoma (OS) is a malignant tumor of mesenchymal origin that produces osteoid. Given that the prognosis can vary considerably between dogs, we aimed to explore whether treatment could be tailored towards patient subgroups, characterized by their predicted risk of mortality. For the current study, a subset of five nonrandomized studies (400 subjects of whom 88 were dead at 5 months follow-up) was used from a previously published 20 study individual patient data meta-analysis. Missing data was dependent on observed variables and was imputed to correct for this dependency. Based on a previously published multivariable prognostic model, the 5-month mortality risk was predicted. Subsequently, in surgically treated dogs, using a logistic regression model with a random intercept for a study indicator, we explored whether chemotherapy effectiveness depended on predicted 5-month mortality risk. After adjustment for potential confounders the main effect of any chemotherapy was 0.48 (odds ratio) (95%CI 0.30; 0.78). Testing for chemotherapy by predicted 5-month mortality risk interaction revealed that the effects of any chemotherapy decreased with increasing predicted risk; interaction OR 3.41 (1.07; 10.84). Results from individually comparing carboplatin, cisplatin, doxorubicin and doxorubicin combination therapy to no chemotherapy, were similar in magnitude and direction. These results indicate that the main treatment effects of chemotherapy do not necessarily apply to all patients.
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, 3508 TB Utrecht, The Netherlands; Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, Utrecht 3584 CL, The Netherlands; Institute of Cardiovascular Science, Faculty of Population Health, University College London, London WC1E 6BT, United Kingdom. Electronic address: amand.schmidt@ucl.ac.uk.
authors.forename: A F
authors.initials: AF
authors.lastname: Schmidt
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: R H H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Department of Companion Animals, Atlantic Veterinary College University of Prince Edward Island, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Amsellem
authors.affiliation: Department of Small Animal Clinical Sciences, University of Florida, Gainesville, FL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bacon
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: O H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: Hoes
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Department of Small Animal Clinical Sciences, University of Florida, Gainesville, FL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kow
authors.affiliation: MedVet Medical and Cancer Centers for Pets, Cincinnati, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Maritato
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, Utrecht 3584 CM, The Netherlands(1).
authors.forename: J
authors.initials: J
authors.lastname: Kirpensteijn
authors.affiliation: Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, Utrecht 3584 CL, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Nielen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000601:surgery / Q000662:veterinary*; D016190:Carboplatin / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D004283:Dog Diseases / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D004285:Dogs; D004317:Doxorubicin / Q000627:therapeutic use; D015999:Multivariate Analysis; D012516:Osteosarcoma / Q000188:drug therapy / Q000401:mortality / Q000601:surgery / Q000662:veterinary*
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D016190:Carboplatin; D002945:Cisplatin
keywords: Bone tumor; Canine; Oncology; Personalized medicine