Survival after treatment of metastatic bone disease in the extremities Evaluation of factors influencing survival and subsequent development and validation of a prediction model for postoperative survival MICHALA SKOVLUND SØRENSEN, M.D. PhD thesis originated from Musculoskeletal Tumor Section, Department of Orthopedics, Rigshospitalet, University of Copenhagen, Denmark & Faculty of Health and Medical Sciences, University of Copenhagen ii Date of submission February 1st, 2018 Academic supervisors Principal supervisor: Michael Mørk Petersen, M.D., DMSc, professor Musculoskeletal Tumor Section, Department of Orthopedics, Rigshospitalet, University of Copenhagen, Denmark Co-supervisor: Klaus Hindsø, M.D., PhD, associate professor Section of Pediatrics, Department of Orthopedics Rigshospitalet, University of Copenhagen, Denmark Assessment committee Chair Jes Bruun Lauritzen, M.D., DMSc, professor Department of Orthopedic Surgery, Bispebjerg Hospital, University of Copenhagen, Denmark International assessor Henrik C. Bauer, M.D., PhD, professor Department Orthopedics/Oncology Service, Karolinska Hospital, Stockholm, Sweden National assessor Alma Becic Pedersen, M.D., PhD, DMSc, associate professor Department of Clinical Epidemiology - Department of Clinical Medicine - Aarhus University, Denmark. iii ACKNOWLEDGEMENT The deepest gratitude to all of the 164 patients who took their time and went the extra miles to participate in the prospective part of current thesis during a period of their life where the risk of ambulatory function and end of life was pending. I would like to thank my principal supervisor, Michael, for your time, your patience, for giving me elbow space, bearing with me during my stubbornness and for making all of this happening. It has been a project in the making for 6 years and I’m sorry for not providing you with a Dark score, but you compensate for the Hindsø score in so many other ways that you do not need one. Klaus, my co-supervisor; thank you for the debate and endless discussion of a definition of a fishing trip, even if it was only for the fun of it, it gave me the best foundation to build a statistical knowledge on. To both of you, I’m sorry for the extra pounds gained due to all of our “project meetings cake”. Most importantly, thank you for taking the time, it has always been more than one could expect. This project was only feasible due to the co-workers from all participating centers (Hillerød (Tobias), Herlev (Stig), Hvidovre (Anders) and Bispebjerg (Tomasz) orthopedic departments), thank you for your time and effort. A special thanks to the people at Musculoskeletal tumor section Rigshospitalet, Lise, Dorrit, Pernille, Mette, Iben, Peter, Claus, Kolja, Thomas, Tine, Elinborg, Thea whom put in voluntary time and effort to answer all of my questions, processing blood samples and managing the administrative of having an outpatient clinic without having a clinic. A great thanks to Gunnar, my roommate for 4 years and my everyday non-official supervisor. Many great ideas and forming of the project is contributed to you. Thank you to the commander in chief, Erik. Thomas A. Gerds, I’m very grateful for your time and patience in the statistical part of this thesis, had I’ve never stumbled into your office and R coding a great part of the thesis would be lacking. iv Sometimes you go travel and stumble into something very useful and very pleasant. Thanks to my PhD (wine) club (Marie, Bente and Sabrina), you have been a very valued partner in this process, thank you for telling me that a prosthesis means more than metal in the femur. Thank you for telling me what’s right and what’s wrong. Thank you for pushing me over the bumps on the way. Also, a very warm thanks to the Forsberg family, Jonathan, Dawn, Linnea and Sofia for taking me into their home and making me a natural part of their family and learning me everything there is to know about clinical decision making and good standard, I’m forever grateful. Thank you for the very nice cover illustration Karen, demanding you to fit all implant used in patients represented in current thesis on the orthopedic tree cannot have been an easy task – but you did to perfection. Last, thanks to my wonderful family, Brian and Karla, mom, Tina, Knud and all of my friends. Brian, you are the best, thanks for just being you, being there, for pushing me to the limit, picking me up and ALWAYS believing in me (with this, at times, silly, time consuming project). v SELECTED ABBREVIATIONS MBD: Metastatic Bone Disease MBDex: Metastatic Bone Disease in the extremities SRE: Skeletal Related Event CT: Computer Tomography THA: Total Hip Arthroplasty CRD: Capital Region of Denmark MTC: Musculoskeletal Tumor Section SSC: Secondary Surgical Center DNPR: Danish National Patient Registry DCRS: Danish Civil Registry System OS: probability of Overall Survival RFS: probability of Revision Free Survival ASA: American Society of Anaesthiologist 95 C.I.: 95% Confidence Interval OR: Odds Ratio rTSA: reverse Total Shoulder Arthrosplasty n/s: Not statistically Significant SPRING: Sørensen PeteRsen, hINdsø, Gerds Funding and Conflict of Interest The following institutions and foundations kindly provided financial support for current thesis: 1. Capital Region of Denmark Research and Innovation Foundation 2. Centre of Head and Orthopedics, Rigshospitalet 3. Board of management Rigshospitalet 4. Rigshospitalets Research Foundation 5. Lykfeldt’s legat. No conflict of interest to report. vi LIST OF PUBLICATIONS I. Sørensen MS, Gregersen KG, Grum-Schwensen T, Hovgaard D, Petersen MM. Patient and implant survival following joint replacement because of metastatic bone disease. A cross-sectional study of 130 patients with 140 joint replacements. Acta Orthopaedica. 2013; 84 (3): 301–306. II. Sørensen MS, Hindsø K, Horstmann PF, Troelsen A, Dalsgaard S, Fog T, Zimnicki T, Petersen MM. Incidence of surgical intervention for metastatic bone disease in the extremities: A population based study. Manuscript ready for submission III. Sørensen MS, Hindsø K, Hovgaard TB, Petersen MM Extent of surgery does not influence 30-day mortality in surgery for metastatic bone disease: An observational study of a historical cohort. Medicine (Baltimore). 2016 Apr;95(15):e3354. IV. Sørensen MS, Gerds TA, Hindsø K, Petersen MM: Prediction of survival after surgery due to skeletal metastases in the extremities. The Bone & Joint Journal. Feb 2016;98-B(2):271-277. V. Sørensen MS, Gerds TA, Hindsø K, Petersen MM: External validation and optimization of the SPRING model: a model for prediction of patient survival after surgery for bone metastasis of the extremities. Accepted for publication in Clinical Orthopaedics and Related Research Jan. 2018 vii ENGLISH SUMMARY Background: Surgical management of metastatic bone disease (MBD) can be a devastating event for cancer patients whom are often very close to the end of life, where the desire for self-care must be balanced with the risk of surgical intervention aiming to perform one surgical procedure that will outlive the patient. Main aim of the current thesis was to identify factors related to or influencing survival after surgery for MBD in the extremities (MBDex), and provide and validate a prediction model for postoperative survival. Methods: Three cohorts comprised the material for the thesis, two retrospective cohorts (n=130 and 140) of patients having bone resection and reconstruction at a highly specialized center and one prospective multicenter population based cohort of all patients living in the Capital Region of Denmark (CRD) having surgical interventions for MBDex during a period of two years (n=164). Main results: We found an estimated probability of one year overall survival after joint replacement surgery for MBDex in a cohort of patient treated at a highly specialized center to be 38% (study I). In comparison, overall one year survival in a multicenter study of population based cohort of patients treated for MBDex was 41% (study II). Survival decreased if treatment was performed at a secondary surgical center compared to patients treated at a highly specialized center (one year survival 34%). Patients was more likely to be referred for treatment at a highly specialized center if they had good prognostic factors for survival (younger age, good prognostic group of cancer, impending fracture, no visceral metastases, good performance status, low ASA score). Multiple regression analysis, adjusted for known risk factors for survival, showed a non- statistically significant (p=0.069) association with increased mortality if patients were treated outside a highly specialized center. The risk of undergoing surgery for MBDex if diagnosed with MBD was found to be 10% per year lived with MBD with an incidence of 48.6 MBDex lesions treated / million inhabitants / year in Denmark (study II). Eighty- eight percent of patients undergoing surgery for MBDex survived 30 days after the surgical trauma, were general health status, measured by Karnofsky performance status, and ASA score, was the only independent risk factors for mortality and no factors describing the extent of the surgical trauma (blood loss, surgery time or major bone viii resection) were associated with increased mortality (study III). Patients receiving surgeries with prolonged surgical time seemed to have a non-statistical significant increased survival 30 days after surgery. A model for prediction of survival 3, 6 and 12 months after surgery for MBDex was developed (SPRING model) using known prognostic variables for survival after surgery for MBDex (hemoglobin, primary cancer, Karnofsky performance status, ASA score, visceral metastases, multiple bone metastases, and complete or impending fracture) (study IV). The prediction model was refitted with a more modern cohort and external validated in an independent prospective population based cohort of patients having surgery for MBDex in multicenter settings. The model showed good calibration, accuracy and discrimination for prediction of survival at 3, 6 and 12 months after surgery. The refitted SPRING model (study V) performed better (p<0.05) at all three endpoints in ROC and Brier evaluation than the old model (study IV).