Radiol Oncol 2025; 59(3): 450-456. doi: 10.2478/raon-2025-0009 450 research article Patient survival after resection of skeletal metastases and endoprosthetic reconstruction: a nation-wide cohort study in a single oncological institution Aljaz Mercun1,2, David Martincic1,2, Blaz Mavcic1,2 1 Department of Orthopaedic Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Chair of Orthopaedics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2025; 59(3): 450-456. Received 28 October 2024 Accepted 19 December 2024 Correspondence to: Aljaž Merčun, M.D., Department of Orthopaedic Surgery, University Medical Centre Ljubljana, Zaloška 9, SI-1000 Ljubljana, Slovenia. E-mail: Aljaz.mercun@kclj.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The aim of this nation-wide 2009−2021 cohort study was to analyze postoperative survival of patients with resected appendicular skeletal metastases and endoprosthetic reconstruction in comparison to sarcoma pa- tients and non-oncological reconstructions. Patients and methods. A single institution nation-wide cohort of 144 consecutive patients with tumor endopros- thetic reconstructions (32 resected metastases, 73 resected sarcomas, 39 non-oncological) were stratified into histo- pathological groups according to the 2013-SPRING prediction model. Their survival was analyzed with the Kaplan- Meier method and Cox regression. Results. The observed patient survival rates after wide resection of fast/moderate/slow growing metastases were 25/55/88% at 2 years and 10/30/83% at 5 years, while in sarcomas the observed survival rates were 80% at 2 years and 69% at 5 years. Estimated mean postoperative survival after resection of skeletal metastases was significantly shorter in comparison to sarcomas (4.6 years vs. 9.1 years, log-rank p < 0.001). Predictors of worse patient survival included higher age, pathologic fracture or >1 metastasis, diagnostic group fast-growing metastases and higher preoperative C-reactive protein (CRP). Conclusions. Wide resection and endoprosthetic reconstruction offer a reliable solution in selected patients with skeletal metastases. Higher age, fast-growing metastases (from bladder cancer, colorectal, hepatocellular, lung can- cer, malignant melanoma, unknown origin), pathologic fracture or >1 metastasis and elevated CRP predict shorter patient survival and may represent a relative contraindication in this regard. Key words: skeletal metastases; wide resection; endoprosthetic reconstruction; patient survival Introduction Endoprostheses are currently used as the preva- lent limb-sparing surgical reconstruction option after wide tumor resections (curative intent for malignant tumours) of bone and cartilage in skele- tally mature patients.1-3 Improvement of carcinoma patients’ survival with skeletal solitary/oligome- tastases in the last decade increased the number of metastatic resections and endoprosthetic recon- structions.3,4 Complex algorithms have been devel- oped to help with the choice of the optimal surgical treatment option for skeletal metastases5, but the final decision and responsibility still lies with the appropriate tumor board. No nation-wide study so far has assessed patient survival after wide resec- Radiol Oncol 2025; 59(3): 450-456. Mercun A et al. / Patient survival after resection of skeletal metastases 451 tion of skeletal solitary/oligometastases in compar- ison to sarcoma patients which is a similar surgi- cal procedure. We decided to perform this cohort study with a single oncological decision-making institution (Oncological Institute) and a single department for wide resections of musculoskel- etal tumors (University Medical Centre Ljubljana, Department of Orthopedic Surgery) where a single modular endoprosthetic system MUTARS® has been used for this purpose since 2009.6 The primary aim of this cohort study was to analyze postoperative survival of patients who underwent wide resection and endoprosthetic re- construction of skeletal metastases in the Republic of Slovenia 2009−2021; to evaluate the impact of covariables (age, gender, histopathological diag- nosis, pathologic fracture or > 1 metastasis, pre- operative CRP / leukocyte count / haemoglobin / thrombocyte count) on this outcome and to com- pare them with sarcoma patients and non-onco- logical revision endoprosthetic patients operated in the same time period. Our secondary goal was to determine and compare implant removal rates between these patient groups, as all reconstruc- tions in the observed period were performed with an identical modular tumor endoprosthetic system (MUTARS®). Patients and methods The retrospective cohort consisted of patients who have undergone bone resection and reconstruction with a tumor endoprosthesis in the Republic of Slovenia between January 1st, 2009 and December 31st, 2021 at a single tertiary tumor center (Department of Orthopedic Surgery, University Medical Centre Ljubljana, Slovenia). This insti- tution is the only department in the Republic of Slovenia to perform MUTARS® endoprosthetic system for tumor reconstructions used 2009−2021. The presented study group of 144 consecutive pa- tients included cohort of resected bone metastases with endoprosthetic reconstruction in the selected observation period. No patients were excluded from the study. Patients were further stratified into five groups according to the 2013-SPRING survival prediction model:1) fast-growing metas- tases (bladder, colorectal, hepatocellular, lung, malignant melanoma, unknown, others), 2) mod- erate-growing metastases (prostate, renal), 3) slow- growing metastases (breast, lymphoma, myelo- ma), 4) sarcomas and 5) non-oncological diagnoses (benign tumor resections, revision arthroplasty cases).5 All indications for wide resection, possible adjuvant radiotherapy or systemic therapies were confirmed by a single oncological decision-mak- ing institution (Institute of Oncology Ljubljana, Ljubljana, Slovenia). The following data was ob- tained for each patient included in this study: age, gender, histopathological diagnosis, anatomical localization of the resected tumor, date of tumor endoprosthesis implantation, number of detected metastases at the time of tumor resection, presence of pathologic fracture(s), date of possible subse- quent implant removal, date of death (if applicable) and living status (alive/deceased) on October 1st, 2022. In the population of 32 metastatic patients (i.e. histopathological groups of fast-, moderate- and slow-growing metastases pooled together) we also analyzed the preoperative laboratory values of inflammation (CRP, leukocyte count, hemo- globin and platelets). Implants The MUTARS® system (Modular Universal Tumor and Revision System; Implantcast, Buxtehude, Germany) was introduced in 1992 and has since FIGURE 1. The Kaplan-Meier estimated mean survival time after surgical resection. Radiol Oncol 2025; 59(3): 450-456. Mercun A et al. / Patient survival after resection of skeletal metastases452 been widely used in Europe and throughout the world in orthopaedic oncology as well as revision surgery.1,7,8 Many studies reported using MUTARS as revision endoprosthesis after failed primary total knee arthroplasty7,9,10, oncological pelvic and lover limb reconstruction11-15 and upper limb reconstruction.16,17 However, no study so far has evaluated nation-wide diagnosis-stratified patient survival after implantation of modular universal tumor and revision system (MUTARS®) or any other comparable modular tumor endoprosthetic system. Statistical analyses Statistical data analysis was performed with Office 365 Excel (Microsoft Corp. Redmond, WA, USA) and SPSS Statistics 27.0 for Windows (IBM Corp, Armonk, NY, USA). Life tables of surviving pa- tients 2 years and 5 years postoperatively were compared with the chi-square test. Estimated mean survival times after the index operation were computed with the Kaplan-Meier method and the differences between groups evaluated with the log-rank test. The impact of age, gender, histopathological group and oncological stage (i.e. presence of pathologic fracture or more than one metastasis) on postoperative patient survival was analyzed with the Cox regression model. In the subcohort of 32 metastatic patients (i.e., histo- pathological groups of fast-, moderate- and slow- growing metastases pooled together), a separate Cox regression model was used to analyze the im- pact of preoperative laboratory values of inflam- mation (CRP, leukocyte count, hemoglobin and platelets) on postoperative patient survival. Ethical issues The presented non-interventional observational retrospective study was approved by the National Medical Ethics Committee of the Republic of Slovenia (case No. 0120-486/2017/4). There was no funding and no conflict of interest. Results Between January 1st, 2009, and December 31st, 2021, a total of 144 MUTARS® reconstructions were performed (10 pelvises, 4 total femoral, 37 proximal femoral, 2 femoral diaphyseal, 38 dis- tal femoral, 21 revisions after primary total knee arthroplasty, 11 proximal tibial and 21 proximal humeral replacements). The mean age at the time of reconstruction was 49.9 ± 20.4 years. When pa- tients were stratified into five groups based on the histopathological diagnosis of the resected tumor5, there were considerable differences in their mean age and percentage of patients in advanced onco- logical stage (pathologic fracture or >1 metastasis) at the time of the index operation (Table 1). TABLE 1. Demographic characteristics, oncological stage and observed survival of patients stratified according to the histopathological diagnosis according to the 2013-SPRING survival prediction model5 Fast-growing metastases Moderate-growing metastases Slow-growing metastases Sarcomas Non-oncological patients No. of subjects 12 11 9 73 39 Mean age [years] 63 ± 14 65 ± 10 64 ± 12 42 ± 21 53 ± 19 Gender [Female/Male] 6 / 6 2 / 9 8 / 1 39 / 34 20 / 19 Percentage of patients with pathological fracture or > 1 metastasis 75% 73% 44% 18% 0% Patients alive 2 years after the operation † 25% 55% 88% 80% 100% Patients alive 5 years after the operation ‡ 10% 30% 83% 69% 97% Implant removed within 2 years after the operation † 0% 9% 13% 9% 11% Implant removed within 5 years after the operation ‡ 10% 10% 17% 18% 19% † in the subcohort of 139 patients with minimum 2 years of postoperative follow-up ‡ in the subcohort of 108 patients with minimum 5 years of postoperative follow-up Radiol Oncol 2025; 59(3): 450-456. Mercun A et al. / Patient survival after resection of skeletal metastases 453 Patient survival Observed percentage of surviving patients after resection of fast- and moderate-growing metasta- ses (2-year survival 25% and 55%, 5-year survival 10% and 30%, respectively) was considerably lower in comparison to slow growing metastases (2-year survival 88%, 5-year survival 83%) or sarcoma pa- tients (2-year survival 80%, 5-year survival 69%) (Table 1) with statistical significance at both 2 years (p < 0.01) and 5 years of follow-up (p < 0.01). The Kaplan-Meier estimated mean survival time (Figure 1) after the index operation was 2.3 years for fast-growing metastases, 3.2 years for moderate-growing metastases, 8.5 for slow-grow- ing metastases. When pooled together, the esti- mated mean postoperative survival of all resected skeletal metastases was significantly shorter in comparison to sarcomas (4.6 years vs. 9.1 years, log- rank p < 0.001). In the Cox multivariate regression of postoperative patient survival after wide tumor resection, statistically significant predictors of worse outcome included higher age (hazard ratio for every additional year 1.021, p = 0.031), patholog- ic fracture or >1 metastasis (hazard ratio 2.809, p = 0.003) and histopathological group of fast-growing metastases (hazard ratio 5.522, p = 0.011), while the trend of shorter survival in moderate-growing me- tastases and sarcoma patients in comparison to the reference group of slow-growing metastases was not statistically significant (Table 2). Additionally, in the subcohort analysis of 32 metastatic patients shown in Table 3 (i.e. histopathological groups of fast, moderate- and slow-growing metastases pooled together), elevated CRP concentration was the only significant laboratory parameter predict- ing shorter survival (hazard ratio 1.018 for increase of 1 mg/L, p = 0.021). Implant survival The cumulative number of implants requiring sub- sequent surgical removal for any reason during the follow-up was 24 (16.7%) out of the entire cohort of 144 MUTARS® endoprostheses. At 2/5 years after the operation, implants had to be removed in 6/8% of patients with skeletal metastases, 9/18% with sarcomas and 11/19% of non-oncological patients (Table 1). The Cox regression analysis of implant survival until removal showed none of the input variables (age, gender, histopathological group, pathologic fracture or > 1 metastasis) significantly affected endoprosthesis removal. Discussion Life expectancy of oncological patients with skel- etal metastases of appendicular skeleton has been extensively studied in the past, but few reports assessed patient survival after wide resection of skeletal metastases in comparison to sarcoma pa- tients. In this nation-wide cohort study, patients with resected skeletal metastases had signifi- cantly shorter estimated postoperative survival (2.3−8.5 years) in comparison to bone sarcomas (9.1 years) or non-oncological revisions, but it was long enough to justify endoprosthetic reconstruction. Higher age, metastases other than plasmacytoma/ renal cell/ breast carcinoma, pathologic fracture TABLE 2. Cox regression analysis of patient survival for the cohort of 144 patients with tumor endoprosthetic reconstructions, stratified into histopathological groups according to the 2013-SPRING survival prediction model B SE Exp(B) 95 % CI for Exp(B) p-value Lower Upper Age [per year] 0.021 0.010 1.021 1.002 1.041 0.031* Gender [male = 1] -0.410 0.304 0.664 0.366 1.205 0.178 Slow-growing-mets (reference) 0.002* Fast-growing mets 1.709 0.674 5.522 1.473 20.703 0.011* Moderate-growing mets 0.853 0.703 2.347 0.592 9.308 0.225 Sarcomas 0.831 0.661 2.296 0.629 8.378 0.208 Non-oncological patients -1.315 0.964 0.269 0.041 1.776 0.173 Pathological fx or > 1 mets 1.032 0.350 2.809 1.414 5.587 0.003* B = Cox coefficient; CI = confidence interval; Exp(B) = risk for a revision; fx = fracture; mets = metastases; SE = standard error Omnibus test of model coefficients p < 0.001. Statistically significant p-values are marked with an asterisk (*) Radiol Oncol 2025; 59(3): 450-456. Mercun A et al. / Patient survival after resection of skeletal metastases454 or >1 metastases and elevated CRP values were independent predictors of shorter postoperative patient survival. While most articles focus mainly on survival of implants in treatment of primary bone tu- mors (2-year survival of 86%, 5-year survival of 70.5−78.3% and 10-year survival of 60−70%)18-20 or revision free survival of implant (5-year survival 71% and 10-year survival 63.3 %)21, some also re- port patient survival at various time points.22 Studies focusing on survival after resection and limb salvage of primary bone tumor in adults re- ported 2-year survival of 77%16, 3-year survival of 45.6 – 66.5% and 5-year survival of 38−67%23-26, with 5-year survival of limb salvage tumor opera- tion around the knee in children of 72.7%.27 In this respect, our results show comparable patient sur- vival rates for primary malignant bone tumors at 2 and 5 years. Survival of patients with skeletal metastases is considerably shorter. Previously reported survival of proximal femur metastatic disease is 60% at 6 months and 35% at 12 months28, but the choice of treatment was significantly biased by initial stage of oncological disease. A recent study reported overall patient survival of 40% at 2 years and 28% at 4 years, no difference in survival between pa- tient with solitary- or oligometastatic disease, and significantly better survival in comparison to mul- tiple metastatic disease29, whereby the tumor diag- nosis had considerable influence on the outcome of surgical metastasis treatment.30 Mean survival after modular endoprosthetic fixation was 860 days compared to 360 days after intramedullary bone fixation, showing statistically significant difference and higher complication rates of endo- prosthetic reconstruction.31 A multicentric study reported mean survival of humerus metastasis of 16.7 months, significantly impacted by the occur- rence of fracture, diaphyseal location and type of primary cancer32, while mean survival of patho- logical fractures of the humerus is reported as low as 8.3 months with 57 out of 87 cases treated by intramedullary nailing.33 Sørensen et. al. implemented 2013-SPRING model for prediction of survival after surgical treatment of bone metastases providing increased quality of life for patients while minimizing po- tential implant failure – 6-month postoperative survival was considered an indication for more durable implant and wider resection of metastat- ic lesion, because it cannot be expected for lesion to heal and internal fixation would likely lead to failure of implant.5 Similar findings were report- ed by Errani et. al. advocating that a postopera- tive survival of 12 months or more should include treatment with a more durable implant, whereby prognosis can be on just two parameters: histo- pathological diagnosis of metastases and elevated CRP values.34 In accordance with these previous findings, CRP was a reliable prognostic factor of shorter postoperative patient survival of metastat- ic patients in the presented study. The presented study has several limitations. Data analysis only considered oncological patients with resected skeletal metastases and endopros- TABLE 3. Cox regression analysis of patient survival for the subcohort of 32 patients with metastases, stratified into histopathological groups according to the 2013-SPRING survival prediction model B SE Exp(B) 95 % CI for Exp(B) p-value Lower Upper Age [per year] 0.039 0.037 1.040 0.967 1.119 0.293 Gender [male = 1] 0.235 0.622 1.265 0.373 4.285 0.706 Slow-growing-mets (reference) 0.022* Fast-growing mets 1.859 0.898 6.419 1.105 37.294 0.038* Moderate-growing mets 0.436 1.014 1.547 0.212 11.289 0.667 Pathological fx or > 1 mets -0.683 0.725 0.505 0.122 2.093 0.346 C-reactive protein [mg/L] 0.018 0.008 1.018 1.003 1.034 0.021* Leukocyte count [109/L] 0.096 0.081 1.100 0.940 1.289 0.234 Hemoglobin [g/L] 0.027 0.029 1.027 0.971 1.087 0.348 Thrombocyte count [109/L] 0.000 0.005 1.000 0.989 1.011 0.980 B = Cox coefficient, CI = confidence interval; Exp(B) = risk for a revision; fx = fracture; SE = standard error, omnibus test of model coefficients p = 0.001. Statistically significant p-values are marked with an asterisk (*). Radiol Oncol 2025; 59(3): 450-456. Mercun A et al. / Patient survival after resection of skeletal metastases 455 thetic reconstruction, while ignoring resections of spinal metastases and patients with intral- esional metastatic tissue removal and palliative non-endoprosthetic stabilizations of long bones. Heterogeneity of patients in terms of age, gender, diagnoses, anatomical localizations, adjuvant ra- diotherapy or systemic therapy was another major limitation, likewise present in most similar studies on skeletal metastases. The confounding effect of added systemic therapy and/or radiotherapy was not controlled in our study. Nevertheless, the im- pact of these confounding factors was mitigated by using nation-wide uniform oncological guide- lines and setting indications for oncological wide resections at a single oncological decision-making institution. 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