Laryngeal Chondrosarcoma Characteristics and Survival Analysis in the National Cancer Database.

OBJECTIVE: To highlight various patient, tumor, diagnostic, and treatment characteristics of laryngeal chondrosarcoma (LC) as well as elucidate factors that may independently affect overall survival (OS) for LCs. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database (NCDB). METHODS: All LC cases from 2004 to 2016 were extracted from the NCDB. Several demographic, diagnostic, and treatment variables were compared between LC subgroups using χ2 and analysis of variance tests. Univariate and multivariate survival analyses were performed for LCs using univariate Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: There were 348 LCs included in the main cohort. LCs were predominantly non-Hispanic white males with similar rates of private and government insurance (49.4% vs 45.4%). Most LCs (81.6%) underwent primary surgery, particularly partial and total laryngectomy. The 1-, 5-, and 10-year survivals for LC were 95.7%, 88.2%, and 66.3%, respectively. On multivariate analysis, lack of insurance (P = .019; hazard ratio [HR], 8.21; 95% CI, 1.40-48.03), high grade (P = .001; HR, 13.51; 95% CI, 3.08-59.26), and myxoid/dedifferentiated histological subtypes (P = .0111; HR, 10.74; 95% CI, 1.71-67.33) correlated with worse OS. No difference in OS was found between partial and total laryngectomy. CONCLUSION: This is the first multivariate survival analysis and largest single cohort study of LCs in the literature. Overall, LCs enjoy an excellent prognosis, with insurance status, grade, and histology as the main predictors of survival.

Proton therapy with a fixed beamline for skull-base chordomas and chondrosarcomas: outcomes and toxicity.

AIM: This study presents an analysis (efficacy and toxicity) of outcomes in patients with skull-base chordomas or chondrosarcomas treated with a fixed horizontal pencil proton beam. BACKGROUND: Chordomas (CAs) and chondrosarcomas (CSAs) are rare tumours that are usually located near the base of the skull and very close to the brain's most critical structures. Proton therapy (PT) is often considered the best radiation treatment for these diseases, but it is still a limited resource. Active scanning PT delivered via a fixed pencil beamline might be a promising option. METHODS: This is a single-centre experience describing the results of proton therapy for 31 patients with CA (n = 23) or CSA (n = 8) located near the base of the skull. Proton therapy was utilized by a fixed pencil beamline with a chair to position the patient between May 2016 and November 2020. Ten patients underwent resection (32.2%), 15 patients (48.4%) underwent R2 resection, and 6 patients had unresectable tumours (19.4%). In 4 cases, the tumours had been previously irradiated. The median PT dose was 70 GyRBE (relative biological efficacy, 1.1) [range, 60 to 74] with 2.0 GyRBE per fraction. The mean GTV volume was 25.6 cm3 [range, 4.2-115.6]. Patient demographics, pathology, treatment parameters, and toxicity were collected and analysed. Radiation-induced reactions were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. RESULTS: The median follow-up time was 21 months [range, 4 to 52]. The median overall survival (OS) was 40 months. The 1- and 2-year OS was 100%, and the 3-year OS was 66.3%. Four patients died due to non-cancer-related reasons, 1 patient died due to tumour progression, and 1 patient died due to treatment-related injuries. The 1-year local control (LC) rate was 100%, the 2-year LC rate was 93.7%, and the 3-year LC rate was 85.3%. Two patients with CSA exhibited progression in the neck lymph nodes and lungs. All patients tolerated PT well without any treatment interruptions. We observed 2 cases of ≥ grade 3 toxicity, with 1 case of grade 3 myelitis and 1 case of grade 5 brainstem injury. CONCLUSION: Treatment with a fixed proton beam shows promising disease control and an acceptable toxicity rate, even the difficult-to-treat subpopulation of patients with skull-base chordomas or chondrosarcomas requiring dose escalation.

Is 2 mm a wide margin in high-grade conventional chondrosarcomas of the pelvis?

AIMS: Controversy exists as to what should be considered a safe resection margin to minimize local recurrence in high-grade pelvic chondrosarcomas (CS). The aim of this study is to quantify what is a safe margin of resection for high-grade CS of the pelvis. METHODS: We retrospectively identified 105 non-metastatic patients with high-grade pelvic CS of bone who underwent surgery (limb salvage/amputations) between 2000 and 2018. There were 82 (78%) male and 23 (22%) female patients with a mean age of 55 years (26 to 84). The majority of the patients underwent limb salvage surgery (n = 82; 78%) compared to 23 (22%) who had amputation. In total, 66 (64%) patients were grade 2 CS compared to 38 (36%) grade 3 CS. All patients were assessed for stage, pelvic anatomical classification, type of resection and reconstruction, margin status, local recurrence, distant recurrence, and overall survival. Surgical margins were stratified into millimetres: < 1 mm; > 1 mm but < 2 mm; and > 2 mm. RESULTS: The disease--specific survival (DSS) at five years was 69% (95% confidence interval (CI) 56% to 81%) and 51% (95% CI 31% to 70%) for grade 2 and 3 CS, respectively (p = 0.092). The local recurrence-free survival (LRFS) at five years was 59% (95% CI 45% to 72%) for grade 2 CS and 42% (95% CI 21% to 63%) for grade 3 CS (p = 0.318). A margin of more than 2 mm was a significant predictor of increased LRFS (p = 0.001). There was a tendency, but without statistical significance, for a > 2 mm margin to be a predictor of improved DSS. Local recurrence (LR) was a highly significant predictor of DSS, analyzed in a competing risk model (p = 0.001). CONCLUSION: Obtaining wide margins in the pelvis remains challenging for high-grade pelvic CS. On the basis of our study, we conclude that it is necessary to achieve at least a 2 mm margin for optimal oncological outcomes in patients with high-grade CS of the pelvis. Cite this article: Bone Joint J 2021;103-B(6):1150-1154.

Prognostic importance of IDH mutations in chondrosarcoma: An individual patient data meta-analysis.

INTRODUCTION: IDH1/2 mutations are prevalent in cartilaginous tumors including chondrosarcoma. This meta-analysis using individual patient data (IPD) aimed to investigate the clinical and prognostic association of these mutations in chondrosarcoma patients. METHODS: Two electronic databases including PubMed and Web of Science were searched for relevant data. We included studies providing IPD of chondrosarcoma with available IDH1/2 mutational status for meta-analysis. Chi-square and t-test were performed to compare the groups with and without IDH1/2 mutations. For survival analysis, log-rank test, and Cox proportional hazards model were used to investigate the association of IDH mutations with patient outcomes. RESULTS: Fourteen studies with 488 patients were analyzed. IDH1 and IDH2 mutations were detected in 38.7% and 12.1% of cases, respectively. IDH1/2 mutations were significantly associated with an older age (p = 0.003), tumor origins (p < 0.001), tumor grades (p < 0.001), larger diameter (p = 0.003), relapse (p = 0.014), and patient mortality (p = 0.04). Multivariate Cox regression analysis adjusted for age, gender, tumor grade, and tumor sites confirmed the negative impact of IDH1/2 mutations on patient overall survival (HR = 1.90; 95% CI = 1.06-3.42; p = 0.03). CONCLUSION: Our meta-analysis demonstrated the distinct characteristics of IDH1/2-mutated chondrosarcomas in comparison to those without mutations. These mutations could serve as an independent prognostic biomarker to better prognosticate patient outcomes and design appropriate treatment plans.

Prognostic Factors and a Nomogram Predicting Overall Survival in Patients with Limb Chondrosarcomas: A Population-Based Study.

INTRODUCTION: We aimed to develop and validate a nomogram for predicting the overall survival of patients with limb chondrosarcomas. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program database was used to identify patients diagnosed with chondrosarcomas, from which data was extracted from 18 registries in the United States between 1973 and 2016. A total of 813 patients were selected from the database. Univariate and multivariate analyses were performed using Cox proportional hazards regression models on the training group to identify independent prognostic factors and construct a nomogram to predict the 3- and 5-year survival probability of patients with limb chondrosarcomas. The predictive values were compared using concordance indexes (C-indexes) and calibration plots. RESULTS: All 813 patients were randomly divided into a training group (n = 572) and a validation group (n = 241). After univariate and multivariate Cox regression, a nomogram was constructed based on a new model containing the predictive variables of age, site, grade, tumor size, histology, stage, and use of surgery, radiotherapy, or chemotherapy. The prediction model provided excellent C-indexes (0.86 and 0.77 in the training and validation groups, respectively). The good discrimination and calibration of the nomograms were demonstrated for both the training and validation groups. CONCLUSIONS: The nomograms precisely and individually predict the overall survival of patients with limb chondrosarcomas and could assist personalized prognostic evaluation and individualized clinical decision-making.

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

INTRODUCTION: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. MATERIALS AND METHODS: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. RESULTS: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. CONCLUSIONS: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Efficacy and safety of regorafenib in patients with metastatic or locally advanced chondrosarcoma: Results of a non-comparative, randomised, double-blind, placebo controlled, multicentre phase II study.

BACKGROUND: This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy. PATIENTS AND METHODS: Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%). RESULTS: From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib. CONCLUSION: Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy. CLINICAL TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT02389244).

Chondrosarcoma of the Temporomandibular Joint: Systematic Review and Survival Analysis of Cases Reported to Date.

The purpose of this systematic review was to summarize the available data on TMJ chondrosarcomas and to perform a survival analysis of cases reported to date. This review was conducted in accordance with the PRISMA. Two authors performed an electronic search of case reports of TMJ chondrosarcoma published until August 02, 2020. Forty-seven studies reporting 53 cases were included. Chondrosarcomas of the TMJ were more prevalent in women, with a male:female ratio of 1:1.4. Survival curves were significantly associated with histological diagnosis (p = 0.004), reconstructive surgery (p = 0.024), recurrence (p < 0.001), and distant metastasis (p = 0.001). Only distant metastasis was independently associated with survival (p = 0.017). TMJ chondrosarcomas presented with low recurrence and higher survival rates than other chondrosarcomas. Synovial subtype, absence of reconstructive surgery, and presence of local recurrence or distant metastasis were associated with poorer prognosis.

Targeting cancer stem cells by disulfiram and copper sensitizes radioresistant chondrosarcoma to radiation.

Overcoming the radiosensitivity of chondrosarcoma (CS), the second most common primary bone tumor, is needed. Radioresistance is attributed to cancer stem cells (CSCs) in many malignancies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, complexed with Cu (DSF/Cu) can radiosensitize epithelial CSCs. This prompted us to investigate the radiosensitizing effect of DSF/Cu on CS CSCs (CCSCs). The radiosensitizing effects of DSF/Cu on CCSCs were investigated in vitro using cell lines SW1353 and CS-1. Stemness was identified independently by flow cytometry for CCSCs (ALDH+CD133+), sphere-forming ability, and Western blot analysis of stemness gene protein expression. The radiosensitizing effect of DSF/Cu was studied in an orthotopic CS xenograft mouse model by analyzing xenograft growth and residual xenografts for stemness. CCSCs were found to be resistant to single-dose (IR) and fractionated irradiation (FIR). IR and FIR increased CS stemness. Combined with DSF/Cu in vitro and in vivo, IR and FIR eliminated CS stemness. RT + DSF/Cu was safer and more effective than either RT ± DSF in inhibiting growth of orthotopic CS xenografts. In conclusion, DSF/Cu radiosensitizes CCSCs. These results can be translated into clinical trials for CS patients requiring RT for improved outcomes.

Primary chest wall sarcoma; a single institution experience of 3 years.

INTRODUCTION: Primary chest wall sarcoma is a rare entity. It can be classified based on its origin, as bone sarcomas or soft tissue sarcomas. Various prognostic factors have been studied in different case series like age, sex, tumor histology, grade, resection margin status, adjuvant treatment, and others. The present study aimed to analyze common histological types, their management by resection and reconstruction and prognosis, in cases presenting at a regional cancer center in western India. MATERIAL AND METHOD: This was an observational study from a prospectively maintained database. 57 patients with chest wall sarcoma treated with curative intent between January 2016 till January 2019 with a minimum follow-up of 3 months were included in the study. The goals of surgical treatment were to obtain a wide resection margin of 3-4 cm, preserve the function of the chest wall and provide stability and rigidity to protect intrathoracic organs. RESULTS: The median follow-up of the present patient's cohort was for 20.2 months. Overall two-year survival was 74.7%. Two-year OS and DFS of bone sarcoma were 62.3% and 35% and soft tissue sarcomas were 91% and 71.3%. Ewing's sarcoma had the worst two-year overall survival of 50.6% and chondrosarcoma and fibromatosis had 100% two-year overall survival. CONCLUSION: Chest wall sarcoma forms a heterogeneous group of tumors. In the present study, Ewing's sarcoma was the most common histology with the worst survival, since they presented in advanced stages. Management should be multidisciplinary and surgical resection should be aggressive to achieve an R0 resection. Reconstruction of chest wall should aim to provide structural and functional stability with minimal morbidity. Frozen section assessment should be utilized whenever in doubt.

Homogenous and Heterogenous Prognostic Factors for Patients with Bone Sarcoma.

OBJECTIVE: The aim of this study was to examine the survival rate of patients with different bone sarcomas and to investigate homogenous and heterogenous prognostic factors for different types of bone sarcomas. METHODS: This is a retrospective analysis of records from the Surveillance, Epidemiology, and End Result (SEER) database. Clear information on the distant metastasis of cancer is provided in the SEER database for patients diagnosed between January 2010 and December 2016. Data for the four types of malignant bone sarcomas were extracted, including osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma. Patients with bone sarcomas originated from other sites, diagnosed at autopsy, or indicated in death certification were excluded. The overall survival was calculated for the entire cohort and across different bone sarcomas using the Kaplan-Meier method. A subgroup analysis of the different survival rates of four types of bone sarcomas in various levels of each variable was conducted and the differences were tested with the log-rank test. Cox proportional hazard regression analysis was performed to determine the prognostic factors. Variables with P < 0.05 in the univariate Cox regression analysis were further analyzed using a multivariate Cox regression analysis. The prognostic factors in four groups of bone sarcomas were compared to determine the homogenous and heterogenous factors. RESULTS: A total of 4732 patients were included with a follow up of 25 (0-83) months. The mean age of patients was 39.7 ± 24.1 years. The 1-year, 3-year, and 5-year overall survival rate for the entire cohort was 86.2% (95% confidence interval [CI]: 85.2%-87.2%), 70.5% (95% CI: 68.9%-72.1%), and 63.0% (95% CI: 61.2%-64.8%), respectively. Factors including age older than 40 years, higher grade, regional and distant stage, tumor in the extremities, T2 stage, bone and lung metastases, and non-surgery were significantly associated with the poor survival of the entire cohort. The mean overall survival duration of patients with chordoma, chondrosarcoma, Ewing sarcoma, and osteosarcoma was 66.86 (95% CI: 64.06-69.66), 63.53 (95% CI: 61.81-65.25), 58.06 (95% CI: 55.49-60.62) and 54.91 (95% CI: 53.14-56.69) months, respectively. Compared with chordoma, the hazard ratio (HR) and 95% CI for patients with chondrosarcoma, Ewing sarcoma, and osteosarcoma were 1.30 (95% CI: 1.04-1.62; P = 0.023), 1.69 (95% CI: 1.33-2.14; P < 0.001), and 2.00 (95% CI: 1.61-2.48; P <0.001), respectively. Different bone sarcomas showed homogenous and heterogenous prognostic factors. CONCLUSION: Different clinicopathological characteristics and prognoses were revealed in patients with osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma. The risk factors can potentially guide prognostic prediction and sarcoma-specific treatment.

Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma.

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR). Firstly EMC-bearing mice were treated with 6 Gy or 12 Gy of EBR (single 6 MV photon). Then for combination of HAP and EBR, animals received 6 doses of ICF05016 (46.8 µmol/kg, intravenously) at 4-day intervals, with 6 Gy EBR performed 24 h after the 3rd dose of HAP. Animals were monitored throughout the study for clinical observations (tumour growth, side effects) and survival studies were performed. From tumour samples, PCNA, Ki-67 and p21 expressions were used as markers of proliferation and cell cycle arrest. Statistical significances were determined using Kruskall-Wallis and log rank tests. The radiosensitivity of the EMC model was demonstrated at 12 Gy with significant inhibition of tumour growth. Then, the HAP strategy potentiated EBR efficacy at a lower dose (6 Gy) by improving survival without generating side effects. Thus, results of this study showed the potential interest of ICF05016 for the combination with EBR in the management of EMC.

Dosimetric analysis of local failures in skull-base chordoma and chondrosarcoma following pencil beam scanning proton therapy.

BACKGROUND: Despite combined modality treatment involving surgery and radiotherapy, a relevant proportion of skull-base chordoma and chondrosarcoma patients develop a local recurrence (LR). This study aims to analyze patterns of recurrence and correlate LR with a detailed dosimetric analysis. METHODS: 222 patients were treated with proton radiotherapy for chordoma (n = 151) and chondrosarcoma (n = 71) at the PSI between 1998 and 2012. All patients underwent surgery, followed by pencil-beam scanning proton therapy to a mean dose of 72.5 ± 2.2GyRBE. A retrospective patterns of recurrence analysis was performed: LR were contoured on follow-up MRI, registered with planning-imaging and the overlap with initial target structures (GTV, PTVhigh-dose, PTVlow-dose) was calculated. DVH parameters of planning structures and recurrences were calculated and correlated with LR using univariate and multivariate cox regression. RESULTS: After a median follow-up of 50 months, 35 (16%) LR were observed. Follow-up MRI imaging was available for 27 (77%) of these recurring patients. Only one (3.7%) recurrence was located completely outside the initial PTV (surgical pathway recurrence). The mean proportions of LR covered by the initial target structures were 48% (range 0-86%) for the GTV, 70% (range 0-100%) for PTVhigh and 83% (range 0-100%) for PTVlow. In the univariate analysis, the following DVH parameters were significantly associated with LR: GTV(V < 66GyRBE, p = 0.01), GTV(volume, p = 0.02), PTVhigh(max, p = 0.02), PTVhigh(V < 66GyRBE, p = 0.03), PTVhigh(V < 59GyRBE, p = 0.02), PTVhigh(volume, p = 0.01) and GTV(D95, p = 0.05). In the multivariate analysis, only histology (chordoma vs. chondrosarcoma, p = 0.01), PTVhigh(volume, p = 0.05) and GTV(V < 66GyRBE, p = 0.02) were independent prognostic factors for LR. CONCLUSION: This study identified DVH parameters, which are associated with the risk of local recurrence after proton therapy using pencil-beam scanning for patients with skull-base chordoma and chondrosarcoma.

Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma.

AIMS: Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma. METHODS: The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot. RESULTS: In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit. CONCLUSION: Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: Bone Joint J 2020;102-B(12):1752-1759.

Primary Tumor Resection Prolongs Survival in Spinal Chondrosarcoma Patients With Distant Metastasis.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To investigate (1) whether resection of primary tumor improves survival of metastatic spinal chondrosarcoma patients and (2) which subgroups of metastatic spinal chondrosarcoma patients benefit more from primary tumor resection. SUMMARY OF BACKGROUND DATA: Surgical resection is the mainstay of treatment for spinal chondrosarcoma, as chondrosarcoma is inherently resistant to radiotherapy and chemotherapy. However, evidence which justifies resection of the primary tumor for patients with metastatic spinal chondrosarcoma is still lacking. METHODS: We retrospectively included 110 patients with metastatic spinal chondrosarcoma in the Surveillance, Epidemiology, and End Results database from 1983 to 2016. The association between primary tumor resection and survival was evaluated using Kaplan-Meier analyses, log-rank tests, and multivariable Cox analyses. The effect of primary tumor resection on survival was further assessed in subgroups stratified by histologic subtype, tumor grade, and age. RESULTS: Overall, 110 patients were divided into surgery group (n = 55, 50%) and nonsurgery group (n = 55, 50%). Primary tumor resection was associated with both prolonged overall survival (hazard ratio 0.262, 95% confidence interval 0.149-0.462, P < 0.001) and cancer-specific survival (hazard ratio 0.228, 95% confidence interval 0.127-0.409, P < 0.001). When we focused on surgical effects in subgroups, primary tumor resection conferred survival advantage on patients with conventional subtype, grade I to III malignancy, and an age younger than 70 years old (P < 0.001 for overall and cancer-specific survival). However, primary tumor resection brought limited survival benefit for patients with dedifferentiated subtype and patients over 70 years old. CONCLUSION: The present population-based study for the first time reports a clear association between primary tumor resection and prolonged survival in metastatic spinal chondrosarcoma patients. Specifically, primary tumor resection was associated with improved survival in patients with conventional subtype, grade I to III malignancy, and an age younger than 70 years old. LEVEL OF EVIDENCE: 4.

Diagnoses, treatment, and oncologic outcomes in patients with calcaneal malignances: Case series, systematic literature review, and pooled cohort analysis.

BACKGROUND AND OBJECTIVES: Malignant tumors of the calcaneus are rare but pose a treatment challenge. AIMS: (1) describe the demographics of calcaneal malignancies in a large cohort; (2) describe survival after amputation versus limb-salvage surgery for high-grade tumors. METHODS: Study group: a "pooled" cohort of patients with primary calcaneal malignancies treated at two cancer centers (1984-2015) and systematic literature review. Kaplan-Meier analyses described survival across treatment and diagnostic groups; proportional hazards modeling assessed mortality after amputation versus limb salvage. RESULTS: A total of 131 patients (11 treated at our centers and 120 patients from 53 published studies) with a median 36-month follow-up were included. Diagnoses included Ewing sarcoma (41%), osteosarcoma (30%), and chondrosarcoma (17%); 5-year survival rates were 43%, 73% (70%, high grade only), and 84% (60%, high grade only), respectively. Treatment involved amputation in 52%, limb salvage in 27%, and no surgery in 21%. There was no difference in mortality following limb salvage surgery (vs. amputation) for high-grade tumors (HR 0.38; 95% CI 0.14-1.05), after adjusting for Ewing sarcoma diagnosis (HR 5.15; 95% CI 1.55-17.14), metastatic disease at diagnosis (HR 3.88; 95% CI 1.29-11.64), and age (per-year HR 1.04; 95% CI 1.02-1.07). CONCLUSIONS: Limb salvage is oncologically-feasible for calcaneal malignancies.

Extraskeletal myxoid chondrosarcoma: A high incidence of metastatic disease to lymph nodes.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (ESMC) is a rare type of soft-tissue sarcoma with limited series reporting outcome of treatment. Currently there is limited data on the incidence and impact on patient outcome in those with metastatic disease to lymph nodes in ESMC. METHODS: Thirty (21 males, 9 females) patients, mean age 50 ± 16 years, with ESMC were reviewed. The tumors were most commonly located in the lower extremity (n = 23, 77%) and the mean tumor size and volume were 9 ± 5 cm and 490 ± 833 cm3 . Mean follow up was 7 ± 4 years. RESULTS: Six (20%) patients either presented (n = 3, 10%) or developed (n = 3, 10%) lymph node metastatic disease. When comparing patients without, with lymph node metastasis and metastasis elsewhere, patients with lymph nodes metastasis had worse survival than those without metastasis, however better 10-year disease specific survival than those with metastasis elsewhere (100% vs 62% vs 0%; P < .001). CONCLUSION: There is a high incidence of lymph node metastatic disease in patients with ESMC. Although survival in these patients is worse compared to those without metastasis, their survival is better than those with metastasis elsewhere. Due to the high incidence of lymph node metastatic disease, preoperative staging of the lymph node should be considered.

Is Surgical Resection of the Primary Site Associated with an Improved Overall Survival for Patients with Primary Malignant Bone Tumors Who Have Metastatic Disease at Presentation?

BACKGROUND: The management of primary malignant bone tumors in patients with metastatic disease at presentation remains a challenge. Although surgical resection has been a mainstay in the management of nonmetastatic malignant bone tumors, there is a lack of large-scale evidence-based guidance on whether surgery of the primary site/tumor improves overall survival in malignant bone tumors with metastatic disease at presentation. QUESTIONS/PURPOSES: (1) Is surgical resection of the primary tumor associated with improved overall survival in patients with primary malignant bone tumors who have metastatic disease at presentation? (2) What other factors are associated with improved and/or poor overall survival? METHODS: The 2004 to 2016 National Cancer Database (NCDB), a national registry containing data from more than 34 million cancer patients in the United States, was queried using International Classification of Diseases, 3rd Edition, topographical codes to identify patients with primary malignant bone tumors of the extremities (C40.0-C40.3, C40.8, and C40.9) and/or pelvis (C41.4). The NCDB was preferred over other national cancer registries (that is, the Surveillance, Epidemiology, and End Results database) because it includes a specific variable that codes for patients who received additional surgeries at metastatic sites. Patients with malignant bone tumors of the head or skull, trunk, and spinal column were excluded because these patients are not routinely encountered and treated by orthopaedic oncologists. Histologic codes were used to categorize the tumors into the following groups: osteosarcomas, chondrosarcomas, and Ewing sarcomas. Patients whose tumors were classified as Stage 1, 2, or 3 based on American Joint Commission of Cancer guidelines were excluded. Only patients who presented with metastatic disease were included in the final study sample. The study sample was divided into two distinct groups: those who underwent surgical resection of the primary tumor and those who did not receive any operation for the primary tumor. A total of 2288 patients with primary malignant bone tumors (1121 osteosarcomas, 345 chondrosarcomas, and 822 Ewing sarcomas) with metastatic disease at presentation were included, of whom 46% (1053 of 2288) underwent surgical resection of the primary site. Thirty-three percent (348 of 1053) of patients undergoing surgical resection of the primary site also underwent additional resection of metastases. Patients undergoing surgical resection of the primary site typically were younger than 18 years, lived further from a facility, had tumors involving the upper or lower extremity, had a diagnosis of osteosarcoma or chondrosarcoma, and had a greater tumor size and higher tumor grade at presentation. To account for baseline differences within the patient population and to adjust for additional confounding variables, multivariate Cox regression analyses were used to assess whether undergoing surgical resection of the primary tumor was associated with improved overall survival, after controlling for differences in baseline demographics, tumor characteristics (grade, location, histologic type, and tumor size), and treatment patterns (resection of distant or regional metastatic sites, positive or negative surgical margins, and use of radiation therapy or chemotherapy). Additional sensitivity analyses, stratified by histologic type for osteosarcomas, chondrosarcomas, and Ewing sarcomas, were used to assess factors associated with overall survival for each tumor type. RESULTS: After controlling for differences in baseline demographics, tumor characteristics, and treatment patterns, we found that surgical resection of the primary site was associated with reduced overall mortality compared with those who did not have a resection of the primary site (hazard ratio 0.42 [95% confidence interval 0.36 to 0.49]; p < 0.001). Among other factors, in the stratified analysis, radiation therapy was associated with improved overall survival for patients with Ewing sarcoma (HR 0.71 [95% CI 0.57 to 0.88]; p = 0.002) but not for those with osteosarcoma (HR 1.14 [95% CI 0.91 to 1.43]; p = 0.643) or chondrosarcoma (HR 1.0 [95 % CI 0.78 to 1.50]; p = 0.643). Chemotherapy was associated with improved overall survival for those with osteosarcoma (HR 0.50 [95% CI 0.39 to 0.64]; p < 0.001) and those with chondrosarcoma (HR 0.62 [95% CI 0.45 to 0.85]; p = 0.003) but not those with Ewing sarcoma (HR 0.7 [95% CI 0.46 to 1.35]; p = 0.385). CONCLUSIONS: Surgical resection of the primary site was associated with an overall survival advantage in patients with primary malignant bone tumors who presented with metastatic disease. Further research, using more detailed data on metastatic sites (such as, size, location, number, and treatment), chemotherapy regimen and location of radiation (primary or metastatic site) is warranted to better understand which patients will have improved overall survival and/or a benefit in the quality of life from resecting their primary malignant tumor if they present with metastatic disease at diagnosis. LEVEL OF EVIDENCE: Level III, therapeutic study.

How Does the Skeletal Oncology Research Group Algorithm's Prediction of 5-year Survival in Patients with Chondrosarcoma Perform on International Validation?

BACKGROUND: The Skeletal Oncology Research Group (SORG) machine learning algorithm for predicting survival in patients with chondrosarcoma was developed using data from the Surveillance, Epidemiology, and End Results (SEER) registry. This algorithm was externally validated on a dataset of patients from the United States in an earlier study, where it demonstrated generally good performance but overestimated 5-year survival. In addition, this algorithm has not yet been validated in patients outside the United States; doing so would be important because external validation is necessary as algorithm performance may be misleading when applied in different populations. QUESTIONS/PURPOSES: Does the SORG algorithm retain validity in patients who underwent surgery for primary chondrosarcoma outside the United States, specifically in Italy? METHODS: A total of 737 patients were treated for chondrosarcoma between January 2000 and October 2014 at the Italian tertiary care center which was used for international validation. We excluded patients whose first surgical procedure was performed elsewhere (n = 25), patients who underwent nonsurgical treatment (n = 27), patients with a chondrosarcoma of the soft tissue or skull (n = 60), and patients with peripheral, periosteal, or mesenchymal chondrosarcoma (n = 161). Thus, 464 patients were ultimately included in this external validation study, as the earlier performed SEER study was used as the training set. Therefore, this study-unlike most of this type-does not have a training and validation set. Although the earlier study overestimated 5-year survival, we did not modify the algorithm in this report, as this is the first international validation and the prior performance in the single-institution validation study from the United States may have been driven by a small sample or non-generalizable patterns related to its single-center setting. Variables needed for the SORG algorithm were manually collected from electronic medical records. These included sex, age, histologic subtype, tumor grade, tumor size, tumor extension, and tumor location. By inputting these variables into the algorithm, we calculated the predicted probabilities of survival for each patient. The performance of the SORG algorithm was assessed in this study through discrimination (the ability of a model to distinguish between a binary outcome), calibration (the agreement of observed and predicted outcomes), overall performance (the accuracy of predictions), and decision curve analysis (establishment on the ability of a model to make a decision better than without using the model). For discrimination, the c-statistic (commonly known as the area under the receiver operating characteristic curve for binary classification) was calculated; this ranged from 0.5 (no better than chance) to 1.0 (excellent discrimination). The agreement between predicted and observed outcomes was visualized with a calibration plot, and the calibration slope and intercept were calculated. Perfect calibration results in a slope of 1 and an intercept of 0. For overall performance, the Brier score and the null-model Brier score were calculated. The Brier score ranges from 0 (perfect prediction) to 1 (poorest prediction). Appropriate interpretation of the Brier score requires comparison with the null-model Brier score. The null-model Brier score is the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for every patient. A decision curve analysis was performed to compare the potential net benefit of the algorithm versus other means of decision support, such as treating all or none of the patients. There were several differences between this study and the earlier SEER study, and such differences are important because they help us to determine the performance of the algorithm in a group different from the initial study population. In this study from Italy, 5-year survival was different from the earlier SEER study (71% [319 of 450 patients] versus 76% [1131 of 1487 patients]; p = 0.03). There were more patients with dedifferentiated chondrosarcoma than in the earlier SEER study (25% [118 of 464 patients] versus 8.5% [131 of 1544 patients]; p < 0.001). In addition, in this study patients were older, tumor size was larger, and there were higher proportions of high-grade tumors than the earlier SEER study (age: 56 years [interquartile range {IQR} 42 to 67] versus 52 years [IQR 40 to 64]; p = 0.007; tumor size: 80 mm [IQR 50 to 120] versus 70 mm [IQR 42 to 105]; p < 0.001; tumor grade: 22% [104 of 464 had Grade 1], 42% [196 of 464 had Grade 2], and 35% [164 of 464 had Grade 3] versus 41% [592 of 1456 had Grade 1], 40% [588 of 1456 had Grade 2], and 19% [276 of 1456 had Grade 3]; p ≤ 0.001). RESULTS: Validation of the SORG algorithm in a primarily Italian population achieved a c-statistic of 0.86 (95% confidence interval 0.82 to 0.89), suggesting good-to-excellent discrimination. The calibration plot showed good agreement between the predicted probability and observed survival in the probability thresholds of 0.8 to 1.0. With predicted survival probabilities lower than 0.8, however, the SORG algorithm underestimated the observed proportion of patients with 5-year survival, reflected in the overall calibration intercept of 0.82 (95% CI 0.67 to 0.98) and calibration slope of 0.68 (95% CI 0.42 to 0.95). The Brier score for 5-year survival was 0.15, compared with a null-model Brier of 0.21. The algorithm showed a favorable decision curve analysis in the validation cohort. CONCLUSIONS: The SORG algorithm to predict 5-year survival for patients with chondrosarcoma held good discriminative ability and overall performance on international external validation; however, it underestimated 5-year survival for patients with predicted probabilities from 0 to 0.8 because the calibration plot was not perfectly aligned for the observed outcomes, which resulted in a maximum underestimation of 20%. The differences may reflect the baseline differences noted between the two study populations. The overall performance of the algorithm supports the utility of the algorithm and validation presented here. The freely available digital application for the algorithm is available here: https://sorg-apps.shinyapps.io/extremitymetssurvival/. LEVEL OF EVIDENCE: Level III, prognostic study.