Real-world evidence on perioperative chemotherapy in localized soft tissue sarcoma of the extremities and trunk wall; a population-based study.

BACKGROUND: Data from the real-world setting on perioperative chemotherapy in high-risk, localized soft tissue sarcoma (STS) is limited. Real-world data (RWD) includes data derived from patients treated outside clinical trials and often captures long-term follow-up not recorded in clinical trials. The aim of this study was to provide population-based, real-world evidence on perioperative chemotherapy in localized STS. MATERIAL AND METHODS: Adult patients with localized STS in the extremities or trunk wall treated at Oslo University Hospital, Oslo, Norway from 1998 to 2017 were included in the study. Data were extracted from a prospectively maintained database, supplemented by retrospective review of medical records. RESULTS: The total study cohort included 806 patients, of whom 154 (19%) received perioperative chemotherapy. A regimen with anthracycline and ifosfamide was given in 141 of 154 cases (92%). During long-term follow-up two patients developed secondary malignancies, cardiac toxicity was registered in 11 patients (7%) and renal toxicity in 12 patients (8%). Seventy-one of 154 patients (46%) were treated outside of clinical trials and constituted the RWD cohort. The median age at surgery was slightly lower and there were more synovial sarcomas and fewer myxofibrosarcomas in the RWD cohort. No difference in chemotherapy dose intensity was observed. The estimated 5-year metastasis-free survival (MFS) in all patients receiving perioperative chemotherapy was 58%. In the RWD cohort 5-year MFS was 53% and in the clinical study cohort 61% (HR 1.24; 95% CI 0.77-2.00). CONCLUSION: Long-term outcome after perioperative chemotherapy was comparable for patients treated in routine clinical practice to those in clinical trials. Secondary malignancy and cardiac toxicity were observed. The risk of serious late side effects should be included in the decision process on perioperative chemotherapy.

A woman in her fifties with a lump in the palm of her hand. / En kvinne i 50-årene med kul i håndflaten.

A previously healthy woman in her fifties contacted her general practitioner due to a troublesome lump on her hand that had progressed over the course of a year. The final diagnosis surprised those involved and serves as a reminder to both general practitioners and specialists.

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial.

AIM: To evaluate the activity and safety of the PD-1 antibody pembrolizumab in adult patients with advanced osteosarcoma. MATERIAL AND METHODS: The study was a single-arm, open-label, phase 2 trial in patients with unresectable, relapsed osteosarcoma. The primary endpoint was clinical benefit rate (CBR) at 18 weeks of treatment, defined as complete response, partial response, or stable disease using RECIST v1.1. The trial had a Simon´s two-stage design, and ≥ 3 of 12 patients with clinical benefit in stage 1 were required to proceed to stage 2. The trial is registered with ClinicalTrials.gov, number NCT03013127. NanoString analysis was performed to explore tumor gene expression signatures and pathways. RESULTS: Twelve patients were enrolled and received study treatment. No patients had clinical benefit at 18 weeks of treatment, and patient enrollment was stopped after completion of stage 1. Estimated median progression-free survival was 1.7 months (95% CI 1.2-2.2). At time of data cut-off, 11 patients were deceased due to osteosarcoma. Median overall survival was 6.6 months (95% CI 3.8-9.3). No treatment-related deaths or drug-related grade 3 or 4 adverse events were observed. PD-L1 expression was positive in one of 11 evaluable tumor samples, and the positive sample was from a patient with a mixed treatment response. CONCLUSION: In this phase 2 study in advanced osteosarcoma, pembrolizumab was well-tolerated but did not show clinically significant antitumor activity. Future trials with immunomodulatory agents in osteosarcoma should explore combination strategies in patients selected based on molecular profiles associated with response.

Risk stratification for central conventional chondrosarcoma of bone: A novel system predicting risk of metastasis and death in the Cancer Registry of Norway cohort.

BACKGROUND AND OBJECTIVES: Interobserver variability in histological grading of central conventional chondrosarcoma (CCCS) limits the quality of patient information and research progression. We aim to quantify known and new prognostic variables and propose a risk stratification model. METHOD: We selected 149 cases from the Cancer Registry of Norway. Cox proportional hazard models were estimated. Based on these results a dichotomous risk classification was proposed and presented by Kaplan-Meier estimates for rates of local recurrence, metastasis, and disease-specific survival. RESULTS: The influence of axial skeletal location (Hazard ratio [HR] = 19.06), a soft tissue component ≥1 cm (HR = 13.45), and histological grade 3 (HR = 16.46) are all significant in predicting the rate of metastasis. The creation of a variable combining axial skeletal location and a soft tissue component ≥1 cm strongly predicts the risk of metastasis (HR = 14.02; P < .001) and death (HR = 2.74; P = .030) at multivariate analysis, making the histological grade insignificant. Together with metastasis at diagnosis (HR = 285.65; P < .001), this forms the basis of our proposed risk stratification, producing a small high-risk group (39 cases with 33% risk of metastasis) and a large low-risk group (103 cases with 2% risk of metastasis) without a histological grade. CONCLUSION: Axial skeletal location and a soft tissue component ≥1 cm combined divides a CCCS cohort into low- and high-risk groups without a histological grade.

Chondrosarcoma in Norway 1990-2013; an epidemiological and prognostic observational study of a complete national cohort.

BACKGROUND: Knowledge of chondrosarcoma (CS) of bone to date is based on institutional reports and registry publications with limits in reporting, detail and quality of data. METHOD: We have performed a retrospective search of CS of bone in the National Cancer Registry in Norway from 1990-2013, cross checked against local tumor databases with further quality control and supplementation of all data from clinical files. The time period is defined by the routine use of axial imaging in clinical practice. A total of 311 cases are included. We performed 108 pathological reviews and 223 radiological reviews. The manuscript was prepared according to the STROBE checklist for strengthening of observational studies. We performed uni-/multivariate cox analyses to define independent prognostic variables from the main cohort of central CS of bone. RESULTS: The incidence of CS of bone in Norway is 2.85/million/yr. for both sexes overall, rising to 3.45/million/yr. in the last 5-year period. There is an increase in the most common central CS subtype, stronger for women than for men. Central CS had, in general 10-15% local recurrence rates, all evident by 5 years while metastasis rate increases with location and grade. Exceptions are extremity grade 1 CS which displayed no metastatic events and axial grade-3 disease with high rates (50%) of both local and metastatic relapse. Peripheral CS had limited metastatic potential (2%), but rates of local relapse (13%) continue to appear towards 10 years of follow up. Malignancy grade 3 independently predicts rate of metastasis and presence of soft tissue component predicts local recurrence, metastasis and survival. CONCLUSION: Rates of local recurrence, metastasis and disease specific survival follow clear patterns depending on subtype, location and grade allowing better tailoring of follow-up regimes. Malignancy grade 3 and the presence of a soft tissue component independently predict behavior for central CS of bone.

Response to preoperative chemotherapy in patients undergoing resection of pulmonary metastasis from soft tissue sarcoma - a predictor of outcome?

UNLABELLED: Approximately 50% of patients with high-grade soft tissue sarcoma (STS) will develop pulmonary metastasis. This is the most frequent cause of death and improving treatment is warranted. Preoperative chemotherapy is used for selected patients, usually those with less favorable prognosis and mainly outside clinical trials. The predicted value of histological and radiological response to preoperative chemotherapy on outcome was the main focus for this investigation. PATIENTS AND METHODS: This retrospective study comprises 93 patients with metachronous lung metastasis from STS who underwent complete metastasectomy alone (n = 41) or metastasectomy following preoperative chemotherapy (n = 52). Clinical data, histological and radiological responses to chemotherapy were recorded and survival analyses performed. RESULTS: The time from initial STS diagnosis to the appearance of metastasis was shorter in the preoperative chemotherapy group than in those treated with surgery alone (p = 0.02). However, no statistical differences in post-metastasis disease-specific survival (DSS) or progression-free survival (PFS) between the groups were demonstrated. Patients in the preoperative chemotherapy group with good (complete) histological response had improved PFS compared with poor responders (p = 0.04). Radiological partial response was an independent, favorable prognostic factor for improved PFS and DSS (p = 0.003). CONCLUSION: Despite having unfavorable disease characteristics, some patients may benefit from preoperative chemotherapy. Both histological and radiological responses to preoperative chemotherapy seem to be prognostic in STS patients undergoing complete pulmonary metastasectomy.

Muscle strength characteristics following megaprosthetic knee reconstruction for bone sarcoma.

OBJECTIVE: To assess muscle strength characteristics in patients with resection and megaprosthetic reconstruction of the knee for bone sarcoma compared to age- and sex-matched controls. METHODS: This was a cross-sectional, case-control study. Muscle strength characteristics for knee extension and -flexion were assessed isokinetically at three different joint velocities: 60, 120 and 180°/s, and by the rate of force development (RDFmax) in knee extension. The Toronto Extremity Salvage Score (TESS) was used in patients. RESULTS: Eighteen patients (91.6 months postop.) and 18 controls were included. Relative to controls, patients generated maximal torques of 19%, 23% and 23% in knee extension at 60, 120 and 180°/s, respectively. For knee flexion, patients generated maximal torques of 58%, 53% and 60% at 60, 120, and 180°/s, relative to the controls. RDFmax of the operated leg was 2.75 ± 2.13 N/ms, 7.16 ± 4.78 N/ms for the non-operated leg, and 7.95 ± 4.29 N/ms for the controls. The mean TESS score was 84.0. CONCLUSION: Patients reached approximately 20% of the maximal knee extension torque. In isometric assessments, they used double the amount of time to generate one-third of the maximal force compared to the controls despite good TESS scores.

Rearrangement of chromosome bands 12q14~15 causing HMGA2-SOX5 gene fusion and HMGA2 expression in extraskeletal osteochondroma.

We describe two cases of extraskeletal osteochondroma in which chromosome bands 12q14~15 were visibly rearranged through a pericentric inv(12). Molecular analysis of the first tumor showed that both transcript 1 (NM_003483) and transcript 2 (NM_003484) of HMGA2 were expressed. In the second tumor, the inv(12) detected by karyotyping had resulted in an HMGA2-SOX5 fusion transcript in which exons 1-3 of HMGA2 were fused with a sequence from intron 1 of SOX5. The observed pattern is similar to rearrangements of HMGA2 found in several other benign mesenchymal tumors, i.e., disruption of the HMGA2 locus leaves intact exons 1-3 which encode the AT-hook domains and separates them from the 3'-terminal part of the gene. Our data therefore show that a subset of soft tissue osteochondromas shares pathogenetic involvement of HMGA2 with lipomas, leiomyomas and other benign connective tissue neoplasms.

Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas.

Periosteal chondroma is a benign cartilage tumor that accounts for <2% of chondromas. In the present study, four cases of periosteal chondromas were cytogenetically investigated and studied for the expression of high-mobility group AT-hook 2 (HMGA2), mutations in codons 132 of isocitrate dehydrogenase (IDH)1 and 172 of IDH2; mutations -C228T and -C250T in the promoter region of telomerase reverse transcriptase (TERT); and for methylation in the promoter regions of O-6-methylguanine-DNA methyltransferase (MGMT) and cellular retinol binding protein 1 (CRBP1). Chromosome aberrations of 12q13-15 were found in two out of the four tumors, while two had a normal karyotype. Two periosteal chondromas carried the mutation IDH1R132C (CGT>TGT), and two carried the mutation IDH1R132L (CGT>CTT). However, none of the four tumors had methylated MGMT and CRBP1 promoters or mutations at codon 172 of IDH2. In addition, -C228T and -C250T mutations were not present in the promoter region of TERT, nor was HMGA2 demonstrated to be expressed. The present study indicated that in periosteal chondromas, the involvement of 12q13-15 in structural rearrangements may be recurrent but that HMGA2 is not expressed. Additionally, the periosteal chondromas investigated in the study carried a heterozygous IDH1R132 mutation, the MGMT and CRBP1 promoters were not methylated, and -C228T and -C250T mutations in the promoter region of TERT were absent.

Management of high-grade bone sarcomas over two decades: the Norwegian Radium Hospital experience.

All cases of high-grade osteosarcoma (OS) (n = 196) and Ewing's sarcoma of bone (ES) (n = 56) treated at the Norwegian Radium Hospital in the period 1980-1999 were analyzed retrospectively. They were allocated to consecutive ten-year periods by their time of diagnosis. Patient and tumour characteristics have been relatively stable. Eighty percent of all patients received surgical treatment and the amputation rate decreased from 64% to 23%. The percentage of patients receiving chemotherapy has remained around 80%. The use of radiotherapy in primary treatment decreased gradually from 33% to 18%. Sarcoma specific survival (SSS) at five years for all patients increased significantly from 39% to 53%. Similar trends for improvement were seen for both OS and ES. In multivariate analysis, independent prognostic factors for improved SSS were non-metastatic disease at diagnosis, age under 40, extremity tumours, small tumours and treatment from 1995 onwards. No major new treatment options have emerged over these 20 years. The improved outcome appears partly to be due to refinements in the use of existing modalities and improved quality and integration of multidisciplinary approaches. Improved formalized organisation of the sarcoma group and annual audited reports of its patient and research activity may also have contributed to improved focus and performance.

[Bone and soft tissue sarcomas treated at the Norwegian Radium Hospital 1980-99]. / Bein- og bløtvevssarkomer behandlet ved Det Norske Radiumhospital 1980-99.

BACKGROUND: The Norwegian Radium Hospital's sarcoma group is a multidisciplinary group with a leading role in the diagnosis and treatment of bone and soft tissue sarcomas in Norway. MATERIAL AND METHODS: From 1980 through 1999, 1,355 patients with soft tissue sarcoma and 458 patients with bone sarcoma were treated. In a retrospective analysis of trends over time, patients were allocated to consecutive five-year periods. RESULTS: Patient characteristics were relatively stable, but there was an increasing proportion of soft tissue sarcomas being referred without prior surgery. Treatment principles have remained unchanged, with surgery with or without radiotherapy dominating in soft tissue sarcoma and surgery with or without chemotherapy in bone sarcoma. The amputation rate for bone sarcoma has fallen from 78% to 17%, and survival has increased significantly for both soft tissue and bone sarcoma patients. INTERPRETATION: The results indicate significant improvements in the quality of treatment of soft tissue and bone sarcoma. More resources for treatment and organizational development of a multidisciplinary group may contribute to improved quality of care.