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Background: The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS)., Patients and Methods: This randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/m 2 every 3 weeks or BSC, stratified into L-STS (liposarcoma/leiomyosarcoma) and non-L-STS groups (other histotypes). Patients from the BSC arm were allowed to cross over to trabectedin at progression. The primary efficacy endpoint was progression-free survival (PFS) confirmed by blinded central review and analyzed in the intention-to-treat population., Results: Between 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months [95% confidence interval (CI) 1.8-5.9 months] in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P < 0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin., Conclusion: Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS., Competing Interests: Disclosure ALC has received honoraria from Deciphera, Bayer, and PharmaMar. J-YB has received research support and honoraria from PharmaMar, Bayer, and Eisai. IR-C reports research support and honoraria from PharmaMar, Roche, AstraZeneca, Clovis, GSK, Mersana, Deciphera, Genentech, Advaxis, MSD, and BMS. OM has served as consultant for Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, Eli-Lilly, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, and Vifor Pharma, and is a shareholder of Amplitude surgical, Ipsen, and Transgene. All other authors have declared no conflicts of interest. Data sharing De-identified individual data might be made available following publication by reasonable request and on a case-by-case basis to the corresponding author, including the clinical study results and statistical analysis plan. A research proposal should be included, which will be evaluated by the French Sarcoma Group and the ethics committee for clinical investigation., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Spermatic cord sarcomas are rare tumors for which the most important is the initial diagnostic procedure. They are frequently misdiagnosed after surgery for inguinal hernia, inguinal lymphadenectomy or testicular malignancy. Any clinical suspicion has to lead to perform imaging with MRI and a core needle biopsy in order to obtain an accurate preoperative diagnosis. Liposarcoma and leiomyosarcoma are the most common histological subtypes in elderly adults, rhabdomyosarcoma in children or in young adults. A CT scan will precede the treatment in order to look for distant metastasis and abdominal involvement. The therapeutic strategy as well as the surgical planning are then adapted to the histological, morphological and prognostic factors. Surgery is the cornerstone for the treatment of spermatic cord sarcoma. The minimum requirements for the surgical procedure are a wide excision of the tumor en bloc with radical orchidectomy, excision of the ipsilateral scrotum and high spermatic cord ligation. It could be enlarged to the anterior abdominal wall and adjacent organs some required a soft tissue flap. Spermatic cord sarcoma and trunk wall sarcoma have the same prognosis for which local recurrence could significantly decrease survival. Consequently, surgeon in charge with these tumors has to be familiar with soft tissue sarcoma and the management of these patients must be carried out under the supervision of a multidisciplinary team within the Netsarc network., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Sarcomas are rare but aggressive diseases. Specialized multidisciplinary management is not implemented for all patients in most countries. We investigated the impact of a multidisciplinary tumor board (MDTB) presentation before treatment in a nationwide study over 5 years., Patients and Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized MDTB, funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients in France. Patients' characteristics and follow-up are collected in a database regularly monitored and updated. The management and survival of patients presented to these MDTB before versus after initial treatment were analyzed., Results: Out of the 12 528 patients aged ≥15 years, with a first diagnosis of soft tissue and visceral sarcoma obtained between 1 January 2010 and 31 December 2014, 5281 (42.2%) and 7247 (57.8%) were presented to the MDTB before and after the initiation of treatment, respectively. The former group had generally worse prognostic characteristics. Presentation to a MDTB before treatment was associated with a better compliance to clinical practice guidelines, for example, biopsy before surgery, imaging, quality of initial surgery, and less reoperations (all P < 0.001). Local relapse-free survival and relapse-free survival were significantly better in patients presented to a MDTB before initiation of treatment, both in univariate and multivariate analysis., Conclusion: The compliance to clinical practice guidelines and relapse-free survival of sarcoma patients are significantly better when the initial treatment is guided by a pre-therapeutic specialized MDTB., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: The natural history of localized high-grade sarcomas of the digestive tract (SDT) excluding GIST has been rarely considered owing to their low incidence and heterogeneity. We describe the histoclinical characteristics of SDT and correlate them with patients' outcomes., Methods: We retrospectively collected medical files from a European database covering connective tissue tumors listed in Europe for about twenty years. Only untreated localized primary high-grade SDT were included. A central histological review was performed for each case. Patients' characteristics were compared and correlated with clinical outcomes., Results: A total of 45 patients were identified. Leiomyosarcomas (LMS) and undifferentiated sarcomas (UDS) were predominant, the former having better overall survival (OS) and progressionfree survival (PFS) while the latter having a worse outcome than the other histological types. Complete remission was obtained in 34 patients (75%) and was associated with male sex, age over 40 years and monofocal tumor. Complete surgery and LMS histology were associated with a better prognosis without any significant difference in baseline characteristics or in treatment modalities., Conclusion: Complete surgery and histological type seem to be prognostic indicators of SDT. These results suggest the importance of treating these patients in a reference center., Competing Interests: The authors declare that they have no conflict of interest., (© Acta Gastro-Enterologica Belgica.)

Background: Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline., Methods: In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743., Findings: From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9-2·3) with regorafenib versus 1·7 months (0·9-1·8) with placebo (HR 0·89 [95% CI 0·48-1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5-5·0) with regorafenib versus 1·8 (1·0-2·8) months with placebo (HR 0·46 [95% CI 0·46-0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4-11·6) with regorafenib versus 1·0 (0·8-1·4) with placebo (HR 0·10 [95% CI 0·03-0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0-7·8) with regorafenib versus 1·0 (0·9-1·9) with placebo (HR 0·46 [95% CI 0·25-0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure., Interpretation: Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib., Funding: Bayer HealthCare., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Sarcoma rarely involves the hand or wrist. Extensive surgical excision is the current standard of care. At the extremities, such as the hand and wrist, limb-sparing surgery with reconstruction to provide optimal function is increasingly performed. A descriptive case-series study of 16 patients with sarcoma of the hand and wrist managed using limb-sparing surgery is reported here., Material and Methods: Of 19 patients with sarcoma of the hand or wrist treated between 1999 and 2012, 16 were managed using limb-sparing surgery. These were consecutive patients managed at a single-centre and studied retrospectively. The tumour involved the hand in 7 patients and the wrist in 9 patients. The procedure was primary in 6 patients, whereas 10 patients underwent secondary revision surgery. In 12 patients, reconstruction was performed for one or more of the following structures: nerves (n=2), tendons (n=3), bone (n=3), and/or skin (n=8). After surgical excision, the margins were R0 in 15 patients and R1 in 1 patient. At last follow-up, survival, pain, and function as reflected by the DASH and MSTS scores were assessed., Results: After the median follow-up of 4.5years [1-13], 15 patients were alive with no local recurrence and 1 patient had lung metastases. Mean values were 18 [0-49] for the DASH score and 88.8% [53-100] for the MSTS score., Discussion: Limb-sparing surgery reconciles the need to achieve complete tumour excision with the need to restore function. No limits should be placed on tumour excision, given the availability of effective reconstructive methods. The functional outcome depends on the tolerance of adjuvant treatments, most notably radiotherapy., Level of Evidence: IV, retrospective study., (Copyright © 2016. Published by Elsevier Masson SAS.)

Purpose: The mainstay of first line treatment in metastatic sarcomas is chemotherapy with response rates of ≈25% but the optimal management of further events is debated. We assessed the benefit of local metastatic treatment in metastatic sarcomas., Results: Local control of local treatment strategies (≈85%) is excellent but highly institution-dependent and subject to selection biases. Formal evidence of an improvement of survival with local ablative treatments has been limited to retrospective studies. On the other hand, some chemotherapy trials are inconclusive because about 20% of patients receive local metastatic ablation as it is considered unethical to omit local treatment in these patients. Further, technology has made surgery, stereotactic irradiation and radiofrequency ablation highly effective on local control with limited morbidity., Conclusion: The benefit on survival of metastatic ablation deserves prospective studies integrating quality of life, cost effectiveness and patient-reported outcomes assessment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas., Methods: We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517., Findings: Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group., Interpretation: The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas., Funding: Sanofi., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Few targeted therapies (TTs) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after standard treatment escape. The French Sarcoma Group - Bone Tumor Study Group (GSF-GETO) created a national registry to evaluate the outcome of patients treated with off-label TTs., Methods: Every consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included. The objective was to describe this patient efficacy and safety data in routine practice., Results: From October 2008 to October 2011, 249 patients in 24 centers received 278 treatment lines with TTs. Twenty-five histological subtypes were included: most frequent were leiomyosarcoma (n=48, receiving sorafenib in 63%, and sunitinib in 27%), GIST (n=39, receiving sorafenib in 79%), and angiosarcoma (n=18, receiving sorafenib in 78%). The overall response rate to TTs was 15% (95% CI [10,6-20,2]), the disease control rate at 2 months was 59%. The median progression-free survival was 4,1 months (IC 95% [3,2-4,8]). Three complete responses were observed. No toxic death occurred, grade 3 and 4 toxicities were reported in 74 (27%) and 14 patients (5%) respectively., Conclusion: Off-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-randomized clinical trials.

Background: We previously demonstrated that interruption of imatinib mesylate (IM) in responding patients (pts) with advanced gastrointestinal stromal tumours (GISTs) results in rapid reprogression. The impact of interruption on residual tumour, quality of response and secondary resistance has not been fully investigated., Patients and Methods: Within the BRF14 study, 71 non-progressing patients were randomly assigned in the interruption arms after 1, 3 or 5 years. IM was resumed in the case of progressive disease (PD). Tumour status at randomisation, relapse and after IM rechallenge, progression-free survival (PFS) and time to secondary resistance were analysed., Results: At data cut-off, 51 of 71 patients had restarted IM following documented PD. Eighteen patients (35%) progressed on known lesions only, while 33 patients (65%) had new lesions, with concomitant progression of known lesions in 17 patients. Only 8 (42%) of complete remission (CR) patients and 12 (52%) of partial response (PR) patients at randomisation achieved a new CR and PR. Patients progressing rapidly after interruption had a poorer prognosis. Tumour status at randomisation influenced time to progression after rechallenge., Conclusion: In advanced GIST patients interrupting IM, quality of response upon reintroduction did not reach the tumour status observed at randomisation. Rapid progression after imatinib interruption is associated with poor PFS after reintroduction.

Background: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients., Patients and Methods: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7., Results: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity., Conclusion: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.

Multidrug chemotherapy increases responses in advanced soft tissues sarcoma. Can a 20% increase of relative dose intensity of the MAID regimen, more improve responses? From 1994 to 1997, 162 patients were randomized in a phase III study to the conventional drug combination (6 cycles of MAID: 60, 7,500, 900 mg/m(2) for doxorubicin, ifosfamide and dacarbazine respectively), or at doses 20-33% higher per cycle (5 cycles of intensified MAID for similar cumulative doses) with systematic G-CSF. Primary endpoint was response rate; secondary were toxicity, event-free and overall survival. The objective response rate in assessable patients was 38% with intensified MAID and 35% with MAID (p = 0.72). Event-free and overall survivals were similar in both arms. Only grade 3-4 thrombocytopenia and anemia were significantly higher in intensified arm. Treatment with intensified MAID did not improve response rate neither survival and cannot be recommended for advanced or metastatic soft tissue sarcoma.

Twenty-seven patients with recurrent soft-tissue sarcoma (STS) entered a multicenter study to determine the efficacy of the combination paclitaxel 200 mg/m and epirubicin 75 mg/m administered every 21 days. Patient characteristics included the following: 14 women and 13 men, median age of 52 years, 12 patients had local recurrence and 20 had metastasis. Eighteen patients had previously received chemotherapy for recurrent disease. The main grade III to IV hematologic toxicities were neutropenia (70%), anemia (3.7%), and thrombocytopenia (7.4%). Febrile neutropenia occurred in 5 patients (18.5%). Severe nonhematologic toxicities were rare. Two patients had a partial response (7.4%; 95% CI: 2.6-12.2%), with a median response duration of 3 and 5 months. Six patients had stable disease (22.2%), and 19 had progressive disease (70.5%). The median overall survival from study inclusion was 8 months. This study suggests the association paclitaxel-epirubicin does not increase the known activity of anthracycline in recurrent STS.

Purpose: This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy., Patients and Methods: Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner., Results: Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles., Conclusion: Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.