Summary Background Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of ...the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. Methods For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day short infusion, days 1 and 2 plus ifosfamide 3 g/m2 per day days 1, 2, and 3, repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2 , given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov , number NCT01710176 , and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010–023484–17, and is closed to patient entry. Findings Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 34% with undifferentiated pleomorphic sarcoma; 64 22% with high-grade myxoid liposarcoma; 70 24% with synovial sarcoma; 27 9% with malignant peripheral nerve sheath tumour; and 28 10% with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75–28·20), the projected disease-free survival at 46 months was 62% (95% CI 48–77) in the standard chemotherapy group and 38% (22–55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22–3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 86%), anaemia (24 19%), and thrombocytopenia (21 17%); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 26%). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. Interpretation In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. Funding European Union grant (Eurosarc FP7 278472).
Summary Background Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment ...failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. Methods We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT01804374. Findings We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28–61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3–4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Interpretation Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. Funding Italian Sarcoma Group.
SummaryBackgroundExtraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment ...option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma. MethodsIn this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285. FindingsBetween June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18–30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% 95% CI 1–36) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine 35% of 26 patients), increased concentration of alanine aminotransferase (six 23%), and increased aspartate aminotransferase (five 19%). InterpretationPazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients. FundingSpanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.
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