Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. The European Organization for Research and Treatment of Cancer [EORTC], Soft Tissue and Bone Sarcoma Group. Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). Efficacy of Adjuvant Radiation Therapy in the Treatment of Soft Tissue Sarcoma of the Extremity: 20-year Follow-Up of a Randomized Prospective Trial Differential sensitivity of liposarcoma subtypes to chemotherapy. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. A Postoperative Nomogram for Local Recurrence Risk in Extremity Soft Tissue Sarcomas After Limb-Sparing Surgery Without Adjuvant Radiation Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Epirubicin and ifosfamide in advanced soft tissue sarcomas. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. Dose-intensive first-line chemotherapy with epirubicin and continuous infusion ifosfamide in adult patients with advanced soft tissue sarcomas: a phase II study. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Randomized, phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.
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 r and omised , 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 r and omly 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 central ly confirmed disease progression . The r and om 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 Clinical Trials.gov , NCT01900743 . FINDINGS From Aug 5 , 2013 , to Nov 26 , 2014 , 182 patients were r and omly 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 clinical ly 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 ) , h and 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 BACKGROUND The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy ( CT ) in localized high- grade soft tissue sarcoma ( STS ) . Both studies failed to demonstrate any benefit on overall survival ( OS ) . The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT .  PATIENTS AND METHODS Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS ( large resection , R0/marginal resection , R1 ) were pooled . Prognostic factors were assessed by univariate and multivariate analyses . Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor . RESULTS A total of 819 patients had been enrolled with a median follow-up of 8.2 years .  Tumor size , high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival ( RFS ) and OS .  Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS . A significant interaction between benefit of adjuvant CT and age , gender and R1 resection was observed for RFS and OS .  Males and patients > 40 years had a significantly better RFS in the treatment arms , while adjuvant CT was associated with a marginally worse OS in females and patients < 40 years . Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms . CONCLUSION Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup . Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS . Based on these data , we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine st and ard of care BACKGROUND A non-r and omised , phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma . In this phase 3 study , we aim ed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine  ( an active control ) . METHODS We did this r and omised , open-label , phase 3 study across 110 study sites in 22 countries . We enrolled patients aged 18 years or older with intermediate- grade or high- grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease ( including an anthracycline ) . Using an interactive voice and web response system , an independent statistician r and omly assigned ( 1:1 ) patients to receive eribulin mesilate ( 1·4 mg/m(2 ) intravenously on days 1 and 8) or dacarbazine ( 850 mg/m(2 ) , 1000 mg/m(2 ) , or 1200 mg/m(2 ) [ dose dependent on centre and clinician ] intravenously on day 1 ) every 21 days until disease progression . R and omisation was stratified by disease type , geographical region , and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six . Patients and investigators were not masked to treatment assignment . The primary endpoint was overall survival in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT01327885 , and is closed to recruitment , but treatment and follow-up continue . FINDINGS Between March 10 , 2011 and May 22 , 2013 , we r and omly assigned patients to eribulin ( n=228 ) or dacarbazine ( n=224 ) . Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine ( median 13·5 months [ 95 % CI 10·9 - 15·6 ] vs 11·5 months [ 9·6 - 13·0 ] ; hazard ratio 0·77 [ 95 % CI 0·62 - 0·95 ] ; p=0·0169 ) . Treatment-emergent adverse events occurred in 224 ( 99 % ) of 226 patients who received eribulin and 218 ( 97 % ) of 224 who received dacarbazine  . Grade 3 or higher adverse events were more common in patients who received eribulin ( 152 [ 67 % ] ) than in those who received dacarbazine ( 126 [ 56 % ] ) , as were deaths ( 10 [ 4 % ] vs 3 [ 1 % ] ) ; one death ( in the eribulin group ) was considered treatment-related by the investigators . INTERPRETATION Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control , suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma . FUNDING Eisai Single‐agent gemcitabine and vinorelbine have activity in treatment of patients with soft‐tissue sarcomas . The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity . This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft‐tissue sarcoma In this phase II study the effect of high-dose ifosfamide ( HDI ) given as a 3-day continuous infusion at a dose of 12 g/m2 repeated every 4 weeks with adequate mesna protection and hydration was evaluated in patients with advanced soft tissue sarcomas . A total of 124 patients entered the trial of which 10 were ineligible .  HDI was given both as first-line and second-line chemotherapy .  Median age was 46 years ( 19 - 66 years ) . Median World Health Organization ( WHO ) performance status was 1 ( 0 - 1 ) . Fifty two per cent of the patients were males . The predominant histology was leiomyosarcoma ( 33 % ) . A maximum of six cycles was given . At the time of analysis 55 patients have died . The partial response ( PR ) rate was 16 % . The median time to progression was 15 weeks . 8 of the 18 responding patients ( 44 % ) had synovial sarcomas , whereas only 5 % of the patients having leiomyosarcomas responded . The grade 3 + 4 haematological toxicity encountered was neutrophils in 78 % and platelets in 12 % . The major grade 3 + 4 non-haematological toxicities encountered were febrile neutropenia in 39 % , infection in 20 % , and acute renal failure in 4 % . In conclusion , it is possible to administer HDI on a multicentre basis , but the toxicity is substantial . HDI given as a continuous infusion at this dose can not be recommended as the st and ard treatment of advanced soft tissue sarcomas , even in selected patients BACKGROUND Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs , inducing cell-cycle arrest and tumour regression in pre clinical models . We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma . METHODS In this non-r and omised multicentre phase 2 study , patients were included if they had progressive or high- grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease . They were stratified by the type of soft-tissue sarcoma they had . Eribulin was given intravenously at a concentration of 1·4 mg/m(2 ) over 2 - 5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks ( RECIST 1.0 ) , which we evaluated in all patients who started treatment . Safety analyses were done in all patients who started treatment . This trial is registered at Clinical Trials.gov , number NCT00413192 . FINDINGS Of 128 patients included , 37 had adipocytic sarcoma , 40 had leiomyosarcoma , 19 had synovial sarcoma , and 32 had other sarcomas . 12 ( 31·6 % ) of 38 patients with leiomyosarcoma evaluable for the primary endpoint , 15 ( 46·9 % ) of 32 patients with adipocytic sarcoma , four ( 21·1 % ) of 19 with synovial sarcoma , and five ( 19·2 % ) of 26 in other sarcomas were progression-free at 12 weeks . The most common grade 3 - 4 adverse events were neutropenia ( 66 [ 52 % ] of 127 patients evaluable for safety ) , leucopenia ( 44 [ 35 % ] ) , anaemia ( nine [ 7 % ] ) , fatigue ( nine [ 7 % ] ) , febrile neutropenia ( eight [ 6 % ] ) , abnormal alanine aminotransferase concentrations ( six [ 5 % ] ) , mucositis ( four [ 3 % ] ) , and sensory neuropathy ( four [ 3 % ] ) . INTERPRETATION Eribulin deserves further study in this setting , based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma . FUNDING Eisai Limited , Hatfield , UK PURPOSE To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine ( DTIC ) in patients with advanced soft tissue sarcoma ( STS ) in a r and omized , multicenter , phase II study using DTIC alone as a control arm . PATIENTS AND METHODS Patients with previously treated advanced STS were r and omly assigned to receive either fixed-dose rate gemcitabine ( 10 mg/m2/min ) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks , or DTIC alone at 1200 mg/m2 every 3 weeks . The primary end point of the study was progression-free rate ( PFR ) at 3 months . RESULTS From November 2005 to September 2008 , 113 patients were included .  PFR at 3 months was 56 % for gemcitabine plus DTIC versus 37 % for DTIC alone ( P = .001 ) . Median progression-free survival was 4.2 months versus 2 months ( hazard ratio [ HR ] , 0.58 ; 95 % CI , 0.39 to 0.86 ; P = .005 ) , and median overall survival was 16.8 months versus 8.2 months ( HR , 0.56 ; 95 % CI , 0.36 to 0.90 ; P = .014 ) ; both favored the arm of gemcitabine plus DTIC . Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone ( 49 % v 25 % ; P = .009 ) . Severe toxicities were uncommon , and treatment discontinuation for toxicity was rare . Granulocytopenia was the more common serious adverse event , but febrile neutropenia was uncommon . Asthenia , emesis , and stomatitis were the most frequent nonhematologic effects . CONCLUSION The combination of gemcitabine and DTIC is active and well tolerated in patients with STS , providing in this phase II r and omized trial superior progression-free survival and overall survival than DTIC alone . This regimen constitutes a valuable therapeutic alternative for these patients Background : The MEK inhibitor , selumetinib , suppresses soft-tissue sarcoma ( STS ) cell proliferation in vitro . Mammalian target of rapamycin inhibitors possess modest activity against STS ; however , resistance develops via MAPK pathway feedback activation . The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth . Therefore , a r and omized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted . Methods : Seventy-one adults with advanced STS who received ⩽2 prior chemotherapeutics  were r and omized to selumetinib 75 mg p.o . bid and allowed to crossover upon progression , or to selumetinib 50 mg p.o . bid plus temsirolimus 20 mg i.v . weekly , with primary endpoint of progression-free survival ( PFS ) . Results : There was no difference in PFS between the two arms for the overall cohort ( median 1.9 vs 2.1 months ) ; an improved median PFS was observed in the combination arm ( N=11 ) over single agent ( N=10 ) in the prespecified leiomyosarcoma stratum ( median 3.7 vs 1.8 months ; P=0.01 ) . Four-month PFS rate was 50 % ( 95 % confidence interval 0.19–0.81 ) with the combination vs 0 % with selumetinib alone in the leiomyosarcoma cohort . Most common grade 3/4 adverse events with the combination were mucositis ( 29 % ) , lymphopenia ( 26 % ) , neutropenia and anaemia ( 20 % each ) . Conclusions : While single-agent selumetinib has no significant activity in STS , the combination may be active for leiomyosarcomas PURPOSE The aim of this trial was to compare the activity and toxicity of single-agent doxorubicin with that of two multidrug regimens in the treatment of patients with adult advanced soft tissue sarcomas . PATIENTS AND METHODS This was a prospect i ve r and omized phase III trial performed by 35 cancer centers within the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer ( EORTC ) . Six hundred sixty-three eligible patients were r and omly allocated to receive either doxorubicin 75 mg/m2 ( arm A ) , cyclophosphamide , vincristine , doxorubicin , and dacarbazine ( CYVADIC ) ( arm B ) , or ifosfamide 5 g/m2 plus doxorubicin 50 mg/m2 ( arm C ) . RESULTS The overall response rate was 24 % ( 95 % confidence interval , 20.7 % to 27.3 % ) among eligible patients and 26 % among assessable patients . No statistically significant difference was detected among the three study arms in terms of response rate ( arm A , 23.3 % ; arm B , 28.4 % ; and arm C , 28.1 % ) , remission duration ( median , 46 weeks on arm A , 48 weeks on arm B , and 44 weeks on arm C ) , or overall survival ( median , 52 weeks on arm A , 51 weeks on arm B , and 55 weeks on arm C ) . The degree of myelosuppression was significantly greater for the combination of ifosfamide and doxorubicin than for the other two regimens . Cardiotoxicity was also more frequent in this arm , but other toxicities were similar . CONCLUSION In advanced soft tissue sarcomas of adults , single-agent doxorubicin is still the st and ard chemotherapy against which more intensive or new drug treatments should be compared . Combination chemotherapy can not be recommended outside a controlled clinical trial with the exclusion of some subsets of sarcoma patients for whom significant tumor volume reduction may be an important end point of a chemotherapy regimen Ifosfamide ( 5 g/m2 ) was compared with its parent analogue cyclophosphamide ( 1.5 g/m2 ) in a r and omized phase II study . Both drugs were given by 24-h intravenous ( i.v . ) infusion every 3 weeks along with i.v . bolus infusions of mesna ( 400 mg/m2 ) , which was given every 4 h for nine administrations . Eligibility criteria included an age of 15 - 75 years , biopsy-proven advanced metastatic soft-tissue sarcoma , and a World Health Organization performance status of 0 - 2 . Exclusion criteria were prior treatment with classic alkylating agents , a creatinine level of > 150 mumol/l , a bilirubin level of > 20 mumol/l , a leukocyte cell count of < 3.5 x 10(9)/l , and a platelet count of < 100 x 10(9)/l . A total of 171 patients were entered , 24 of whom were ineligible and 12 , inevaluable , leaving 135 patients evaluable . In all , 67 patients were treated with cyclophosphamide , and the overall response rate was 7.5 % . All responders to cyclophosphamide were patients who had not received prior chemotherapy ( 13 % of 38 patients ) . Another 68 patients were given ifosfamide , 18 % of whom responded to treatment . Of the 28 ifosfamide-treated patients who had received prior chemotherapy , 7 % were responders . The response rate for the remaining 40 patients was 25 % . The higher overall response rate ( P = 0.13 ) obtained with less myelosuppression in ifosfamide-treated patients suggests that this agent may have advantages over cyclophosphamide in combination therapy BACKGROUND Ombrabulin ( AVE8062 ) disrupts the vasculature of established tumours and has shown pre clinical synergistic anti-tumour activity when combined with cisplatin . In this phase 3 trial , we aim ed 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 , r and omised , 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 r and omly 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 r and omisation scheme ( block size of four ) via an interactive voice-response system , and stratified by histological subtype . Patients , medical staff , study investigators , and individuals who h and led 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 r and omised patients who received at least one dose of study drug . This trial is now closed , and is registered with Clinical Trials.gov , number NCT00699517 . FINDINGS Between June 13 , 2008 , and April 26 , 2012 , we r and omly 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 BACKGROUND The benefit or harm of trabectedin discontinuation in patients with non-progressive soft-tissue sarcoma remains unclear . We report the final analysis of a phase 2 trial investigating the clinical benefit of continuation of trabectedin treatment until progression versus interruption of therapy after six treatment cycles in patients with advanced soft-tissue sarcoma . METHODS For this open-label , non-comparative , multicentre , phase 2 study , eligible adult patients with advanced soft-tissue sarcomas , who had previously received doxorubicin-based chemotherapy and were able to receive trabectedin , were enrolled from 14 centres of the French Sarcoma Group .  Trabectedin was administered at a dose of 1·5 mg/m(2 ) through a central venous line as a 24-h continuous infusion every 3 weeks . After the initial six cycles of trabectedin , patients who were free from progressive disease were r and omly assigned in a 1:1 ratio either to continuous treatment or therapy interruption . R and omisation was done central ly by a computer-generated system using permuted blocks of four patients , stratified by tumour grade and performance status . Patients allocated to the interruption group were allowed to restart trabectedin in case of progressive disease . The primary endpoint was progression-free survival at 6 months after r and omisation , analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT01303094 . RESULTS In 178 evaluable patients , 91 ( 51 % ) patients had not progressed after six cycles . Of these patients , 53 patients were r and omly assigned to the two treatment groups : 27 to the continuation group and 26 to the interruption group . Overall , patients in the two groups received a similar median number of trabectedin cycles ( continuation group : 11 cycles [ range 6 - 31 + ] vs interruption group : 11 [ range 6 - 23 + ] ) . After r and omisation , progression-free survival at 6 months was 51·9 % ( 95 % CI 31·9 - 68·6 ) in the continuation group versus 23·1 % ( 9·4 - 40·3 ) in the interruption group ( p=0·0200 ) . The occurrence of treatment-related grade 3 adverse events ( four [ 16 % ] of 25 patients in the continuation group vs three [ 14 % ] of 21 in the interruption group ) and grade 4 adverse events ( one [ 4 % ] vs none ) was similar in both groups . The most common grade 3 and 4 toxicities were alanine aminotransferase or aspartate aminotransferase increases ( one [ 4 % ] in the interruption group vs three [ 14 % ] in the continuation group ) , neutropenia ( two [ 8 % ] vs two [ 10 % ] ) , and intestinal occlusion ( one [ 4 % ] vs one [ 5 % ] ) . INTERPRETATION We do not recommend trabectedin discontinuation in patients with advanced , doxorubicin-refractory soft-tissue sarcoma who have not progressed after six cycles of treatment . FUNDING The French National Cancer Institute ( INCa ) and PharmaMar SA PURPOSE Given the importance of angiogenesis in soft tissue sarcoma ( STS ) , pazopanib , an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor , was explored in patients with advanced STS . PATIENTS AND METHODS Patients with intermediate- or high- grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease , who had documented progression , who had adequate performance status , and who had good organ function were eligible .  Pazopanib 800 mg was given daily . The primary end point was progression-free rate at 12 weeks ( PFR(12 weeks ) ) . Secondary end points were response , safety , and overall survival . Four different strata were studied : adipocytic STS , leiomyosarcomas , synovial sarcomas , and other STS types . A Simon two-stage design was applied ( P1 = 40 % ; P0 = 20 % ; alpha = beta = .1 ) for each stratum . Results One hundred forty-two patients were enrolled . The adipocytic STS stratum was closed after the first stage , given insufficient activity ( PFR(12 weeks ) , five [ 26 % ] of19 ) . PFR(12 weeks ) was 18 ( 44 % ) of 41 patients in the leiomyosarcoma cohort , 18 ( 49 % ) of 37 in the synovial sarcomas , and 16 ( 39 % ) of 41 in the other STS types . Compared with historical controls who were treated with second-line chemotherapy , progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached . The most frequent drug-related toxicities were hypertension , fatigue , hypopigmentation , and nausea . Other toxicities included liver enzyme elevations , myelosuppression , and proteinuria , all of which were mostly grade s 1 to 2 . The most frequent grade s 3 to 4 toxicities were hyperbilirubinemia ( 6.3 % ) , hypertension ( 7.7 % ) , and fatigue ( 7.7 % ) . CONCLUSION Pazopanib is well tolerated in patients with relapsed , advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas , synovial sarcomas , and other STS types Abstract Background This up date of a r and omized , prospect i ve study presents the effect of external beam radiation therapy ( EBRT ) on long-term overall survival , local control , and limb function following limb-sparing surgery ( LSS ) for the treatment extremity soft tissue sarcoma ( STS ) . Methods Following LSS , patients with extremity STS were r and omized to receive EBRT or surgery alone . All patients with high- grade STS received adjuvant chemotherapy .  Long-term follow-up was obtained through telephone interviews using a question naire based on vali date d methods . Overall survival ( OS ) was determined by Kaplan – Meier method . Results A total of 141 patients with extremity STS were r and omized to receive adjuvant EBRT ( n = 70 ) or LSS alone ( n = 71 ) . Median follow-up was 17.9 years . The 10- and 20-year survival was 77 % ( 95 % CI 66–85 % ) and 64 % ( 95 % CI 52–75 % ) for patients receiving LSS alone and 82 % ( 95 % CI 72–90 % ) and 71 % ( 95 % CI 59–81 % ) for patients receiving EBRT ( p = 0.22 ) . Of the 54 patients who completed telephone interviews , the incidence of local recurrence during the follow-up period was 4 % ( 1 of 24 ) in the LSS alone cohort compared with 0 % ( 0 of 30 ) in those who received EBRT ( p = 0.44 ) . Patients treated with EBRT tended to have more wound complications ( 17 vs. 12.5 % , p = 0.72 ) , clinical ly significant edema ( 25 vs. 12 % , p = 0.31 ) , and functional limb deficits ( 15 vs. 12 % , p = 0.84 ) . Conclusions Adjuvant EBRT following surgery for STS of the extremity provides excellent local control with acceptable treatment-related morbidity and no statistically significant improvement in overall survival Liposarcoma is one of the most common soft tissue sarcomas and has a number of different subtypes : well-differentiated ; dedifferentiated ; myxoid/round cell ; and pleomorphic . However , the response of these subgroups to chemotherapy is not well documented . In this study , we have conducted a retrospective analysis of a prospect ively maintained data base of soft tissue sarcoma patients treated at the Royal Marsden Hospital . Eighty-eight liposarcoma patients who received chemotherapy between August 1989 and June 2004 were identified . The response rates to chemotherapy of the different histological subtypes and overall and progression free survival were investigated . Survival according to histological grade was also assessed . A statistically significant higher response rate to first-line  chemotherapy  was observed in patients with myxoid liposarcoma compared to de- and well-differentiated tumours , 48 % ( 95%CI ; 28 - 69 ) and 11 % ( 95%CI ; 2 - 29 ) , P = 0.005 . Similarly , those with myxoid liposarcoma had a significantly higher response rate compared to all other liposarcoma patients , 48 % ( 95%CI ; 28 - 69 ) and 18 % ( 95%CI ; 8 - 31 ) . Patients with lower grade tumours had better overall survival . This retrospective analysis suggests that myxoid liposarcoma is relatively chemosensitive in comparison to a combination of other liposarcomas , and in particular de- and well-differentiated tumours . Further confirmation of these results should be sought by similar analyses of other data bases PURPOSE The study was design ed to assess the toxicity and activity of high-dose ifosfamide ( HDI ) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas ( ASTS ) pretreated with doxorubicin and /or a st and ard-dose ifosfamide (SDI)-containing regimen .  PATIENTS AND METHODS Between January 1991 and November 1993 , 40 patients with progressive ASTS were entered onto the study . Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows : SDI-refractory ( n = 21 ) , SDI-resistant ( n = 2 ) , and indeterminate SDI-sensitive ( n = 5 ) . Patients were treated until progression or major toxicity . RESULTS One hundred forty-seven cycles of HDI were administered . Neutropenia was dose-limiting , with 100 % of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia ( 30 % of patients ) . Neurotoxicity ( 17 % of patients ) was significantly associated with acute renal failure ( n = 4 ) ( P < .001 ) , grade 4 thrombocytopenia ( P < .01 ) and febrile neutropenia ( P = .048 ) . Chronic renal toxicity ( n = 4 ) was significantly associated with retroperitoneal masses and /or prior nephrectomy ( P = .008 ) . Partial responses ( PRs ) were observed in 12 of 36 assessable patients ( 33 % ) and eight patients ( 22 % ) experienced disease stabilization . All but one response occurred in patients pretreated with SDI , with five PRs among SDI-refractory patients . Leiomyosarcomas appear resistant to HDI . The median response duration was 8 months ( range , 6 to 13 + ) and the median overall survival time was 12 months . CONCLUSION The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation . Although toxic , this treatment appears feasible and manageable using routine clinical support . Since prophylaxis of ifosfamide-induced renal damage remains unknown , frequent monitoring of renal and tubular functions during therapy is highly recommended IMPORTANCE More than 90 % of well-differentiated or dedifferentiated liposarcomas ( WD/DDLS ) have CDK4 amplification . The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts . Our prior phase 2 study demonstrated that treatment with palbociclib ( 200 mg daily for 14 days every 21 days ) result ed in clinical benefit in WD/DDLS but moderate hematologic toxic effects . It is important to underst and whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days- results in clinical benefit and manageable toxic effects . OBJECTIVE To determine the progression-free survival ( PFS ) at 12 weeks of patients with WD/DDLS treated with palbociclib ( PD0332991 ) . DESIGN , SETTING , AND PARTICIPANTS In this phase 2 , nonr and omized , open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center , 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015 . Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles . MAIN OUTCOMES AND MEASURES Primary end point was PFS . Secondary end points included response rate and toxic effects . RESULTS Overall , 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort . Median ( range ) age was 61.5 ( 35 - 87 ) years ; 31 patients ( 52 % ) were male ; median ( range ) Eastern Cooperative Oncology Group score was 0 ( 0 - 1 ) . Progression-free survival at 12 weeks was 57.2 % ( 2-sided 95 % CI , 42.4%-68.8 % ) , and the median PFS was 17.9 weeks ( 2-sided 95 % CI , 11.9 - 24.0 weeks ) . There was 1 complete response . Toxic effects were primarily hematologic and included neutropenia ( grade 3 , n = 20 [ 33 % ] ; grade 4 , n = 2 [ 3 % ] ) but no neutropenic fever . CONCLUSIONS AND RELEVANCE In patients with advanced WD/DDLS , treatment with palbociclib was associated with a favorable PFS and occasional tumor response . This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01209598 Purpose : To develop a nomogram based on clinicopathologic factors to quantify the risk of local recurrence ( LR ) after limb-sparing surgery without adjuvant radiation ( RT ) . Methods : Review of our prospect i ve sarcoma data base identified 684 patients with primary , nonmetastatic , extremity STS treated with limb-sparing surgery alone between June 1982 and December 2006 . No patient received adjuvant radiation or chemotherapy .  Age , sex , grade , depth , size , site , margin status and histology were analyzed for prognostic significance with respect to local recurrence rates using Gray 's test . Variables which were significant in univariate analysis at the 0.05 level were entered into a multivariate competing risk regression model . On the basis of the multivariate analysis , a nomogram for predicting the 3- and 5-year risk of LR was developed using R libraries cmprsk and QHScrnomo . Concordance index ( C-index ) was calculated to evaluate the discriminatory power of the prognostic model . Results : With a median follow-up of 58 months for censored patients ( 73 months for all patients ) , the overall 3- and 5-year actuarial local recurrence rates were 11 % and 13 % , respectively . Factors included in the nomogram were age ( ⩽50 vs. > 50 ) , size ( ⩽5 vs. > 5 cm ) , margin status ( negative vs. positive ) , grade ( low vs. high ) , and histology ( atypical lipomatous tumor/well differentiated liposarcoma vs. other ) . The STS nomogram predicted the local recurrence rate with a C-index of 0.73 . Conclusions : A nomogram for extremity STS that includes age , size , margin status , grade of tumor , and histology predicts the 3- and 5-year risk of local recurrence after limb-sparing surgery in the absence of adjuvant RT PURPOSE Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results . The present study was design ed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents . PATIENTS AND METHODS Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas ( primary diameter > or = 5 cm or any size recurrent tumor ) in extremities or girdles were eligible . Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm . One hundred four patients were r and omized , 51 to the control group and 53 to the treatment group ( five cycles of 4'-epidoxorubicin 60 mg/m(2 ) days 1 and 2 and ifosfamide 1.8 g/m(2 ) days 1 through 5 , with hydration , mesna , and granulocyte colony-stimulating factor ) . RESULTS After a median follow-up of 59 months , 60 patients had relapsed and 48 died ( 28 and 20 in the treatment arm and 32 and 28 in the control arm , respectively ) . The median disease-free survival ( DFS ) was 48 months in the treatment group and 16 months in the control group ( P = .04 ) ; and the median overall survival ( OS ) was 75 months for treated and 46 months for untreated patients ( P = .03 ) . For OS , the absolute benefit deriving from chemotherapy was 13 % at 2 years and increased to 19 % at 4 years ( P = .04 ) . CONCLUSION Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months . Therefore , our data favor an intensified treatment in similar cases . Although cure is still difficult to achieve , a significant delay in death is worthwhile , also considering the short duration of treatment and the absence of toxic deaths BACKGROUND Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery . Pre clinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas . We aim ed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma . METHODS We did a multicentre r and omised open-label study in Japan . Eligible patients had pathological diagnosis of translocation-related sarcoma , were aged 19 years or older , were unresponsive or intolerant to st and ard chemotherapy regimens , no more than four previous chemotherapy regimens , Eastern Cooperative Oncology Group performance status 0 or 1 , adequate bone marrow reserve , renal and liver functions , and had measurable lesions . Patients were r and omly assigned ( 1:1 ) by the minimisation method to receive either trabectedin ( 1·2 mg/m(2 ) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle ) or best supportive care , which was adjusted central ly by pathological subtype . Investigators , patients , and the sponsor were unmasked to the treatment assignment . Progression-free survival and objective responses were assessed by a masked central radiology imaging review . Efficacy was assessed by masked central radiology imaging review . The primary endpoint was progression-free survival for the full analysis set population . Follow-up is ongoing for the patients under study treatment . The study is registered with Japan Pharmaceutical Information Center , number JapicCTI-121850 . FINDINGS Between July 11 , 2012 , and Jan 20 , 2014 , 76 patients were enrolled and allocated to receive either trabectedin ( n=39 ) or best supportive care ( n=37 ) . After central review to confirm pathological subtypes , 73 patients ( 37 in the trabectedin group and 36 in the best supportive care group ) were included in the primary efficacy analysis . Median progression-free survival of the trabectedin group was 5·6 months ( 95 % CI 4·1 - 7·5 ) and the best supportive care group was 0·9 months ( 0·7 - 1·0 ) . The hazard ratio ( HR ) for progression-free survival  of trabectedin versus best supportive care was 0·07 ( 90 % CI 0·03 - 0·14 and 95 % CI 0·03 - 0·16 ) by a Cox proportional hazards model ( p<0·0001 ) . The most common drug-related adverse events for patients treated with trabectedin were nausea ( 32 [ 89 % ] of 36 ) , decreased appetite ( 21 [ 58 % ] ) , decreased neutrophil count ( 30 [ 83 % ] ) , increased alanine aminotransferase ( 24 [ 67 % ] ) , and decreased white blood cell count ( 20 [ 56 % ] ) . INTERPRETATION Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after st and ard chemotherapy such as doxorubicin , and should be considered as a new therapeutic treatment option for this patient population . FUNDING Taiho Pharmaceutical Co. , BACKGROUND To evaluate the feasibility , toxicity and efficacy of the combination of ( IFO ) ifosfamide and epirubicin ( EPI ) given at conventional doses for monochemotherapy , we started a phase II study in advanced/metastatic soft tissue sarcoma patients . PATIENTS AND METHODS Treatment consisted of : epirubicin 75 mg/m2 i.v . day 1 ; IFO 1.8 g/m2 days 1 to 5 ; MESNA 20 % of the IFO dose at 4-hour intervals three times a day during IFO administration . Cycles were given every 3 - 4 weeks for at least three cycles . RESULTS The overall response rate for non-visceral sarcomas ( 51 pts ) was 31 % ( 95 % confidence limits + /- 13 % ) . Among the 13 visceral sarcomas no response was seen for the leiomyosarcomas of the gastrointestinal tract , whereas one complete and one partial remission were observed for the uterine sarcomas . The duration of response was 10 months ( range 5 - 34 + ) for complete responses and 9 ( range 4 - 42 + ) for partial responses . The median survival for responders is 18 months ( range 2 - 60 + ) and for non-responders 10 months ( range 1 - 33 ) ( p < 0.004 ) . CONCLUSIONS This combination proved to be feasible and tolerable . The overall response rate does not appear to be superior to those with other st and ard treatments , but it should be pointed out that our patient population was totally unselected BACKGROUND Previous studies have suggested that trabectedin ( ecteinascidin-743 ) could have antitumour activity in soft-tissue sarcoma . We aim ed to study the usefulness of trabectedin in the treatment of patients with myxoid liposarcomas , a subtype of liposarcoma that is associated with specific chromosomal translocations t(12;16)(q13;p11 ) or t(12;22)(q13;q12 ) that result in the formation of DDIT3-FUS or DDIT3-EWSR1 fusion proteins . METHODS 51 patients with advanced pretreated myxoid liposarcoma who started treatment with trabectedin between April 4 , 2001 , and Sept 18 , 2006 at five institutions in a compassionate-use programme were analysed retrospectively . Central ised radiological and pathological review s were done for most patients . Trabectedin was given either as a 24-h continuous infusion or as a 3-h infusion , every 21 days , at 1.1 - 1.5 mg(2 ) . 558 courses of trabectedin were given in total , with a median of ten courses for each patient ( range 1 - 23 ) . The primary endpoints were response rate and progression-free survival , and the secondary endpoint was overall survival . FINDINGS According to Response Evaluation Criteria in Solid Tumors ( RECIST ) , after a median follow-up of 14.0 months ( IQR 8.7 - 20.0 ) , two patients had complete responses ( CR ) and 24 patients had partial responses ( PR ) ; the overall response was 51 % ( 95 % CI 36 - 65 ) . Five patients had early progressive disease . In 17 of the 23 patients who achieved PR or CR as defined by RECIST and who had central ised radiological review , tissue-density changes , consisting of a decrease in tumour density on CT scan or a decrease in contrast enhancement on MRI ( or both ) , preceded tumour shrinkage . Median progression-free survival was 14.0 months ( 13.1 - 21.0 ) , and progression-free survival at 6 months was 88 % ( 79 - 95 ) . INTERPRETATION Trabectedin was associated with antitumour activity in this series of patients with myxoid liposarcoma . The noted patterns of tumour response were such that tissue density changes occurred before tumour shrinkage in several patients . In some patients , tissue-density changes only were seen . Long-lasting tumour control was noted in responsive patients . The compassionate-use programme is still ongoing . This analysis has result ed in the initiation of two prospect i ve studies to assess the role of trabectedin in the treatment of patients with myxoid liposarcoma in preoperative and metastatic setting s. Furthermore , the selective mechanism of action for trabectedin in this translocation-related sarcoma is being studied The aim of this phase II study was to evaluate the efficacy and toxicity of two regimens of ifosfamide in metastatic soft tissue sarcoma patients given as first- and second-line chemotherapy . Two different schedules of ifosfamide were investigated in a r and omised manner : Ifosfamide was given either at a dose of 5 g/m(2 ) over 24 h ( 5 g/m(2)/1 day ) , every 3 weeks or at a dose of 3 g/m(2 ) per day , administered over 4 h on three consecutive days ( 3 g/m(2)/3 days ) , every 3 weeks . Both schedules were given as first-line or second-line chemotherapy . A total of 182 patients was entered , 103 in first- and 79 in second-line , of whom 8 patients were ineligible , 5 in the first- and 3 in the second-line study . Most patients had a leiomyosarcoma , 46 of the 98 in the first-line and 34 of the 76 in the second-line . The two study arms were well balanced in both the first- and second-lines with respect to sex , age and performance status . In first-line treatment , 5 g/m(2)/1 day yielded five partial responses ( PR ) ( Response Rate ( RR ) 10 % ) , versus 12 PR ( RR 25 % ) for the 3 g/m(2)/3 days . As second-line treatment , the 24-h infusion yielded : one CR and one PR ( RR 6 % ) and the 3-day schedule one CR and two PR ( RR 8 % ) . Survival did not differ between the two regimens . The major World Health Organization ( WHO ) grade 3 and 4 toxicities encountered were : leucopenia in 19 % of all courses in the first-line and 32 % in the second-line with the 5 g/m(2)/1 day , while for the 3 g/m(2)/3 days schedule the rates were 57 and 63 % respectively . Grade 3 or 4 infections were seen in 4 % of patients treated with 5 g/m(2)/1 day first-line and 10 % of patients given 3 g/m(2)/3 days , both as first- and second-lines . No such infections were seen in patients receiving 5 g/m(2)/1 day as second line treatment . In advanced soft-tissue sarcomas in the first-line , ifosfamide 3 g/m(2 ) , given over 4 h on three consecutive days , is an active regimen with acceptable toxicity while the 5 g/m(2 ) over 24 hours schedule result ed in a disappointing response rate PURPOSE AND METHODS Doxorubicin alone or with dacarbazine ( DTIC ; AD ) is considered the best available therapy for metastatic adult sarcomas .  Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen . This study was design ed to determine if ifosfamide added to doxorubicin and DTIC ( ADI ) significantly effects toxicity , response rate , and survival .  Patients with measurable metastatic or unresectable sarcoma were r and omized to receive AD or ADI .  Patients with chondrosarcomas , fibrosarcomas , and other sarcomas of bone were eligible , although those with osteosarcoma , rhabdomyosarcoma , Ewing 's sarcoma , Kaposi 's sarcoma , and mesothelioma were excluded , as were patients with prior chemotherapy for sarcoma or prior doxorubicin .  RESULTS Between 1987 and 1989 , 340 eligible patients were r and omized . Significantly more myelosuppression , a higher response rate ( 17 % v 32 % ; P < .002 ) and longer time to progression ( 4 v 6 months ; P < .02 ) were observed for patients who received ifosfamide . An overall survival advantage for the two-drug regimen ( 12 v 13 months ; P = .04 ) was not significant by multivariate analysis . CONCLUSION In all three r and omized trials of doxorubicin with and without ifosfamide ( Eastern Cooperative Oncology Group [ ECOG ] , European Organization for Research and Treatment of Cancer [ EORTC ] , and this study ) , the response rate was higher for the ifosfamide-containing arm , significantly so in this and the ECOG studies . An improved response rate may be particularly important for the preoperative management of high- grade , borderline resectable lesions or pulmonary metastases , particularly in younger patients . In older patients , or for low-to intermediate- grade lesions , doxorubicin and DTIC followed by ifosfamide on progression is preferred This phase II study was design ed to verify the activity and safety of an intensive epirubicin/ifosfamide schedule in untreated soft tissue sarcoma ( STS ) patients by using both the agents at the identified maximal tolerated doses . 39 adult patients were treated with epirubicin at 55 mg/m2 , on days 1 and 2 ( total dose per cycle 110 mg/m2 ) combined with ifosfamide at 2.5 g/m2 days 1 - 4 ( total dose per cycle 10 g/m2 ) , with equidose mesna uroprotection and G-CSF support . Treatment was given on an ambulatory basis , at 3-week intervals . The overall objective response ( OR ) rate was 59 % ( 95 % confidence interval , CI , 43 - 72 % ) , with 5 complete responses ( 13 % ) at 18 partial responses ( 46 % ) ; 12 partial responders were rendered disease-free following surgery . The median survival time was 19 months , being 23 and 13 months , respectively , for responding and non-responding patients . The median time to response was 40 days ( range 21 - 60 ) . Treatment-related toxicity was overall acceptable . The OR of 59 % was the highest ever reported in our consecutive studies in advanced STS , confirming that improved therapeutic efficacy can be obtained with intensified regimens in such a disease ; both the response duration and survival were also longer . The observed activity proved to be interesting with regard to the high response rate in the lung ( 86 % ) , as well as the proportion of patients rendered disease-free by early surgery after the achievement of a partial response ( 55 % ) . Both these findings may be important in the multimodality approach to patients with lesions potentially resectable for cure BACKGROUND The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown . We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas . METHODS In this multicentre r and omised trial , patients with macroscopically resected , Trojani grade II-III soft-tissue sarcomas at any site , no metastases , performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery . Patients were r and omly assigned to receive adjuvant chemotherapy or no chemotherapy ( control group ) . R and omisation was done with a minimisation technique , stratified by hospital , site of primary tumour , tumour size , planned radiotherapy , and isolated limb perfusion therapy . Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2 ) , ifosfamide 5 g/m(2 ) , and lenograstim every 3 weeks . Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent . The primary endpoint was overall survival and analyses were done by intention to treat . The final results are presented . This trial is registered with Clinical Trials.gov , NCT00002641 . FINDINGS Between February , 1995 , and December , 2003 , 351 patients were r and omly assigned to the adjuvant chemotherapy group ( 175 patients ) or to the  control group  ( 176 ) . 258 ( 73 % ) of 351 patients received radiotherapy , 129 in each group . Overall survival did not differ significantly between groups ( hazard ratio [ HR ] 0·94 [ 95 % CI 0·68 - 1·31 ] , p=0·72 ) nor did relapse-free survival ( HR 0·91 [ 0·67 - 1·22 ] , p=0·51 ) . 5-year overall survival rate was 66·5 % ( 58·8 - 73·0 ) in the chemotherapy group and 67·8 % ( 60·3 - 74·2 ) in the  control group . Chemotherapy was well tolerated , with 130 ( 80 % ) of 163 patients who started it completing all five cycles . 16 ( 10 % ) patients had grade 3 or 4 fever or infection , but no deaths due to toxic effects were recorded . INTERPRETATION Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival . Future studies should focus on patients with larger , grade III , and extremity sarcomas PURPOSE Sarcomas are among the most proangiogenic malignancies in pre clinical models . Phase I study results for ABT-510 , which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism , suggested activity in soft tissue sarcoma ( STS ) patients . This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients . PATIENTS AND METHODS Patients with metastatic or unresectable STS were r and omly assigned to treatment with one of two ABT-510 dose schedules ( 20 mg once a day [ 20 mg ] , n = 42 ; or 100 mg twice a day [ 200 mg ] , n = 46 ) , which were self-administered subcutaneously in 28-day treatment periods . End points included progression-free survival ( PFS ) , objective response rate ( ORR ) , overall survival ( OS ) , and safety . RESULTS Median PFS for the 20-mg arm was 94 days , with 4- and 6-month PFS rate estimates of 42 % and 24 % , respectively . Median PFS for the 200-mg arm was 64 days , with 4- and 6-month PFS rate estimates of 41 % and 32 % , respectively . Although only one objective response was noted , stable disease was observed in 52 % ( 20 mg ) and 48 % ( 200 mg ) of patients . Median OS was 431 days ( 20 mg ) and 295 days ( 200 mg ) . ABT-510 was well tolerated . Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension , deep vein thrombosis , and hypophosphatemia .  ABT-510 pharmacokinetics were dose proportional , time independent , and consistent with those in previous studies . CONCLUSION ABT-510 had a favorable safety profile , and the rate of disease control and OS times were encouraging . However , with low ORR and lack of dose response , the study failed to yield compelling evidence of strong single-agent activity in STS PURPOSE A previous r and omized clinical trial by the Italian Sarcoma Group ( ISG ) had shown a survival benefit of adjuvant chemotherapy ( CT ) in high-risk extremity soft tissue sarcoma ( STS ) . However , the dose-intensity of the last two cycles was suboptimal . We then undertook a multicentric international phase III study to compare three and five cycles of the same CT . PATIENTS AND METHODS Patients were r and omly assigned either to receive three cycles of preoperative CT with epirubicin 120 mg/m(2 ) and ifosfamide 9 g/m(2 ) and granulocyte colony-stimulating factor ( arm A ) or to receive the same three cycles of preoperative CT followed by two further cycles of postoperative CT ( arm B ) . Noninferiority of the primary end point , overall survival ( OS ) , was assessed by the CI of the hazard ratio ( HR ; arm A/arm B ) obtained from the Cox model . RESULTS Between January 2002 and April 2007 , 328 patients were recruited ( 164 patients in each arm ) . At a median follow-up of 63 months ( interquartile range , 49 to 77 months ) , 100 deaths were recorded , 49 in arm A and 51 in arm B. Five-year OS probability was 0.70 for the entire group of patients ( 0.68 in arm A and 0.71 in arm B ) . The HR of arm A versus arm B was 1.00 ( 90 % CI , 0.72 to 1.39 ) . CONCLUSION In this population of patients with high-risk localized STS , three cycles of full-dose preoperative CT were not inferior to five cycles . The outcome compares favorably with the expected survival of patients with high-risk STS and was superimposable on the CT arm of the previous ISG trial
BACKGROUND Prognosis for patients with metastatic soft tissue sarcomas ( STS ) is dismal , with median overall survival ( OS ) of 8 - 12 months .
The role of second-line therapy has been inconsistently investigated over the last 20 years .
This systematic review and meta- analysis was performed to assess the efficacy of salvage treatment in pretreated adult type STS , gastrointestinal stromal tumor ( GIST ) excluded .
IMPLICATION S FOR PRACTICE There is some evidence that salvage therapies after first-line failure are able to improve outcome in metastatic soft tissue sarcoma ( STS ) .
Trabectedin , gemcitabine-based therapy , and pazopanib are currently approved drugs used after conventional upfront treatment .
This meta- analysis review s the benefit of new agents used in r and omized trials in comparison with no active treatments or older agents for recurrent/progressed STS .