title: Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial.
abstract: 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 randomly assigned in a 1:1 ratio either to continuous treatment or therapy interruption. Randomisation was done centrally 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 randomisation, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01303094.
  
  
  RESULTS
  In 178 evaluable patients, 91 (51%) patients had not progressed after six cycles. Of these patients, 53 patients were randomly 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 randomisation, 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%]).
  
  
  CONCLUSIONS
  We do not recommend trabectedin discontinuation in patients with advanced, doxorubicin-refractory soft-tissue sarcoma who have not progressed after six cycles of treatment.
  
  
  BACKGROUND
  The French National Cancer Institute (INCa) and PharmaMar SA.
authors: Medical Oncology Department, Gustave Roussy, Villejuif, France.
authors: Axel
authors: A
authors: Le Cesne
authors: Medical Oncology Department, Centre Léon Bérard and Claude Bernard University, Lyon, France.
authors: Jean-Yves
authors: JY
authors: Blay
authors: Medical Oncology Department, Gustave Roussy, Villejuif, France.
authors: Julien
authors: J
authors: Domont
authors: Biostatistics Unit, Centre Oscar Lambret, Lille, France.
authors: Emmanuelle
authors: E
authors: Tresch-Bruneel
authors: Medical Oncology Department, Institut Claudius Regaud, Toulouse, France.
authors: Christine
authors: C
authors: Chevreau
authors: Medical Oncology Department, Institut Paoli Calmette, Marseille, France.
authors: François
authors: F
authors: Bertucci
authors: Medical Oncology Department, Centre François Baclesse, Caen, Lille.
authors: Corinne
authors: C
authors: Delcambre
authors: Medical Oncology Department, Centre Antoine Lacassagne, Nice, France.
authors: Esma
authors: E
authors: Saada-Bouzid
authors: Medical Oncology Department, Insitut Curie, Paris, France.
authors: Sophie
authors: S
authors: Piperno-Neumann
authors: Medical Oncology Department, Institut Paoli Calmette, Marseille, France.
authors: Jacques-Olivier
authors: JO
authors: Bay
authors: Medical Oncology Department, Gustave Roussy, Villejuif, France.
authors: Olivier
authors: O
authors: Mir
authors: Medical Oncology Department, Centre Léon Bérard and Claude Bernard University, Lyon, France.
authors: Isabelle
authors: I
authors: Ray-Coquard
authors: Medical Oncology Department, Centre Oscar Lambret, Lille, France.
authors: Thomas
authors: T
authors: Ryckewaert
authors: Medical Oncology Department, Institut Claudius Regaud, Toulouse, France.
authors: Thibaud
authors: T
authors: Valentin
authors: Medical Oncology Department, Centre Georges-François Leclerc, Dijon, France.
authors: Nicolas
authors: N
authors: Isambert
authors: Medical Oncology Department, Institut Bergonié, Bordeaux, France.
authors: Antoine
authors: A
authors: Italiano
authors: Clinical Research Unit, Centre Oscar Lambret, Lille, France; Methodology and Clinical Research Platform of SIRIC OncoLille, Lille, France.
authors: Stéphanie
authors: S
authors: Clisant
authors: Medical Oncology Department, Centre Oscar Lambret, Lille, France; Methodology and Clinical Research Platform of SIRIC OncoLille, Lille, France. Electronic address: n-penel@o-lambret.fr.
authors: Nicolas
authors: N
authors: Penel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004149:Dioxoles / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D005602:France; D006801:Humans; D007262:Infusions, Intravenous; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D000077606:Trabectedin; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D000077606:Trabectedin