title: Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database.
abstract: The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network ("Rete Tumori Rari"; RTR).
  
  
  
  We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15-20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
  
  
  
  Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic; WWTR1 rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1-45), with four patients progression-free at 24 months. The clinical benefit (complete response [CR] + PR + SD >6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1-8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients.
  
  
  
  A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.
authors.affiliation: Medical Oncology Unit 2 - Adult Mesenchymal Tumours and Rare Cancers, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. silvia.stacchiotti@istitutotumori.mi.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stacchiotti
authors.affiliation: Medical Oncology Unit 2 - Adult Mesenchymal Tumours and Rare Cancers, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Provenzano
authors.affiliation: Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Dagrada
authors.affiliation: Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Negri
authors.affiliation: Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Brich
authors.affiliation: Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto IOV IRCCS, Padua, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Basso
authors.affiliation: Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto IOV IRCCS, Padua, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Brunello
authors.affiliation: Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Grosso
authors.affiliation: Oncology, Santa Chiara Hospital, Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Galli
authors.affiliation: Medical Oncology Unit 2 - Adult Mesenchymal Tumours and Rare Cancers, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Palassini
authors.affiliation: Medical Oncology Unit 2 - Adult Mesenchymal Tumours and Rare Cancers, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Libertini
authors.affiliation: Medical Oncology Unit 2 - Adult Mesenchymal Tumours and Rare Cancers, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colia
authors.affiliation: Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy.
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Dei Tos
authors.affiliation: Department of Nuclear Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Crippa
authors.affiliation: Department of Radiology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Morosi
authors.affiliation: Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Medical Oncology Unit 2 - Adult Mesenchymal Tumours and Rare Cancers, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D001202:Ascitic Fluid; D016208:Databases, Factual; D018450:Disease Progression; D018572:Disease-Free Survival; D015321:Gene Rearrangement; D018323:Hemangioendothelioma, Epithelioid / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D010996:Pleural Effusion / Q000139:chemically induced; D066066:Response Evaluation Criteria in Solid Tumors; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D015996:Survival Rate; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D020123:Sirolimus