title: External beam radiotherapy for unresectable hepatocellular carcinoma, an international multicenter phase I trial, SAKK 77/07 and SASL 26.
abstract: OBJECTIVE
  To assess feasibility and safety of conventionally fractionated radiotherapy (cfRT) in patients with hepatocellular carcinoma (HCC).
  
  
  METHODS
  Patients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh Score (CPS) A or B disease were included in a phase I multicenter trial. Metastatic HCC were allowed if ≥90% of total tumor volume was located within the liver. Patients were enrolled onto five dose-escalation levels (54-70Gy in 2Gy fractions) based on a modified 3 + 3 design, with cohorts of five patients instead of three patients in dose levels 4 and 5. Primary trial endpoint was dose-limiting toxicity (DLT), as specifically defined for 17 clinical and nine laboratory parameters as grade ≥3 or ≥4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of ≤16.7% in dose levels 1-3, and ≤10% in dose levels 4-5. Best objective response of target liver lesions and adverse events (AE's) were assessed as secondary endpoints.
  
  
  RESULTS
  The trial was terminated early in DL 3 due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary and 18 for the secondary endpoints. Maximum tolerated dose was not reached. One patient in dose level 1, and one patient in dose level 2 experienced DLT (lipase > 5xULN, and neutrophils <500/μL respectively). However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients. Overall, 56% of patients had a partial response and 28% showed stable disease according to RECIST. No signs of radiation induced liver disease (RILD). Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact.
  
  
  CONCLUSIONS
  Conventionally fractionated radiotherapy of 58Gy to even large HCC was safe for patients with CPS A and B. 62Gy was delivered to three patients without any sign of clinically relevant increased toxicity. The maximum tolerated dose could not be determined.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier NCT00777894 , registered October 21st, 2008.
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. evelyn.herrmann@bluewin.ch.
authors.forename: Evelyn
authors.identifier: http://orcid.org/0000-0002-1306-7306
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Division of Radiation Oncology, Basel University Hospital, Basel, Switzerland.|Department of Radiation Oncology, Lifehouse at RPA, Sydney, NSW, Australia.
authors.forename: Diana
authors.initials: D
authors.lastname: Naehrig
authors.affiliation: Department of Radiation Oncology and Division of Medical Radiation Physics, Bern University Hospital, Bern, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Sassowsky
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Bigler
authors.affiliation: Department of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biolog, Maastricht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Buijsen
authors.affiliation: Department of Radiation Oncology, University of Zurich, Zurich, Switzerland.|Department of Radiotherapy and Radiation Oncology, Dessau City Hospital, Dessau, Germany.
authors.forename: Ilja
authors.initials: I
authors.lastname: Ciernik
authors.affiliation: Department of Radiation Oncology, Hospital Graubuenden, Chur, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zwahlen
authors.affiliation: Radiation Oncology Department, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.|Radiotherapy Service, Clinica Luganese SA, Lugano, Switzerland.
authors.forename: Alessandra Franzetti
authors.initials: AF
authors.lastname: Pellanda
authors.affiliation: Centre for Radiation Oncology, KSA-KSB, Kantonsspital Aarau, Aarau, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meister
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Brauchli
authors.affiliation: Department of Radiation Oncology and Division of Medical Radiation Physics, Bern University Hospital, Bern, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Berardi
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Erika
authors.initials: E
authors.lastname: Kuettel
authors.affiliation: Department of Hepatology, University Clinic of Visceral Surgery and Medicine, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Aebersold
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000532:radiotherapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000379:methods*
keywords: Conformal radiotherapy; Hepatocellular carcinoma; Liver; Radiation toxicity