title: A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma.
abstract: BACKGROUND
  Proton-beam radiotherapy (PBT) has been shown to be effective to hepatocellular carcinoma (HCC) as a nonsurgical local treatment option. However, HCC still remains as one of the most difficult cancers to be cured because of frequent recurrences. Thus, methods to inhibit the recurrence need to be explored. To prevent the HCC recurrence, we here report on a prospective phase I study of 'in situ' tumor vaccination using CalTUMP, a newly developed immunoadjuvant consisting of BCG extract bound to hydroxyapatite and microparticulated tuberculin, following local PBT for HCC.
  
  
  METHODS
  Patients with locally advanced recurrent HCC, which had been heavily pretreated with various treatments, were enrolled. PBT was performed with the conventional method to the target HCC. Subsequently, CalTUMP was injected into the same irradiated-tumor three times at one-week intervals. Three dose-levels of CalTUMP (1/10, 1/3, and 1/1) were administered to 3 patients each. Vital signs, blood samples, ultrasound, and computed tomographic scans were monitored to evaluate the safety.
  
  
  RESULTS
  Three intratumoral injections of CalTUMP following PBT (median dose: 72.6 GyE) were accomplished in 9 patients. Transient low-grade fever and minor laboratory changes were observed in 7 patients after CalTUMP injections. No other treatment-related adverse events were observed. Median progression-free survival was 6.0 months (range: 2.1-14.2) and 4 patients were progression-free for more than 1 year.
  
  
  CONCLUSIONS
  Intratumoral injection of CalTUMP following PBT was feasible and safe in patients with heavily pre-treated HCC. Further clinical studies to evaluate the efficacy of this in situ tumor vaccination are warranted.
authors.forename: Masato
authors.initials: M
authors.lastname: Abei
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Okumura
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Fukuda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Araki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ishige
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.forename: Ayae
authors.initials: A
authors.lastname: Kanemoto
authors.forename: Haruko
authors.initials: H
authors.lastname: Numajiri
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizumoto
authors.forename: Takeji
authors.initials: T
authors.lastname: Sakae
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Junko
authors.initials: J
authors.lastname: Zenkoh
authors.forename: Gerelchuluun
authors.initials: G
authors.lastname: Ariungerel
authors.forename: Yu
authors.initials: Y
authors.lastname: Sogo
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ito
authors.forename: Tadao
authors.initials: T
authors.lastname: Ohno
authors.affiliation: Proton Medical Research Center, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennohdai, Tsukuba, Ibaraki 305-8575, Japan. tsuboi-k@md.tsukuba.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuboi
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000368:Aged; D019496:Cancer Vaccines / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000628:therapy*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D017886:Durapatite / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000276:immunology; D061766:Proton Therapy / Q000379:methods*; D014373:Tuberculin / Q000627:therapeutic use; D014611:Vaccination / Q000379:methods*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D014373:Tuberculin; D017886:Durapatite