title: A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer.
abstract: The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival.
  
  
  
  Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5min. SonoVue® was injected intravenously (0.5ml followed by 5ml saline every 3.5min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy.
  
  
  
  The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n=10) tolerated an increased number of gemcitabine cycles compared with historical controls (n=63 patients; average of 8.3±6.0cycles, versus 13.8±5.6cycles, p=0.008, unpaired t-test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients (n=10) was also increased from 8.9months to 17.6months (p=0.011).
  
  
  
  It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.
authors.affiliation: National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: Georg.dimcevski@helse-bergen.no.
authors.forename: Georg
authors.initials: G
authors.lastname: Dimcevski
authors.affiliation: National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Spiros
authors.initials: S
authors.lastname: Kotopoulis
authors.affiliation: Laboratory of Clinical Biochemistry, Section of Clinical Pharmacology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Tormod
authors.initials: T
authors.lastname: Bjånes
authors.affiliation: Department of Surgical Sciences, Haukeland University Hospital, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Hoem
authors.affiliation: Laboratory of Clinical Biochemistry, Section of Clinical Pharmacology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Schjøtt
authors.affiliation: Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Department of Radiology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Martin
authors.initials: M
authors.lastname: Biermann
authors.affiliation: Department of Pathology, Haukeland University Hospital, Bergen, Norway; Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.affiliation: Department of Oncology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Halfdan
authors.initials: H
authors.lastname: Sorbye
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warszawa, Poland; School of Electrical and Information Engineering, Chamber of Mines Building, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Michiel
authors.initials: M
authors.lastname: Postema
authors.affiliation: National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Odd Helge
authors.initials: OH
authors.lastname: Gilja
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D045423:Microbubbles / Q000627:therapeutic use*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D016896:Treatment Outcome; D014464:Ultrasonic Therapy / Q000379:methods*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Clinical trial; Image-guided therapy; Microbubbles; Pancreatic cancer; Sonoporation; Ultrasound