title: A phase I-II study on the combination of rapamycin and short course radiotherapy in rectal cancer.
abstract: OBJECTIVE
  This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of the combination of rapamycin, an mTOR inhibitor, with short-course radiotherapy in rectal cancer patients. Antitumor activity, changes in metabolic activity and perfusion on imaging, and changes in phosphorylation status of the mTOR pathway were also assessed.
  
  
  METHODS
  Patients with primary resectable rectal cancer were treated with short-course hypofractionated radiotherapy (5×5 Gy) combined with oral rapamycin 1 week before and during radiotherapy, followed by surgical resection.
  
  
  RESULTS
  Thirteen patients were entered in phase I. One patient developed a dose-limiting toxicity, consisting of a grade 4 leak and grade 4 bleeding. Because of an unexpected high rate of grade 3 postoperative toxicity, it was decided to treat patients with delayed surgery in phase II. Primary endpoint for phase II was tumor blood flow (K(trans)) assessed by perfusion CT. Thirty-one patients were treated with the MTD of 6 mg rapamycin daily. One patient (3%) developed a pathological complete response (pCR) and 3 patients (10%) had a ypT1N0 tumor at the time of resection. No change in tumor perfusion was observed on perfusion CT, but a significant decrease of metabolic activity was found on PET-scan.
  
  
  CONCLUSIONS
  The combination of short-course radiotherapy and rapamycin turned out to be feasible, provided that the interval between neo-adjuvant treatment and surgical resection is at least 6 weeks. Although from this cohort no clear increase in pCR could be observed, a clear metabolic response after rapamycin run-in was observed, indicating a biological activity of this drug in rectal cancer.
authors.affiliation: Dept. of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands. Electronic address: jeroen.buijsen@maastro.nl.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Buijsen
authors.affiliation: Dept. of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Jørgen
authors.initials: J
authors.lastname: van den Bogaard
authors.affiliation: Dept. of Radiation Oncology (MAASTRO lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Barry
authors.initials: B
authors.lastname: Jutten
authors.affiliation: Dept. of Surgery, Atrium Medical Centre, Heerlen, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Belgers
authors.affiliation: Dept. of Surgery, Atrium Medical Centre, Heerlen, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Sosef
authors.affiliation: Dept. of Surgery, Laurentius Hospital, Roermond, The Netherlands.
authors.forename: Jeroen W A
authors.initials: JW
authors.lastname: Leijtens
authors.affiliation: Dept. of Surgery, Maastricht University Medical Centre, The Netherlands.
authors.forename: Geerard L
authors.initials: GL
authors.lastname: Beets
authors.affiliation: Dept. of Internal Medicine, Maastricht University Medical Centre, The Netherlands.
authors.forename: Rob L H
authors.initials: RL
authors.lastname: Jansen
authors.affiliation: Dept. of Pathology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Riedl
authors.affiliation: Dept. of Pathology, Atrium Medical Centre, Heerlen, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Clarijs
authors.affiliation: Dept. of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Guido
authors.initials: G
authors.lastname: Lammering
authors.affiliation: Dept. of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D059248:Chemoradiotherapy / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011300:Preoperative Care; D012004:Rectal Neoplasms / Q000628:therapy*; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus
keywords: Phase I/II; Radiotherapy; Rapamycin; Rectal cancer; mTOR