title: Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention.
abstract: Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5-34) and 8 (0-37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (-69% to 143%), -18.6 (-83% to 160%), -3.6 (-88% to 83%), and -10.0 (-100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12-0.59) nor between-arm (P = 0.30-0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P > 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size.
authors.affiliation: Mayo Clinic Rochester, Rochester, MN 55905, USA. limburg.paul@mayo.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.forename: Katie L Allen
authors.initials: KL
authors.lastname: Ziegler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sontag
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schoen
authors.forename: Richard
authors.initials: R
authors.lastname: Benya
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lawson
authors.forename: David S
authors.initials: DS
authors.lastname: Weinberg
authors.forename: Elena
authors.initials: E
authors.lastname: Stoffel
authors.forename: Michael
authors.initials: M
authors.lastname: Chiorean
authors.forename: Russell
authors.initials: R
authors.lastname: Heigh
authors.forename: Joel
authors.initials: J
authors.lastname: Levine
authors.forename: Gary
authors.initials: G
authors.lastname: Della'Zanna
authors.forename: Luz
authors.initials: L
authors.lastname: Rodriguez
authors.forename: Ellen
authors.initials: E
authors.lastname: Richmond
authors.forename: Christopher
authors.initials: C
authors.lastname: Gostout
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
mesh_terms: D058739:Aberrant Crypt Foci / Q000473:pathology / Q000517:prevention & control*; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D015179:Colorectal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D004043:Dietary Fiber / Q000627:therapeutic use*; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use*; D013467:Sulindac / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004043:Dietary Fiber; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013467:Sulindac; D000069059:Atorvastatin