Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention

Paul John Limburg, Michelle R. Mahoney, Katie L Allen Ziegler, Stephen J. Sontag, Robert E. Schoen, Richard Benya, Michael J. Lawson, David S. Weinberg, Elena Stoffel, Michael Chiorean, Russell Heigh, Joel Levine, Gary Della'Zanna, Luz Rodriguez, Ellen Richmond, Christopher Gostout, Sumithra J Mandrekar, Thomas Christopher Smyrk

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)259-269
Number of pages11
JournalCancer Prevention Research
Volume4
Issue number2
DOIs
StatePublished - Feb 2011

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Aberrant Crypt Foci
Sulindac
Prebiotics
Chemoprevention
Dietary Fiber
Colorectal Neoplasms
Apoptosis
Inulin
Risk Reduction Behavior
Clinical Protocols
Caspase 3
Adenoma
Sample Size
Colonic Neoplasms
Atorvastatin Calcium
Mucous Membrane
Clinical Trials
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention. / Limburg, Paul John; Mahoney, Michelle R.; Ziegler, Katie L Allen; Sontag, Stephen J.; Schoen, Robert E.; Benya, Richard; Lawson, Michael J.; Weinberg, David S.; Stoffel, Elena; Chiorean, Michael; Heigh, Russell; Levine, Joel; Della'Zanna, Gary; Rodriguez, Luz; Richmond, Ellen; Gostout, Christopher; Mandrekar, Sumithra J; Smyrk, Thomas Christopher.

In: Cancer Prevention Research, Vol. 4, No. 2, 02.2011, p. 259-269.

Research output: Contribution to journalArticle

Limburg, PJ, Mahoney, MR, Ziegler, KLA, Sontag, SJ, Schoen, RE, Benya, R, Lawson, MJ, Weinberg, DS, Stoffel, E, Chiorean, M, Heigh, R, Levine, J, Della'Zanna, G, Rodriguez, L, Richmond, E, Gostout, C, Mandrekar, SJ & Smyrk, TC 2011, 'Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention', Cancer Prevention Research, vol. 4, no. 2, pp. 259-269. https://doi.org/10.1158/1940-6207.CAPR-10-0215
Limburg, Paul John ; Mahoney, Michelle R. ; Ziegler, Katie L Allen ; Sontag, Stephen J. ; Schoen, Robert E. ; Benya, Richard ; Lawson, Michael J. ; Weinberg, David S. ; Stoffel, Elena ; Chiorean, Michael ; Heigh, Russell ; Levine, Joel ; Della'Zanna, Gary ; Rodriguez, Luz ; Richmond, Ellen ; Gostout, Christopher ; Mandrekar, Sumithra J ; Smyrk, Thomas Christopher. / Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 2. pp. 259-269.
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AU - Mahoney, Michelle R.

AU - Ziegler, Katie L Allen

AU - Sontag, Stephen J.

AU - Schoen, Robert E.

AU - Benya, Richard

AU - Lawson, Michael J.

AU - Weinberg, David S.

AU - Stoffel, Elena

AU - Chiorean, Michael

AU - Heigh, Russell

AU - Levine, Joel

AU - Della'Zanna, Gary

AU - Rodriguez, Luz

AU - Richmond, Ellen

AU - Gostout, Christopher

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N2 - 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.

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