Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial

Ramesh K Wali, Laura Bianchi, Sonia Kupfer, Mart De La Cruz, Borko Jovanovic, Christopher Weber, Michael J Goldberg, L M Rodriguez, Raymond Bergan, David Rubin, Mary Beth Tull, Ellen Richmond, Beth Parker, Seema Khan, Hemant K Roy, Ramesh K Wali, Laura Bianchi, Sonia Kupfer, Mart De La Cruz, Borko Jovanovic, Christopher Weber, Michael J Goldberg, L M Rodriguez, Raymond Bergan, David Rubin, Mary Beth Tull, Ellen Richmond, Beth Parker, Seema Khan, Hemant K Roy

Abstract

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention.

Trial registration: ClinicalTrials.gov NCT00828984.

Conflict of interest statement

Competing Interests: Drs. Roy and Wali are co-founders and shareholders in Pegasus Biosolutions LLC which has licensed the PEG for head and neck cancer prevention. Dr. Roy is a co-founder of American BioOptics and Nanocytomics LLC which are also not relevant to current work. All other authors do not have any competing interests.

Figures

Fig 1. CONSORT diagram.
Fig 1. CONSORT diagram.
Fig 2. Reduction in the number of…
Fig 2. Reduction in the number of rectal ACF after PEG treatment.

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