A Randomized Phase IIb Trial of myo-Inositol in Smokers with Bronchial Dysplasia.
Stephen Lam, Sumithra J Mandrekar, Yaron Gesthalter, Katie L Allen Ziegler, Drew K Seisler, David E Midthun, Jenny T Mao, Marie Christine Aubry, Annette McWilliams, Don D Sin, Tawimas Shaipanich, Gang Liu, Evan Johnson, Andrea Bild, Marc E Lenburg, Diana N Ionescu, John Mayo, Joanne Eunhee Yi, Henry Tazelaar, William S Harmsen, Judith Smith, Avrum E Spira, Jennifer Beane, Paul J Limburg, Eva Szabo, Cancer Prevention Network
Author Information
- Stephen Lam: British Columbia Cancer Agency, Vancouver, British Columbia, Canada. slam2@bccancer.bc.ca.
- Sumithra J Mandrekar: Mayo Clinic, Rochester, Minnesota.
- Yaron Gesthalter: Boston University Medical Center, Boston, Massachusetts.
- Katie L Allen Ziegler: Mayo Clinic, Rochester, Minnesota.
- Drew K Seisler: Mayo Clinic, Rochester, Minnesota.
- David E Midthun: Mayo Clinic, Rochester, Minnesota.
- Jenny T Mao: New Mexico Veteran's Health Care System, Albuquerque, New Mexico.
- Marie Christine Aubry: Mayo Clinic, Rochester, Minnesota.
- Annette McWilliams: Fiona Stanley Hospital, Palmyra DC, Western Australia.
- Don D Sin: St. Paul's Hospital, Vancouver, British Columbia, Canada.
- Tawimas Shaipanich: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
- Gang Liu: Boston University Medical Center, Boston, Massachusetts.
- Evan Johnson: Boston University Medical Center, Boston, Massachusetts.
- Andrea Bild: University of Utah, Salt Lake City, Utah.
- Marc E Lenburg: Boston University Medical Center, Boston, Massachusetts.
- Diana N Ionescu: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
- John Mayo: Vancouver General Hospital, Vancouver, British Columbia.
- Joanne Eunhee Yi: Mayo Clinic, Rochester, Minnesota.
- Henry Tazelaar: Mayo Clinic, Scottsdale, Arizona.
- William S Harmsen: Mayo Clinic, Rochester, Minnesota.
- Judith Smith: Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland.
- Avrum E Spira: Boston University Medical Center, Boston, Massachusetts.
- Jennifer Beane: Boston University Medical Center, Boston, Massachusetts.
- Paul J Limburg: Mayo Clinic, Rochester, Minnesota.
- Eva Szabo: Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland.
Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906-14. ©2016 AACR.
Aged
Biomarkers, Tumor
Biopsy
Bronchi
Bronchoalveolar Lavage Fluid
Bronchoscopy
Chemoprevention
Dose-Response Relationship, Drug
Double-Blind Method
Female
Glucose
Humans
Hyperplasia
Inositol
Ki-67 Antigen
Lung Neoplasms
Male
Metaplasia
Middle Aged
Optical Imaging
Phosphatidylinositol 3-Kinases
Smoking
Tomography, Spiral Computed
Vitamin B Complex
Biomarkers, Tumor
Ki-67 Antigen
Vitamin B Complex
Inositol
Phosphatidylinositol 3-Kinases
Glucose