Nutrition Intervention Trials - Linxian
Lead Contact and/or Principal Investigator (PI):
- Philip Taylor, M.D., Sc.D.
Division of Cancer Epidemiology and Genetics (DCEG)
National Cancer Institute (NCI)
Funded Since: 1984
Funding Source: NCI Intramural Program (DCEG)
Year(s) of Enrollment: 1984 and 1985
Two nutrition intervention trials were conducted in Linxian, China, where the esophageal/gastric cardia cancer mortality rates are among the highest in the world, and there is suspicion that the population's chronic deficiencies of multiple nutrients are etiologically involved. Both trials were randomized, double-blind, and placebo-controlled, and tested the effects of multiple vitamin and mineral supplements in lowering the rates of cancer.
Dysplasia Trial. The dysplasia trial, conducted in three communes (Yaocun, Rencun, and Donggang) in northern Linxian, enrolled 40- to 69-year-old adults who had evidence of esophageal dysplasia on a balloon cytology examination but had no history of malignancy. These individuals were randomized to receive multiple vitamin/mineral supplements or placebos daily for a period of six years.
The micronutrients provided in the supplements included 14 vitamins and 12 minerals (i.e., beta-carotene as Solatene, Hoffmann-La Roche, Inc., and multivitamins as Centrum, Lederle Laboratories, Inc.) in doses typically 2 to 3 times the U.S. Recommended Daily Allowances. A total of 3,318 persons were randomized and started intervention in May 1985. The median age of participants at the start of intervention was 54 years of age, 56 percent were female, 29 percent smoked tobacco, 18 percent reported alcohol use in the past year, and 43 percent had a family history of esophageal or stomach cancer.
The treatment groups were similar for all characteristics examined, except that more participants in the supplement group had dysplasia 2 (high-grade dysplasia) on their pretrial cytology examination than in the placebo group (25 versus 22%). Village doctors distributed pills monthly throughout the trial. Compliance was assessed by counting all residual pills monthly and by assaying nutrient levels in blood on a sample of persons each quarter.
The overall pill disappearance rate was 94 percent in both treatment groups, and the blood assays showed significantly greater increases in nutrient status for persons in the supplement group (e.g., serum beta-carotene levels rose 10-fold in the supplement group compared with an 11% increase in the placebo group). Incident cancers and deaths were identified through several methods that assured essentially complete ascertainment of events. The daily doses and types of micronutrients were: beta-carotene (15 mg), vitamin A (10,000 IU), vitamin E (60 IU), vitamin C (180 mg), folic acid (800 µg), vitamin B1 (5 mg), vitamin B2 (5.2 mg), niacinamide (40 mg), vitamin B6 (6 mg), vitamin B12 (18 µg), vitamin D (800 IU), biotin (90 µg), pantothenic acid (20 mg), calcium (324 mg), phosphorus (250 mg), iodine (300 µg), iron (54 mg), magnesium (200 mg), copper (6 mg), manganese (15 mg), potassium (15.4 mg), chloride (14 mg), chromium (30 µg), molybdenum (30 µg), selenium (50 µg), and zinc (45 mg). During the trial, there were monthly visits by village doctors, reviews conducted of local and regional hospital records and the local cancer registry, and cytology and endoscopy surveys performed.
A total of 448 incident cancers were identified during the trial (13.5% of the total trial population), including 251 esophageal and 159 gastric cardia cancers; 324 deaths occurred during the intervention, of which 54 percent were due to cancer.
General Population Trial. The general population trial, conducted in four communes (Yaocun, Rencun, Donggang, and Hengshui) in northern Linxian, enrolled 40- to 69-year-old adults from the general population who had no history of malignancy. These individuals were randomized to intervention groups receiving daily vitamin/mineral supplementation by using a one-half replicate of a 2x4 factorial experimental design for a period of 5.25 years. This design enabled simultaneous testing for the effects of four different combinations of nutrients or treatment factors. Nutrients and doses ranged from 1 to 2 times the U.S. Recommended Daily Allowances.
A total of 29,584 persons were randomized and started intervention in March 1986. The median age of participants at the start of intervention was 52 years, 55 percent were female, 30 percent smoked tobacco, 23 percent reported alcohol use in the past year, and 32 percent had a family history of esophageal or stomach cancer. Treatment groups were similar for all characteristics examined.
As with the dysplasia trial, each month village doctors distributed new pills and counted residual ones, and each quarter a sample of persons had nutrient levels assayed in blood. The overall pill disappearance rate was 93 percent and did not differ by intervention group. Likewise, nutrient assays confirmed compliance for each of the 4 different treatment factors (e.g., serum beta-carotene levels rose 14-fold in persons receiving this nutrient compared with a less than 2-fold increase in persons not receiving it). Incident cancers and deaths were identified in the general trial population in a manner similar to the dysplasia trial, and ascertainment was considered essentially complete.
A total of 1,298 incident cancers were identified during the trial (4.4% of the total trial population), including 640 esophageal and 435 gastric cardia cancers. More than 2,100 deaths occurred during the intervention, of which 37 percent were due to cancer.
With the conclusion of the intervention phase in 1991 and determination that the micronutrient combination of selenium/vitamin E/beta-carotene reduced total mortality, total cancer mortality, and gastric cancer mortality, objectives now include determination of post-trial effects of the interventions and further evaluation of etiologic hypotheses.