A Systematic Literature Review and Meta-Regression Analysis on Early-Life Energy Restriction and Cancer Risk in Humans

<div><p>Background</p><p>In animal models, long-term moderate energy restriction (ER) is reported to decelerate carcinogenesis, whereas the effect of severe ER is inconsistent. The impact of early-life ER on cancer risk has never been reviewed systematically and quantitatively based on observational studies in humans.</p><p>Objective</p><p>We conducted a systematic review of observational studies and a meta-(regression) analysis on cohort studies to clarify the association between early-life ER and organ site-specific cancer risk.</p><p>Methods</p><p>PubMed and EMBASE (1982 –August 2015) were searched for observational studies. Summary relative risks (RRs) were estimated using a random effects model when available ≥3 studies.</p><p>Results</p><p>Twenty-four studies were included. Eleven publications, emanating from seven prospective cohort studies and some reporting on multiple cancer endpoints, met the inclusion criteria for quantitative analysis. Women exposed to early-life ER (ranging from 220–1660 kcal/day) had a higher breast cancer risk than those not exposed (RR_{RE all ages} = 1.28, 95% CI: 1.05–1.56; RR_{RE for 10–20 years of age} = 1.21, 95% CI: 1.09–1.34). Men exposed to early-life ER (ranging from 220–800kcal/day) had a higher prostate cancer risk than those not exposed (RR_RE = 1.16, 95% CI: 1.03–1.30). Summary relative risks were not computed for colorectal cancer, because of heterogeneity, and for stomach-, pancreas-, ovarian-, and respiratory cancer because there were <3 available studies. Longer duration of exposure to ER, after adjustment for severity, was positively associated with overall cancer risk in women (<i>p</i> = 0.02). Ecological studies suggest that less severe ER is generally associated with a reduced risk of cancer.</p><p>Conclusions</p><p>Early-life transient severe ER seems to be associated with increased cancer risk in the breast (particularly ER exposure at adolescent age) and prostate. The duration, rather than severity of exposure to ER, seems to positively influence relative risk estimates. This result should be interpreted with caution due to the limited number of studies and difficulty in disentangling duration, severity, and geographical setting of exposure.</p></div

PRISMA flow diagram showing a breakdown of the study selection.

<p>PRISMA flow diagram showing a breakdown of the study selection.</p

Forest plot showing a meta-analysis of cohorts on the association between transient early-life energy restriction and the relative risk and mortality of breast cancer, using the relative risk estimate as summary statistic.

<p>Note: Subgroup analyses were performed for childhood (in utero-10 years old) and adolescent (10–20 years old) exposure to ER in relation to breast cancer risk. If individual studies provided risk ratio estimates for different birth cohorts, these were pooled and the pooled estimate was taken along in the meta-analysis. Abbreviations: CI, confidence interval; BC, breast cancer.</p

Meta-regression for exposure to early-life energy restriction and all type cancer risk/mortality including moderators.

<p>Meta-regression for exposure to early-life energy restriction and all type cancer risk/mortality including moderators.</p

An overview of some of the contextual aspects of energy restriction that might modulate the association of early-life energy restriction with cancer risk.

<p>Note: The estimated caloric intake (in units of 100 kcal/day) was based on the mid-point caloric intake reported in the publications and was plotted against the reported relative risk ratios from the individual studies separately for women (panel A) and men (panel C). The estimated duration of ER (in months) was plotted against the reported relative risk ratios from the individual studies separately for women (panel B) and men (panel D). In women, the data points indicated in red represent studies reporting on breast cancer risk or mortality; the data points indicated in blue represent studies reporting on colorectal cancer risk or mortality; the data points indicated in green represent studies reporting on stomach cancer risk or mortality; the data points indicated in grey represent studies reporting on lung cancer risk or mortality; and the data points indicated in yellow represent a report on ovarian cancer risk. In men, the data points indicated in red represent studies reporting on prostate cancer risk or mortality; the data points indicated in blue represent studies reporting on colorectal cancer risk or mortality; the data points indicated in green represent studies reporting on stomach cancer risk or mortality; and the data points indicated in grey represent studies reporting on lung cancer risk or mortality. The dashed lines indicate the confidence intervals of the meta-regression line.</p

Forest plot showing a meta-analysis of cohorts on the association between transient energy restriction during (pre)adolescence and the relative risk and mortality of prostate cancer.

<p>Note: If individual studies provided risk ratio estimates for different birth cohorts, these were pooled and the pooled estimate was taken along in the meta-analysis. Abbreviations: CI, confidence interval; PC, prostate cancer.</p

Forest plot showing a meta-analysis of cohorts on the association between transient energy restriction during (pre)adolescence and the relative risk and mortality at sites other than prostate cancer risk in males and breast cancer risk in females.

<p>Note: If individual studies provided risk ratio estimates for different birth cohorts, these were pooled and the pooled estimate was taken along in the meta-analysis. Abbreviations: CI, confidence interval; CRC, colorectal cancer; SC, stomach cancer; PaC, pancreatic cancer; LC, lung cancer; OC, ovarian cancer.</p

Hazard ratios (HR) ^* and 95% confidence intervals (CI) for a methylation index ^† according to anthropometric risk factors and physical activity in the NLCS 7.3 years of follow-up.

<p>*All models were adjusted for age and sex. Models with BMI and BMI at age 20 were additionally adjusted for trouser/skirt size, models with BMI change were additionally adjusted for BMI at ahe 20, models with trouser/skirt size were additionally adjusted for BMI, and models with height were additionally adjusted for body weight.</p>†<p>methylation index including the five CIMP markers (<i>CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1</i>), <i>MLH1</i>, and the <i>APC</i> gene.</p>‡<p>Based on baseline non-occupational physical activity for women (low≤30 minutes/day, intermediate = 30–90 minutes/day, high≥90 minutes/day) and occupational physical activity at the longest held job for men (low≤8 kj/minute, intermediate  = 8–12 kj/minute, and high≥12 kj/minute).</p

Hazard Ratios (HR) and 95% Confidence Intervals (CI) for colorectal cancer characterized by CIMP, according to physical activity status in the NLCS after 7.3 years of follow-up.

<p>*models adjusted for age and sex.</p>†<p>models adjusted for age, sex, and additionally for trouser/skirt size, family history of CRC (yes/no), smoking status (never smoker, ex-smoker, current smoker), socioeconomic status (level of education: primary school, junior high school, senior high school, higher vocational school, or university), total energy intake (kcal/day), alcohol intake (0, 0.1–4, 5–14, 15–29, ≥30 g/day), and consumption of red meat, fruit, vegetables, and grains (g/day).</p>§<p>P value for test that HR for two tumor subtypes are equal.</p>||<p>Physical activity variable is based on baseline non-occupational physical activity for females, and occupational physical activity in males, as described in the methods.</p

Hazard Ratios (HR) and 95% Confidence Intervals (CI) for colorectal cancer characterized by CIMP, according to measures of anthropometry in the NLCS after 7.3 years of follow-up.

<p>*models adjusted for age and sex.</p>†<p>models adjusted for age, sex, and additionally for family history of CRC (yes/no), smoking status (never smoker, ex-smoker, current smoker), socioeconomic status (level of education: primary school, junior high school, senior high school, higher vocational school, or university), total energy intake (kcal/day), alcohol intake (0, 0.1–4, 5–14, 15–29, ≥30 g/day), and consumption of red meat, fruit, vegetables, and grains (g/day). Models with anthropometric variables were additionally adjusted for baseline physical activity (based on recreational physical activity for women (low≤30 minutes/day, intermediate = 30–90 minutes/day, high≥90 minutes/day) and occupational physical activity at the longest held job for men (low≤8 kj/minute, intermediate  = 8–12 kj/minute, and high≥12 kj/minute).</p>‡<p>Models adjusted for age and sex, and mutually adjusted for other anthropometric variables. Models with BMI and BMI at age 20 were additionally adjusted for trouser/skirt size; the model for BMI change was additionally adjusted for BMI at age 20; the model with trouser/skirt size was additionally adjusted for BMI; the model with height was additionally adjusted for body weight.</p>§<p>P value for test that HR for two tumor subtypes are equal (based on model 3).</p