There is now convincing evidence that a substantial proportion of cancers are attributable to obesity. Indeed, the World Cancer Research Fund (WCRF)¹ estimates that between 15-45% of cancers are directly related to obesity. However, while the relationship between obesity and cancer is increasingly well recognised, the impact of weight loss on cancer risk is less well defined. 

Weight loss trials in cancer prevention

Despite a wealth of literature describing the relationship between obesity and several cancers, there is a considerably smaller amount of studies describing the relationship between intentional weight loss and cancer risk. This is partly due to the fact that intentional weight loss, and maintenance of long-term normal body weight, is relatively uncommon. There are very few reports of successful non-surgical weight loss intervention studies and cancer outcomes. Indirect evidence from cohort studies shows that intentional weight loss is associated with subsequent reduced cancer risk and improved cancer outcome, but prospective evidence is lacking, and there are major challenges for intervention effect.² 

There are several reasons why a prevention trial with cancer as an endpoint is not feasible. Aside from resource issues there are serious challenges of sustaining preventive interventions over the long time periods necessary for primary prevention of cancer. In addition, non-compliance would reduce the power of the study, and participants in weight loss trials frequently regain lost weight once the study intervention stops, thus negating the long-term effects of cancer prevention. Finally, and perhaps most importantly, recruiting overweight/obese participants into a cancer prevention trial would raise substantial ethical concerns regarding stopping rules based on prevention of diabetes and other short-term health benefits likely to be observed long before cancer risk reduction is detected.³

Thus, the scientific community relies on observational studies of non-surgical (diet and exercise) and surgical-induced weight loss (bariatric surgery) to examine effect on cancer risk. To date, all indicate an almost immediate reduction in cancer incidence with intentional weight loss, especially in females. 

Intentional non-surgical weight loss and cancer 

Birks et al,⁴ in a systematic review of the impact of weight loss on cancer incidence and mortality, identified 34 publications, 33 of which were observational studies. Sixteen studies found a significant reduction in cancer risk in those who experienced weight loss – an association stronger for women than men. The majority (28 out of 34) did not state the intentionality of weight loss and only three (two in women; one in men) investigated whether the incidence of, or mortality from, cancer was decreased after intentional (non-surgical) weight loss. 

Parker and Folsom,⁵ in a prospective cohort study (1993-2000) of 21,707 postmenopausal women, found significantly decreased incidence of all cancers in women who had intentionally lost > 9kg since aged 18 years (14% risk reduction for any obesity related cancers, 19% for breast cancer, 9% for colon cancer and 4% for endometrial cancer). Furthermore, women who intentionally lost > 9kg and were not currently overweight, were observed to have an incidence of cancer similar to non-overweight women. 

Williamson et al,⁶ in a prospective study of 43,457 overweight women aged 40-64 years, followed for 12 years, showed that those who lost > 9kg had a hazard ratio (HR) of mortality from cancer of 0.84 (95% CI: 0.62-1.15). In 1999, the same author⁷ reported a prospective study of 49,337 men (aged 40-64 years, followed for 12 years) found no significant difference in the risk of cancer mortality with intentional or non-intentional weight loss. 

Surgical weight loss and cancer

Studies have shown that although many obese people can lose weight through dietary manipulation, only 5-10% are able to sustain significant weight reduction.⁸ Bariatric surgical procedures have thus emerged to provide significant and sustained weight loss and, to date, this surgery has offered a successful treatment for diabetes and cardiovascular disease, suggesting that cancer prevention may also be a positive consequence. 

Adams et al⁹ followed 6,596 US patients who had gastric bypass between 1984-2002, and 9,442 severely obese controls for 12.5 years, and reported that total cancer incidence and cancer mortality was significantly lower in the surgical group (HR= 0.76; 95% CI: 0.65-0.89; p = 0.0006; HR = 0.54; 95% CI: 0.37-0.78; p = 0.001, respectively). Although the apparent protective effect of surgery was limited to cancers known to be obesity related, the inverse association for mortality was seen for all cancers. 

Christou et al¹⁰ performed an observational cohort study of 1,035 bariatric surgery patients (1986-2002) and 5,746 age-matched morbidly obese controls for five years. Surgery patients had significantly fewer cancer diagnoses (n = 21, 2.0%) compared with controls (n = 487, 8.45%; RR 0.22, 95% CI: 0.143-0.347; p = 0.001). Put simply, there was a 78% lower risk of cancer in the bariatric surgery group over just five years of follow-up. 

Sjostrom and colleagues¹¹ reported the long-term effects of bariatric surgery on cancer incidence in 2,010 bariatric surgery patients and 2,037 obese controls, who received conventional treatment over 10 years. They reported that bariatric surgery is associated with a reduced risk of cancer – an effect favouring women (RR 0.58, 95% CI: 0.44-0.77) rather than men (RR 0.97,
95% CI: 0.62-1.52). 

These studies indicate that the effects of major weight loss following bariatric surgery can be quite large and the latency between weight loss and that reduction may be quite short.¹²

Plausible mechanisms of weight loss and cancer prevention

Several cancer-related biomarkers can be assessed with intentional weight loss. 

Inflammatory cytokines

Obesity causes an overall pro-inflammatory state, which is recognised by elevated C-reactive protein (CRP) levels, commonly present in centrally-obese people.¹³ The amount of body fat predicts CRP levels in adults¹⁴ and a significant relationship has been reported between plasma CRP, measures of adiposity, insulin resistance and cancer.^15,16

In addition, inflammation decreases apoptosis, increases cancer invasiveness and decreases prognosis.¹⁷ Metabolically active fat cells secrete a number of adipokines, as well as tumour necrosis factor-alpha (TNF-α), Interleukin (IL)-1, IL-6, IL-8, IL-10, monocyte chemo-attractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1).^18,19

By upregulating vascular endothelial growth factor (VEGF) expression, IL-6 promotes angiogenesis. TNF-α inhibits PPAR-γ, a powerful lipid regulator and protectant against carcinogenesis, inflammation and insulin resistance, while it activates the nuclear factor NF-ΚB, dysregulating apoptosis and promoting cell survival.²⁰

Inflammatory biomarkers such as CRP, TNF-α and IL-6 are very sensitive to weight loss. For CRP, levels are reduced at a ratio of two to threefold on a percentage scale with weight loss. TNF-α and IL-6 are on a scale of 1:1. Intentional weight loss of 10% usual body weight could be expected to produce drops in inflammatory markers of a third or more.¹²

A one-year lifestyle intervention for weight loss in obese individuals (n = 1,759) with diabetes (Look AHEAD trial) showed that a weight loss of 8.8% substantially reduced CRP by 43.6% from baseline to one year.²¹

Insulin, bio-available sex steroids and insulin-like growth factors

The obesity-cancer link may also be accounted for by alterations in endogenous hormone metabolism including insulin, bio-available sex steroids, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs). Hyperinsulinaemia, resulting from visceral fat-induced insulin resistance, reduces production of IGFBP1 and 2, allowing free insulin and IGF-1 to stimulate cell proliferation, inhibit apoptosis and enhance angiogenesis.²²

While increasing adiposity amplifies peripheral oestrogen production from adipose tissue in both men and women, insulin and IGF-1 also inhibit sex-hormone binding globulin (SHBG) synthesis. This increases the bio-availability of androgens and oestrogen, dysregulates the control of cellular differentiation, proliferation and apoptosis, favouring the growth of neoplastic cells.¹⁵

Insulin has been consistently shown to decrease with intentional weight loss. As insulin is a driver of cellular proliferation, reductions in circulating levels with weight loss could be very relevant. Even modest levels of weight loss can result in reductions in free sex hormones and increases in binding globulins.¹² SHBG levels increase in a two-to-fivefold fashion, and oestradiol reduces at a ratio of two-to-threefold on a percentage scale with weight loss by dietary restriction.²³

Weight loss leads to marked reductions in infiltrating macrophages and significant changes in gene expression of various cytokines, eg. increased IL-10, an anti-inflammatory cytokine.²⁴ Enhanced insulin sensitivity (through increased adiponectin levels) and decreased leptin have also been observed.^11,24

The fact that to date the cancer benefit of weight loss is only seen in women points to the effect of sex steroids, specifically oestrogen, which is most relevant to postmenopausal breast cancer. Another explanation is the paucity of data available studying weight loss in men. In designing future studies there are logistical issues to consider and, given the relative rarity of cancer, issues such as sample size and length of follow-up required to demonstrate benefit with sufficient power, would be large. 

Birks et al⁴ estimate that around 2,000 participants would be needed to show a risk reduction of all-cancer incidence over 10 years of follow-up with 80% power. The costs associated with such a trial, as well as ethical problems, are significant. 

Diet and cancer prevention

Results from EPIC investigations (European Prospective Investigation into Cancer) have observed the following significant associations: high intake of dietary fibre, fish, calcium and plasma vitamin D were associated with a decreased risk of colorectal cancer; while red and processed meat intake and alcohol were associated with an increased risk. High intake of fruit and vegetables in current smokers were associated with a decreased risk of lung cancer. 

An increased risk of breast cancer was associated with high saturated fat and alcohol intake. High intake of dairy protein and calcium from dairy products was associated with an increased risk of prostate cancer.  These results contribute to scientific evidence for appropriate public health strategies and prevention activities aimed at reducing the global cancer burden.²⁵

Currently, the WCRF¹ recommends that, aside from maintenance of a healthy body weight, dietary strategies for cancer prevention should be recommended, and include: 

• Limit consumption of energy-dense foods, avoid sugary drinks, avoid processed foods high in added sugar and fat, and low in fibre 
• Eat mostly foods of plant origin with at least five portions of fruit and vegetables per day
• Eat relatively unprocessed cereals (grains) and/or pulses with every meal. Limit refined starchy foods
• Limit consumption of red meat to 11oz per week. Avoid processed meats 
• Limit alcohol. If consumed at all, limit to two drinks for men and one for women per day
• Limit consumption of salty foods and foods processed with salt to 5g salt or 2g of sodium daily 
• Avoid multivitamin/mineral supplements. 

Physical activity

Physical activity, obesity and cancer are inextricably linked in the context of intentional weight loss. It is difficult to evaluate the evidence for physical activity as it so often results in weight loss, and is a crucial determinant of maintenance of weight loss. However, for certain cancers (eg. breast and colorectal cancer) there is evidence that physical activity has independent beneficial effects on risk, apart from its effects on obesity.¹

Physical activity most likely influences the development of cancer in many ways including its role in energy balance, metabolism of sex hormones, insulin regulation, and alteration of a number of inflammatory factors, which may influence cancer risk. 

There are more than 50 studies examining the association between colorectal cancer and physical activity. These have consistently found that adults, who increase their physical activity, can reduce their risk of developing colon cancer by 30-40% relative to those who are sedentary regardless of BMI, with the greatest risk reduction seen among those who are most active.^26-29

For breast cancer, most studies indicate that physically active women have a lower risk of developing breast cancer than inactive women; however, the amount of risk reduction achieved through physical activity varies widely (between 20-80%).^27,30

High levels of moderate and vigorous physical activity during adolescence may be especially protective, although a lifetime of regular, vigorous activity is thought to be of greatest benefit. However, some studies highlight that substantial postmenopausal weight gain may eliminate the benefits of regular activity.³⁰

Most studies suggest that 30-60 minutes per day of moderate-to-high-intensity physical activity is associated with a reduction in both colorectal²⁷ and breast cancer risk.²⁸ The WCRF recommendation for cancer prevention is to be physically active for at least 30 minutes per day. 

Conclusion

Weight loss should be the principal factor to be targeted for cancer risk reduction among obese individuals. This is due to the striking findings of an almost-immediate and substantial impact of weight loss on cancer risk, in a setting where physical activity is not a critical factor, and the various hormonal and inflammatory mechanisms tied directly to obesity.¹²

Scientists do not yet understand if the risk of cancer is totally reversible, if it is age, site, or gender dependent, or if later weight regain is important. Large-scale intervention trials are costly, lengthy and raise ethical issues regarding limitations of maintaining randomisation long enough to assess cancer endpoints. Among cancer survivors, whether intentional weight loss might impact on quality-of-life outcomes, and eventually recurrence risk, are currently under investigation. 

A projection of the future health and economic burden of obesity in 2030 estimated that continuation of existing trends in obesity will lead to about 500,000 additional cases of cancer in the US by 2030. 

If every adult reduced their BMI by 1%, which would be equivalent to a weight loss of roughly 1kg (or 2.2 lbs) for an adult of average weight, this would prevent the increase in the number of cancer cases and actually result in the avoidance of about 100,000 new cases of cancer.³¹

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