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Combination of exercise, omega-3 fatty acids and vitamin D reduces cancer risk in the elderly

13th May 2022

A randomised trial has found that a combination of exercise, omega-3 fatty acids and vitamin D significantly reduces cancer risk in patients over 70

Cancer is the second leading cause of death globally and in 2018, it accounted for approximately 9.6 million deaths. Although cancer can strike at any age, many types of cancer become more prevalent with increasing age. However, recent research has found that for most adults, cancer does not have to be an inevitable consequence of growing older. In fact, adoption of healthy lifestyle measures based on a combination of exercise, diet, smoking status, alcohol consumption, and anthropometry, in other words, simple behavioural modifications, have been shown to produce a sizeable reduction in the risk of some cancers. Among healthy interventions, there is evidence that physical activity is associated with a lower risk of several cancers. Equally, use of vitamin D supplements has some evidence to support its use in reducing the incidence of advanced (metastatic or fatal) cancer. Finally, an omega-3 fatty acid-rich diet, can significantly delay mouse tumour growth when compared with a monounsaturated fatty acid-rich diet. Nevertheless, whether a combination of exercise, vitamin D and omega-3 fatty acids provides a synergistic and preventative effect against cancer is less clear.

For the present study, the researchers undertook a randomised controlled trial, which sought to examine the combination of exercise, supplementation with vitamin D and omega-3 fatty acids in older adults and how this impacted on the subsequent development of cancer. Their DO-HEALTH trial examined the combined effect of simple home strength exercise (SHEP), vitamin D (2000 IU/day) and/or 1g/day of marine omega-3 fatty acids, in healthy adults 70 years of age and older. For the primary outcome, the team considered the time to the development of a verified invasive cancer.

Combination of exercise, omega-3 fatty acids, vitamin D and cancer development

A total of 2157 individuals with a mean age of 74.9 years (61.7% female) were included in the study and followed for a median of 2.99 years. During this period of time there were 81 invasive cancers diagnosed and verified.

For the three separate interventions, the adjusted hazard ratios (compared to controls) were 0.76 (95% CI 0.49 – 1.18) for vitamin D, 0.70 (95% CI 0.44 – 1.09) for omega-3 fatty acids and 0.74 (95% CI 0.48 – 1.15) for SHEP). In other words, while there were beneficial effects from the individual interventions, the effects were not statistically significant, but when two of the interventions were combined, the effect did become statistically significant. For instance, the combination of SHEP and omega-3 resulted in an adjusted hazard ratio of 0.52 (95% CI 0.28 – 0.97, p = 0.039). However, the greatest benefit was derived from the combination of exercise, vitamin D and omega-3 fatty acids, with an adjusted hazard ratio of 0.39 (95% CI 0.18 – 0.85, p = 0.017).

The authors calculated that the number needed to treat to prevent one incident case of cancer after three years with the three treatments combined was 35.

They concluded that future studies should focus on the benefit of combining interventions as a means of cancer prevention.

Citation
Bischoff-Ferrari HA et al. Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial Am J Clin Nutr 2022

Higher dairy consumption associated with increased risk of cancer in Chinese adults

12th May 2022

A large prospective study has found that a higher dairy consumption among Chinese adults is associated with an increased risk of cancer

A higher level of dairy consumption in Chinese adults has been found to be linked to an increased overall risk of developing cancer and in particular, liver and female breast cancers. This was the key finding of a prospective study by researchers from the UK and China.

Across the globe in 2020, it has been estimated that cancer was responsible for an estimated 19.3 million new cases and almost 10.0 million cancer deaths. Several dietary factors are linked with a reduced risk of developing cancer, including for example, a higher intake of fruit and vegetables, which is associated with a 17% lower cancer mortality. Another food linked with cancer is dairy products and a higher dairy consumption lowers the risk of developing colorectal cancer. However, intake of egg, fish and dairy consumption has remained at a low level among Chinese people with other work finding that dairy consumption was seriously inadequate in Chinese elderly and appears to be reducing. As a result, for the present study, researchers were interested in determining if, despite low levels of intake among the Chinese (compared to Westernised countries), dairy intake was associated with the incidence of cancer.

Turning to data held within the China Kadoorie Biobank, which represents a population-based prospective analysis with over 0.5 million adults across China, the researchers obtained information on the frequency of dairy consumption and which was categorised as daily, 4 – 6 day/week, 1 – 3 days/week, monthly or never/ready and which served as a baseline. The information on dairy intake was re-collected at two follow-up surveys and used to estimate mean intake of dairy foods. Cox regression analysis was used to link incident cancers with dairy consumption and adjusted for several covariates including a family history of cancer, alcohol intake and levels of smoking.

Dairy consumption and incident cancer

Among a population of 510,146 individuals with a mean age of 52 years (59% women), 20.4% reported intake of dairy foods at least once a week (subsequently referred to as ‘regular dairy consumers’) and which was largely for milk. Participants were followed for a mean of 10.8 years, during which time there were 29,277 incident cancer cases recorded. In the fully adjusted models, each 50g/day increase in dairy consumption was associated with a 7% increased risk of total cancer (hazard ratio, HR = 1.07, 95% CI 1.04 – 1.11) when compared to those who never consumed dairy foods. Furthermore, among regular dairy consumers, there was a significant increased risk of liver cancer (HR = 1.12, 95% CI 1.02 – 1.22) and for female breast cancer (HR = 1.17, 95% CI 1.07 – 1.29). There was no significant association for any other form of cancer including colorectal cancer.

The authors concluded that higher dairy consumption was associated with a greater risk of cancer among Chinese individuals even though levels of dairy intake are low compared to Westernised countries.

Citation
Kakkoura MG et al. Dairy consumption and risks of total and site-specific cancers in Chinese adults: an 11-year prospective study of 0.5 million people. BMC Med 2022

Cohort study finds artificial sweeteners associated with slight increased risk of cancer

30th March 2022

Consumption of artificial sweeteners in foods and beverages has been found to be associated with a slight increased risk of cancer

The consumption of foods and beverages which contain artificial sweeteners has been found to be associated with a slight increased risk of cancer according to the results of a large, French cohort study by researchers from the Sorbonne Paris Nord University, University of Paris, France.

The World Health Organization recommends that both adults and children should reduce their intake of free sugars to less than 10% of total energy intake. Consequently, manufacturers developed alternatives to sugar and artificial sweeteners were developed, one of which is aspartame, that has been used since 1981 and is present in more than 6,000 products. Although aspartame contains the same number of calories as sugar, it is around 200 times sweeter than sugar. The potential carcinogenicity of artificial sweeteners like aspartame has always been controversial and one review in 2014 suggested that the studies performed in the 1970s did not provide adequate scientific support for the safety of aspartame and that more recent life-span carcinogenicity data undertaken with rodents provide consistent evidence of aspartame’s carcinogenic potential. Moreover, a 2021 review of aspartame and cancer concluded that new findings confirm that aspartame is a chemical carcinogen in rodents. Nevertheless, it has been unclear from studies in humans whether artificial sweeteners are associated with an increased risk of cancer. For example, one 2012 prospective study that evaluated whether the consumption of aspartame- and sugar-containing soda is associated with risk of haematopoietic cancers, concluded that the apparent cancer risk in individuals who consume regular soda do not permit the ruling out of chance as an explanation. In contrast, a second study concluded that higher levels of aspartame intake were not associated with the risk of overall hematopoietic cancer.

With some uncertainty over the association between cancer and intake of artificial sweeteners, for the present study, the French team prospectively followed participants in the NutriNet-Sante study. This prospective trial was designed to determine, among adults, any associations between nutrition and health. Nutritional intake information is collected at baseline and every year on various factors such as health status, physical activity, smoking status and diet using 24-hour dietary recall questionnaires through which the intake of artificial sweeteners can be assessed.

Artificial sweeteners and cancer risk

A total of 102,865 participants with a baseline mean age of 42.2 years (78.5% female) were followed for a median of 7.8 years and consumption of artificial sweeteners was recorded for 36.9% of participants.

A total of 3,358 incident cancers developed during the follow-up period. Compared those who did not consume artificial sweeteners, among high consumers, there was an increased risk of cancer development (hazard ratio, HR = 1.13, 95% CI 1.03 – 1.25, p-trend = 0.002). Two sweeteners in particular, aspartame (HR = 1.15, p = 0.002) and acesulfame-K (HR = 1.13, p = 0.007) were associated with higher cancer risks. In addition, aspartame was associated with an increased risk of breast cancer (HR = 1.22, 95% CI 1.01 – 1.48, p = 0.036).

Based on these findings, the authors concluded that while the study could not establish causal links, their findings did not support the use of artificial sweeteners as a safe alternative to sugar in food and beverages.

Citation
Debras C et al. Artificial sweeteners and cancer risk: Results from the NutriNet-Santé population-based cohort study PLoS Med 2022

Prospective analysis shows regular meat eaters at higher risk of several types of cancer

21st March 2022

A UK study has found that meat eaters have an increased risk of developing cancer compared with either low meat eaters, pescatarians or vegetarians

Individuals who are regular meat eaters have been found to be at a higher risk of all and some specific cancers compared to those who are either low meat eaters, pescatarians or vegetarians. This was the finding of a study of the UK Biobank database by researchers from the Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

Cancer has been declared by the World Health Organization (WHO) as a leading cause of death worldwide accounting for nearly one in six of all deaths (10 million in 2020). Moreover, according to WHO, breast, lung, colorectal and prostate cancers are the most common forms of the disease. Understanding the causal relationship between dietary patterns or even particular dietary components and cancer aetiology and prevention is a challenge. For example, undertaking randomised controlled intervention trials to examine the association between diet and cancer outcomes are not feasible, for a number of reasons including cost, the difficulty of ensuring compliance among control and intervention groups as well as the long time-frame and exposure necessary to affect the carcinogenesis process. Although it has been shown that the risk of some cancers is lower in fish eaters and vegetarians than in meat eaters, it is not universally true with other work showing no statistically significant associations with dietary pattern and risk of premenopausal breast cancer.

For the present analysis, the Oxford team examined the relationship between those who ate meat at least 5 times a week, low meat consumers (< 5 times/week), pescatarians and vegetarians and the risk of all cancers and in particular, colorectal, postmenopausal breast and prostate cancers. They used data held in the UK Biobank and excluded individuals with a cancer diagnosis at recruitment. Participants completed an online questionnaire at recruitment into the database which asked about consumption and frequency of meat intake. The team also assessed whether specific hormones such as insulin-like growth factor-1 and testosterone as well as body mass index, might have potential mediator effects on the association between dietary patterns and cancer risk. The risks for the development of all and any of the specific cancers, were assessed using meat eaters as the reference group.

Meat eaters and cancer risk

A total of 247,571 individuals with a mean age of 56 years (46.4% female) were classed as meat eaters, 205,385 as low-meat eaters, 10,696 as pescatarians and 8,685 as vegetarians. After an average follow-up of 11.4 years, 54,861 incidence cases of cancer occurred; 5882 colorectal, 7537 women with postmenopausal breast cancer, 9501 men with prostate cancer.

After adjustment for several factors such as smoking status, physical activity etc, a vegetarian diet was associated with a 14% lower risk of all cancers compared to the reference group. (hazard ratio, HR = 0.86, 95% CI 0.80 – 0.93). This risk was also significantly reduced for breast cancer (HR = 0.82) and prostate cancer (HR = 0.69).

For pescatarians, there was also a lower risk of all cancers (HR = 0.90) compared to the reference meat group and for prostate cancer (HR = 0.80). For those categorised as low-meat eaters, the risks were only significantly lower for colorectal cancer (HR = 0.91).

After adjustment for possible mediators, only body mass index was found to be relevant and the risk of all cancers was slightly attenuated for vegetarians (HR = 0.88) and pescatarians (HR = 0.92) but remained significant. Furthermore, the reduced cancer risk remained significant among pescatarians and vegetarians but only for prostate cancer.

The authors concluded that being a pescatarian or vegetarian was associated with a lower risk of all cancers and that this might be attributable to differences in dietary factors in comparison to those who regularly eat meat. However, they added that it was unclear if these associations are causal or due to residual confounding, i.e., due to other, but unmeasured factors.

Citation
Watling CZ et al. Risk of cancer in regular and low meat-eaters, fish-eaters, and vegetarians: a prospective analysis of UK Biobank participants BMC Med 2022

Meta-analysis shows angiotensin receptor blocker use linked to increased risk of cancer

18th March 2022

Using an angiotensin receptor blocker (ARB) drug is associated with an increased risk of cancer, especially lung cancer, according to a meta-regression analysis of randomised trials by a cardiologist from the Department of Cardiology, Acibadem University Medical School, Istanbul, Turkey.

The angiotensin receptor blockers have been used clinically since 1995 and represent an effective class of antihypertensive agents with an excellent tolerability profile. Nevertheless, in 2018 the FDA in the US and the EMA in Europe, alerted health care professionals and patients of a voluntary recall of several drug products containing the active ingredient valsartan. This was due to the presence of an impurity, N-nitrosodimethylamine, which has been classified as a probable human carcinogen based on animal tests. After an initial evaluation, the EMA estimated that there could be one extra case of cancer for every 5000 patients taking the affected medicines at the highest valsartan dose (320 mg) every day for 7 years. Furthermore, the EMA has stated that there is a very low risk that nitrosamine impurities at the levels found in medicines could cause cancer in humans. However, a meta-analysis published in 2010, concluded that the use of an angiotensin receptor blocker is associated with a modestly increased risk of a new cancer diagnosis, though the authors also stated that it was not possible to draw conclusions about the exact risk of cancer associated with each particular drug.

For the present analysis, the author set out to re-examine the relationship between ARB use and the development of cancer, through an examination of information derived from randomised, controlled trials in which the drug class had been used. The study looked at cumulative exposure, i.e., the intensity and duration of exposure to the drug and specifically, the relationship with the development of lung cancer, which was found to be increased in the earlier meta-analysis.

Angiotensin receptor blocker use and cancer

A total of 15 randomised trials were included in the analysis with 74,021 patients given an ARB which included telmisartan (38.9%) and valsartan (33%).

In trials where the duration of use (reflecting cumulative exposure), exceeded 3 years, there was a statistically significant excess of new cancers in those assigned to an ARB (relative risk, RR = 1.12, 95% CI 1.02 – 1.24, p = 0.006). In contrast, this increased risk was absent trials where the drug was used for < 3 years. In relation to lung cancer, there was also an increased risk (RR = 1.21, 95% CI 1.02 – 1.44, p = 0.03) when the drugs were used for > 3 years but again, no increased risk when used for < 3 years.

Interestingly, there was also a higher cancer risk when an ARB was used alongside an angiotensin converting enzyme inhibitor for longer than 3 years (RR = 1.11, 95% CI 1.0 – 1.23, p = 0.05) and which, as before, was absent when used for a shorter period of time.

The author concluded that the risk of cancer and in particular lung cancer, increases with greater cumulative exposure to an angiotensin receptor blocker drug, adding that the widespread use of these drugs has profound implications for patients.

Citation
Sipahi I. Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials PloS One 2022

Spironolactone use not associated with increased risk of cancer

15th February 2022

Spironolactone use is not associated with an increased risk of any type of cancer but may actually reduce the risk of prostate cancer

Use of spironolactone does not appear to be linked with a higher incidence of any form of cancer and may even be protective against prostate cancer. This was the conclusion from a systematic review and meta-analysis by researchers from the University of Miami Miller School of Medicine, Florida, US.

Spironolactone is a potassium-sparing diuretic with a number of licensed indications including oedema, ascites, nephrotic syndrome and resistant hypertension. In addition, the drug is often prescribed ‘off-license’ for the treatment of acne in women, female pattern hair loss and hirsutism. In fact, a recent and retrospective analysis of 403 women concluded that spironolactone improves clinical outcomes and is well tolerated for many adult women with acne using it for an extended duration.

Despite being used for a wide range of indications, the US Food and Drug Administration carries a warning that spironolactone has been shown to be a tumourigen in chronic toxicity studies in rats and that it should be used only for licensed indications, adding that unnecessary use of this drug should be avoided. Similarly, the summary of product characteristics (SPC) for the drug states that spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. While the SPC adds that the ‘significance of these findings with respect to clinical use is not certain‘, it does advise that the ‘long-term use of spironolactone in young patients requires careful consideration of the benefits and the potential hazard involved‘.

With some uncertainty over possible associations between the use of spironolactone and cancer, the US team undertook a systematic review and meta-analysis to synthesize the available evidence on the topic. They searched for studies that reported on the risk of cancer development in adults in both sexes who were exposed to spironolactone, irrespective of its primary use. The main outcome of interest was cancer occurrence.

Spironolactone use and incidence of cancer

A total of 7 observational studies including a total population of 4,528,332 individuals with a mean age of 62.6 to 72 years and between 17.2 and 54.4% women, were included in the analysis. These studies examined the incidence of breast, ovarian, bladder, kidney, gastric and oesophageal cancers. Furthermore, all of the studies were deemed to be at a low risk of bias.

There was a non-significant association between spironolactone use and breast cancer (risk ratio, RR = 1.04, 95% CI 0.86 – 1.22), bladder cancer (RR = 0.89, 95% CI 0.71 – 1.07) and kidney cancer (RR = 0.96, 95% CI 0.85 – 1.07). In addition, similar non-significant associations were calculated for the other cancer examined. However and contrast, in relation to prostate cancer and based on a total of 4 studies, there was a significantly reduced risk in those using spironolactone (RR = 0.79, 95% CI 0.68 – 0.90), although the certainty of evidence for this estimate was considered to be low.

Commenting on these findings, the authors considered their results to be reassuring and that treatment with spironolactone appeared unlikely to be associated with a meaningful increased risk of cancer when prescribed at typical clinical doses. Nevertheless, they concluded that the certainty of evidence was low and that future studies are needed to examine this relationship in more detail.

Citation
Bommareddy K et al. Association of Spironolactone Use With Risk of Cancer: A Systematic Review and Meta-analysis JAMA Dermatol 2022

Heart failure patients at increased risk of cancer and cancer-related mortality

28th January 2022

Heart failure (HF) patients have a higher risk of cancer and cancer-related mortality compared to matched-controls according to research by a team from the Cardiovascular Disease Unit, Genoa, Italy.

There is emerging evidence that the incidence of cancer is higher among those with cardiovascular disease and heart failure and this latter group frequently die from cancer. In fact, research has uncovered the increased risk of cancer among HF patients, persists beyond the first year after their HF diagnosis and that their prognosis is worse compared to non-heart failure patients with cancer. Despite this purported association, other work among 28,341 Physicians’ Health Study participants, has shown that HF is not associated with an increased risk of cancer among male physicians. It has also been suggested that while heart failure patients did have a slightly increased risk of various cancer subtypes, these increased risks were largely drive by comorbidities.

Given this potential uncertainty over the HF-cancer association, the Italian team attempted to provide greater clarity by undertaking a retrospective cohort study of healthcare records in Puglia, a region of southern Italy. They included patients aged 50 years and older, diagnosed with heart failure but without a history of cancer in the three years prior to their inclusion in the analysis. The team included a control group without HF who were matched on age and sex. The primary outcomes of the study were cancer incidence as well as mortality. In an effort to examine whether HF severity influenced the study outcomes, the researchers also explored patients use of doses in excess of 80 mg/day of furosemide and equivalents for longer than 30 days in the year before the index date.

Heart failure patients and cancer

A total of 104,020 HF patients with a mean age of 76 years were matched to an equal number of control patients. The researchers identified a total of 12,036 new diagnoses of cancer in HF patients and 7,045 in controls after a median follow-up period of 5 years. This gave an incidence cancer rate of 21.36 per 1000 person-years among those with HF and 12.42 in the control arm (Hazard ratio, HR = 1.76, 95% CI 1.71 – 1.81).

The cancer mortality rate was also higher among HF patients compared with controls (HR = 4.11, 95% CI 3.86 – 4.38). This difference was also seen among HF patients aged less than 70 years (HR = 1.66, 95% CI 1.58 – 1.75) and in those over 80 years of age (HR = 2.07).

High dose loop diuretics also showed an important effect with a higher cancer incidence (HR = 1.11, 95% CI 1.03 – 1.21) and cancer-related mortality (HR = 1.35).

The authors concluded that HF patients had both a higher incidence of cancer and cancer mortality than matched controls and speculated that given that the risk was elevated among those with high dose loop diuretics, it was possible that the overall cancer risks were potentially higher in those with decompensated, i.e., more severe HF.

Citation

Bertero E et al. Cancer Incidence and Mortality According to Pre-Existing Heart Failure in a Community-Based Cohort JACC CardioOncology 2022

Increased cancer risk among those with heart failure

6th July 2021

A retrospective cohort study of heart failure patients has revealed a significantly higher incidence of all types of cancer.

Patients with heart failure (HF) have both a functional impairment and a poor health-related quality of life. However, it is not always the HF which has the biggest impact on quality of life. For example, one study of over 700 HF patients, found that less than half (48%) reported that their quality of life was limited by heart failure, with nearly a fifth (18%) citing other medical problems as the dominant factor. Similarly, a Swedish study of 10,500 patients observed that depression and anxiety had the strongest associations with functional limitations and patient-rated health. In fact, Heart failure has a poor prognosis and a UK study estimated 10-years survival to be only 26.2%.

Interestingly, other data point to a potential relationship between the presence of heart failure and cancer. In 2020 it was observed that among patients with ejection fractions less than 45%, cancer accounted for 6 to 14% of all deaths and was independent of treatment. This led the authors to conclude that cancer is a major, yet overlooked cause of non-cardiovascular death in heart failure. Given this potentially overlooked cause of death, a team from the Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Dusseldorf, Germany, undertook a retrospective analysis of the incidence of cancer in patients after a diagnosis of HF. The team turned to the German Disease Analyser database, which contains information on prescriptions, diagnoses together with basic demographic and medical data in an anonymous format that comes directly from a sample of general practitioners and specialists throughout the country. For their analysis, included patients were over 18 years of age with an initial diagnosis of HF and individuals already diagnosed with cancer were excluded from the dataset. Patients with HF were propensity-matched by sex, age, yearly consultation frequency together with the presence of two co-morbidities; obesity and diabetes and followed for a period of 10 years.

Findings
A total of 100,124 patients with a mean age of 72.6 years (54% female) were matched with a non-heart failure cohort. Diabetes and obesity were present in 37.4% and 15.9% respectively in the heart failure group and patients visited their general practitioner an average of six times per year. The prevalence of cancer in HF patients was 25.7% compared with 16.2% in the control cohort (p < 0.001). This pattern was similar for both sexes, with 23.2% vs 13.8% (males) and 28.6% vs 18.8% (females). In regression analysis, heart failure was significantly associated with the incidence of cancer (hazard ratio (HR) = 1.76, 95% CI 1.71–1.81, p < 0.001), with a similar and significant effect seen in the two sexes, i.e., males (HR = 1.69) and females (HR = 1.69). When examining the relationship between cancer location and HF, the strongest association was for the lip, oral cavity and pharynx (HR = 2.10, 95% CI 1.66–2.17, p < 0.001), followed by respiratory organs (HR = 1.91) and female genital cancer (HR = 1.86).

While the authors suggested that these associations were not indicative or a direct causal relationship, they noted evidence from other work indicating how circulating levels of cardiovascular peptides such as N-terminal pro BNP are elevated in heart failure patients with cancer. They concluded by calling for future studies to clarify this relationship.

Citation
Roderburg C et al. Heart failure is associated with an increased incidence of cancer diagnosis. ESC Heart Fail 2021