HOW TO PREVENT CANCERS

A new federal report out yesterday may put some wind in the sails of those who work in the field of cancer prevention.  The July 5 issue of CDC's Morbidity and Mortality Weekly Report shows that rates of screening for colorectal cancer have been climbing steadily between 2002 and 2010, with a related drop in rates of new cases and mortality from the disease (report).  Over that eight year period, the percentage of people between ages 50 - 75 who got recommended screening tests rose from 52 percent to 65 percent.  Rates of new cases (incidence rate) and death from colorectal cancer over that period declined by three percent each year (see figure).

Unlike screening for some other cancers, screening for colon cancer can both find the disease early when its most treatable and prevent the disease by finding and removing pre-cancerous growths.  For more on screening and lowering the risk of colorectal cancer, visit Your Disease Risk (www.yourdiseaserisk.wustl.edu).

The figure above shows declines in colorectal cancer (CRC) incidence from 59.5 per 100,000 population in 1975 to 44.7 in 2007 and in the CRC death rate from 28.6 per 100,000 population in 1976 to 16.7 in 2007 and the corresponding Healthy People 2020 targets of 38.6 per 100,000 and 14.5, respectively. Source CDC MMWR, July 5, 2011 (Fig 3)

The documented benefits of aspirin go back, literally, thousands of year.  As early as the fifth century B.C., Hippocrates noted that a bitter willow bark extract - which contained chemicals very similar to today's aspirin - was effective at relieving pain.  Since then, aspirin has become the most commonly used medicine in the world, and its benefits have been shown to reach well beyond pain relief to include the prevention of heart attack, stroke, and now cancer.

Studies have shown for a number of years that taking a daily aspirin could lower the risk of developing and dying of colon cancer, with the latest large analysis by Rothwell and colleagues finding a 25 percent drop in the risk of developing the disease, and a 35 percent risk of dying from it, with as little as 75mg of aspirin a day (previous post; study).

Now, a new analysis by Rothwell and colleagues - which combined data on over 25,000 participants in eight randomized controlled trials - shows big reductions in the risk of cancer deaths with aspirin use, not only for colon cancer, but for a broad range of individual cancers, and for cancer overall (study).   Daily aspirin use for five or more years lowered the risk of cancer death overall by 34 percent compared to placebo.

Strikingly, the benefits persisted, and even expanded, long after the end of the trials and the aspirin treatment.  After up to 20 years of follow-up, overall cancer deaths were 22 percent lower in the aspirin group compared to placebo.  The risk of esophageal cancer death was 58 percent lower.  The risk of colorectal cancer death was 40 percent lower, and lung cancer deaths nearly 30 percent lower.

In general, the longer the daily aspirin use, the more robust the cancer benefits.

The findings of this latest study, combined with all the previous ones, could possibly rebalance the discussion of the risks and benefits of aspirin use.  When looking at aspirin's benefits in the past, the focus was largely on the heart benefits, and while these benefits could be substantial, they still needed to be balanced with the risks that go along with aspirin use, most commonly an increased risk of bleeding in the GI tract and possibly the brain.

With long term demonstrated benefits in lowering cancer deaths, which persist even after daily aspirin use of 5 - 10 years, the balance may be tipping toward the benefits of aspirin outweighing the risks for a broader swath of the population than is currently recommended (which is largely limited to those at high risk of heart attack).

At the cost of just pennies a day, it may just be what the doctor ordered.

Related CNiC Posts
Aspirin
Data Snapshot

That obesity had deleterious health consequences isn’t news, especially around here. Yet, we still find the results of a study out of Australia, published in Cancer Epidemiology Biomarkers and Prevention this week on weight gain and colon cancer risk compelling. Most adults experience weight gain over the course of their lives and this weight gain, even if your BMI remains within the “normal” range, can increase your risk of colon cancer. Bassett and colleagues found that each 5 kg (11 lbs) of weight gain in men significantly increased risk of colon cancer. Reports on the effects of weight gain for women are less consistent, and this report found no association.

Why might gender matter? Men and women tend to gain weight differently in adulthood. Men, in particular, tend to see a shift in body fat from the periphery to the trunk - that is, they put more weight around the middle - something called abdominal adiposity, or abdominal obesity if it gets bad enough. This central weight gain may be a stronger predictor than overall weight of cancer risk (along with other health outcomes). Abdominal obesity is associated with hyperinsulinemia, which likely plays a role in colon cancer risk. Men tend to accumulate more visceral fat.

Does this mean women are off the hook? Sadly, no – as regular CNiC readers have surely realized by now – “cancer” isn’t one disease with uniform risks. And weight gain increases risk of breast cancer in women as we’ve discussed before. So the findings on colon cancer are evidence that EVERYONE benefits from avoiding weight gain.

And since avoiding weight gain is easier than losing weight once you’ve gained it, watching weight gain is a good strategy for all of us.

New evidence has emerged that adds further insight into the risks and benefits of aspirin for prevention of colorectal cancer. Aspirin has been extensively studied in observational epidemiologic settings that address duration of use, dose, and magnitude of risk reduction. The observational evidence is consistent with evidence from randomized primary prevention trials, which have shown that use of at least 300 mg of aspirin per day for at least 5 years is effective in preventing colon cancer, reducing risk by about 25% (Flossmann and Rothwell 2007). A latency of about 10 years is observed. Like all chemoprevention strategies, risks and benefits must be balanced (Glasziou and Irwig 1995). To date, the risk-benefit considerations of cardiovascular disease, bleeding complications, stomach pain, and heartburn have precluded recommendations for aspirin use as a widespread prevention strategy (Gralow, Ozols et al. 2008; Cuzick, Otto et al. 2009).

In the Lancet, a new study combining data from four randomized trials of aspirin versus control in both primary and secondary prevention of vascular events evaluated risk of colorectal cancer over 20 years (study). A fifth trial compared doses of aspirin. After combining the data on individuals in these five trials the investigators observed that aspirin use reduced the 20-year risk of colon cancer but not rectal cancer. Risk of cancer was reduced by 25% and colon cancer mortality was reduced by 35%. Similar to previous reports, benefit of aspirin use increased with duration of use indicating that aspirin use operates early in the pathway to colon cancer and leading to long-term therapy as the necessary approach for prevention of colon cancer. This study, in contrast with previous evidence suggests that the benefit for colon cancer prevention is obtained with as little as 75 mg per day.

Importantly, this study separately evaluated colon cancer rectal cancers. We have previously shown that the risk factors for these two cancers sites vary substantially (Wei, Giovannucci et al. 2004). The evidence for aspirin adds further support for strategies to be specific to risk, particularly among those who are at increased risk, as is the case for family history.

New research results out today suggest that 1 in 13 colon cancers may be missed on colonoscopy. There are a few reasons this may happen - some you can control and some you can't. Completing the colonoscopy prep is one you can control - having a clean, prepped colon reduces the changes that a tumor is missed during the exam. But the results also highlight that colon cancer screening is just one part of colon cancer prevention.

A study from Wei and colleagues showed that even among those who are compliant with colon cancer screening recommendations, other lifestyle factors (maitaining a healthy body weight, limiting red and processed meat intake, regular physical activity, taking a folate supplement) contributed to a significant risk reduction.


This means even if you get the "all clear" after a colonoscopy, you shouldn't sit back and think you've done all you can. You've taken a great first step, so use that momentum to make other healthy choices too.

Soy foods have been studied a great deal for their potential protection against a range of chronic conditions, including breast and prostate cancer, heart disease, osteoporosis, and menopausal symptoms.

It’s not known exactly how a diet rich in soy results in such benefits. It could be due to some of the individual components of soy, such as isoflavones which have some qualities similar to naturally occurring hormones. Or it could be the collective make up of soy, all its components together, which have the beneficial effects.

Because most pre-menopausal symptoms are linked to dropping levels of the hormone estrogen, it’s been considered that soy, and the insoflavones it contains, could help mimic natural estrogen and therefore quell things like hot flashes. Current evidence, though, suggests that soy intake actually has little impact on hormone levels. Still, research also suggest that a diet rich in soy may reduce menopausal symptoms (1).

The potential cardiovascular benefits from higher soy intake may be due to soy’s being a healthier replacement for some higher fat choices. Soy has only about 20 percent of its calories from fat, which is predominantly “healthy” polyunsaturated fat (2), whereas chicken can have nearly half of its calories from fat, and beef can have as much as 80 percent of its calories from fat, much of it in the form of “unhealthy” saturated fat. Studies looking at the relationship between soy intake and heart disease suggest that a diet rich in soy can improve blood pressure, blood cholesterol, and insulin levels (3).

Much of the interest in the links between soy intake and cancer risk is motivated by the historically low breast and prostate cancer risk among Asians, whose diets are traditionally high in soy. Detailed reviews by Wu and colleagues shows that at high intakes typical of Asian diets, soy is significantly related to a reduced risk for breast cancer, and the effect may be strongest for high intake in childhood and adolescence. A meta-analysis found that diets with high amounts of soy (20 mg per day of isoflavone) in Asian women was associated with a decreased risk for breast cancer, compared to Asian women consuming lower amounts (5 mg daily) (4). What this means for most American women is unclear. Studies in the US have typically not found a link between soy intake and breast cancer, but this could largely be due to widely different diets between the two regions. The highest intake in the US is typically 80 percent below the lowest intake in Asia (0.3 mg isoflavones/day in the US versus 25-50 mg isoflavones/day in Asia, which is equivalent to 1 g of soy food versus 80-160 g of soy food). Should diets shift to resemble those of Asia, it’s more than likely that studies would begin to reveal breast cancer benefits with soy as well.

Looking at the data on soy and prostate cancer, a number of studies show benefits from a higher intake of soy and soy-products. Soy milk intake was shown to be inversely related to risk of prostate cancer among US men in the Seventh Day Adventist Cohort study (5). As soy milk consumption went up, the risk of prostate cancer went down. A similar relationship has been seen between total soy intake and the risk of prostate cancer in other cohort and case-control studies (6), even though the amount of the effect on risk varied a bit from study to study. The only potential evidence that soy might increase the risk of prostate cancer comes from research of fermented soy (Miso), which has been positively related to risk in some studies.

Overall, there is currently little evidence that a diet high in soy is bad for health, and a growing body of evidence that it could have substantial health benefits. Realizing such potential benefits though, would likely take intake levels beyond what most people in the US typically eat.


Literature cited:

1. Kurzer, M.S., Soy consumption for reduction of menopausal symptoms. Inflammopharmacology, 2008. 16(5): p. 227-9.
2. van Ee, J.H., Soy constituents: modes of action in low-density lipoprotein management. Nutr Rev, 2009. 67(4): p. 222-34.
3. Carlson, S., et al., Effects of botanical dietary supplements on cardiovascular, cognitive, and metabolic function in males and females. Gend Med, 2008. 5 Suppl A: p. S76-90.
4. Wu, A.H., et al., Epidemiology of soy exposures and breast cancer risk. Br J Cancer, 2008. 98(1): p. 9-14.
5. Jacobsen, B.K., S.F. Knutsen, and G.E. Fraser, Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control, 1998. 9(6): p. 553-557.
6. Jian, L., Soy, isoflavones, and prostate cancer. Mol Nutr Food Res, 2009. 53(2): p. 217-26.

Despite some pretty timid headlines, like “Sigmoidoscopy May Reduce Deaths From Colorectal Cancer,” the results of a UK-based randomized controlled trial seemed pretty resounding and further confirm the importance of regular colon cancer screening tests between ages 50 – 75 (USPSTF recommendations).

The studied appeared early-online this Wednesday in the Lancet (study) and tested the hypothesis that a single flexible sigmoidoscopy screening between 55 and 64 years of age could substantially reduce colorectal cancer incidence and mortality. Just over 170,000 eligible men and women were randomly placed either in the intervention group and offered screening with a flexible sigmoidoscope, or in the control group and not contacted further. Participants were followed for colorectal cancer incidence and morality.

Screening significantly reduced mortality from colorectal cancer among those in the screening group. Mortality was reduced by 33%, a significant reduction compared to the control group. The screened group also had a lower incidence of colorectal cancer compared to the control group – presumably as a result of removal of premalignant polyps detected on the initial screening test.

Regular screening is the single best way to lower the risk of colorectal cancer. Along with sigmoidoscopy, other recommended tests include colonoscopy and fecal occult blood tests. Together with their doctors, patients can choose which one of these is best suited to them.

Our related material
Your Disease Risk – Colon Cancer
You Can Prevent Colon Cancer – a Knol
Cancer Prevention – a Knol

A recent study in the British Medical Journal adds further evidence that use of oral contraceptives reduces cancer mortality (full study). In the long term study of over 46,000 women who were followed for up to 39 years, Hannaford and colleagues reported that women who used oral contraceptives (OCs)  had lower mortality from cancers of the ovary, uterine body and colon (Hannaford, Iversen et al. 2010). OC use was not related to breast cancer mortality.

Approximately half of the women who had used OCs had used them for more than 4 years, and the risk of cancer death decreased the longer women had used OCs. These data extend previous work from the Nurses’ Health Study, which showed no overall adverse effect from use of OCs (Colditz and for the NHS research group 1994).

Oral contraceptives are one of the most widely used medications. Use of oral contraceptives (OCs) for 5 years halves a woman’s risk of developing ovarian cancer (see figure) and substantially reduces the risk of endometrial cancer  (Collaborative Group on Epidemiological Studies of Ovarian, Beral et al. 2008).



The protection is long lasting and in high income countries rates of use approach 80 per cent. Adverse effects are largely limited to an increased risk of breast cancer and stroke while women are currently using OCs, a risk which seems to disappear within about ten years of stopping. These side-effects are strongly age-dependent - being more common the older a woman is. Thus use of OCs during late teens and early 20s could be expanded for greater reduction in ovarian and endometrial cancers and overall net public health benefit (Kawachi, Colditz et al. 1994).

Strong scientific evidence supports several other medications as either causing cancer  (e.g. postmenopausal hormone therapy with estrogen plus progestin) (Colditz 2007), or reducing cancer (e.g aspirin and colon cancer) (Chan, Giovannucci et al. 2005).

Postmenopausal hormones
For combination oestrogen plus progestin, the International Agency for Research on Cancer (IARC) has now classified this combination hormone therapy as carcinogenic in humans (2007), and estimates indicate that the reduction in use of hormones after the widespread publicity of the results of the Women’s Health Initiative (stopped early due to excess breast cancer) accounts for approximately a 10 per cent decline in breast cancer incidence among women 40 to 70 years of age (Colditz 2007). Thus for this combination therapy evidence shows that risk rises with duration of use and that acting as a late promoter, removal of the drug leads to a rapid decline in incidence (Colditz 2007), though among women with longer durations of use risk may not return to that of women who have never used combination therapy (Colditz and Rosner 2000).

Other less widespread drugs may also contribute to cancer risk (e.g., DES), but the population impact will be substantially smaller than the examples based on much more widespread use described above.

For some medications that reduce cancer risk, the benefits have been limited to date to those who have had the specific indications to use the medication. Broader population strategies may be developed for more widespread protection, such as could be achieved if all women took oral contraceptives as a chemopreventive for a minimum of 5-years.

Aspirin
Aspirin has been extensively studied in observational studies that address duration of use, dose, and magnitude of risk reduction. This evidence is consistent with evidence from randomized primary prevention trials showing that the use of 300 mg or more of aspirin a day for 5 years or more is effective in preventing colon cancer; reducing risk by approximately 25 per cent (Flossmann and Rothwell 2007). A latency of about 10 years is observed between onset of use of aspirin and the reduction in cancer. Like all chemoprevention strategies, risks and benefits must be balanced (Glasziou and Irwig 1995). To date, the risk-benefit considerations of cardiovascular disease, bleeding complications, stomach pain and heart burn caused by aspirin have precluded recommendations for aspirin use as a widespread prevention strategy (Gralow, Ozols et al. 2008).

Selective estrogen receptor modulators (SERMs)
Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have been shown in randomized controlled prevention trials to reduce incidence of pre-invasive and invasive breast cancer (Fisher, Costantino et al. 1998; Martino, Cauley et al. 2004). While tamoxifen increases risk of uterine cancer, this is not so for raloxifene and the risk profile for raloxifene looks considerably safer (Chen, Rosner et al. 2007).

Based on these risks and benefits of therapy, we have estimated the potential for risk reduction among women over age 50 who are postmenopausal. Our estimates indicate that if the trade-off of excess adverse events versus cases of breast cancer prevented must be less than 1, then approximately 30 per cent of the 27 million women between ages 50 and 69 in the United States have benefits exceeding risks, and would achieve a 50 percent reduction in the burden of breast cancer by taking a SERM. This is a population benefit of 42,900 fewer cases of invasive breast cancer among the more than 7 million women with sufficiently high risk to justify chemoprevention (Chen, Rosner et al. 2007).

The reduction in breast cancer risk observed in the chemoprevention randomized trials is very rapid; within 2 years of beginning SERM therapy, incidence curves have clearly separated. This is consistent with the pharmacologic action of these agents inhibiting estrogen receptors. Importantly these agents show protection against estrogen receptor (ER) positive breast cancers (risk reduction up to 76 per cent) and no protection against receptor negative cancers (Martino, Cauley et al. 2004).

While statistical models to predict and classify risk of breast cancer have been developed and validated, to date, prediction of receptor positive tumors is no more accurate than prediction of risk overall (Colditz, Rosner et al. 2004).  Refining risk stratification and developing tools to aid women in considering trade-offs of risks and benefits of chemoprevention therapy are necessary next steps to informed choices for prevention for women at elevated risk of breast cancer.

Conclusions
While all drugs have risks and benefits, some of the agents described here have the potential to substantially reduce risk of cancer. Balancing risks and benefits remains an important decisions that should be reviewed with a heath care provider.


Literature cited