14

Nutrition and Cancer

IN 1981, THE U.S. Congress Office of Technology Assessment asked Sir Richard Doll, the preeminent cancer epidemiologist of his era, and Sir Richard Peto, an esteemed professor of medical statistics and epidemiology at Oxford University, to estimate the known root causes of cancer. Their 117-page landmark document¹ was updated in 2015, and overall, researchers agreed that the original estimates would “generally [hold] true for 35 years.”²

W. J. Blot and R. E. Tarone, “Doll and Peto’s Quantitative Estimates of Cancer Risks: Holding Generally True for 35 Years,” Journal of the National Cancer Institute 107, no. 4 (2015): djv044.

Figure 14.1

Tobacco was, and still is, the most important contributor to cancer. Smoking in the United States peaked in the 1960s, although about 20 percent of the adult population still smokes, accounting for approximately one third of the known risk of cancer (see Figure 14.1).

Dietary factors, including obesity and inactivity, are a very close second, at 30 percent attributable risk of cancer, although they may plausibly account for up to 60 percent of risk. It was clear that the link between diet and cancer was a singularly important one, but the question remained: what specific dietary factor is responsible for cancer? Pinning down the precise relationship is incredibly difficult. Was it some kind of vitamin deficiency? Were we lacking some crucial protective factor? Was the problem too much of something in the diet, or not enough?

DIETARY FIBER

The legendary Irish surgeon Denis Burkitt noted in 1973 that “A number of diseases of major importance are characteristic of modern Western civilization.”³ These diseases, which were noticeably absent in African populations following traditional lifestyles, included heart disease, obesity, type 2 diabetes, osteoporosis, and certain types of cancers. Colorectal cancer, so common in the West, was virtually unknown in the African populations Burkitt was treating. However, native Africans adopting a Western lifestyle suffered increased rates of colorectal cancer, so it was not simply a genetic problem. Diet was the main suspect, but what particular part of the diet was the culprit?

The traditional African diet contained a lot of fiber—a lot. This bulked up the stool, leading to frequent and large-volume bowel movements. The Western diet contained little fiber because of the predominance of refined grains, which lost most of their natural fiber during processing. The result? Fewer, smaller bowel movements.

Fiber is the indigestible part of plant foods; it is either water soluble or insoluble. In both cases, it is not absorbed by the body, and adds bulk to the stool. Burkitt, putting two and two together, hypothesized that the high dietary fiber of the traditional African diet prevented colon cancers. Perhaps the regular movement of the stool cleared the intestinal system, preventing decaying and putrefying of foods inside the colon, which might be carcinogenic. The high stool volume meant frequent “cleansing” bowel movements. Eating more fiber was enthusiastically championed as an easy way to improve health and reduce cancer.

It was a pretty good hypothesis. However, the early studies on precancerous lesions, known as adenoma or polyps, were not encouraging. In the mid-1990s, two large trials, the Toronto Polyp Prevention Trial⁴ and the Australian Polyp Prevention Project,⁵ failed to detect any health benefits to eating more fiber.

By 1999, the Nurses’ Health Study, a sixteen-year study involving more than sixteen thousand women, found that a high-fiber diet did not reduce the risk of precancerous adenomas. Yes, there were all those glorious bowel movements, but no, it did not lower the risk of cancer.⁶ There was more bad news to come.⁷ In a randomized controlled trial, the gold standard of experimental medicine, 1,303 patients were assigned to eat either their usual diet or a low-fat, high-fiber diet emphasizing fruits and vegetables. The high-fiber group ate a whopping 75 percent more fiber and 10 percent less fat than in a standard diet. Unfortunately, from a cancer-prevention standpoint, this dietary intervention was essentially useless. Yes, fiber makes your bowel movements better, but it does not prevent colorectal cancer.

Eating lots of dietary fiber was not the protective factor against colorectal cancer. It must have been one or more of the many other dietary and lifestyle factors that differed between the Africans and the Europeans. The Inuit of the Far North, following their traditional lifestyle, ate little or no fiber, as little plant material grew in the region. But they, too, had little or no colorectal cancer. Cancer was not simply a disease of too little fiber, and thus, eating more fiber didn’t translate into less cancer. Rats!

DIETARY FAT

The next suspect was dietary fat, particularly saturated fats. There was no real reason to suspect that dietary fat should cause cancer. After all, humans had been eating fats, including saturated fats such as animal fats (e.g., meat, dairy) and plant fats (e.g., coconut oil, olive oil) for millennia. Traditional societies often ate large amounts of fat. The Inuit ate whale and seal blubber. Peoples of the South Pacific islands ate large amounts of coconut, which is high in saturated fat. Neither high-fat-eating population suffered particularly from cancers, heart disease, or obesity. There was simply no suggestion that dietary fat was carcinogenic in any manner. Why did we even consider this a reasonable possibility?

From the late 1960s to the 1990s, we were gripped in a hysterical fat phobia. After World War II, seemingly healthy middle-aged men were suffering heart attacks at an alarming and increasing rate. But nobody knew why. When President Eisenhower suffered a heart attack, it suddenly became the most important medical topic of its day. Obesity, type 2 diabetes, and lack of exercise were not major health issues yet. What was the culprit?

The most significant lifestyle changes from 1900 to 1950 were not dietary, but rather, the widespread adoption of cigarette smoking, a trend that accelerated after World War II. The connection between smoking and disease was obscured for decades as tobacco companies strenuously denied that the habit caused heart disease, lung disease, or cancer. Indeed, in the 1960s, doctors were happily puffing away with the rest of their generation.

Dr. Ancel Keys, a prominent nutrition researcher, pointed to dietary fat as the villain causing heart disease. This never made any sense. Americans, living in the land of plenty, had always eaten more animal fats than virtually anybody else in the world. The huge farmlands of the Midwest provided feed for the vast cattle ranches of Texas. Americans had always consumed a lot of beef and milk. Even at a superficial glance, it is hard to see how anybody could have concluded that eating more fat caused more heart disease. Consumption of fat was not rising, yet incidence of heart disease was increasing at an alarming rate.

But every story needs a villain, and dietary fat became nutritional public enemy number one. The American Heart Association (AHA) wrote the world’s first official recommendations in 1961, suggesting that Americans reduce their intake of total fat, saturated fat, and cholesterol. Following that advice, people started to drink low-fat dairy products and switch from eating eggs and meat to consuming low-fat foods such as white bread and pasta.

But the anti-fat crusade didn’t stop at heart disease. The phantom menace of dietary fat was blamed for almost everything bad. It caused obesity. It caused high cholesterol. It caused heart disease. It probably caused bad breath, hair loss, and paper cuts, too. There was no actual proof that dietary fat, which humans had been eating since . . . well, since we became human, caused harm. But it didn’t really matter, because the entire scientific world had hopped on the fat-is-bad bandwagon. Because they thought dietary fat caused heart disease, they logically concluded that it probably caused cancer, too. Who needs proof if you have dogma?

Still, nobody had any idea how dietary fat caused cancer. Even anecdotally, there were few observations suggesting that people who ate a lot of fat got a lot of cancer. Not only have the Inuit and South Pacific Islanders, two populations with low cancer rates, been eating plenty of fat for centuries, but the vegetarians of India were eating very low-fat diets of mostly grain and weren’t protected from cancer. It didn’t matter. Blame-dietary-fat-for-everything-bad was the name of the game. So, play on!

In 1991, the Women’s Health Initiative, an enormous randomized controlled trial, tested the theory that dietary fat caused not only weight gain and heart attacks but also breast cancer. Close to fifty thousand women took part, with one group of women instructed to follow their usual diet and the other instructed to reduce their dietary fat to 20 percent of calories and increase their intake of grains, vegetables, and fruits.

Over the next eight years, these women faithfully reduced their dietary fat and their overall caloric intake. Did this strict diet reduce the rates of heart disease, obesity, and cancer? Not even close. Published in 2007, the study found no benefit for heart disease.⁸ The women’s weight was unchanged. And their rates of cancer—well, they were no better, either. Specifically, there was no benefit for breast cancer,⁹ and there was no benefit for colon cancer.¹⁰ It was a stunning defeat. Did dietary fat play a tiny role in causing cancer? The answer was irrelevant. The effect was so small as to be undetectable, even by the biggest nutritional trial in history.

Lowering dietary fat resulted in no measurable health benefits, directly contradicting the prevailing beliefs of the time. Eating more dietary fat did not cause cancer. Eating less fat did not protect against cancer. In terms of causation of cancer, dietary fat was a dud. So, what was next?

VITAMINS

Could it be that cancer is caused by vitamin deficiency, and if so, could supplements reduce the risk of cancer? Vitamins are big business. People love taking supplements. It is a beautiful dream that simply taking some vitamins can reduce our risk of cancer. So, we put them to the test, but the results were not good.

Beta-carotene

First up was beta-carotene, a precursor to vitamin A that gives carrots their orange color and serves as a potent antioxidant in the body. A randomized controlled trial in 1994 asked whether beta-carotene supplementation could lower heart disease and/or cancer.¹¹ Hopes were high, but unfortunately, the answer was no. Cancer was not simply a beta-carotene-deficiency disease in the way that scurvy is a vitamin C–deficiency disease. Bad news for vitamin lovers.

But there was worse to come: taking beta-carotene supplements actually increased the rates of both cancer and overall death. At first, this effect was considered a fluke, but a similar 1996 study found the same cancer-causing effect.¹² How could taking seemingly benevolent vitamins worsen cancer risk? It would be a few more years before this mystery was solved: Cancer behaves like an invasive species. Vitamin supplementation benefits these fast-growing cells more than slower-growing normal cells.

Cancer cells grow and grow and grow and never stop. But not even cancer can grow without nutrients. Erecting a brick wall without any bricks is impossible, even for the best builders in the world. The rapidly growing cancer cells require a constant supply of nutrients. Vitamins don’t cause a cell to turn into a cancer, but if a cancer is already present, they can certainly help it grow. Feeding cancer lots of vitamins is like sprinkling fertilizer onto an empty field in the hope of getting a nice, lush lawn. You want the grass to grow, but the weeds, being the fastest-growing plants in the field, also take up the nutrients and grow like . . . well, weeds. When vital nutrients like beta-carotene are available in large doses, cancer cells are highly active and grow like weeds. In cancer medicine, you don’t want more growth; you want less.

Folic Acid (Vitamin B₉)

Next up was folate, the water-soluble B vitamin found in leafy greens, legumes, and cereals. It is so important for proper cell growth that the United States mandates that folate supplements be added to fortify flour. Folate supplementation was one of the more spectacular success stories of the modern era. Even in well-nourished Western societies, routine supplementation of pregnant women with folate (folic acid) significantly reduced the incidence of neural tube birth defects. A flurry of observational studies in the 1980s and ’90s suggested that a low-folate diet increased the risk of heart disease and colorectal cancer. A huge wave of enthusiasm for B vitamin supplementation in the early 2000s led to large studies to see if we could reduce those diseases.

The 2006 HOPE2 randomized trial unfortunately found that both folate and vitamin B₁₂ supplementation failed to reduce heart disease.¹³ But what about cancer? The study saw a worrying trend toward increased risk of both colon (36 percent increased risk) and prostate cancer (21 percent increased risk) with supplementation. By itself, this was a big red flag, but more bad news was yet to come. The Aspirin/Folate Prevention of Large Bowel Polyps clinical trial found that six years of folate supplementation increased the risk of advanced cancer by 67 percent.¹⁴ Another study found that breast cancer patients using vitamin B₁₂ supplements had a higher risk of recurrence and death.¹⁵

Two large trials, the Norwegian Vitamin (NORVIT) trial¹⁶ and the Western Norway B Vitamin Intervention Trial (WENBIT),¹⁷ confirmed that high-dose B vitamin supplements did not reduce heart disease. Cancer? There was a significant effect, but not a good one. Folate supplementation increased the risk of cancer by 21 percent and cancer death by 38 percent.¹⁸ Not good. We weren’t preventing cancer; we were giving it to patients.

Winston Churchill once reminded us that “Those who fail to learn from history are condemned to repeat it.” If we had only remembered a bit of the medical history, this sorry chapter in medicine might have been avoided. In 1947, the father of modern chemotherapy, Dr. Sidney Farber, tested folate supplementation in ninety human patients with incurable cancer.¹⁹ Some cases, particularly the leukemia patients, responded with a marked acceleration of cancer growth. Patients got worse, not better.

The mark of a truly great scientist, though, is the ability to change one’s mind when the facts change. Realizing that folic acid worsened cancer, Farber switched to administering aminopterin, a folate blocker, reasoning correctly that if folate was making patients worse, then blocking it might make them better. This seminal discovery launched the modern era of chemotherapy. Leukemic patients showed almost miraculous, although temporary, improvement.

Modern chemotherapy was based on the single observation made in the 1940s that giving folate worsened cancer. Yet, in the early 2000s, millions of cancer research dollars were spent to prove a fact well-known for decades. With hindsight, it’s not difficult to figure out why high-dose vitamin supplementation worsens cancer risk. Cancer cells grow like crazy. High-dose vitamins promote cell growth. It is really just that simple.

Vitamin C

Deficiency of vitamin C causes the disease of scurvy, which was a constant danger for sailors in the years AD 1500 to 1800. The long voyages without adequate vitamin C resulted in easy bruising, swollen extremities, and inflamed gums. This disease was eventually cured by providing sailors with oranges and lemons to eat during the long sea journeys. Vitamin C could cure scurvy, but could it cure cancer?

In the 1970s, Linus Pauling—the only person to have won two unshared Nobel Prizes (in Chemistry, as well as the Peace Prize)—became a vocal proponent of vitamin C supplementation, believing it could cure the common cold and cancer, too.²⁰ Unfortunately, more recent studies have failed to confirm the anticancer effect of vitamin C in humans. A 2015 review of all available studies concluded that “there is no evidence to support the use of vitamin C supplements for prevention of cancer.”²¹ Vitamin C supplementation is important if you are a pirate of the Caribbean, but it cannot prevent or treat any form of cancer.

Vitamin D and Omega-3 oils

It was 1937 when scientists first speculated that sunlight exposure might lower the risk of cancer.²² By 1941, studies were finding that living at higher latitudes (with less sunlight) was associated with a higher risk of cancer death.²³ This link could be explained by a protective effect of vitamin D, which is produced in the skin when it is exposed to ultraviolet B (UVB) rays from the sun.²⁴

Sunlight exposure is the only significant source of vitamin D for most people, as few foods naturally contain significant amounts of vitamin D. Increasing UVB exposure might increase the risk of melanoma, so a promising alternative strategy was vitamin D supplementation, which gained significant popularity by the mid-2000s.

Animal and human studies²⁵ hinted at the vast potential for vitamin D as an anticancer agent.²⁶ Vitamin D could reduce cancer cell proliferation, increase apoptosis (a key anticancer defense), reduce new blood vessel formation, and decrease a tumor’s invasiveness and its propensity to metastasize.²⁷ The Third National Health and Nutrition Examination Survey (NHANES),²⁸ a large American study involving more than thirteen thousand adults, found that low vitamin D levels were associated with a stunning 26 percent increase in total mortality, primarily from heart disease and cancer, the two biggest killers of Americans.

To find some definitive answers, the NIH randomized more than twenty-five thousand participants in a massive trial on vitamin D supplements and another popular supplement at the time, marine-derived long-chain n-3 (also known as omega-3 fatty acids) over 5.3 years. Unfortunately, the Vitamin D and Omega-3 Trial (VITAL) found no evidence that either supplement prevented cancer in any way. Not for breast cancer. Not for prostate cancer. Not for colon cancer. Similarly, there were no benefits for the prevention of heart disease.²⁹ This lack of benefit was confirmed in 2018 by the Vitamin D Assessment Study (ViDa).³⁰ There were no harmful effects detected, but neither were there any benefits.

Vitamin E

Vitamin E is a group of fat-soluble antioxidant vitamins that became very popular in the 1990s, gaining a reputation for potentially reducing heart disease and cancer.³¹ Unfortunately, large-scale randomized trials since then have found that vitamin E supplementation did not reduce the risk of colon,³² lung,³³ prostate, or total cancers.³⁴

Once again, there was a whiff of danger. The large-scale Selenium and Vitamin E Cancer Prevention Trial (SELECT) in 2009³⁵ found no benefit to reducing prostate cancer. But longer follow-up led researchers to conclude that “Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.”³⁶ This was just ugly. Vitamin E supplements were causing the very cancers they were supposed to be preventing.

HOW NOT TO CURE CANCER

Cancer is simply not a disease of nutrient deficiency, and therefore taking supplements is not likely to make much difference. We tested vitamin A (beta-carotene), which failed to reduce cancer. We tested B vitamins, which failed. Then we tested vitamins C, D, and E . . . which all failed. We were running out of letters to test! So, here’s what we are left with:

• Diet plays a large role in cancer.
• Cancer is not caused by lack of dietary fiber.
• Cancer is not caused by too much dietary fat.
• Cancer is not caused by a vitamin deficiency.

While it may sound trivial, these four bits of knowledge cost, literally, hundreds of millions of dollars of research money and many decades of work. This left unanswered the most important question of all: what component of the diet is responsible for so much cancer?

Beginning in the late 1970s, one nutritional measure began to eclipse all others in importance: obesity. The obesity epidemic began as an American phenomenon, but it has since gone global. Cancer is increasingly known as an obesity-related disease, accounting for 20 to 30 percent of the risk of common cancers.

OBESITY

Obesity is estimated to have caused 4.5 million deaths in 2013 worldwide, due primarily to the increased risks of both heart disease and cancer.³⁷ It is often clinically assessed by a measure known as the body mass index (BMI), which is one’s weight in kilograms divided by their height in meters squared, or BMI = kg/m².

It’s important to keep in mind that this simple calculation does not consider many factors, such as body composition (including muscularity and bone density), and as such, it is a flawed metric at the individual level. But over large populations, it is a reasonably useful measure. A generally accepted classification is as follows:

BMI < 18.5	Underweight
BMI 18.6–24.9	Normal weight
BMI 25–29.9	Overweight
BMI 30–39.9	Obese
BMI > 40	Morbidly obese

The obesity epidemic in the United States accelerated in the late 1970s, followed about ten years later with rising rates of type 2 diabetes. It was not until the 2000s that most researchers realized that obesity influences cancer, too. Because cancer often requires decades to develop, the worsening obesity crisis was just then making its presence felt.

The Cancer Prevention Study II, a large prospective cohort study, began in 1982. This massive scientific undertaking required 77,000 volunteers simply to enroll all the participants, which numbered over 1 million. The participants (average age: fifty-seven) were healthy and free of any detectable cancer at the beginning of the study. Every two years, they were tracked to see who had died and why.³⁸ In 2003, the data reached a then-novel and stomach-churning conclusion: obesity, already a well-known risk factor for diabetes, heart disease, and stroke, also significantly raised the risk of cancer.

The risk of cancer began to rise at a BMI greater than 30 (obese) and accelerated in those with a BMI over 40, who suffered 52 to 62 percent more overall cancer death (see Figure 14.2). The risk differed by cancer site. The risk of liver cancer is increased by 452 percent, and the highly lethal pancreatic cancer risk is increased by 261 percent.

Figure 14.2

This is devastating news, but the truth is almost certainly worse for two reasons. People found to have lung cancer from smoking tend not to be obese because of smoking’s slimming factor. Because lung cancer is the most significant cause of cancer deaths, this means that the 52 to 62 percent increased risk of cancer with obesity is almost certainly an underestimate. Looking at nonsmokers only, the increased risk of cancer for a BMI over 40 is a disastrous 88 percent.

Second, advanced cancer patients tend to lose weight, a phenomenon known as cancer cachexia. This will similarly obscure the true link between obesity and cancer and, once again, lead to an underestimation of obesity’s true risk.

Over the ensuing years, the news on obesity and cancer has only gotten worse. In 2017, the CDC released a report highlighting the “Trends in Incidence of Cancers Associated with Overweight and Obesity: United States, 2005–2014.”³⁹ Some of the most common cancers, including breast and colorectal, are related to obesity and excess body fatness (see Figure 14.3). Together, these accounted for an astounding 40 percent of all cancers. The specific cancers most tightly linked to obesity are liver, endometrial, esophageal, and kidney cancers, with two to four times the risk. Breast and colorectal cancer are more moderately associated, at one and a half to two times the risk. In 2016, the International Agency for Research on Cancer (IARC), after reviewing more than a thousand studies, concluded that thirteen different cancers are clearly obesity-related. Three other cancers had limited data, but were suggestive.⁴⁰

Even mild weight gain is associated with increased cancer risk. Adult weight gain of only five kilograms (eleven pounds) increases the risk of breast cancer by 11 percent, ovarian cancer by 13 percent, and colon cancer by 9 percent.⁴¹ Being overweight or obese (BMI > 25) almost doubled the risk of cancers of the esophagus, liver, and kidney and increased colorectal cancer risk by about 30 percent.

Figure 14.3

From 2005 to 2014, the incidence of all weight-related cancers actually dropped slightly, but a closer look at the numbers tells a vastly different story. This improvement was limited to only one single type of cancer: colorectal. Increased screening with colonoscopy detected and removed precancerous adenomas before they could turn into full-blown cancer, dropping colorectal cancer rates by 23 percent. But excluding colon cancer, the other weight-related cancers increased by 7 percent overall. Cancers not related to weight (like lung cancer) had decreased by 13 percent during that same period. Our steady progress against many cancers is being significantly impeded by the obesity epidemic.⁴²

The news gets even worse for the children of baby boomers, those born in the 1980s and ’90s, a generation sometimes called the “echo boom.” Not only are they the heaviest generation in history, but their risk of cancer is higher even at comparable weights, likely due to hyperinsulinemia (discussed in the next chapter). In Millennials, six obesity-related cancers (colorectal, endometrial, gallbladder, kidney, pancreatic, and multiple myeloma) are developing at an age-adjusted rate almost double that for their baby boomer parents.⁴³ For example, those born in 1970 (Generation X) had a 98 percent higher risk of kidney cancer compared to those born in 1950. This seems bad until you realize that those born in 1985 (Millennials) had almost five times the risk!

Cancer in young adults is a warning for future disease burden. If you think it’s scary now, wait until this generation gets older. The obesity epidemic is affecting younger and younger patients, and cancer is following closely behind. For example, the rate of pancreatic cancer is increasing by 0.77 percent per year for those ages forty-five to forty-nine, but for those ages twenty-five to twenty-nine, it is increasing six times more quickly. The youngest people are facing the steepest rises in cancer rates. By contrast, most cancers not related to obesity are decreasing, especially those related to viruses, smoking, and HIV.

If weight gain increases cancer risk, does weight loss lower it? The first animal studies that suggested this possibility were published over a century ago, by 1914 Nobel laureate Peyton Rous. In mice, severely restricting food availability cut their risk of cancer by half.⁴⁴ In the 1940s, Dr. Albert Tannenbaum, former president of the American Association for Cancer Research, discovered that, astoundingly, carbohydrate restriction alone in mice provided greater protection against cancer than overall calorie restriction.⁴⁵ He concluded that “tumor formation is dependent on the composition of the diet, as well as the degree of caloric restriction,” a remarkably prescient observation.⁴⁶ In the Nurses’ Health Study, women who lost ten kilograms or more after menopause and kept the weight off lowered their risk of breast cancer by an astounding 57 percent.

Obesity clearly increases the risk of cancer. Obesity also clearly increases the risk of type 2 diabetes. What is the link? The master hormone of metabolism: insulin.