The Cancer Chronicles (21 page)

“The nineteen-eighties was an extremely challenging period,” Riboli recalled. Cancer researchers polarized into two
factions. He was reminded of Dante’s Florence, where the warring Guelphs divided into the Neri and the Bianchi, the Blacks and the Whites. “We had two parties, one saying it’s all
environmental carcinogens and the other saying cancer can develop without them. I moved from the carcinogenesis party to the lifestyle party.” He became interested not only in the factors that might cause cancer but also in the ones that might prevent it.

During the decade that followed, he helped with an effort, organized by the
World Cancer Research Fund and the
American Institute for Cancer Research, to
review some four thousand studies on
nutrition and cancer and see what patterns emerged. In 1997 the groups issued their report,
Food, Nutrition and the Prevention of Cancer: A Global Perspective
—inspiration for the
5 A Day program that was all the rage in the years before Nancy’s
diagnosis. Based on the best available evidence, fruits and vegetables appeared to have remarkable powers: “
Diets containing substantial amounts of a variety of vegetables and fruits may on their own reduce the overall incidence of cancer by over 20 percent.” The number-one recommendation was to eat “
predominantly plant-based diets” with five or more servings every day. In her widely read column in
The New
York Times,
Personal Health,
Jane Brody gave her summary of the study’s remarkably specific recommendations:

If only it had turned out to be so easy. A decade later, in 2007, came
the disappointing
follow-up. Riboli was again a key member of the study. As more and better evidence accumulated, the case for fruits and vegetables was unraveling. There was still “limited” to “probable” evidence that some of these foods might slightly lower the risk of certain
cancers. But the authors concluded that “
in no case now is the evidence of protection judged to be convincing.”

The problem with the earlier report (and to a lesser extent with its sequel) is that the conclusions were based so heavily on
retrospective studies, those where you must rely on people to remember in detail what they had eaten years and even decades earlier—the gestation period for many cancers. “If you ask someone who is seventy years old who has colon cancer what his diet was when he was forty-five or fifty, it’s a tough call,” Riboli said. “For things like smoking or drinking it’s more clear-cut. These are things that are very repetitive and stable.” Things that you remember. “But how often do you eat carrots? How often do you eat pears? Quantify how many pears, how many strawberries, how many eggs—including all the eggs you don’t know about because they are in recipes.” Riboli believed better answers lay in
prospective studies, the kind that followed a large population of people as they went about their lives. Then those who developed cancer could be compared with those who did not. “We wouldn’t need to go to someone who is there in a bed with cancer and ask how often he was consuming salads,” Riboli said. “We collect information from people who are living their normal life.”

While the projects by the World Cancer Research Fund were under way, Riboli had been pushing to form EPIC,
the
European Prospective Investigation into Cancer and Nutrition. During the 1990s, researchers had begun monitoring the health of 520,000
people in ten countries. Blood samples were drawn periodically and preserved with liquid nitrogen. Heights, weights, and medical history were recorded. Information was collected on diet and physical activity. As, year by year, the database grew, investigators at various universities and government agencies began looking for correlations.

A few early results had found their way into the 2007 report, helping to tip the balance away from a preoccupation with fruits and vegetables. Since then more surprises have appeared. By the time I talked to Riboli, about 63,000 of the half-million people in the study had
cancer. There was now
only the slightest evidence that eating a lot of fruits and vegetables had made much difference. They did not obviously reduce the overall risk of getting cancer
or even of specific cancers like those of the breast,
prostate,
kidneys, and pancreas. There were suggestions of
a small protective effect, especially among smokers, for cancer of the
lungs, mouth, pharynx, larynx, and esophagus. But it was
too early to make more than tentative conjectures. Besides smoking, a risk
factor for many of these cancers was heavy drinking, and
people who smoke and drink excessively have been shown, as might be expected, to be less likely to eat fruits and vegetables. A preliminary study found that these foods
possibly played a small part in reducing cases of
colon cancer but
that too remains in dispute.

In an editorial for the
Journal of the National Cancer Institute,
Walter C. Willett, a prominent nutritionist (he was the head of the influential
Nurses’ Health Study on diet and lifestyle) and one of Riboli’s longtime colleagues, concluded that researchers had been “
overly optimistic” and that the EPIC findings only added to the evidence “that any association of intake of fruits and vegetables with risk of cancer is weak at best.” It had become clear with
Doll and
Peto that synthetic carcinogens were not the smoking gun, and now it appeared that fruits and vegetables were not a magic bullet.

Diet was not irrelevant. It was EPIC researchers who estimated that for a 50-year-old who ate a lot of red and processed
meat (160 grams, or more than a third of a pound a day)
the ten-year risk of
getting colorectal
cancer was 1.71 percent—0.43 percent higher than for someone who ate less than 20 grams. A third of a pound a day is a lot of hamburgers and hotdogs, and again there are complications to bear in mind. The study made adjustments for smoking, drinking, and other confounding
factors. But there may be something else about the behavior of carnivores that skewed the results, and other studies
have come to conflicting conclusions. There will always be uncertainties with observational epidemiology and the inevitable question of what is cause and what is effect. Getting closer to the answers would require very large randomized trials in which one population would faithfully eat more of some food and the other would eat less. After twenty or thirty years of draconian enforcement, maybe you could say with some confidence whether there was a difference in the risk of cancer. The data EPIC hopes to collect in the coming decades might be the next best thing.

Moving beyond purely culinary issues, EPIC has strengthened the case against obesity. One study found that
older women who had gained 15 to 20 kilograms, or roughly 40 pounds, since they were twenty had an increased breast
cancer risk of 50 percent. As in the old animal experiments,
fatness itself, whatever its cause, appeared to be the driving force. Along with lack of exercise, it may account for as much as 25 percent of cancer, with dietary specifics falling to as little as 5 percent. This is the message emerging from decades of nutritional and medical research: Understanding cancer lies less in the foods we eat than in how the body stores and uses energy.

At the center of this
metabolic puzzle is the hormone
insulin. As we eat and our level of
glucose (blood sugar) rises, it is insulin, secreted by the
pancreas, that signals our cells to burn the fuel directly and to store the excess as
glycogen (starch) or body fat. As blood sugar falls, the cells draw on their reserves by converting glycogen back into glucose. When still more energy is needed, fat cells release their long-term supplies. Sometimes, however, something
goes wrong. The body produces too little
insulin or becomes numbed to its effects. When the latter occurs the pancreas responds by producing more insulin. The cells react by becoming even more resistant and so more insulin is secreted. This pathological spiral—a condition called
metabolic syndrome—is involved in chronic conditions like
hypertension, cardiovascular disease,
diabetes, and obesity. It also plays a role in cancer.
The reasons are complex. Insulin and closely related hormones called IGFs (insulin-like growth
factors) can stimulate a cancer cell, feeding the expansion of tumors and even encouraging
angiogenesis. Insulin is also involved in regulating
sex hormones. Moreover, a rise in insulin accelerates the accumulation of body fat, and fat cells synthesize
estrogen. Insulin, estrogen, obesity, cancer—all are tied into the same metabolic knot.

It makes sense that connections like these would have evolved. A woman must be well nourished in order to produce healthy babies. In times of famine, there is no excess energy to store, and the metabolic machinery reacts by lowering the availability of estrogen. It is not a good time to conceive. As more food becomes available, fat accumulates—energy the mother will need during pregnancy and nursing—and more estrogen is released, stimulating ovulation and, after conception, the production of breast milk. Here is the basis of the “
mysterious sympathy”
Ramazzini wondered about more than three centuries ago. But in a civilization where food becomes abundant, and overly so, the sympathy is upset. The
age of
menarche decreases, adding to the number of estrogen cycles and raising the risk of breast cancer. Increased nutrition may also unleash the hormones that produce
greater body height—another risk factor for cancer. “What this shows,”
Riboli said, “is how something which is just a modulation of a normal
physiological process—which remains normal and doesn’t cause any disease—has a major impact later in life with cancer. This is not chemical or physical or viral carcinogenesis. It is metabolic carcinogenesis.” The ancient idea of cancer as a disposition of the whole body has returned in a more sophisticated form.

The amount of fat in storage
also affects the
immune system in ways that might promote malignancy. In addition to fat cells, fatty tissue contains gobs of
macrophages—cells that flock to infected trouble spots to ingest invaders and that can also be diverted to aid in a
cancerous attack. And the fat cells themselves secrete other agents that promote
inflammation—a healing mechanism that involves the rapid creation of new tissues. There is a thin line between that and tumorous growth. More than a century ago
Rudolf Virchow suggested that chronic inflammation, with its power to accelerate cellular proliferation, was a cause of cancer. (That might explain why
aspirin and other
anti-inflammatory drugs appear in some studies to lower cancer risk.) Obesity has been described as a kind of “
low grade chronic inflammatory state” and tumors as “
wounds that do not heal.” Chemokines, integrins,
proteases … neutrophils, monocytes, eosinophils—there is so much invisible apparatus behind the crude feel of a throbbing joint or a hot, pus-filled wound. Inflammation has
also been tied to metabolic syndrome and
diabetes. Cancer, obesity, diabetes—the strength of these connections is hinted at in studies of grossly overweight people who undergo
gastric bypass surgery in a last-ditch attempt for relief. As their body mass decreases their
diabetes recedes, and there is evidence that they get less cancer.

The deeper you look the more convoluted this all becomes.
Cortisol, the stress hormone, and
melatonin, which regulates sleep, are also hooked into the metabolic loops involving energy, estrogen flux,
and inflammation. Epidemiological studies have suggested that women who work at night may have a higher risk of breast cancer. Considering that and other evidence of the effect of sunlight and sleep cycles on the body, the World Health Organization added “
shiftwork that involves
circadian disruption” to its list of probable carcinogens—one more avenue that may warrant exploration. All these phenomena are joined at the cellular roots and understanding cancer will require sorting them all out. The overall incidence of cancer has leveled off in recent decades. Are our bodies learning to adjust to the new rhythms? We can never know for sure how cancer
rates in the
twenty-first century compare with those hundreds of years past. If over the long run there has been an increase, then part of the story could be the modern changes shaking our metabolic core.

By the time I caught up with
Riboli, he and his colleagues were talking less about broccoli, cauliflower, bok choy, kale, and brussels sprouts and more about the body’s energy balance and how the fulcrum has shifted since ancient times. I’d read the debates about the so-called
paleo diet—was it richer in fruits and vegetables or in meat and fat? In any case it was low in refined carbohydrates and sugar—energy-packed foods that hit the blood so quickly, causing spikes in insulin and potentially disrupting so many biochemical cascades. Toward the end of our interview Riboli pulled from his bookcase a binder of charts. “At the end of 1800 the usual
consumption of sugar in most European countries was two to three kilograms per person per year,” he said. “
Now it is between fifty and sixty kilograms.” I pictured a hundred-pound pile of sugar and eating it over the course of twelve months. I was reminded of the journalist
Gary Taubes,
who argues that carbs and sugar, rather than dietary fat and overeating, drive the modern obesity epidemic and the damage it causes, including
cancer, by skewing how the body uses energy.

Riboli and his colleagues suspect that all energy-rich foods are a problem. Although they are high in calories they can leave us unsated and wanting more. “If I go and buy a burger or a sandwich, most often it contains between five hundred fifty and six hundred kilocalories,” he said. “If I prepare a nice pasta dish, Italian style—with some sauce, pimento, some vegetables—I barely reach five hundred kilocalories. But I have something so voluminous that I feel full. I eat a sandwich and have the impression that I haven’t eaten anything, but I’ve had more kilocalories—more energy.” That empty feeling might spur the desire for a candy bar. Maybe that is reason enough to eat more fruits, vegetables, and fiber. They fill your stomach,
reducing your energy intake and therefore your insulin load.