SAN DIEGO – When Dawn Lemanne, MD, MPH, meets with cancer patients and their families, the question invariably comes up: “What should I eat?”
Dr. Dawn Lemanne
“The answer always is, ‘It depends,’” Dr. Lemanne, an oncologist who founded Oregon Integrative Oncology in Ashland, said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine. “The answers are not the same for each of these patients.”
According to Dr. Lemanne, targeted nutrition is evolving as a key component of cancer care. One of the goals of this approach is to decrease mTOR signaling. Normally, mTOR signaling promotes cell proliferation and metabolism; aberrant mTOR signaling can contribute to cancer initiation and progression.
“When mTOR speaks it says, ‘grow,’” said Dr. Lemanne, who is also an assistant professor of clinical medicine at the Andrew Weil Center for Integrative Medicine at the University of Arizona in Tucson. This message is meant to be heard by normal tissues, to stimulate normal tissue proliferation, such as in growing children or when a wound needs to be healed.
“However, cancer cells can hear and respond to mTOR’s message,” she said. “Normal cells may listen to mTOR’s ‘grow’ message or not, depending on the task they perform. Once we reach adulthood, we all likely have some precancerous or cancerous cells around, but they’re usually dormant. That’s why once you’re an adult, however, you don’t want too much mTOR signaling, because that might stimulate growth of things you definitely don’t want to grow.”
Having excessive levels of the growth hormone insulin-like growth factor-1 (IGF-1) also appears to play a role in cancer risk. Researchers studying members of a South American clan with Laron dwarfism – an inherited IGF-1 deficiency – found that besides being very short, affected members of this family rarely develop cancer (Cells. 2019;8[6]:596). “They also don’t get diabetes,” Dr. Lemanne said. “What we see in those with Laron dwarfism is that mTOR signaling is missing.”
She went on to note that studying type 2 diabetes gives physicians “a clue as to what dietary measures we might offer our patients in terms of decreasing their risk of dying from cancer or getting cancer.” The most common types of cancer are indeed more common in patients with type 2 diabetes. In addition, once someone with type 2 diabetes is diagnosed with cancer, their prognosis is poorer, compared with a cancer patient without diabetes.
“Metformin is often prescribed to patients with type 2 diabetes because it helps keep blood sugar low,” she said. “What’s fascinating is that diabetics on metformin develop cancer less frequently than diabetics not taking this drug. And also interesting, those diabetics who do develop cancer seem to do better if they’re on metformin before and after diagnosis.”
On the other hand, exogenous insulin therapy given to people with type 2 diabetes doubles the risk of cancer. Consistent with this is the two-decades-old finding that an elevated fasting insulin level also is associated with a poor breast cancer prognosis (J Clin Oncol. 2002 Jan 1;20[1]:42-51). “It’s really important to understand that, in a person destined to become a type 2 diabetic, the level of fasting insulin rises long before fasting glucose becomes abnormally high,” Dr. Lemanne explained. “A normal fasting glucose doesn’t let you off the hook in terms of checking your patient for insulin resistance.
“We will miss diagnosing many patients with dangerous insulin resistance and prediabetes if we don’t check the fasting glucose and the fasting insulin levels together. If the fasting insulin level is high, it’s important to limit carbohydrate intake enough to bring it down permanently, even when the fasting glucose is normal, or the patient is likely at increased risk for developing cancer.”
Two large, prospective randomized trials have examined breast cancer and diet: the Women’s Intervention Study (WINS) and the Women’s Health Eating and Living Study (WHEL). Patients in both trials had early stage breast cancer and were put on low-fat diets. In the end, there was a weak to negligible connection between breast cancer survival and dietary fat restriction. “That kind of shook up the oncology world,” Dr. Lemanne said, “because before these two studies, everyone ‘knew’ that dietary fat was related to breast cancer risk. These studies showed that wasn’t the case at all.”
According to Dr. Lemanne, unexpectedly, moderate carbohydrate restriction has been associated with lower risk of breast cancer recurrence in patients with postmenopausal hormone-receptor expressing breast cancer. Researchers at the University of California, San Diego, conducted a subanalysis of 265 postmenopausal patients with estrogen receptor positive breast cancer from the WHEL cohort (Cancer Epidemiol Biomarkers Prev. 2014 23[7]:1273-9). The recurrence risk was halved in those who cut their carbohydrate intake after diagnosis. The amount of decrease was modest, only 27 grams per day – the equivalent of one banana. “That is on par with a lot of our drugs, and maybe a little bit better,” she said. The effect was strongest if the breast tumor expressed IGF-1 receptor. Dr. Lemanne pointed out that decreasing dietary carbohydrate load was not the only treatment. These patients also had appropriate conventional cancer treatments, including surgery, radiation, and chemotherapy. “If we cut just some of the daily carb load in these patients, they might have a better cancer prognosis,” she said.
Overweight or obese patients with colon cancer also may benefit from moderate carbohydrate restriction. The CALGB 89803 study assessed 1,011 subjects with stage III colon cancer. It found that the subjects in the highest quintile of daily glycemic load and total carbohydrate intake had an increased risk of cancer recurrence and mortality (hazard ratio, 2.26; J Nat Cancer Inst. 2012;104[22]:1702-11). “This is pretty strong evidence that glycemic load and total carbohydrate intake play a role in colon cancer recurrence, but there’s a caveat here,” she said. “The effect was seen only in patients who were overweight or obese.” There was no association between carbohydrate intake and colon cancer recurrence in the absence of overweight or obesity.
Based on existing evidence, she said,
“That’s pretty modest; that’s 400 calories of carbohydrates per day,” Dr. Lemanne said. “I tell patients that they can have fruit, starchy vegetables, and even very small amounts of healthy whole grains, although I’m not a fan of grains due to the heavy carbohydrate load. All those things are OK. We’re not talking about jelly beans and white sugar.
“I also have them measure their fasting glucose each day, because different people have different blood glucose responses to the same food.” The goals she aims for with many of her patients are a fasting morning glucose between 79 and 83 mg/dL consistently, an HbA1c of 5.4 or less, and a BMI of 24.9 kg/m2 or less. “This set of goals, however, has to be individualized,” she said.
The ketogenic diet is another form of carb restriction, “but it’s much more drastic,” Dr. Lemanne said. “Most people require a carbohydrate load below 30 grams a day to enter a state of ketosis. But ketosis lowers the blood sugar and dampens the mTOR signaling.”
Evidence is emerging to support the use of a ketogenic diet as an adjunct to radiation therapy and as part of a complete course of treatment for glioblastoma multiforme and cancer cachexia. As an adjunct to radiation, a ketogenic diet decreases insulin and IGF-1 signaling. “This causes normal cells to enter dormancy, decreasing oxidative damage in normal cells,” Dr. Lemanne said. “There is also suppression of tumor angiogenesis, and thus poor DNA repair of radiation damage in tumor cells (Cancer Metastasis Rev. 2014;33[1]:217-29). Being in ketosis widens the therapeutic window. There are many animal studies which show that the ketogenic diet is helpful in cancer, mainly when combined with other anticancer treatments, such as radiation. Unfortunately, the evidence in humans is very anecdotal.”
One study found that if you feed mice with cancer ketogenic chow versus standard chow, they have a modestly improved survival (a mean of 43 days vs. 33 days; PLoS ONE. 2012;7[5]:e36197). However, when radiation was added to the keto diet, there was a dramatic improvement in survival (P less than 0.001). In fact, 75% survived to 250 days. “That’s pretty spectacular,” Dr. Lemanne said.
A ketogenic diet is standard therapy for several nonmalignant conditions, including glucose transporter 1 deficiency syndrome, pyruvate dehydrogenase deficiency syndrome, and refractory infantile epilepsy. The three major ketone bodies involved in human nutrition are acetoacetate, beta hydroxybutyrate, and acetone. Dr. Lemanne said beta hydroxybutyrate decreases inflammation and inhibits hexadecynoic acids (which induces apoptosis in cancer cells). Beta hydroxybutyrate also increases sirtuins, innate immunity, and seizure threshold; modulates circadian rhythm; and decreases insulin levels, she said.
In one case report from the scientific literature, a 38-year-old male with glioblastoma multiforme was placed on a hypocaloric ketogenic diet (Front Nutr. 2018 Mar 29;5:20). The patient had surgery, radiation, chemotherapy, and hyperbaric oxygen, and was given high doses of green tea extract in an attempt to antagonize glutamine metabolism. Two years after the beginning of his treatment, he was alive and had maintained a good level of tumor regression.
“We’ll see how he does,” said Dr. Lemanne, who was not involved in the report. “In my experience, I have a patient right now with a diagnosis of glioblastoma multiforme. She’s getting a keto diet in combo with intensive chemo, radiation, and surgery. She’s also had some hyperbaric oxygen and IV ozone therapy and is taking repurposed drugs. She has exceeded her expected survival, but she continues to have disease and symptoms. We are by no means out of the woods with this patient. But the keto diet has been quite feasible for her, because she has a lot of family and outside support.”
A ketogenic diet also may benefit patients with cancer cachexia, which is a loss of lean tissue. “Cancer cachexia is not completely understood,” Dr. Lemanne said. “What we know is that it is caused by inflammation created by the tumor itself, and this, in turn results in severe insulin resistance. Therefore, giving more calories as carbohydrate makes the cancer cachexia situation worse. Animal models of cancer cachexia have shown that the ketogenic diet normalizes metabolism and prevents lean tissue loss. Human studies are underway; we’ll see how they turn out.”
She closed her presentation by noting that in copious amounts of animal studies, fasting has been linked to improvements in chemotherapy efficacy and decreased side effects. In one study carried out at the University of Southern California in Los Angeles, volunteers fasted up to 140 hours before chemotherapy and an additional 156 hours afterward (Aging. 2009;1[12]:988-1007). The researchers found that the fasting was well-tolerated.
“The patients had some mild light-headedness, but there were no adverse effects on tumor volume or serum tumor markers,” Dr. Lemanne said. A more recent study of patients on cisplatin found that acaloric fasting led to decreased DNA damage in white blood cells, decreased IFG-1, and better white blood cell counts (BMC Cancer. 2016 Jun 10;16:360). “The benefits are immediate, and the optimal fasting time appears to be 48 hours,” Dr. Lemanne said.
One of her patients is a 64-year-old man on adjuvant cisplatin-based chemotherapy for cholangiocarcinoma. He fasts 24 hours before and 24 hours after each infusion, and has experienced no emesis or nausea. “His immune suppression and anemia are much milder than we expected, and he has not required any treatment for chemotherapy-related side effects,” Dr. Lemanne said. “That’s a big monetary value.”
Fasting 13 hours overnight has been associated with fewer breast cancer-related problems in patients already diagnosed with the disease. Chronic caloric restriction, just cutting calories by 25%-40% daily, has been shown to delay all diseases of aging, including cancer, and is associated with increased longevity in many species. “Chronic caloric restriction is difficult, however, because it results in chronic hunger and weight loss,” she said. “Occasional fasting is superior to chronic caloric restriction because it maintains normal weight, preserves lean muscle mass, enhances tumor sensitivity to chemotherapy and radiotherapy, and diminishes the side effects of chemotherapy.”
Dr. Lemanne reported having no financial disclosures.
dbrunk@mdedge.com