War on Cancer

by Ralph W. Moss, PhD

Nuts Against Cancer

One of the most intriguing health stories of the year established a link between the consumption of tree or ground nuts and sharply lower rates of mortality from cancer, cardiovascular disease, and other causes of death (Bao 2013).

The bottom line is that daily nut consumption over time causes about a 20% decline in most causes of death. Very few drugs can provide similar health benefits.

Of course, advocates of natural health have long postulated the benefit of nuts. Not for nothing are they called “health nuts”! But in 1992, the Adventist Health Study gave scientific evidence that eating nuts prevented death, specifically from heart disease (Fraser 1992).

This was a controversial finding at the time. Some physicians simply could not believe that a common food could prevent death from serious illness. Writing in JAMA Internal Medicine, one author, Gabe Mirken, MD, postulated that the health benefit seen among Seventh Day Adventists came from the absence of whole-milk dairy and eggs, not the presence of nuts. He went so far as to say: “Nuts do not prevent heart attacks.”

Two decades later, it turns out that nuts do prevent heart attacks, and also prevent deaths from diabetes, stroke, and several forms of cancer. There was also a 25% reduction in deaths from cardiovascular disease, 29% for heart disease, 24% for respiratory disease, and so on. The exact reason for this benefit remains unclear, but nuts are a good source of unsaturated fatty acids, as well as fiber, phytosterols, and certain antioxidants.

Even the FDA now concedes that 1.5 ounces of nuts per day, taken as part of a low-fat diet, “may reduce the risk of heart disease.”

Adventist Study

In 1998, as part of the Adventist study, it was shown that nut consumption reduced the risk of colorectal cancer. However, this news was obscured at the time because the Adventist study focused on the harm of high red meat consumption, low legume intake, and high body mass index. Those three factors led to a “threefold elevation in risk” of colorectal cancer (Singh 1998).

In the latest study, there was an 11% reduction in cancer overall. Admittedly, the present study was funded by the Tree Nut Council, which of course raised some skeptical eyebrows. However, given the high quality of this study, and its breadth (76,000+ participants from the Nurses’ Health Study and 42,000+ from the Health Professionals’ Follow-up Study), I think we can accept the authors’ assertion that the sponsors had nothing to do with the positive outcome of the paper.

Simply put, nuts are good for you. They help prevent some cancers as well as a host of other illnesses. They are also delicious. So, unless you are allergic to them, the only good reason not to eat them is that they are too delicious and may add unwanted pounds. But even that risk is overstated, since they may reduce the number of empty calories that people eat.

My “gut” instinct is that raw nuts may have some health benefits that are missing in roasted nuts, and I personally try to include pecans, walnuts, or other unprocessed nuts in my daily regimen.

How Effective Are Targeted Therapies?

The Case of Liver Cancer

“Targeted” therapies are those drugs that attack specific molecules present in or around cancers. These are mostly classified as “kinases.” This type of therapy tries to avoid the indiscriminate killing of good as well as bad cells, which is more characteristic of conventional chemotherapy. Such targeted drugs include trastuzumab (Herceptin), Gleevec (imatinib), and Tarceva (erlotinib).

I will focus here on the treatment of hepatocellular carcinoma (HCC), better known as primary liver cancer. It is a disease with an enormous worldwide impact: the fifth most common malignancy worldwide and the second most common cause of death, especially in Asia.

There are various forms of liver cancer, and various treatments are effective and appropriate for particular stages. But for the present I am not concerned with surgery, transplantation, radioisotopes, or other potential treatments. I am also not speaking right now about complementary and alternative medicine (CAM). I am exclusively concerned here with the use of drugs in treating advanced HCC.

For decades, researchers tried to discover forms of chemotherapy that were effective against HCC, but the results were always unimpressive. Doxorubicin (Adriamycin), when used as a single agent, resulted in a response rate of less than 25%. In addition, in one nonrandomized phase II study, 32 patients given a combination of gemcitabine and oxaliplatin (called GEMOX) had a partial response (PR) rate of 18%, with an overall survival time of 11.5 months (Louafi 2007).

But, as a rule, toxic chemotherapy had “no proven benefits on survival in HCC,” to quote from the authoritative DeVita, Hellman, and Rosenberg textbook Cancer: Principles and Practice of Oncology (2014 online edition).

SHARP Trial

Then came the SHARP trial, whose results were presented at the 2007 annual meeting of the American Society of Clinical Oncology (Llovet 2008). SHARP stands for “Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.” This large trial established a new targeted drug sorafenib (Nexavar) as the most effective treatment for metastatic HCC.

The National Comprehensive Cancer Network (NCCN) guidelines states that “for selected patients, a randomized clinical trial has demonstrated survival benefits.”

The SHARP paper’s principle author was Josep Llovet of Barcelona (and Mount Sinai Hospital, New York). It had over 130 coauthors from all over Europe and was published in a major journal.

A total of 602 patients with advanced HCC, who had not received any previous systemic treatment, were randomized to receive either sorafenib at a dose of 400 mg twice daily vs. placebo.

“Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety,” Llovet and his colleagues wrote.

After 1 year, 321 deaths had occurred and the trial was stopped. The median overall survival at that point was 10.7 months in the sorafenib group vs. 7.9 months in the placebo group. The survival benefit of sorafenib was thus 2.8 months. This was statistically significant.

Some other figures: the time to progression by X-ray assessment was 5.5 months vs. 2.8 months. There was actually a small decrease in the time to symptomatic progression (4.1 months vs. 4.9 months for placebo), but this was not statistically significant.

Although “responses” (i.e., tumor shrinkages) were not included in the study design, only 7 patients in the sorafenib group (2%) and 2 patients in the placebo group (1%) had a partial response. Not a single patient had a complete response. I think it is a good thing that the authors were not so focused on shrinking tumors but looked instead at the actual effect on survival.

How predictive would the SHARP results be for other, possibly more typical, HCC patients? Perhaps not much, since, like most clinical trials, this one had many exclusion and inclusion criteria. The paper states that 300 patients who were considered for inclusion were then excluded because they did not meet the protocol’s criteria, withdrew their consent, had an adverse event, died or were lost to follow-up. A total of 602 patients then underwent randomization to either treatment or placebo.

In addition, half of the patients had had no previous treatment at all, and none of them had received any form of chemotherapy. They were thus, relatively speaking, “virgin” patients. One cannot expect the results to be the same in patients with more advanced, or heavily pretreated, disease.

Perhaps the biggest departure from the norm was that patients in this trial all had well-preserved liver function (this was called Child-Pugh class A). This is very important, since many HCC patients have concurrent liver diseases such as hepatitis B, hepatitis C, or cirrhosis. This can complicate matters.

As to side effects, the study noted: “Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia [a low level of phosphorus in the blood, ed.] were more frequent in the sorafenib group.”

I shall return to this point in a moment.

Asia-Pacific Trial

The SHARP trial was based in Europe. But in the following year, a similar trial, called Asia-Pacific, was published in Lancet Oncology (Cheng 2009).This did not have quite so positive an outcome. In Asia, HCC more typically presents with an underlying hepatitis B infection (not hepatitis C, as is more frequently the case in Europe).

Asia-Pacific enrolled a total of 271 patients, of whom 150 received sorafenib while 76 received placebo. Median overall survival was 6.5 months in the sorafenib group vs. 4.2 months in the placebo group, for a difference of 2.3 months. The median time to progression was 2.8 months in the sorafenib group vs. 1.4 months in the placebo group. The reader will notice that sorafenib-treated patients in Asia had shorter overall survival time than placebo patients in Europe!

The benefit of sorafenib seems very much related to the selection of patients (and their underlying disease state).

The Asia-Pacific authors concluded: “Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated.” But “effective” in this case means extending survival by a total of 2.3 months (i.e., from 4.2 months to 6.5 months).

As Manish Shah, MD, pointed out at the DeVita textbook website: “Both the SHARP and Asia-Pacific studies were limited to patients with unresectable or metastatic HCC who also had preserved liver function. The benefit of sorafenib in patients with [more advanced disease, ed.] has not been established” (2014, emphasis added).

Sorafenib is produced by Onyx Pharmaceuticals and Bayer HealthCare Pharmaceuticals. The pharmacy price is $5400 per month, although discounts may be available for poor patients.

Inflated Results?

I cannot help mentioning one factor that may have inflated the results of this as well as other targeted agents. That was the effect of treatment on total intake of calories by those getting the drug as opposed to the placebo. In 2013, calorie restriction (CR) was called “one of the most potent broadly acting dietary interventions for … inhibiting cancer in experimental models” (Hursting 2013).

The SHARP trial reported that “weight loss” was the second major side effect of sorafenib. How then can we be sure that at least some of the modest life extension seen in this and the Asia-Pacific trial were not due at least in part to the decrease in calories? I agree with the suggestion of Thomas Seyfried, PhD, of Boston College (Massachusetts) that there should be a “third arm” in cancer treatment clinical trials, in which patients do not get the drug in question but simply have their caloric intake adjusted to equal that of the treatment-arm participants. We then could know how much of the resulting effect was due to the drug per se and how much to the overall reduction in food intake.

In any case, the effect of sorafenib is very modest in advanced HCC. Under optimal conditions, it seems to result in an overall increase in survival or two to three months.

References

Bao Y, Han J, Hu FB, et al. Association of nut consumption with total and cause-specific mortality. N Engl J Med. 2013;369:2001–2011.

Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.

Fraser GE, Sabaté J, Beeson WL, Strahan TM. A possible protective effect of nut consumption on risk of coronary heart disease: the Adventist Health Study. Arch Intern Med. 1992;152:1416–1424.

Hursting SD, Dunlap SM, Ford NA, Hursting MJ, Lashinger LM. Calorie restriction and cancer prevention: a mechanistic perspective. Cancer Metab. 2013;1(1):10.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857.

Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer. 2007;109:1384–1390.

Mirkin G. Nuts do not prevent heart attacks. Arch Intern Med. 1993;153(1):125–125.

Scanga A, Kowdley K. Sorafenib: A glimmer of hope for unresectable hepatocellular carcinoma? Hepatology. 2009;49(1):332–334.

Seyfried T. Cancer as a Metabolic Disease. Hoboken: Wiley; 2012.

Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.