Cancer Survival and Matrimony: A Marriage Made In Heaven

The November 1, 2013 issue of the Journal of Clinical Oncology (Marital Status and Survival in Patients with Cancer, Aizer, A. et al J Clin Oncol, 2013), reports a study by investigators from Harvard University. Using the Surveillance, Epidemiology and End Results (SEER) data they examined more than 1.2 million cancer patients diagnosed between 2004 and 2008 to measure the impact of marital status on overall survival. Results reveal a statistically significant impact of marriage on cancer survival. The benefit slightly favored males over female, but remained significant across different diseases and for never married, separated, divorced or widowed. The authors note, “The survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.”

Epidemiologic studies that correlate disease states with socioeconomic status, level of education, geographic location, lifestyle or diet are fraught with confounding variables. Nonetheless, well-done studies can open a wealth of interesting questions regarding non-treatment related aspects of our health and well-being. This study is provocative for it identifies the interaction between marital status and stage at diagnosis, as well as overall survival.

There are many ways one might interpret the findings. The accompanying editorial (Marriage Is as Protective as Chemotherapy in Cancer Care, Kissane, D) notes that non-married status may reflect “reduced adherence to state-of-the-art treatment.” That, we presume, would include such variables as regular physicals, frequency of mammograms, PSA evaluations, willingness to undergo surgery or the use of adjuvant treatments. The role of depression is also noted. While all of these may apply, they have a self-serving ring, whereby good health, it would seem, can only be attributed to good doctoring. Controversies surrounding PSA screening or the impact of “annual physicals” on general health are but a few examples where more may not necessarily be better.

While it may be argued that unmarried individuals fail to obtain adequate medical care, the data may reflect something more profound, the psychoneuroimmunology of cancer survivorship. That is, each patient’s capacity to will-themselves better. The will-to-live is enhanced by close human relationships. We are all witness to patients who survive against all odds. They are usually filled with zeal, willing to go to whatever lengths are required to overcome their illness and most have close interpersonal relationships, nurturing environments, loving families or husbands and wives who dote on them.

Norman Cousins spoke at length about the healing force of one’s emotional and spiritual belief systems in his own battle with ankylosing spondylitis (Anatomy of An Illness, As Perceived by the Patient, 1979). Might his experience reflect a similar dynamic to that described in the current study? My patient Alan Kapuler’s excellent outcome over Non-Hodgkin’s lymphoma, described in my book (Outliving Cancer, 2013, chapter 12) exemplifies this same mind-over-matter dedication, characteristic of many of our long-term survivors.

I applaud Dr. Aizer and his co- investigators for examining this aspect of cancer survivorship. I am impressed that such a report would find its way onto the pages of the Journal of Clinical Oncology. However, I am less certain that these good outcomes reflect state-of-the-art treatment and more of the opinion that married patients may be part of a happier, healthier, better adjusted and more humanly connected population. Interpersonal relationships are not devices. They cannot be patented or sold. However, as can be seen from this study, they may be among the most powerful interventions at our disposal in the management of advanced cancer.

Nut Consumption, Pancreatic Cancer and Woody Allen

In the 1973 Woody Allen movie ”Sleeper,” Miles Monroe (played by Allen), is the nerdy owner of the Happy Carrot health food store who undergoes cryostasis (deep freeze) only to be awakened 200 years later. He finds himself in a place where all that he had come to know has disappeared. Two physicians observing him from a distance comment on his unusual dietary request: wheat germ, organic honey and tiger’s milk. Puzzled, one physician asks why he would want such odd foods. The second physician explains that 200 years earlier, low fat foods were considered healthy. “What, no deep fat, no steak, no cream pies, or hot fudge?” she asks incredulously. “No”, he explains, “those were thought to be unhealthy…. precisely the opposite of what we now know to be true.”

I was reminded of this scene by a paper published in the British Journal of Cancer (BJC). Based on observations from 75,680 women in the Nurses’ Health Study, investigators showed that the regular consumption of nuts was inversely associated with the risk of pancreatic cancer. Indeed, those who consumed one ounce of almonds, Brazil nuts, cashews, hazelnuts, macadamias, pecans, pine nuts, pistachios or walnuts, three times per week had a 35 percent reduction in the risk of pancreatic cancer (P = 0.007). This was found to be independent of age, height, obesity, smoking, diabetes, or other dietary factors. Although the study was funded by the International Tree Nut Council Nutrition Research and Education Foundation, they had no participation in the design or analysis of the data.

The consumption of nuts has previously been shown to be highly beneficial. In a Spanish study of 7,000 people, ages 55 to 90, those who ate three servings per week had a 55 percent reduction in death from cardiovascular disease and a 40 percent reduction in death from cancer. Clearly, the association between nut consumption and health is both strong and broad based, as it extends from cardiovascular disease to cancer.

The majority of the calories in nuts come from lipids (fats) including monounsaturated and polyunsaturated fats like oleic acid, found in olive oil, linoleic, gamma-linolenic and alpha-linolenic acids as well as the saturated fats, stearic and palmitic acids. Of the nuts commonly consumed the highest lipid content is in macadamia nut, followed by peanuts, pecans, cashews, walnuts, pine nuts, hazel nuts, pistachios, almonds and chestnuts. The protein content of nuts favors peanuts and pine nuts. A number of micronutrients are also found in nuts including flavonoids, stilbenes, proanthocyanidins, calcium, iron, B6 and magnesium.

The BJC study stands in strong contradistinction to the oft-repeated admonition that nuts should be avoided, as voiced for many years by health experts and dieticians. The fat avoidance craze of recent decades held that foods containing lipids were to be eschewed. Health conscious individuals were encouraged to eat grains and carbohydrates.

Today we recognize the important benefits of lipids and find that higher fat and high protein diets are gaining traction over the older food pyramid. We now find that high carbohydrate intake may in part be responsible for many contemporary maladies suggesting that the agrarian revolution of 10,000 years ago that made high calorie/low fiber grains readily available may ultimately prove to have been more a curse than a blessing.

An expert is one whose “faculty for judging or deciding rightly, justly, or wisely” is recognized and granted sway over society. But who judges the experts? The current BJC study suggests that in many fields of science and medicine the experts can be wrong. How many people denied themselves the pleasure and, we now come to learn, the health benefits of nuts based upon expert recommendations?

In our contemporary diagnosis and management of cancer, might the experts be leading us astray in other areas? Perhaps we should all ponder that point as we nibble on a few Macadamia nuts.

Cancer Patients Who Get Better, Get Better

A study published in the October 20 Journal of Clinical Oncology (Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with Cetuximab, Piessevaux H. et al, 31:3764-3775,2013) described “early tumor shrinkage” as a predictor of long-term survival in patients with metastatic colorectal cancer. These Belgian and German investigators re-analyzed two large clinical trials in colon cancer, CRYSTAL and OPUS, to evaluate the impact of early tumor shrinkage at eight weeks of therapy. Both studies were in patients with wild type (non-mutated) KRAS colon cancer who received chemotherapy with or without the monoclonal antibody Cetuximab.

They used a cutoff of 20 percent tumor shrinkage at eight weeks to separate “early responders” from “non-responders.” Early responders were found to have a significantly better survival. The accompanying editorial by Jeffrey Oxnard and Lawrence Schwartz (Response phenotype as a predictive biomarker to guide treatment with targeted therapies, J Clin Oncol 31:3739-3741, 2013) examined the implications of this study.

The measurement of tumor response has been a lynchpin of cancer therapeutics for decades. This was later refined under what is known as RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Despite this, there remained controversy regarding the impact of early response on long term survival. The current Piessevaux trial however, is only the most recent addition to a long history of studies that established the correlation between tumor shrinkage and survival. Earlier studies in colorectal, kidney, esophagus and lung cancers have all shown that early response correlates with superior outcomes.

What is gratifying in the accompanying editorial is the discussion of the “response phenotype” as a predictor of survival. Phenotype, defined as “the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment” reflects the totality of human biology not just its informatics (genotype). This renewed appreciation of tumor phenotype in oncology is important for it re-focuses on tumor biology over tumor genetics.

The  ex-vivo analysis of programmed cell death (EVA-PCD) that we utilize, is itself a phenotypic platform that measures actual cellular behavior, not gene profiles, to gauge drug sensitivity. We have previously shown that the measurement of chemotherapy effect on human tumor tissue predicts response, time to progression and survival. The current study used clinical response (early tumor shrinkage) to successfully measure the same.

This analysis of early response by Piessevaux is bringing our most sophisticated investigators back to what they should have known all along.
1. Responding patients do better than non-responding patients.
2. Early measurement of response is predictive of long term outcome.
3. These measurements can and should be done in the laboratory.

Taken together, the current study supports early tumor shrinkage and by inference, ex vivo analyses, as important predictors of patient response and survival.