Cancer Survival and Matrimony: A Marriage Made In Heaven

JCO coverThe 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 somethinAA010368g 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.

Melanoma, the Immune System, and Targeted Therapies

For those of you who have been following the recent news coming from the American Society of Clinical Oncology (ASCO) held in Chicago, you have heard of the breakthroughs for the treatment of malignant melanoma.

Melanoma, the most lethal form of skin cancer, arises as a pigmented lesion (mole or large freckle), generally in sun-exposed areas. Though curable in its earliest stages, once these malignancies disseminate, they can be the most aggressive and hard to treat cancers known to oncologists. That is, until recently when two important discoveries were made.

The first discovery actually dates back many years. It turns out that melanoma is one of those cancers that occasionally, spontaneously, regresses and that a subset of patients respond to interferon (an immune protein). This suggested a role for the immune system.

The next piece of evidence came from work in the 1980s, conducted by Steven Rosenberg, MD, PhD, at the National Cancer Institute. Using a genetically engineered human protein (interleukin 2-IL2), these investigators reported responses in patients with metastatic melanoma. Again, an immune component to this dreaded disease.

Fast-forward two decades. Investigators unraveling the complexities of human immunity realized that the cancer cells weren’t being recognized and effectively controlled by lymphocytes. Something was dampening the immune response. With the discovery of ipilumumab, an antibody directed against CTL4, scientists could now turn off the “off” switch, thereby turning on the immune system.

Survival advantages have been substantial. This therapy is now available to patients in need.

The second discovery represents a triumph for “targeted” therapy. As the gene BRAF, was recognized to be mutated in the majority of melanoma patients, drugs were developed to turn off this important pathway. Unfortunately, the first generation BRAF inhibitor sorafenib, could not shut down what proved to be the most common variant of the BRAF mutation, known as V600E.

To the rescue came a compound now known as vemurafenib. By turning off the V600E signal, those patients with this specific mutation (about 60 percent) responded dramatically.

While both these discoveries are meritorious, the responses in most patients unfortunately have not been very durable, with relapses generally occurring months or the first year after starting therapy. Interestingly, secondary pathways, like N-RAS and C-RAF, may step to the fore and overtake the effect of the BRAF inhibition. This offers hope that third generation small molecules will address these resistant clones.

In our laboratory, we are currently examining small molecules that inhibit the RAS and other pathways to determine whether new strategies may overcome these resistance mechanisms in melanoma. As a proof of concept, these reports from ASCO establish that the era of targeted therapy in melanoma is here.