Of Prostate Cancer, Glucose, Metabolism and Metformin

A study conducted by Canadian investigators and reported in the September 1, 2013 issue of the Journal of Clinical Oncology examined the impact of Metformin use on mortality in men with diabetes and prostate cancer (Margel D. Urbach DR., Lipscombe LL, Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men with Diabetes, Journal of Clinical Oncology, volume 31, #25, pgs 3069-3075, 2013). The investigators examined 3837 patient with a median age of 75 years. They conducted a retrospective analysis examining the Ontario Province heath care records. The intent was to examine duration of exposure to Metformin as a diabetes management in patients with prostate cancer to assess the impact on all-cause and prostate cancer-specific mortality.

The results are impressive and instructive. There was a significant decrease in the risk of prostate cancer-specific and all-cause mortality, which related to the dose and duration of exposure to Metformin. The adjusted hazard ratio for the study of 0.76 indicates that there is a 24% reduction in mortality for prostate cancer-specific events with the use of Metformin. This study was not perfect, as it was retrospective, there was no randomization and it was impossible to control for all other variables such as exercise, smoking history and clinical parameters of prostate cancer. Nonetheless, there is a clear and important trend toward reduced prostate cancer and even overall mortality. This is but one of a series of clinical studies that have examined the impact of Metformin upon not only prostate cancer but also breast cancer. Much of this work was originally pioneered by Dr. Michael Pollack from McGill University in Montreal.

The biguanide class of antidiabetic drugs, originates from the French lilac or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries.  (Wikipedia)

The biguanide class of antidiabetic drugs, originates from the French lilac or goat’s rue (Galega officinalis). (Wikipedia)

Metformin and the closely related Phenformin are members of the class of drugs known as biguanides. While the exact mode of action of the biguanides is not fully understood, they are known to disrupt mitochondrial respiration at complex I. This upregulates an enzyme known as adenosine monophosphate kinase (AMPK) thereby altering energy metabolism within the cell and down regulating mTOR. In diabetics, this drives down blood glucose to control the disease. However, in cancer patients, a profound effect is observed that suppresses synthetic pathways necessary for energy metabolism, cellular survival and cellular proliferation. These effects appear responsible for the impact upon prostate cancer. Interestingly, these drugs are more effective in controlling already transformed cells and less effective in the prevention of cancer. This is consistent with the observation that malignantly transformed cells change their state of metabolism.

This article is interesting on many levels. The first and most obvious is that this relatively inexpensive and well-tolerated drug can have an impact on prostate cancer.

Secondly, these effects appear to cross the lines of different cancer types, such that breast cancer and other forms of cancer might also be successfully treated.

The third note of interest shows that even patients without diabetes can tolerate Metformin, suggesting this as an adjunct to many different treatments. Finally and most importantly this represents the new and important recognition that cancer is not a genomic disorder, but a metabolic disorder. Cancer may utilize normal genetic elements to its own advantage. AMP kinase, LKB1 and mTOR are not unique to cancer, but instead, are found in every cell. These normal proteins are simply altered in their function in malignantly transformed cells. Metformin is one of what will soon be a large number of metabolomic agents entering the clinical arena as cancer research moves from the nucleus to the mitochondrion.

Cancer Gets Personal

Early in the morning of Nov 21, I suffered the loss of my father. However prepared one might be for this eventuality, there is nothing that can really prepare you.

At 95 years of age, he had lived longer than many. I had cared for my father as a patient since 1974, when he was first diagnosed with inoperable prostate cancer. I remember the day I received notification of the diagnosis. I felt a sense of deep sorrow that my father at 74 would soon die of high-grade locally advanced prostate carcinoma. As a member of the generation that forgot to have children, I was saddened that my father would not live to see grandchildren.

I remember traveling to Connecticut for his initial evaluation and then scouring the literature for the best possible options. Fortunately, despite the aggressiveness of the disease it had not metastasized.

I arranged for my father to travel to California where I then oversaw his care in collaboration with Dr. A.M. Nisar Syed in radiation oncology. There is a well-known dictum in medicine that only doctors and their families suffer unexpected complications. In my father’s case it certainly rang true. First, the radiation implants did not penetrate the tumor and needed to be removed and replaced. As a result of this double procedure, he then developed bleeding that required emergency hospitalization several days later.

Despite these hiccups, the combination of implant and external beam radiation provided excellent control. With a full recovery my father returned to his normal activities.

As so often happens in medicine a personal experience provides a focused interest. I delved into the prostate cancer literature and became increasingly interested in the biology of this disease. One area of particular interest was the role of hormonal therapy. When? How much? How long?

When my father’s PSA began to rise the second year, I had a unique opportunity to examine these questions at a very personal level. Would the early institution of androgen blockade induce the hormone refractory state? Was there a “trigger” value of the PSA that dictated the institution of the therapy? I remember discussing these questions with a prostate cancer expert and chairman of the ECOG committee, Dr. Basil Kasimis, whom I had had the pleasure of working with several years earlier. I agonized over starting hormonal therapy as my father’s PSA rose from 4 to 10, to 25, to 54, and up to 150. Despite these frightening PSA values, there was no evidence of metastatic disease on serial bone scans, which I performed religiously every six to 12 months.

Almost a decade passed but there was still no metastatic disease. And then my father developed severe coronary artery disease in his early 80s. Coronary artery bypass graft was the only option. To avoid the possibility of seeding the sternal wound, I bit the bullet and treated him with hormonal suppression – immediately driving the PSA to nearly 0.

With his coronary artery bypass surgery a success, he came off hormonal therapy and I let his PSA drift upward again.

As he had returned to Connecticut, his urologist became increasingly concerned by the rising PSA, and, without my knowledge, decided to rechallenge him with hormonal ablation. While I understood the motivation for this intervention, I didn’t agree and took him off all hormones for a prolonged period of time. Over the subsequent years, I would intervene occasionally to shepherd my father through pneumonia, a broken hip, a bleeding ulcer, and a variety of other maladies so common in patients who transition from their 80s to their 90s. On several occasions, we gave brief courses of hormonal ablation to suppress the PSA, when the steepness of the rise gave concern. Twenty-one years after his diagnosis my father died of natural causes, with no evidence of metastatic prostate cancer.

The experience was instructive on many levels. First, I realized how important it is to treat all patients as if they are a member of your own family. Second, it takes a lot of guts to step outside the normal guidelines and to do what you believe to be best. Third, I realize that in medical oncology it is the most “aggressive” physician who has the courage not to treat.

So often in this field doctors institute treatment, not because it is needed, nor because it will work, but because by doing so they have “done their job,” the rest is no longer their responsibility.

But “doing your job” as a physician, particularly in medical oncology may demand that you step outside of the NCCN guidelines, however uncomfortable it may make you, to do the right thing. Virtually every urologist or oncologist in America would have treated my father for his rising PSA 20 years ago. While I cannot say with certainty, I feel fairly confident that he lived the past 21 years in part because I didn’t treat him. Every patient needs an advocate. I feel a sense of personal satisfaction that I was there to be my father’s. He lived a long and productive life, I hope and believe that I helped him to do so.

Every experience, even traumatic ones, can have a silver lining. My father’s diagnosis lead me to develop a combined modality approach for locally advanced prostate cancer that has provided among the best biochemical relapse-free survival rates ever observed in this disease. Had I known then what I know today, I would have certainly treated my father with this approach.

Secondly, my interest in prostate cancer lead me to examine the lifestyle, nutritional, and micro-nutritional aspects of this disease – knowledge that I apply to this day. This lead to my analysis of an herbal remedy for prostate cancer that unfortunately uncovered the adulteration of an herbal mixture as we reported. (Herbal Composition PC-SPES for Management of Prostate Cancer: Identification of Active Principles: Journal of National Center Institute, Vol. 94, No. 17, September 4, 2002.) Despite our disappointment at the discovery, it lead me to reexamine the use of estrogenic substances as therapies in this disease, insights that have provided benefit to many of my patients ever since.

In retrospect, it may have been my father’s natural inquisitiveness (that he imparted to me) that leads to my pursuit of these lines of investigation. And for that I will always be grateful.

To read more about Alphonse Nagourney, click here.