Expert Advice – Another Wrinkle

Few dictates of modern medicine could be considered more sacrosanct than the prohibition of excess salt intake in our daily diets. For more then five decades every medical student has had the principle of dietary salt reduction drummed into his or her heads. Salt was the bane of human health, the poison that created hypertension, congestive heart failure, stroke, renal failure and contributed to the death of untold millions of people in the western society. At least so it seemed.

Three articles in the 08/14/2014 New England Journal of Medicine raise serious questions about the validity of that heretofore established principle of medical therapeutics.

Two of the articles utilized urinary sodium and potassium excretion as a surrogate for dietary intake to examine impact on blood pressure, mortality and cardiovascular events overall. A third article applied a Bayesian epidemiologic modeling technique to assess the impact of sodium intake on cardiovascular mortality.

salt shaker-nihThe first two articles were unequivocal. Low sodium intake, that is, below 1.5 to 2 grams per day was associated with an increase in mortality. High sodium intake that is, greater than 6 grams per day, was also associated with an increase in mortality; but the middle ground, that which reflects the usual intake of sodium in most western cultures did not pose a risk. Thus, the sodium intake associated with the western diet was safe. What is troubling however is the fact that very low sodium diets, those promulgated by the most established authorities in the field, are in fact hazardous to our health.

It seems that every day we are confronted with a new finding that refutes an established dogma of modern medicine. I have previously written blogs on the intake of whole milk or consumption of nuts, both of which were eschewed by the medical community for decades before being resurrected as healthy foodstuffs in the new millennium. One by one these pillars of western medicine have fallen by the wayside. To this collection, we must now add the low-salt diet.

Thomas Kuhn in his 1962 book, The Structure of Scientific Revolutions, stated that a new paradigm would only succeed if a new one arises that can replace it. Perhaps these large meta-analyses will serve that purpose for sodium intake and health. One can only wonder what other medical sacred cows should now be included in these types of inquiries?

As a researcher in the field of human tumor biology and purveyor of the EVA-PCD platform for prediction of chemotherapy drug response and oncologic discovery, I am intrigued but also encouraged, by the scientific community’s growing ability to reconsider its most established principles as new data forces a re-examination of long held beliefs. It may only be a matter of time before more members of the oncologic community re-examine the vast data supporting the predictive validity of these Ex Vivo Analyses and come to embrace these important human tumor phenotypic platforms. At least we can hope so.

A “Clinical Trial” Too Far

An interesting paper was published in the January 10 NEJM (Abiraterone in Metastatic Prostate Cancer with Previous Chemotherapy, Ryan et al). The study randomized 1,088 hormone-refractory prostate cancer patients to receive abiraterone plus prednisone, or placebo plus prednisone.

Abiraterone works by blocking the syntheses of testosterone (the critical survival factor for prostate cancer cells), both in the adrenal glands and within the tumor cells themselves. The drug had previously been approved for patients who had failed hormone therapy, but was only approved for those who had also failed Taxotere chemotherapy.

The results were so strongly positive in favor of the treatment arm, revealing a significant progression-free survival 16.5 versus 8.3 months (p < .001) and overall survival hazard ratio 0.75 (p = .01) that the monitoring committee invoked early stoppage rules. Virtually all of the other markers of disease also strongly favored the treatment arm. All of this speaks for an effective therapy in hormone-refractory prostate cancer and we applaud their success.

The question remains: Did we really need to conduct this study?

On a biochemical level, abiraterone represents an effective mechanism for androgen ablation. The drug has been established to work well in patients who have failed prior hormone and Taxotere chemotherapy. In that prior exposure to Taxotere would not be expected to substantively influence abiraterone efficacy, the wisdom of committing 1,088 hormone-refractory patients to a “placebo controlled” randomized trial to prove its efficacy in the Taxotere naive population seems questionable.

Prostate cancer generally afflicts older men. While most patients respond to hormonal ablation, hormone-refractory disease develops in virtually all patients over time. A comparatively mild oral therapy like abiraterone represents a demonstrably superior alternative to a comparatively toxic alternative intravenous cytotoxic drug like taxotere. Did we need to marshal a multi-million dollar trial to prove that abiraterone worked in people who had not received Taxotere, when there was absolutely no reason to believe that it wouldn’t?

The reason that this trial was conducted was to meet an increasingly onerous regulatory environment that demands that every use of every drug in every situation be proven with a large and enormously expensive clinical trial.

Registration trials cost between $10,000 and $20,000 per accrued patient. Using these figures, we can guess that this clinical trial cost between $10,000,000 and $20,000,000 to conduct. Those costs must now be recouped from patients and insurers. Thus, the very agency whose purpose is to protect patients and limit the inappropriate use of drugs has created an environment that adds to those expenses and it can be argued, prevents the appropriate use of drugs.

To put this into perspective, let’s examine the female counterpart – breast cancer. Once aromatase inhibitors showed activity in postmenopausal women, they were rapidly incorporated into clinical therapeutics. Dovetailing nicely with the established antiestrogen tamoxifen, these drugs became second line hormonal therapies. While these drugs naturally assumed their roles in hormonal management of breast cancer, no one would ever demand that a breast cancer patient with ER positive cancer first receive chemotherapy before being allowed to use the well-established aromatase inhibitors. Had the FDA demanded that no one could receive anastrozole, letrozole or Aromasin until they had had Adriamycin, there would have been a march on Washington to reverse the policy. It was obvious to all those engaged in the field that these drugs worked and that they would work at different points in hormonal management of the disease.

The physiology of and clinical experience in breast cancer management allowed smart scientists with the approval of the regulatory agencies to “crosswalk” the application of these important agents. It is time for the American public to demand that clinical trials be conducted (and resources allocated) when the questions they address can only be answered through the expenditure of these vast financial and human resources.

What Goes Around Comes Around

On a recent morning, I found myself listening to an analysis of the public defender program in America. It seems that defendants who are provided with publically funded lawyers are almost uniformly advised to submit pleas. Regardless of the strength of their cases or their apparent innocence, plea bargains have become the preferred legal defense.

As I listened, the reason became increasingly apparent. It seems that in many states, legal fees paid to public defenders are bundled into a single, one-time payment. Lawyers are provided the same amount of money whether the client is convicted or found innocent. If the lawyers choose to vigorously defend their clients and prove their innocence, they receive precisely the same amount of money that they would receive if the accused pleaded guilty on the spot. It has not taken long for the legal community to figure out that plea bargains are good for business.

As a physician, I found this analysis of more than passing interest. After all, the movement toward managed care and the DRG (diagnosis-related groups) system make lump sum payments for medical care the norm. Using arbitrary metrics like per member/per month, physicians receive the same amount of the money whether they save your life or not. The defenders of this approach explain that it was designed to limit the profit motive and curtail physician avarice. What it has succeeded in doing however, is to incentivize physicians to give up. If there is no return on investment, then there will be no investment of time, energy, skill or ability. If physicians receive no more payment, accolades, or recognition for good outcomes than for bad ones, how long can we realistically expect good outcomes to continue?

The district attorneys, who were interviewed for the piece on public defenders, pointed out, in their defense, that this has succeeded in “clearing the dockets” of backlogged court cases. However, if we were to extend that line of reasoning into the realm of medical care delivery, we would need to confront a number of distinctly unappealing ramifications.

The corporatization of medicine, expanding regulation, creation and promotion of the HMO model, and recent legislation are all the products of legal minds. While NCCN cancer therapy guidelines are increasingly employed, not as guidelines, but instead as dictates to limit the ability of well-trained, sophisticated oncologists to practice their art; a recent article in the New England Journal of Medicine on bending the healthcare curve had the “underutilization” of hospice care as a principal focus. It is interesting to observe how lawyers, faced with “lump sum” payments, are responding. Is the reported deterioration of legal representation, especially for the under privileged in America, the jurisprudence counterpart to policies already underway in the medical system? Will the same disincentives in place for physicians now come home to roost for lawyers?