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.

The Meaning of Meaningful Improvement in Lung Cancer

When asked to define what constituted pornography in his 1964 Supreme Court decision (Jacobellis versus Ohio 1964) Justice Potter Stewart stated, “I know it when I see it.” When I reviewed an article on the changing landscape of clinical trials in non-small cell lung cancer (NSCLC) (Shifting patterns in the interpretation of phase 3 clinical trial outcomes in advanced non-small cell lung cancer: The bar is dropping, Sacher A. G. et al, J Clin Oncol May 10, 2014), Justice Stewart came to mind.

The authors selected 203 NSCLC trials from a total of 245 studies conducted between 1980 and 2010. They compared how often the studies met their endpoints with how often the study authors’ called the results “positive.” Among the findings, it seems that earlier studies (before the year 2000) were geared for overall survival, while later studies (after 2000) overwhelmingly favored progression free survival. Although patient survivals changed little, the number of trials reported as successful increased dramatically.

Non-small cell lung cancer

Non-small cell lung cancer

Progression-free survival measures how long it takes for a patient to fail treatment. That is, for the disease to worsen on therapy. Its use increased after 2000 when Docetaxel, for the first time, provided a survival advantage in recurrent disease.

The FDA’s willingness to accept progression-free survival for drug approval was originally based on their expectation that the benefit would be “substantial and robust” but they did not define the term. One group has suggested that improvements should be of the magnitude of 50 percent. Another went even further suggesting a doubling of the survival advantage.

Unfortunately, the trend has been just the opposite. Trials from the 1980s on average gave a 3.9 month improvement, which fell to a meager 0.9 months after 2000.

What are patients and their physicians to make of these trends? First, the large clinical trials, that are so common today, are much more likely to achieve significance. The troubling corollary is that statistical significance is not the same as clinical relevance. The “publish or perish” climate, combined with the skyrocketing cost of drug development has placed inordinate demands upon investigators and their sponsors to achieve “positive results.” Fearing failure, many pharmaceutical companies sponsor “safe” trials that provide incremental advances but few breakthroughs.

Meaningful advances in oncology are generally quite evident. The first use of Interferon alpha for the treatment of hairy cell leukemia provided a response rate of 100 percent and earned a lead article in the New England Journal of Medicine (NEJM) with only seven patients!

Similarly the 57 percent response rate for Crizotinib in ALK positive lung cancer required only 82 patients for a place in the NEJM. Unfortunately, the failure of contemporary investigators to identify more “paradigm changing therapies” has forced many to lower the bar.

The clear solution to the problem is the better selection of candidates for therapy. Despite advances in molecular biopsy a paucity of truly effective companion diagnostics exist. Outside of EGFR, ALK, and ROS-1, it is anybody’s guess how to manage the vast majority of non-small cell lung cancer patients.

While we expand our armamentarium and develop better companion diagnostics, today we can apply measures of cellular response (as found in an EVA-PCD assay)
that capture all of operative mechanisms of sensitivity for all classes of drugs. While it is not always possible to know why a patient will respond, it is possible to know that they will respond. In the words of Judge Stewart, when it comes to a responsive lung cancer patient “I know it when I see it.”