In Cancer Research: An Awakening?

In 2005, as the Iraq War reached a low point with casualties mounting and public support dwindling, Sunni tribesman in the Anbar Province arose to confront the enemy. Joining together as an ad hoc army these fighters turned the tide of the war and achieved victories in the face of what had appeared at the time, to be overwhelming odds.

I am reminded of this by an article in The Wall Street Journal by Peter Huber and Paul Howard of the Manhattan Institute that examined the bureaucracy of drug development. It raised the question: Are new cancer treatments failures or is the process by which they are approved a failure? They describe “exceptional responders” defined as patients who show unexpected benefits from drug treatments. Using molecular profiles, they opine, scientists will unravel the mysteries of these individuals and usher in an era of personalized medicine. Thus, rigid protocols that use drugs based upon tumor type e.g. lung vs. colon fail because they do not incorporate the features that make each patient unique – an awakening.

The example cited is from Memorial Sloan-Kettering where a patient with bladder cancer had an unexpected response to the drug Everolimus (approved for kidney cancer). Subsequent deep sequencing identified a genetic signature associated with sensitivity to this drug. While it is a nice story, I already knew it very well because it had been repeated many times before and would in the past have been dismissed as an “anecdote.” It is precisely because of its rarity that it has been repeated so many times.

The WSJ analysis strikes a familiar chord. For decades, we have decried the failure of rigid clinical trials that underestimate a patient’s unique biology yet cost millions, even billions of dollars, while denying worthy candidates new treatments under stultifying disease-specific designs.

Well Tray Closeup2 smallWe pioneered phenotypic (functional) analyses (the EVA-PCD platform) to examine whole cell models as we explored drug response profiles, novel combinations and new targets. It is regrettable that these WSJ authors, having raised such important issues, then stumble into the same tantalizing trap of molecular diagnostics, and call for bigger, better, faster genomic analyses.

Cancer patients need to receive treatments that work. They do not particularly care why or how they work, just that they work. These authors seem to perpetuate the myth that we must first understand why a patient responds before we can treat them. Nothing could be further from the truth.

Alexander Fleming knew little about bacterial cell wall physiology when he discovered penicillin in 1928, and William Withering knew nothing about the role of muscle enzymes in congestive heart failure when he discovered digoxin extracts in 1785. Would anyone argue that we should have waited decades, even centuries to apply manifestly effective therapies to patients because we did not have the “genes sequenced?’

We may be witness to an awakening in cancer drug development. It may be that a new understanding of individualized patient response will someday provide better outcomes, but platforms with the proven capacity to connect patients to available treatments should be promoted and applied today.

Breakthroughs In Cancer?

Coco Chanel, the icon of 20th century fashion once said, “Only those with no memory insist on their originality.” I am reminded of this quote as I review recent discoveries in cancer, among them, the recognition that cancer represents a dysregulation of cellular metabolism.

The field of metabolomics (the systematic study of cellular energy production), explored by investigators over the last decade is little more than the rediscovery of enzymology (a branch of biochemistry that deals with the properties, activity, and significance of enzymes), biochemistry (the science dealing with the chemistry of living matter) and stoichiometry (the part of chemistry that studies amounts of substances that are involved in reactions), pioneered by investigators like Albert Lehninger, Hans Krebs, Otto Warburg, and Albert Szent-Gyorgyi. These innovators used crude tools to explore the basis of human metabolism as they crafted an understanding of bioenergetics (the study of the transformation of energy in living organisms) and oxidative phosphorylation (processes occurring in the cell’s mitochondrion that produce energy through the synthesis of ATP (energy carrier of the body).

More recently, scientists wedded to genomics have slowly come to recognize the limitations of their approach and have returned to the field of phenotypic (the observable physical or biochemical characteristics of an organism analysis.

While newcomers to the field claim to be the first to recognize the role of cellular biology in tumor biology, a cadre of dedicated investigators had already charted these waters decades earlier. Beginning with the earliest studies by Siminovitch, McCulloch and Till, subsequent investigations by Sydney Salmon and Anne Hamburger, developed the earliest iteration of cellular studies for the examination of cancer biology in primary culture.

Ovarian Cancer

Ovarian Cancer

The work of Black and Spear, published in the 1950s similarly explored the study of human cellular behavior for the study of cancer research. While Larry Weisenthal, Andrew Bosanquet and others established useful predictive methodologies to study cellular phenotype, their seminal contributions have gone largely unrecognized.

Today, start-up companies are examining cellular biology to predict cancer outcomes, each claiming to be the first to recognize the importance of cell death events in primary culture. The most recent and widely touted in the literature is the use of mouse avatars. Implanting biopsied explants of tissue from patients into nude mice, they grow the cancers to desired size and then inject the drugs of interest to show tumor shrinkage. To the discerning eye however, it obvious that this represents little more than an expensive, inefficient, and extremely slow way to achieve that, which can be done more easily, inexpensively, and quickly in a tissue culture environment.

When I read the promotional material of some of the new entrants to this field, I am reminded of another quote, that of Marie Antoinette, who said, “There is nothing new except what has been forgotten.”

A New Use for One of the Oldest “New” Drugs

With the profusion of new targeted agents entering the clinical arena, a report from the American Society of Hematology bears consideration.

The trial known as the SORAML trial enrolled 276 patients with newly diagnosed acute myelogenous leukemia. The patients were between the ages of 18 and 60. All patients received a standard chemotherapy regimen. The patients were then randomized to receive Sorafenib or placebo. Patients on the Sorafenib arm then remained on a maintenance therapy for twelve months.

While the achievement of complete remission was almost identical between the two arms at 59% and 60%, the event free survival demonstrably favored the Sorafenib group at 20.5 months versus 9.2 months. At three years of follow-up 40% of the Sorafenib group were well with only 22% of the placebo group still in remission. This corresponds to a three-year relapse free survival of 38% for placebo and 56% for Sorafenib (P=0.017).

The results are of interest on several levels.
1.    Sorafenib a multitargeted tyrosine kinase inhibitor was approved in December 2005 for the treatment of renal cell carcinoma. This makes Sorafenib one of the first targeted agents to achieve FDA approval.

2.     Sorafenib has many modes of action and it is not entirely clear which of its functions were responsible for the superior survival in this AML study.

3.    Sorafenib’s approval reflects a rather convoluted and interesting history. When first developed the drug was designed to target the oncogene B-Raf. As a result the drug was introduced into early clinical trials for the treatment of advanced melanoma, a disease known to be associated with B-Raf mutation. As the drug proved ineffective, it appeared unlikely to gain FDA approval. That is, until it showed cross reactivity with VEGF pathway associated with tumor cell vascularity. A successful trial published in the New England Journal of Medicine then led to the approval.

Now, nine years later this old new drug has gained new life. This time in acute myelogenous leukemia.

The term “dirty drug” refers to agents that target many kinases at the same time. Sorafenib is an example of a “dirty drug.” However it is Sorafenib’s “dirty drug” quality that led first to its approval and most likely now leads to its application in AML. This reflects the fact that Sorafenib may be inhibiting B-Raf signaling associated with the common mutation in Ras upstream of B-Raf or it may reflect Flt3 a secondary activity associated with Sorafenib.

Indeed B-Raf and Flt3 may not be upregulated in every patient, but could serve a function of permissive activity granting an additional survival signal to the AML cells as they go through induction therapy. These subtleties of drug effect may escape genomic analysis as the true “target” may not be mutated, upregulated or amplified. No doubt the investigators in this study will conduct gene sequencing to determine whether there is a driver mutation associated with the advantage reported in this clinical study. What will be intriguing is to determine whether that advantage is an abnormal gene functioning within these cancerous cells or possibly a normal gene functioning abnormally in these cancer cells. More to come.

Genomic Profiling for Lung Cancer: the Good, the Bad and the Ugly

Genomic profiling has gained popularity in medical oncology. Using NextGen platforms, protein coding regions of human tumors known as exomes can be examined for mutations, amplifications, deletions, splice variants and SNPs. In select tumors the results can be extremely helpful. Among the best examples are adenocarcinomas of the lung where EGFr, ALK and ROS-1 mutations, deletions and/or re-arrangements identified by DNA analysis can guide the selection of “targeted agents” like Erlotinib and Crizotinib.

An article published in May 2014 issue of JAMA reported results using probes for 10 “oncogenic driver” mutations in lung cancer patients. They screened for at least one gene in 1,007 patients and all 10 genes in 733. The most common was k-ras at 25%, followed by EGFR in 17% and ALK in 8%. The incidence then fell off with other EGFr mutations in 4%, B-raf mutations in 2%, with the remaining mutations each found in less than 1%.

Median survival at 3.5 vs 2.4 years was improved for patients who received treatments guided by the findings (Kris MG et al, Using multiplex assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA, May 2014). Do these results indicate that genomic analyses should be used for treatment selection in all patients? Yes and no.

Noteworthy is the fact that 28% of the patients had driver mutations in one of three genes, EGFr, HER2 or ALK. All three of these mutations have commercially available chemotherapeutic agents in the form of Erlotinib, Afatinib and Crizotinib. Response rates of 50% or higher, with many patients enjoying durable benefits have been observed. Furthermore, patients with EGFr mutations are often younger, female and non-smokers whose tumors often respond better to both targeted and non-targeted therapies. These factors would explain in part the good survival numbers reported in the JAMA article. Today, a large number of commercial laboratories offer these tests as part of standard panels. And, like k-ras mutations in colon cancer or BCR-abl in CML (the target of Gleevec), the arguments in favor of the use of these analyses is strong.

Non-small cell lung cancer

Non-small cell lung cancer

But what of the NSCLC patients for whom no clear identifiable driver can be found? What of the 25% with k-ras mutations for whom no drug exists? What of those with complex mutational findings? And finally what of those patients whose tumors are driven by normal genes functioning abnormally? In these patients no mutations exists at all. How best do we manage these patients?

I was reminded of this question as I reviewed a genomic analysis reported to one of my colleagues. He had submitted a tissue block to an east coast commercial lab when one of his lung cancer patients relapsed. The results revealed mutations in EGFr L858R & T790M, ERBB4, HGF, JAK2, PTEN, STK11, CCNE1, CDKN2A/B, MYC, MLL2 W2006, NFKB1A, and NKX2-1. With a tumor literally bristling with potential targets, what is a clinician to do? How do we take over a dozen genetically identified targets and turn them into effective treatment strategies? In this instance, too much information can be every bit as paralyzing as too little.

Our preferred approach is to examine the small molecule inhibitors that target each of the identified aberrancies in our laboratory platform. We prefer to drill down to the next level of certainty e.g. cellular function. After all, the presence of a target does not a response make.

In this patient I would conduct a biopsy. This would enable us to examine the drugs and combinations that are active against the targets. A “hit” by the EVA-PCD assay would then isolate the “drivers” from the “passengers” and enable the clinician to intelligently select effective treatments. Combining genomic analyses with functional profiling (phenotypic analyses) provides the opportunity to turn speculative observations into actionable events.

This is the essence of Rational Therapeutics.

Pigment, Color and Cancer

An interesting story reported by National Public Radio on November 12 described the origins of color in biology. Andrew Parker, a biologist from London’s Natural History Museum, described the development of sightedness in living organisms.

Until 600 million years ago animals were sightless. Then predatory organisms developed vision and used it to pursue prey. From that point color became an integral part of biological existence. Colors could attract mates, serve as camouflage, protect against predators and attract other organisms such as pollinating bees.

One of the more interesting aspects of the discussion was the fact that vertebrates have no capacity to produce the color blue. Indeed green is also quite difficult. So how, one might ask, do butterflies, peacocks and people with blue eyes create the appearance of the color blue? The answer is quite interesting and may be instructive when we examine other biological phenomena.

Pigments, known as biochromes, are substances produced by living organisms that have the capacity to absorb or reflect light o220px-Lightmatter_flamingo2f specific wavelengths. Their chemical structure captures the energy of the light wave resulting in the excitation of electrons to higher energy states. Among the colors commonly found are heme porphyrins, chlorophyll, carotenoids, anthocyanins, and betalains. While it is comparatively easy for plants to produce a broad spectrum of colors, animals have a more limited palate. They can borrow pigments from other species, like the flamingo whose pink hue is borrowed from the shrimp it eats. It seems however, that blue and green pose unique problems and must be created through an ingenuous melding of chemical biochromes and what is known as “structural pigmentation.”

The wings of a bluebird or those of a Morpho butterfly use specialized structures that are capable of capturing light at just the right angle. In so doing, they selectively reflect light and combine specific wavelengths with chemical pigments to create the illusion of color. Blue butterflies and green parrots are, in reality, sophisticated illusionists.

So what of other biological phenomena, specifically cancers? Quite a lot it seems. We have come to think of cancer as a product of genetic information. Our linear thinking with origins in cancer biology dating to the 1950s has long held that biological phenomena reflect the presence (or absence) of genes. The principal known as Central Dogma dictated that DNA produced RNA, that RNA produced protein and that protein produced function.

Our tidy principles were dealt their first blow by the discovery of epigenetics and then by small interfering RNAs. Most recently noncoding DNAs have further clouded the picture. It seems that the behavior of cancers may be every bit as deceptive as the bright blue hue that we ascribe to our avian and insect brethren.

Like butterflies or birds, cancers cloak themselves in a mixture of genetic and structural elements. While their behavior may appear to reflect genetic aberrancies, it may be structural (e.g. micro-environmental) perturbations that confer their unique biology. One can no more grind up and extract a parrot’s wings to find blue pigment than can we grind up and extract the genetic information of cancer to recreate its cobrilliance-clipart-canstock1498651mplexity. This however has not prevented the reductionists among us from trying. Unfortunately for them, cancers are demonstrably more complex than their genetic makeup.

Like a bird or a butterfly we must witness the creature in its entirety to grasp its function and behavior. Genomic analyses conducted in a vacuum cannot define the complexity of cancer biology. To create successful cancer treatment outcomes, we need to determine cellular phenotype. And, the EVA-PCD assay is quintessentially phenotypic. This is why the functional profile resulting from the EVA-PCD assay can identify accurate targets and select therapies.

The Cost of Chemotherapy Comes Home to Roost

NY TImes rotatedMedical care in the United States is a $2.7 trillion industry. That translates into almost $8,000 per person per year. One of the most expensive aspects is cancer care. This has caught the attention of the medical oncology community. A highly touted editorial in the October, 2012 New York Times described the unwillingness of physicians at Memorial Sloan Kettering Cancer Center to add a new and expensive drug to their formulary. The authors opined that the new drug provided outcomes similar to those for an existing drug, yet cost twice the price.

A subsequent editorial in the Journal of Clinical Oncology from MD Anderson (Cancer Drugs in the United States: Justum Pretium – The Just Price) further examined the cost of cancer therapy, profit margins and some of the drivers. Among the points raised was the fact that the monthly cost of chemotherapy had more than doubled from $4,500 to $10,000 in just one decade. Furthermore, of twelve anticancer drugs approved in 2012, only three prolonged survival and for 2 of 3 by less than two months. Despite these marginal benefits, nine of the twelve drugs were priced at more than $10,000 a month.
60 Minutes
This caught the attention of the media with 60 Minutes recently conducting an interview with the authors of the New York Times editorial. While Lesley Stahl pointedly decried the rather marginal 4 – 6% markups that many physicians apply to cover their costs of chemotherapy drug administration, there are in fact much darker forces at work.

The cost of cancer drug development reflects the expense of human subject trials, cost of R & D, the regulatory burden, as well as an extraordinary new drug failure rate. Fully 50% of new agents fail at Phase III (the last and most expensive type of study). Phase III trials cost tens to hundreds of millions of dollars. An article in Forbes magazine stated that the average drug approved by the FDA now costs, not the one billion dollars often cited but instead five billion dollars when one factors in the failures against the rare successes.

Drug development begins with a novel idea, a small molecule and a few preliminary results. At this point the expenses are low but the drug is of little commercial value. As one moves from cell lines to animal models, the price goes up but the value remains low. The cost of formulation, toxicology and animal studies continue to add up but doesn’t influence interest in the agent. Then come human studies as the Phase I trials begin. Specialized institutions across the United States accept contracts with the pharmaceutical industry to examine the tolerability of the drug. I use that term advisably as the intent of Phase I trials is only to determine safety not efficacy. If the drug proves tolerable, it then moves to Phase II to explore it’s activity against cancer. This is where the money starts flowing.

Phase II clinical trials are conducted by university medical centers. Each patient accrued costs the pharmaceutical sponsors from $25,000 to more than $50,000 per patient. As drugs are tested in many schedules against many diseases it can take hundreds or even thousands of patients for statistical analysis. Nonetheless, a successful Phase II trial showing meaningful benefit in a cancer population generates a buzz and the drug’s value begins to gain traction. With hundreds of millions already expended, the final testing pits the new drug against an existing standard in one or more Phase III trials. Endpoints like progression-free-survival must then fold into overall survival if the drug has any hope to gain full approval by the FDA. These registration triaus-money-with-black-backdrop-1024x640ls at the national or international Phase III level cost up to $100,000 per patient and most of the participating institutions are university-based medical centers or their affiliates.

So, why do chemotherapy drugs cost so much? While it may be convenient to point fingers at the pharmaceutical industry, private practitioners or the smaller institutions, the university medical centers and their affiliates have added greatly to the costs of drug development as have the increasingly byzantine regulatory standards that have so encumbered the process that it is now increasingly only a rich man’s game.

We applaud the investigators at Memorial Sloan-Kettering for focusing attention upon this important matter. We applaud 60 Minutes and the authors of the Journal of Clinical Oncology editorial for their exploration of the same. While the willingness of these physicians to raise the issue is laudable, the solution may be somewhat more complex than these authors have been willing to admit. Before we vilify private practitioners who have time and again proven to be more efficient and less expensive purveyors of cancer care than their university brethren we should examine other drivers.

To wit, a review of one of the NY Times editorial author’s conflicts of interest statement listed in the 2012 American Society of Clinical Oncology proceedings revealed that his co-presenters at this national meeting disclosed fully 16 separate pharmaceutical affiliations for employment or leadership positions, consultant or advisory roles, stock ownership, honoraria, research funds, expert testimony, or other remuneration. With the research community enjoying these levels of compensation, it must be surmised that the costs of clinical trials reflect in part these expenditures. When one adds to this, the increasingly burdensome regulatory environment, the cost of cancer chemotherapy development appears to have plenty of blame to go around.

Future (Cancer) Shock

Two related clinical trials were reported in the last several months describing the use of heat shock protein 90 (HSP90) inhibitors in lung cancer. Both trials fell short of their pre-specified endpoints casting a pall upon these drugs. However, the study of HSP90 inhibitors should not be abandoned based on these finding, as this is a fertile area of investigation and offers opportunities for the future.

Human cells marshal many defenses against stress. Thermal injury can damage basic cellular functions by denaturing (inactivating) proteins. The machinery of cells is largely comprised of protein enzymes. Excessive heat coagulates proteins much the way the albumin of an egg turns white during cooking. The loss of fluidity and function ultimately results in cell death. The heat shock proteins come to the rescue by shepherding these proteins away from injury and protecting them from denaturation.

220px-Hsp90There are many different heat shock proteins found in human cells, but one of the most abundant and active in cancer cells is known as HSP90 for its molecular weight in the range of 90-kilodaltons. Over the last two decades investigators have explored the use of small molecules to inhibit these important proteins. Among the first compounds to be isolated and applied were derivatives of geldenamycin. Although geldenamycin itself is a poison that causes severe liver damage, its derivative 17-AAG, also known as tanespimycin, has successfully entered clinical trials.

The current studies examined two other HSP90 inhibitors. One retaspimycin, has been developed by Infinity Pharmaceuticals. This clinical trial combined retaspimycin with docetaxel and compared results with docetaxel alone in 226 patients with recurrent lung cancer. None of the patients had received docetaxel prior to the trial. Drugs were administered every three weeks and the efficacy endpoint was survival with a subset analysis focused on those with squamous cell cancer. The trial fell short of its pre-designated endpoint. Interestingly, the study failed to provide benefit even in patients who were specifically targeted by their tumor’s expression of the K-Ras, p53 or by elevated blood levels of HSP90, the putative biomarkers for response.

The second trial examined a different HSP90 inhibitor developed by Synta Pharmaceuticals. The drug ganetespib was combined with docetaxel and the combination was compared with docetaxel alone. The results just reported indicate that the combination provided a median survival of 10.7 months, while docetaxel alone provided a median survival of 7.4 month. Although this represented a three month improvement, it did not meet the pre-specified target.

Taken together, these results could dampen enthusiasm for these agents. This would be unfortunate, for this class of drugs is active in a number of human tumors. We observed favorable activity and synergy for the HSP90 inhibitor geldenamycin and its derivative 17-AAG as we reported (Nagourney RA et al Proc. AACR, 2005). More importantly, 17-AAG (tanespimycin) provided objective responses in 22% and clinical benefit in 59% of patients with recurrent HER2 positive breast cancer after these patients had failed therapy with Herceptin. This clearly supports the role of HSP90 inhibition in breast cancer and would suggest that other more carefully selected target diseases could benefit as well.

The function of HSP90 is not completely understood as it influences the intracellular trafficking of dozens ofHsp90cycle proteins. One of the complexities of this class of drugs is that they protect and enhance the function of both good and bad proteins. After all, the HSP90 protein doesn’t know which proteins we, as cancer doctors, would like it to protect.

When we apply the EVA-PCD analysis to these and related classes of compounds we focus our attention upon the downstream effects, namely the loss of cell survival. That is, whatever proteins are influenced, the important question remains “did that effect cause the cells to die?” Classes of compounds with nonspecific targets like the HSP90 inhibitors will surely be the most difficult to characterize at a genomic or proteomic level: What protein? What gene?

Functional platforms like the EVA-PCD offer unique opportunities to study these classes of agents. We are convinced that the HSP90 inhibitors have a role in cancer therapy. It would be unfortunate if these setbacks led us to “throw the baby out with the (hot) bathwater,” thus slowing or preventing their use in cancer treatment.

A Tribute to Loretta Stamos 1939 – 2014

RAN & Loretta cropped lo res

Dr. Nagourney and Loretta Stamos

On Monday, September 22, 2014, we lost a great ally and a better friend.

Loretta Stamos lost her own fight with cancer, the very disease that she had worked so tirelessly to defeat. I first met Loretta in 1995 when her brother Jake was diagnosed with advanced lung cancer. His physicians didn’t offer much hope. At our meeting, I explained my approach to cancer therapy using each patient’s cells to select drugs (EVA-PCD functional profile).

“Let’s do it,” said Loretta.

“Now?” I asked.

“Why not?” she replied. As I would come to know over our 20 year friendship, Loretta didn’t mince words and was not one to take no for an answer.

A simple two drug combination was recommended for Jake, but his physicians declined. Loretta asked if I would assume his care. As I was out-of-network for his HMO, each time we treated her brother, Loretta generously covered the chemotherapy costs. After two cycles of treatment, the pleural fluid stopped accumulating. Jake gained weight and returned to some of his normal activities.

The in-network physicians began to realize that they were on the wrong side of this equation and suddenly offered to continue the treatments at their facility. Jake’s cancer ultimately progressed. His extensive metastatic disease involving his lung and bones was too aggressive for even the best chemotherapy to cure. Despite the sad loss, we had succeeded in showing that every patient deserved the chance to get better regardless of their insurance or finances.

Loretta wondered what would have happened if she had not been there to help. I explainRAN_LS_JS2 lo resed that the laboratory analyses were too costly for me to donate. Though they came in at a fraction of the price of a single dose of chemotherapy, many insurers refused to cover them. Loretta said, “I’m going to make sure that people who need these tests will never be denied.” And the Vanguard Cancer Foundation (VCF) was born.

Months of work, committee meetings and planning sessions culminated in a “A Night in Brazil,” a gala benefit that raised $100,000. John Stamos, Dave Coulier and Bob Saget turned in stellar performances as the MCs and a great time was had by all. More importantly, for the first time we could to say to patients, “We can find the treatment that’s right for you and if you can’t afford it, we’ll give it to you.” With each passing year the fund grew as did the number of patients we could help.

John and Loretta Stamos w-Sarah AmentoWhat a luxury to never turn a patient away. What an opportunity to help uninsured and younger patients. What a pleasure to see the good responses, even in some patients considered previously “untreatable.” I was overwhelmed by Loretta’s dedication and the kindness that she and the VCF members showed to patients in need. Every year we would recognize Loretta and her family for their hard work and generous contributions, and every year Loretta would say that she did this because “I made her brother smile.”

There is a silver lining to even the darkest cloud. It was Loretta who put it most poignantly when she defined the mission of the Vanguard Cancer Foundation as providing lifesaving care to “persons of worth but not of means.” The most fitting tribute of all for this noble soul is the more than 400 patients who can thank Loretta Stamos for a second chance at life.

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.

Cancer Centers and Advertising: The Truth Be Told

Screen shot 2014-08-06 at 5.08.23 PMSome of the most interesting literature on cancer comes from journals that are not directly involved in the field. I was reminded of this by an article that appeared in the June 17, 2014 Annals of Internal Medicine entitled “What Are Cancer Centers Advertising to the Public?”

The authors examined the types of clinical services that are promoted by commercial advertising. They reviewed advertisements that appeared in the top media markets during the year 2012, including both television and magazine ads. They excluded duplicates, public service announcements, fund raising and research subject recruitment. Of 1,427 total advertisements, 409 were considered to be unique ads that promoted clinical programs at 102 different cancer centers.

Screen shot 2014-08-06 at 5.13.29 PMTo analyze the content, the investigators developed a “code book” that included four domains; the types of clinical services, information provided, the use of emotional advertising appeals and the use of patient testimonials. Among the centers analyzed, 59% were for profit and the same percent were accredited by the Commission on Cancer. Sixteen percent were NCI designated centers. Advertising was also characterized by region of the United States. The results are interesting and instructive.

Of the 409 unique clinical advertisements, 88% promoted treatment. This was demonstrably higher than the percentage promoting cancer screening at 18% or supportive services at only 13%. While the benefits of therapies were described in 27% of the ads, the risks were only mentioned in 2%. Emotional appeals were frequent with 85% of the ads evoking hope for survival. Cancer was often described as a fight or battle, and the use of fear (of death, etc.) was found in fully 30% of the advertisements.

Screen shot 2014-08-06 at 5.15.28 PMIn their discussion, the authors pointed out several interesting findings. Among them, the “frequent use of emotional appeals and scarce mention of risk of services or quantification of benefit.” They also found “that NCI designated centers more frequently used emotional appeals related to survival or potential for cure.” These same centers “omitted information about risks, benefits and alternatives with similar frequency as non-NCI designated centers.” They concluded that “emotional appeals coupled with incomplete information are being widely used to promote services even among the nation’s most prestigious cancer centers.” Interestingly while only 5% of cancer centers in the United States are NCI designated, fully 16% of the clinical cancer advertising in 2012 was conducted by NCI-designated centers, a three-fold higher use.

What are we to gather from this analysis? First a journal like the Annals of Internal Medicine, removed from the direct delivery of cancer care, has the gravity to review processes that would rarely be reported in the oncology literature. Second, NCI designated (academic) cancer centers, who claim to eschew dissemination of unsScreen shot 2014-08-06 at 5.23.56 PMubstantiated information, appear to be the very centers that engage in such promotion. As the authors note, “clinical advertisements that use emotional appeal uncoupled with information about indications, benefits, risks, or alternatives may lead patients to pursue care that is either unnecessary or unsupported by scientific evidence.”

We applaud the authors of this Annals of Internal Medicine article for their unbiased and informative analysis. We must all strive to provide patients practical and actionable information about cancer and its treatment. It appears from this study that the practice of self-promotion crosses all lines of cancer care delivery from the most august academic institutions to the for-profit cancer centers. As with all activities in life, cancer patients are to be reminded of the ancient Roman admonition “Caveat Emptor” (Buyer Beware!).