The Tyranny of Medical Experts

Over the last several years a number of decisions have been handed down from medical experts, I use the term “handed down” advisedly. Like the Olympian Gods or appellate court judges, these dictates are provided to the unsuspecting medical public as fiats. Among these are the roles of mammograms for women under 50 (not recommended), PSA screening for men (not recommended), and a variety of determinations that seem to many counterintuitive. In the past, similar recommendations have been handed down regarding a series of “unnecessary” tests, the cessation of which could save millions of dollars annually.

These topics were the subject of a recent article by Drs. Pamela Hartzband and Jerome Groopman, members of the faculty at Harvard Medical School. Published in the Saturday, March 31, 2012, Wall Street Journal, their article “Rise of the Medical Expertocracy,” focuses on the new paternalism that has come to define “Best Practices” in the healthcare. What most concerns these authors is the transition from physicians as experts, to governmental entities as experts. With this new bureaucracy comes an entirely new industry dedicated to the generation of medical metrics designed to provide doctors and hospitals report cards on their performance. Like evidence-based medicine, yesterday’s catchphrase for improving treatments, “Best Practices” are now being forced upon practitioners.

Where the purveyors of these approaches have gone wrong, is their misguided attempt to apply average treatments to average patients with the expectation of average outcomes. Despite the appeal of simplified treatment algorithms, there are no average patients and it follows that there are no average outcomes.

In a recent presentation at the American Association for Cancer Research meeting held in Chicago March 31 – April 4, 2012, one of the presenters at the melanoma session described whole genome sequencing on 21 human melanomas. To their chagrin they found 21 completely different phosphoprotein signatures. From the macroscopic to the most microscopic mankind in general and his tumors in particular, distinguish themselves for their unique attributes.

The theme of Drs. Hartzband and Groopman’s article echoes loudly in our study of cancer patients. We will only succeed in saving money and saving lives when we stop banging round pegs into square holes and get down to the challenging, but very doable work of matching each individual to their best treatment option – truly personalized medicine.

English Patients Denied Access to Ipilimumab

Among the more interesting discoveries in recent years have been two breakthroughs in the management of malignant melanoma. One drug, vemurafenib, a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation. The second drug ipilimumab, offered commercially from Bristol-Meyers Squibb as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While vemurafenib has a somewhat narrow target population, ipilimumab targets may extend to a broader range of melanoma patients and will likely find a role in other cancers.

The data supporting ipilimumab’s use in advanced melanoma was reported in a 2010 Phase III trial, which provided a superior median survival for those treated with the drug over those who received a placebo. Superior one and two-year survivals were also reported. Unfortunately, this did not rise to the level that met the standards of the English watchdog organization, National Institute for Health and Clinical Excellence (NICE). The chief executive of NICE did admit that the drug could “potentially be very effective for a small percentage of patients.” Unfortunately, under current NICE guidelines, that small percentage of patients will not have access to the drug.

This is not the first time that a drug, found effective for the treatment of a subpopulation of patients has been denied approval based upon cost efficacy and the comparatively limited population of patients who stand to gain.

The role of Avastin in breast cancer represents a similar dilemma for those patients who might benefit but cannot afford the out-of-pocket expenses. Indeed, NICE originally denied approval to bortezomib, a highly active drug for the treatment of multiple myeloma, based upon similar cost considerations.

What ipilimumab, Avastin and bortezomib have in common is that they are harbingers of the coming conflict between patients-in-need and society’s capacity to cover the increasing costs of cancer therapy. Cost efficacy questions will only be resolved when we have the capacity to identify likely responders prior to therapy, enabling us to use drugs only in those patients with the highest expectations of response. Marginal overall benefits that come at high price will continue to fail until we redouble our efforts to refine the process of drug selection for individual patients. Janet Woodcock, MD, from the FDA once said, that we need “a critical path” from bench to bedside to guide clinical decisions. The human tumor primary culture functional analyses that we employ can provide that critical path and we would hope limit the need for the broad-brush policy decisions that are being handed down by NICE and similar entities both here in the U.S. and abroad.

Faster than the Speed of Light

Last week, scientists at CERN, the European particle physics laboratory located outside Geneva, Switzerland, conducted an experiment, the results of which now challenge one of the most fundamental principles of modern physics. I speak of Albert Einstein’s 1905 declaration that the speed of light is an absolute and that nothing in the universe could travel faster.

E = MC2, the principle under which nuclear energy and weapons have been developed, as well as all of the corollaries of the theory of relativity were called into question when a series of sub atomic particles, known as neutrinos traveled from Switzerland to Italy at a speed that was 1/60 of a billionth of a second faster than the speed of light. What has followed has been a flurry of interest by departments of physics all over the world. Confronted with this new finding, these investigators will diligently seek to reproduce or refute the findings.

This was not the first time that someone challenged the primacy of Einstein’s 1905 theory. Indeed, during the 1930s, for largely political and anti-Semitic reasons, the Nazi party attempted to disprove Einstein. Yet, all of the political meanderings, personal vendettas and intellectual jealousy could not unseat Einstein’s guiding principle. That is, until objective evidence in the form of the CERN experiments came to the fore.

Science — however lofty — and scientists — however highly regarded — dwell in the same realm as all the rest of us mere mortals. Their biases and preconceived notions often cloud their vision. Comfortable with a given paradigm, they hold unyieldingly to its principles until they are forced, however unwillingly, to relinquish their belief systems in favor of a new understanding. I write of this in the context of laboratory-based therapeutics – a field of scientific investigation that has provided firm evidence of predictive validity. These technologies have improved response, time to progression and survival for patients with leukemia, ovarian, breast and lung cancers, as well as melanoma and other advanced malignancies. Thousands of peer-reviewed published experiences have established the merit of human tumor primary cultures for the prediction of response. Investigations into the newest classes of targeted therapies are providing new insights into their use and combinatorial potential.

Yet,  while the physicists of the world will now rise to the challenge of data, the medical oncologists and their academic counterparts refuse to accept the unimpeachable evidence that supports  the validity of assay-directed therapy. Perhaps if our patients were treated at CERN in Geneva,  their good outcomes would receive the attention they so richly deserve.

Lots of Heat No Light – ASCO Technology Assessment Update 2011

“Once more unto the breach, dear friends.”

This famous line from Shakespeare’s Henry V, describes the Battle of Agincourt and England’s unexpected victory over the French. Not unlike Henry V a small coterie of relatively underfunded and embattled investigators around the world continue to fight an entrenched medical community who refuse to relinquish their grip on the clinical trial process.

Their re-review updated from 2004, sheds no new light on the field, as the authors conclude that their 2004 recommendations stand without modification.

The authors, to their credit, have updated their database to include cell death endpoints. They cite the ovarian cancer study by Dr. Ian Cree, that assigned 180 patients, (of which 147 were evaluable), with recurrent disease, and reported a response rate of 40.5 percent for assay directed versus 31.3 percent for physician choice, yet failed to achieve significance. The reasons for this trial’s failure however were obvious, as it was underpowered and more importantly allowed the physician’s choice arm to include Dr. Cree’s own drug combinations as the trial accrued. This left Dr. Cree in the uncomfortable position of having to compete with himself.

More disturbing is their dismissal of a paper by Selma Ugurel, MD, from Clinical Cancer Research 2006 in which, patients with metastatic melanoma received assay-directed treatment for this otherwise chemo resistant and lethal disease. Patients found drug sensitive in the laboratory had a response rate of 36.4 percent, while those found drug resistant had a response rate of only 16.1 percent (a two-fold improvement). The overall survivals were similarly improved with assay-directed patients 14.6 months vs. drug resistant patients of 7.4 months. Again a doubling. Furthermore these results achieved statistical significance.

The ASCO group concludes with the comment, “However, the investigator did not compare the two interventions.” As I know this paper well, and was extremely impressed that some of the responders went out to 30 months, I find the ASCO group’s insouciance surprising.

This reminds me of an old joke by the comedian Jerry Seinfeld. It seems that he had watched a television program where a man caught bullets shot from a gun with his bare teeth. Seinfeld went on to say, that despite being immensely impressed by this man’s prowess, he just couldn’t seem remember his name. “What do you got to do to impress people”?

As I am familiar with the Ugurel paper, I have been very impressed with these investigators completing a study by dint of their dedication to the field. Stranded without funding or cooperative group support, laboratory-based therapeutics remains unconfirmed, not by the unwillingness of the investigators but by the unwillingness of the cooperative and funding agencies to test the hypotheses.

While we squander billions of dollars on genomic analyses that are increasingly leading us nowhere, these ASCO study groups and their colleagues continue to refuse to formally evaluate human tissue studies. In light of the lack of improvement in survival for most cancers over the past 50 years, despite the expenditure of hundreds of billions of dollars on research, perhaps assay-directed therapy is just the solution that medical oncology needs.