In Cancer Care, It Appears that More Is Less

With the interest in “value oncology” and cost containment, a report appeared in the December 2014 Journal of Clinical Oncology that analyzed the impact of the Medicare Prescription Drug Act of 2003 (MMA) on chemotherapy administration in an environment of diminishing reimbursement to physicians.

Prior to the passage of the MMA, oncologists were compensated at 95% of the average wholesale price of a drug. The government accounting office found that the larger medical oncology practices could form “buyers groups” and purchase drugs at lower prices allowing them to pocket the difference. A 2003 New York Times article decried the practice as a “Chemotherapy Concession” and Medicare responded. The MMA of 2003 changed the policy so that chemotherapy drugs were reimbursed at the national average sale price plus 6%. It was hoped that this would result in cost savings.

Practices were divided into Fee-For-Service and Integrated-Health-Networks, the latter largely HMOs and the Veterans’ Administration. It was expected that integrated networks would be less affected since their physicians are salaried and an 11% disparity between the two groups was noted for MMA agents. However, a number of interesting, unexpected and instructive trends emerged.

First, contrary to expectations, the overall use of chemotherapy actually increased following the passage of the MMA.

Second, the cost of cancer care continued to increase unabated following the passage of the MMA.

Finally, changes in drug use appeared to be disease-specific. Colorectal and small cell lung cancer patients saw a decline in the use of MMA affected drugs while non-small lung cancer showed an increase for both fee-for-service and integrated networks. With the overall use of MMA drugs in lung cancer increasing by 1.6 fold, the same drug use increase in the integrated (salaried) groups was 6.3 fold higher.

Among the findings the authors note “reimbursement after MMA passage appears to have had less impact on prescribing patterns in fee for service than the introduction of new drugs and clinical evidence.” This gives the lie to the idea that practicing oncologists are driven by self-gain, a popular narrative in the current political environment.

The authors did find that passage of MMA “resulted in consolidations and acquisitions of practices by hospitals, many of which were able to purchase chemotherapy drugs at discounted rates through the federal 340B* program. Although the full impact of these changes is not known, the shift of chemotherapy from community practices to hospital outpatient settings is associated with higher total costs.”

Community fee-for-service oncologists represent a qualified, yet under-appreciated resource for patients. While their academic brethren bask in the limelight, it is private practitioners who must make sense of the complex and overly dose-intensive treatment schedules handed down to them by ivory tower investigators. We now come to learn that while fee-for-service doctors have been forced to consolidate, join hospital systems, or retire, the cost of cancer care has actually climbed by 66% since the passage of MMA.

It would appear that this experiment has failed. Costs were not contained and drug use was not curtailed. What other bright ideas can we expect from policymakers who seem intent on bending medical care to their wishes at the expense of doctors and their patients?

 

*The 340 B program was originally created by the Federal government to allow charitable hospitals to save money on expensive drugs by allowing them to purchase them at deep discounts. Over time a growing number of “not-for-profit” hospitals demanded the same consideration. Subsequent analyses have found that the majority of the hospitals that now take advantage of 340B actually provide less charity care than the national average. Hospitals that charge full fee for drug administration can then pocket the difference.

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.

New Cancer Drug: Breakthrough or Just Hype?

Having just passed through Ontario’s Pearson International airport on route from eastern Canada, I was struck by an email from one of my patient’s mothers who shared with me a 6/20/2013 article from the Toronto Globe and Mail, “Take news of cancer breakthrough with a big grain of salt,” by staff writer André Picard.

The author describes an announcement by two prominent cancer researchers, Tak Mak, PhD, of Princess Margaret Hospital Toronto, CA and Denis Slamon, MD, from UCLA, who reported the results from a new class of compounds known as “polo-like kinase 4 inhibitors.” Picard goes on to note, “This seemingly miraculous ‘breakthrough’ drug has not been tested on a single person. The experimental drug CFI-400945 has ‘prevented cancer growth’ in a bunch of mice.”

What troubles the author (and should probably trouble us all), is the lack of substance in this report. After all, many drugs reveal activity in animal models, yet most seemingly promising drugs fail to provide clinical benefit. Only 8 percent of cancer chemotherapy drugs that enter the earliest form of human clinical trials (Phase I) ever achieve FDA approval. According to a study published in the New England Journal of Medicine, fully 50 percent of drugs that make it to the final stage (Phase III) of clinical testing nonetheless fail to gain approval. Thus, there is ample reason for concern when “breakthrough” drugs achieve this level of public recognition, because it is distinctly unlikely that they will ever deliver on their promises.

When I attend the AACR meetings, I’m impressed by the level of scientific discovery. When I then attend the ASCO meetings, I’m even more concerned by the lack of clinically relevant progress. The divide between clinicians and scientists seems to grow ever wider. While TIME magazine and The New York Times (to use Andre Picard’s term) genuflect before these scientists’ reports of dramatic advances, most cancer patients continue to suffer through largely ineffective toxic therapies. The disconnect is becoming painfully evident. What we need is a better pathway from discovery to clinical application. What we don’t need is more hype.

Stalking Leukemia Genes One Whole Genome at a Time

An article by Gina Kolata on the front page of the July 8, Sunday New York Times, “In Leukemia Treatment, Glimpses of the Future,” tells the heartwarming story of a young physician afflicted with acute lymphoblastic leukemia. Diagnosed in medical school, the patient initially achieved a complete remission, only to suffer a recurrence that led him to undergo a bone marrow transplant. When the disease recurred a second time years later, his options were more limited.

As a researcher at Washington University himself, this young physician had access to the most sophisticated genomic analyses in the world. His colleagues and a team of investigators put all 26 of the University’s gene sequencing machines to work around the clock to complete a whole genome sequence, in search of a driver mutation. The results identified FLT3. This mutation had previously been described in acute leukemia and is known to be a target for several available small molecule tyrosine kinase inhibitors. After arranging to procure sunitinib (Sutent, Pfizer Pharmaceuticals), the patient began treatment and had a prompt and complete remission, one that he continues to enjoy to this day.

The story is one of triumph over adversity and exemplifies genomic analysis in the identification of targets for therapy. What it also represents is a labor-intensive, costly, and largely unavailable approach to cancer management. While good outcomes in leukemia have been the subject of many reports, imatinib for CML among them, this does not obtain for most of the common, solid tumors that lack targets for these new silver bullets. Indeed, the article itself describes unsuccessful efforts on the part of Steve Jobs and Christopher Hitchens, to probe their own genomes for effective treatments. More to the point, few patients have access to 26 gene-sequencing machines capable of identifying genomic targets. A professor of bioethics from the University of Washington, Wiley Burke, raised additional ethical questions surrounding the availability of these approaches only to the most connected and wealthiest of individuals.

While brute force sequencing of human genomes are becoming more popular, the approach lacks scientific elegance. Pattern recognition yielding clues, almost by accident, relegates scientists to the role of spectator and removes them from hypothesis-driven investigation that characterized centuries of successful research.

The drug sunitinib is known for its inhibitory effect upon VEGF 1, 2 and 3, PDGFr, c-kit and FLT3. Recognizing the attributes of this drug and being well aware of C-KIT and FLT3’s role in leukemias, we regularly add sunitinib into our leukemia tissue cultures to test for cytotoxic effects in malignantly transformed cells.  The insights gained enable us to simply and quickly gauge the likelihood of efficacy in patients for drugs like sunitinib.

Once again we find that expensive, difficult tests seem preferable to inexpensive, simple ones. While the technocrats at the helm of oncology research promise to drive the price of these tests down to a level of affordability, everyday we wait 1,581 Americans die of cancer. Perhaps, while we await perfect tests that might work tomorrow, we should use good tests that work today.

Cancer Research Becomes “Curiouser and Curiouser”

Following the Gina Kolata New York Times article on July 8, 2011, which described the failure of the Duke University gene profile program in lung cancer, a second New York Times article popped up on the radar screen.  “Cancer’s Secrets Come into Sharper Focus” by George Johnson, examined the growing complexity of cancer research.

This article explored the growing realization that human biology is not linear. Included were references to work that we have previously described in this blog, including the groundbreaking work of Pier Paolo Pandolfi. It also described the interaction between the human body and its microbial flora. We have long recognized that human health is, in part, associated with our interaction with microbes in our environment. The gastrointestinal tract has numerous species that are increasingly believed to contribute to our health. The growing field of probiotics, wherein people consume “healthy organisms,” has gone from quackery to community standard in less than a decade.

What is interesting over the past years is the growing recognition that many cancers are related to infections. Viral infections are known to be oncogenic, with the Epstein-Barr virus, HPV and other viruses now known to be causative of lymphomas, cervical, head and neck, and other cancers. The association between helicobacter and ulcers, gastric lymphoma, and esophageal malignancies are of interest both epidemiologically and therapeutically.

What is most interesting of all is the growing recognition that the cancer cell is but a small component of the cancer.

Here at Rational Therapeutics we recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to our focus on the human tumor primary culture microspheroid, which contains all of these elements. In our earlier work, we endeavored to isolate tumor cells from their benign constituents so as to study “pure” tumor cells. As time went on, however, we found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in 3-dimensional structures, lead to the realization that cancer cells inhabit a microenvironment. Our lab now studies cancer response to drugs within this microenvironment, enabling us to provide clinically relevant predictions to our patients.

It is our capacity to study human tumor microenvironments that distinguishes us from other platforms in the field. And, it is this capacity that enables us to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of notch, hedgehog and WNT, among other (Gonsalves, F, et al. (2011). An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of WNT/wingless signaling pathway. PNAS vol. 108, no. 15, pp. 5954-5963).  With this clinically validated platform we are now positioned to streamline drug development and advance experimental therapeutics.