Bevacizumab In Colon Cancer – “A Shot Across The Bowel”

An E-Publication article in the February Journal of Clinical Oncology analyzes the cost efficacy of Bevacizumab for colon cancer. Bevacizumab, sold commercially as Avastin, has become a standard in the treatment of patients with advanced colorectal cancer. Indeed, Bevacizumab plus FOLFOX or FOLFIRI, are supported by NCCN guidelines and patients who receive one of these regimens are usually switched to the other at progression.

A Markov computer model explored the cost and efficacy of Bevacizumab in the first and second line setting using a well-established metric known as a Quality-Adjusted Life Year (QALY). In today’s dollars $100,000 per QALY is considered a threshold for utility of any treatment. To put this bluntly, the medical system values a year of your life at $100,000. The authors confirmed that Bevacizumab prolongs survival but that it does so at significantly increased costs. By their most optimistic projections, Bevacizumab + FOLFOX come in at more than $200,000 per QALY. Similar results were reported for Canadian, British and Japanese costs. Though more favorable, the results with FOLFIRI + Bevacizumab still came in above the $100,000 threshold.

No one doubts that Bevacizumab provides improved outcomes. It’s the incremental costs that remain an issue. Society is now confronting an era where the majority of new cancer agents come in at a cost in excess of $10,000 per month. Where and how will we draw the line that designates some treatments unaffordable? On the one hand, clinical therapies could be made available only to the “highest bidder.” However, this is contrary to the western societal ethic that holds that medical care should be available to all regardless of ability to pay. Alternatively, increasingly narrow definitions could be applied to new drugs making these treatments available to a shrinking minority of those who might actually benefit; a form of “evidence-based” rationing. A much more appealing option would be to apply validated drug predication assays for the intelligent selection of treatment candidates.

In support of the latter, the authors state, “Bevacizumab potentially could be improved with the use of an effective biomarker to select patients most likely to benefit.” This is something that genomic (DNA) profiling has long sought to achieve but, so far, has been unable to do. This conceptual approach however is demonstrably more attractive in that all patients have equal access, futile care is avoided and the costs saved would immediately provide highly favorable QALY’s as the percentage of responders improved.

Similar to the recent reports from the National Health Service of England, the American public now confronts the challenge of meeting the needs of a growing population of cancer patients at ever-higher costs. It is only a matter of time before these same metrics described for colon cancer are applied to lung, ovarian and other cancers for which Avastin is currently approved.

At what point will the American medical system recognize the need for validated predictive platforms, like EVA-PCD analyses, that have the proven capacity to save both money and lives? We can only wonder.

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.

Rationed or Rational: The Future of Cancer Medicine

Disturbing news from Britain’s Health Service on Monday, January 12, described the National Health Services’ decision to “delist” 25 of the nation’s 84 currently available chemotherapy drugs from their formulary. Citing the rising cost of cancer therapy Professor Peter Clark, chair of the Cancer Drug Fund said that the CDF, originally established in 2011, had already exceeded its annual budget. From ₤280 million in 2014 the costs for 2015 are projected to rise to ₤340 million. In defense of the policy Dr. Clark said the delisted drugs “did not offer sufficient clinical benefit.”

An examination of the delisted drug should raise concern for medical oncologists. Among those delisted are Bevacizumab (Avastin) for colorectal cancer, Eribulin (Haloven) and Lapatinib (Tykerb) for breast cancer and Pemetrexed (Alimta) for advanced lung cancer. Additional deletions include Bendamustine (Treanda) for some non-Hodgkin’s lymphoma, Bortezomib (Velcade) for relapsed mantle cell lymphoma and Waldenström’s macroglobulinemia. Bortezomib will also be limited in some cases of myeloma, while Cetuximab will be unavailable as second or third line treatment in colorectal cancer. For American oncologists these agents have become standards of care.

Many physicians in England are outraged. Mark Flannagan, executive chief of the Beating Bowel Cancer Fund described this as “bad news for bowel cancer patients” suggesting that 65% of patients with advanced colorectal cancers will confront the risk of an earlier death. Despite these draconian measures physicians may still have the opportunity to request delisted drugs under what is described as “exceptional cases.”

The breadth and scope of the drug restrictions are surprising. After all, Pemetrexed is one of the most widely used treatments for advanced lung cancer, Bevacizumab has become an established part of colorectal cancer management and Eribulin is a favored salvage regimen in recurrent breast. The withdrawal of Bortezomib, an active agent in mantle cell, Waldenström’s and myeloma, will not be suffered lightly by patients in need.

Are the problems confronting the UK an early harbinger of the same for the American medical system?

With aging populations in western societies and increasingly sophisticated medical technologies, the cost of medical care, particularly cancer care may soon become unmanageable. UK’s centralized medical care delivery through the National Health Service, a single payer system, was designed to save money. Despite its high-minded intentions, the NHS appears to be failing. While spending more money each year the dissatisfaction with medical delivery only grows. A nearly 12% increase in health care per person expenditures in England between 2009 and 2013 (₤1712 to ₤1912) was met with an 18% increase in patient complaints.

Among the problems are progressive layers of middle management that add cost without providing care.  Physicians find it more difficult to do their jobs while people inexpert in the delivery of medical care have been given decision-making power. As the English population has come to look upon health care as a right, some overuse medical services, even ER’s, for non-serious conditions. Reformers have suggested the solution may lie in charging fees for appointments or requiring an annual membership fee. In today’s political milieu however, few elected officials are likely to relish policies that end “free health care” in England.

What might solve this dilemma for medical oncology? An obvious solution is to apply resources where they are most likely to benefit patients, e.g. personalized care. While this seemed a pipe dream 20 years ago when we first introduced the concept, a growing chorus of scientists now embraces the idea. With their focus almost exclusively on genomics this new cadre of clinical investigators describe a future where each patient gets exactly the right treatment.

We applaud this thinking and fully agree. However, we must be prepared to use all platforms to achieve this worthy goal. To fill the current void phenotypic analyses offer substantive benefits. By capturing cancer biology at a functional level, these studies identify true “driver mutations,” and have the capacity to examine synergy and sequence-dependence, both beyond the scope of genomic analyses.

As human tumor primary culture analyses (such as EVA-PCD) have already been shown to double objective response rates and improve one-year survival, it is time for government officials and policymakers to re-examine the benefits of drug selection technologies that are available today.

Will the future of cancer medicine in the UK and the US be rationed under the duress of rising costs, or rational, through the application of available technologies capable of making intelligent cost- and life-saving decisions? That remains to be seen.

The Cost of Chemotherapy Comes Home to Roost

Medical 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.

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 trials 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.

What is Cancer Research?

According to Wikipedia, cancer research is “basic research into cancer in order to identify causes and develop strategies for prevention, diagnosis, treatments and cure.” At face value this seems self-evident, yet “cancer research” means different things to different people.

Most cancer patients think of cancer research as the effort to achieve the best possible outcome for individual patients. Taxpayers and donors to charitable organizations also tend to view the process through the lens of therapeutics. But patient treatment is but a small part of cancer research. One of the largest cancer research organizations, the American Cancer Society, was the subject of an investigative report by Channel 2 in Atlanta, Georgia. They found that this billion dollar organization spent 32% of the money it raised on raising money. What of the other 68%? How much of that money actually goes to patient care? When one factors in education, transportation, administration, PR, salaries and basic research, actual patient care support is close to the bottom of the list.

More instructive is an examination of how people engaged in cancer research define their work. On one side are clinical investigators (trialists) who administer the treatments developed in the laboratories of scientists after pre-clinical analyses. On the other side are the basic researchers whose job it is to answer questions and resolve scientific dilemmas. They are granted enormous amounts of money to delve into the deepest intricacies of cancer biology, genomics, transcriptomic and proteomics in an effort to better understand the etiology (causation) of this dreaded disease.

In examining this disjointed field, I considered my own area of work. I am a clinical investigator who also conducts research in a laboratory. As such, I straddle the fence between basic research and clinical science. This is increasingly dangerous ground, as the gap between scientists and clinicians grows wider by the day. Most clinical investigators have, at best, a passing understanding of molecular biology, and most molecular biologist have absolutely no idea what clinical medicine is. This is unfortunate, for it is the greater blending of science with clinical therapy that will lead to better outcomes. Pondering this dichotomy I recognized that my job is first and foremost to save lives and to alleviate suffering. For me, the laboratory is a means to an end. It is a tool that I use to resolve clinical questions. What drug, what combination, what sequence? These questions are best answered in the laboratory, not in patients, wherever possible.

For the basic scientist the task is to answer a question. For them the laboratory is an end unto itself. They use multiple parameters to examine the same question from different angles, seeking to control every variable. A good scientific paper will use genomic (DNA), transcriptomic (RNA), and proteomic (protein expression) analyses until the issues have all been resolved to their satisfaction. In the literature this is known as “elegant” science. The operative term here is control. The scientist controls the experiment, controls the environment, controls the outcome, and controls the publication process. They are in charge.

What of the poor clinical investigator, who must, per force of necessity, be humble. They are not in control of the clinical environment and rarely understand the intricacies of the metabolic, genomic and proteomic events taking place before their eyes. They must approximate, sometimes guess and then act. For the clinician, the laboratory is an opportunity to answer practical real-world questions, not nuanced theoretical principles.

The greatest criticism that a scientist can level at an opponent is a lack of focus, defined as the inability to drill down onto the essence of the question. These scientists sit on study sections, review manuscripts and fund grants. Over decades they have been allowed to define the best research as the most narrowly focused. Incrementalists have out-stripped, out-funded and out-maneuvered big thinkers. While basic researchers examine which residue on the EGFr domain becomes phosphorylated, clinical physicians must do hand-to-hand combat with the end result of these mutations: non-small cell lung cancer.

Medical history instructs that big questions are best answered when prepared minds (William Withering, Ignaz Semmelweis, etc.) pursue scientific answers to real clinical questions. Unfortunately, today’s clinicians have been relegated to the role of “hypothesis testers.” This has led to a profusion of blind alleys, failed clinical trials and the expenditure of billions of dollars on extremely “interesting questions.”

George Bernard Shaw said, “England and America are two countries separated by a common language.” Increasingly, cancer research has become two distinctly different disciplines divided by a common name.

The Rising Cost of Cancer Research: Is It Necessary?

For anyone engaged in developmental therapeutics and for those patients who need new approaches to their cancers, an editorial in the Journal of Clinical Oncology casts a disturbing light on the field The authors examine the impact of the growing research bureaucracy upon the conduct of clinical trials. They use Thomas Edison, who filed 1,093 U.S. patents, to exemplify successful trial and error research. By inference, they suggest that if Mr. Edison were working today in the modern regulatory environment we would all be reading this blog by candlelight. While much of Edison’s work focused upon household conveniences like light bulbs and phonographs, the principals that underlie discovery work are every bit the same.

Although regulations have been put in place to protect human subjects, the redundancies and rigorous re-reviews have outstripped their utility for the patients in need. The process has become so complex  that it is now necessary for many institutions to use professional organizations to conduct trials that could easily have done in the past by an investigator with a small staff. These clinical research organizations (CRO’s) are under the gun to adhere to an ever growing collection of standards. Thus, every detail of every consent form is pored over sometimes for years. This has had the effect of driving up the cost of research such that the average Phase III clinical trial conducted in the 1990s that cost $3,000 to $5,000 per accrued patient, today costs between $75,000 and $125,000 per patient. Despite this, the safety of individuals is no better protected today than it was 30 years ago when all of this was done easily and cheaply.

While funding for cancer research has increased slowly, the cancer research bureaucracy has exploded. One need only visit any medium to large size hospital or university medical center to witness the expansion of these departments. Are we safer? Do our patients do better? The answer is a resounding “No.” In 2013, according to the authors,  the average patient spent a mere 53 seconds reviewing their consent forms before signing them, while the average parent, signing on behalf of their child, spent only 13 seconds.

The take home messages are several. First, the regulatory process has become too cumbersome. Were this the cost of scientific advance we would accept it as a fact of life, but patients are not safer, trials are not faster and outcomes are not being enhanced. Second, the cancer research process has overwhelmed and undermined cancer researchers. In keeping with Pournelle’s Iron Law of Bureaucracy, “. . . in any bureaucratic organization there will be two kinds of people: those who work to further the actual goals of the organization, and those who work for the organization itself.”Is there anyone who donates to the American Cancer Society who wants their money to go toward more regulation?

The problem is not with the academic physician. Medical scientists want to do studies. Marching alongside are the patients who are desperate to get new treatments. While many criticize the pharmaceutical industry, it is highly unlikely that these companies wouldn’t relish the opportunity to see their drugs enter the market expeditiously. Standing between patients and better clinical outcomes is the research bureaucracy. Should we fail to arrest the explosive growth in regulatory oversight we will approach a time in the near future when no clinical trials will be conducted whatsoever.

Mammography – The Evolving Story of a Diagnostic Tool

The use of low-dose radiation to detect occult breast malignancies can be traced to work done at the MD Anderson Cancer Center in the 1950s. Early published studies conducted by the “Egan technique,” correctly identified the majority of palpable cancers subsequently proven malignant at the time of surgery. As a diagnostic tool, mammography is an effective means of confirming the presence, and defining the extent, of breast pathology in woman at high risk for cancer, or who note a palpable lump. No one is arguing the diagnostic use of this technique. Where the controversy has arisen over the last years is the use of mammography as a screening technique.

To clarify the use of terminology, screening techniques are applied to the general population to identify unrecognized disease. The popularity of mammography as a screening technique led to the recommendation that every woman over 40 should have an annual mammogram. The problem with screening techniques is that they apply a diagnostic tool to a population at low risk. This burdens the technology with numerous false positives, engendering  costs, risks, and toxicity for those who undergo unnecessary biopsies and surgery. The entire discussion came into sharper focus in the past week with the publication of a large Canadian study that examined the impact of mammographic screening over a 25-year follow up in women ages 40-59.

In this study, launched in 1980, more than 89,000 women were divided into two groups. One group underwent routine physical examination and the second group had routine physical examination combined with mammogram. There were 3,250 diagnoses of cancer in the 44,925 women who underwent mammography and 3,133 cancers diagnosed in the 44,910 women who underwent physical examination alone. Five hundred patients in the mammography group and 505 women in the control group died of their disease. While women who had mammograms were more likely to be diagnosed with breast cancer, this did not have an impact on their risk of dying from the disease. Furthermore, 22 percent of women with positive mammograms did not have cancer at definitive workup. The conclusion of paper and the accompanying editorial by Mette Kalager from Oslo, Norway, was that ”the rationale for screening by mammography needed to be urgently reassessed.”

What are the shortcomings of the study? Mammographers have claimed that the equipment used was suboptimal, leading to less sensitive detection that might have occurred with modern, high-quality digital equipment. There was also no group over 60. It is also theoretically possible that some patients obtained mammography after concluding the study, or had mammograms done during the study, contaminating the final results. Nonetheless, this is a high quality randomized study in a large population that fails to provide an impact upon survival for a widely used technique.

Prior meta-analyses conducted between the 1960s and 1980s revealed a reduction in deaths in breast cancer between 15 percent and 25 percent in the population of women age 50 to 69. Explanations for the disparity between the current study and those older studies may include the relative lack of sophistication of the population during the 1960s through 1980s, who might fail to evaluate a breast lump, thus, earlier detection would have a significant impact on those not responding to even physical evidence of disease.

A second confounding variable is the broad use of Tamoxifen, which has so profoundly influenced the natural history of breast cancer, that the earlier detection of breast cancer may be less important than the potent efficacy of anti-hormonal agents. This is an interesting wrinkle in the story, as it is contrary to most contemporary thinking that holds that early detection, not treatment is the principal influence upon better outcomes today.

So where does this study leave us?  There are several points that must be considered. The first is that mammography is a test not a treatment. Tests perform according to their performance characteristics, described as “sensitivity and specificity.” Within this framework mammograms are sensitive and specific enough to provide immense value ….in the right patient population, e.g. those at some risk for the disease in question. How you define that “risk” is the rub.

Mammograms identify the disease; they do not influence its biology. While some may demand that more sensitive equipment for the detection of disease be implemented, a different principle may underlie the findings. This would be that cancer, at virtually any stage of diagnosis, is a systemic disease with its own trajectory. Under this scenario, mammograms in an unselected population provide little more than a lead-time bias. This term is applied when a test identifies an event earlier than it might have been found, but has no impact on the ultimate outcome. Lead-time bias is a common phenomenon in screening techniques and has been the rallying cry for those who argue against PSA screening for men. Once again, the number of patients diagnosed versus the number of patients requiring intervention is the overarching dilemma.

While we seek to decipher the genetic basis of cancer using increasingly sophisticated genomic techniques, we recognize that cancer is common and that a substantial percentage of patients may not die of their disease. Cancer results from stresses that force cells to either die or seek novel mechanisms to survive. Deprived of estrogen, testosterone, nutrients, oxygen or growth factors, cells within the aging human body discover novel ways to stay alive, albeit to the detriment of the organism as a whole. However humbling, it can be argued, that it is pathways that aberrant cells pursue that guides the trajectory of the disease, largely independent of our roles as diagnosticians and treating physicians.

Barretos Cancer Center of Brazil – The Asymmetric War On Cancer

I recently returned from a lecture tour at the Barretos Cancer Center of Brazil located 300 miles from Sao Paulo. This cancer center, founded in 1968, has become one of the world’s leading programs for the diagnosis and treatment of malignant disorders. Before this small town became famous for cancer care, however, it was a recognized site for rodeos. The city of Barretos sits in the middle of Brazil’s agricultural region with sugar cane and cattle the principal industries. The hospital itself is a charity where all care is delivered free of charge. Patients from all over the country arrive by bus and ambulance to undergo high-level diagnostic, surgical and medical treatment. Much of the funding comes from the government, but a large amount of the money comes from charitable donations in the form of cattle that are auctioned off to provide money. In addition, donations from the leading musicians of the nation, including Michel Telo, help in the fundraising efforts.

We arrived at Ribeiro Preto airport where we were met by a driver who brought us the 1-1/2 hour trip to Barretos. I was accompanied by a reconstructive plastic surgeon who was donating a month of her time to the Barretos program. The following morning, the director of the program, Dr. Andre Lopes Carvalho, brought me to the hospital for the lecture. The audience consisted of MDs and MD/PhDs, with many scientists and technical staff. It was well received and followed by a small coffee reception.

From there, the Director of Molecular Biology and the Chief of Pathology gave me a tour of the facility. There, in the center of Brazil was a sophisticated research institution with every capability. DNA sequencing performed on Illumina and Ion Torrent equipment. In a tour of the pathology department I was shown archived blocks from tens of thousands of cancer patients, all maintained in a central repository. My discussion with the Chief of Pathology, Dr. Cristovam Scapulatempo-Neto, was most instructive.

It must be remembered that Brazil is a nation of stark contrasts, on the one hand, abject poverty and on the other, extreme wealth. The dilemma for the medical system is to deliver care that meets the needs of the greatest number of patients at the lowest possible cost. Dr. Scapulatempo-Neto confronts an almost impossible dilemma. He cannot possibly afford the companion diagnostics so common in America, which match patients to the drugs of interest under FDA regulation, like the COBAS BRAF mutation test for Vemurafenib or the VYSIS ALK Break Apart FISH probe for Crizotinib. At several thousand dollars per test, these tests are beyond the reach of the Brazilian system. More to the point, many of the drugs are not covered by the national insurance.

To address the need, this physician has redoubled his efforts in immunohistochemistry. This technique uses special stains and antibodies to measure the presence or absence of proteins. Unlike DNA tests, which identify amplifications and mutations, immunohistochemistry identifies the end-product, the business end of cancer abnormalities. I was amazed by the accuracy and affordability of these increasingly sophisticated IHC tests. While a COBAS or VYSIS test might run thousands, he can conduct high quality IHC for 100 dollars. With a medical center that sees 10,000 new cancer patients per year, the cost savings are significant.

I realized that this was indeed an asymmetric war on cancer; low tech answers to high tech problems. I became increasingly enthusiastic about the prospect of utilizing our EVA-PCD platform in this population. After all, these medically indigent patients are barely able to receive even standard cytotoxic chemotherapies, only generic drugs, and very few newer classes of agents are available. The cost saving associated with doubling responses and restricting futile care could be enormous. While gene sequencing technologies become faster, better, and less expensive, the information that they provide for most common malignancies remains to be determined. A practical, comparatively inexpensive tissue culture platform capable of testing both cytotoxic drugs and targeted agents would be a remarkable step forward for the population in Brazil. It is my hope to collaborate with this group and bring our technology to the Brazilian population.

Evidence Based Medicine and the Cost of Cancer Care

Before I attended the ASCO meeting in Chicago, I penned a blog about a Forbes magazine article that described increasing restrictions placed on access to newer diagnostic tests for patients covered by Medicare.

Among the presentations that I attended at ASCO, (more to follow), was a study entitled “The cost per patient of deviations from evidence-based (EB) standards of oncology care.”  The presentation caught my eye as it addressed the cost of care associated with adherence to evidence-based guidelines versus treatment plans that varied from these guidelines. Utilizing a database developed to analyze the cost of treatment, these investigators explored costs incurred when physicians used treatments that were not within the confines of the evidence-based formulae.

A total of 2,775 consecutive patients had their treatment plans (TPS) submitted and 730 (26 percent) of these patients were described as receiving, “unjustified, non-Evidence Based Treatment Plans.” The authors then examined the costs associated with these treatments. Their phraseology for treatment that varied from guidelines was those “that did not confirm to Evidence Based standards or could not be medically justified.” Apparently the practice on the part of qualified, skilled oncologists of making drug choices that vary from evidence-based medicine is synonymous with “not being medically justified.” Their conclusion “conservative estimate(s) of the average per patient overspend (first order) on inappropriate treatment validates the potential for quality care to lower cost and deliver huge value to patients, physicians and payors.”

What’s wrong with this picture?

First, clinical oncology as it is practiced today through the available guidelines (NCCN, etc.) has failed to improve 5-year survival for advanced cancer in 50 years. Thus, this “regression to the mean” thinking, if followed, would increasingly demand that medical oncologists scrupulously adhere to largely ineffective therapy guidelines.

The second problem is that this analysis provides no data on response, time to progression, survival or toxicity. For all we know, the 26 percent of patients who received non-evidence based treatment plans may have been the best responders with better survivals and lower toxicities.

Finally, in keeping with the Forbes article previously described, medical oncologists are rapidly abdicating control of their cancer patients’ treatments in favor of econometric analyses.  Should this trend continue, patients may soon be forgoing the opinions of their MDs, in favor or the opinions of  MBAs.

The High Cost of Cancer Care

An article by Scott Gottlieb, MD, in Forbes (Medicare Nixes Coverage for New Cancer Tests), described Medicare reimbursement for new molecular diagnostics. As many readers are aware, there have been a growing number of diagnostic tests developed and marketed over recent years designed to identify and monitor the progress of cancer. Many of these tests are multiplexed gene or protein panels that identify prognostic groups using nomograms developed from prospective or retrospective analyses. The 21-gene Oncotype DX and related Mammoprint, are among the most widely used. Related tests for lung, colon, and other cancers are in development.

With the explosion of assays designed to personalize cancer care, comes the expense associated with conducting these analyses. Medicare, as the largest provider of medical insurance in the United States, is at the leading edge of cost containment. Not surprisingly, HHS has a jaundiced view of adding tests without clear cost benefit.

The issue is far broader than cost analysis. It goes to the very heart of what we describe as personalized medicine. Every patient wants the right treatment for their disease. Every laboratory company wants to sell their services. Where the supply and demand curve meet however, is no longer set by market forces. In this instance, third party reimbursers set the fee and the companies then need to determine whether they can provide their service at that cost.

The problem, as with all economic analysis, is meeting patient’s unlimited wants with limited resources. Two solutions can be envisaged. On the one hand, medical care progressively moves to a scenario of haves and have nots wherein only wealthier individuals can afford to obtain those drugs and interventions that are beyond the price range of most. On the other hand, care is rationed and only those treatments and interventions that rise to the highest level of evidence are made available.

While the subject of this article was sophisticated diagnostic tests, it will only be a matter of time before these same econometric analyses begin to limit the availability of costly drugs like highly expensive targeted agents. In a recent editorial published in blood, leading leukemia experts pointed out that 11 of the 12 recently approved drugs each cost $10,000 or more per month.

As we examine the rather grim prospect of unaffordable or rationed care, a glimmer of hope can be seen. Using expensive and relatively insensitive molecular diagnostic tests to select expensive targeted agents could be replaced by less expensive testing platforms. The dramatic, yet brief responses observed for many targeted agents reflect the shortcoming of linear thinking applied to the manifestly non-linear human biology, characterized by cross talk, redundancies and unrecognized hurdles. To address these complexities phenotypic analysis (the phenotype being the end product of genomic, transcriptomic and proteomic events) provide global assessments of tumor response to drugs, combinations and signal transduction inhibitors. These more discriminating results identify cellular response at the level of biology, not just informatics. While it is theoretically possible that high-throughput genomic analyses using neural networks and high throughput computer analyses may ultimately provide similar information, it is unlikely that most patients will have ready access to a Cray computer to decipher their results.

We need to stop working hard and start working smart. The answers to the many questions raised by the Forbes article regarding resource allocation in cancer treatment may already be at hand.