With an EVA-PCD Assay, It Can Be That Simple

Shortly after I left the university and joined a medical oncology group, one of the junior members of the practice asked if I would cover for him during his summer vacation. Among the patients he signed over to me was a gentleman in his 60s with what he described as “end-stage” chronic lymphocytic leukemia (CLL). As the patient had already received the standard therapies, second line regimens and experimental drugs available at the time, the physician had run out of options. My charge was to keep him comfortable. I asked if it would be all right for me to study his cells in my lab and the doctor agreed.

CLL 130611.06I met the patient the next day. He was a very pleasant tall, slender black man lying in bed. He had lost a great deal of weight making the already enlarged lymph nodes in his neck appear that much more prominent. As I was engaged in the study of CLL as my principal tumor model, I asked if I might examine his circulating CLL cells as part of our IRB-approved protocol. He graciously obliged and I obtained a few ccs of blood. We were deeply ensconced in tumor biology analyses and his cells were used to explore membrane potentials, DNA degradation and glutathione metabolism as correlates with drug response profiles by EVA-PCD analysis. A large number of those studies have since been published.

What struck me about the patient’s EVA-PCD profile was the exquisite sensitivity to corticosteroids. Corticosteroids in the form of prednisone, Medrol, Solu-Medrol and Decadron are the mainstays of therapy for lymphoid malignancies like CLL. Everyone receives them. Indeed this patient had received them repeatedly including his first line chlorambucil plus prednisone, his second-line CHOP and his third line ESHAP. It was only after he had failed all of these increasingly intensive regimens that he finally moved on to an experimental agent, homoharringtonine, a drug that finally received FDA approval in 2012, after almost 40 years of clinical development. Unfortunately for him homoharringtonine did not work and it seemed we were well beyond conventional therapies, or were we?

I pondered the corticosteroid sensitivity finding and decided to start the patient on oral prednisone. It would be another two weeks before his physician returned and there really weren’t many options. The patient responded overnight. The lymph nodes melted away. The spleen diminished. He began to eat and gained weight. Within a few days he felt well enough to go home. I discharged the patient and remember writing his prednisone prescription, 40 mg by mouth each morning.

A week later, my colleague returned from his retreat in the Adirondacks. He inquired about his patients and surmised that this gentleman, no longer in the hospital, had died. I explained that he had been discharged.

“Discharged . . . how?” he asked. I described the findings of our EVA-PCD study, the sensitivity to steroids and the patient’s miraculous clinical response to this, the simplest of all possible treatments. The physician then turned to me and said “Prednisone . . . hmmm . . . I could have done that.”

I am reminded of this story almost daily. It is emblematic of our work and of those who choose not to use it. Good outcomes in cancer do not occur by chance. They also do not require blockbuster new drugs or brilliant doctors. They require individualized attention to the needs of each patient.

A recurring theme, exemplified by this patient among others, is that cancer cells can only defend themselves in a limited number of ways. Once a selection pressure, in a Darwinian sense, is removed (e.g. corticosteroids were not used during the homoharringtonine treatments) the surviving cells, sensitive to steroids, re-emerge to be identified and captured in our laboratory platform.

It is remarkable how often heavily pretreated patients with ovarian cancer are found sensitive to Taxol after they had received it years earlier, but not since; or breast cancer patients who fail every new agent only to prove responsive to CMF, the earliest of all of the breast cancer drug combinations developed in the 1970s. Our job as oncologists is to find those chinks in armor of cancer cells and exploit them. The EVA-PCD platform, in the eyes of some, may not be groundbreaking . . . it just happens to work!

 

With Cancer, Don’t Ask the Experts

I was recently provided a video link to a December 2013 TEDx conference presentation entitled, “Big Data Meets Cancer” by Neil Hunt, product manager for Netflix. Mr. Hunt’s background has nothing to do with cancer or cancer research. His expertise is in technology, product development, leadership and strategy and has personally shepherded Netflix to its current market dominance. With his background and lack of expertise in cancer, he is an ideal person to examine cancer research from a fresh perspective.

The Long Tail of CancerMr. Hunt begins with a (admittedly) simplistic look at cancer research today. Because he is a data guy, naïve to all of the reasons why cancer cannot be cured, he can look anew at how it might be cured. Using a graphic, he defines cancer as “a long-tail disease” made up of outliers. He points out that most 20th century medical successes have been in the common diseases that fall close to the thick end of the curve. As one moves to the less common illnesses data becomes more scant. Echoing a new conceptual thinking, he points out that cancer is not a single disease but many, possibly thousands.  His concept is to accumulate all of the individual patient data to allow investigators to explore patterns and trends: a bottom up model of cancer biology. Many of his points bear consideration.

For those of you who have read these blogs, you know that I am an adherent to the concept of personalized cancer care. I have articulated repeatedly that cancer patients must be treated as individuals. Each tumor must be profiled using available platforms so that time and resources will not be wasted. We have used the same term “N-of-1” (a clinical trial for one patient) that Mr. Hunt uses in his discussion. He provides two anecdotes regarding patients who benefitted dramatically from unexpected treatment choices. His rallying cry is that contemporary clinical trials are failing. Again, this is an issue that I have addressed many times. He then describes broad-brush clinical protocols as the “tyranny of the average.”

The remainder of the discussion focuses upon possible solutions. Among the obvious hurdles:
1.    Cancer centers are hesitant to share data.
2.    The publication process is slow.
3.    Few are willing to publish negative trials.

To counter these challenges, he points out that small organizations are more incentivized to share and that successes in long-tail diseases can resurrect failed drugs, thereby repaying the costs. Several points were particularly resonant as he pointed out that early adopters face outsized resistance but their perseverance against adversity ultimately evolves the field. He sees this as a win-win-win scenario with patients receiving better care, physicians witnessing better outcomes, and pharmaceutical companies gaining more rapid approval of drugs.

As I watched, it occurred to me that Mr. Hunt was articulating many points that we have raised for over the last decade. As an outsider, he can see, only too clearly, the shortcomings of current methods. His clear perceptions reflect the luxury of distance from the field he is describing. Mr. Hunt’s grasp of cancer research is direct and open-minded. Many problems need fresh eyes. Indeed as we confront problems as complex as cancer it may be best not to ask the experts.

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.

Well Tray Closeup2 small 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?

JCO coverFor 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.

Every Cancer Patient’s Outcome is Important

Clinical oncologists can be divided into different camps. There are those who see patient outcomes as a means-to-an-end. Each clinical response provides a data point and when those data points reach critical mass they become reportable. These are the trialists. They see the world through a utilitarian lens. They use aggregate data, through sufficient patient accrual, to achieve significance. This, they hope, will lead practice-changing observations. Trialists populate academic centers and an ever-expanding number of “mega medical groups” that are now gobbling up private oncology practices. They apply metrics to gauge success, as their focus has moved away from individual patient needs toward the achievement of a “greater good” for the population as a whole. Statistical significance is the currency of their realm and clinical protocols their preferred tool.

In the other camp reside physicians, that dwindling cadre of doctors whose principal focus is the good response of each individual patient. They are the practitioners who eke out a living in an environment of diminishing returns. Having relinquished both autonomy and income over recent years, their one remaining reward is the benefit they can bring to each patient. With neither the desire nor ability to publish their results, individual patient survival becomes their paramount goal. Their job is to alleviate suffering, provide comfort and sponsor the health of their clients. Patients preparing to meet with a cancer specialist should consider carefully who is treating them – and why.

I was reminded of this when a 48-year-old gentleman recently requested an opinion. He had presented to an emergency room with a month-long history of sharp abdominal pain. The CT scan revealed extensive intra-abdominal disease, which upon endoscopic biopsy, proved to be of gastric (stomach) origin. He was immediately referred to an accomplished university-based clinical investigator for consultation.

Metastatic gastric cancer is a very difficult disease to treat. One bright spot has been the discovery that 20 percent of patients carry an epidermal growth factor receptor (HER-2) mutation that enables them to receive Herceptin-based therapy. As luck would have it, this patient did not carry the HER-2 mutation. The university investigator explained that there were limited treatment options. In light of his metastatic presentation, the doctor felt that aggressive, multi-agent chemotherapy might only engender toxicity. The patient was offered either single agent 5-FU for palliation or the opportunity to participate in a clinical trial. The patient considered his options and chose to seek an opinion with me.

20 percent response rateI reviewed the patient’s status and explained that while the opinion of the university investigator was valid it might underestimate the patient’s individual chance of response. I explained that gastric cancer statistics, like all medical statistics, are population based. That is, a 20 percent response rate does not mean that every patient gets 20 percent better, but instead, that 20 out of every 100 respond while 80 do not. Our job was to find out which group he belonged to.

The patient decided to undergo a biopsy and submitted tissue to Rational Therapeutics for EVA-PCD® analysis. The results were strikingly favorable with several drug combinations revealing both activity and synergy. After careful comparison, I recommended the combination of a Cisplatin, Taxotere and 5-FU (DCF), a regimen originally developed at the MD Anderson almost 10 years earlier.

On March 12th, the patient began treatment on an every-other-week schedule. As he did not circulate tumor markers like CEA or CA 19-9, there was no easy measure of his response so I elected to repeat the PET/CT after just two cycles. Much to my delight, the patient had achieved a complete remission with resolution of all measurable disease, including the bulky abdominal masses, numerous lymph nodes and the stomach. As I described the remarkable PET/CT results, the patient’s wife began to weep. Her husband, the father of their two young children, wasn’t dying after all. He was no longer a grim cancer statistic. With mother’s day approaching, this was the first good news that they had received in six months. At once, the patient began to discuss business trips, travel plans and family outings. He breathed a slow sigh of relief as he realized that, once again, he had a life.

Good outcomes, even in the worst diseases, occur in all oncology practices. Every doctor can regale you with the story of a patient who responded beautifully and went on to survive years beyond everyone’s expectations. The reason we remember these stories is because they occur so infrequently. Complete remissions in metastatic gastric cancer are vanishingly rare. That is the reason that the university investigator offered single agent 5-FU. It’s easy, nontoxic, well tolerated, but it also cures no one. The rationale is well established: Why poison patient’s you cannot cure? Playing the averages, this strategy is a winner. Yet, on an individual patient basis it may, in fact, be a very big loser.

What are we to do with the “non-average” patient? What about the outliers? Should we not, at least, try to find them? We do it with stocks, racehorses, Indy-drivers, real-estate investments and every underdog sports team in every league. It’s the outliers after all that we call winners.

Cancer patients are not clinical trial subjects. They are unique individuals with their own very unique biology. Every patient is an experiment in real time, an “N of 1.” We must respect the dignity of each individual and we are duty-bound to apply every tool at our disposal to assist him or her in the pursuit of his or her own very personal best outcome – providing truly personalized cancer treatment. This patient did not have a 20 percent response. Instead, he was one of the fortunate few who responded very well. And for him that response was 100 percent.

Cancer Patient’s Need to Know – Whose Avatar is it?

The 1984 celebrated case of Baby Fae described the efforts of intrepid investigators at Loma Linda University in California to save the life of an infant born with a hypoplastic heart (the left side of the heart was severely underdeveloped). To salvage this unfortunate child, the heart of a baboon was transplanted into her chest, which successfully maintained her cardiac function. Unfortunately, the child died 21 days later after rejecting the heart.

The experience nonetheless spawned a lively discussion of ethics in human experimentation and the lengths to which we will go to save a life. A friend residing in New York contacted me shortly thereafter. Knowing that I was in medical training in California, he was intrigued by this report and posed the question. “What is the fastest animal in the world?” When I suggested a cheetah or African gazelle, he answered “No, a baboon running past Loma Linda Medical Center.”

I am reminded of this quip following a news report about Champions Oncology. This biotech company located in Hackensack, NJ, founded by investigators from Johns Hopkins University has developed a technique to transplant human tumors into immunocompromised (known as nude for their loss of hair) mice to test drugs and combinations. They use the term “avatar” to describe these human-tumor-bearing mice and like their video-game counterparts these mice serve as surrogates for their patient “users.” It takes 20 to 30 mice to complete the analyses for each patient. Although the work is based on sound science, the practicality, predictive validity and ultimate utility of this approach has yet to be established. This has not dampened the enthusiasm of desperate cancer patients who have proven willing to spend tens of thousands of dollars to undergo a Champion analysis.

Nude-mouseSo what are the upsides of the avatar model? For one, this is a living organism with a functioning blood supply, liver, kidneys and the capability of metabolizing pro-drugs (precursor) into active species. The process utilizes cell clusters, not individual single cells in their analysis. Responses are ultimately “phenotypic” in as much as they reflect cellular responses to injury and not genotypic profiles. Finally, toxicities can also be assessed by measuring the animal’s tolerance of the drug or combination administered.

But let’s drill down for a moment and take a closer look. The avatar approach requires months of preparation, the operation of a vivarium (animal zoo) and several mice for every single drug or combination tested. It requires prolonged (many months) maintenance of the animals with highly unpredictable engraftment of the transplanted tumors. Furthermore, significant time, energy and skill are needed to maintain these in-vivo systems.

Ultimately, only a handful of drugs can be examined, lest the number of mice required becomes unmanageable. At the end of the day these investigators are making a valiant effort to approximate work that we, and our colleagues, have successfully conducted for more than two decades – the accurate selection of chemotherapies and drug combinations for individual patients.

If we allow for the obvious downsides of expense, difficulty, time, limited sample size, low efficiency and resource intensity required to conduct even a single patient’s study there are more daunting concerns.

First, these cells are not actually in their “native state.” Over a period of time the tumors will no longer be host to human immune cells, nor will they be exposed to human cytokines and VEGF. The observed growth of the implanted tumors in the mice-avatars may, in part, reflect an ingrowth of mouse-derived fibroblasts and blood vessels, which have distinctly different biology from those of a human host.

Even if we accept the expense and difficultly of avatars, there is no clear evidence on an individual patient basis, that this approach holds any advantage over the much simpler and direct evaluation of human primary culture microspheroids. That is, the avatar approach appears to be a difficult, cumbersome, inefficient and a very expensive way to do something that we can already do inexpensively, rapidly and efficiently. Further, the purported advantages of in vivo-avatar system are actually less than meets the eye.

After all, most clinical drugs have “active” derivatives that can be utilized for testing in short-term culture without the need for a mouse liver. Our careful calibration of in vitro drug exposures against actual patient responses (P < 0.001) has established the predictive validity of these culture conditions. Finally, the toxicities of virtually all clinically relevant drugs that patients would request for testing (and likely receive) are already well-known to clinicians from existing Phase I and Phase II clinical data sets.

Human tumor sensitivity to chemotherapy (or targeted agents) is driven by what might be described as “response elements.” These unique features of each patient’s tumor can be accurately probed at the phenotypic level through the use of simple assays conducted in short-term culture. Our microspheroid model has proven highly predictive of clinical outcome in virtually every tumor type ever tested.

Our analyses are conducted in seven days, with samples that are the same size or smaller than those required for avatar generation. Furthermore, short-term platforms can analyze dozens of drugs and combinations at a price that is far less expensive. While it might be argued that avatars, once established, can be used as repositories for future research, that is small comfort to patients in need of immediate answers who find themselves paying handsomely for a service that will not be available in a timely manner, e.g. that which can help them in their need for immediate drug selection.

It seems that the medical science community is less interested in results than process. The fact that short-term cultures are predictive of clinical outcome seems less important than the provocative scientific results that these avatar models can provide Avatars enable scientists to interrogate cancer cells for genomic and proteomic signals, offering the opportunity to conduct interesting science. But has that science become more important than the clinical utility of the tests that were purportedly developed (and sold) to improve patient outcomes?

Patients who are considering spending tens of thousands of dollars for these glorified chemosensitivity tests would do themselves a service to first carefully examine the predictive validity, breadth of data, cost and turn-around-time of short-term culture methods, like the EVA-PCD® assay before they commit their precious time and resources to so “interesting” an endeavor as an avatar analysis. After all, it is the patient and their good outcome that should be at the top of the list when the advantages of any system or method are being weighed. Truly personalized cancer care should be just that – personalized.

With the rise of avatars it may be timely to re-examine the original question and wonder whetherNude-mouse the fastest animal in the world will soon be a nude mouse running past Johns Hopkins University.

Outliving Hospice

Outliving CancerFor those of you who have read my book Outliving Cancer you will recognize the chapter entitled “Outliving Hospice.” It is the description of one of my lung cancer patients.

The saga began in 2005, when this gentleman with metastatic lung cancer under the care of the Veteran’s Administration in Los Angeles presented to our group requesting a biopsy for an EVA-PCD assay to select therapy. Diagnosed some months earlier his lung cancer had progressed following first line platinum-based chemotherapy. He was deemed untreatable and placed on hospice.

At his request, one of our surgical colleagues conducted a biopsy and identified a treatment combination borrowed from work done some years earlier by Japanese investigators. It worked perfectly for a year allowing him to return to a normal life.

At year two however, he relapsed. At that point, we confronted a dilemma – would we accept the inevitability of his progressive disease, fold our tent, and allow the patient to return to hospice care; or conduct yet another biopsy to determine the next line of therapy? If you have read the book, then you know how the story plays out. The new biopsy revealed the unexpected finding that the tumor had completely clocked around to an EGFR-driven cancer, highly sensitive to erlotinib (Tarceva). Placed upon oral Tarceva, he has been in remission ever since.

When I saw Rick, two weeks ago at our six month routine follow up he provided a copy of his February 2014 PET/CT scans which, once again, RickHelm Small Imagerevealed no evidence of progressive disease. With the exception of the skin rashes associated with the therapy, he maintains a completely normal life. During our discussion he apprised me of an interesting fact. His survival, now approaching 10 years, according to him, constitutes not only the longest survivorship for any patient under the care of the Los Angeles VA, nor any patient under the care of the VA in California, no, he is the longest surviving actively treated metastatic non-small cell lung cancer under the care of the Veteran’s Administration. Period! While I cannot, with certainty, vouch for this fact, I am quite certain that he is among the best outcomes that I have seen.

There are several points to be gleaned. The first is that every patient deserves the best possible outcome. The second is that hospice care is in the eye of the beholder. The third is that patients must take charge of their own care and demand the best possible interventions available. As an aside, you might imagine that a federal agency responsible for the costly care of tens of thousands of lung cancer patients every year would pay attention to results like Rick’s. Might there be other patients who could benefit from Ex-Vivo Analysis for the correct selection of chemotherapeutics?  One can only wonder.

Is It Ethical to Deny Cancer Patients Functional Analyses?

The ethical standards that govern human experimentation have become an important topic of discussion. Clinical trials are conducted to resolve medical questions while protecting the rights and well-being of the participants. Human subject committees known as Institutional Review Boards (IRB’s) not only confront questions of protocol design and patient protection but also the appropriateness of the questions to be answered. The Belmont Report (1979) defined three fundamental principles i) respect for persons, ii) beneficence and iii) justice. These have been incorporated into regulatory guidelines codified in the code of federal regulations like 45 CFR 46.111. One historical experience offers an interesting perspective upon contemporary oncologic practice.

With advances in cardiac surgery in the1970s and 1980s, in both valvular and coronary artery bypass, an alarming amount of post-operative bleeding was being observed. To address this complication an enzyme inhibitor named Aprotinin was developed by Bayer pharmaceuticals. The drug works by preventing the body from breaking down blood clots (thrombolysis). This is critical for the prevention of postoperative bleeding. Concerns regarding its safety led to Aprotinin’s temporary withdrawal from the market, but those have been resolved and the drug is again available.

After Aprotinin’s introduction, clinical trials were conducted to test its efficacy. Initial results were highly favorable as the drug consistently reduced post-op bleeding. By December 1991, 455 patients had been evaluated providing strong statistical evidence that Aprotinin reduced bleeding by more than 70 percent. Despite this, trialists continued to accrue patients to Aprotinin versus “no treatment” studies. By December 1992, more than 2,000 patients had been accrued and by October of 1994, the number had increased to more than 3,800 patients. Yet the 75 percent risk reduction remained entirely unchanged. Thus, 3,400 patients at untold cost and hardship were subjected to the risk of bleeding to address a question that had long since been resolved.

In a 2005  analysis, Dean Fergusson et al, decried that it should have been evident to anyone who cared to review the literature that Aprotinin’s efficacy had been established. Further accrual to clinical trials beyond 1991 only exposed patients to unwarranted risk of bleeding, and had no possible chance of further establishing the clinical utility of the intervention. This stands as a striking lack of consideration for patient well-being. Fergusson’s review raises further questions about the ethics of conducting studies to prove already proven points. With this as a backdrop, it is instructive to examine functional profiling for the prediction of response to chemotherapy.

Beginning in 1997, a cumulative meta-analysis of 34 clinical trials (1,280 patients), which correlated drug response with clinical outcome was reported. Drug sensitive patients had a significantly higher objective response rate of 81 percent over the response rate of 13 percent for those found drug resistant (P < 0.0000001). This was met by the ASCO/Blue Cross-Blue Shield Technology Assessment published in Journal of Clinical Oncology (Schrag, D et al J Clin Oncol, 2004) that cried for further clinical trials. A subsequent meta-analysis correlated the outcome of 1929 patients with leukemia and lymphoma against laboratory results and again showed significantly superior outcomes for assay directed therapy (P <0.001) (Bosanquet AG, Proc. Amer Soc Hematology, 2007). In response, a second ASCO Guideline paper was published in 2011. (Burstein H et al J Clin Oncol, 2011) Although the authors were forced to concede the importance of the field, they concluded that “participation in clinical trials evaluating these technologies remains a priority.” Most recently we conducted a cumulative meta-analysis of 2581 treated patients that established that patients who receive laboratory “sensitive” drugs are 2.04 fold more likely to respond (p < 0.001) and 1.4 fold more likely to survive one year or more (p <0.02) (Apfel C. Proc Am Soc Clin Oncol 2013).

Slide Detail-smallEach successive meta-analysis has concluded, beyond a shadow of a doubt, that human tumor functional analyses (e.g. EVA-PCD) identify effective drugs and eliminate ineffective drugs better than any other tool at the disposal of cancer physicians today. Not unlike those investigators who continued to accrue patients to trials testing Aprotinin, long after the result were in, oncologists today continue to clamor for trials to prove something which, to the dispassionate observer, is already patently obvious. If we now pose the question “Is it ethical to deny patients functional analyses to select chemotherapy?” the answer is a resounding No!

Barretos Cancer Center of Brazil – The Asymmetric War On Cancer

Barretos logoI 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.

In Cancer – If It Seems Too Good to Be True, It Probably Is

The panoply of genomic tests that have become available for the selection of chemotherapy drugs and targeted agents continues to grow. Laboratories across the United States are using gene platforms to assess what they believe to be driver mutations and then identify potential treatments.

Among the earliest entrants into the field and one of the largest groups, offers a service that examines patient’s tumors for both traditional chemotherapy and targeted agents. This lab service was aggressively marketed under the claim that it was “evidence-based.” A closer examination of the “evidence” however, revealed tangential references and cell-line data but little if any prospective clinical outcomes and positive and negative predictive accuracies.

I have observed this group over the last several years and have been underwhelmed by the predictive validity of their methodologies. Dazzled by the science however, clinical oncologists began sending samples in droves, incurring high costs for these laboratory services of questionable utility.

In an earlier blog, I had described some of the problems associated with these broad brush genomic analyses. Among the greatest shortcomings are Type 1 errors.  These are the identification of the signals (or analytes) that may not predict a given outcome. They occur as signal-to-noise ratios become increasingly unfavorable when large unsupervised data sets are distilled down to recommendations, without anyone taking the time to prospectively correlate those predictions with patient outcomes.

Few of these companies have actually conducted trials to prove their predictive values. This did not prevent these laboratories from offering their “evidence-based” results.

In April of 2013, the federal government indicted the largest purveyor of these techniques.  While the court case goes forward, it is not surprising that aggressively marketed, yet clinically unsubstantiated methodologies ran afoul of legal standards.

A friend and former professor at Harvard Business School once told me that there are two reasons why start-ups fail.  The first are those companies that “can do it, but can’t sell it.”  The other types are companies that “can sell it, but can’t do it.”  It seems that in the field of cancer molecular biology, companies that can sell it, but can’t do it, are on the march.