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.

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!

Triple Negative Breast Cancer: Worse or Just Different?

The term “triple negative breast cancer” (TNBC) is applied to a subtype of breast cancers that do not express the estrogen or progesterone receptors. Nor do they overexpress the HER2 gene. This disease constitutes 15 – 20 percent of all breast cancers and has a predisposition for younger women, particularly those of black and Hispanic origin. This disease may becoming more common; although, this could reflect the greater awareness and recognition of this disease as a distinct biological entity.

On molecular profiling, TNBC has distinct features on heat maps. The usual hormone response elements are deficient, while a number of proliferation markers are upregulated.  Not surprisingly, this disease does not respond to the usual forms of therapy like Tamoxifen and the other selective estrogen response modifiers known as SERMs. Nonetheless, TNBC can be quite sensitive to cytotoxic chemotherapy. Indeed, the responsiveness to chemotherapy can provide these patients with complete remissions. Unfortunately, the disease can recur. Complete remission maintained over the first three to five years is associated with a favorable prognosis, with recurrence rates diminishing over time and late recurrences more often seen in estrogen receptor-positive cancers.

Triple negative breast cancer is not one, but many diseases.

MTOR-pathway-ger Among the subtypes are those that respond to metabolic inhibitors such as the PI3K and mTOR directed drugs. Another subset may respond to drugs that target epidermal growth factor. There are basal-types that may be somewhat more refractory to therapy, while a subset may have biology related to the BRCA mutants, characterized by DNA repair deficiencies and exquisite sensitivity to Cisplatin-based therapies. Finally, a last group is associated with androgen signaling and may respond to drugs that target the androgen receptor.

Some years ago, we used the EVA-PCD platform to study refractory patients with breast cancer and identified exquisite sensitivity to the combination of Cisplatin plus Gemcitabine in this patient group. We published our observations in the Journal of Clinical Oncology and the combination of Cisplatin or Carboplatin plus Gemcitabine has become an established part of the armamentarium in these patients.

The I-SPY-2 trial has now used genomic analyses confirming our observations for the role of platins in TNBC. This iSignal_transduction_pathways.svgn part reflects the DNA repair deficiency subtype associated with the BRCA-like biology. More recently, we have examined TNBC patients for their sensitivity to novel therapeutic interventions. Among them, the PI3K and mTOR inhibitors, as well as the glucose metabolism pathway inhibitors like Metformin. Additional classes of drugs that are revealing activity are the cyclin-dependent kinase inhibitors, some of which are moving forward through clinical trials.

One feature of triple negative breast cancer is avid uptake on PET scan. This reflects, in part, the proliferation rate of these tumors, but may also reflect metabolic changes associated with altered glucose metabolism. In this regard, the use of drugs that change mitochondrial function may be particularly active. Metformin, a member of the biguanide family influences mitochondrial metabolism at the level of AMP kinase. The activity of Metformin and related classes of drugs in triple negative breast cancer is a fertile area of investigation that we and others are pursuing.

When we examine the good response of many triple negative breast cancers to appropriately selected therapies, the potential for durable complete remissions and the distinctly different biology that TNBC represents, the question arises whether TNBC is actually a worse diagnosis, or simply a different entity that requires different thinking. We have been very impressed by the good outcome of some of our triple negative breast cancer patients and believe this a very fertile area for additional investigation

Rallying the Troops to Confront Cancer

The recent blog “Stand Up To Cancer Research!” described some of the pitfalls of modern cancer research and the clinical trial process. It has engendered an active discussion. It may be helpful to address some of issues raised. For those of you who did not have the opportunity to read that blog, it defined the difficulty that many patients encounter when they seek experimental treatments. Clinical trials are often only available at select centers, sometimes at great distances from patient’s homes. There can be rigid inclusionary and exclusionary criteria, and the pre-entry evaluations e.g. re-biopsy, CT/PET, etc. can be daunting, time consuming and inconvenient. Travel and accommodations may come at great personal expense.

I penned the blog, in part, to remind patients that they are ultimately in control of the process. One patient asked how can “we stand up to the system” describing herself a consumer while “they’ve got the goods.” This is the frustration many people feel. It should be remembered, however, that a substantial portion of research support comes from tax dollars and charitable donations. These are your dollars. If the system is not working, then those responsible must be held accountable. The American public has the power of the vote. Patient advocates can approach and lobby their representatives and demand improvements in the clinical trial process. To wit, the level of scrutiny and restriction upon access to new drugs must be re-examined. There is an army of well-trained clinical oncologists capable of delivering experimental drugs today. Not just the fully vetted, just-about-ready-for-prime-time agents currently found in phase III trials, but the really new exciting drugs. Once a drug has passed Phase I and found to be safe in patients, open up the accrual process. “Compassionate use” has virtually disappeared from the lexicon of cancer research. Twenty years ago I made a discovery in the laboratory. Working with the pharmaceutical company and the FDA, we were almost immediately granted access to a yet-to-be approved agent. The combination proved so effective that today it is one of the most widely used regimens in the world. That would not happen today. We simply cannot get access to the best drugs for our patients.

Microscope Detail2-lo resWith the industrialization of medical care, growth of mega-medical systems and the increasing role of government, medicine must be viewed through a different lens. Changes in cancer research will require changes in cancer policy, and policy comes from political power. Cancer patients will need to identify legitimate spokespeople to take their concerns forward to their elected officials. While the current clinical trial process slowly grinds out new development, even the smartest, fastest trials take years to change practice. Every day, more than 1,500 cancer patients die in the United States alone. Cancer patients do not have time for clever doctors to pose interesting questions while they suffer the slings and arrows of ignoble, ineffective therapy. It is time for a change in cancer research, and patients must be the instrument for that change.

Stand Up to Cancer Research! The Downside to Clinical Trials.

As the practice of medicine has moved from a profession to an industrial undertaking, this most human of experiences has fallen prey to the dictates of the American business model. Patients are no longer the purchasers of medical care and services, but instead, the consumers of those goods and services that meet the needs of the purveyors. Whether this is a governmental entity, academic institution, or pharmaceutical company, individuals have become cogs in the wheel of the medical-industrial complex.

Cancer from dictionaryThis has become glaringly apparent in the field of cancer research. Cancer patients were once, for better or worse, in charge of their own destinies. They could choose their surgeon, oncologist, and institution, even to some degree the treatments that they wished to undergo. As the HMO model came into play, patients were increasingly told what doctor, what treatment, and what hospital. The capacity of individuals to make decisions was eliminated in favor of standardized care, cost guidelines and treatment protocols. While much of the academic community described this as progress with adherence to standardized protocols, these protocols have not provided superior outcomes in most settings. Instead, they offer hospital administrators the opportunity to anticipate costs, allocate resources, codify drug administration and regulate care delivery.

Recent experience has brought several disturbing examples to the fore. Working in the laboratory, we have been able to select candidates for new combinations, sometimes years before these regimens became broadly available. We then identify centers with access to these drugs under protocol. Many of the drugs have well-established safety records from prior phase 1 and 2 clinical trials, but have not achieved full FDA approval. When several of our patients with lung cancer revealed sensitivity to a regimen that we had identified years earlier (Kollin, C et al Abs 2170, Proc AACR, 2005) we immediately explored sites offering this combination of an oral agent with an IV antibody. The closest we could find was in Colorado. The injection, a widely established monoclonal antibody, FDA approved for gastrointestinal cancer, was not yet approved for lung cancer while the pill had been administered safely in hundreds of patients. Indeed, the combination had also been safely administered to dozens of patients by the time we inquired. Nonetheless, to participate in this potentially life-saving treatment my patients were forced to commute from LA to Colorado every other week.

It would have been quite easy, once the patients were formally accrued, for them to return to California and receive the same drugs under our care. After all, we were the ones who identified them as candidates in the first place and we were very familiar with the trial. Despite this, the rigidity of the protocol forced these lung cancer patients to become frequent fliers. The good news was that the treatments worked.

More recently a patient, who had failed experimental therapy for advanced uterine carcinoma at a large academic center in Texas, returned to LA five years ago to seek my assistance. A lymph node biopsy at the time revealed exquisite sensitivity to a drug combination developed and published by our group and she achieved a prompt complete remission. She has since relapsed and required additional chemotherapy. My concern for her long-term bone marrow tolerance, with repeated exposure to cytotoxic drugs, led me to seek alternatives. Her EVA-PCD functional profile had revealed excellent activity for PARP inhibitors. Here, I thought, would be the solution to her problem. After all, the PARP inhibitors had been in development for years. Several had revealed compelling activity in clinical trials and they are well tolerated. Despite this, no PARP inhibitor has been FDA approved.

When we pursued opportunities to accrue the patient to one of the PARP inhibitor trials, however, she did not qualify. Having received low dose Carboplatin several months earlier she ran afoul of an exclusion criterion in the protocol that dictated no platinum exposure for six months. “Six months?” I exclaimed. Few cancer patients can wait six months to start treatment and virtually no cancer patients can wait six months once they have relapsed. I was flabbergasted.

What exactly were the protocol designers thinking when they demanded a six-month wash out, fully four, five or six times longer than any protocol I’d ever encountered?  The absurdity of this demand virtually eliminated patients-in-need from consideration. As I considered the dilemma it became increasingly clear. When one examines the thinking behind clinical protocols it becomes evident that they are not designed to help patients or cure cancer. Instead, they are created to answer specific questions. In so doing they further the careers of investigators, expand medical center market share, standardize treatments and simplify the activities of clinical research organizations. Patient outcomes, well-being and convenience are far down the ladder of expectations.

As I pondered the inconvenience, hardship and lost opportunities associated with clinical trial participation for many patients around the United States, I began to wonder whether patients should throw off the yoke of this oppressive system. After all, it is not the academic centers that own the process, it is the patients. It is those brave individuals willing to participate in these studies. It is the patients whose tax dollars support these institutions. It is the patients who purchase either directly or indirectly the drugs they receive and it is the patients that are necessary for the process to succeed.

Patients should demand more user-friendly, convenient, patient-centric therapy programs. Perhaps patients should simply refuse to participate. A ground swell of patient advocacy could re-orient the discussion away from the convenience and ease of the treating physicians and toward the good outcome and ease of the treated patient. While we applaud the investigators for their brilliance and prowess, we forget that no clinical investigator would receive accolades were it not for the hundreds or thousands of patients who martyr themselves at the altar of clinical research. Patients, not their doctors, are the heroes.  Perhaps it is time for cancer patients to stand up to cancer research.

Cancer Survival and Matrimony: A Marriage Made In Heaven

JCO coverThe November 1, 2013 issue of the Journal of Clinical Oncology (Marital Status and Survival in Patients with Cancer, Aizer, A. et al J Clin Oncol, 2013), reports a study by investigators from Harvard University. Using the Surveillance, Epidemiology and End Results (SEER) data they examined more than 1.2 million cancer patients diagnosed between 2004 and 2008 to measure the impact of marital status on overall survival. Results reveal a statistically significant impact of marriage on cancer survival. The benefit slightly favored males over female, but remained significant across different diseases and for never married, separated, divorced or widowed. The authors note, “The survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.”

Epidemiologic studies that correlate disease states with socioeconomic status, level of education, geographic location, lifestyle or diet are fraught with confounding variables. Nonetheless, well-done studies can open a wealth of interesting questions regarding non-treatment related aspects of our health and well-being. This study is provocative for it identifies the interaction between marital status and stage at diagnosis, as well as overall survival.

There are many ways one might interpret the findings. The accompanying editorial (Marriage Is as Protective as Chemotherapy in Cancer Care, Kissane, D) notes that non-married status may reflect “reduced adherence to state-of-the-art treatment.” That, we presume, would include such variables as regular physicals, frequency of mammograms, PSA evaluations, willingness to undergo surgery or the use of adjuvant treatments. The role of depression is also noted. While all of these may apply, they have a self-serving ring, whereby good health, it would seem, can only be attributed to good doctoring. Controversies surrounding PSA screening or the impact of “annual physicals” on general health are but a few examples where more may not necessarily be better.

While it may be argued that unmarried individuals fail to obtain adequate medical care, the data may reflect somethinAA010368g more profound, the psychoneuroimmunology of cancer survivorship. That is, each patient’s capacity to will-themselves better. The will-to-live is enhanced by close human relationships. We are all witness to patients who survive against all odds. They are usually filled with zeal, willing to go to whatever lengths are required to overcome their illness and most have close interpersonal relationships, nurturing environments, loving families or husbands and wives who dote on them.

Norman Cousins spoke at length about the healing force of one’s emotional and spiritual belief systems in his own battle with ankylosing spondylitis (Anatomy of An Illness, As Perceived by the Patient, 1979). Might his experience reflect a similar dynamic to that described in the current study? My patient Alan Kapuler’s excellent outcome over Non-Hodgkin’s lymphoma, described in my book (Outliving Cancer, 2013, chapter 12) exemplifies this same mind-over-matter dedication, characteristic of many of our long-term survivors.

I applaud Dr. Aizer and his co- investigators for examining this aspect of cancer survivorship. I am impressed that such a report would find its way onto the pages of the Journal of Clinical Oncology. However, I am less certain that these good outcomes reflect state-of-the-art treatment and more of the opinion that married patients may be part of a happier, healthier, better adjusted and more humanly connected population. Interpersonal relationships are not devices. They cannot be patented or sold. However, as can be seen from this study, they may be among the most powerful interventions at our disposal in the management of advanced cancer.

Nut Consumption, Pancreatic Cancer and Woody Allen

In the 1973 Woody Allen movie ”Sleeper,” Miles Monroe (played by Allen), is the nerdy owner of the Happy Carrot health food store who undergoes cryostasis (deep freeze) only to be awakened 200 years later. He finds himself in a place where all that he had come to know has disappeared. Two physicians observing him from a distance comment on his unusual dietary request: wheat germ, organic honey and tiger’s milk. Puzzled, one physician asks why he would want such odd foods. The second physician explains that 200 years earlier, low fat foods were considered healthy. “What, no deep fat, no steak, no cream pies, or hot fudge?” she asks incredulously. “No”, he explains, “those were thought to be unhealthy…. precisely the opposite of what we now know to be true.”

I was reminded of this scene by a paper published in the British Journal of Cancer (BJC). Based on observations from 75,680 women in the Nurses’ Health Study, investigators showed that the regular consumption of nuts was inversely associated with the risk of pancreatic cancer. Indeed, those who consumed one ounce of almonds, Brazil nuts, cashews, hazelnuts, macadamias, pecans, pine nuts, pistachios or walnuts, three times per week had a 35 percent reduction in the risk of pancreatic cancer (P = 0.007). This was found to be independent of age, height, obesity, smoking, diabetes, or other dietary factors. Although the study was funded by the International Tree Nut Council Nutrition Research and Education Foundation, they had no participation in the design or analysis of the data.

The consumption??????????????????????????????????????????????????????????????????????????? of nuts has previously been shown to be highly beneficial. In a Spanish study of 7,000 people, ages 55 to 90, those who ate three servings per week had a 55 percent reduction in death from cardiovascular disease and a 40 percent reduction in death from cancer. Clearly, the association between nut consumption and health is both strong and broad based, as it extends from cardiovascular disease to cancer.

The majority of the calories in nuts come from lipids (fats) including monounsaturated and polyunsaturated fats like oleic acid, found in olive oil, linoleic, gamma-linolenic and alpha-linolenic acids as well as the saturated fats, stearic and palmitic acids. Of the nuts commonly consumed the highest lipid content is in macadamia nut, followed by peanuts, pecans, cashews, walnuts, pine nuts, hazel nuts, pistachios, almonds and chestnuts. The protein content of nuts favors peanuts and pine nuts. A number of micronutrients are also found in nuts including flavonoids, stilbenes, proanthocyanidins, calcium, iron, B6 and magnesium.

The BJC study stands in strong contradistinction to the oft-repeated admonition that nuts should be avoided, as voiced for many years by health experts and dieticians. The fat avoidance craze of recent decades held that foods containing lipids were to be eschewed. Health conscious individuals were encouraged to eat grains and carbohydrates.

Today we recognize the important benefits of lipids and find that higher fat and high protein diets are gaining traction over the older food pyramid. We now find that high carbohydrate intake may in part be responsible for many contemporary maladies suggesting that the agrarian revolution of 10,000 years ago that made high calorie/low fiber grains readily available may ultimately prove to have been more a curse than a blessing.

An expert is one whose “faculty for judging or deciding rightly, justly, or wisely” is recognized and granted sway over society. But who judges the experts? The current BJC study suggests that in many fields of science and medicine the experts can be wrong. How many people denied themselves the pleasure and, we now come to learn, the health benefits of nuts based upon expert recommendations?

In our contemporary diagnosis and management of cancer, might the experts be leading us astray in other areas? Perhaps we should all ponder that point as we nibble on a few Macadamia nuts.