What Can You Do to Improve Your Odds Against Cancer?

I sometimes joke with my patients that a new diagnosis of cancer rarely provides them enough time to get an MD or PhD. Yet it is that level of preparation that may be required to answer the myriad questions that lie ahead.

Although it’s a joke, it is only partly in jest. Unlike buying a house or a car for which one’s life experiences can prepare you, medicine is opaque, complicated and ever changing. At the bleeding edge of medical complexity sits medical oncology and its dizzying array of genomics, transcriptomics, proteomics, epigenomics and metabolomics. Not only is it difficult for patients to keep up with all the changes, it is increasingly beyond the ken of their doctors who have spent entire careers training in the specialty, many of whom may have an MD and a PhD.

So how can patients improve their odds when the obstacles seem so daunting?

My first recommendation is that you develop a personal diary or record book of the procedures, staging studies, pathologic diagnosis, tumor markers, and physician recommendations. This can be accomplished by requesting that your doctors provide either electronic or physical copies of CT scans, pathology reports, blood tests and other clinically relevant information. While there has been some controversy surrounding their overuse, I am a believer in the simple blood tests used as barometers of your cancer with names like CEA, CA19.9, CA125, CA27.29, and CA 15.3. Although they are not perfect, they are easy to obtain, relatively inexpensive and can be repeated regularly to assess progress with therapy.

The second thing that I recommend is that you gain a working knowledge of your diagnosis. While there are no perfect sources of information, the internet can provide useful basic information as a starting point. Begin by obtaining from your doctor the most accurate definition of the cancer. If it is breast cancer, is it infiltrating ductal or lobular? Are you ER positive? Is your tumor HER-2 positive? If it is stomach cancer, is it intestinal type or diffuse, etc? This will facilitate your searches, as well as your future conversations with consultants.

Once you know what you’ve got, the next thing you will need to know is where it is. That is what is known as your stage. The older classification used Roman Numerals I-IV with local disease (early) as stage I and metastatic (disseminated) as stage IV. The more modern system is known as TNM, where T stands for tumor size (1-4), N stands for lymph involvement(1-3), and M stands for metastatic involvement (0 or 1). Most contemporary pathology reports include TNM staging. With the diagnosis and stage established, you now know what you have and where it is.

This is where it gets interesting. Now, what do you do about it?

It is at this point that therapeutic choices must be made. Most physicians will rely upon standard established guidelines. Among the most widely used guidelines are those published by the National Comprehensive Cancer Network known as NCCN. While these guidelines can be useful, they can also be stultifying, limiting patients to what might be considered the lowest common denominator of care. While they may be better than haphazard treatment selection, they may very much miss the mark for your unique needs.

Here the process degenerates into a plethora of confusing choices.

Should you have genomic profiling? If so, should it be based on a tissue biopsy, circulating cell free tumor analysis, or even the newer urine tests that measure the presence or absence of abnormal genes? All of these technologies have merit and over the coming years the best ones will shake out. Despite these tests being widely touted (and profitable for the purveyors), none of these test have been put to formal trials that establish their capacity to influence survival. This is interesting because many of these tests have obtained insurance and Medicare coverage without even remotely rising to this standard. Nonetheless, these tests can be used for specific diseases like lung and leukemia where actionable targets are known to exist. Beyond that, caveat emptor (buyer beware).

One of the problems with genomic profiles is that they do very good job of telling you what the problem may be, but a very bad job at telling you the solution. It is a rare genomic mutation that comes with a drug to treat it. Most of the findings wind up asking more questions rather than providing more answers.

With the diagnosis established, the stage known and in certain circumstances molecular profiles complete, it is time for you to choose treatments and the centers that will provide them. Many seek the care of academic centers. These centers may offer clinical trials as a first line therapy for those who meet criteria.

It should be remembered that clinical trials are conducted in three principal formats. Phase I trials examine brand new drugs. These trials determine the safety of the drugs at different dose schedules. Phase II trials take the established safe doses and develop experience in each type of disease, e.g. lung versus colon versus breast. Phase III trials then compare the new drugs with existing treatments to see if there is any real improvement.

It is critical to recognize the functions of these different types of trials. Phase I studies classically have no therapeutic intent (your benefit is secondary to their measurement of your ability to tolerate the drug).

Phase II trials seek evidence of clinical activity by disease, but your specific disease may not be right for that drug.

Finally, Phase III allows a comparison of standard treatment to the new one. Many of these drugs do not make the grade and fall off the development wagon. In addition, you must be willing to be randomly assigned.

It is here that my approach diverges from those outlined. I have long maintained that each patient is unique and that their cancers must be treated individually. Recognizing that no genomic, proteomic or transcriptomic platform can answer the very complex questions of therapeutic response, we at Rational Therapeutics have developed functional analyses through the use of the EVA-PCA assay, which studies each patient’s tumor by exposing it to the drugs of interest. The most active, least toxic combinations are then recommended. In a report at the American Society of Clinical Oncology meeting of 2013, we showed a 2.02 higher response rate (P < 0.001) and a 1.44 improvement in one year survival (P < 0.02) for patients who received assay-guided therapy. This established the predicative validity of the functional approach.

It is important for patients to realize that cancer is an unbalanced system, not just an abnormal cell. Cancer as a disease goes beyond the cell or even the tumor to affect the body itself. Alterations in immunity, metabolism and physiology contribute to the good or bad outcomes of every patient. Patients should seek to normalize their lifestyle, improve their diets, maintain an active exercise program, reduce their weight to lean body weight, and may in some circumstances consider nutritional supplements and/or appropriately selected natural products that may augment their wellbeing.

The human body is a complicated machine and each part resonates with every other part. A good diet, a good night’s sleep and avoidance of an unhealthy lifestyle, as much as they may sound like your mother’s advice, is indeed very good advice.

Every cancer patient has the right to get better. As a patient, you should take charge of your cancer and make smart decisions. Afterall, no one is more interested in saving your life than you.

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.

This 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.

Gastric Cancer: A Call for Patient Selection

Gastric cancer is the fourth most common cancer worldwide with more than 930,000 diagnoses and 800,000 deaths attributed to this disease each year. Although relatively uncommon in the U.S., constituting only 2 percent of new cancers, in countries like Korea it makes up 20 percent of all new malignancies.

Among the causes are Helicobacter pylori infection, diets rich in smoked food, a high intake of nitrates and nitrites and cigarette smoking. A rare but aggressive form of the disease is associated with a gene mutation known as CDH1. The high frequency of metastatic disease at the time of initial diagnosis often precludes surgery, leaving systemic chemotherapy as the principal treatment option.

A recent report in The Annals of Oncology (No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy: Bernards N. et al, Annals of Oncology. November, 2013) describes a retrospective analysis by Dutch investigators who examined the use of chemotherapy in patients with inoperable gastric cancer.

In total, 4,797 cases were examined from 1990 to 2011. Over this time, the proportion of patients presenting with metastatic disease increased from 24 percent in 1990 to 44 percent in 2011. At the same time, palliative chemotherapy use increased from 5 percent to 36 percent. Younger patients and those of higher socioeconomic status had the largest increase in chemotherapy use, while older patients, those with linitis plastica and those with multiple metastases had lower chemotherapy use. Despite the significant increase in the use of chemotherapy, the median survival for patients was unchanged at 15 weeks in 1990 and 17 weeks in 2011 (P = 0.1).

Over this period, early treatment regimens like 5-fluorouracil (5FU) and FAM were largely replaced by combinations like Docetaxel/Cisplatin/5-FU (DCF), Cisplatin/Irinotecan, Epirubicin/Oxaliplatin/Capecitabine (EOX) and Carboplatin/Taxol. While response rates and palliative benefits have continued to improve, this has not translated into improved overall survival. This reflects a dilemma that has confronted medical oncologists for decades.

For many years, clinical trialists have held that one cannot assess the benefit of a treatment by comparing responders to non-responders. That is, time to progression and survival must compare all patients on a given treatment arm to those on the control arm. Their rationale was that “one must treat all patients to obtain the benefit seen in some.”  Put differently you cannot “cherry pick” your winners and losers. It was said that this proscription was needed to avoid selection bias. But as any medical or nonmedical person would recognize, people who respond to treatment do better than those who do not. Lacking the ability to identify responders upfront, these trialists have insisted upon a one-size-fits-all approach to the detriment of clinical therapeutics and drug development.

With the dawn of the molecular era we see chinks in the armor of these trial designs as investigators now question why everyone should receive a treatment if only a small percentage will benefit. In gastric cancer, HER2 over-expression, found in 20-25 percent of patients, is now routinely used to identify patients who will respond to trastuzumab. But what of the other 75-80 percent of patients who do not carry HER2 and for whom there are no widely used determinants of clinical response? Do the results of Bernard article suggest that these patients should not receive therapy?

The Bernard article offers an interesting insight into what may be the future of medical oncology. As cancer therapy is increasingly scrutinized, not only for response or palliation but also for overall survival, patients may soon be denied treatments unless the results of the therapy rise to this, the highest level of evidence, for the entire population of treated patients.

Would it not be preferable to use laboratory analyses, like the EVA-PCD®, to select among treatment candidates before subjecting all patients to the risk and expense of toxic chemotherapy? In this regard, the author’s comments are poignant: “Identification of the subgroup of patients which benefit from palliative chemotherapy is of the utmost importance to avoid unnecessary treatment.” As a laboratory investigator engaged in the field of drug selection science (functional profiling), I couldn’t agree more.

The Tyranny of Medical Experts

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

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

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

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

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

Is Rationed or Rational Medical Care In Our Future?

We are witness to a sea change in medicine. Doctors and nurses are being replaced by “healthcare providers;” medical judgment is being phased out in favor of therapeutic algorithms; and the considered selection of treatments is giving way to rigid therapy guidelines. All the while, the regulatory environment increasingly precludes the use of “off label” drugs. It is understandable why insurers, governmental entities and hospital chains might welcome these changes. After all, once therapies have been reduced to standardized formulae, one can predict costs, resource allocations and financial exposures to the twentieth decimal place. For many medical conditions, these approaches will provide adequate care for the majority of patients.

But, what of the outliers? What of those complicated disease entities like cancer, whose complexity and variability challenge even the best minds? How do we bang the round peg of cancer therapy into the square hole of formulaic care?

There are several answers. The first is the least attractive: In this scenario, predicated upon cancer’s incidence in an older population, at the end or beyond their productive (and reproductive) years, we simply don’t allocate resources. Most civilized modern societies haven’t the stomach for such draconian measures and will seek less blunt instruments.

The second is a middle of the road approach. In this scenario, standardized guidelines that provide the same treatment to every patient with a given diagnosis are developed. Every medical oncologist knows the drill: FOLFOX for every colon cancer, Cytoxan plus Docetaxel for every breast cancer and carboplatin plus paclitaxel for ovarian cancer. The treatments work adequately well, the schedules are well established, the toxicities are well known and no one is cured. The beauty of this approach is that the average patient has an average outcome with the average treatment. By encompassing these regimens into standardized algorithms, we may soon be able to eliminate physicians entirely — first, with nurse practitioners and physician’s assistants and, ultimately, with computers. What is perhaps most surprising about this scenario has been the willingness of the medical oncology community to embrace it, a sort of professional self-induced extinction. At the time of this writing, this is the predominant model and is becoming increasingly entrenched under the auspices of NCCN and related guidelines. The operative term being guidelines, in as much as these “guidelines” are rapidly becoming “dictates.”

The final approach, and the one I find most appealing, is that which utilizes the clinical, scientific, laboratory and technical acumen of the physician to the maximum. Combining diagnostic skill with scientific insight, the physician becomes the captain of the ship, who must assume control from the autopilot once the vessel has entered the tempest and use his/her experience and training to guide the patient to a soft landing. This requires the capacity to think and demands an up-to-date knowledge of many disciplines. The judicious application of laboratory-directed approaches can further enhance the skillset, introducing objective data that is then used to guide drug and treatment selections. Predicated upon an understanding of the patient’s tumor biology, cancer therapy becomes an intellectual exercise that draws upon literature, and a knowledge of pharmacology and physiology. Adding the wealth of newly developed signal inhibitors to the mix only enhances the odds of a good outcome.

This approach improves responses and eliminates futile care. It provides patients the opportunity to participate in their own management. Correctly delivered, it would make available to every patient any FDA-approved drug. While it would seem to some that this would open the floodgates of drug use, I would strenuously disagree. It would instead limit drug administration to those patients most likely to respond, a goal currently pursed by virtually every major institution, yet accomplished by none. While a handful of targeted approaches have come to fruition in the last few years — erlotinib for EGFR mutation, and sunitinib in kidney cancers — most of the molecular profiling being done today doesn’t aid in the selection of therapy but instead provides negative information (e.g. RAS in colon cancer, ERCC1 over expression in lung) enjoining the physician against the use of a given agent but then leaving the unfortunate patient to fend for themselves amidst a panoply of randomly chosen options.

This is the approach that I have chosen to adopt in my own care of cancer patients. Our rapidly growing successes in ovarian, breast, lung, melanoma, leukemias and other diseases could and should serve as a model for others.