Empowering Patients Towards Personalized Cancer Care

We have one more guest blogger to introduce during Dr. Nagourney’s absence: Patricia Merwin. Pat just celebrated her fourth anniversary of wellness after receiving a diagnosis of metastatic lung cancer.

In July of 2011, I attended a local TEDx conference in Long Beach, CA where Dr. Robert Nagourney gave a compelling talk about the nature of his work and the future of cancer care. TED is a global organization with a mission to “share ideas worth spreading,” a very appropriate forum for Dr. Nagourney to share his insights into cancer and how to defeat it.

Just three months earlier, at another TEDx event in the Netherlands, Dave deBronkart also gave a talk about the future of cancer care.  Dave deBronkart, better known as “E-patient Dave,” was diagnosed in January 2007 with a rare and terminal kidney cancer.  Given a dismal prognosis, Dave refused to cede his life to “standard care.”  Instead, he turned to a group of fellow patients online and found the information that eventually led to a treatment that saved his life. Dave deBronkart has since become a prolific online patient advocate and an internationally renowned speaker on the subject of patient empowerment and participatory medicine.

Like e-Patient Dave, I was given a “dismal prognosis” when I was diagnosed in 2008 with advanced metastatic lung cancer.  I too refused to cede my life to the standard protocol of the day. But it was not my health care providers who led me to Dr. Nagourney, it was a close friend.  Empowered with the knowledge that it was possible to improve my odds for survival, I chose functional profile testing (EVA-PCD®) to help determine my personalized treatment plan. It was a wise, informed decision resulting in the best possible outcome.  I have since become an online patient advocate, spreading the word to thousands of other patients so that they can become knowledgeable about this important test that could save their lives.

According to Dr. Nagourney, “Every system performs exactly as it was designed to perform. The current system of medical oncology provides adequate care for the average patient. There is little room for true, individualized care, for it disrupts the norm.”  But every patient with cancer has the same objective. To find the treatment that will work for “me.”  With a system skewed toward averages and away from the individual, the path to personalized medicine must be to empower the person with the most at stake – the patient. Dr. Nagourney says, “Today’s patient must become his or her own best advocate.”

More and more, patients are turning to online forums and other patient groups, not just for support, but to seek and share the latest news and information about treatments, side effects, tests, etc. If two heads are better than one, then thousands of engaged patients should, at the very least, provide good food for thought, “ideas worth spreading.”

Dr. Nagourney believes that “it’s in the online trenches where the real, personal war of cancer is being waged.  The old paradigm, that knowledge runs downhill from academics to practitioners to patients is being turned upside down as empowerment goes from the bottom up, not just from the top down.”  I’m sure e-Patient Dave would agree, along with countless other e-patients like him.

Cancer Treatment – A Husband’s View

Guest blogger – Gary Brutsch

Dr. Nagourney is currently attending an international conference where he is an invited speaker. During his absence we will have guest bloggers sharing their views on chemosensitivity testing and the EVA-PCD® assay. Our first guest is Gary Brustch.

Five years ago, my wife of otherwise good health was diagnosed with Stage IV uterine cancer. Following a surgical “solution,” we commenced our search for the next best alternative to just waiting for the disease to take its course.

We settled on a protocol supervised by a major cancer treatment center in Texas. For a total of six months, my wife, Tina, was treated with a combination of chemotherapies. During this treatment we continued to look for medical care that was more scientific-based.

At the conclusion of their protocol, we were notified that the course of treatment had not been successful. At this time Tina’s cancer marker numbers were approaching 800. Two days after this notification we decided that our final option was to contact Robert Nagourney, MD, at Rational Therapeutics in Long Beach, CA.

Our decision was based on the belief that his tumor sensitivity based chemo architecture was probably a more effective method to treat her tumor growth.

After obtaining a tumor sample from Tina and subjecting it to a laboratory process (assay testing), Dr. Nagourney prescribed a specific chemotherapy cocktail for her treatment. After one month of supervised treatment, Tina’s cancer marker number was under one hundred.

We are now into our fourth year of maintenance supervised by Dr. Nagourney. Our united opinion seems to say that, as health challenged individuals we must demand that caregivers treat our health challenges on a focused, individual basis.

We cannot accept that one category of chemotherapy is good for all.

No One is More Interested in Curing Your Cancer Than You

A diagnosis of cancer thrusts a, heretofore, healthy individual into the strange and unfamiliar territory of medical oncology. Many of my patients describe this transition as “entering the cancer bubble.” Suddenly, you are on the inside and everyone on the outside is talking at you about what to do, where to go, whom to see, and what treatments to receive.

From the inside of the bubble however, all of this has a hollow ring as you ponder many options, few good and some, positively frightening. Unfortunately, few patients have the time to complete a MD, or PhD, between diagnosis and the initiation of treatment. Lacking the requisite expertise, they turn to the “authorities” for advice.

Depending on which “authority” one consults, the recommendations may be colored by prejudices and biases. Some physicians adhere strictly to the National Comprehensive Cancer Network guidelines. Others insist upon accrual to Cooperative Group and Phase II trials. University-based investigators will often recommend developmental studies. And some physicians will follow the path of least resistance, examining such issues as cost, chair time and reimbursement, before considering what treatment to deliver.

It is in this milieu, that patients find themselves adrift. Who exactly should you trust? What is their motivation? To put it crassly, when they recommend a specific treatment, what’s in it for them: Cooperative Group points (provided to the most active accruers), academic accolades (the currency of junior faculty), cost containment (the purview of the managed care physicians), or finally, profit margins? Yes, there are a small number of physicians whose choices reflect their own pecuniary interests.

The antidote to all this uncertainty lies within each patient; answers to vexing questions crying out to be heard. These answers reflect the biologic features of each individual’s tumor. What pathway, what repair mechanism, what survival signal drives your tumor? No one has a perfect answer, not the genomic investigators (despite their protestations to the contrary), nor the immunohistochemists, despite the significant appeal of the platform. And not the immunologist (despite brilliant progress in this field over recent years). The closest approximation to human tumor biology is, well, human tumor biology. Using cellular constructs, in the form of native state microspheroids, we can today approximate the response profiles of patients undergoing systemic therapies. Using systems approaches to complex questions, the multitude of factors that contribute to objective response can be examined and elucidated.

No test is perfect. No patient is guaranteed a good outcome. Yet, doubling the objective response rate, and as we and others have documented, improving the time to progression and overall survival can be achieved with available methodologies that apply functional profiling to individual tumors.

No one would walk away from an investment formula that doubled the value of their portfolio. Few would turn down the opportunity to enhance their real estate positions predicated on reliable information from a realtor. Yet everyday, physicians convince patients to walk away from available, published, established methods that can improve response rates, diminish toxicities and avoid futile care. In this environment it is critical for patients to take charge of their own cancer management. Patients must not be dissuaded from seeking the best possible outcomes. Physicians, no matter how well intentioned, are human. Their opinions can be colored by misconceptions and an incomplete understanding of the questions at hand. Laboratory analysis empowers patients to make smart decisions.

In the game of cancer we need all the help we can get. After all, no one is more interested in saving your life than you.

What is Personalized Cancer Therapy?

Personalized therapy is the right treatment, at the right dose for the right patient. Like the weather, however, it seems that everyone’s talking about it, but no one is doing anything about it.

In its simplest form personalized care is treatment that is designed to meet an individual’s unique biological features. Like a key in a lock, the right drug or combination opens the door to a good outcome.

When over the years I lectured on the development of the cisplatin/gemcitabine doublet, my two boys were quite young. I would show a slide depicting a doorknob with a key in the keyhole. I likened our lab’s capacity to identify sensitivity to the cisplatin/gemcitabine combination as “unlocking” an individual’s response.

At the time my wife and I would leave the key in the inside of the front door enabling us to unlock it when going out. We reasoned at the time that our 2-year-old would not be strong enough, nor tall enough to turn the key and let himself outside.  We reasoned wrong, for one day our son Alex reached up, turned the key and opened the door right in front of us. Lesson learned: Given the right key, anyone can open a door.

I continued my analogy by saying that even Arnold Schwarzenegger would be unable to open a door given the wrong key, but might, if he continued trying, snap it off in the lock.

The right key is the right treatment, effortlessly unlocking a good response, while the wrong key is the wrong treatment more often than not too much, too late, akin to a solid tumor bone marrow transplant.

In recent years, personalized care has come to be considered synonymous with genomic profiling. While we applaud breakthroughs in human genomics today, there is no molecular platform that can match patients to treatments.  The objective response rate of just 10 percent, almost all in breast and ovarian cancer patients in one study (Von Hoff J Clin Oncol 2010 Nov 20:28(33): 4877-83), suggests that cancer biology is demonstrably more complex than an enumeration of its constituent DNA base pairs. The unilateral focus on this area of investigation over others might be described as “the triumph of hope over experience” (James Boswell, Life of Samuel Johnson, 1791).

But hope springs eternal and with it the very real possibility of improving our patients outcomes. By accepting, even embracing, the complexity of human tumor biology we are at the crossroads of a new future in cancer medicine.

William Withering (1741-1799) the English physician and botanist credited with discovering digitalis as the therapy for dropsy, e.g. congestive heart failure (An Account of the Foxglove and some of its Medical Uses, Withering W. 1785), had absolutely no idea what a membrane ATPase was, when he made his remarkable discovery. It didn’t matter. Cardiac glycosides provided lifesaving relief to those who suffered from this malady for fully two centuries before Danish scientist, Jens Christian Skou, identified these membrane bound enzymes, for which he was awarded a Nobel Prize in 1997.

Similarly, penicillin, aspirin, and morphine were in all use for decades, centuries, even millenia before their actual modes of action were unraveled. Medical doctors must use any and all resources at their disposal to meet the needs of their patients. They do not need to know “how” something works so much as they (and their patients) need to know “that” it works.

The guiding principle of personalized medicine is to match patients to therapies. Nowhere in this directive is there a prescription of the specific platform to be used. Where genomic signatures provide useful insights for drug selection, as they do in APL (ATRA, Arsenic trioxide); NSCLC (EGFr, ROS1, ALK); CML (Imatinib, Dasatanib) then they should be used.

However, in those disease where we haven’t the luxury of known targets or established pathways, i.e. most human malignancies, then more global assessments of human tumor biology should, indeed must, be used if we are to meet the needs of our patients.  Primary culture analyses like the EVA/PCD® provide a window onto human tumor biology. They are vehicles for therapy improvement and conduits for drug discovery.  Scientists and clinicians alike need to apply any and all available methodologies to advance their art. The dawn of personalized medicine will indeed be bright if we use all the arrows in our quiver to advance clinical therapeutics and basic research.

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.

The I-SPY 2 Clinical Trial

For those of you who read the Wall Street Journal, an article appeared in the Friday, October 1 issue that described the I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) clinical trial. This is an adaptive phase II trial designed to facilitate the introduction of new forms of therapy into clinical practice.

The reporter presents the trial as a dramatic advance, suggesting that the era of “personalized care” is finally upon us. I applaud the intent of a trial to apply “window therapy” (i.e. using the window of time before definitive intervention to introduce and test new therapies) to facilitate drug introduction. However, despite the author’s enthusiasm, the design and application of this trial is demonstrably less than meets the eye.

I-SPY2 uses several molecular markers and established prognostics in conjunction with a new molecular profile (mammaprint) to subgroup candidates prior to randomization. The randomization then allows patients to receive either a standard treatment, or one of five investigational drugs combined with standard agents. Sophisticated imaging technologies are used as surrogates for clinical response, while additional biopsies will provide insights into genomic events.

What this trial does not do is utilize molecular markers (beyond those already available to most clinicians) to select patients for therapy. As such, despite the WSJ author’s glowing review, the trial is, at its core, a randomized selection of candidates. While it may enable the investigators to interrogate the tissue biopsies to answer scientific questions of interest, it does so with no immediate benefit to the patients who participate. Indeed, patients who gain benefit (after being randomized to the investigational arm and then receiving a new combination that actually works) receive said benefit by what could best be described as blind luck. The suggestion that this is “personalized care” falls flat when one realizes that a good outcome is nothing more than a chance event!

Truly personalized care represents the application of validated predictive models to select candidates for specific therapies. Good outcomes can then be ascribed to the intelligent selection and application of effective treatments. The cancer research community’s single-minded focus on genomic platforms, to the exclusion of functional platforms, forces patients to continue to participate in “randomized” trials to test hypotheses of interest to the investigators, largely at the expense of the patients in need. These types of advances could be more rapidly made utilizing functional profiles, such as the one offered at Rational Therapeutics.

What these genomic investigators are expecting their patients to say to them is “You may not be able to treat me any better, but I like the way you think.” What informed patients should be saying instead is, “I don’t care how you think. I want you to treat me better!”