Outliving Cancer

gpawelski

Robert A. Nagourney, M.D. 
Laboratory Director 
Rational Therapeutics, Inc. 

What is Cancer? 

This is a question that has vexed scientific investigators for centuries, and for the last century, our belief was predicated upon physical observation that cancer reflected altered cell growth. After all, to the untrained eye, or even to the rather sophisticated eye, the mass in the pelvis or the lymph node under the arm, or the abnormality on a chest x-ray, continued to expand upon serial observation. This was "growth" (at least since the time of Rudolph Virchow); and growth it was reasoned represented cell division. 

Based upon the cell growth model, cancer therapists devised drugs and treatments that would stanch cellular proliferation. If cells were growing, then cells needed to reproduce the genetic elements found in chromosomes leading to the duplication of the cell through mitosis. If chromosomes were made of DNA, then DNA would be the target of therapy. From radiation to cytotoxic chemotherapy, one mantra rang through the halls of academia, "Stop cancer cells from dividing and you stop cancer." 

As in many scientific disciplines, nothing spoils a lovely theory more than a little fact. And, the fact turned out to be that cancer does not grow too much, it dies too little. Cancer doesn't "grow" its way into becoming a measurable tumor, it "accumulates" its way to that end. 

In 1972, we realized that the most basic understanding of cancer biology up to that point was absolutely, positively wrong. 

Working in a laboratory during my fellowships, I began to realize that something was wrong with the principles that guided cancer therapeutics. My first inkling came from the rather poor outcomes that many of my patients experienced despite high-dose, aggressive drug combinations. 

Then, it was the failure of the clonogenic assay to predict clinical outcomes that further raised my suspicions. I began to ponder cell growth – cell death, cell growth – cell death. With each passing day the laboratory analysis that I conducted identified active treatments that worked. Using short-term measures of cell death (not cell growth),. I could predict which of my patients would get better. All of the complicated and inefficient clonogenic assay investigations could not. Cell growth – cell death – what was I missing? 

It would be years before I would attend a special symposium on the topic of cell death that it all became abundantly clear. 

My "eureka" moment is captured in Chapter 6 of my book, Outliving Cancer. 

http://www.basichealthpub.com/detail.php?ProductID=278

gpawelski

Robert A. Nagourney, M.D. 
Laboratory Director 
Rational Therapeutics, Inc. 

Chemosensitivity Testing: Lessons Learned 

Like all physicians and scientists engaged in the study of cancer biology and cancer treatment, I had accepted that cancer was a disease of abnormal cell growth. I remember reading the lead article in the New England Journal of Medicine (NEJM) that described the clonogenic assay (Salmon, S. E., Hamburger, A. W., Soehnlen, B. S., et al. 1978. Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. N Engl J Med 298:1321–1327). 

I sat in a laboratory at Georgetown University reading about a lab test that could accurately predict the outcome of cancer patients, without first having to give patients toxic drugs. It seemed so logical, so elegant, so inherently attractive. Sitting there as a medical student, far removed from my formal cancer training, I thought to myself, this is a direction that I would like to pursue. 

But I was only a first year student and there were miles to go before I would treat cancer patients. Nonetheless, selecting drugs based on a laboratory assay was something I definitely wanted to do. At the time I had no idea just how difficult that could prove to be. 

After medical school I found myself in California. There I met an investigator from the National Cancer Institute who had recently joined the faculty at the University of California, Irvine. He too had read the NEJM paper. Being several years ahead of me in training he had applied the clonogenic technique at his laboratory at the National Cancer Institute. Upon his arrival in California, he had continued his work with the clonogenic assay. 

All was going along swimmingly until the NEJM published their report documenting the results of five years experience with the clonogenic assay. It wasn't a good report card. In fact the clonogenic assay got an "F." 

Despite the enthusiastic reception that the assay had previously enjoyed, the hundreds of investigators around the world who had adopted it and the indefatigable defense of its merits by leading scientists, it seemed that something was very wrong with the clonogenic assay and I desperately needed to know what that was. 

It so happens that in parallel to clonogenic assays, my colleague was working on a simpler, faster way to measure drug effects. Using the appearance of cells under the microscope and their staining characteristics, one could skip the weeks of growth in tissue culture and jump right to the finish line. The simple question to be answered was: Did the drugs and combinations kill cancer cells in the test tube? And if they did kill cancer cells in the test tube, would those drugs work in the patient? The answer was, "YES!" 

Despite the clonogenic assay's supporters, it turned out that killing cancer cells outright in the test tube was a much, much better way to predict patient's outcomes. It would be years before I understood the depth of this seemingly simple observation and the historical implications it would have for cancer therapy. 

In Chapter 7 of my book, Outliving Cancer I examine the impact of programmed cell death on human biology. 

http://www.basichealthpub.com/detail.php?ProductID=278

gpawelski

Robert A. Nagourney, M.D. 
Laboratory Director 
Rational Therapeutics, Inc. 

HER2 Two 

I met a charming patient in my office this week. A gentleman with advanced gastric cancer. Upon further examination of his cancer, the adenocarcinoma cells were found to be strongly positive for human epidermal growth factor receptor 2 (HER2). 

Many of my readers are familiar with this surface receptor, a member of the epidermal growth factor family. It's discovery, and the subsequent development of treatments directed toward this target, are well described in the literature. While most people are familiar with this protein in breast cancer, it is only in the last several years that we have recognized the importance of HER2 expression in diseases like gastric and esophageal cancer. 

Discussing the implications with the patient and his sons, I realized that this attractive therapeutic target might not be available for use due to the patient's underlying heart disease. One of the toxicities of HER2-targeted therapies is congestive heart failure. As I pondered the dilemma, I was reminded of one of my patients from 16 years earlier. 

At that time, a strapping 69-year-old woman arrived in my office with a large, high-grade breast cancer and 13 positive lymph nodes. She was also HER2 positive. The problem was that in 1997, the drug trastuzumab was not widely available and never (not ever), used in the adjuvant setting. With that as a backdrop, I treated the patient based on laboratory analysis using the best combinations I could identify. Now, 16 years later, still free of disease, she represents a rare success for someone afflicted with such aggressive (and yes, HER2-positive) disease. 

The reason this former patient came to mind was that her excellent success 16 years earlier had not required the use of HER2-directed therapy. Ingrid Ottesen had done very well using assay-directed therapy chemotherapy without the addition of trastuzumab. All we needed for Ingrid was the best use of available drugs. Despite the possible contraindication for trastuzumab in this gentleman's case, we can still hope for a good outcome if we use the available drugs that best meet his need. After all, it worked perfectly for Ingrid.

gpawelski

Robert A. Nagourney, M.D. 
Laboratory Director 
Rational Therapeutics, Inc. 

Outliving Cancer: Surviving Even the Deadliest Forms of Cancer 

My book of the same title (Outliving Cancer, Basic Health 2013) is an exploration of cancer biology through the lens of individual patients. 

The conceptual framework within which my laboratory operates, reflects the basic premise that cancer doesn't grow too much it dies too little. Thus, effective cancer therapy (regardless of contemporary wisdom) provides benefit only when the drugs induce cell death. While the forms of cell death may vary from necrotic, to apoptotic, autophagic and others, it is, in the end, the death of the cell that heralds a successful outcome. 

We, along with a small group of collaborators, have pioneered the concept of individualized cancer care using each patient's tumor as the study model. Fresh biopsies exposed to chemotherapies and signal transduction inhibitors, live or die depending upon their relative sensitivity to the drugs in question. 

The simple elegance of our platform has provided immense insight into cancer biology, insights we describe in the book, which may ultimately lead to a greater understanding of all human diseases. 

Having successfully applied this approach in many diseases, we have published findings in leukemia, breast, ovarian, and most recently, in lung cancers. We are now very excited by observations in one of the most difficult cancers – pancreatic. Ongoing work in this disease will be the subject of upcoming clinical trials. 

One patient with pancreatic cancer comes to mind. Steve Lockwood presented to medical attention in the Spring of 2010 with weight loss, abdominal pain, and unrelenting low back pain. He was seen by a local medical oncologist after a CT scan revealed a large mass in the pancreas, extensive liver metastases and disease throughout the abdomen. He then sought the opinion of UCLA and the City of Hope. Neither institution could offer any solutions. Luckily his wife, a nurse, had heard about our work and brought him to Rational Therapeutics. 

His tumor markers were doubling every week. He couldn't eat and required daily intravenous hydration, as well as high dose narcotics to get through each day. He was deteriorating so rapidly that I had concerns that he might be too ill for me to help. We decided to conduct an open liver biopsy. As his tumor markers, CA19.9, climbed into the multiple thousands, we found a three-drug combination to be the most active for his tumor. 

Within a week, the pain began to subside. After two weeks, it was demonstrably better. By the time we began treatment cycle two, he had begun to gain weight and came off pain medications entirely. 

Two cycles later, his tumor markers were normal and his PET CT remarkably improved. An additional cycle later, his PET CT was normal. 

While there are many difficult cancers, metastatic pancreatic cancer figures among the worst. The fact that we could find a treatment was cause for celebration. The fact that Steven now remains in remission, after three years, is nothing short of a miracle. As I have written before, there are two kinds of cancer patients: those we can treat and those we can't. Steve Lockwood turned out to be one of those patients we could. 

Like Niebuhr's Serenity prayer, oncologists need the serenity to accept the cancers they cannot treat, the courage to treat those that they can, and the wisdom to know the difference. It is our use of laboratory assays to select treatments that provides us with that particular form of wisdom. 

http://www.amazon.com/Outliving-Cancer-Better-Smarter-Treat/dp/1591203066/ref=sr_1_1?ie=UTF8&qid=1363111912&sr=8-1&keywords=outliving+cancer

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Customer Review @ Amazon.com

Outliving (and Re-Writing) History, April 13, 2013

By Larry Weisenthal

This review is from: Outliving Cancer: The Better, Smarter Way to Treat Your Cancer (Paperback)

I have known Robert Nagourney, the author of this book, both as a friend and colleague. I am not surprised to find that he has written a book that is both highly readable and which also carries much information of real value to cancer patients. My concerns with this book stem from glaring inaccuracies which, if left uncorrected, will unjustly damage the reputations of several clinicians and scientists who, to at least the same degree as Dr. Nagourney, have eschewed the easy path and instead have dedicated their careers to improving cancer care and extending lives by personalizing cancer treatments for individual patients.

Apart from a pervasive theme throughout the book wherein Dr. Nagourney seems, both overtly and by inference, to credit himself with the work of others (this is wholly unnecessary, by the way, as Dr. Nagourney has indeed accomplished much of which he rightfully can be proud without the need for embellishment), is his characterization of all "cell proliferation" technologies - and particularly that which was offered by a company called Oncotech, as, basically, worthless. It should be noted that Dr. Nagourney and I were co-founders of Oncotech (no longer in business). The company originally was founded upon my technology, the DiSC assay, which is based upon the "cell death" endpoint. Dr. Nagourney still uses a re-branded modification of this (DiSC) assay in his own commercial laboratory. Dr. Nagourney's quarrel with Oncotech appears to lie not with my DiSC technology but instead in its use of a completely different technology, added later on. His strong language of condemnation implies that, using this "cell proliferation" technology, Oncotech basically provided a worthless service to more than 50,000 cancer patients.

I will not burden the reader with specifics except to state that Dr. Nagourney's assertion, if not deliberate, bespeaks an incomplete understanding of the technology which he carelessly trashes - and, apparently, also of the considerable body of published literature which supports it. Unaccountably, Dr. Nagourney presents himself as a hero who courageously battles opposition within the company, in order to protect cancer patients from being victimized. In fact, I and others at Oncotech, aware that every laboratory test has both strengths and weakness, devoted ourselves to assuring that the tests were performed accurately and that physicians clearly understood what the tests could tell us and what they could not. Hundreds of physicians were long-time users of Oncotech's tests precisely because they found them to be useful in treating cancer patients, and many positive, independent, peer-reviewed studies published in esteemed medical journals attested to their predictive accuracy.

There is just one more point (though many other exist) I'll mention here. It relates to Dr. Nagourney's representation of the "Medicare controversy." I would excuse Dr. Nagourney's taking a bit of self-serving liberty with the facts if, in seeking to inflate his own contribution, he did not attempt to undermine my reputation by misstating my position in the matter. Dr. Nagourney paints his opposition to Medicare reimbursement for these tests (something thousands of Medicare patients had wished for over the years) as being based on scientific and ethical principle.

In point of fact, Dr. Nagourney was opposed for reasons of financial self-interest. He feared approval at a reimbursement rate to his lab at a level below what he already was charging Medicare patients as a non-covered service. He sought to prevent all cancer patients from receiving Medicare coverage for not only Oncotech's services but also for services provided by laboratories in competition with him which used the same cell death-based technologies used in his own laboratory. If he couldn't make a go of it at levels of reimbursement provided by Medicare, he sought (unsuccessfully, it turned out, contrary to the false impression given in his book) to prevent other laboratories from offering services which would be covered by Medicare, to the detriment of cancer patients who could benefit from these services, but couldn't afford to pay the full cost of these tests out of pocket, as in the case of his own clientele.

In any case, the Medicare issue isn't a matter of debate. Verbatim transcripts from the relevant meetings clearly show that my role and my statements were not as Dr. Nagourney portrays them. I argued in favor of Medicare patients, with proven scientific facts - not in favor of Oncotech, of which I was no longer a part and which was, in fact, a competitor to my own personalized chemotherapy testing lab.

I am in the process of preparing a point by point rebuttal of many other historical liberties which appear in Dr. Nagourney's book. These will be available on my website as soon as I am able to complete them (I am a medical oncologist with an active laboratory-based practice):

This could have been an excellent book. Much of what appears in it is, indeed, excellent. Sadly, egregious inaccuracies in some areas will force the reader to ask the question, "Which portions of this book can I believe and which portions can I not?" It didn't have to be this way.

- Larry Weisenthal, MD

gpawelski

I've been involved in internet cancer research for 17 years and I've been following cell function analysis over 12 years. I've read and studied the history of it dating back decades.

While reading the book, when I came across the information about Oncotech and Medicare reimbursement, I knew Dr. Nagourney was wrong. I thought Dr. Weisenthal's comments were a very helpful review of the book.

There were "others" that were running Oncotech at the time Drs. Nagourney & Weisenthal decided to leave the company. It was taken over by venture (vulture) capitalists, like a lot of private laboratories.

There was one individual running the company that steered the EDR (extreme drug resistance) assay into dominance, the one that Dr. Nagourney is more critical of than Dr. Weisenthal is.

When business people take over a medical laboratory, common sense and science is generally sacrificed.

Dr. Nagourney is a practicing oncologist as well as a medical director of an assay lab. As a physician, he could not recommend his patients use his laboratory assay, it's against the Stark law - named after former Rep. Pete Stark - which restricts physicians on self referral patterns.

Dr. Weisenthal is a medical director of an assay lab only. He always had fought for Medicare reimbursement of assays (any assays). After the Medicare meeting in Baltimore in 1999, CMS decided to reimburse for the drug "resistance" part of the testing (half the science is better than no science at all).

It allowed at least one-third of the more accurate assay to be reimbursed for Medicare patients. They only had to pay for two-thirds (not 100%). In 2006, however, CMS decided to reimburse 100% for both resistance AND sensitivity testing.

But when Palmetto, GBA took over for NHIC, they "arbitrarily" decided to drop reimbursing for the assay, period. They've been doing the same kind of stuff with not reimbursing for Avastin. So it's nothing new with them.

gpawelski

Sorry about the thread. The moderators found in their finite wisdom to arbitrarily censor it. So much for openness.