The Emperor of All Maladies’ New Clothes

Ken Burn’s series “The Emperor of All Maladies” from Siddhartha Mukherjee’s book of the same title provides an interesting and informative historical perspective on mankind’s efforts to confront cancer as a disease.

Beginning with ancient references to human malignancy, the series goes on to explore radical surgery and the earliest use of radiation but really gains traction in the mid-20th century with the discovery of the first chemotherapy drugs. While the nitrogen mustard derivatives were being studied under a veil of military secrecy, Dr. Sidney Farber in Boston explored the B-vitamin analogue, aminopterin, for the treatment of childhood leukemia. (You can read more about this in my book Outliving Cancer.)

Through the ensuing decades, seemingly stunning victories ultimately fell in crushing defeats, while the promise of single agents, then multi-drug combinations, followed by dose-intensive therapies, and finally bone marrow transplantation yielded few cures but delivered ever increasing toxicities. Clifton Leaf, a cancer survivor himself who created a stir with his controversial 2003 Fortune Magazine article entitled “Why We Are Losing the War on Cancer and How to Win It” described his own disappointment with the slow pace of progress.

The last episode examined our growing understanding of human genomics and segued by interviews with Richard Klausner, former director of the National Cancer Institute; and Harold Varmus, the current NCI director; to Michael Bishop, Eric Lander and Francis Collins who luxuriated in the clinical potential of human genomics and the coming era of big science.

The final part was an interview with Steven Rosenberg, one of the earliest pioneers in immunotherapy and Carl June whose groundbreaking work with chimeric antigen receptor T-cells is among the most recent applications of this important field.

The take-home message would seem to be that despite the fits and starts we are now at the dawn of a new age of big science, big data and genomic breakthroughs. What was missing however was an examination of where we had gone wrong. It would seem that the third rail for this community is an honest assessment of how a small coterie of investigators who championed only certain ways of thinking over all others commandeered all the money, grants, publications, chairmanships and public attention, while patients were left to confront a disease from which survival has changed very little, at ever increasing costs and toxicities.

Another thing that came through was the very human side of cancer as a disease and the kindness and emotional support that family members and parents provided to those afflicted. I couldn’t help but feel that these individuals had been cheated: cheated of the lives of their family members, cheated of the resources that could have pursued other options and cheated of the well-being that these poisonous and dose-intensive regimens rained upon them in their last days.

As science has become the new religion and scientists the new gurus, one message that resonated was that many of these gurus were false prophets. They are too self-absorbed to question their own dogmatic belief systems in dose-intensity or multi-agent combinations, all of which fell painfully by the way side as the next therapeutic fad emerged. Will our current love affair with the gene prove to be little more than the most current example of self-congratulatory science conducted in the echo chamber of modern academia?

Victories against cancer will be won incrementally. Each patient must be addressed as an individual, unique in their biology and unique in their response probability. No gene profile, heat map, DNA sequence or transcriptomic profile has answered the questions that every patient asks; “What treatment is best for me?” Dr. Mukherjee himself used the analogy of the blind men and the elephant. Unfortunately, there was little discussion of how much that parable may apply to our current scientific paradigms.

It is time for patients to demand better and refuse to participate in cookie-cutter protocols.

Physicians should become more familiar with the fundamentals of physiology and biochemistry to better understand the principles of cancer prevention at the level of diet and lifestyle.

Finally, while we wait with bated breath, for the arrival of glorious gene profiles widely touted as the future answer to all of cancer’s most vexing questions, patients should throw off the yoke of one-size-fits-all approaches and demand laboratory platforms, such as the EVA-PCD assay, that are available today to make better use of existing treatments.

Cancer Patients Need Answers Now!

I read a sad editorial in the Los Angeles Times written by Laurie Becklund, former LA Times journalist. It is, in essence, a self-written obituary as the patient describes her saga beginning almost 19 years earlier, when she detected a lump in her breast. With stage I breast cancer she underwent standard therapy and remained well for 13 years until recurrence was heralded by disease in bone, liver, lung and brain. Given a dire prognosis she became a self-made expert, conducting research, attending conferences, and joining on-line forums under the name “Won’t Die of Ignorance.” Despite her heroic effort Ms. Becklund succumbed to her illness on February 8. She was 66.

Ms. Becklund experienced the anguish that every patient feels when his or her own individual and highly personal needs simply aren’t being addressed. She opines that entities like the Susan G. Komen Fund, which has raised over $2.5 billion in the last 20 years, “channels only a fraction of those funds into research or assistance to help those who are already seriously sick.” She continues, “We need people, patients, doctors, scientists, politicians, industry and families to make a fresh start.” Her frustration is palpable as she states her outcome seemed to be based on the roll of the dice, like playing “Chutes and Ladders.”

The author’s plight is shared by the millions of patients who are confronting advanced cancers. They are not interested in “why” or “how” their cancers came to be. They can no longer benefit from early detection or cancer awareness campaigns. They need practical, actionable, clinical answers today.

Ms. Becklund’s commentary resonates with me and with everyone who has cancer or knows someone who does. As an oncology fellow at Georgetown, I found myself losing patient after patient to toxic and largely ineffective treatments, all despite my best efforts. I described this in my book “Outliving Cancer.” It was then that I decided that I would dedicate myself to meeting the individual needs of each of my patients and I have used a laboratory platform (EVA-PCD) to do so. I have encountered surprising resistance from clinicians and researchers who seem to prefer the glacial pace of incremental advancement found in population studies over individual solutions found in the study of each patient’s unique biology. Ms. Becklund correctly points out that every treatment must meet each individual’s need.

The role of the scientist is to answer a question (treatment A vs. treatment B) while that of the clinical physician must be to save a life. Every patient is an experiment in real time. It may well be that no two cancer patients are the same. Indeed, the complexity of carcinogenesis makes it very possible that every patient’s cancer is an entirely new disease, never before encountered. Although cancers may look alike, they may be biologically quite distinct. Meaningful advances in cancer will only occur when we learn to apply all available technologies to treat patients as the individuals that they are. Let us hope that Ms. Becklund’ s final essay does not fall upon deaf ears.

Outliving Hospice

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

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

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

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

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

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

Cancer Survival and Matrimony: A Marriage Made In Heaven

The 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 something 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.

Functional Profiling Leads to Identification of Accurate Genomic Findings

The 2013 American Society of Clinical Oncology annual meeting, held May 31 – June 1, in Chicago, afforded the opportunity to report three studies.

Crizotinib (Xalkori)
Mechanism of Action

The first, “An examination of crizotinib activity in human tumor primary culture micro-spheroids isolated from patients with advanced non-small cell lung cancer,” reports our experience using the EVA-PCD platform to examine the drug crizotinib. This small molecule originally developed as an inhibitor of the oncogenic pathway MET, was later found to be highly active in a subset of cancer patients who carried a novel gene rearrangement for anaplastic lymphoma kinase (ALK). It was this observation that lead to the drug (sold under the name Xalkori) being approved for the treatment of advanced ALK positive lung cancer. The subsequent observation that this same drug inhibited yet another gene target known as ROS-1 found in a subset of lung cancer patients, has led to its use in this patient population.

Our exploration of crizotinib activity identified a series of patients who received the drug and responded dramatically. This included both ALK positive and ROS-1 positive patients. One patient however, appeared highly sensitive to the drug in our studies, but was found negative for the ALK gene rearrangement by genomic analysis. We repeated our functional analysis only to the find again, the same high degree of crizotinib sensitivity. I felt confident the patient should receive crizotinib, but at the time the drug was not yet commercially available and he didn’t qualify for the protocols, as he was ALK negative.

I scoured the country looking for a way to get the patient treated with crizotinib. From Sloan Kettering to UCLA, no one could help. And then, in collaboration with my abstract co-author Ignatius Ou from UC Irvine, we decided to repeat the ALK analysis. That proved to be a very good idea. For the patient was indeed positive for ALK gene rearrangement by second analysis and subsequently responded beautifully to a treatment for which he would not otherwise qualify. Once again, phenotype trumped genotype. (The complete story of this patient can be found in Chapter 19 of Outliving Cancer.)

A final patient in the series represented a particularly interesting application of functional analysis. The patient, a young woman with an extremely rare pediatric sarcoma, had failed to respond to multiple courses of intensive chemotherapy and her family was desperate. As she approached the end of her third year in high school, it looked unlikely that she would reach her senior year. A portion of her tumor was submitted for analysis. The results confirmed relative resistance to chemotherapeutics, many of which she had already received and failed, but showed exquisite sensitivity to crizotinib. Indeed, our inclusion of crizotinib in the analysis reflected our intense effort to identify any activity for this previously refractory patient.

We reported our findings to the pediatric oncologist and encouraged them to consider an ALK rearrangement analysis, despite this particular pathway not being on anyone’s radar prior to our study. The result – a positive gene rearrangement. This led to a successful petition to the drug company for the use of this agent for an off-label indication. The response was prompt and dramatic, and remains durable to this day, nearly a year later. Again, the phenotypic analysis guided us to the correct genomic finding.

Our other presentations at this year’s meetings will be reported in future blogs.

Is There a Role for Maintenance Therapy in Cancer Treatment?

There is a long tradition of maintenance therapy in pediatric oncology. Children with acute lymphoblastic leukemia uniformly receive three stages of therapy: induction, consolidation, and finally maintenance. The maintenance stage consists of weekly, or even daily therapies.

The historical experiences of relapse in this population lead investigators to consistently expose these patients to drugs for a period of years. Despite the apparent success of this approach in childhood cancers, long-term maintenance therapy did not gain popularity in adult oncology. Why?

There are probably several reasons. One reason is that childhood leukemia is among the most chemo-responsive diseases in medicine. As such, there are many active drugs available for treatment and many non-cross-resistant maintenance schedules that can be employed.

A second reason is the relative tolerability of drugs like oral thioguanine or mercaptopurine that are used in chronic maintenance therapy. By contrast adult tumors rarely achieve complete remissions. The number of active drugs has historically been very limited and the tolerance of long-term treatments characteristically poor.

Despite this, there is an appealing rational for maintenance therapy. Once we recognized and incorporated the tenents of apoptosis and programmed cell death into cancer management, we were forced to reconsider many of the principles of older treatment protocols.

Conceptually, maintenance allows for a cytotoxic exposure when the cell enters a “chemosensitive” period in its life cycle.  Cancer cells that are “out surviving” their normal counterparts often do so in a quiescent stage (G0 Gx). In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy. As we have now achieved increasingly durable remissions in diseases like breast cancer, small cell lung and ovarian, we are confronting patients in long-term complete remission. When you add to this newfound population the availability of comparably mild agents, like the low dose Gemcitabine/Cisplatin doublet, we now have at our disposal active drugs that can be safely continued for long periods of time.

Using laboratory selection to identify first line (induction), second line (consolidation) and finally third line (maintenance) schedules, we can now offer our patients well-tolerated combinations that offer the hope of more durable remissions.

The GOG 178, in which continued taxol dosing provided more durable remission in ovarian cancer, provided the first inklings of this. Unfortunately, taxol is toxic. And the more durable remissions came at an increasingly high price: neuropathy, myelosuppression, alopecia, fatigue and malaise, which greatly limited the utility of this approach. Yet it does not limit its theoretical attractiveness as we continue to develop targeted agents with more selective activity and modified toxicity profiles. We anticipate maintenance therapies will become more widespread.

Based upon our experiences to date, we are successfully using this approach with our patients who achieve good clinical remissions.

You can find more information about our use of maintenance therapy, in Chapter 14 of the book Outliving Cancer.

This blog was originally posted in August 2011.

Cancer Patients: Cure the Curable, Treat the Treatable and Avoid Futile Care

During my interview with Jeff Michaels on the March 28, 5:00 P.M. Fox News, we explored the themes of my current book, Outliving Cancer. One of the points that most interested my interviewer was the appropriate use of our laboratory platform for the selection of therapy. He asked, “Are there some patients for whom there is no cure?” I responded by explaining what it is, that our laboratory test is designed to do: “Cure the curable, treat the treatable, and avoid futile care.” Jeff Michaels stopped me and asked that I might repeat what I had just said. It seemed that my succinct description resonated.

However simple this distillation of our work may seem, I realized it was actually rather profound. After all, we are confronting an escalating crisis in medicine. How do we meet the needs of a growing population of cancer patients with shrinking resources? How do we allocate treatments to those most likely to respond and finally, how do we avoid the misadventures of toxic and ineffective therapies for those destined to fail chemotherapeutic intervention? On every level, laboratory models can assist us. For those patients with early stage breast cancer, ovarian cancer, small cell lung cancer, non-Hodgkin lymphoma and many leukemias, the expectation of a cure is well within our reach. These patients must receive the very best treatments from the start.

The larger population of patients we confront are those with diseases like gastric, colon, non-small cell lung, recurrent breast, recurrent ovarian or sarcoma for whom cures are less likely and effective therapies must be tolerable so that they can provide benefit without undue toxicity. These are the patients for whom cancer can become a “chronic disease.”

Finally, we must all confront patients for whom treatments offer little likelihood of benefit, yet significant risks of toxicity. These heavily pretreated patients, or those who present with refractory malignancies like pancreatic, kidney cancer or melanoma – represent a special subset. Here the role of the physician is to decide that almost Shakespearean question, “To treat or not to treat.”

This is a particularly delicate circumstance as it forces the doctor, the patient and the family to confront the most difficult question of all, “Am I dying?” The answer is “maybe.” Without seeming flip, every patient no matter what diagnosis, has some chance of response to therapy. If we examine the performance characteristic of our laboratory analyses, they consistently double response rates. With this group however a doubling of response rate may still provide a rather low likelihood of meaningful benefit. If the laboratory finds drug resistance in this group, it is a near certainty that the patient will not respond.

However distressing this data may be, it may be comforting to know that the patient has left no stone unturned. For those patients where a treatment appears active, despite their diagnosis or treatment history, then the discussion surrounding tolerance, toxicity and realistic likelihood of benefit can be undertaken intelligently. This is the embodiment of rational therapeutics.

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.

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.

You can read about Ingrid in Chapter 14 in Outliving Cancer, to be released later this month.

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 soon-to-be-released book, Outliving Cancer.