With an EVA-PCD Assay, It Can Be That Simple

Shortly after I left the university and joined a medical oncology group, one of the junior members of the practice asked if I would cover for him during his summer vacation. Among the patients he signed over to me was a gentleman in his 60s with what he described as “end-stage” chronic lymphocytic leukemia (CLL). As the patient had already received the standard therapies, second line regimens and experimental drugs available at the time, the physician had run out of options. My charge was to keep him comfortable. I asked if it would be all right for me to study his cells in my lab and the doctor agreed.

I met the patient the next day. He was a very pleasant tall, slender black man lying in bed. He had lost a great deal of weight making the already enlarged lymph nodes in his neck appear that much more prominent. As I was engaged in the study of CLL as my principal tumor model, I asked if I might examine his circulating CLL cells as part of our IRB-approved protocol. He graciously obliged and I obtained a few ccs of blood. We were deeply ensconced in tumor biology analyses and his cells were used to explore membrane potentials, DNA degradation and glutathione metabolism as correlates with drug response profiles by EVA-PCD analysis. A large number of those studies have since been published.

What struck me about the patient’s EVA-PCD profile was the exquisite sensitivity to corticosteroids. Corticosteroids in the form of prednisone, Medrol, Solu-Medrol and Decadron are the mainstays of therapy for lymphoid malignancies like CLL. Everyone receives them. Indeed this patient had received them repeatedly including his first line chlorambucil plus prednisone, his second-line CHOP and his third line ESHAP. It was only after he had failed all of these increasingly intensive regimens that he finally moved on to an experimental agent, homoharringtonine, a drug that finally received FDA approval in 2012, after almost 40 years of clinical development. Unfortunately for him homoharringtonine did not work and it seemed we were well beyond conventional therapies, or were we?

I pondered the corticosteroid sensitivity finding and decided to start the patient on oral prednisone. It would be another two weeks before his physician returned and there really weren’t many options. The patient responded overnight. The lymph nodes melted away. The spleen diminished. He began to eat and gained weight. Within a few days he felt well enough to go home. I discharged the patient and remember writing his prednisone prescription, 40 mg by mouth each morning.

A week later, my colleague returned from his retreat in the Adirondacks. He inquired about his patients and surmised that this gentleman, no longer in the hospital, had died. I explained that he had been discharged.

“Discharged . . . how?” he asked. I described the findings of our EVA-PCD study, the sensitivity to steroids and the patient’s miraculous clinical response to this, the simplest of all possible treatments. The physician then turned to me and said “Prednisone . . . hmmm . . . I could have done that.”

I am reminded of this story almost daily. It is emblematic of our work and of those who choose not to use it. Good outcomes in cancer do not occur by chance. They also do not require blockbuster new drugs or brilliant doctors. They require individualized attention to the needs of each patient.

A recurring theme, exemplified by this patient among others, is that cancer cells can only defend themselves in a limited number of ways. Once a selection pressure, in a Darwinian sense, is removed (e.g. corticosteroids were not used during the homoharringtonine treatments) the surviving cells, sensitive to steroids, re-emerge to be identified and captured in our laboratory platform.

It is remarkable how often heavily pretreated patients with ovarian cancer are found sensitive to Taxol after they had received it years earlier, but not since; or breast cancer patients who fail every new agent only to prove responsive to CMF, the earliest of all of the breast cancer drug combinations developed in the 1970s. Our job as oncologists is to find those chinks in armor of cancer cells and exploit them. The EVA-PCD platform, in the eyes of some, may not be groundbreaking . . . it just happens to work!

 

Why I Do Chemosensitivity Testing

My earliest experience in cancer research came during my first years of medical school. Working in a pharmacology laboratory, I studied the biology and toxicity of a class of drugs known as nitrosoureas. My observations were published in a series of articles in the journal Cancer Research.

The work afforded me the opportunity to interact directly with some of the country’s leading cancer investigators. Many of the fellows with whom I worked went on to famous careers in academia and the biotech industry. I remember the rather dismal outcomes of patients treated in the early 80s; but I felt confident that there had to be a better way to treat cancer patients than just throwing drugs at them and hoping they worked.

It was then that I decided that testing cancer patients’ cell samples in the laboratory, using the drugs they might receive, could help select the most active agents. Several years later, as an oncology fellow, I had the opportunity to test this hypothesis, and it worked. I reported my first observations in leukemia patients in 1984, a successful study that proved that relapsed leukemia patients could be effectively treated when the drugs were first selected in the laboratory. (Nagourney, R et al, Accurate prediction of response to treatment in leukemia utilizing a vital dye exclusion chemosensitivity technique. Proc ASCO abs # 208, 1984)

Unfortunately, this was an era when the field of in vitro chemosensitivity testing had fallen on hard times. A negative study published in the New England Journal of Medicine, using a growth-based assay endpoint, soured the community on the concept and our cell-death based assay results fell upon deaf ears. Yet, I knew it worked. And, based upon my continued efforts in the field, I developed the EVA/PCD^® platform that we use today.

With response rates two to three fold higher than national averages, and successes that include the development for the most widely used treatments for low grade lymphoma and CLL (Nagourney, R et al Br J Cancer 1993), recurrent ovarian cancer (Gyn Onc 2003) and refractory breast cancer (J Clin Oncol 2000), the question really should be why doesn’t everyone do assays for their patients?