Recurrent Small Cell Cancer of the Lung: A Therapeutic Challenge

I recall as a junior medical oncology Fellow, one of my senior Fellows describing small cell cancer of the lung as “leukemia of the lung.” The reason he used this description was because leukemia is among the most rapidly progressive and aggressive forms of cancer.

Arising in the bone marrow, an afflicted patient’s white blood cell count can double every day, a remarkable achievement when one considers the hundreds of billions of cells involved. What this doctor meant was that the lung cancer of small cell type (also known as oat cell), grew so rapidly that in untreated patients, survival can be measured in weeks to months. With the discovery of effective chemotherapy this disease became a comparatively easy mark for the treating oncologist. Ironically, where it was the worst form of lung cancer during the 70s, by the 1990s it was the best form to have. Most patients responded to treatment and some lived years. The problem is, treating patients who recur.

For unknown reasons this otherwise chemosensitive disease has a tendency to recur with a vengeance. Attempts to control recurrent disease with second line therapies have characteristically been unsuccessful. Drug combinations that are generally quite active in the first line setting, are almost universally inactive in second line use.

As a result, recurrent small cell lung cancer is tantamount to a death sentence.

Two months ago, a slender woman arrived at Rational Therapeutics carrying a biopsy kit and a bottle filled with straw-colored fluid. She explained that her husband had recurrent small cell lung cancer and his surgeon had inserted a chest tube. He then provided us with both biopsy material and fluid. She went on to say that she herself was a laboratory scientist and was familiar with laboratory techniques.

We processed the specimen, which provided amble cells for analysis. Not surprisingly, the tumor was resistant to many (most) of the drugs tested. However, the class of drugs known as alkylating agents revealed persistent activity. More importantly, the combination of an alkylating agent and topotican revealed activity and synergy.

Having published a paper on this topic several years ago, (Nagourney et al, British Journal of Cancer 2003) I was quite familiar with this combination. Referencing work by investigators at Yale University, using the combination of cytoxan and topotican, I provided my recommendation to a colleague who administered this combination with a very tolerable weekly dose schedule.

The patient responded immediately. So much so, that between cycle one and cycle two he took a vacation to San Diego with his wife.  Further response was documented following cycle two.  Most gratifying has been the very limited amount of toxicity in the treatment itself.

The TEDx Experience

On Saturday July 16, I had the opportunity to present at the TEDxSoCal conference held here in Long Beach. The overall theme for this event was “thriving,” and appropriately, I presented in the afternoon session called, “well-being.” My lecture was entitled “The Future of Cancer Research Lies Behind Us.”

I chose this topic in light of the growing recognition that genomic analyses are not providing the therapeutic insights that our patients so desperately need. As I have written before in this blog, the Duke University lung cancer gene program, which has received much attention recently, is emblematic of the hubris associated with contemporary genomic analytic platforms.

I reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

I described insights gained using our ex-vivo analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.

Many attendees stopped me after my lecture to thank and congratulate me for my presentation. Fearing that my topic might have been too esoteric, I was delighted by the reception and more convinced than ever that there are many enlightened individuals who thirst for new approaches to cancer treatment. It is these people who will forge the next generation of therapy.

Looking Forward to TEDxSoCal

I remember my first recollection of the TED (Technology Entertainment Design) conferences, which have been held annually for almost two decades. Drawing together innovators in a broad spectrum of disciplines, these programs have become an institution unto themselves. With invited speakers ranging from Harvard’s Edward O. Wilson to business leaders, like Microsoft’s Bill Gates, the lectures cover a panoply of interesting topics.

It was with a sense of delight that I received an invitation to speak at the TEDxSoCal conference on July 16 at the Long Beach Terrace Theater. As the date approaches, I am looking forward to the event with great anticipation. Since the event is sold out, I understand I’ll have 800 attendees in the audience.

What an interesting opportunity to engage this group in a discussion of cancer biology with our focus on biochemistry and metabolism. This is timely in the context of Gina Kolata’s recent article in the New York Times on the failures of genomics platforms in the field of functional profiling for cancer treatment.

I will report next week on this experience.

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?

The Avastin Saga Continues

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.