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.

A Tale of Two Lung Cancers

I was recently asked to speak at a community outreach mixer to describe our work in lung cancer. I invited two patients to join me:

  1. A woman in her early 50s who presented to medical attention with metastatic adenocarcinoma of the lung with brain involvement.
  2. A woman in her early 60s, also with metastatic adenocarcinoma with brain involvement.

Under the microscope their tumors appeared almost identical. But, in the laboratory, the profiles were distinctly different. Patient no. 1 revealed a highly sensitive profile to the EGFR-TKI erlotinib (Tarceva) that was demonstrably enhanced by VEGF inhibition (e.g. Bevacizumab, Avastin). The second patient was resistant to erlotinib and VEGF inhibition, but was highly sensitive to the doublet of platinum plus gemcitabine.

Both patients attended the mixer and spoke to the crowd. They both looked the picture of health, sporting their own hair with no significant toxicities from therapy. Both had completed Cyberknife brain radiation and had gone on to exactly the right treatment for them. Despite their similarities in presentation and histology, their treatments were extremely different. Yet, both have had excellent and durable responses.

Every lung cancer patient has the capacity to do well. It is our job to find out which drugs and combinations are most likely to achieve that end. Functional profiling provided both of these patients exactly the right treatment for them. With the Rational Therapeutics EVA-PCD platform, every patient is treated as an individual.