The fact that these men and women would choose to spend 6 weeks in a hospital under treatment with the most toxic of chemotherapies is a testament to their strength and hope.
—Paul A. Bunn, Jr, MD
The following essay by Paul A. Bunn, Jr, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.
I grew up in upstate New York and was heavily influenced by my parents and my high school sweetheart, who became my wife of 45 years. My father, an infectious disease physician, developed tuberculosis while he was in medical school, as did most of his classmates, and dedicated his life to the elimination of tuberculosis as a medical scourge worldwide. He was largely successful. Ironically, he died at a young age in part due to his generation’s smoking habits, diet, and lack of physical activity.
I graduated from Amherst College after majoring in biology. My mentors were most interested in teaching students how to think. I was disappointed by my first 2 years at Cornell University Medical College, where the emphasis seemed to be on how to memorize rather than how to think. However, my second 2 years were much more rewarding. I was exposed to unbelievable clinicians like Rees Pritchett, MD, and Martin Gardy, MD, who taught me how to put patients first; and to scientists like Walter F. Riker, MD, who taught me many of the principles of medical research.
Choosing a Career Path
This was in the 1960s. The Vietnam War had a major influence on my career. Nearly all medical students were being drafted and sent to Vietnam. This happened to my cousin, who was also an internist and developed tuberculosis while checking for rats on the ships. He told me that unless I wanted to become a surgeon, it might be best to avoid being drafted.
So, like thousands of other students, I applied to the National Institutes of Health (NIH) for a fellowship after medical residency and was accepted into the Leukemia Branch of the National Cancer Institute (NCI). During my internship at the University of California, San Francisco, I was assigned to the NCI’s Pediatric Branch. Since I was most interested in adult medicine, I was reassigned to the Medicine Branch. During my residency, many of the early combination chemotherapy regimens were showing improved results in lymphomas, adult leukemias, and breast cancer.
Because the NIH Clinical Center was not a complete hospital, we had to draw all the blood; start patient IVs; complete all procedures, including pleural, liver, and lymph node biopsies; and perform laparoscopies, and even dialysis procedures, ourselves. The combination of preclinical, clinical, pathologic, staging, and therapeutic trials, especially in Hodgkin and non-Hodgkin lymphoma, led to improved outcomes and cures for many patients with cancer. My experience there taught me the importance of having a multidisciplinary approach, combination therapy, and well-conducted clinical trials in the treatment of cancer.
By the completion of my fellowship, the NCI had decided to dedicate one of its branches to lung cancer, which was—and still is—the leading cause of cancer death. The branch was located at the Washington DC VA Medical Center, because there were a large number of patients with lung cancer in treatment there.
At the time, the treatment for lung cancer was very unsatisfactory. Very little was known about lung cancer biology, and nothing was known about the molecular biology or molecular pathogenesis of the disease. Several drugs had shown activity in small cell lung cancer, but each had considerable toxic side effects, and complete remissions were rare. To address the issues of biology and molecular biology, the group attempted to establish cell lines from every patient’s tumor biopsy.
They were called human tumor cell lines and numbered sequentially (the first was human tumor cell 1, and so on). Much of what we know of lung cancer biology and molecular biology today originated from these lines. Some of our earliest observations were that the cell lines produced their own growth factors, they had frequent losses of portions of human chromosomes and tumor suppressor genes, and they expressed antigens to which monoclonal antibodies could be produced.
Strength and Hope of Patients
Drugs that inhibited cell line growth frequently produced responses in patients with lung cancer. They could be grown in laboratory mice to test new therapies in vivo. Our initial trials in small cell lung cancer included a three-drug chemotherapy regimen containing cyclophosphamide, methotrexate, and lomustine. Unfortunately, it was so toxic that all patients developed severe neutropenia, and all were hospitalized for a minimum of 6 weeks. The fact that these men and women would choose to spend 6 weeks in a hospital under treatment with the most toxic of chemotherapies is a testament to their strength and hope.
Years later, I was recruited to the University of Colorado School of Medicine, where I continued my lung cancer studies. One of my early patients was a physician who had bilateral lung metastases (he had never smoked) but was asymptomatic. Convinced that chemotherapy would only decrease his quality of life, he elected to avoid any therapy. I followed him for 11 years, observing his slowly progressive nodules.
When he became symptomatic, he agreed to platinum-based chemotherapy. He suffered considerable toxicity and had some response, but he died within a year.
Prolonging the Duration and Quality of Life
This patient taught me that our goal as oncologists is to prolong both the duration and the quality of life, which is something the patient decides with support from the physician. His case also illustrated the variability in outcomes, our inability to predict an outcome, and the importance of science in making advances in cancer treatment.
At the time, there was an odd perception that patients with lung cancer were somehow morally suspect—tobacco addicts or worse—rather than victims of a devastating disease. When this doctor presented with lung cancer, this was the prevailing view: Lung cancer was associated with the stigma of guilt associated with tobacco, and treatments were solely unscientific poisons.
The past decade has changed this view. We have witnessed profound new possibilities in the treatment of lung cancer with molecularly tailored therapies and checkpoint immune therapies. These new therapies provide much higher response rates and much longer responses, and they do so with considerably less toxicity than cytotoxic chemotherapy.
It’s now clear that patients should have their tumors tested for the presence of molecular drivers and biomarkers associated with improved outcomes. These therapies are providing new hope and meaningful prolongation of life with more acceptable levels of toxicity. The promise that rational combinations may further improve outcome and lead to some cures may now justify the long periods of research.
And yes hope. ■