Aug 31, 2017
By A. Kate MacDougall
Oncology luminaries. Thought leaders. The soul of chemotherapy. These are just a few of the phrases used to describe Emil Frei, MD, FASCO, Emil J. Freireich, MD, FASCO, James F. Holland, MD, FASCO, Georges Mathé, MD, and their historic contributions to the world of oncology. Inspired by these oncologists and their work, filmmaker and cancer survivor Germaine McCormack-Kos set out to tell their story in her documentary, Walk on the Wild Side.
After being diagnosed with stage IV ovarian cancer, dealing with the unknown and uncertainty of intense treatments, and eventually being cured, Ms. McCormack-Kos, an Irish national who lives in Paris, France, sought to understand how medicine had advanced to be able to cure her. With the help of her own oncologist and others she met along her journey, Ms. McCormack-Kos soon discovered some of the pioneers of oncology and chemotherapy—Dr. Frei, Dr. Freireich, Dr. Holland, and Dr. Mathé—and immersed herself in their epic stories.
“I took a leap into the world of chemotherapy, a walk on the wild side, allowing my body and mind to be taken over for many solitary, scary hours, with poison running through my veins, questions racing through my mind,” Ms. McCormack-Kos says in her film. “Who are these unsung heroes responsible for giving us the greatest treatment in Western medicine and giving me a second chance?”
In addition to telling her own diagnosis, treatment, and survival story, the film includes Ms. McCormack-Kos’ interviews with many current leaders in oncology across the world, as well as the last in-person meeting of Dr. Frei, Dr. Freireich, and Dr. Holland before Dr. Frei passed away in 2013.
“[This film] goes beyond a survivor’s story and puts a human face on the early pioneers in cancer treatment who have saved many thousands of lives. Germaine drew a lot of strength from the fact that these pioneers inspired her physicians,” said Franco Muggia, MD, of NYU Langone Medical Center. Dr. Muggia is chair and medical director of The Chemotherapy Foundation, which will host a special screening of the film at a benefit in November.
A Lasting Impact on the Oncology World
“The impact of understanding what happened in the 1950s, and the beginning of medical oncology, is part and parcel of what this film is about,” Dr. Holland aptly summarizes in an introduction to the film trailer, shown on ASCO Live during the 2017 ASCO Annual Meeting.
In the 1950s, acute lymphoblastic leukemia (ALL) was treated with one drug, and inevitably patients would develop a resistance against it. In 1955, Dr. Frei and Dr. Freireich, who were working at the National Cancer Institute, and Dr. Holland, hailing from Roswell Park Cancer Institute, asked the question, why not use multiple drugs to attack all angles of the disease?
“We knew there were three drugs that could induce temporary remissions [in children with ALL],” Dr. Freireich said, so they began exploring the idea of combining those drugs, instead of administering them sequentially—a new and radical approach to cancer treatment.
As part of their cross-institutional research on this groundbreaking idea of combination chemotherapy, the doctors and their colleagues also formed the first cooperative cancer research group in the United States: Acute Leukemia Group B, later known as Cancer and Leukemia Group B and now as the Alliance for Clinical Trials in Oncology.
“We found that a single institution couldn’t realistically provide the kind of critical scientific evidence that people demand today,” Dr. Holland explains in the film.
Within their collaborative group, Dr. Frei, Dr. Freireich, and Dr. Holland began comparing combinations of the drugs mercaptopurine (6-MP) and methotrexate against sequential therapy, with very encouraging results. So they pushed further and began testing 6-MP in children with ALL who were already in remission after treatment with prednisone. Despite a high relapse rate, this trial set yet another oncology milestone as the very first adjuvant chemotherapy study.
“This study turned out to be fantastically important,” Dr. Freireich said. “At the end of the year, when all the other children had otherwise relapsed, there were still some children in remission. Now we really had something to think about!”
After another promising adjuvant chemotherapy trial involving vincristine in which 90% of patients with ALL experienced a response, Dr. Freireich approached his colleagues with another revolutionary idea.
“I felt very strongly that we had enough knowledge to know that we could give all four drugs [vincristine, amethopterin (now methotrexate), 6-MP, and prednisone] at the same time,” Dr. Freireich said. “But we took this to our group, which had about 12 institutions at the time, and they felt it was too dangerous.”
After overcoming this initial skepticism from their peers and collaborative group, as well as opposition from the broader cancer research community and the government, the oncologists proceeded with studying the combination that evolved into what today is known as the VAMP regimen and, later, the more intensive POMP regimen. It was in these trials that the investigators incorporated the then unstudied methodologies of early intensification and intermittent re-induction—now common elements of many clinical trials and standard chemotherapy regimens.
Finally, after 10 years of handling experimental challenges, dealing with high toxicities and relapses, and refining the regimen in several clinical trials, Dr. Frei, Dr. Freireich, and Dr. Holland created a combination treatment for ALL that is responsible for the current 90% cure rate and which has become the template for most cancer treatments today.
“The same principle was immediately applied to the treatment of lymphoma with CHOP, to breast cancer, to Hodgkin disease, to other tumors, and it’s now the method we use to improve the control of cancer,” Dr. Freireich said.
Since then, all three oncologists have continued to make strides in the treatment of childhood and adult leukemia and other cancers. They’ve also contributed to the broader oncology community in many ways, including each serving as ASCO president (Dr. Frei, 1968-1969; Dr. Holland, 1976-1977; and Dr. Freireich, 1980-1981).
“A Man Ahead of His Time”
Ms. McCormack-Kos’ film also highlights the work of world-renowned French oncologist and immunologist Dr. Mathé, including the lasting contributions he made through pioneering the idea of immunotherapy for leukemia.
“[He] did some very remarkable work in classifying leukemias and in immunizing children with leukemia in a way that others in the United States were not doing at the time,” Dr. Holland remarked about Dr. Mathé in the film.
Dr. Frei referred to Dr. Mathé as “a man ahead of his time,” explaining in the film that “he was a stimulus for doing new things and interpreting things in different ways.”
Dr. Mathé passed away in 2010 before the film’s completion.
Laying the Groundwork for Generations to Come
Walk on the Wild Side explores how the work of these pioneers will continue to change the face of cancer treatment in the future—including through the growth of precision medicine and immunotherapy, advanced surgical procedures, and improved new drug regulations.
“In 10 years’ time, not only will we have a lot of treatments that help many different cancers and leukemias, but also we’ll be able to design treatments for the particular cancer of a particular patient,” Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center, explains in the film.
By telling her own story and the historic contributions of these pioneers, Ms. McCormack-Kos wants to inspire many people in many ways. “I hope my film gives courage to all those involved in cancer—particularly those going through treatment,” she said. “This is my tribute to all of the dedicated oncologists, especially these influential men and their dedication to the world of oncology.”