Since the mid-1950s, when he witnessed some of the first patient experiments using combination chemotherapy, David G. Nathan, MD, has played a pivotal role in the dramatic history of cancer care and research.
Dr. David Nathan — an acclaimed pediatric hematologist who served as Dana-Farber's president from 1995 to 2000 and has long been affiliated with Children's Hospital Boston — recounts that history's triumphs and struggles in a book called The Cancer Treatment Revolution: How Smart Drugs and Other New Therapies Are Renewing Our Hope and Changing the Face of Medicine.
Published by John Wiley & Sons, the work recounts the stories of three patients with invasive cancers treated at Dana-Farber and its partners in care: Mario, a 19-month-old boy diagnosed with leukemia; Joan, a 62-year-old woman facing metastatic breast cancer; and Ken, a 48-year-old who endured multiple clinical trials for gastrointestinal stromal tumor before his death in 2005. The pages are peppered with the insights of current and former Dana-Farber physicians, researchers, and other staff members.
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David G. Nathan, MD is a graduate of Harvard College (1951) and Harvard Medical School (1955). He was an intern and senior resident in medicine at the then Peter Bent Brigham Hospital and a clinical associate at the National Cancer Institute. From 1959 to 1966, he was a hematologist at the Peter Bent Brigham Hospital and then became chief of the Division of Hematology and Oncology at Children's Hospital and Dana-Farber Cancer Institute. From 1985 to 1995, Dr. Nathan served as physician-in-chief of Children's Hospital and, from 1995 to 2000, was president of Dana-Farber Cancer Institute.
Dr. Nathan's research has focused on the inherited disorders of red cells and granulocytes and particularly on thalassemia. He has trained over 100 hematologists, many of whom hold leading positions in pediatrics and internal medicine. His textbook, titled Hematology of Infancy and Childhood, is the leading text in the field. He is the author of two popular books: Genes, Blood and Courage, published by the Harvard University Press in 1995, and The Cancer Treatment Revolution: How Smart Drugs and Other New Therapies Are Renewing Our Hope and Changing the Face of Medicine, published by John Wiley in 2007.
Dr. Nathan is a member of the American Society for Clinical Investigation, the Association of American Physicians, the American Pediatric Society, the Institute of Medicine, the American Academy of Arts and Sciences and the American Philosophical Society. He is the recipient of numerous awards, including the National Medal of Science, the Stratton medal of the American Society of Hematology (of which he was president), the Walker Prize of the Boston Museum of Science, the John Howland Medal of the American Pediatric Society, and the George M. Kober Medal of the Association of American Physicians. He is one of only three physicians to receive both the Howland and Kober medals.
David G. Nathan, MD
President Emeritus, Dana-Farber Cancer Institute
Robert A Stranahan Distinguished Professor of Pediatrics and Professor of Medicine, Harvard Medical School
450 Brookline Ave
Boston, MA 02215
Below is an excerpt from The Cancer Treatment Revolution: How Smart Drugs and Other New Therapies Are Renewing Our Hope and Changing the Face of Medicine. Copyright © 2007 by David G. Nathan, MD. Reprinted with permission from the publisher, John Wiley & Sons, Inc.
One night eight years ago all hell broke loose in Ken Garabadian's abdomen. He suddenly awoke with terrible abdominal pain. If fast-moving EMTs and a savvy surgeon at his community hospital had not realized that something terrible had happened, Ken would not have survived the night.
Emergency surgery revealed a grapefruit-sized tumor attached to his small intestine. Some of the tumor cells had grown into his bowel, leaving a hole through which the contents of Ken's gut had poured into his abdomen, causing terrible inflammation and shock. Worse, the tumor cells scattered all over his belly.
He was diagnosed with gastrointestinal stromal tumor, or GIST, and was doomed to have multiple cancers grow in his abdomen — tumors that could not be removed by surgery and would be resistant to radiation or standard chemotherapy.
Ken's subsequent willingness to participate in clinical trials and take experimental "smart" medications gave him almost three years of high-quality life after the diagnosis was made.
It also made him part of the first wave of a radically new era in cancer therapy using drugs that are "smart" in that they precisely block the abnormal genetic pathways or mutations that cause and maintain cancer. These new compounds destroy cancer cells yet cause minimal damage to normal cells.
Like most novel treatments, smart drugs developed from an amalgam of basic and clinical research that stretched over many decades before patients were successfully treated. The experiments that ultimately produced the first such drug, Gleevec, led to three Nobel prizes and ranged from research on nerve cells in the gut to studies of viruses that cause cancer in chickens and on to the cause of a fatal and relatively rare form of leukemia known as CML.
Immediately after his surgery, Ken's wife, Peggy, went on the Internet and learned that Dr. George Demetri, an oncologist at the Dana-Farber Cancer Institute, where I was then president, was just a few months away from starting a clinical trial with Gleevec, the first smart drug treatment for GIST.
Demetri and his colleagues had recently found that, like CML, GIST is caused by a unique tiny mutation in a single gene in one of the billions of cells that form the gastrointestinal tract. The mutated gene, named kit, alters a protein that figuratively shouts without end at GIST cells to divide constantly — in other words, to be cancerous.
Furthermore, though the altered kit protein becomes like drink to a confirmed alcoholic and GIST cancer cells cannot live without it, Demetri and his associates had found that Gleevec blocks the function of the altered protein and kills the GIST cancer cells. What's more, the drug did not appear to seriously damage any other system in the body.
"You're here at the perfect point in history," Demetri told Ken. "You've got a cancer that we know a lot about genetically, and we're going to know a lot more about it as we go down the road together."
When Ken first appeared in Demetri's clinic, he showed no signs of cancer. Demetri confirmed that with a PET (positron emission tomography) scan. The test is based on the well-known fact that living cancer cells are always hungry for sugar. When they eat sugar tagged with a radioactive isotope, the tumors "light up" with radioactivity in the PET scan and can be seen as living nodules. If the tumors are "cold" in the PET scan, they are dead.
Several months after his emergency surgery, a follow-up CAT scan demonstrated several lumps in Ken's abdomen, and the PET scan showed that the lumps were avidly absorbing sugar. Clearly the thousands of GIST cells that had spread in Ken's abdomen had begun to grow into multiple tumors.
Demetri started treating Ken with Gleevec, making Ken the second patient in the world to receive Gleevec for GIST. The first patient, a woman from Finland, had been treated by Demetri's team and a group of Finnish physicians, and her tumors had disappeared. Ken waited anxiously after he began to take Gleevec.
A month later, Demetri ordered new scans. The CAT scan still showed tumors in the abdomen, but the PET scan was "cold." The tumors were dead, and Ken felt entirely well.
This was the first time in the United States that any solid tumor had ever been stopped in its tracks with no major side effects after a relatively short period of treatment. To Demetri's amazement and Peggy's and Ken's joy, the tumors shrank and remained invisible in Ken's abdomen for the next two years.
Ken became a poster boy for advanced cancer clinical and basic research. He spoke widely about the importance of optimism and determination in dealing with cancer and for being on the cutting edge of cancer research.
"I don't believe in that old saw 'When life gives you lemons, make lemonade,'" Ken told me. "I believe when life gives you lemons, it's lemon season — enjoy them."
But Demetri knew that despite Ken's excellent response, there was a good chance he'd relapse because his cancer cells would mutate again and create a shouting kit protein that would be resistant to Gleevec. Though a substantial number of GIST patients have done very well on Gleevec for many years, resistance to the drug ultimately develops in most of them. Indeed, that is what happened.
Two years almost to the day after Ken began Gleevec, a PET scan revealed living tumors avidly consuming sugar. Demetri gave him three different experimental Gleevec-like drugs but from that day on was unable to stop Ken's tumors.
The resistance to Gleevec was not unexpected, because single agents eventually fail in the treatment of most highly aggressive cancers. Scientists are now exploring new and promising ways to inhibit kit protein. One drug, already in encouraging clinical trials, blocks a small protein that kit requires to traverse the GIST cell. Responses in GIST patients are dramatic. More Gleevec-like drugs and compounds that attack the growth-signaling pathways "downstream" from the sensitive proteins are also in the process of development. Used in combination, such drugs are likely to reduce the impact of Gleevec resistance.
During his remission, Ken once told me that the main message he wanted other people to get from his story is the importance of pushing for the best treatment you can find, even if it's experimental.
"Demand that second opinion, get the experts, get the cutting-edge technology available to you," Ken said. "My life will be worthwhile if I have helped someone else to do that."
Below are comments about Dr. David Nathan's book, The Cancer Treatment Revolution: How Smart Drugs and Other New Therapies Are Renewing Our Hope and Changing the Face of Medicine.
"A wonderful journey through modern medical science, told with warmth and insight, brought to life through the stories of people confronting cancer. This book will inspire and educate both laymen and caregivers."
—Jerome Groopman, MD, author of The Measure of Our Days and The Anatomy of Hope and Recanati and Professor, Harvard Medical School
"This is probably the best book on cancer that exists — beautifully written and unfailingly interesting, conveying a clear sense of hope for cancer patients and survivors. Cancer treatment has come a long way but not without intense struggles and passions, which David Nathan narrates from the inside as one of the leading players. He explains cancer more clearly than anyone else, and his portraits of great cancer doctors are sharp and unforgettable, a contribution to history."
—Richard Preston, author of The Hot Zone and The Demon in the Freezer
"No one is better positioned to tell the tale of the cancer treatment revolution of the last half century than David Nathan. A brilliant physician-scientist, he has been present at the cusps of history in this life-and-death field. The story he tells here is fascinating, and his book is captivating."
—Atul Gawande, MD, author of Complications: A Surgeon's Notes on an Imperfect Science and Better: A Surgeon's Notes on Performance and Assistant Professor of Surgery, Harvard Medical School
"David Nathan is a true storyteller. In The Cancer Treatment Revolution, he tells stories that bridge cancer patients and cancer research as few others could. These gripping tales will be appreciated by those who live with cancer and those who strive to create new therapies."
—Thomas Cech, PhD, recipient of the 1989 Nobel Prize in Chemistry and President of the Howard Hughes Medical Institute
"David Nathan, one of the nation's preeminent clinician-scientists, tells the stories of three cancer patients, revealing compelling human facets — the dedication of the remarkable teams that care for these patients and, even more, the bravery and fortitude of the patients and their families."
—Harold Varmus, MD, recipient of the 1989 Nobel Prize in Medicine, President of the Memorial Sloan-Kettering Cancer Center, and former director of the National Institutes of Health
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