One patient's role in the cancer treatment revolution
A rapidly developing revolution in cancer treatment has prompted David G. Nathan, M.D., president emeritus of Dana-Farber Cancer Institute, to detail three patients experiences in a forthcoming book, to help nonscientific readers understand the promise and pitfalls of this new research. In doing so, he also aims to clarify three well-established principles of medical research:
- that the determination, positive outlook, and persistence of patients, their families, and their physicians strongly influence medical progress;
- that most novel treatments are derived from an amalgam of basic research and clinical observations that may stretch over decades before a successful application can be made in patients; and
- that the first effective treatments for a heretofore incurable disease are usually incompletethey form the basis of the next steps.
One of the patients, Ken Garabadian, was afflicted by a gastrointestinal stromal tumor (GIST) that posed severe treatment challenges, and his struggle highlights a fundamental thread in this medical revolution. Nathan explains the establishment of precise, DNA-based understanding of how a cancer grows; the description of the mutant proteins derived from abnormal cancer DNA; and the recent discovery of new smart drugs such as Gleevec that interact chemically in very specific ways with those proteins and arrest tumor growth. Smart drugs were critical as Ken dealt with GISTand the same tools will be essential for managing more common cancers, particularly those resistant to classic chemotherapy treatments.
Kens Storythe patient narrative and the accompanying history of biomedical researchare adapted here from chapters 16 through 18 of Nathans forthcoming book, The Cancer Treatment Revolution, to be published by John Wiley & Sons, Inc.
Ken Garabadian was built like a fireplug. I had a few inches on him, but his compact physique and firm handshake left the sound impression that I would fare poorly in a physical contest against this former wrestler. I met him because he had a type of cancer that was absolutely untreatable until just a few years ago: a highly aggressive and widespread sarcoma, a type of cancer that can afflict muscles, nerves, brain, and bone, as well as fat, cartilage, and fibrous tissue and in his case involved his gastrointestinal tract.
Ken was overweight, but never had health problems until a single cell mutated and brought on his cancer. He moved quickly and gracefully and his bright eyes darted around to take in new surroundings. He regularly walked five miles a day, had normal blood pressure and cholesterol, and felt well. His life at home and work was also fine. His marriage with Peggy, who had been his sweetheart since they were 11 years old, was ideal. They had an adult son and a daughter, and a grandchild. The couple also enjoyed their jobs. Ken, a salesman, called his work wonderful and his fellow employees at a Massachusetts manufacturing company great to me. With two secure incomes on hand, a nearly paid-off mortgage, and good health insurance, the couple were financially secure and very happy.
SidebarsExcerpted with permission of the publisher, John Wiley & Sons, Inc., from The Cancer Treatment Revolution: How Smart Drugs and Other New Therapies Are Renewing Our Hope and Changing the Face of Medicine, by David G. Nathan. Copyright © 2007 by David G. Nathan.
In 1998, when he was 49, Ken began to notice some weakness and mild shortness of breath when he walked briskly or climbed stairs. The symptoms were slowly but inexorably progressive. He reported them to his primary physician, who tested his blood and found him seriously anemic. He also tired quite easily. The primary physician referred Ken to a blood specialist, who noted that his red blood cells looked as though he had become iron deficient.
But the case was puzzling. Iron deficiency does not occur out of the blue: bleeding is the only way to eliminate iron from the body. The only bodily site for significant but invisible bleeding by men is the gastrointestinal tract. A doctor who sees a man with iron deficiency of unknown cause must become what I call a stool pigeonhe or she has to hunt for blood in the stools until it is found. Next, the physician must locate the bleeding point somewhere in the 25 feet of intestines.
The specialist was well-trained and repeatedly tested Kens stools for blood, but could not find any trace of it. Then he made a mistake. Instead of concluding that his diagnosis must be flawed, he decided to treat Ken with iron, believing that the blood loss must be subtle and that his tests had simply missed it.
|The dramatic effect of Gleevec on Ken Garabadian's cancer led the manufacturer, Novartis, to feature this photograph of him in an ad.|
|Photograph courtesy of Novartis Pharmaceuticals|
In fact, Ken turned out to fall in the group of one out of every 10 patients who seems to have an iron deficiency yet is not bleeding. When people have chronic inflammation from an abscess, rheumatoid arthritis, colitis, or a large tumor, the liver overproduces a small signaling protein that commands the storage cells that normally release iron into the blood to hold tightly to the metal. The resulting lack of iron in the blood starves newly formed blood cells and patients become anemic. Ken had no obvious abscess on his body, was free of rheumatoid arthritis or colitis, and showed no external signs of having a tumor, so the hematologist did not sufficiently worry about those possibilities.
Most good medical care is built on a solid basis of paranoia. Doctors must always suspect that someone or something is out to get their patients. The best physicians try to cover up their excessive worry to spare the patient impossible anxiety, but they always live suspiciously, trusting no one, especially themselves and their diagnoses and even mistrusting the patient, who may not be following necessary instructions. The art of medicine lies in invisible suspicion and silent self-criticism. Ken did not know it yet, but he desperately needed just this sort of doctor on his team.
If the hematologist had been more critical of his own reasoning and had used modern imaging techniques such as computerized tomography (CT) to make a clear picture of the organs in his patients abdomen, he might have correctly diagnosed the situation and prevented what would become a disaster. Unbeknownst to Ken or his doctors, a mass of rapidly dividing cancer cells was emerging from his small intestine in the form of a growing tumor. The cancer cells were releasing proteins that interrupt many normal body systems. One or more of those proteins had entered the liver and instructed it to release a large amount of the signaling protein that blocks iron from returning to the blood from storage cells. Ken thus developed all the signs of anemia even though he had plenty of iron in his body.
|Peggy Garabadian at home in November 2006; Ken said of his wife, “She has been a tiger through this.”|
|Photograph by Stu Rosner|
When iron pills did nothing and Ken grew weaker, he received repeated red blood cell transfusions. That alarmed his primary physician, who insisted on further inquiry. Ken had a colonoscopy, but it, too, was utterly unrevealing. The primary physician was not quite suspicious enough. Like the specialist, he did not order a CT scan of Kens abdomen.
Two years later, Ken talked to me about his reaction to the mistaken diagnosis. I think we have a responsibility to ourselves in every way, but [in the past] I forfeited that when it came to medical matters. In every other area of my lifefinancially, intellectually, spiritually and emotionallyI always took care of myself and took responsibility for myself. When it came to the [possibility of the] physical end of my life, I abdicated. I simply said, These people have degrees; Im going to trust them.
|Ken as a varsity wrestler at Bergenfield (N.J.) High School, 1966; Ken and Peggy O’Connell at their graduation party in 1967; the newlyweds on July 25, 1970, and on a thirty-fifth anniversary cruise four months before Ken’s death|
|Photographs courtesy of Peggy Garabadian|
Ken continued the blood transfusion and iron regimen without incident until July 1999. Peggy was out of town the night disaster struck. Afterwards, Ken hazily recalled awakening with a start in the middle of the night because he felt what he described as a pop in my abdomen. Suddenly his stomach muscles contracted violently and became rigid. He tried to roll into a ball to relieve the terrible pain, but it began to consume him. He shrieked in pain and terror and broke out into an enormous sweat that soaked the sheets in seconds. Then he started to lose consciousness as his blood pressure began to collapse. He was going into shock, but he had the presence of mind to grab the phone from the bedside table and call 911.
He groaned his name and address to the operator and told her he thought he was dying. The operator told him to stay on the phone and talk to her until the ambulance could get to him. She kept talking and making him answer. The police and EMTs found him moments later babbling incoherently, rolled up in the soaked sheets, sweat still pouring from his body. His bowels had opened and he was smeared with feces. They could feel a pulse at the neck, but his blood pressure was almost unobtainable. His belly was as hard as a board. They knew immediately that Ken was dying of an abdominal catastrophe and rushed him to the emergency ward of the local community hospital.
The surgeon who took care of Ken that night had about two minutes to make a decision. One look convinced him that Ken was suffering from peritonitis, a profound inflammation of the abdominal cavity probably due to rupture of the intestine or appendix. No time was available for imaging assays like routine X-rays or CT scans. The doctor had to rely on the history and his physical examination, experience, and skills.
As soon as Kens belly was opened the surgeon realized that his overall diagnosis was correct. The cavity was filled with gas and greenish foul-smelling fluid that could only come from the contents of the bowel. The surgeon learned exactly what was happening when he sucked out buckets of the mess. A grapefruit-sized tumor was growing out of the small bowel. The cells in the center of the tumor had died from lack of blood and the bowel wall under those cells had virtually liquefied, leaving a large hole through which the bacterial-laden bowel contents were pouring into the abdomen. Along with bacteria, the cancer cells that had formed the tumor had been spreading throughout the belly.
After cleaning out the cavity, the surgeon began the delicate process of removing the tumor and the 18 inches of small intestine to which it was attached. He sewed the severed ends of the intestine together to maintain its continuity. He repeatedly washed and sucked out any remaining loose contents of the cavity, trying to remove some of the bacteria and cancer cells. He counted on a high level of intravenous antibiotics to finish off the bacteria, but he feared that one or moreperhaps many moreof the loose cancer cells would find a hospitable niche somewhere in the abdomen, and begin to replicate.
Despite the excellence of that surgical care, Ken barely survived. Scar tissue from the initial operation caused problems that required further surgery. Stretching of the small intestine caused a reversal of the normal waves of contraction when he ate, leaving him nauseous and vomiting after meals. His digestive system needed several months to adjust to its reconstruction. Even more dangerous, inflammation and multiple surgeries often cause a large increase of clotting proteins in the blood, and Ken developed clots in his leg veins. Some broke off as embolisms and traveled into his lungs, obstructing blood flow, which could have caused a heart attack. He required prolonged intravenous and oral drugs known as anticoagulants to clear his legs and lungs of the clotsand because such drugs induce a risk of gastrointestinal bleeding, he needed regular blood tests to ensure that his clotting system was reduced but not abolished. Weeks of anticoagulants and blood tests nearly destroyed the veins in his arms.
|The Garabadians teasingly thanked Demetri for pulling rabbits out of a hat repeatedly on Ken's behalf.|
|Courtesy of George Demetri|
As Ken was fighting off blood clots, his doctors and then Peggy learned about the nature of his cancer. They thought the tumor looked like the kind that arises in supporting tissues such as muscle, tendon, and bone, called sarcomas. (The Greek words sarkos and oma mean flesh and swell- ing, respectively.) They waited for a few days before they told him what was going on, because no effective treatment for a gastrointestinal stromal tumor was known, apart from complete removal by surgeryan opportunity lost when the tumor ruptured.
Meanwhile, Ken had begun to gain weight again, after having lost 40 pounds. His body again started to make red cells filled with hemoglobin. With good care from his doctors and Peggys ceaseless monitoring, he slowly regained strength. His short walks lengthened from around his room to trips down the hospital corridors.
When, after a few weeks, the surgeon concluded that Ken was healthy enough to take the bad news, his doctors told him he had an incurable cancer. Ken took it stoically. He was one tough patient, just as he had been a wrestler.
But Peggy was not willing to accept that nothing more could be done. She had begun to explore the Internet for information about the disease, and had learned that no combination of standard anticancer drugs had proven effective in treating GIST. She also found an Internet article about the treatment of sarcomas by Dr. George Demetri at Dana-Farber Cancer Institute in Boston. She called Demetri and made an appointment for her husband. That decision would be a turning point for Ken.
By the time Ken was strong enough to see Demetri, he and Peggy were already more knowledgeable about gastrointestinal stromal tumors than most physicians are, and they wanted to learn much more. Ken rapidly became fascinated by the energy and expertise that Demetri and his team were pouring into sarcoma research.
For the moment, Ken did not need treatment; he had no detectable disease. But sooner or later, his abdomen would become full of GIST tumors that would kill him if they were not stopped in their tracks.
Demetri acknowledged that, while offering some realistic hope. Youre here at the perfect point in history, he said. Theres a tremendous amount of work going on in this field right now. Youve got a cancer that we know a lot about genetically and were going to know more about it as we go down the road together. The doctors team was about to conduct tests on a drug that might combat GIST: Gleevec, a new smart drug that had just been tested successfully against an unusual leukemia, chronic myelogenous leukemia (CML).
In June 2000, a positron emission tomography (PET) scan, which measures the uptake of radioactive sugar by cells to assess whether they are living or dead, showed that Ken had at least 40 small but growing GIST tumors and four larger ones, each caused by a cell spewed out of the original tumor. He needed treatment, but Gleevec had not yet been cleared for use in GIST. George tried me on an experimental drug called ET-743, Ken noted. It had no effect on me. He just kept smiling and saying, Dont worry, weve got this thing coming along called STI-571 [Gleevec]. The mice seem to love it.
So we were patient, and fortunately nothing was pressing a major organ. He started me on the Gleevec in July 2000. It was almost exactly a year to the day that the tumor had burst into my belly. Within two weeks, all the tumors in my belly were cold [the PET scan showed no uptake of sugar]which I never expected. I expected 5 or 10 percent. When he came inside and said, Your whole scan is cold, I think it was just one of the happiest days of my life. Some weeks later a CT scan of Kens belly found that the tumors were shrinking. Ken became a poster boy for Gleevec and the treatment of GIST for two years. He spoke on the radio as a cancer survivor, appeared on a cancer special that played on cable TV, and was featured in a long New York Times article on new anticancer drugs.
But he was certain he would encounter more difficulty. He knew that the emergence of resistance is virtually the rule in single-agent chemotherapyand he was right. In July 2002, a routine PET scan showed that a few of his tumors were consuming sugar.
Ken became a subject of new clinical trials focusing on other smart-drug possibilities. In late 2002 a new drug, SU 11248 (sunitinib), produced by Sugen Pharmaceuticals (now part of Pfizer), became available to Demetri for a special attempt to treat GIST. The drug had been designed to inhibit tumor blood flow, but laboratory studies showed that it also inhibited the activity of other cancer-causing enzyme proteins. Demetri decided to ask his patient to try the drug, and Ken accepted with alacrity. Although the tumors occasionally regressed or became much colder, they slowly recovered. Then Ken would receive another combination of drugs or a single agent.
Ken maintained a strong, positive attitude. I dont believe in that old saw When life gives you lemons, make lemonade, he told me. I believe when life gives you lemons, its lemon seasonenjoy them. If you can smile with a lemon, the rest of its downhill, the rest of its just going to happen.
Ive tried to figure out the meaning of life since I was 10 years old, Ken continued. Its been the point of my existence to answer it. Sometime around my fortieth birthday, I realized I was asking the wrong question. Its not, Whats the meaning of life in general? but, Whats the meaning of my life?
Ken found answers in Viktor Frankels book Man's Search for Meaning. “Frankel survived Auschwitz and came out with a philosophy of life that means something to me. We each have to find that meaning in our life. Maybe my meaning is to be a compass needle that points to Demetri…[maybe I’m here to] say to another confused and frightened cancer patient, ‘Look, at least go to a cancer hospital with experts and get that second opinion. Demand that second opinion; get the experts, get the cutting-edge technology available to you.’ If that’s all my cancer does for me, that’s okay. My life will be worthwhile if I have helped someone else.”
Though Ken followed instructions to the letter, his tumors continued to grow even as new combinations, often including Gleevec, were administered. Both doctor and patient were bitterly disappointed, but Demetri maintained an optimistic stance. The Bristol Meyers Squibb drug desatinib, an excellent inhibitor of the enzyme that causes CML and very active against the enzyme that causes GIST, was now ready for clinical trials. Ken agreed to join a dose-escalation trial in the summer of 2004 and became the first solid tumor patient in the world to receive the new drug.
The course of the trial proved disappointing and discouraging. There were three immediate difficulties. First, a system of measurement had to be devised that would provide some quantitative assessment of tumor growth, because the PET and CT results could vary from day to day. Only measurements of trends over a prolonged period could provide accurate data. (PET scanners have become an expensive but absolutely necessary approach to measuring the responses of solid tumors to treatment. No other method gives as much information so quickly. But positron-labeled sugar is not an ideal detector because it is not specific for cancer. With more cancer-specific positron-emitting agents now in development, PET scanning will be much more accurate within a few years.)
The second difficulty was related. Because serial measurements were required to determine efficacy, the number of days required at each dose was necessarily very high. Each dose required a commitment of two months before the patient could move to the next dose, and the actual increments in dose were very small. Months could drift by with no evidence of any efficacy.
The most serious difficulty was a toxic side effect at higher doses. The phase 1 trial focused on dose escalation in an effort to determine toxicity. As is the norm, effectiveness was secondary, relegated to a phase 2 trial once a tolerable dose had been found. Unfortunately, Ken began to experience serious psychiatric problems at the higher doses—and only at those doses was there any evidence, however uncertain, that the drug was shutting down the ability of his tumors to consume glucose. He became increasingly listless, his appetite declined, and he had persistent abdominal pain that he knew must be due to one or more tumors pressing on a nerve in his belly. He did not want to give up on the new drug, but pain and depression began to consume most of his waking hours. He thought of suicide.
Demetri sought an opinion from a psychiatrist who immediately diagnosed acute depression. The question that had to be faced was very complex. Was the depression due to the drug or due to abdominal pain and severe discouragement in a man who had expected the drug to relieve him? There was no obvious way to tell.
No matter how “smart” a drug may be, all drugs are essentially poisons that interrupt metabolic pathways. The purpose of a phase 1 clinical trial is to find a dose at which toxicity occurs, with the hope that therapeutic benefit is achieved at a lower dose. The therapeutic:toxic dose ratio of a drug is calculated by dividing the dose that achieves a favorable response by the dose that causes toxic side effects. The lower that ratio, the better the drug. But the ratio must be carefully described. Many forms of toxicity are of little consequence and patients usually tolerate them very well. Gleevec is such a drug. It does cause side effects, but almost all patients can live quite comfortably with the symptoms.
There is a further and entirely unpredictable aspect of the therapeutic:toxic dose ratio that may or may not be detected in a phase 1 clinical trial unless it involves a large number of patients. Though almost all individuals have the same complement of 20,000 to 25,000 genes, there may be many variations in genes that affect the absorption of a drug from the gastrointestinal tract, its clearance from the circulation, its breakdown in the liver, excretion in the bile and the urine, or penetration of the organs such as the brain. Such genetic variations may lead to unique drug reactions in individual patients that are entirely unexpected and may occur without warning. These so-called idiosyncratic reactions are often unrelated to dosage and may produce severe toxic side effects. An entire field of medicine, pharmacogenetics, has developed to find ways to detect such patients before reactions occur.
Severe depression is not a common manifestation of desatinib toxicity, but Demetri had to conclude that the drug might have penetrated Ken’s brain in some unique way and damaged the function of the delicate network of nerves that control emotion. Demetri had no choice. In late February 2005 he stopped the drug to see what would happen to Ken’s spirits. Within a few days, Ken’s depression lifted, his suicidal ideas vanished and, despite his abdominal pain, his optimism returned.
Demetri then decided to pursue a possibly useless gamble. He unleashed a drumbeat campaign to persuade Novartis to release yet another new drug, AMN107 (nilotinib), for a single-patient trial in Ken.
Pharmaceutical companies loathe single-patient drug trials. The chances of improvement of a single sick patient are small, but the chances of trouble and a complication that may or may not be due to the drug are high. An accumulation of toxic side effects in single patients from whom little useful clinical data could be obtained represents a foolish investment to any sensible pharmaceutical executive.
But Novartis had not often dealt with an investigator as persistent as Demetri. Scores of e-mails later, Novartis officials reluctantly agreed to allow him to treat Ken, and Demetri immediately petitioned the Dana-Farber institutional review board (IRB) to permit him to use the new drug. To his surprise and fury, the IRB wanted much more information first.
The life of a clinical investigator, a physician who wants to translate the fruits of biomedical science into patient care, can be discouraging. Arguments with pharmaceutical companies about the availability of new drugs in development, and endless debates with IRBs about the ethics of research protocols, can create incredible delays.
Prior to World War II, and for two or three decades after the war, physicians were largely free to use their own judgment and their own ethical standards to determine the suitability of a given patient for a particular research procedure. Clinical research flourished. But the demonic corruption of Nazi physicians and the shocking revelation that career officers of the United States Public Health Service had withheld penicillin from poor, uneducated black citizens of Tuskegee, Alabama, who were afflicted with syphilis destroyed that assumption. Congress heard cries for tighter regulation of clinical research. An initial trickle of rules became a torrent as more cases of research malfeasance emerged.
One of the best regulations was the creation of IRBs in 1979. Each grantee institution, usually an academic health center, was charged with forming a local IRB—a group of scientists, physicians, nurses, and local citizens whose task is to read a research proposal carefully and judge its ethical soundness. Close attention is paid to the quality of informed consent of the patient/subjects, and also to the research protocol, to be certain that the risk of the research does not approach or surpass its purported benefit.
Informed consent is a procedure in which the researcher or an agent of the researcher carefully explains the intended benefits and the attendant risks of a research proposal to a patient who will be the subject of that research. Such procedures are not unduly time consuming, and they are rewarding because they offer an opportunity for the physician to have an intimate discussion with a frightened patient who may gain a lot of reassurance from the encounter. The patient’s questions may also uncover some areas of confusion in the research protocol, clarification of which can help the investigator to establish a better protocol or justify the one that is under discussion.
But urged by their apprehensive institutions to comply fully with informed consent procedures, physician scientists have gained “assistance” from institutional lawyers who help them to write documents that may be sound legally but often adopt arcane language that covers all perils; the result, of course, is nowhere near the quality of a simple conversation between the would-be researcher and the patient. So it is imperative for the physician or the physician’s agent to write a note in plain English in the medical record that describes the conversation between the researcher and the patient in some detail. (Sadly, the requirement for such a note is often honored in the breach.)
In Demetri’s case, the IRB wanted to be sure that a single-patient study could provide useful information. Many board members shared the skepticism of Novartis. (Though Dana-Farber had created that particular IRB, the members were entirely independent of the cancer center. They made up their own minds, and were free to demand any and all corrections as they saw fit.)
Seeing that a delay was inevitable, Demetri decided on a different tack. Ken had not taken Gleevec for two years. On the chance that a majority of his tumors had mutated enough to regain sensitivity to Gleevec, Demetri recommended a new course of that drug for Ken. To the delight of patient and physician, many of Ken’s tumors grew “cold” on the PET scan after two weeks of Gleevec treatment and began to shrink. Ken’s abdominal pain decreased. He felt like a new man again. Demetri, meanwhile, dealt with the criticism of the IRB and prepared to start Ken on AMN107 when the tumors inevitably mutated again and became Gleevec resistant.
While all this progress swirled around him, Ken remained reflective and philosophical. “I’m working and I’m trying to stay interested,” he told me. “You certainly get distracted in a situation like this, where every two or three weeks there’s a new protocol. By the same token, that’s what I’m asked to do right now. I’m trying to do it with dignity.
“Of course it’s not easy to be focused. I have to be in for checkups very frequently. So I don’t have long periods when I do not think about the cancer and what is going on in me. But I always get a lift from this place. When friends tell me about cancers in the family, I always tell them, ‘Just do yourself a favor, just call, get a second opinion. If you don’t like Dana-Farber, go to M.D. Anderson, go to Memorial in New York, go to some other reputable hospital that specializes in cancer and cancer research.’”
I asked Ken whether he thought some patients avoid cancer centers because they are afraid of the word and afraid of the finality of coming to such a place.
“Sure, it’s the reality—‘I really have cancer,’” he said. “I think it’s also about our perennial denial of how our own book ends. I know how my book ends. I know there’s an Author writing it right now. My argument with Him is what page it ends on—but not how. And it’s a one-sided argument. I’m saying, ‘Not page 54!’ He’s going, ‘Well, it’s a mystery, my friend. At least for you.’
“But people are in such denial about it. Cancer is a disease where you’re more afraid of the cure than the disease. They’ve seen the horror stories of chemo, and they’re terrified. They saw Uncle Vinnie: ‘Oh, his death was horrible; I’m not going to go that way.’ Well, my God, you’ve got to try to beat the cancer as best you can, with as much dignity as you can, and not be afraid of the word ‘cancer.’
“There are other words to be afraid of that are more debilitating to the human spirit than cancer. Fear is one of them; to live in fear your whole life, when you know the outcome. If this is going to be my last day, I want it to be a day of my authorship. You can’t die with dignity if you don’t live with it. So you have cancer, and you face it, and you say, ‘I am going to try to hold my head up. I am going to go home tonight and cry maybe, but I’m going to try to spend 20 of these hours today with my head up’—as best I can.”
I asked Ken how Peggy, who had insisted that he see George Demetri, was holding up during the long struggle.
“People meet my wife and they say, ‘Sweet Peggy.’ Peggy is this calm, gentle spirit. You would think she is Betty Crocker incarnate. She has been a tiger through this. She is my advocate and she’s my guardian. She’s got her moments of weakness, as I do, but we both try to do the same thing—we try to be prepared for the worst but to enjoy the best, while we have the best. And she’s done a great job with that. She’s done her best to live this thing true to her values. I think she’s done a great job on that. I owe her everything. I owe her to keep trying to win. And I will!”
But Ken’s will and upbeat philosophy could not stop the march of mutation in his tumors. They became resistant to Gleevec once again. The Novartis drug, AMN107, that had been so effective in CML, had no effect on the multiple GIST tumors in Ken’s belly that grew until they impinged on the sensitive nerves in his abdomen. The pain became severe and Demetri had finally run out of new tricks for his patient. He wrote out prescriptions for pain relief and sent Ken home to spend his last days with his devoted Peggy. He died peacefully in the winter of 2005.
Ken was a persistent patient and George Demetri is a persistent physician. Together they marched down a century-old path of progress in basic biology that was translated in the 1980s and 1990s from neuroanatomy and viruses to an understanding of the plight of constipated mice and then to the mechanism of cancer in the specific cells that cause gastrointestinal stromal tumors. Ken was the direct beneficiary of that history, and became in turn part of the vanguard of smart-drug cancer treatment.
But his story also reiterates the absolute necessity for combination therapy to prevent drug resistance. Smart drugs like Gleevec will make cancer a treatable chronic disease—but we need more of them, we need to learn how to use them in combinations, and we need more knowledge of the pathways that cancer cells are forced to take to survive. Fortunately the stream of effective new smart drugs is growing. A cancer-treatment revolution has clearly begun. We must win that revolution for Ken and the patients who will follow him.
David G. Nathan ’51, M.D. ’55, president emeritus of Dana-Farber Cancer Institute and physician-in-chief emeritus of the Children’s Hospital in Boston, is Stranahan Distinguished Professor of pediatrics and professor of medicine at Harvard Medical School. Nathan is the recipient of numerous awards, including the National Medal of Science, the Howland Medal of the American Pediatric Society, and the Kober Medal of the Association of American Physicians. He is a member of the Institute of Medicine of the National Academies of Science, the American Academy of Arts and Sciences, and the American Philosophical Society.
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