Cancerland
Page 11
Even with typing, however, the process of transplantation was still brutal for patients. The immune system of donor and host battling each other required use of intensive therapies to suppress immunity. That was so harsh that transplantation was seen as only the course of last resort. It was used in people who had no other options. Those people often had aggressive blood cancer so they also got intensive therapy to kill the tumor cells. With the early success of intensive therapy curing some people with blood cancers, it was hypothesized that maybe bone marrow could be used not just for transplanting from one person to another, but as a backup for oneself. The major toxicity of intensive cancer therapy was in killing bone marrow cells and intestinal cells. At least one of those could be collected before intensive therapy and stored in the freezer while the chemotherapy poisons did their work on the cancer. The bone marrow could then be thawed and infused, rescuing the ability of bone marrow to make new blood cells. That is known as autologous bone marrow or a stem cell transplant. It worked powerfully well, for some.
Success using people’s own bone marrow or blood stem cells to rescue the effects of intensive therapy was curative for about 40 percent of those who had specific lymphomas and had failed every other therapy. People who had run out of options got their life back—nothing short of wondrous. So the question became, “Why not try this for patients with other cancers?”
At the hospitals where I worked in Boston, we began using high-dose chemotherapy and radiation followed by bone marrow transplants to treat malignant blood and immune systems. Among the first patients enrolled in trials of this treatment were women with breast cancer that had relapsed and metastasized after conventional treatment. Because they possessed healthy marrow, we first drew their own cells from their bones and then processed and preserved them in liquid nitrogen. (This is the first step in what’s called autologous transplantation.) After patients endured life-threatening treatments with chemicals and radiation, we put the marrow back in with the hopes that their immune systems would recover fast enough to save them from death due to infection.
Autologous transplants to treat solid tumors were eventually done at research hospitals across the United States and Europe, but no one was more assertive about using this strategy than Emil “Tom” Frei. Like all oncologists, Tom was unhappy about the limited success of chemotherapy. In far too many cases, cancers seemed to be eliminated only to return in a genetically new form resistant to the treatment that had seemingly succeeded. Frei had reason to feel almost personally offended by the slow progress in our field. He had, with Emil Freireich, devised the combination treatment called VAMP—vincristine, amethopterin, methotrexate, and a derivative of the drug prednisone—to treat children with leukemia at the National Cancer Institute (NCI) in Bethesda, Maryland. VAMP was exceedingly and sometimes lethally toxic, but they ultimately made the regimen work with the help of interventions that rescued their young patients from side effects and infections.
In developing VAMP, Frei endured the trauma of giving the treatment as a last hope for dying children, only to see it fail. He heard protests from colleagues who deemed his methods unacceptably brutal and, presumably, wondered if he was doing the right thing. But like everyone else, doctors live with a confirmation bias that elevates successes and pushes failures into the far recesses of the mind. We need this psychological defense because, contrary to the widely held belief that caregivers always maintain professional distance, we get attached to the people we treat. We wouldn’t be human if we didn’t. Add the natural self-doubt that comes with the responsibility of directing the care of a person in crisis, and a focus on our successes makes it possible to carry on after experimental therapies fail and patients die. How else could we console a family in one hospital room and then walk down the hallway to greet someone who is very much alive and depending on our care?
In Frei’s case, experience might have encouraged the development of an especially strong confirmation. As recalled in a book by his colleague Vincent DeVita, Frei was generally regarded as a “maniac” when he began treating children with VAMP. Words like butcher were hurled at him during meetings, and his patients suffered terribly. But his unorthodox methods sometimes worked, and every time a child endured the treatment, recovered, and seemed cured, he was motivated to continue. With enough of these successes, he was able to refine his protocols and increase the odds that VAMP would cure a previously incurable disease. With every child saved, the brutal treatment regime gained more acceptance among doctors who helped their patients, and their families, endure the process that brought them to a cure.
Decades after he left the NCI, Frei was director of Dana-Farber and could count hundreds of acolytes among the world’s prominent oncologists. When he raised the possibility of using aggressive therapies followed by autologous transplants to treat solid tumors, he encountered no real resistance. An imposing figure, certain in his own mind and respected by other giants of the field, he was not someone who would tolerate much dissent or pleas for less aggressive science. At the time, the use of toxic chemicals against leukemia represented state-of-the-art practice, and many doctors hoped that chemotherapies would be developed for many other cancers if we had the courage to push beyond the usual boundaries.
In an echo of his early work, Frei devised STAMP (Solid Tumor Autologous Marrow Program), which involved high-dose chemotherapy and bone marrow transplant. He declared it to be “the cure for breast cancer.” In a short time, Dana-Farber became a world leader in this kind of therapy for solid tumors. One of his partners in this endeavor was a colleague named George Canellos, whom he had known since the 1950s when they both worked at the NCI. Doctors like Canellos, Frei, and others enjoyed such high status that they found broad support for their ideas. Among their first STAMP patients, they saw solid tumors shrink markedly in a matter of weeks. Frei kept tweaking his technique, as he had in the development of VAMP, driving toward a combination of drugs and supportive care. The number of breast cancer patients who would get high-dose chemotherapy and bone marrow transplants (HDC/ABMT) would rise steadily from about one hundred per year in 1985 to four thousand in 1994. Although truly definitive data was lacking, patients and their advocates pressured insurance companies to pay for the treatment, and some who were denied filed lawsuits to win coverage.
The press was filled with reports of women and their families fighting to receive the treatment, which cost, on average, $200,000 per patient. Despite the limited evidence of effectiveness, the debilitating nature of the treatment, and all the risks, the high-dose chemotherapy and transplant protocol for breast cancer spread to centers around the world. In the United States, advocates argued that those who denied breast cancer patients access to this treatment were discriminating against women on the basis of gender. The demand became so great that investors backed dozens of new for-profit clinics that undercut the prices charged at more established cancer centers. (An early example of what came to be called “entrepreneurial oncology.”) Some doctors also began offering the treatment to patients with ovarian cancer and prostate cancer even though, in the latter case, chemotherapy was generally considered ineffective.
Those breast cancer patients who survived bone marrow transplants sometimes suffered permanent damage to their heart, kidneys, or other organs, and as the years passed, we saw their cancers could return. More, it seemed, was not always better when it came to chemotherapy. As a fierce debate raged, advocates for this aggressive treatment thought their patients deserved the option of waging a last-ditch battle against death. Although randomized trials had not offered definitive proof that it worked, they considered it unethical to deny patients a treatment that showed promise. This is always the argument made by those who believe a useful intervention is being delayed unnecessarily as researchers dot their i’s and cross their t’s. At the Albert Einstein Cancer Center, the director of oncology wrote that he did not consider bone marrow transplants for breast cancer experimental. Why, he and others asked, should some people die
for the sake of a research protocol that denied some patients the treatment just to prove a scientific point?
For those of us who treated patients and knew that one person’s suffering and death rippled outward to affect great numbers of people, experimental treatments could be painfully tantalizing. I have had to tell people they were not eligible for studies, and these conversations were devastating. I also tried to push people on to trials when, by objective standards, they didn’t belong in them. In these cases, I usually had a hunch that they might do well and felt pressure to find help for someone with a profound will to live. In most cases when these patients were admitted, the cure didn’t come, and it was often hard to tell whether our effort brought any benefit other than a feeling that we—the person with cancer, his or her loved ones, and the caregivers—had done everything possible. I don’t discount the reassurance people feel when they know that everything possible has been tried, but in making the maximum effort, we put a burden on the health care system and often diminished the quality of someone’s last days. Prolonging death is not a kindness.
The treatment picture was further complicated by the fact that for every instance where it seemed someone died awaiting a drug’s regulatory approval, there were cases where severe and unexpected side effects arose in medicines that had been approved for patients. Those who were skeptical about bone marrow transplants for breast cancer—I was one because the tumors rarely had a “complete response” to any chemotherapy—thought it was unfair to ask people who were already in crisis to risk their lives on a hell-on-earth experience, or tell loved ones they refused a choice that offered a glimmer of hope. This was, it seemed, no choice at all.
In the Boston medical community, the controversy reached a kind of breaking point in the mid-1990s when Tom Frei’s longtime colleague and collaborator George Canellos backed away from STAMP. This was as the number of patients who died while recovering from treatment reached 10 percent nationwide. Even with this risk, so many women sought access to the treatment through their physicians that researchers conducting formal trials, in which some patients got the medicine and others did not, were having trouble attracting patients.
Everything came to a head in 1995. First the press in Boston reported that an HDC/ABMT patient at Dana-Farber (who was also the science reporter for the Boston Globe) had died of heart damage after receiving a massive accidental overdose of chemotherapy drugs. Thirty-nine-year-old Boston Globe writer Betsy Lehman’s death devastated her family and friends and shook the medical community. It also focused attention on the treatment she had been prescribed. Months later, at a big national conference called to review the BMT for solid tumors, it was compared to Halsted’s radical mastectomy as an example of a severe therapy that turned out to be no better, in many cases, than a less debilitating one. In the years immediately following this meeting, a flood of data called the protocol into question. In 1999, results from four big trials were set for release at the annual meeting of the American Society of Clinical Oncology, but before this happened, the press reported that the studies showed the treatment was not reliably beneficial. The final blow came when a team sent to check the data cited in the single-most encouraging study, published by a South African group, discovered it was fraudulent.
In the end, roughly thirty thousand American women underwent the STAMP procedures, but fewer than one thousand were ever part of a formal research program. Many of the thirty thousand had chosen the grueling treatment as a last and only lifesaving option. Those who died may well have endured an unnecessarily miserable end of life because of the treatment. Those who survived could never know if it was because of the radical treatment or despite it. In the meantime, too little progress has been made toward a structural solution to the clash of values—scientific rigor versus compassionate care—that set the conditions for the race to an unproven cure. A move toward evidence-based medicine and more rigorous reviews of clinical trials was galvanized and continues, but the same tensions still arise as innovation competes with caution in an arena of life and death. The main sign of progress toward creating a more rational system for regulating experimental treatment is an evolving system for permitting “compassionate use” of drugs being tested for safety and effectiveness in carefully chosen cases where no other options are available, patients are fully informed, caregivers are protected from liability, and drug trials are not affected by the outcome.
As science gradually showed the limitations of bone marrow transplant, physicians began to see a new and dreadful disease that made people vulnerable to the same kinds of infections that we saw in patients whose immune systems had been ravaged by chemotherapy. These patients developed, among other illnesses, pneumonia, tuberculosis, herpes, toxoplasmosis, and even cancers associated with immune disorders. The most notable of the cancers was Kaposi’s sarcoma, which shows itself in the form of purplish, dark-colored raised lesions on the skin.
First called GRID (gay-related immune deficiency), the mysterious illness that was reported by the federal Centers for Disease Control in 1981 appeared in Boston that same year when a single patient was identified at a health center serving the gay, lesbian, and transgender community. A year later, the disease was renamed acquired immunodeficiency syndrome (AIDS), and the number of cases nationwide grew to 771, with 618 deaths. In 1983, the death rate rose to 100 per month. Massachusetts governor Michael Dukakis created a task force to plan a response to this health crisis, which was sparking fear and prejudice. At Boston City Hospital, one doctor even ordered a patient to leave when he arrived for a lymph node biopsy and said he had AIDS. This was not an isolated incident. In 1987, Nathan Link of New York University published a study that found 25 percent of doctors he surveyed believed they had the right to refuse treatment to people with AIDS.
By this time, it was clear the infection was spread by blood and perhaps other bodily fluids. Veteran doctors and nurses, me included, had to adjust to taking precautions about exposure to blood, which had previously been of such limited concern that young interns considered a splash of red a sign that one was a real doctor. When I worked in the intensive care units, we sometimes worried about transferring the virus by mistake. In one case, a technician who had finished using an ultrasound machine on a man with AIDS asked me if it was okay to then use it on a pregnant woman in the room next door. We were so early in our experience with this disease that I didn’t know the right answer. We opted to forgo the ultrasound on the second patient, just to be on the safe side.
The first big breakthrough in AIDS science came when Luc Montagnier and Françoise Barré-Sinoussi of the Pasteur Institute in Paris, identified a retrovirus—the human immunodeficiency virus—as the cause. Robert Gallo, who worked at the National Cancer Institute, is credited with demonstrating that the virus was the cause of AIDS. He had previously discovered the only other known human retroviruses, HTLV-1 and HTLV-2. Like all viruses, retroviruses have to invade a host in order to replicate, but retroviruses are a bit more devilish. They literally insert themselves into the genome of their host cells and turn them into factories, producing large quantities of new viruses that depart to spread the infection. Retroviruses were known to cause cancer in some animals, so Gallo’s work on HTLV-1 and HTLV-2 was of keen interest to everyone in oncology. The discovery of HIV gave impetus to everyone who had turned to AIDS research or took care of people with the disease. In Boston, that included people still in training, like Bruce Walker and me.
In the early days, we had no treatments to use against HIV itself, only its many complications like infections and cancers. Much of what we did for patients seemed like fighting one complication only so they could develop another that was often worse. The physical wasting, severe pneumonias, and endless diarrhea was misery writ large. Often without meaningful therapy to offer, care reverted to just fighting infections and trying to help patients feel a bit more comfortable. In many cases, we employed the same medications used to treat the effects of chemotherapy, including anti-diarrheal,
antinausea, and, in one of my cases, you may be surprised to read, cocaine to relieve severe nosebleeds. Not quite identical to the street version, this drug does constrict blood vessels and is used by some doctors who perform sinus surgery to limit bleeding. But if our dying patients also got some momentary relief from their psychological distress, this was a positive secondary benefit. In these cases, I was often guided by one of my more difficult experiences in the intensive care unit at the Brigham. We were treating a man who was teetering on the edge of death when we saw his blood pressure and other vital signs decline. Doctors can find it too easy to start thinking in terms of the numbers, and in this case, I went in and I gave a drug that reversed all the narcotics and that brought all the numbers back to normal. But it made this man feel miserable, and of course, he died the next day anyway.
When I saw my patient’s daughter after he died, I said, “You know, we tried our best to keep him alive.” And she said, “But why did you do that?” When her question sank in, I found it hard to breathe. I just realized I had acted for me and for my peers who I worried were judging my decisions. By intervening, I had improved the numbers for a few hours, but it was not the right thing to do for the patient and his family. Inevitable death is a diagnosis no doctor should miss because to act against it costs much in agony experienced and resources squandered.