By Jonathan Shikes
By Michael Roberts
By Jonathan Shikes
By Michael Roberts
By Michael Roberts
By Michael Roberts
By William Breathes
By Melanie Asmar
Linda McLaughlin sits on an examining table in the blood- and marrow-transplant unit of Rocky Mountain Cancer Centers. Though she's a heavyset woman, there's a fragility about her. Her voice, sweet and light like a child's, trembles between exultation and grief and sometimes explodes in a mini-burst of laughter. She has just returned from the dark shores of death, and she still carries with her all the terror and wonder of that experience. Next to her, sometimes putting a protective arm around her shoulders, sometimes helping fill in a detail or two of her story, sits her sister Rosemary Pagano.
Their family has a history of breast cancer; Pagano herself was treated for the disease five and a half years ago. "Our grandmother died when my mom was seven," Pagano says. "My mother, one of her sisters and then our older sister had it, also. Out of six females in our family, four have had breast cancer." She pauses momentarily. "You almost wonder what's worse," she asks, "having had it or wondering when you will?"
In October of last year, McLaughlin noticed a painful spot on her breast. "In my family, we automatically go to the doctor and say, 'What is this? Get it out of me,'" she says, laughing. She had a needle biopsy, and the results came on Halloween. "We were all dressed up at work," she remembers, "and I found out I had suspicious cells." The tears come as quickly and unexpectedly as the laughter.
The lump was large: seven centimeters. McLaughlin had chemotherapy to shrink it before surgery. Fearing there might be cancerous cells in her other breast, she opted for a double mastectomy. During surgery, seven cancerous lymph nodes were found under her arm. Then came four doses of chemotherapy and a choice: Did she want regular chemotherapy treatments or a program of high-dose chemotherapy, which used to be (and often still is) known as a bone-marrow transplant? This treatment is offered when breast cancer has metastasized to other parts of the body or, as in McLaughlin's case, is extremely likely to do so.
McLaughlin was 32 years old. Her doctor had told her that with conventional treatment, there was an 80 percent chance her cancer would recur within five years. At ten years, the chance of recurrence was 100 percent. She wasn't given numbers on the high-dose chemo but was told that it offered her the best chance of survival. Fifty-fifty, she thinks she heard somewhere. "I was in a fog," she says. "My thought process was, I want to be as aggressive as possible to get as much of the cancer as I can, to live as long as I can. And I figure any improvement over 100 percent is good."
Although in practice it's highly sophisticated, high-dose chemotherapy is based on a fairly primitive concept: Chemotherapy kills tumor cells; the cure fails when some of those cells escape or become resistant. So the solution would seem to be a high enough dose to wipe out each and every one of the little beasts. Unfortunately, chemotherapy is a clumsy instrument that poisons healthy cells along with cancerous ones and destroys bone marrow. A dose sufficient to wipe out all of a patient's tumor cells would likely kill the patient as well. But what, early researchers wondered, if some of that patient's bone marrow were taken out before chemo and then reinjected afterward and allowed to regenerate? Such transplants (using donated marrow rather than the patient's own) had been successfully used against leukemia and lymphoma for decades. Why not use them against solid tumors like breast cancer?
The experimentation began in the early 1980s. In 1990 Dr. Roy Jones and his wife, Dr. Elizabeth Shpall, major pioneers in bone-marrow transplant for breast cancer, came to Denver to head a unit at the University of Colorado Health Sciences Center. Presbyterian/St. Luke's, which is now affiliated with Rocky Mountain Cancer Centers, began offering the treatment in 1991.
Many breast-cancer patients are young; they often have children. They are desperate to live, and metastasis is almost always fatal. Sick women began begging for the treatment; activists pressed for broader access; reluctant insurance companies were shamed, pressured and sued into paying. More and more transplants were being done around the country. Some were given in a research setting such as that at University Hospital; others were simply offered by hospitals in search of revenue or responding to need.
In the early days, data collection was spotty, and it was difficult to get enough patients for the randomized trials that would provide definitive proof that the treatment worked. Many women, convinced that a transplant offered salvation, refused the possibility of being randomized to the non-transplant arm of a study. But transplant patients did seem to be living longer than expected, and the high mortality rate from the procedure itself was rapidly decreasing--from 15 percent to less than 5. New drugs came on line that aided bone-marrow regeneration. And researchers discovered that stem cells--immature bone-marrow cells--could be taken from the blood, obviating the need to drill into bone.
Up until this point, there had been little progress in breast-cancer treatment. Bone-marrow transplant seemed a shining beacon in the otherwise bleak landscape.
McLaughlin found her three-day high-dose drug bombardment less traumatic than she'd feared. It was perhaps a little less difficult than regular chemo, she says, because of the careful support and monitoring she received at the hospital. But the days that followed were far worse. "Here I am," she says. "They've killed off all my white cells, which are the ones who do repair, who fight off infection. I've got a sore throat from the mucus running down the back of my throat. I've got a really dry mouth. I've gotten mouth sores, because my body can't heal itself. Vaginal bleeding. Vomiting. I got to where I couldn't swallow."
Pagano takes her sister's hand. "She's a very brave one, I'll tell you," she says. McLaughlin is shaking her head; once again the tears are leaking. "You are," Pagano says. "Brave."
"Everybody comes up and says, 'You're doing such a good job handling this,'" McLaughlin says finally. "I said, I've got two choices. I've got this disease. I can either curl up in a ball and let it get me, or I can laugh and joke and I can fight. That's all you can do. There's no other choice."
"On Saturday her vehicle was falling apart," adds Pagano. "She needed two pints of blood and she needed platelets. She really had to be picked back up. But they gave her a tuneup, and then she felt a lot better." The women have their heads together--Pagano's dark curls close to McLaughlin's bald skull--and they're giggling. Clearly this is a sister joke. "You know," Pagano continues, "a change of oil..."
"Go over the chassis..." her sister chimes in.
"New transmission fluid..."
They sputter into amused silence.
Last week, 20,000 cancer experts from all over the world converged on Atlanta for the annual meeting of the American Society of Clinical Oncology (ASCO). Bone-marrow transplant was the hottest topic on the agenda.
The first well-constructed, randomized studies--five of them--were scheduled for discussion. But even before the convention, the findings had leaked out--and they did not bring good news. Four indicated that women who had bone-marrow transplants, whether for aggressive or metastasized cancer, did no better than those who had conventional chemotherapy. Only one small study, from South Africa, showed positive results. (The results of all five studies have been published at www.asco.org.)
A cancer diagnosis topples the world into chaos. If there's one thing a patient needs from her doctor, it's calmness and authority. And here were the best cancer doctors in the world, arguing passionately about the one treatment for advanced breast cancer that had offered the possibility of cure.
Activist organizations were quick to join the discussion. "We have not seen the study results," the National Breast Cancer Coalition announced blandly before the conference, but "it has become clear that the results will not show that this treatment benefits women with breast cancer." Barbara Brenner of the San Francisco-based Breast Cancer Action says she found the results "pretty unambiguous." But while she supports further, highly controlled clinical studies, Brenner also believes that resources should be redirected toward "less toxic, more targeted" therapies.
The ramifications are enormous--and they hit close to home. Across the country, researchers like Jones and Shpall have staked their reputations and careers on bone-marrow transplant. Thousands of women have undergone the procedure; many are convinced it saved their lives. Thousands more are trying to decide whether to enter a transplant program.
"People who do what I do for a living have justifiably been criticized for too much high-dose therapy in breast cancer," says Dr. Jeffrey Matous, who works for Rocky Mountain Cancer Centers. "We need to be skeptical of our data; we need to be very truthful with our patients. There's a lot that we do not know yet."
But, he adds, "when you look at these studies, in no study is high-dose therapy inferior to standard therapy. The question you have to ask is, [has the transplant method] adversely impacted quality of life?"
Quality of life is the primary issue for Shonda Cortez. The Carbondale woman was diagnosed with inflammatory breast cancer, which is almost always fatal, and underwent a bone-marrow transplant of a particularly focused kind in January. "It was nightmarish," she says. "I really don't like to hear my family tell me much about the first week. They give you drugs that help you forget, but my mother said I would just roll back and forth in bed and say, 'I'm so miserable.'"
She also had psychotic episodes. One night she unhooked her catheter, got her walker and tried to leave. When the nurse came in, Cortez was terrified and made her empty her pockets. On another occasion, she kept begging her parents to get rid of the flies in her room. One of the drugs she was given causes nerve damage in the hands and feet. For a while she could hardly stand up, and the mere touch of the bedcovers on her feet caused excruciating pain.
Cortez's thinking was affected. Sometimes she meets other women who have been through the treatment and is relieved, she says, to find "their brains aren't too bad. Maybe mine will come back."
When she learned of the transplant studies, Cortez was devastated. "I want to know--where did University Hospital get those figures they were giving me?" she asks. "I was in radiation when I heard the results of those studies on the NBC Nightly News. I talked to the radiation oncologist. She said she had always thought the numbers of 70 to 80 percent [disease-free survival for some high risk patients] were inflated, just given what she was seeing in her practice. But she also said that she felt that those studies were so generalized that, very likely, given the extreme aggressiveness of my particular cancer, I might be in a group of women who would benefit from transplant."
Cortez is still glad she had the treatment--and grateful she doesn't have to make the decision now, because "it's not as clear-cut and hopeful as everyone had thought. It's sad and scary to think that it might not help me and that I went through what I went through--all of us did--for no real reason.
"Maybe part of the problem is our culture, that we think we have the right to those kinds of answers. It's easier to believe the doctors than to face your own mortality."
Pat Nettles does have to make the decision now. She's currently in remission and, after years of surgeries, treatments, invasive tests and ambiguous symptoms, she's eager to rest. But if a transplant is to help her, it should take place immediately, before there's any sign of returning disease, and she's heard from her New York doctors that the University of Colorado is considered "a center of excellence" for the procedure. "I'm not wild about the toxicity and the invasiveness of it," Nettles says. "One doctor I talked to likened it to dropping a napalm bomb. It's a really tough decision."
But Dr. Roy Jones has no doubts about the value of his work. "There's a broad and rich literature that shows that for many kinds of drugs, the more you give, the more cancer you kill," he says, adding that his statistics come from thirty to forty years of experience and from twenty to thirty centers that have compiled data on thousands of women. They show that where metastasis is widespread, high-dose chemo has a 20 percent chance of eradicating all signs of cancer for five years. If there is metastasis to only one site, the rate goes up to 50 percent. For an aggressive localized tumor, the patient's chances of five disease-free years go from 20 to 70 percent.
These are not abstract numbers to Vicki Tosher, director of the Colorado Breast Cancer Coalition, who falls into the latter group. She was diagnosed in May 1991 and was one of the first patients at Presbyterian/St. Luke's to have stem-cell therapy. The experience was less traumatic than she'd feared, she remembers. She was given liberal amounts of medication to counter her symptoms, as well as drugs that induced amnesia. The staff was warm and supportive. But she did feel some trepidation when she saw the large bags of drugs she was to be given. "You go to the doctor's office for chemo and you get a vial, a syringe," she notes. "Well, this is a big bag and it drips into your body for hours. Perry--my significant other--that was when he flipped out, seeing them hang bags of chemotherapy. He said, 'I knew that if I was going to lose you, that was when it was going to happen.'"
At one point, just before receiving her drugs, Tosher had a dream in which inanimate objects turned animate and "rocks became birds and flew away." When she woke up in the morning, she says, "an incredible sense of calm had come over me. I knew that whatever happened, live or die, it was going to be okay."
Because Tosher has talked to many women who have had transplants, she has questions about the validity of those studies. Some of the women received different drugs from those she was given, or they had the same drugs at different dosages. She knows the treatment she got in 1991 was based on studies that had begun many years earlier and that current treatment is shaped by trends and figures that have since evolved. Conventional chemotherapy has changed, too. So when a researcher says that in his study, this group of women did or didn't do better than that group, what exactly were the women taking, and do those numbers still have relevance?
"We reinvent ourselves every three years," says Jones. "I take the heretical position that these random trials are obsolete. They're considered the gold standard, but they're a bankrupt way to evaluate treatment."
Jones believes the studies were released prematurely: The time frames involved are too short, since many of the women have been followed for fewer than three years. Most women with metastatic or advanced breast cancer will live that long no matter which treatment they choose; whether or not transplant prolongs life will become clear only four, five or six years later.
"In my opinion, ASCO decided to make a big splash at the meeting," Jones says. "A big media splash. A number of authors--including my wife--were not given the opportunity to review the data before it was scheduled for publication. There was a rush to judgment. I'm pretty confident what the trial will show, but it's going to take three more years to show it. It's too early."
Instead, procedures should be judged by two things, Jones says: their toxicity and whether they kill more cancer than earlier treatments. "Statistics tell us we have to look at tumor shrinkage by waiting to see how long patients live. But what if you could measure more accurately how much of the tumor is killed? The doctor says, I have two treatments, equal in toxicity, but one kills more tumor than the other. Which are you going to pick?"
Meanwhile, all the debate is taking place under the far-from-disinterested scrutiny of the insurance industry. For the time being, ASCO is recommending that insurance companies continue to pay for bone-marrow transplants--a position Jones passionately supports. "Dose intensity is only a component of what we're trying to do here," he says. "How are we supposed to do this work in a health-care system that denies experimental treatment? We've spent ten years creating a model on which we can build. We're working with the immune system, with monoclonal antibodies...The bio-tech people are creating ideas five times faster than we can test them. You don't want me to be ten years behind the loop in terms of testing what these companies are able to produce."
And you don't want patients to be stuck in the middle, either. "Think of what patients are going through when they see us wringing our hands about this and nerding out when it's all opinion," says Jones. "It's all editorial."
Patty Kealiher has seen a lot in her seventeen years as an oncology nurse. A brisk, healthy-looking woman, she has mixed and given chemos, held patients' hands, cleaned up vomit, offered advice, memorized jokes to amuse and distract her patients. She has watched people she's come to love die; she has celebrated with those who outlived all predictions.
Kealiher has worked with bone-marrow transplant for the last eight and a half years--most of them with Jones and Shpall at University Hospital. She began work at Presbyterian/St. Luke's on April 1--"my favorite holiday," she says.
"High dose is the only thing that works," she says unequivocally. "Wimpy chemo doesn't cure cancer."
In her work, she has seen people thrive who were not expected to live. She speaks of Connie, diagnosed with terminal cancer in 1991 and now apparently disease-free. "She would be dead by now," Kealiher says, "if she hadn't gone through the bone-marrow transplant." She remembers Gladys, who collapsed at work and was diagnosed with breast cancer that had spread to her spine. "She went to see a local oncologist who said, 'Dang, I'm really sorry--how about some tamoxifen?'" Since tamoxifen only prolongs life, Kealiher encouraged her to see another doctor, and Gladys ultimately opted for a more aggressive approach that included bone-marrow transplant. "She's a year out, and she still continues to improve," says Kealiher. "I don't know if we cured her, but she would have gotten only a few years doing tamoxifen."
Eventually, Kealiher hopes, advanced breast cancer will be a chronic disease to be managed rather than a fatal one. "My career is very rewarding," she says. "This is the most intense, frightening time of my patients' lives--God help them if they have to go through something worse--but we're giving them a chance they might not have ever gotten."
Still, the work can be difficult. Kealiher speaks of a patient--another nurse--who got an infection and died during chemo. "She was young and healthy, doing the treadmill, and dead two days later. It was horrible.
"Sometimes you're just so zapped, so emotionally and physically drained," she says. "Often I'd get home, make some dinner, sit in front of the TV and just stare at it. Oncology nurses pretty much give everything they've got."
Boulder oncologist Dr. John Fleagle believes the studies must be taken seriously. "I think it would be fair to say that the longer you practice medicine, the harder it is to be dogmatic," he says. "Things change, treatments change, even concepts change...One thing I've learned is that all those anecdotal and life experiences that help you make decisions really need to be filtered through an understanding of research. Because truth, at least as I understand it, is based on research. And I have to listen even if the research is counter-intuitive or it hasn't been my belief system.
"Practicing medicine is not just a matter of opinion; if it were, it would be dangerous. More dangerous than it is.