High-dose chemotherapy and bone marrow transplant (HDC/BMT), also high-dose chemotherapy with autologous bone marrow transplant (HDC/ABMT or just ABMT), was an ineffective treatment regimen for metastatic breast cancer, and later high-risk breast cancer, that was considered promising during the 1980s and 1990s. With an overall idea that more is better, this process involved taking cells from the person's bone marrow to store in a lab, then to give such high doses of chemotherapy drugs that the remaining bone marrow was destroyed, and then to inject the cells taken earlier back into the body as replacement. It was ultimately determined to be no more effective than normal treatment, and to have significantly higher side effects, including treatment-related death.
From its birth in the 1980s to its denouncement in the late 1990s, HDC/BMT transformed clinical practice, activist-driven legislation on healthcare insurance coverage, public health policy and drove a two-decade long period of entrepreneurial oncology. It also gave rise to one of the most serious cases of research misconduct of the 20th century.
History
The idea for high-dose chemotherapy (HDC) with autologous bone marrow transplant (ABMT) originated in the 1950s as a leukemia treatment, when E. Donnall Thomas had shown that bone marrow could be harvested from a person and transplanted into the same or another person. It was promoted as a treatment for advanced breast cancer starting in the 1980s.
The treatment of high-dose chemotherapy with autologous bone marrow transplant had serious, lasting, and sometimes deadly side effects for the patient, including cardiac toxicity, sepsis, pulmonary failure, and nephrotoxicity, among others. Chronic consequences of the treatment included development of leukemias and lymphomas and heightened vulnerability to infections soon after the transplant. Randomized clinical trials reported treatment-mortality rates from 0% to 7% for women who received the HDC/BMT treatment, versus no such deaths within the control groups that received the typical chemotherapy regimen.
In HDC, the bone marrow transplantation was used to maximise chemotherapeutic dosage. By harvesting and freezing bone marrow, then implanting the marrow after HDC, doctors were theoretically able to break through the frontier of toxicity, the so-called "red ceiling". Early proponents of the technique were George Canellos and Emil Frei of the Dana–Farber Cancer Institute, and William Peters, whom Frei had recruited to the institute in 1982. Howard Skipper and Frank Schabel demonstrated efficacy in mouse models for megadose therapy in 1983.
Frei and Peters developed the Solid Tumor Autologous Marrow Program (STAMP) regimen. Researchers in the National Cancer Institute (NCI) did not believe that the treatment would be effective and were wary of the consequences of this treatment. For example, George Canellos, one of the original members of the NCI, had noticed that a long-term side effect of megadose chemotherapy regimens was myelodysplasia, a condition that tended to progress to leukemia. During the early stages of the STAMP clinical trial, the first patients were those who were hopeless cases—women with advanced, metastatic breast cancer that had already received, and did not respond to, existing treatments. However, about halfway through the trial, a previously untreated woman with metastatic breast cancer enrolled in the STAMP program, and many of Peters's colleagues began to take notice. The results of her treatment were unprecedented—her tumor and metastatic deposits had shrunk significantly. From then until the end of this preliminary clinical trial, Peters had transplanted and treated more cases and also obtained significant remissions similar to that of this woman's. They then believed that STAMP produced more durable remissions than those by conventional chemotherapy, and so Peters left to set up a randomized clinical trial at Duke University.
By December 1984, 32 women had completed the Phase I study of the regimen, designed to investigate safety. The researchers proceeded with Phase II trials, which showed very promising results. However, only women who were healthier and responded better to conventional chemotherapy were eligible for the Phase II studies. The problem with Phase II studies was explained thus:
This selection bias makes the treatment look better, because candidates who would have fared better under any condition were selected. To belabour the point further Hortobagyi, using data from the University of Texas M. D. Anderson Cancer Center in Houston, reported in May 1995 that those eligible for high-dose chemotherapy survived 65% longer on conventional chemotherapy than those who would not have been eligible for the protocol. Subsequent research on doxorubicin-containing protocols for the treatment of metastatic breast cancer, found that median progression-free survival (PFS) was 16 and 8 months and median overall survival (OS) was 30 and 17 months, respectively for women who met eligibility criteria versus those who did not, when all received the conventional treatment.
Stage III randomised controlled trials were needed to confirm the benefit of HDC/BMT. In 1985, William Peters left the National Cancer Institute to set up the trial at Duke University in North Carolina. He persuaded the Cancer and Leukemia Group B (CALGB) to sponsor a multicenter, randomised controlled trial.
Clinical use of this treatment was driven by women with breast cancer and advocacy groups, such as ACT UP; they believed that the FDA treatment approval process was too slow. Health Net's denial of Nelene Fox's transplant—a case involving insurance coverage of HDC/ABMT—ignited a public reaction and prompted change in access to treatment. Unlike new drugs, which are evaluated and approved by the Food and Drug Administration (FDA), medical procedures are not officially regulated by any agency nor does there exist any statutory requirement to serve a similar function. Around 30,000 women received the HDC/ABMT procedure in the 1989–2002 period; the medical profession was divided in its commitment to clinical trials and sanctioned the procedure as better than existing treatment before there was proof from the scientific community—of the women who received the procedure, only about 1000 of them were enrolled in randomized clinical trials in the United States. In contrast, repeated assessments concluded that existing data did not support claims of the effectiveness of HDC/ABMT, leading to the high-priority phase 3 clinical trials in 1990–1991, which were supported by the effort of the National Cancer Institute (NCI), skeptical scientists, health insurance companies, and cancer groups.
The results of clinical trials ended up showing that HDC/BMT for breast cancer was not an effective treatment and did not increase survival rates compared to existing treatment. These conclusions were drawn from a combination of studies, including that of Peters and a large study executed by the Netherlands Cancer Institute, both of which drew the conclusion that HDC/BMT was not superior to standard breast cancer treatment. Another study, done by researcher Werner Bezwoda, reached the conclusion that the treatment was effective, but his study was later discredited due to scientific misconduct, including the falsification of data. The treatment was discontinued for breast cancer, although it is still used to combat other types of cancers, like leukemias and lymphomas.
Funding mechanisms and litigation
With the rise in popularity of this treatment, more and more women with breast cancer wanted it to be available to the public—not just offered in clinical trials. Inspired by HIV/AIDS activism, several cancer advocacy groups began to lobby for the general availability of HDC/BMT. This drew potential patients away from clinical trials, such as that of Peters. As a result, by the late 1980s, most hospitals and private clinics had transplant wards to provide HDC/BMT to those women who sought it.
Most women could not afford to pay for the treatment themselves, due to high cost of US $50,000 to $400,000 per patient. As long as health maintenance organizations (HMOs) and other insurers regarded the regime as experimental or investigational, there was no contractual obligation to cover it. While, in the mid-1980s, fewer than 100 bone marrow transplants a year were performed on breast cancer patients, the uptake of HDC/BMT increased six-fold between January 1, 1989 and June 30, 1995. Between those dates 19,291 autotransplants were reported to the Autologous Blood and Marrow Transplant Registry; 5,886 were for breast cancer. After 1992, breast cancer was the most common indication for autotransplant. Only 11% of women with stage 2/3 disease, and less than one percent of those with stage 4 disease, participated in randomized trials. The International Bone Marrow Transplant Registry estimated that at least 4,000 women were treated with HDC/BMT from 1989 through 1993, with fewer than 10% doing so within trials. Based on the unsubstantiated belief in the success of HDC/BMT, women refused to be randomised to conventional treatment conditions, and doctors were not reimbursed for additional time spent administering protocols. Simultaneously, the treatment was highly profitable for hospitals who, by 1995, were billing the procedure at $80,000 to $100,000 (), at a cost to the hospital of less than $60,000. Hospitals, like Beth Israel in Boston, devoted entire floors to transplant units.
In 1993, a landmark court case, Fox v. Health Net. changed the existing policy of HMOs toward paying for the treatment. A public-school teacher named Nelene Hiepler Fox (1953–1993) was diagnosed with breast cancer in 1991. She requested her HMO to pay for High-Dose Chemotherapy and Bone Marrow Transplant (HDC/BMT) to treat her cancer. Her health maintenance organization, Health Net, declined her request, stating this therapy was an unproven, experimental therapy. Fox's brother, Mark Hiepler, took her HMO, Health Net, to court to force them to pay for HDC/BMT, which they had refused to do. Despite raising $220,000 herself and receiving the treatment regime, Fox died on April 22, 1993. Mark Hiepler sought damages from Health Net for delaying his sister's treatment. On December 28, Fox's family was awarded $89 million by a Californian jury, including $12.1 million for bad faith and reckless infliction of emotional distress, and $77 million in punitive damages. Jim Fox and the estate of Nelene Fox v. Health Net is considered a watershed case in that most health insurers subsequently began approving HDC/BMT for advanced breast cancer.
Between 1988 and 2002, 86 cases were filed to force HMOs to pay for transplants, of which 47 resulted in HMOs being required to pay for the transplants. The legislatures of Massachusetts, New Hampshire, Virginia, and Minnesota mandated insurance coverage for all high-dose chemotherapy with ABMT or peripheral blood stem cell (PBSCT) transplant for women with breast cancer.
The media, both newspapers and television, played an important role in promoting HDC/ABMT to people, especially through their portrayals of women with breast cancer, which ignited public protests and prompted legislative change that mandated insurance coverage of HDC/ABMT. For example, the Boston Globe published a story regarding Charlotte Turner, a woman with breast cancer whose HMO would not pay for her treatment, which spurred the lobbying of the Massachusetts state legislature. In response to the lobbying and public pressure generated by the story, the Massachusetts state legislature passed legislation requiring HMOs to cover the HDC/BMT treatment in late 1993. Journalists portrayed HDC/ABMT as a miracle treatment, with patients playing the victims, doctors the saviors, and breast cancer and health insurers the villains. Most articles made three major points: