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.
[3] 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.
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.
[6] 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.
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.
The problem with Phase II studies was explained thus: If you have a hundred patients and you give them a treatment applicable to all 100, and two are alive after 10 years, that is a 2% absolute survival rate.
[7] 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.
[7] In 1985, William Peters left the National Cancer Institute to set up the trial at Duke University in North Carolina.
[6] 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.
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,[11] the uptake of HDC/BMT increased six-fold between January 1, 1989 and June 30, 1995.
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.
[6] 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.
[7] 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.
[4] Journalists portrayed HDC/ABMT as a miracle treatment, with patients playing the victims, doctors the saviors, and breast cancer and health insurers the villains.
[9] Most articles made three major points: This led to many people having the wrong impression of HDC/ABMT, which in reality, was a treatment that was not supported by clinical trials.
[4] Academic researchers wanted to wait for the results of the clinical trials, while breast cancer oncologists and bone marrow transplanters supported the procedure.
General strategies for the defendant, or insurer, included stating that the coverage plans did not believe HDC/BMT was in the patient's best interests because of the high mortality rates and reduced quality of life; stating that the treatment had not been clinically proven to be beneficial and more effective than existing treatments—the results of the clinical trials had not yet been reported.
[9] In May 1992, researchers from the University of the Witwatersrand (Wits) in South Africa presented early results of a randomised control trial (RCT) at the annual meeting of the American Society of Clinical Oncology (ASCO) in San Diego.
[13] Bezwoda published the first randomised controlled trial of high-dose versus conventional-dose chemotherapy as first-line treatment for metastatic breast cancer in October 1995.
The Philadelphia Intergroup Study (PBT-1) was the largest randomized trial of HDC versus conventional dose chemotherapy in responding metastatic breast cancer.
[21] Principal investigator Jonas Bergh reported no overall survival benefit to high-dose therapy versus a tailored regimen, after a median follow-up time of 27 months.
[23] Raymond Weiss of Georgetown University, who had also seen the presentation, and Roy Beberidge helped organize an audit of the South African's research.
Peter Cleaton-Jones, chair of the University’s Institutional Review Board, responded to the findings in the March 18, 2000 issue of The Lancet.
[29] Weiss and his team concluded:The Bezwoda study should not be used as the basis for further trials to test the efficacy of the cyclophosphamide, mitoxantrone, etoposide regimen for high-dose chemotherapy in women with high-risk primary breast cancer.George Canellos, editor-in-chief of the Journal of Clinical Oncology raised further concerns about Bezwoda's earlier research.
[3][32] The Journal of Clinical Oncology retracted the 1995 paper on April 26, 2001, concluding: "the trial was not conducted in a scientifically acceptable manner.