High-dose chemotherapy and bone marrow transplant

High-dose chemotherapy and bone marrow transplant (HDC/BMT), also high-dose chemotherapy with autologous bone marrow transplant (HDC/ABMT or just ABMT), was a treatment regimen for metastatic breast cancer, and later high-risk breast cancer, that was considered promising during the 1980s and 1990s. 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, 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.^[1]:3

History of the treatment

High-dose chemotherapy (HDC) with autologous bone marrow transplant (ABMT) was a treatment developed in the 1980s^[2] but had its antecedents in 1957 when E. Donnall Thomas had shown that bone marrow could be harvested from a patient and transplanted into the same or another patient.^[3]

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.^[4] Howard Skipper and Frank Schabel demonstrated efficacy in mouse models for megadose therapy in 1983.^[5]

Frei and Peters developed the Solid Tumor Autologous Marrow Program (STAMP) regimen. 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:

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. If you have 100 patients and you have a treatment applicable to 20 of the 100, and 20% of those 20 are alive after 10 years, that's only a 4% absolute survival rate, not a 20% survival rate.

— Gabriel N. Hortobagyi, M.D., Journal of the National Cancer Institute, July 5, 1995^[6]

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 patients eligible for high-dose chemotherapy survived 65% longer on conventional chemotherapy than those who would not have been eligible for the protocol.^[6] 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 patients who met eligibility criteria versus those who did not, when all received the conventional treatment.^[7]

Stage III randomised controlled trials were needed to confirm the benefit of HDC/BMT.^[6] In 1985, William Peters left the Faber 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.^[5]

Funding mechanisms and litigation

Treatment remained exclusive of most patients due to high cost; $50,000 to $400,000 per patient. As long as HMOs regarded the regime as experimental or investigational, there was no contractual obligation to cover it. This changed dramatically, in 1993, after a landmark court case, Fox v. Health Net.^[5]

A public-school teacher named Nelene Hiepler Fox (January 9, 1953 – April 22, 1993) was diagnosed with breast cancer in 1991.^[1]:74 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 for bad faith and reckless infliction of emotional distress, and $77 million in punitive damages.^[8] 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.^[5] This judgment was subsequently negotiated down to $5 million.

Between 1988 and 2002, 86 cases were filed to force HMOs to pay for transplants, of which 47 were successful.^[5] 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.^[6]

While, in the mid-1980s, fewer than 100 bone marrow transplants a year were performed on breast cancer patients,^[8] 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.^[9] 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.^[6] 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.^[8] Hospitals, like Beth Israel in Boston, devoted entire floors to transplant units.^[5]

Randomised controlled trials

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. The lead investigator was Werner Bezwoda, professor of haematology and oncology at Wits. This was the first scientific evidence of clinical benefit to emerge.^[10]

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.^[11] Ninety patients were randomised to compare two cycles of high-dose cyclophosphamide, mitoxantrone, and etoposide (HD-CNV) versus six to eight cycles of conventional-dose cyclophosphamide, mitoxantrone, and vincristine (CNV). The overall response rate for HD-CNV was 95%, with 23 of 45 patients achieving complete response (remission).^[11]

The apparent success of the 1995 study drew immediate notice for its authors; as of February 2001, the 1995 article had been cited 354 times.^[2] Patients were also enthused; in the Autologous Blood and Marrow Transplant Registry (ABMTR) database, the number of patients treated with high-dose therapy increased rapidly after the Bezwoda study was published.^[12] Many centers in the United States moved to offer HDC/BMT on the basis of Bezwoda's work. By 1999/2000 perhaps as many as 35,000 women had been treated with the regime.^[13] However, Bezwoda's research work was seriously flawed, and an audit concluded that the results were essentially fabricated.

American Society of Clinical Oncology (ASCO) Annual Meeting 1999

During May 15–18, 1999, the American Society of Clinical Oncology (ASCO) held its 35th annual meeting in Atlanta. At the plenary session, held on May 17, four studies on HDC/BMT were presented to some 20,000 attendees.^[14]

The Philadelphia Intergroup Study (PBT-1) was the largest randomized trial of HDC versus conventional dose chemotherapy in responding metastatic breast cancer.^[15] The study showed no difference in overall survival and no substantial toxicity difference between the groups.^[16]

This largest randomized trial of bone marrow transplant in metastatic breast cancer demonstrates no improvement in overall survival with transplant, no improvement in time to progression or progression-free survival with transplant, no substantial difference in lethal toxicity. Non-lethal serious toxicities were greater in the transplant arm, particularly hematologic, infection, nausea and diarrhea. Obviously, from the survival curves, these results will not change with more follow-up in this study.

— Edward .A. Stadtmauer, ASCO Annual Meeting, May 17, 1999^[14]

William Peters presented preliminary results from his CALGB study (fully described as CALGB 9082/SWOG 9114/NCIC MA-13). Peters found no significant difference in either event-free or overall survival between the randomized groups. There were 31 deaths related to therapy in the high-dose arm; a rate of 7.4%. The study design called for an additional three years of follow-up before final conclusions could be drawn.^[14][17]

The Scandinavian Breast Cancer Study Group 9401 randomised 525 high risk breast cancer patients between March 1, 1994 to March 4, 1998.^[18] 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.^[14]

Finally, Werner Bezwoda presented his randomised, controlled clinical trial of 154 patients.^[19] The majority of the patients were black, and all were under age 55. The study differed from the others in that no induction therapy was used; patients were immediately randomized to either high-dose or standard therapy. After five years, 21 of 75 patients on the high-dose arm had relapsed, compared to 55 of 79 patients on the standard dose arm. Relapse-free survival and overall survival was significantly better in the high-dose arm.^[14]

High-dose chemotherapy using the CMVP combination was found to be able to be given safely to younger patients with high-risk breast cancer. The high-dose chemotherapy resulted in a significantly low relapse rate, and high-dose chemotherapy was associated with significantly longer disease-free and overall survival in this patient population.

— Werner R. Bezwoda, ASCO Annual Meeting, May 17, 1999^[14]

Research misconduct

At the time of the 1999 ASCO meeting, Bezwoda's 1995 and 1999 studies were the only trials supporting the use of HDC/BMT. While still at the meeting, Gabriel Hortobagyi had called for the replication of the South African study.^[20] Raymond Weiss of Georgetown University, who had also seen the presentation, and Roy Beberidge helped organize an audit of the South African's research.^[8]

The audit team found Bezwoda had patient records for only 62 patients out of 154. Many records had unsigned, handwritten entries and there was no evidence that Bezwoda had randomly assigned patients. There were no records showing that any patients had received the standard treatment.^[8] The audit team informed the ethics committee at Wits of probable ethical problems with Bezwoda's research on January 28, 2000.^[21]

On January 31, 2000 the head of the Department of Medicine gave the ethics committee chairman a signed statement, dated January 30, from Bezwoda, admitting to "a serious breach of scientific honesty and integrity in a presentation made at the American Society for Clinical Oncology (ASCO) in May 1999". A disciplinary hearing was set for March 10.^[21][22][23] Max Price, dean of the Faculty of Health Sciences, was appointed acting head of haematology and oncology.^[24] Bezwoda was dismissed by the university on March 11.^[25]

Peter Cleaton-Jones, chair of the University’s Institutional Review Board, responded to the findings in the March 18, 2000 issue of The Lancet. He made clear that studies had to be approved by the Committee for Research on Human Subjects (Medical) at Wits, and could not be done unless such approval was obtained. The ethics committee at Wits had no record of the Bezwoda clinical trial.^[21] Lancet editor Richard Horton questioned whether Bezwoda could have acted alone to fabricate the study without the knowledge of his colleagues.^[26] 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.

— Weiss et al., The Lancet, March 18, 2000^[27]

George Canellos, editor-in-chief of the Journal of Clinical Oncology raised further concerns about Bezwoda's earlier research.^[28] The 1995 paper was audited in 2001, along with reviews of other published studies to determine whether they had been subject to the required institutional oversight.^[2]

The investigators could only find 61 of 90 patients. Only 27 had enough recorded information to evaluate eligibility for the trial by the published criteria. Of these 27, 18 did not meet one or more eligibility criteria. Only 25 patients appeared to have been treated with their assigned therapy around the time of their enrolment, and only three of these 25 did not receive HDC (i.e. could have been in a control group). Treatment details bore little resemblance to the published data. Additionally, nine other Bezwoda trials were not reviewed or approved by the appropriate institutional committee and contained at least one major untruth.^[2][29]

The Journal of Clinical Oncology retracted the 1995 paper on April 26, 2001, concluding: "the trial was not conducted in a scientifically acceptable manner. The protocol was apparently written 9 years after the study was started and only after another study by the same investigator was to be audited. No patient signed a consent form, and there is little evidence of true randomisation."^[30][31] ASCO President Lawrence H. Einhorn called the fraud "a stunning betrayal of public trust".^[29][32]

Status in breast cancer

High-dose chemotherapy with bone marrow or peripheral blood progenitor cell (PBPC) transplantation is no longer used. It is an expensive and toxic treatment modality. Quality of life during treatment and in the first few months following treatment is worse than that of patients who receive conventional chemotherapy. Acute toxicities commonly include nausea, vomiting, hair loss, mucositis, diarrhea, fatigue, and skin abnormalities. Given these issues, the burden of proof for a benefit over standard treatments is high.^[33] High-dose therapy is also associated with an increase in second malignancies, including myelodysplastic syndromes and leukemias.^[5]

A 2011 overview of six randomized trials concluded:

Overall survival of patients with metastatic breast cancer in the six randomized trials was not significantly improved by high-dose chemotherapy; any benefit from high doses was small. No identifiable subset of patients seems to benefit from high-dose chemotherapy.

— Berry et al., Journal of Clinical Oncology, August 20, 2011^[34]

Additional sources

• Anders, George. Health Against Wealth: HMOs and the Breakdown of Medical Trust. Houghton Mifflin Books, 1996, 299 pages, ISBN 0-395-82282-3.
• Mariner, Wendy. Patients' Rights afterr Health Care Reform: Who Decides What Is Medically Necessary?. American Journal of Public Health, September 1994, Vol. 84, No. 9.
• Rodenhuis S, Bontenbal M, Beex LVAM, et al. High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for High-Risk Breast Cancer. N Engl J Med. July 3, 2003 2003;349(1):7-16.
• Stadtmauer EA, O'Neill A, Goldstein LJ, et al. Conventional-Dose Chemotherapy Compared with High-Dose Chemotherapy plus Autologous Hematopoietic Stem-Cell Transplantation for Metastatic Breast Cancer. N Engl J Med. April 13, 2000 2000;342(15):1069-1076.
• Tallman MS, Gray R, Robert NJ, et al. Conventional Adjuvant Chemotherapy with or without High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in High-Risk Breast Cancer. N Engl J Med. July 3, 2003 2003;349(1):17-26.
• Schulman KA, Stadtmauer EA, Reed SD, et al. Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2003;31(3):205-210.
• Lief M, Caldwell HM. And the Walls Came Tumbling Down: Greatest Closing Arguments Protecting Civil Libertie, pp. 303-53
• Eckholm, Erik. "$89 Million Awarded Family Who Sued H.M.O.". New York Times, December 30, 1993.

References