ALEXANDRIA, Virginia-Documentation of widespread fraud in a 1985 study supporting high-dose chemotherapy/transplant for metastatic breast cancer patients has led the Journal of Clinical Oncology to retract the influential report and the American Society of Clinical Oncology (ASCO) to recommend that breast cancer patients not receive high-dose chemotherapy with autologous bone marrow transplants outside of clinical trials.
ALEXANDRIA, VirginiaDocumentation of widespread fraud in a 1985 study supporting high-dose chemotherapy/transplant for metastatic breast cancer patients has led the Journal of Clinical Oncology to retract the influential report and the American Society of Clinical Oncology (ASCO) to recommend that breast cancer patients not receive high-dose chemotherapy with autologous bone marrow transplants outside of clinical trials.
At a press conference, ASCO’s outgoing president Lawrence H. Einhorn, MD, called the study "outright scientific fraud." ASCO president-elect, now president, Larry Norton, MD, said there is unequivocal evidence to show that principal author Werner Bezwoda, MD, PhD, of South Africa "really duped us all."
ASCO audited the1985 study because serious scientific misconduct was found in a similar study of high-dose chemotherapy/transplant in high-risk breast cancer patients that Dr. Bezwoda presented at the Society’s 1999 annual meeting in Atlanta.
The University of the Witwatersrand in Johannesburg fired Dr. Bezwoda last year. He is now in private practice, according to Raymond B. Weiss, MD, clinical professor of medicine, Georgetown University Medical Center, who conducted both audits as an independent consultant.
The audit team reviewed more than 15,000 patient records from two hospitals in a search for records of the 90 patients in the 1985 study. It also looked at research documents and minutes covering 15 years of meetings by the University of the Witwatersrand Committee for Research on Human Subjects in an attempt to verify that the trial’s protocol had been reviewed and approved.
The auditors found records for just 61 participants. Only 27 were sufficiently documented to determine whether they were eligible for the study; of these, 18 clearly were not. Only 25 seemed to have received the therapy they had been assigned; all but three of these were in the high-dose therapy/transplant group.
Although Dr. Bezwoda reported that no treatment-related deaths occurred, the auditors said they found at least three possible treatment-related deaths in the high-dose group. No patient consent forms were found, and the auditors concluded that the protocol was not written until the 1999 study was audited.
The study had two co-authors, one of whom flew from Canada to South Africa to help the auditors find records of patients she had treated. The other declined to participate. Both told auditors they did not know their names were on the paper until shortly before or after it was published.
"This study was really never a study," Dr. Weiss said. "There was no protocol, no consent, no randomization, no attempt to determine whether the patients were eligible, and most of the patients received something other than what was described in the published paper."
The auditors also concluded that Dr. Bezwoda lied in this study and reports of nine other clinical trials when he wrote that his institution approved the protocol. It had never been reviewed.
Prior to the scandal, no one at the University of the Witwatersrand questioned whether a published study had met internal requirements, according to Peter Cleaton-Jones, MB, BCh, PhD, DSc (Dent), DPH, chair of the University’s Institutional Review Board. "We have a very strict policy before a study is done, but up to the present time, we have not checked backwards. The logistics of this are overwhleming," he said, adding that the University is reconsidering its policy.
Dr. Bezwoda has been listed as co-author of 188 papers since 1974. The breast cancer research attracted greater scrutiny than most because it was in a prestigious journal and it was the first report of a randomized clinical trial supporting high-dose chemotherapy/transplant for advanced breast cancer.
The number of women who received the controversial, highly toxic therapy as a result of the fraudulent study is not known. In a policy statement, ASCO said that after current patients complete treatment, insurers should not be obligated to cover it for new patients outside of "a high-quality clinical trial." Only one clinical trial is in progress, and it has stopped taking patients.
The audit is reported in the June issue of the Journal of Clinical Oncology with an editorial by Dr. Norton. "That the original publication . . . has influenced major thinkers in this field and may have put patients in danger raises the stakes," he wrote, "as we consider how we can improve the process to make sure that this never happens again."