We discussed in last week’s article the potential use of autologous bone marrow transplantation (BMT) for giving dramatically higher doses of chemotherapy than would normally be possible with conventional methods. This has been successfully utilized for hematologic malignancies, like leukemia. For most solid tumors, there is not good evidence to suggest that increasing the chemotherapy dose would matter, or improve survival.
Theoretically, one would want to target an aggressive treatment like autologous BMT to a tumor where there was evidence from prior research that suggested that more intensive chemotherapy could be more successful. Among the solid tumors, perhaps the best-known example is breast cancer, which is known to be more responsive to dose-dense, i.e., more intensive chemotherapy. Indeed, most women with localized breast cancer are treated with dose-dense chemotherapy as the preferred approach, and thus they do experience worse side effects than patients with many other types of malignancies.
In the 1970s and early 1980s, investigators at Harvard suggested that autologous BMT might provide a means of increasing the dose-intensity of chemotherapy for breast cancer, and some small studies were launched in patients with metastatic breast cancer to investigate its effects. These small studies suggested an improved outcome compared to previous conventional therapy, but the patients selected for these studies, in order to undergo what was recognized as an unusually aggressive treatment approach, were above average from a physical point of view. Furthermore, in order to afford the expensive procedure, they were also generally middle or upper social class.
There was extensive criticism by David Eddy, a physician and expert on medical decision making at Blue Cross/Blue Shield, who pointed out the selectivity and potential bias of those undergoing the procedure in these early trials as well as the high mortality rate for those undergoing this procedure (5% or more) versus the low mortality rate for conventional chemotherapy. In contrast, there were those who argued that the benefits were so clear cut that a randomized trial would be unethical.
However, the dramatic response rates for desperate patients reported in these studies created widespread demand for the procedure. And hospitals, enticed by the $80,000-$100,000 price tag, a fortune at the time, were racing to create BMT units to lure patients with breast cancer. Insurance companies were increasingly concerned about paying the high price tag, but there were numerous lawsuits that essentially compelled them to provide the expensive treatment.
What brought the issue to a boil was a presentation by Bill Peters of Duke University (a classmate of mine at Columbia P&S) at the 1990 meeting of the American Society of Clinical Oncology (ASCO) on the use of autologous BMT for women with high-risk non-metastatic breast cancer, showing excellent outcomes. This study threatened to extend the use of autologous BMT from those with metastatic disease to its use for adjuvant therapy, a much larger potential group and thus a potentially much larger financial drain for the insurance companies.
Finally, the insurers insisted that randomized trials be conducted or they would withhold reimbursement. The first randomized trial was published in 1995 by Werner Bezwoda, an oncologist from Johannesburg, that randomized 90 women with metastatic breast cancer to either autologous BMT or conventional dose-dense chemotherapy. The BMT arm did dramatically better than the control group (95% response rate versus 53%, with a significantly better duration of response and survival). However, several other randomized studies were also published, but found no benefit, including studies of BMT in the setting of adjuvant therapy.
Bezwoda then presented another study in a plenary session at the 1999 Annual Meeting of the ASCO that purported to show a dramatic benefit for BMT over conventional chemotherapy. Again, his study was the only one (of five) that showed the superiority of BMT.
To explore why Bezwoda’s results differed from other studies, he was asked to submit his data to review. A committee of oncologists, biostatisticians and others was dispatched to South Africa to meet with him and his team. When they did, they discovered missing or incomplete records; multiple control patients given inadequate chemotherapy doses; no consent forms for anyone in the study—in essence, the data was mostly fabricated and there was no data supporting his trials. The article that had been published was retracted. Bezwoda left his university and went into private practice; he was never punished legally.
This was probably the largest case of fraud in the history of medical oncology. It sounded the death knell for autologous BMT for breast cancer. Before it was over, more than 40,000 women with breast cancer underwent the procedure. Many institutions had to revamp their plans for future treatments going forward.
The National Cancer Institute revised its methods for monitoring ongoing trials. trial sites and patient data. It also reinforced the power of the insurance companies to demand randomized trials or other evidence before they would reimburse. (David Eddy is credited with coining the term “evidence-based medicine.”) If you think insurance companies are issuing many denials for physician prescriptions or recommendations, at least part of that stems from this deception.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.