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Position
Currently, there is no scientific evidence to support the use of high-dose chemotherapy with bone marrow or stem cell transplant for the treatment of breast cancer. Recent results from ongoing clinical trials have shown that this procedure is not more effective than standard therapy. Based on the weight of available evidence, NBCC believes that no breast cancer patient should receive high-dose chemotherapy with bone marrow or stem cell transplant unless she is participating in a randomized, controlled clinical trial. The Treatment
During the past two decades, approximately 30,000 breast cancer patients worldwide (16,000 in the US) have undergone high-dose chemotherapy with bone marrow transplant or stem cell support. This therapy involves treating a woman with extremely high doses of chemotherapy drugs. The treatment destroys the body's bone marrow, which produces essential white blood cells, red blood cells, and platelets. Therefore, oncologists must replace the patient's bone marrow once the chemotherapy has been given. This process can be done in two ways: bone marrow transplant and stem cell support.1 Hereafter, these therapies will be collectively referred to as HDC (high-dose chemotherapy). In clinical trials, the side effects of HDC included severe infections, hearing loss, nerve and heart damage -- and even death. About 15%-20% of patients who underwent this therapy in its early years died from the treatment. The mortality rate from HDC has since decreased, but the treatment is still high-risk and life-threatening.2 The Theory
Since chemotherapy drugs work by killing cancer cells, oncologists theorized that higher doses of the drugs might kill more cancer cells. In certain cancers, such as lymphomas and acute leukemia, the treatment has been shown to be highly effective. Based on this theory, some hospitals started offering HDC to women with metastatic (advanced) breast cancer.3 Early reports and non-randomized studies seemed to suggest that women who received HDC fared much better than the average patient with metastatic breast cancer. However, these results can be explained by the fact that the patients who received HDC were different from the average patient with metastatic breast cancer. Hospitals screened patients carefully, and offered the new treatment to women who were 1) already responding to standard chemotherapy (not everyone does) and 2) healthier and younger than the average patient with metastatic breast cancer. Unfortunately, based on these early and limited studies, many oncologists began to strongly recommend HDC to patients with metastatic breast cancer outside of clinical trials. Faced with the choice between standard chemotherapy and a new, allegedly promising therapy, many terminally ill breast cancer patients opted to try HDC. Eventually, women with non-metastatic, but very high-risk early breast cancer were encouraged to get the treatment as well. At $80,000 to $200,000 per treatment, hospitals, oncologists, and even private corporations brought in huge revenues from HDC. For years, many women were told that it was their only hope for survival, although no one really knew if the treatment worked better -- or worse -- than standard treatment. The Evidence
Results from five major studies showed that HDC was no more effective than standard chemotherapy treatment at reducing mortality (death rate). For detailed information about HDC research see NBCCF's Analysis of High-Dose Chemotherapy Trials. In light of all the evidence, NBCC believes that no breast cancer patient should receive HDC unless she is participating in a randomized, controlled clinical trial. The Coalition also believes that it is unethical for any physician to recommend this treatment to a breast cancer patient outside of a clinical trial. FDA Process
Why were so many women encouraged to undergo this risky and unproven therapy outside of clinical trials? One reason is the lack of government regulation. When a new drug is developed, it must be approved by the Food and Drug Administration (FDA) before it can be marketed and offered to patients. For approval, the FDA requires that an experimental drug be tested in randomized, controlled clinical trials and proven safe and effective. However, the government does not regulate the medical community's use of surgical procedures, new doses of approved drugs, or new combinations of approved drugs. Thus, treatments like HDC can be performed on patients without first being scrutinized by regulators for efficacy and safety. NBCC believes that, as in the case of experimental drugs, medical and surgical procedures must be proven both safe and effective before they are used as treatments. When patients are able to receive a new therapy outside of a clinical trial, it is very difficult to recruit them into a clinical trial. This was the case with HDC. Thus, definitive studies of HDC were delayed for many years. We would have had the answers much sooner if HDC had not been given outside of trials. Insurance Coverage
NBCC believes that health insurers were shortsighted and irresponsible when they refused to cover costs for participation in clinical trials for HDC. This refusal discouraged women and their physicians from participating in these trials, thus prolonging the debate about their effectiveness, and encouraging women and their physicians to use this intervention despite the lack of scientific evidence. NBCC agrees with the decision by a major health insurance carrier to cover the costs only within clinical trials. The Coalition supports this decision for a number of reasons. First, the decision to deny coverage for HDC outside of quality clinical trials was based on the lack of evidence supporting the efficacy and safety of HDC for breast cancer patients. Second, this decision is an important step away from viewing HDC as an acceptable treatment for breast cancer. And third, this decision should encourage expanding support of clinical trials by third-party payers, which is crucial to finding the answers to breast cancer. Evidence-Based Medicine
NBCC is committed to evidence-based medicine. Hospitals and the oncology community should recognize that they have a financial stake in HDC, and may not be in a position to make unbiased assessments of the research and of the future use of this treatment. This bias is precisely why advocates must be at the table whenever decisions are made about breast cancer research, policy, and treatment. Physicians must base their medical practice on the highest level of available evidence from randomized, controlled clinical trials. It is unethical to tell a terminally ill patient that her life depends on a treatment when there is only limited and flawed data available on the efficacy of that treatment. Instead physicians should explain what is known and not known, and they should encourage participation in clinical trials. Conclusion
NBCC is keenly aware that because there is no cure for breast cancer, patients are often forced to make treatment decisions under circumstances in which there is no best answer and hope is paramount. Yet NBCC remains committed to evidence-based medicine and understands that more care is not always better care. Breast cancer patients need and deserve health care that works, and access to a wide range of well-designed and efficiently run clinical trials that help us learn what treatments are most effective. NBCC does not want women to risk their lives or health -- or limited resources -- on treatments that are unproven. About NBCCF
The National Breast Cancer Coalition Fund is a grassroots organization dedicated to ending breast cancer through the power of action and advocacy. The Coalition's main goals are to increase federal funding for breast cancer research and collaborate with the scientific community to implement new models of research; improve access to high quality health care and breast cancer clinical trials for all women; and expand the influence of breast cancer advocates in all aspects of the breast cancer decision making process.
NBCCF's Analysis of High-Dose Chemotherapy Trials In 1999, the results of five randomized trials on HDC4 in breast cancer patients were presented at the annual meeting of the American Society of Clinical Oncology (ASCO). One of these studies, a South African trial,5 was invalidated because it was discovered that the researchers falsified the data. The results of the four remaining trials are summarized below, along with another trial that was published in a scientific journal. Trials involving patients with metastatic breast cancer - The Philadelphia Bone Marrow Transplant Group initiated a trial that randomized 199 women to receive either HDC or standard chemotherapy.6 After a median follow-up of three years, the survival rate was 32% in the HDC group and 38% in the standard treatment group. Although survival was higher with standard treatment, the difference was not statistically significant. One woman died from HDC, and no women died from standard chemotherapy. There was no difference in time to cancer progression between the two treatment groups.
- A randomized French trial compared HDC to standard therapy and followed 61 women for a median of 5 years.7 This study was small. The survival rates were 29.8% in the HDC group 18.5% in the standard chemotherapy group. Although survival was higher in the HDC group, the difference was not statistically significant. After three years, the relapse rate was higher in the standard treatment group, but, after five years, the relapse rates were the same. Neither therapy caused any deaths.
Trials involving high-risk breast cancer patients (early breast cancer that has spread to at least 10 lymph nodes) - One group of researchers studied 783 women who were randomized to receive either HDC or standard chemotherapy treatment.8 All women received radiation therapy, and all women who were hormone receptor-positive were given tamoxifen. After a median follow-up of three years, the survival rates of the two groups were similar - 78% in the HDC group and 80% in the standard treatment group. There were fewer breast cancer relapses in the HDC group. However, 29 women died from the HDC treatment and no women died from the standard treatment. This study is scheduled to continue for another 3 years, and survival rates will be re-evaluated at that point.
- In a Scandinavian trial, 525 women were randomized to receive HDC or chemotherapy at doses 'tailored' according to each patient's blood count.9 Thus, the comparison group in this trial actually received doses of chemotherapy that were higher than standard chemotherapy doses. All women received radiation therapy and tamoxifen. After a median follow-up of 20 months, there were more deaths and relapses in the HDC treatment group than in the 'tailored' chemotherapy group. In the 'tailored' treatment group, 55 relapses and 15 deaths occurred, while in the HDC group, there were 78 relapses and 25 deaths. Two deaths were caused by HDC treatment, and there were 8 cases of myloid leukemia and myelodysplastic syndrome (a precursor to leukemia) in the 'tailored' arm.
- Researchers at the University of Texas randomized 78 women to receive either HDC or standard treatment.10 This study was small. All women received radiation therapy, and all women who were hormone receptor-positive were given tamoxifen. After three years, the survival rate in the HDC group was 58%, compared to 77% percent for the standard chemotherapy group. This difference was not statistically significant. There was greater morbidity (sickness) in the HDC group and one death was caused by the treatment.
All five of the above studies found that HDC was no more effective than standard chemotherapy treatment at reducing mortality. Footnotes
1In bone marrow transplant, bone marrow is taken from the patient before the treatment (autologous transplant) and returned after the chemotherapy has been given. Bone marrow can also be donated from another person (allogeneic transplant) and transplanted into the patient after treatment, however this type of transplant is rare and more risky. In stem cell support, stem cells are taken from the patient before the treatment and returned after the chemotherapy has been given. Stem cells are found in the blood and can restore bone marrow function. 2In recent clinical trials, approximately 1% of patients who received HDC died from the treatment while no patients who received standard chemotherapy died from the treatment. 3With standard chemotherapy, patients with metastatic breast cancer have a very poor prognosis for survival; they and their doctors are more willing to try experimental treatments. 4HDC is defined here as of high-dose chemotherapy with bone marrow transplant or stem cell support in breast cancer patients. 5Bezwoda WR. Randomised, controlled trial of high dose chemotherapy (HD-CNVp) versus standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Proc ASCO 1999;18 (abstr 4). 6Stadtmauer 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 2000;342(15):1069-76. 7Lotz JP, Cure H, Janvier M, et al. High-dose chemotherapy (HD-CT) with hematopoietic stem cells transplantation (HSCT) for metastatic breast cancer (MBC): results of the French portocol PEGASE 04. Proc ASCO 1999;18 (abstr 161). 8Peters WP, Rosner G, Vredenburgh J, et al. A prospective, randomized comparison of two doses of combination alkyating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc ASCO 1999;18 (abstr 2). 9The Scandinavian Breast Cancer Study Group 9401. Results from a randomized adjuvant breast cancer study with high-dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose esculated and tailored FEC therapy. Proc ASCO 1999;18 (abstr 3). 10Hortobagyi GN, Buzdar AU, Theriault RL, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92(3):225-33. |
