BETHESDA, Md--The Oncologic Drugs Advisory Committee (ODAC) has concluded that the Breast Cancer Prevention Trial (BCPT) was a risk-reduction and not a prevention trial. The panel specifically rejected the word prevention in recommending that the Food and Drug Administration approve Nolvadex (tam-oxifen citrate, Zeneca Pharmaceuticals) for "reducing a risk of breast cancer" in otherwise healthy women at high-risk of developing the disease. The drug is currently approved as adjuvant therapy for early and advanced breast cancer.
Zenecas request, the first ever for approval of a cancer prevention drug, propelled ODAC into unknown terrain, and its members clearly felt the responsibility. Risk is not disease, noted panel member Richard M. Simon, DSc, chief of the National Cancer Institutes Biometric Research Branch, and while relatively few healthy women would benefit from prophylactic Nolvadex, all who took it would face a danger of developing its serious side effects. "That is why prevention is different from treatment," he said.
During a lengthy hearing, ODAC members praised the BCPTs design and analysis. But they wrestled with whether BCPT showed prevention; debated two European studies that found no significant preventive effect for Nolvadex; and urged the FDA, if it granted Zenecas supplemental new drug application, to ensure an extensive patient-education effort and monitoring of women taking the drug.
George Sledge, MD, an ODAC consultant, said it was quite reasonable to question whether the BCPT data actually showed prevention. "I think doctors and patients should be allowed to decide this issue on an individual basis," said Dr. Sledge, professor of medicine and pathology, Indiana Cancer Pavilion, Indianapolis. "Having said that, I am tremendously concerned about how [Nolvadex] is going to be used." So were several advocacy groups that opposed Nolvadexs approval, including the Cancer Support Community, SHARE, the Center for Medical Consumers, and a Canadian group, Breast Cancer Action, Montreal.
Cindy Pearson, executive director of the National Womens Health Network, expressed concern that practicing physicians would fail to assiduously assess their patients risks and that Nolvadexs approval would lead to direct advertising of the drug to consumers. "Busy doctors are going to respond to womens desires," she said.
Other groups voiced their support at the meeting. Carolyn Aldige of the Cancer Research Foundation of America, called the ODAC hearing a landmark event. "We believe the compelling results of BCPT warrant approval," she said. "Approval will mean that patients and physicians will not have to seek the drug off-label."
The BCPT Data
Zeneca relied on the BCPT to support its application. Joseph Costantino, DrPH, associate director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), reviewed the findings (recently published in JNCI). BCPT randomized 13,388 women--6,681 to drug and 6,707 to placebo--for a 5-year study, primarily to evaluate Nolvadexs efficacy in preventing invasive breast cancer.
Researchers terminated BCPT 14 months early, in late March 1998, after an independent monitoring committee determined that women in the drug arm had a 45% reduction in breast cancer incidence, compared with the placebo group. At the time, 57% of participants had completed 4 years or more on the trial.
To enter the study, women had to be at high-risk of developing the disease. For women age 60 or older, age alone was deemed a high risk. For younger women, and depending on their age group, a combination of risks factors was used to weight risk. These included having a first-degree relative with breast cancer, the number of breast biopsies, and a history of atypical hyperplasia.
Among the key BCPT findings: 154 women on placebo developed invasive breast tumors, compared with 85 women taking Nolvadex, and 59 women on placebo developed noninvasive breast cancer, compared with 31 on the drug. The reduced incidence was seen in women in all age groups.
The study also demonstrated some significant side effects. Thirty-three women taking the drug developed invasive endometrial cancer vs 14 on placebo. Eighteen pulmonary emboli and 30 deep-vein thrombi developed in the Nolvadex arm, compared with 6 emboli and 19 thrombi in the placebo group. More women on Nolvadex developed cataracts for the first time, 540 vs 483.
"The weight of the evidence from the BCPT is substantial in comparison to the recently published preliminary findings of the two smaller and differently designed European studies," Dr. Costantino said. "Thus, women who are at higher risk as defined in BCPT should be considered as candidates for the use of tamoxifen(Drug information on tamoxifen) to prevent breast cancer."
The European Trials
FDA reviewer Susan Honig, MD, said she had examined recently published data from a study at Royal Marsden Hospital in London (2,494 women, 8 years) and the Italian Tamoxifen Prevention Study (5,408 women, 5 years), both of which failed to find a significant reduction in breast cancer incidence. [See Oncology News International, August, 1998, page 26.] She attributed the negative findings to the different populations in the three studies.
For example, Dr. Honig said, the Italian study made no effort to enroll only high-risk women, and a large percentage of the women in the English study were on hormone replacement therapy (compared with less than 2% in BCPT), and the women appear to be at lower risk than originally thought.
Trevor Powles, MD, who directed the Royal Marsden trial, agreed that the differences lay largely in different study populations. However, he expressed concern at the early termination of BCPT, which eliminated the possibility of obtaining mortality data. He suggested that had BCPT finished, the three studies together would have clearly defined Nolvadexs prevention value by 2005.
"The question is, what is the effect on a young, healthy woman going out 20 to 25 years, and we really cant address that," Dr. Powles said.
Delay or Prevention?
Several ODAC members suggested that Nolvadex may only delay the onset of invasive tumors and may not have any significant affect on mortality. Indeed, oncologist Kim A. Margolin, MD, of the City of Hope National Medical Center, Duarte, California, questioned whether anything will confer lifetime protection against breast cancer.
BCPT researchers acknowledged their data do not and cannot show improved survival in high-risk women taking the drug. Nonetheless, Norman Wolmark, MD, NSABP chair and the principal investigator for BCPT, argued his belief that the reduced incidence of invasive tumors seen with the drug will translate into improved mortality.
Dr. Wolmark said BCPT scientists will soon begin a genetic analysis to see if women with the BRCA1 and BRCA2 genes differed in their results from the overall study findings. "We will be able to determine definitely what the benefits are for women who have BRCA1 and 2 abnormalities," he said.
ODAC members also expressed concern about the ability of physicians to properly counsel healthy women about their risk-to-benefit ratio in taking Nolvadex to reduce their risk of breast cancer and the complexity of the combination of risk factors needed to determine if a women is indeed at high-risk, as defined by the BCPT study.
The committee urged an extensive education and information program to give physicians and their patients a clear understanding of how to determine whether a woman might want to take Nolvadex. "I can tell you this is absolutely essential," Dr. Sledge said.
Leslie Ford, MD, the National Cancer Institutes associate director for the Early Detection and Community Oncology Program, said that the Institute continues to refine its education materials on Nolvadexs use in high-risk women, which are available at the NCI website: www.cancertrials.nci.nih.gov.
"Weve clearly gotten the message that a special education campaign is needed," the FDAs Richard Justice, MD, told the committee.