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
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,"
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
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
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