An expert panel of 10 international cancer researchers and practicing
oncologists met in Boston to discuss the past, present, and future uses
of antiestrogens in the treatment of breast cancer.
BOSTON--When epidemiologic tools are used to dissect clinical trial
results, potential biases abound, said panel member Robert W. Morgan, MD,
an epidemiologist and president of Environmental Health Strategies, Menlo
"Epidemiology is a blunt instrument and delivers rough justice,"
he said, so that small increases in risk found by epidemiologic methods
may not be meaningful, as appears to be the case in the analyses of endometrial
cancer risk in patients enrolled in trials of tamoxifen (Nolvadex).
Dr. Morgan described six potential areas of bias in cohort studies that,
he said, severely limit our ability to gather conclusions from these studies
about the risk of second cancers in women taking tamoxifen therapy. The
same problems can apply to case-control studies, he added. The possible
- Post hoc design. The original tamoxifen studies were designed
to look at efficacy, not at endometrial cancer risk, so that all the necessary
data to analyze a possible relationship were not collected. The studies
looking at a possible relationship of tamoxifen and endometrial cancer
were designed after the fact.
- Surveillance bias. "Any time you have a group of people
under study, they will report an increased rate of almost any disease imaginable,"
Dr. Morgan said.
- Ascertainment bias. This is the likelihood of diagnosing a preexisting
disease through increased medical surveillance. At least two of the cohort
studies have shown that women in the tamoxifen arm have triple the rate
of gynecological exams as the control group. "If you're tripling the
rate of examination, then you are more likely to find the underlying tumors
if they are there," he said.
- Patient compliance problems. In many of these studies, it was
found that not all patients in the study group actually received tamoxifen
and that some control patients did manage to get the drug.
- Latency issues. Endometrial cancer can exist in a latent, subclinical
phase for many years, Dr. Morgan said. When endometrial cancers are found
just a few months after initiation of tamoxifen treatment, "it seems
against common sense to attribute these to tamoxifen," he said.
- Lack of data concerning estrogen replacement therapy (ERT).
Although ERT is not generally recommended in breast cancer patients, Dr.
Morgan said that it is being prescribed on a fairly regular basis for women
with breast cancer without regard as to whether they are enrolled in a
trial, and "virtually none of these studies have good data on ERT,
which, I believe, is a major confounder of the findings."
The effect of each of these biases, he said, is to increase the apparent
relative odds and relative risk of endometrial cancer attributed to tamoxifen.
In his review of 18 studies of endometrial cancer risk in tamoxifen
trials, Dr. Morgan found that only two showed any significant increased
risk for tamoxifen users. "And in both these studies, the magnitude
of the risk depends on how you look at it," he said. For example,
in NSABP B-14, the relative risk ranged from as low as 2.1 to as high as
infinity, depending on which set of controls were used as a comparison
The NSABP researchers used three comparison groups: the nontamoxifen
control group within the study (which had no endometrial cancers, prompting
the investigators to seek other comparison groups); a control group from
another study; and a control group based on SEER data on cancer incidence.
The last group gave the lowest relative risk of 2.1. "And in epidemiology,
relative risks of 2 are not very high," Dr. Morgan said.
He also pointed out that since breast cancer and endometrial cancer
share a common epidemiology, women who have had breast cancer are already
at increased risk of endometrial cancer whether or not they take tamoxifen.
Thus, much of the increased risk seen when the incidence of endometrial
cancer in tamoxifen users was compared with that of the general population
from SEER data could be explained by the common epidemiology.
The other study to show a significant increase in risk (Stockholm, 1993,
reported by Fornander) gave a range of relative risk of 3 to 6, depending
on which assumptions the investigators made, "whether you throw out
the people who did not have true cancer, whether you include people who
never received the drug and cross over the controls who did take it,"
Furthermore, in both of these studies, many of the endometrial cancer
cases were reported within the first 2 years after tamoxifen therapy began.
"This short latency period makes it implausible that tamoxifen is
the primary cause, although the data are compatible with tamoxifen either
promoting an existing tumor or producing changes such as bleeding that
lead to diagnosis," he said.
Dr. Morgan ended with the plea that investigators plan clinical studies
with epidemiologic concerns in mind from the beginning. This would include
close monitoring of patient compliance, to make sure patients are not crossing
over to the other side of the trial, and data on confounders such as use