An expert panel of 10 international cancer researchers and practicingoncologists met in Boston to discuss the past, present, and future usesof antiestrogens in the treatment of breast cancer.
BOSTON--When epidemiologic tools are used to dissect clinical trialresults, potential biases abound, said panel member Robert W. Morgan, MD,an epidemiologist and president of Environmental Health Strategies, MenloPark, Calif.
"Epidemiology is a blunt instrument and delivers rough justice,"he said, so that small increases in risk found by epidemiologic methodsmay not be meaningful, as appears to be the case in the analyses of endometrialcancer 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 studiesabout the risk of second cancers in women taking tamoxifen therapy. Thesame problems can apply to case-control studies, he added. The possiblebiases are:
- Post hoc design. The original tamoxifen studies were designedto look at efficacy, not at endometrial cancer risk, so that all the necessarydata to analyze a possible relationship were not collected. The studieslooking at a possible relationship of tamoxifen and endometrial cancerwere designed after the fact.
- Surveillance bias. "Any time you have a group of peopleunder study, they will report an increased rate of almost any disease imaginable,"Dr. Morgan said.
- Ascertainment bias. This is the likelihood of diagnosing a preexistingdisease through increased medical surveillance. At least two of the cohortstudies have shown that women in the tamoxifen arm have triple the rateof gynecological exams as the control group. "If you're tripling therate of examination, then you are more likely to find the underlying tumorsif they are there," he said.
- Patient compliance problems. In many of these studies, it wasfound that not all patients in the study group actually received tamoxifenand that some control patients did manage to get the drug.
- Latency issues. Endometrial cancer can exist in a latent, subclinicalphase for many years, Dr. Morgan said. When endometrial cancers are foundjust a few months after initiation of tamoxifen treatment, "it seemsagainst 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 womenwith breast cancer without regard as to whether they are enrolled in atrial, 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 apparentrelative odds and relative risk of endometrial cancer attributed to tamoxifen.
In his review of 18 studies of endometrial cancer risk in tamoxifentrials, Dr. Morgan found that only two showed any significant increasedrisk for tamoxifen users. "And in both these studies, the magnitudeof 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 asinfinity, depending on which set of controls were used as a comparisongroup.
The NSABP researchers used three comparison groups: the nontamoxifencontrol group within the study (which had no endometrial cancers, promptingthe investigators to seek other comparison groups); a control group fromanother 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 cancershare a common epidemiology, women who have had breast cancer are alreadyat increased risk of endometrial cancer whether or not they take tamoxifen.
Thus, much of the increased risk seen when the incidence of endometrialcancer in tamoxifen users was compared with that of the general populationfrom 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, dependingon which assumptions the investigators made, "whether you throw outthe people who did not have true cancer, whether you include people whonever received the drug and cross over the controls who did take it,"he said.
Furthermore, in both of these studies, many of the endometrial cancercases were reported within the first 2 years after tamoxifen therapy began."This short latency period makes it implausible that tamoxifen isthe primary cause, although the data are compatible with tamoxifen eitherpromoting an existing tumor or producing changes such as bleeding thatlead to diagnosis," he said.
Dr. Morgan ended with the plea that investigators plan clinical studieswith epidemiologic concerns in mind from the beginning. This would includeclose monitoring of patient compliance, to make sure patients are not crossingover to the other side of the trial, and data on confounders such as useof ERT.