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Carcinogenicity of Depo-Provera: The Waters Are Still Muddy
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Carcinogenicity of Depo . . Provera: The Waters Are Still Muddy Beca use of confusion over the actual site of origin of tumors found in two monkeys treated with 50 times the human dose of medroxyprogesterone acetate (Depo-Provera-Upjohn), the Food and Drug Administration's scientific board of inquiry appointed a special panel to review the pathology of the monkey tissue. Their findings, though, as reported at a recent hearing, didn't help most people feel any more comfortable about making a final judgment on the drug's cancer-causing potential. As reported earlier in American Pharmacy (March 1983, p. 5), FDA regulators are caught in an odd bind with medroxyprogesterone (DMPA). The drug has already been used in an estimated 10 million women worldwide, with no observed excess of cancers or other adverse effects. Yet at the same time, there is a nagging problem in trying to analyze the human data: little systematic follow-up has been done on any defined group using the drug.
Conflicting Evidence The animal data are rife with conflicting evidence, too. The studies done in beagles, which showed a higher rate of malignancies in treated anilnals than in controls, should probably be discounted since dogs are particularly sensitive to progesterone-any excess is likely to induce bizarre tissue hyperplasias. Because interpretation of the canid and human studies remains under a cloud, a great deal has come to ride on how the findings of 10-year trials in monkeys are construed. To further confound matters, the only two monkeys in the study that developed cancer were not part of the original cohort-they were replacements for monkeys that had died at 6 months and 9 months into the study. Nonetheless, the panel of pathologists at the hearing seemed confi-
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den t enough. According to their consensus, the tumor in the first animal was "a poorly differentiated adenocarcinoma located in the corpus of the uterus ... with no microscopical evidence of involvement of the cervix." The verdict was the same for the second animal. These cond usions could be taken to mean that the tumors were not relevant to human use of DMP A, since the initiation of malignancy in the primate uterus is often triggered by the prior formation of endometrial plaques after progesterone treatment, and plaques don't develop in humans after similar treatment.
Ambiguities Persist Yet a host of ambiguities and unanswered questions persist. First, an earlier examination of the same slides by German pathologists produced the conclusion that the tumors origina ted in the cervix, and were therefore relevant to human physiology. The American panel, in overturning the decisions of their German colleagues, ascribed the differences in diagnosis to such factors as poor slide labeling and inadequate descrip-
tions of gross pathology. Further, the American panel noted that the tumors contained the secretory product mucin, usually a classic marker for cervical tumors, serving to differen tia te them from endometrial malignancies, which do not produce the substance. But adenocarcinoma, the specific type of malignancy determined by the panel to have been present in the monkeys, is also characterized by mucin-secreting cells. For this reason, pathologists recognize that there is a wide margin of error in classifying these kinds of tumors: 20 % of endocervical cancers look like endometrial cancers; conversely, 5 0/0 of endometrial cancers look like endocervical neoplasms. So the whole hearing, which had something of the atmosphere of a party because of Upjohn's open exultation about the panel's findin gs, I may have been but a tempest in a teapot. It seems that the final answer to the question of the relative safety of DMP A will only come from well-designed new trials in humans, or rigorous statistical manipulation of the da ta already on file .
FDA special panel reports on its Depo-Provera findings. American Pharmacy Vol. NS23, No. 11 , November 1983/554
Carcinogenicity of Depo . . Provera: The Waters Are Still Muddy Beca use of confusion over the actual site of origin of tumors found in two monkeys treated with 50 times the human dose of medroxyprogesterone acetate (Depo-Provera-Upjohn), the Food and Drug Administration's scientific board of inquiry appointed a special panel to review the pathology of the monkey tissue. Their findings, though, as reported at a recent hearing, didn't help most people feel any more comfortable about making a final judgment on the drug's cancer-causing potential. As reported earlier in American Pharmacy (March 1983, p. 5), FDA regulators are caught in an odd bind with medroxyprogesterone (DMPA). The drug has already been used in an estimated 10 million women worldwide, with no observed excess of cancers or other adverse effects. Yet at the same time, there is a nagging problem in trying to analyze the human data: little systematic follow-up has been done on any defined group using the drug.
Conflicting Evidence The animal data are rife with conflicting evidence, too. The studies done in beagles, which showed a higher rate of malignancies in treated anilnals than in controls, should probably be discounted since dogs are particularly sensitive to progesterone-any excess is likely to induce bizarre tissue hyperplasias. Because interpretation of the canid and human studies remains under a cloud, a great deal has come to ride on how the findings of 10-year trials in monkeys are construed. To further confound matters, the only two monkeys in the study that developed cancer were not part of the original cohort-they were replacements for monkeys that had died at 6 months and 9 months into the study. Nonetheless, the panel of pathologists at the hearing seemed confi-
6
den t enough. According to their consensus, the tumor in the first animal was "a poorly differentiated adenocarcinoma located in the corpus of the uterus ... with no microscopical evidence of involvement of the cervix." The verdict was the same for the second animal. These cond usions could be taken to mean that the tumors were not relevant to human use of DMP A, since the initiation of malignancy in the primate uterus is often triggered by the prior formation of endometrial plaques after progesterone treatment, and plaques don't develop in humans after similar treatment.
Ambiguities Persist Yet a host of ambiguities and unanswered questions persist. First, an earlier examination of the same slides by German pathologists produced the conclusion that the tumors origina ted in the cervix, and were therefore relevant to human physiology. The American panel, in overturning the decisions of their German colleagues, ascribed the differences in diagnosis to such factors as poor slide labeling and inadequate descrip-
tions of gross pathology. Further, the American panel noted that the tumors contained the secretory product mucin, usually a classic marker for cervical tumors, serving to differen tia te them from endometrial malignancies, which do not produce the substance. But adenocarcinoma, the specific type of malignancy determined by the panel to have been present in the monkeys, is also characterized by mucin-secreting cells. For this reason, pathologists recognize that there is a wide margin of error in classifying these kinds of tumors: 20 % of endocervical cancers look like endometrial cancers; conversely, 5 0/0 of endometrial cancers look like endocervical neoplasms. So the whole hearing, which had something of the atmosphere of a party because of Upjohn's open exultation about the panel's findin gs, I may have been but a tempest in a teapot. It seems that the final answer to the question of the relative safety of DMP A will only come from well-designed new trials in humans, or rigorous statistical manipulation of the da ta already on file .
FDA special panel reports on its Depo-Provera findings. American Pharmacy Vol. NS23, No. 11 , November 1983/554