Epidemiologic Evaluation of Pharmaceuticals With Limited Evidence of Carcinogenicity

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Int J Cancer. Author manuscript; available in PMC 2010 November 1.
Published in final edited form as: Int J Cancer. 2009 November 1; 125(9): 21732178. doi:10.1002/ijc.24545.
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Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity

Gary D. Friedman, Sheng-Fang Jiang, Natalia Udaltsova, Charles P. Quesenberry Jr., James Chan, and Laurel A. Habel Division of Research, Kaiser Permanente Medical Care Program, Oakland, California
Abstract
Thorough review by the International Agency for Research on Cancer (IARC) has resulted in classifying many substances, including pharmaceuticals, as probably or possibly carcinogenic to humans, based on experiments on animals or limited data on humans. We evaluated nine such pharmaceuticals for evidence of carcinogenicity in patients receiving them in a large medical care program with automated pharmacy records and a cancer registry. Nested case-control analyses were performed in a cohort of 6.5 million subscribers with up to 12 years of follow-up, focusing on cancer sites suggested by previous evidence and other sites with odds ratio of at least 1.50, p < 0.01, and some evidence of dose-response.. Unmeasured confounding was estimated in sensitivity analyses. We found some supportive evidence for carcinogenicity of griseofulvin, metronidazole, and phenytoin and for the known carcinogen, cyclophosphamide, which was added for validation of our data and analyses. Findings for chloramphenicol, iron-dextran complex, phenoxybenzamine, and phenobarbital were essentially non-contributory. Confounding by cigarette smoking and prior thyroid disease could account, respectively, for associations of oxazepam with lung cancer and propylthiouracil with thyroid cancer. Although not definitive, these findings should be considered in the evaluations of these pharmaceuticals.
Keywords pharmacoepidemiology; pharmaceuticals; cancer Based on reviews of scientific and medical literature by expert committees, the International Agency for Research on Cancer (IARC) has conducted extensive evaluations of pharmaceuticals and other chemicals for carcinogenic effects in humans (17). Because evidence on humans has been limited or carcinogenicity has been demonstrated only in experimental animals, many of these substances have been judged to be probably or possibly, but not definitely carcinogenic (8).
Corresponding author: Dr. Friedman, Address: Kaiser Permanente Division of Research, 200 Broadway, Oakland, CA 94612, USA, Phone: 510 891 3542 Fax: 510 891 3606 gdf@dor.kaiser.org. Novelty/Impact: After extensive review of the evidence, the International Agency for Research on Cancer has classified several drugs as possibly or probably carcinogenic. We have evaluated the cancer risk of nine of these drugs as used in a large medical care program. Disclosures: Dr. Friedman served on an advisory committee to Roche Laboratories in June, 2008 and in the past 3 years has consulted for law firms serving both plaintiffs and Ortho-McNeil-Janssen Pharmaceuticals regarding litigation concerning celecoxib and OrthoEvra, respectively. During the last 5 years, Dr. Habel has had research support through contracts with Kaiser Foundation Research Institute from Eli Lilly, Inc; Genomic Health, Inc; Takeda; Merck; AviaraDx; Genentech; and Roche. None of these sponsors or associated firms had any role in this manuscript; they did not sponsor the research, have any role in its study design, data collection, analysis, interpretation of results, or drafting.
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Data concerning prescription dispensing and cancer occurrence in a comprehensive integrated medical care organization has made it possible to analyze several of these pharmaceuticals for associations with subsequent cancer incidence, to provide additional information on possible carcinogenic effects in humans. We here report findings on: chloramphenicol, griseofulvin, iron-dextran complex, metronidazole, oxazepam, phenobarbital, phenoxybenzamine, phenytoin, and propylthiouracil. The anti-retroviral drug, zidovudine was excluded because HIV patients are at risk for several cancers due to immunosuppression and other factors (9.10) and anti-retroviral drugs are being studied much more intensively at this institution (personal communication, Michael Silverberg). We did not have sufficient data for meaningful results on the other drugs and excluded 5methoxypsoralen because our cancer registry does not record non-melanoma skin cancers. Although judged definitely carcinogenic to humans by IARC, we included cyclophosphamide, which served as a test of our ability to detect definite carcinogenicity. These analyses are part of a surveillance program and, although not definitive studies, they can suggest the need for them or can provisionally indicate some lack of evidence for carcinogenicity in humans.
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Setting
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The study setting is the Kaiser Permanente Medical Care Program in northern California (KPMCP). The KPMCP is an integrated prepaid health care delivery system that provides comprehensive inpatient and outpatient care, including pharmacy services to over 3 million current members, who comprise about 30 percent of the residents of the areas served surrounding San Francisco Bay and in the Central Valley. The membership is fairly representative of the local population except for some under-representation of both extremes of the economic spectrum (11). Reflecting their local communities, the members are ethnically diverse. In the 2005 Member Health Survey (http://www.dor.kaiser.org/dor/mhsnet/public/pdf_05_public/mhs05reg-html_e.htm) adults age 20 years and older were: 62% white non-Hispanic, 17% Asian non-Hispanic, 12% Latino/Hispanic, 6% African-American, and 3% other ethnicities. Pharmaceuticals Ascertainment of pharmaceutical use was based on the programs Pharmacy Information Management System (PIMS), which records all prescriptions dispensed to outpatients. Surveys of subscribers with drug coverage, i.e., at least partial payment for prescriptions by KPMCP, indicate that they fill nearly 100% of their prescriptions at KPMCP pharmacies (12). A total of 6,465,309 KPMCP subscribers with drug coverage during the period of study, defined below, were identified and constitute the study cohort. The numbers of recipients of each drug studied are shown in Table 1. The classes and indications for the drugs studied are as follows: chloramphenicol antibacterial, now just used topically in our setting, mainly as eye drops; cyclophosphamide cancer chemotherapy and for auto-immune conditions and immune suppression in organ transplant patients; griseovulvinanti-fungal; iron-dextran complexinjected for iron deficiency anemia; metronidazoleanti-infective used to treat protozoal and susceptible anaerobic bacterial infections; oxazepamtranquillizer; phenobarbitalsedative, hypnotic and anti-convulsive; phenoxybenzamineanti-adrenergic used to treat pheochromocytoma and hypertensive crisis; phenytoinanti-convulsive; propylthiouracilanti-thyroid drug. These drugs are available only by prescription in our program.
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Cancer occurrence Occurrence of invasive cancer, plus non-invasive cancers of the urinary bladder, was ascertained through KPMCPs Cancer Registry, which covers all subscribers and contributes to the local Surveillance, Epidemiology, and End Results (SEER) program (13). The period of study for both prescription dispensing and cancer occurrence was from August 1994, when PIMS was implemented in all facilities, through June 2006. Altogether there were 131,743 patients with at least one incident cancer in this database. The numbers of patients with cancer at each site included in this report are shown in Table 2. We grouped cancers of the tongue, floor of mouth, gum, tonsil, oropharynx, hypopharynx, and other oral/pharynx into one category, mouth/pharynx and analyzed cancers of the lip, tonsil and nasopharynx each as separate sites. The index date for analysis was the date of first diagnosis of the cancer of interest. Control selection For each of the case-patients, ten control subscribers free of the cancer of interest on the date of the cases diagnosis were randomly selected from all of the programs subscribers of the same sex, same year of birth and same year of starting drug coverage. Controls were not excluded if they developed the same cancer later and they could be included more than once for different cancer cases but not for the same case. Fewer than ten matched controls could be found for some very elderly cancer patients. For example, three women, age 99, 100, and 101 years at breast cancer diagnosis, could be matched with only 2, 8, and 3 controls, respectively. The index date for controls was the date in the same year as their matched cases diagnosis, which provided equal follow-back time. Analyses For these analyses we used a nested case-control approach with risk-set controls (14). The odds ratio of cancer at 56 sites including unspecified and all cancers combined was estimated by conditional logistic regression using the SAS system (15). The three comparisons made were: any use vs. no use before index date, any use vs. no use at least two years before index date to rule out pre-diagnostic prescribing for symptoms possibly related to cancer (2-year lag), and one, two, and at least three prescriptions dispensed vs. no use to ascertain possibly greater risk for longer use. Statistical significance is claimed for odds ratio estimates if their 95% confidence intervals do not overlap 1.0. The findings presented for the cancer sites previously associated with the drugs based on animal experiments and/or limited data in humans (Table 3) are for two-year lag and three or more prescriptions dispensed. To reduce the probability of false positive findings due to chance or confounding, for a newly associated site to be presented (Table 4) the two-year lag/three or more dispensings odds ratio had to be at least 1.50, with p < 0.01, and greater than the odds ratio for one dispensing as some indication of dose-response. The matching variables, age, sex, and length of time with drug coverage in the program, were the only characteristics available on the entire study population. Increased risk of cancer of the anus and other skin (sometimes Kaposis sarcoma) was noted for cyclophosphamide and metronidazole. Since HIV-positive patients are at increased risk for these cancers, analyses for these two drugs were repeated excluding 1) any case-control sets with cases listed in the programs HIV registry and 2) any controls so listed regardless of set. Sensitivity analysis Due to our inability to control for most cancer risk factors we conducted sensitivity analyses, using the method of external adjustment of Schneeweiss (16), to estimate bias in our risk
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estimates that might be due to unknown and uncontrolled confounding. The method requires specification of the risk of cancer associated with the confounder, the prevalence of the confounder and of users of the drug in the study population, and the strength of association between the confounder and the drug. Since this method allows adjustment for only a single variable, we assumed that confounding from all sources combined entailed a dichotomy of cancer risk in our subjects, ranging in risk ratios from 3.0 to 0.33. Compared to weaker associations with cancer, these two values had the most effect and were used to set upper and lower sensitivity analysis limits on the odds ratio. When the prevalence of the increased/ decreased cancer risk subgroup was set at 10%, 25% and 50%, we found that 25% for positive confounding and 50% for negative confounding yielded the largest change in the observed odds ratio and they were used to set the sensitivity limits. The odds ratio for the association of use of the drug with the subgroup was set at 2.0. Varying the prevalence of use of the drug in the population between 10% and 0.1% produced virtually the same result; 1% was used here. The spreadsheet program (available for downloading at www.drugepi.org) generates the percent bias under these various assumptions, which is applied to the observed odds ratio. For example, if the percent bias is +10% and the observed odds ratio is 1.50, the adjusted odds ratio is 1.50/1.10 = 1.36. With the assumptions used, the percent bias was always approximately 20.0% for positive confounding and 16.8% for negative confounding, which is equivalent to decreasing/increasing the odds ratio by approximately 16.8%. When positive associations were noted with lung cancer, we accounted for the possibility that cigarette smoking might be a confounder and applied a 10-fold, instead of the 3-fold, positive confounder-cancer relationship to set the lower sensitivity limit for that site, which decreased the odds ratio by 41.6%.
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Griseofulvin
Chloramphenicol Because of past concerns about its causing aplastic anemia and leukemia (8) this antibiotic was prescribed almost exclusively in topical form, mostly to apply to eyes or ears. No cancer sites showed positive associations that met our criteria for reporting of screening analyses. One case of myeloid leukemia was observed among recipients of just one prescription of chloramphenicol after two years of lag, yielding a non-significant odds ratio with wide confidence interal, 2.00 (0.2317.12). There were none after more than one prescription. Cyclophosphamide Two cancers for which carcinogenicity in humans has been established (2), that of urinary bladder and non-lymphocytic leukemia showed positive findings (Table 3. Non-Hodgkin lymphoma, and all cancers combined also showed notable associations with this drug (Table 4). We were able to ascertain the indications for cyclophosphamide prescriptions from computer storage for about half of the site-specific patients in the tables and none had received it for the associated cancer. The only notable effect of excluding subjects in the HIV registry was to delete the two cases with anal cancer, both after two prescriptions, and thus any findings for this site.
Of the previously-reported cancer sites, increased risk for breast cancer noted previously in this setting (17) was confirmed, but increased risk for liver cancer and thyroid cancer were not. However, the small number of cases and wide confidence intervals did not provide reliable evidence against those associations (Table 3). No other sites met our screening criteria.
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Iron-dextran complex No soft-tissue cancers (2) were observed among the 1,042 recipients and no other sites met our screening criteria. Metronidazole Several sites, both previously suspected (8) (Table 3) and unsuspected (Table 4) were positively associated. Removing subjects listed in the HIV registry, reduced moderately the associations with anal cancer but had virtually no effect on the odds ratios for other sites. The odds ratio (95% confidence interval) for anal cancer among HIV-free subjects became 1.94 (1.023.69) based on 12 cases, compared to 2.39 (1.334.30) (Table 4) based on 15 cases but still met our screening criteria Oxazepam Positive associations were noted for the suspected cancer sites, liver and thyroid, but these were not statistically significant (Table 3) Screening other sites yielded an association with lung cancer (Table 4). Phenobarbital This drug was studied in its pure form, not in commonly prescribed mixtures such as phenobarbital and belladonna. No statistically significant associations were noted with cancers of the previously suspected sites, gallbladder, lung, ovary, and brain (6,8).. Our previous finding of reduced risk for urinary bladder cancer (8) was neither well-supported nor contradicted; the odds ratio (95% confidence interval) for three or more prescriptions, two-year lag, was 0.91 (0.621.34). An association with cancer of the small intestine was noted on screening (Table 4). Phenoxybenzamine The previously suspected association with lung cancer (1) did not receive statistically significant confirmation but risk appeared elevated and there were few cases. There were no cases of the previously suspected peritoneal cancer (1). No other sites met our screening criteria. Phenytoin Previously reported associations were confirmed for cancers of the esophagus, liver, lung and lymphocytic leukemia, but not for breast cancer or non-Hodgkin lymphoma (4,8). A positive association was noted with brain cancer (Table 4).
Propylthiouracil A non-significant association with thyroid cancer (6) was noted (Table 3). Suspicion of a connection with anterior pituitary tumors (6) was not confirmed, in that no propylthiouracil user developed a cancer diagnosed as other endocrine.
Discussion
Overall perspective on our findings In view of previous evidence for at least possible carcinogenicity for each drug, no adjustment was made for multiple comparisons. However, our screening of 56 possible associations for each drug, implies that some nominally significant associations could readily be due to chance. We have tried to limit this problem by requiring an odds ratio of at least 1.50 and p<0.01 for any associations we present for sites not previously reported to be
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associated with the drugs studied. In addition, for these sites we added the dose-response criterion that the odds ratio for three or more prescription dispensings had to be greater than for one dispensing. Although this comparison never reached statistical significance in these data, it does add an additional safeguard for purposes of screening. The sensitivity analyses, based on estimated external adjustment for possible confounding by a combination of factors, did not have a substantial effect on most of these findings. However, these were rough estimates and additional confounding must be added to chance as casting doubt on the odds ratios reported here. It is notable, however, that the sensitivity limits generally fell well within the confidence limits, suggesting that chance sampling variation is of greater concern than likely confounding. The exception was the lower sensitivity limits for lung cancer, which were based on an assumed ten-fold association with cigarette smoking. Of course, it is possible that chance and confounding can both bias a finding in the same direction, adding to uncertainty. Confidence limits for the sensitivity limits can be calculated by applying the correction factors used for the odds ratio to its confidence limits (personal communication, S. Schneeweiss, as used in of (18). Although we have emphasized the possibility of false positive findings in our screening of multiple cancer sites, it should also be acknowledged that our follow-up may not be long enough or doses may be insufficient to detect real positive associations and statistical power is limited for the less common cancer sites and the less frequently prescribed drugs. Although not suspected to be as powerfully carcinogenic as cyclophosphamide, it is somewhat reassuring that griseofulvin, metronidazole, oxazepam, phenobarbital and phenytoin had been received by substantially more patients than cyclophosphamide. Another limitation of pharmacy-based evidence of drug exposure is that patients may not take all, if any, of a dispensed drug. However our focus on dispensing of three or more prescriptions would seem to minimize this problem, since patients are not likely to refill a prescription they decide not to take or continue taking. Chloramphenicol Since this antibiotic was only used topically in our setting, mostly in eye drops, its suspected causal association with leukemia was probably not adequately tested in these analyses. Cyclophosphamide Regarding our study, it is reassuring to note that the known carcinogenicity of cyclophosphamide for bladder cancer and non-lymphocytic leukemia was confirmed in these data and that we found no evidence that these and other associated cancers were the indication for treatment with this drug. Several other sites were also associated.

Griseofulvin
We confirmed the suspected link to breast cancer but no other associations were noted . There was a transient association with thyroid cancer in previous studies of a different cohort from this department (19) but it was not confirmed with longer follow-up (20,21) or in this study. Iron-dextran complex High iron stores have been reported in association with several cancer sites, including colon (8) but the absence of an association with 2-year lag in our data suggests confounding by indication, that is, treatment of colon-cancer-induced bleeding and anemia before the cancer was diagnosed. We found no previously-associated (2) soft-tissue sarcomas among the recipients of iron-dextran complex.
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Metronidazole Suspicion that metronidazole might be carcinogenic in humans was raised in studies from the Mayo Clinic (22,23), but not confirmed in our earlier data (21,24,25). Evidence after excluding known HIV positive patients did not show that HIV infection was responsible for most cancers but the odds ratio was reduced moderately for anal cancer. At least two of the associations found in screening (Table 4), anus and other skin, are more common in homosexual men, regardless of HIV status, as are amebiasis and giardiasis, two parasitic infections often treated with metronidazole. So some of the associations, but not most, may be readily attributable to confounding by indication. Surprisingly, the odds ratio was not elevated for cancer of the cervix. This cancer has long been suspected of being spuriously associated with metronidazole because metronidazole is often used to treat trichomonal vaginitis, which is correlated with multiple sex partners and therefore with HPV infection, a necessary cause of cervical cancer (8). There was weak confirmation of the suspected association with breast cancer but sensitivity analyses suggested that confounding could be responsible. Oxazepam The association with lung cancer could be due to confounding by cigarette smoking, as suggested by the sensitivity analysis (Table 4). However, receptors for drugs of this class, benzodiazepines, have been found in lung tissue (26). This drug caused benign and malignant liver tumors and thyroid adenomas in mice with evidence that it was a promoter of liver cancer development in mice and rats (4). Our data provided some support, although not statistically significant, for an effect on the thyroid gland. Phenobarbital Previous evidence from studies of humans has focused largely on a positive association with lung cancer and a negative association with bladder cancer (8). Both of these trends appeared in the present analyses but neither was statistically significant. Previously noted associations with cancer of the gallbladder and ovary (6) were not confirmed in these data. The association with brain cancer is likely to be due to confounding by indication, since this drug is used to treat seizures, often beginning more than two years before the tumor is evident, as previously noted for phenytoin (listed as diphenylhydantoin) (27). The association with cancer of the small intestine was unsuspected. Phenobarbital has long been known to be a promoter of liver tumor growth in experimental animals (6). Phenoxybenzamine There was no clear confirmation of an association with lung cancer because of the small number of cases and wide confidence interval and we found no prior users of phenoxybenzamine among the cases of peritoneal cancer. No other sites met our screening criteria. Phenytoin All of the previously suspected cancer sites except breast and non-Hodgkin lymphoma were confirmed in these data. In addition three other sites showed associations. The associations with brain and liver cancer could well be due to confounding by indication for this anticonvulsant drug. As noted for phenobarbital, the diagnosis of brain tumor could have been made long after starting treatment of seizures, and both seizures and liver cancer can occur with heavy alcohol consumption. It is less easy to explain the other sites but confounding by cigarette smoking could explain the association with lung cancer and therefore may have contributed to that with esophageal cancer.
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Propylthiouracil Both antithyroid drugs such as propylthiouracil and other non-cancerous thyroid conditions including hyperthyroidism have been suspected, but not proven, to predispose to the development of thyroid cancer (8,28). Thus, it is not possible to determine whether the positive but non-significant association we observed is causal or simply due to confounding by indication or by thyroid cancer present but not yet diagnosed. Suggesting the last possibility is the much stronger association noted for three or more prescriptionsodds ratio 8.03 (3.5018.39) based on 10 caseswhen the analysis included no lag. Further investigation is needed but it will be difficult to separate the benign diseases from their specific treatment in human studies. A possible mechanism for propylthiouracil-induced cancer is increased secretion of thyroid-stimulating hormone (28). Conclusion Although not conclusive, the evidence here adds to the suspicion that griseofulvin, metronidazole, and phenytoin are carcinogenic in humans and confirms the established link of cyclophosphamide to cancer development. There is considerable uncertainty as to whether anything new and important has been learned about chloramphenicol, iron-dextran complex, phenoxybenzamine, or phenobarbital. The evidence regarding propylthiouracil and thyroid cancer is equivocal due to the strong possibility of confounding by indication. Oxazepam was associated with lung cancer but confounding by smoking is a clear possibility. In view of previous evidence concerning oxazepams causing thyroid adenomas in mice, the positive association with thyroid cancer is interesting but not confirmatory given its wide confidence intervals.
Abbreviations
KPMCP PIMS IARC Kaiser Permanente Medical Care Program Pharmacy Information Management System International Agency for Research on Cancer
Acknowledgments
Supported by Grant R01 CA 098838 from the National Cancer Institute.
References
1. Some pharmaceutical drugs. World Health Organization, International Agency for Research on Cancer; 1980. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 2. Overall evaluations of carcinogenicity: an updating of IARC Monographs. World Health Organization, International Agency for Research on Cancer; 1987. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 3. Pharmaceutical drugs. World Health Organization, International Agency for Research on Cancer; 1990. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 4. Some pharmaceutical drugs. World Health Organization, International Agency for Research on Cancer; 1996. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 5. Some antiviral and antineoplastic drugs and other pharmaceutical agents. World Health Organization, International Agency for Research on Cancer; 2000. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 6. Some thyrotropic drugs. World Health Organization, International Agency for Research on Cancer; 2001. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.
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7. Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy. World Health Organization, International Agency for Research on Cancer; 2007. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 8. Habel, LA.; Friedman, GD. Pharmaceuticals other than hormones. In: Schottenfeld, D.; Fraumeni, JF., Jr, editors. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press; 2006. p. 489-506. 9. Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA. 2001; 285:17361745. [PubMed: 11277828] 10. Silverberg MJ, Abrams DI. AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era. Curr Opin Oncol. 2007; 19:446451. [PubMed: 17762569] 11. Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health. 1992; 82:703710. [PubMed: 1566949] 12. Selby, JV.; Smith, DH.; Johnson, E.; Raebel, MA.; Friedman, GD.; McFarland, BH. The Kaiser Permanente Medical Care Program. In: Strom, BL., editor. Pharmacoepidemiology. 4th ed. New York: John Wiley & Sons, Inc; 2005. p. 241-259. 13. Oehrli, MD.; Quesenberry, CP.; Leyden, W. Northern California Cancer Registry: 2006 Annual Report on Trends, Incidence, and Outcomes. Kaiser Permanente, Northern California Cancer Registry; 2006 November. 14. Rothman, KJ.; Greenland, S.; Lash, TL. Modern Epidemiology. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 125 15. SAS Institute Inc.. SAS OnlineDoc 9.1.2. Cary, NC: SAS Institute Inc.; 2004. 16. Schneeweiss S. Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics. Pharmacoepidemiol Drug Saf. 2006; 15:291303. [PubMed: 16447304] 17. Friedman GD, Jiang S-F, Udaltsova N, Chan J, Habel LA. Pharmaceuticals that cause mammary gland tumors in animals: findings in women. Breast Cancer Res Treat. in press. 18. Schneeweiss S, Wang PS. Claims data studies of sedative-hypnotics and hip fractures in older people: exploring residual confounding using survey information. J Am Geriatr Soc. 2005; 53:948954. [PubMed: 15935016] 19. Friedman GD, Ury HK. Screening for possible drug carcinogenicity: second report of findings. J Natl Cancer Inst. 1983; 71:11651175. [PubMed: 6581357] 20. Selby JV, Friedman GD, Fireman BH. Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res. 1989; 49:57365747. [PubMed: 2571410] 21. Van Den Eeden SK, Friedman GD. Prescription drug screening for subsequent carcinogenicity. Pharmacoepidemiol Drug Saf. 1995; 4:275287. 22. Beard CM, Noller KL, OFallon WM, Kurland LT, Dahlin DC. Cancer after exposure to metronidazole. Mayo Clin Proc. 1988; 63:147153. [PubMed: 3339906] 23. Beard CM, Noller KL, OFallon WM, Kurland LT, Dockerty MB. Lack of evidence for cancer due to use of metronidazole. N Engl J Med. 1979; 301:519522. [PubMed: 460304] 24. Friedman GD. Cancer after metronidazole [Letter]. N Engl J Med. 1980; 302:519. [PubMed: 7351980] 25. Friedman GD, Selby JV. Metronidazole and cancer [Letter]. JAMA. 1989; 261:866. [PubMed: 2913382] 26. Bribes E, Carrire D, Goubet C, Galigue S, Casellas P, Simony-Lafontaine J. Immunohistochemical assessment of the peripheral benzodiazepine receptor in human tissues. J Histochem Cytochem. 2004; 52:1928. [PubMed: 14688214] 27. Friedman GD, Ury HK. Initial screening for carcinogenicity of commonly used drugs. J Natl Cancer Inst. 1980; 65:723733. [PubMed: 6932525] 28. Ron, E.; Schneider, AB. Thyroid cancer. In: Schottenfeld, D.; Fraumeni, JF., Jr, editors. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press; 2006. p. 975-994.
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Table 1
Total numbers of recipients of each drug
Drug Chloramphenicol Cyclophosphamide Griseofulvin Iron-dextran complex Metronidazole Oxazepam Phenobarbital Phenoxybenzamine Phenytoin Propylthiouracil
Number 1,571 6,573 56,351 1,042 530,474 84,234 16,924 592 37,464 4,252
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Table 2
Total numbers of persons with cancer at any site and each site included in this report; listed in descending order of frequency.
Cancer site ANY CANCER Breast Prostate Lung, bronchus Colon Melanoma Urinary bladder Non-Hodgkin lymphoma Corpus uteri Rectum, rectosigmoid Unspecified cancer Kidney, renal pelvis No. 131,743 24,315 24,013 16,975 10,298 6,623 6,286 6,157 4,465 3,975 3,802 3,267 3,084 2,433 2,404 2,254 2,072 1,789 1,577 Cancer site Liver, intrahepatic bile ducts Myeloid leukemia Esophagus Cervix uteri Other skin Heart, soft tissue Testis Hodgkin lymphoma Larynx Anus, anal canal, anorectum Small intestine Salivary glands Peritoneum, omentum, mesentery Gallbladder Other endocrine Other leukemia Ureter Other nervous system Retroperitoneum No. 1,568 1,488 1,164 1,133 960 936 892 868 849 485 415 413 242 230 200 167 141 120 73
Pancreas Stomach Ovary Mouth, pharynx Thyroid Brain Lymphocytic leukemia
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Table 3
Findings regarding cancer sites previously associated with the drugs studied. Two-year lag, three or more dispensings.
Odds ratio (95% confidence interval) [sensitivity limits]* -2.76 (1.455.25) [2.303.22] 4.17 (1.4711.83) [3.474.87] 10.00 (1.63159.9) [8.3211.68] 0.91 (0.213.87) [0.761.06] 1.59 (1.112.27) [1.321.86] 0.50 (0.073.73) [0.420.58] -0.80 (0.660.97) [0.670.93] 0.88 (0.531.45) [0.731.03] 0.93 (0.811.06) [0.541.09] 1.13 (1.021.24) [0.941.32] 0.87 (0.520.1.47) [0.721.05] 0.59 (0.084.44) [0.490.69] 1.89 (0.546.68) [1.572.21] 1.06 (0.841.33) [0.881.24] 1.48 (0.762.89) [1.231.72] 1.68 (0.833.42) [1.401.96] 0.57 (0.074.34) [0.470.67] 1.01 (0.821.26) [0.591.18] 1.08 (0.641.82) [0.901.26] 1.15 (0.582.31) [0.961.34] --
Drug Chloramphenicol Cyclophosphamide
Cancer site Leukemia, any type Urinary bladder Myeloid leukemia Other leukemia
No. exposed cases 0 12 5 1 2 35 1 0 120 17 226 498 16 1 3 84 10 9 1 92 16 9 0
Griseofulvin
Liver, intrahepatic bile ducts Breast Thyroid
Iron-dextran complex Metronidazole
Soft tissue, heart Colon Liver, intrahepatic bile ducts Lung, bronchus Breast Cervix uteri Testis Other endocrine, thymus Non-Hodgkin lymphoma
Oxazepam
Liver, intrahepatic bile ducts Thyroid
Phenobarbital
Gallbladder Lung, bronchus Ovary Brain
Phenoxybenzamine
Peritoneum, omentum, mesentery
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Drug
Cancer site Lung, bronchus
No. exposed cases 5 15 15 126 81 27 11 3 0
Odds ratio (95% confidence interval) [sensitivity limits]* 1.62 (0.634.16) [0.951.89] 2.54 (1.444.51) [2.112.97] 1.66 (0.962.88) [1.381.94] 1.51 (1.251.82) [0.881.76] 1.02 (0.811.28) [0.851.19] 0.96 (0.651.43) [0.801.12] 1.91 (1.003.64) [1.592.23] 2.79 (0.7810.02) [2.323.26] --
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*
Phenytoin
Esophagus Liver, intrahepatic bile ducts Lung, bronchus Breast Non-Hodgkin lymphoma Lymphocytic leukemia
Propylthiouracil
Thyroid Other endocrine
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Sensitivity analysis limits: odds ratio decreased and increased by 16.8% except lung cancer decreased by 41.6% (see text for assumptions).
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Table 4
Findings regarding cancer sites newly associated with the drugs studied based on applying screening criteria to two-year lag, three or more dispensings as follows: odds ratio 1.50 and > odds ratio for one dispensing, p<0.01.
Odds ratio (95% confidence interval) [sensitivity limits]* -2.51 (1.294.88)) [2.092.93] 2.38 (1.743.26) [1.982.78] --2.45 (1.314.57) [2.042.86] 2.39 (1.334.30) [1.992.79] 2.21 (1.313.72) [1.842.58] 1.93 (1.322.84) [1.582.22] 1.54 (1.261.88) [0.901.80] 5.12 (2.3711.03) [4.265.98] -2.95 (1.735.05) [2.453.45] --
Drug Chloramphenicol Cyclophosphamide
Cancer site None Non-Hodgkin lymphoma Any cancer
No. exposed cases -11 48 --13 15 18 33 114 10 -18 --
Griseofulvin Iron-dextran complex Metronidazole
None None Salivary glands Anus, anal canal, anorectum Other skin Myeloid leukemia
Oxazepam Phenobarbital Phenoxybenzamine Phenytoin Propylthiouracil *
Lung, bronchus Small intestine None Brain None
Sensitivity analysis limits: odds ratio decreased and increased by 16.8% except lung cancer decreased by 41.6% (see text for assumptions).

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