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In screening pharmaceuticals for possible carcinogenic effects we noted an association between lip cancer risk and the photosensitizing antihypertensive drugs hydrochlorothiazide (HCTZ) and nifedipine. Here we further characterized risk of lip cancer associated with these and other commonly used antihypertensive drugs.
In a comprehensive medical care program we ascertained prescriptions dispensed and cancer occurence from August 1994 to February 2008. We identified 712 patients with lip cancer (cases) and 22,904 age, sex, and cohort year of entry-matched comparison subjects (controls) in the susceptible group, non-Hispanic whites. We determined their use at least two years before diagnosis or control index date of the commonly prescribed diuretics, HCTZ and HCTZ combined with triamterene (HCTZ/TR), the angiotensin-converting-enzyme inhibitor lisinopril, the calcium channel blocker nifedipine, and the beta adrenergic blocker atenolol, the only non-photosensitizer studied. We analyzed use of each drug both exclusively and regardless of use of others, and focused on duration of use. Analysis employed conditional logistic regression for matched case-control sets with control for cigarette smoking.
At least a five-year supply yielded the following odds ratios, respectively, compared to no use: HCTZ: 4.22 (2.82–6.31); HCTZ/TR: 2.82 (1.74–4.55); lisinopril: 1.42(0.95–2.13); nifedipine 2.50 (1.29–4.84); atenolol: 1.93 (1.29–2.91). When the other drugs were excluded the odds ratios for atenolol were reduced to 0.54 (0.07–4.08).
These data support an increased risk of lip cancer in non-Hispanic whites treated for hypertension with long term use of photosensitizing drugs.
In screening pharmaceuticals for possible carcinogenic effects, we found an increased risk of cancer of the lip in persons who received three or more prescriptions of the diuretic, hydrochlorothiazide (HCTZ), and the calcium channel blocker, nifedipine 1. A causal relationship is biologically plausible since sun exposure is an established risk factor for lip cancer 2 and hydrochlorothiazide and nifedipine are photosensitizers 3,4. For the present study we conducted more extensive analyses of the risk of lip cancer in relation to HCTZ, nifedipine, and the following commonly used antihypertensive drugs: the combination of HCTZ with triamterene, a potassium sparing diuretic (HCTZ/TR), lisinopril, an angiotensin converting enzyme (ACE) inhibitor, and atenolol, a beta-adrenergic blocker. In addition to HCTZ and nifedipine, triamterene is established, and lisinopril is likely, to be a photosensitizer whereas atenolol is not recognized as such 4,5. Associations were analyzed by number of prescriptions received and duration of use of the drug with adjustment for cigarette smoking, a known lip cancer risk factor.
The study cohort consists of subscribers of the Kaiser Permanente Medical Care Program (KPMCP) in northern California during the period August 1994, when all of the program’s pharmacies had begun computer-storage of dispensed prescriptions, through February 2008. KPMCP is a comprehensive integrated health care program. The population served is centered around the San Francisco Bay Area and Central Valley of California. The membership is currently about 3.2 million and is ethnically and socioeconomically diverse with some under-representation of persons at the highest and lowest ends of the economic spectrum 6. The target cohort is the over 90 percent of subscribers with at least partial coverage of payment for prescriptions. Ascertainment of cancer including lip cancer is through the program’s cancer registry, which contributes to the Surveillance, Epidemiology and End Results (SEER) program (http://www.seer.cancer.gov).
Case-control analyses have been performed within this cohort using conditional logistic regression implemented with the SAS system 7. In the initial screening of commonly used drugs 1, up to 50 risk-set controls 8 were randomly selected for each case, matched on age, sex, and year of entry into the cohort. Relative risk is represented by the odds ratio. The index date for cases is the date of cancer diagnosis and, for controls, the date which gives them equal follow-back time to cohort entry. Cohort entry is the date when at least partial drug coverage started if later than August 1, 1994 Duration of use of a drug is based on summing the number of days supplied recorded for each dispensed prescription in the pharmacy database. Our analyses allow for a lag period of two years so that drug exposure within two years before index date is ignored.
The drugs selected for study were, in this setting, by far the most commonly prescribed representatives of the four classes of antihypertensives listed in the program’s formulary. Diuretics, ACE inhibitors, calcium channel blockers and beta-andrenergic blockers were represented respectively by HCTZ and combined HCTZ/TR, lisinopril, nifedipine and atenolol. In the entire study cohort, the numbers of patients age 20 years and older who received three or more prescriptions for these drugs were as follows: HCTZ: 353,695, HCTZ/TR: 178,290, lisinopril: 567,620, nifedipine: 141,132, and atenolol: 415,638. Because more than one antihypertensive drug may be given to achieve adequate blood pressure control, we assessed risk associated with each of the single drug preparations, both without regard to use of the others before the index date and excluding patients who received any of the others before the index date. Triamterene alone was rarely prescribed and the combination of lisinopril and HCTZ was not prescribed frequently until the last year of case ascertainment. Therefore these preparations were not analyzed.
Organ transplantation followed by immunosuppressive drug therapy and HIV infection increase risk of lip cancer 9–12 and cases and controls with these conditions before diagnosis or index date were excluded. Race/ethnicity was determined from demographic datasets in which approximately 81% of the data was derived from either administrative systems or self-report. The remainder was imputed based on last name and census tract using the Bayesian Improved Surname and Geocoding (BISG) algorithm 13. Categories were white/non-Hispanic, white/Hispanic, Asian, African-American, other or multiracial, and unknown. We found very few cases and evidence of markedly reduced risk of lip cancer among all of the minority groups and therefore restricted the present analysis to non-Hispanic whites. Cigarette smoking status was based on computer-stored information collected at outpatient clinic visits starting in 1996. An algorithm (available from the authors on request) was applied to this information to determine as well as possible whether a person smoked at any time during the observation period between first use of the drug studied and index date, or if not, whether he or she smoked formerly or never, or whether smoking status was unknown.
This study was approved by the Institutional Review Board, Kaiser Foundation Research Institute.
In our initial screening analysis there were 812 lip cancer cases age 30 and above and 40,434 controls, or on average 49.8 controls per case. The step-by-step exclusion of organ-transplant and HIV-positive patients and persons who were not of non-Hispanic white race/ethnicity led to a final study group of 712 cases and 22,904 controls, or an average of 32.2 controls per case. The disproportionately greater loss of controls was mainly due to the relatively few non-whites and Hispanic whites among cases as compared to controls. The derivation and characteristics of subjects in the current study are shown in Figure 1 and Table 1. Almost all of the cancers were of squamous cell histology. Men predominated by about a three-to-one ratio.
The disproportionately greater exclusion of controls resulting from our race/ethnicity criteria also led to a mean age 2.4 years higher in controls than cases.
Current cigarette smokers were relatively more frequent among cases, whereas former smokers and persons with unknown smoking habits were more frequent among controls
In the four analyses of single drug use, exclusion of users of other drugs left 438 to 464 cases and 15,135 to 16,329 controls for analyses.
Three or more prescriptions were received by a higher proportion of cases than of controls for all of the drugs studied except lisinopril only and atenolol, and the excess use in cases was statistically significant except for the smaller number of single-drug-only users of HCTZ. The deficit of use of atenolol only by cases was statistically significant. (Table 2). Percentages of users of each drug regardless of use of the others were considerably larger than percentages using only that drug, indicating that many patients received more than one of these drugs (“all” vs. “only” in Table 2).
When the analysis of HCTZ was controlled for smoking habits, the results were little affected and restricting attention to users of HCTZ only made little difference (Table 3). The increased susceptibility of cigarette smokers was confirmed but reduced risk was observed in former smokers.
Findings for the other antihypertensive drugs unadjusted and adjusted for cigarette smoking are shown in Table 4. The odds ratios for smoking categories in the multivariable analyses of these drugs were very similar to those shown for HCTZ and HCTZ alone, respectively, in Table 3 (available from the authors on request). These analyses confirmed the statistically significant associations of HCTZ, HCTZ/TR, and nifedipine with lip cancer. Lisinopril’s weaker association lost statistical significance when other drugs were excluded. Atenolol was not associated with increased risk and when studied alone was associated with reduced risk.
Risk of lip cancer increased with duration of use for HCTZ, HCTZ/TR and nifedipine, with the relative risk associated with HCTZ use for over five years exceeding a four-fold increase. Risk for lisinopril was highest among those with 1–5 years of use. Risk was increased for patients who received a 5-or-more year supply of atenolol. Since this was inconsistent with the observed lack of association with atenolol already noted, the atenolol analysis was repeated excluding patients who received any of the other drugs. Cases exposed to atenolol for at least five years fell from 29 to one and the odds ratio dropped below unity (Table 5). Of the 28 cases who had received other drugs 24 had received HCTZ with or without others, 8 had received nifedipine with or without others, and 19 had received lisinopril with or without others.
We found that the commonly used photosensitizing antihypertensive drugs, HCTZ, HCTZ/TR, and nifedipine were associated with increased risk of lip cancer. Risk appeared to increase with increasing duration of use and was not explained by confounding by cigarette smoking. Non-photosensizing atenolol, when used alone, was not associated with increased risk. Findings for lisinopril, a photosensitizer, were equivocal.
Lip cancer includes malignant neoplasms of the vermilion border, commissure, and labial mucosa but excludes cancers originating on the skin of the lip 2, 14. The histology is predominantly squamous cell and most occur on the lower lip 2. Based on SEER data, the overall age-adjusted incidence in the USA in 2003–2007 was low, 0.7/100,000 per year, and the incidence in men (1.2) was four times that in women (0.3) 15. The relative protection of women has been linked to less engagement in outdoor occupations and use of lipstick and other lip-coatings 16–18. Incidence in SEER was eight-fold higher in whites (0.8) than blacks (0.1). In fact, the incidence in black women was not calculated because there were fewer than 16 cases in the five-year interval 15. We did not find published incidence data for other ethnicities. Lip cancer is usually detected and treated early and as a result, regional metastases occur in only 5–7% of cases and distant metastases in only 0.5–2.0% 19
The protection afforded by darker pigmentation and this cancer’s more frequent occurrence on the lower lip correspond with the main known risk factor, prolonged sun exposure 2,18. Although pipe smoking was believed to be a risk factor in the past, it has become quite infrequent in our setting and findings concerning cigarette smoking have varied considerably and have been considered inconclusive 2, 20, 21. Our data confirmed current cigarette smoking as a risk factor. We did not expect former smokers to have a reduced risk and can only speculate that this finding was due to chance or that persons who quit smoking also have relatively low sun exposure or some other protective characteristic. Also confirming cigarette smoking as a risk factor was that in our screening study1 the only other drug associated with lip cancer beside HCTZ and nifedipine was nicotine, mostly in skin patch form, which was prescribed as an aid to discontinuing smoking.
When we narrowed our focus to the susceptible group of non-Hispanic whites, we lost a disproportionate number of control subjects, which led to the mean age at index date of the controls being 2.4 years higher than that of the cases. Before the exclusions, the mean ages were virtually identical (cases 66.95, controls 66.84 years). This age discrepancy did not bias our results or require further adjustment because conditional logistic regression analysis bases the odds ratio on the findings within each case-plus-matched-controls risk set where the ages were matched within one year.
We were not able to adjust for sun exposure, the most important lip cancer risk factor along with relative lack of pigmentation of the lips. However, it does not seem likely that users of the antihypertensive drugs associated with lip cancer experience a great deal more sun exposure than nonusers or than users of atenolol. To account for the two- to four-fold associations observed for at least five years use of HCTZ, HCTZ/TR and nifedipine, a much greater than two- to four-fold difference in carcinogenic sun exposure would be required 22. Aside from a few self- or case-reports (http://www.ehealthme.com/ds/atenolol/photosensitivity+reaction) the absence of a scientifically established association of atenolol alone with lip cancer adds specificity to these findings and suggests that hypertension, the condition being treated, is not responsible. There may also have been uncontrolled confounding based on different characteristics of patients related to which drug was prescribed for them. Again these differences would have to be quite strongly related to risk of lip cancer to account for the associations that we observed.
Thiazide diuretics, triamterene, some ACE inhibitors and lisinopril are photosensitizing drugs 3, 4, 23–25. Photosensitizing drugs are believed to absorb energy from ultraviolet and/or visible light causing release of electrons. This leads to the generation of reactive oxygen intermediates and free radicals which damage DNA and other components of skin cells and produce an inflammatory response 24,25. The causation of squamous cell skin cancer by the treatment of psoriasis with repeated exposures to photosensitizing psoralen and ultraviolet radiation (PUVA) 26 and the association of HCTZ and other antihypertensive drugs with risk of squamous cell skin cancer 27 both support the biological plausibility of an increased risk of lip cancer due to photosensitizing antihypertensive drugs. However, another study 28 surprisingly found more evidence for an association of short-term than long-term use of photosensitizing drugs with skin cancer.
We were not able to include basal cell and squamous cell skin cancers in this study because these diagnoses have not been recorded in our cancer registry. Melanoma is also related to sun exposure, but none of the antihypertensive drugs studied screened positive for an association with this cancer in our screening study1. Melanoma has been more strongly associated with intermittent exposures, especially those producing sunburn, than with chronic exposure, so the timing of use of photosensitizing drugs could be an important consideration 29.
In the study that brought our attention to antihypertensive drugs and lip cancer our screening criteria for drug/cancer associations of interest were: odds ratio for three or more prescriptions of at least 1.5 and greater than odds ratio for one prescription, as a rough indicator of dose-response, and p <0.011. HCTZ and nifedipine met these criteria but lisinopril did not since its odds ratio was 1.36 (p=0.004) and the odds ratio for one prescription was 1.38. The findings regarding lisinopril in the present study were also weaker in that the clear positive association became only of borderline statistical significance when subjects who received other antihypertensive drugs were excluded.
One of the main reasons for the analysis of single drug exposures was the unexpected finding of a positive association five or more years of use of atenolol with lip cancer. These proved to be attributable to the associated use of the other antihypertensive drugs.
Because lip cancer is a relatively infrequent form of cancer, it is not surprising that associations with antihypertensive drugs have not been observed in large clinical trials of their efficacy. For example, 33,357 patients, mean age 66.9 years, were followed up for a mean 4.9 years in the ALLHAT study 30 About half were not non-Hispanic white and about half were women who have a lower incidence of lip cancer than white men. However, if all 33,357 were white males age 65–69 whose overall annual incidence of oropharyngeal cancer in 2003–2007 was 55.1/100,000 person-years, of which 8 percent were lip cancers15, approximately 7 lip cancers would have been expected during follow-up in all three treatment groups combined.
Although the relatively high odds ratios, the evidence for specificity and the known biological mechanism are consistent with a causal relationship, causality cannot usually be established by a single observational study such as ours. Further investigations are needed to confirm and characterize relationships between photosensitizing antihypertensive drugs and lip cancer.
Search of the clinical literature revealed considerable attention to the effects of photosensitivity on the skin 25, 31,32, some attention on its effects on the eye 33,34, but little or no attention directed toward the lips except for a listing of a few lip sunscreens in the review by Ting et al 35.
Antihypertensive drugs are commonly prescribed 36 and most are photosensitizing as are many other commonly prescribed drugs 3,4. Lip cancer is rare and an increased risk of developing it is generally outweighed by the benefits of drugs that are effective for other conditions. However, physicians prescribing photosensitizing drugs should ascertain whether patients are at high risk of lip cancer by virtue of fair skin and long-term sun exposure and discuss lip protection with them. Although not yet confirmed by clinical trials, likely preventive measures are simple: a hat with sufficiently wide brim to shade the lips and lip sunscreens.
Supported by Grant # R01 CA 098838 from the National Cancer Institute.
Presented as poster at the Bay Area Clinical Research Symposium, San Francisco, November 4, 2011
Dr. Chan has no potential conflicts of interest.
Authors’ contributions:Friedman, Asgari, Habel: Study design with modifications as analysis progressed, interpretation of results, manuscript preparation and modifications.
Warton: Data analysis with modifications in design as analysis progressed, manuscript review and modifications.
Chan: Expertise in drug usage in our setting and drug effects, which affected data analysis and interpretation. Review of manuscript.
All of the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Financial disclosures: Dr. Friedman has consulted for The Degge Group, Inc., Robinson Law Firm, Williams and Connolly Law Firm, and Allergan, Inc. None of these associations are related to, or have had any effect on the present study. Dr. Asgari and Ms. Warton have a grant from Genentech, Inc. unrelated to, and not affecting the present study. Dr. Habel’s research in the Kaiser Permanente Division of Research has received support from the following companies: Takeda, Sanofi-Aventis, Merck, and Genentech unrelated to, and not affecting the present study.