by ecancer reporter Clare Sansom

Lip cancer is a rare malignancy, and one with a good prognosis: almost 90% of those diagnosed with the disease will be alive five years later.

Like almost every cancer of the mouth and throat, it is more common in smokers and those who chew tobacco, and alcohol, HPV infection and sun exposure are also risk factors.

That last factor provides a biologically plausible explanation for the observation from pharmaceutical screening programmes that some drugs that are known to be photo-sensitisers also confer an increased risk of lip cancer development.

A number of drugs that are commonly prescribed for hypertension, including the diuretic, hydrochlorothiazide and the calcium channel blocker, nifedipine, fall into this category and there is evidence to suggest that patients prescribed these drugs are at increased risk of lip cancer.

Gary Friedman of the Kaiser Permanente Medical Care Program, Oakland and Stanford University, California, and his colleagues have now conducted a more extensive study of the risk of lip cancer associated with long-term exposure to a wider range of antihypertensive drugs.

Friedman and his colleagues identified 712 cases of lip cancer and 22,904 controls matched by age, sex and year of study recruitment from the patients of the Kaiser Permanente Medical Care Program in southern California between 1994 and 2008.

The study was restricted to non-Hispanic whites, who have been assumed to be at a higher risk of this disease; HIV positive people and those who had received solid organ transplants were also excluded from the study.

The researchers recorded the duration of use of several antihypertensive drugs by each case and control before lip cancer diagnosis or enrolment into the study.

Besides hydrochlorothiazide and nifedipine, the drugs studied were a combination of hydrochlorothiazide with triamterene (a further potassium-sparing diuretic); lisinopril (an angiotensin-converting enzyme inhibitor); and atenolol (a beta blocker).

The study therefore included a representative of all main types of anti-hypertension apart from direct renin inhibitors and angiotensin receptor blockers.

The results were controlled for the known risk factor of cigarette smoking. Multivariate analysis confirmed a strong, statistically significant association between prolonged use of hydrochlorothiazide, hydrochlorothiazide-triamterene, and nifedipine with lip cancer.

There was a weaker association with lisinopril that lost statistical significance when other drugs were excluded and, interestingly, use of atenolol alone seemed to confer a slight reduction in lip cancer risk. In the three cases where there was a significant increase of risk with drug use, the risk increased with the duration of that use.

The greatest increase in risk recorded was for over five years’ exposure to hydro-chlorothiazide alone, with an odds ratio of 4.22 (95% CI, 2.82-6.31).

The fact that there was very little evidence of an increase in lip cancer with lisinopril and none at all with atenolol suggested to Friedman and his colleagues that it was the photo-sensitising effects of the drugs under test that were responsible for this increased risk, rather than the condition being treated, hypertension.

They commented further that they had not been able to find any association between these drugs and melanoma, suggesting that this might be because that more common and more deadly cancer is associated more with intermittent, acute exposure to ultra-violet radiation than with the chronic moderate exposure that arises from the long-term use of photo-sensitising drugs.

The researchers concluded that these results are sufficient to establish a positive association between several types of photo-sensitising antihypertensive drugs and lip cancer, although further experiments will be necessary to establish the exact nature of the relationship.

They further recommended that light-skinned people who are prescribed diuretics or calcium channel blockers for hypertension should take extra care in the sun. This warning was echoed in an accompanying note by Archives of Internal Medicine editor Mitchell H. Katz, who further suggested that these drugs might also increase the risk of basal and squamous cell carcinomas of the skin, cancers that are not tracked by the Kaiser Permanente Medical Care Program registry.

Reference: Friedman, G.D., Asgari, M.M., Warton, E.M., Chan, J. and Habel, L.A. (2012). Antihypertensive Drugs and Lip Cancer in Non-Hispanic Whites. Arch. Intern. Med, published online ahead of print 6 August 2012.

DOI: 10.1001/archinternmed.2012.2754