In an attempt to shed further light on associations between cancer and prescription drugs, researchers at the Kaiser Permanente Medical Care Program (KPMCP) in northern California—a behemoth of a healthcare organisation, if there ever was one—mined the organisation’s considerable medical records for an association between prescription drugs and cancer risk, and published their results in Cancer Causes & Control. The seven broad associations they discovered were novel and are worth a closer look.

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Countless adults and children take prescription medications on a daily basis, yet, despite such incalculable levels of exposure, little is known about long-term effects, as insufficient data on post-marketing is often the norm. Among other health concerns, it is unclear whether certain drugs increase cancer risk.

Study design

In the study, researchers performed nested case-control analyses in a cohort of 6,608,681 patients, with study participants followed between August 1994 and December 31, 2006. The researchers ended up screening 105 of 230 commonly used prescription drugs, with an arbitrary cut-off of at least 25,000 users for each drug.

They found 101 associations of interest covering 61 drugs, with 66 associations involving confounding. Of the remaining 36, they ruled out the null hypothesis for the following: fluoxetine and paroxetine with testicular cancer, hydrochlorothiazide with renal and lip cancer, hyoscyamine with non-Hodgkin lymphoma, nifedipine with lip cancer, nortriptyline with oesophageal and hepatic cancer, oxazepam with lung cancer, and sulindac with gallbladder cancer and leukemia.

Positive associations entailed a relative risk (RR) of at least 1.50, with P ≤ 0.01, and higher risk exhibited for three or more prescriptions vs just one prescription. Assessments were bolstered by additional literature searches, analyses, and clinical judgment.

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Fluoxetine and paroxetine

Both of these selective-serotonin reuptake inhibitors (SSRIs) were linked to testicular cancer by the researchers. With respect to fluoxetine, the researchers observed 14 cases of cancer with a relative risk of 2.51 after a median duration of use of 10 months. With paroxetine, they observed 11 cases and a relative risk of 2.44, with a median duration of use of 10 months. Between fluoxetine and paroxetine users, there were only three cases of overlap.

“Antidepressants including selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have been evaluated in laboratory experiments and epidemiologic studies with mixed results, including some findings of possible prevention,” the authors wrote. “Attention in humans has been focused primarily on breast cancer and no relationship has been established. No human data concerning testicular cancer were found,” they added.

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Hydrochlorothiazide

In the study cohort, the researchers noted 147 cases of lip cancer in patients who took the diuretic hydrochlorothiazide for a median of 58 months. The relative risk of lip cancer was 2.29. There was only a weak association between lip and lung cancer observed, thus making confounding by smoking less likely. With respect to renal cancer, the researchers noted 537 cases in hydrochlorothiazide users, with a relative risk of 1.71. However, they noted that this increased frequency of renal cancer could be due to hypertension.

At the level of the oral cavity, the most common cancer is lip cancer, which accounts for 25% to 30% of such lesions. Sun exposure is a well-known risk factor for lip cancer, distinguishing it from other oral cavity cancers. Intriguingly, 90% of lip cancers affect the lower lip because of higher sun exposure, with the upper lip shielded from the sun by the nose.

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Hyoscyamine

Hyoscyamine is a naturally occurring belladonna alkaloid derivative found in plants. Once upon a time, women used belladonna, which is Italian for “pretty woman,” to dilate their pupils for cosmetic reasons. Apparently, dilated pupils were believed to soften their look.

Hyoscyamine is an isomer of atropine and a gastrointestinal agent that competes with acetylcholine at the site of muscarinic receptors in the bronchial, salivary, and sweat glands, as well as receptors at the level of the heart, eye, and gastrointestinal tract. This agent decreases bronchial, salivary, gastric, and sweat gland secretions. It also leads to mydriasis, cycloplegia, heart rate changes, contraction of the bladder detrusor muscle/gastrointestinal muscle, as well as decreasing gastrointestinal motility. 

Typically, this drug is used to relieve gastrointestinal spasms, peptic ulcers, irritable bowel syndrome, cystitis, pancreatitis, and colic. It can also treat heart problems and curb symptoms of Parkinson disease, as well as decrease respiratory secretions in a palliative-care setting. Serious adverse effects include skin rash, diarrhea, eye pain, and tachycardia/arrhythmia. 

In the cohort, researchers identified 23 cases of non-Hodgkin lymphoma related to hyoscyamine after a median of 4 months of use, with a relative risk of 2.45. These findings were similar in those with and without HIV, and could not be accounted for by confounding due to other autoimmune disorders such as celiac disease.

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Nifedipine

This drug is a first-generation calcium-channel blocker, which was first developed by Bayer in 1972 and granted FDA approval in 1981. Since its discovery, second- and third-generation alternatives have become more popular due to their longer duration of action and slower onset. Serious adverse effects of this drug include angina, swelling, difficulty breathing/swallowing, rash, fainting, and jaundice.

After a median use of 40 months, researchers observed 46 cases of lip cancer in nifedipine users, with a relative risk of 1.81. After a median use of 50 months, they counted 39 cases of laryngeal cancer, with a relative risk of 1.60. Although the lung cancer relative risk was slightly elevated at 1.15 in patients taking the drug, this boost in relative risk was dwarfed by relative risks of lip or larynx cancer, suggesting that smoking played only a small confounding role.

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Nortriptyline

Nortriptyline is a tricyclic antidepressant and the active metabolite of amitriptyline. It is indicated for major depression and used off-label for chronic pain and other conditions. With respect to oesophageal cancer, the researchers observed 12 cases related to nortriptyline use, with median drug use of 9 months and a relative risk of 2.56. With respect to liver cancer, they noted 19 cases, with median drug use of 14 months and a relative risk of 2.21.

According to the authors, tricyclic antidepressants have been hypothesised as carcinogenic, but results from empiric and observational research on the topic have been mixed⸺some studies showed preventive effects on cancer. Although alcoholism could contribute to oesophageal and liver cancers observed in this cohort, the researchers ruled this out as a confounder.

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Oxazepam

This intermediate-acting benzodiazepine is slowly transformed in the body after absorption, and it is therefore less likely to undergo pharmacokinetic reactions, making it ideal for use in the elderly or those with liver disease. This drug is used for treatment of alcohol withdrawal and anxiety disorders. Like other benzodiazepines, toxicity is related to central nervous system depression.

In the current study, researchers found that oxazepam use was tied to 117 cases of lung cancer after a median duration of use of 9 months, with a relative risk of 1.54. Results could be confounded by smoking. Lung cancer is far and away the leading cancer-related cause of death, accounting for nearly 25% of the total. Every year, more people die of lung cancer than from colon, prostate, and breast cancers combined. Most people diagnosed with the disease are aged 65 and older, with few people diagnosed aged 45 years or younger.

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Sulindac

The mechanism for this NSAID remains to be fully understood, but it could be due to inhibition of prostaglandin synthetase. It has anti-inflammatory, analgesic, and antipyretic properties, and increases risk of major cardiovascular thrombotic events, heart attack, and stroke. Increased risk is likely related to duration of use, with patients with heart disease at even more added risk. On absorption, sulindac is first reversibly reduced to the sulfide metabolite, which is biologically active, and then irreversibly oxidised to the sulfone metabolite.

In the current study, researchers identified 9 cases of gallbladder cancer and 5 cases of leukemia linked to the drug, with relative rates of 2.88 and 5.78, respectively. Median use of the drugs among patients was 6 months.

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It should be noted that the distinct nature of the study presented certain strengths and limitations, which are best explained by the researchers. “Strengths of this study include the large numbers of drug recipients with complete cancer follow-up while they are members, often long-term, in a comprehensive health care system,” the authors wrote. “We have objective data on the filling of prescriptions not subject to failure of recall or recall bias. Limitations include our lack of readily accessible information about use of the drugs of concern before August 1994 and follow-up that may not be long enough to detect effects that are early in the carcinogenic process. We were not able to control for important confounders directly. Accordingly, we emphasise the fact that these findings are the result of screening and not of definitive epidemiologic studies that include more detailed information about cancer risk factors,” they added.

Finally, as could probably be expected, although significant, the associations cited in the study need to be further sussed out.

This story is contributed by Naveed Saleh and is a part of our Global Content Initiative, where we feature selected stories from our Global network which we believe would be most useful and informative to our doctor members.