Amiodarone-cancer link reemerges in observational study

Roxanne Nelson and Steve Stiles

April 11, 2013

Taipei, Taiwan - Amiodarone may be associated with an increased risk of cancer in men as well as anyone with prolonged exposure to the drug, according to an observational study published online April 8, 2013 in Cancer[1].

Experts interviewed for this story said the amiodarone-cancer link observed in the study "is not entirely new" but deserves some attention and yet should be "taken with a grain of salt."

Researchers in Taiwan report that, compared with the general population, patients who received amiodarone in their analysis based on a >6000-person community-based cohort showed a borderline significant 12% increase in overall risk of cancer (p=0.067). Risk was calculated as standard incidence ratios (SIRs).

The risk of any cancer was significantly increased in men, by 18% (p=0.022), but not in women.

The risk also appeared to be dose dependent. Patients with cumulative defined daily doses (DDD) within the first year that exceeded 180 had a 28% increased risk of cancer (p=0.046), but among men whose cumulative DDD exceeded 180, the risk was 46% increased (p=0.008).

"Although extensive screenings for occult cancers in patients currently undergoing treatment with amiodarone appears to be impractical, we suggest that cancer events should be routinely reported in future amiodarone trials, and further observational research is necessary," write the authors, led by Dr Vincent Yi-Fong Su (Taipei Veterans General Hospital, Taiwan)

The Food and Drug Administration (FDA) has reported the development of lung masses, thyroid cancer, and skin cancer following treatment with amiodarone in postmarketing surveillance, the authors point out.

"I think its adverse effects are not widely appreciated," Dr Albert L Waldo (University Hospitals of Cleveland, OH) said for heart wire . "It's so widely used because it's probably our most effective antiarrhythmic medication for so many rhythm disorders, especially atrial fibrillation." But it has a range of toxicities and can be especially hard on the thyroid.

Waldo, who isn't connected with the current study, said that a cancer risk "is one of the least appreciated [potential] adverse effects" of amiodarone. "There have been signals along the way that this in fact is true." He called the current findings "definitely another signal."

He said that in the AFFIRM trial[2], significant for helping to show that rhythm control and rate control are similarly effective in patients with AF, there was an excess of cancer cases among patients taking the drug. Waldo was on AFFIRM's executive committee.

And two influential trials from the 1990s, he said, found similar signals of elevated cancer risk with amiodarone: AVID and EMIAT [3,4].

The current analysis, Waldo said, "reminds people that amiodarone has a long list of toxicities, that this may be another one, and that it should be taken seriously. What to do about it is the issue. What it needs is a really first-rate study, not just a retrospective look."

Not practice changing yet

Another expert cautions that while we should pay attention to the findings of this study, "we need to take it with a grain of salt." Dr James Marshall (Roswell Park Cancer Institute, Buffalo, NY), who wasn't involved in the analysis, pointed out that it has a number of limitations.

It is based on the use of SIRs, he noted, which compare the number of observed cancer cases with the "expected" number of cases within a population or geographic area.

"There was only a 12% increase for the whole group, and that is a small increase," Marshall said. "If this were a pristine study, it might mean something, but they are using standard incidence ratios, and those are notoriously difficult to interpret."

The use of the cumulative DDD is a little cleaner, he said. "They can then compare high exposure and low exposure."

Marshall also noted that while the authors did adjust for age, gender, and comorbidities, they did not look at potential risk factors such as smoking, environmental exposure, family history of malignancy, alcohol use, and obesity.

"We do want to make note of these results," he said, "And not just toss the data out. But I don't think cardiologists are going to change treatment based on this one study alone. We need to be careful about coming to conclusions until we see some confirmation of this in other studies."

Waldo further pointed out that there were "small numbers" of cancer cases in the cohort, "and they didn't follow a lot of patients long." He agreed that the findings are only "hypothesis generating."

National health-insurance data

Su and colleagues used the Taiwan National Health Insurance Research database to identify patients treated with amiodarone. The final cohort consisted of 6418 such patients, for whom there were 21 684 person-years of follow-up data from 1997 to 2008. A total of 280 cancers developed during a median follow-up of 2.6 years. In a subgroup analysis by age at cancer diagnosis (20-59, 60-79, and >80 years), usually the SIRs were not significantly raised; exceptions included men aged 20 to 59 years (SIR 1.67; p=0.025) and >80 years (SIR 1.41; p=0.016). The group notes that the incidence of cancer rose within one year of amiodarone therapy (SIR 1.32; p=0.002), but not after one year (SIR 1.02).

In an analysis by cumulative-DDD tertiles, patients in the intermediate and highest cumulative DDD levels had adjusted hazard ratios for cancer of 1.70 (p=0.042) and 1.98 (p=0.006), respectively, compared with those in the lowest level.

As for types of malignancies observed, there appeared to be a preponderance of gastrointestinal cancers, 124 cases out of 280. There were also 47 genitourinary cancers, 22 head and neck cancers, 11 hematologic, and only one case of thyroid cancer.

The variety "is a bit of a surprise," according to Waldo. "Usually if something causes cancer, it's a certain type of cancer."

The study was supported by Taipei Veterans General Hospital. The authors reported no financial conflicts . Waldo has previously reported to heart wire that he has served on the data safety monitoring boards of trials associated with device companies that make treatments for AF and that he has receiving consulting fees or honoraria from Sanof i , Bristol-Myers Squibb, Boehringer Ingelheim, Astellas, Portola, Daiichi Sankyo, and Ortho-McNeill-Jannsen. In the AFFIRM publication, Waldo reported that he received research support from AstraZeneca and Guidant, "was on the speakers' bureaus of many companies," and was a consultant to Procter & Gamble, 3M Pharmaceuticals, AstraZeneca, Pfizer, Solvay, and CryoCor.




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