Lung Cancer Patients on Beta Blockers Live Longer

Zosia Chustecka

January 09, 2013

In patients with nonsmall-cell lung cancer (NSCLC) undergoing definitive radiotherapy who were taking beta blockers for another condition, such as hypertension or heart disease, overall survival was significantly better than in patients not taking these drugs.

In fact, there was a 22% improvement in median overall survival in those taking beta blockers, compared with those who were not (23.7 vs 18.6 months; hazard ratio, 0.878; P = .02).

In addition, disease-free survival and distant-metastasis-free survival were significantly better in those taking beta blockers.

These findings come from a retrospective study of 722 patients, which was published online January 8 in the Annals of Oncology.

However, there was no improvement in locoregional progression-free survival, which measures disease progression in the area of the lungs where the disease first appeared. This suggests that beta blockers affect the tumor metastatic cascade, rather than the primary tumor, the authors explain.

"Our results suggest that the use of beta blockers during radiotherapy may help to prevent the formation of metastases and could lead directly or indirectly to improved care for patients with NCSLC," said senior author Daniel Gomez, MD, assistant professor at the Department of Radiation Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

However, Dr. Gomez emphasized the need for prospective studies to investigate these findings further.

So did Mark Kris, MD, chief of thoracic oncology at the Memorial Sloan-Kettering Cancer Center, in New York City, who writes the Medscape Kris on Oncology blog.

"Retrospective studies like these need to be considered preliminary and interpreted with caution," Dr. Kris told Medscape Medical News. "To take this forward, the finding first needs to be confirmed in similar patients at another institution, then in other groups, like patients with resected lung cancers," he said. "This is pretty easy with modern hospital databases," he added.

Potential Lead Welcome

Nevertheless, Dr. Kris welcomes this research as a potential lead in understanding and preventing metastases, which he described as "the nemesis" for patients with lung cancer and their oncologists.

"The metastatic process is very complex and occurs over months or years," he noted. "Only now are we beginning to explore it in lung cancers, [but] we don't really know the mechanism," he said.

In their study, Dr. Gomez and colleagues suggest that the mechanisms underlying the development of metastases might involve chronic stress conditions and prolonged exposure to adrenaline/norepinephrine. "Norepinephrine has been shown to directly stimulate tumor cell migrations, and this effect is mediated by beta-adrenergic receptors," they add.

"We propose that the pathway that is involved is the beta-adrenergic pathway. Several preclinical studies (in cells and in animal models) have shown that this pathway can induce proliferation, invasion, and migration of tumor cells, which can then lead to the development of tumor in distant sites throughout the body (such as the brain, liver, bones, and adrenal glands)," Dr. Gomez explained to Medscape Medical News. These metastases are the most common cause of death in patients with this type of cancer, he added.

"Our specific hypothesis is that beta blockers abrogate this signaling pathway and, in doing so, they inhibit the development of distant metastasis (i.e., tumor spread)," he said.

A number of previous clinical studies have hinted at the antitumor effects of beta blockers, the study authors note. Studies of breast cancer patients have shown a reduction in tumor recurrence and cancer-specific mortality (J Clin Oncol. 2011;29:2635-2644 and 2645-2652), and a study in patients with malignant melanoma patients reported improved survival (Cancer Epidemiol Biomarkers Prev. 2011;20:2273-2279). However, a study of lung cancer patients showed no correlation between beta blockers and overall survival (Br J Clin Pharmacol. 2011;72:157-161).

"The association of beta blockers with cancer has been interesting." said Sripal Bangalore, MD, director of the cardiovascular outcomes group and assistant professor of medicine at the New York University School of Medicine in New York City."In the 90s, there was concern about increased risk of cancer with beta blockers," he told Medscape Medical News.

More recently, epidemiologic studies have shown that beta blockers can help prevent locoregional recurrence and metastases and improve survival free of cancer, he noted. "This is based on the biological plausibility that chronic norepinephrine stimulation is likely carcinogenic, and drugs that oppose the action, such as beta blockers, may be beneficial," Dr. Bangalore explained.

"However, the results from all these observational studies have been highly variable, with a few studies showing a beneficial effect, others showing a neutral effect, and a few others showing a harmful effect," he said.

Beta blockers have lost favor as a treatment for hypertension, and are now relegated to fourth-line therapy by various national and international guidelines, Dr. Bangalore noted. "It is possible that these medications may be beneficial for other indications, such as use in cancer patients," he said. "However, prospective studies are needed to conclusively prove this association."

Theodore Hong, MD, associate clinical director of radiation oncology at the Massachusetts General Cancer Center in Boston, was asked by Medscape Medical News to comment on the study. "My first couple thoughts are that [the findings are] potentially feasible but need more preclinical validation," he said.

These sorts of findings have been noted before, for example, with metformin and hydroxychloroquine in pancreatic cancer and with vitamin D and aspirin in colon cancer, he explained. However, he cautioned that these types of findings are subject to publication bias (that is, only positive results are reported).

Study Details

Dr. Gomez and colleagues analyzed data from 722 patients with NSCLC who had undergone definite radiotherapy from 1998 to 2010 at the M.D. Anderson Cancer Center. Most patients also received chemotherapy; only 10% were treated with radiation alone. All patients received fairly homogenous radiation doses, the authors note, undergoing radiation 5 days per week to a total dose of around 60.0 to 87.4 Gy.

In this cohort, 155 patients were taking beta blockers while they were undergoing radiotherapy. Most of them had hypertension, but one third had other cardiovascular disease, most often coronary heart disease. The most commonly prescribed agents (accounting for more than 85% of cases) were metoprolol and atenolol.

Most of these NSCLC patients had stage III disease. The median age was 65 years, but patients who were on beta blockers were more likely to be older and have a poorer performance status, and were less likely to have received concurrent chemotherapy and higher radiation doses. However, the multivariate analysis remained significant after adjustment for all of these variables, suggesting that beta blocker use is independently associated with improved survival, the authors conclude.

Ann Oncol. Published online January 8, 2013. Abstract