Certain Antidepressants Are Associated With Worse PFS in Pancreatic Cancer

Michael Feigin, PhD

Benzodiazepine lorazepam (Ativan) may be linked to shorter progression-free survival (PFS) in patients with pancreatic cancer, while benzodiazepine alprazolam (Xanax) may be linked to a longer PFS, according to research published in Clinical Cancer Research.¹

When investigators at Roswell Park performed mechanistic studies to understand the impact of these agents on a pancreatic tumor at a cellular level, the introduction of any benzodiazepine was associated with a 30% reduced risk of pancreatic cancer-related death after adjusting for age, race, sex, disease stage, progression, and treatments received.

Yet, individual benzodiazepines were revealed to have distinct associated outcomes. For instance, patients receiving lorazepam (n = 40) were found to have a 3.83-fold higher risk of disease progression or death compared to those not taking lorazepam (n = 29; HR, 3.83; 95% CI, 1.53-9.57). Conversely, patients who took alprazolam had a 62% lower risk of disease progression or death compared with those who did not take alprazolam (n = 42; HR, 0.38; 95% CI, 0.16-0.92).

Investigators theorized that the mechanism of actions may be related to the differences. Lorazepam may activate a protein called GPR68, a protein that is highly expressed on fibroblasts supporting the tumor. GPR68 also promoted cytokine IL-6 expression, which in turn can promote inflammation in the pancreatic tumor microenvironment, increasing tumor growth.²

However, not all benzodiazepines activate GPR68. One class, known as n-unsubstituted benzodiazepines (including lorazepam, clonazepam, nordiazepam, and oxazepam) are able to activate GPR68. N-substituted benzodiazepines (alprazolam, diazepam, and temazepam) have shown no effect on GPR68.

“We think the mechanism comes down to a difference in structure between different benzodiazepines,” Michael Feigin, PhD, an associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center in Buffalo, New York, said in a news release. “Alprazolam has the opposite effect as lorazepam; it has no impact on GPR68, but it potently decreases IL-6, and we think this decreases the inflammatory potential of these tumors.”

According to investigators, there has been relatively little investigation on the correlation between antidepressants and tumor reduction, despite the high percentage of patients with cancer who take these treatments. Benzodiazepines function by suppressing activity within the central nervous system, and patients with cancer are often prescribed them to manage symptoms of anxiety, insomnia, and seizures.

“When we study response to therapy, we think of treatments like chemotherapy or immunotherapy, but patients are also given a lot of medicines for anxiety and pain,” Feigin said. “We wanted to understand the impact of some of these palliative care drugs on the tumor.”

Investigators also considered whether these antidepressants were associated with improved or worsened outcomes in other cancer types and found that alprazolam was rarely linked to a significantly different outcome. In contrast, lorazepam use was associated with worse overall survival across prostate, ovarian, head and neck, uterine, colon, and breast cancer, as well as in melanoma. The percentage risk increased ranged from 25% to 116%.

Although these are early phase findings, and study authors acknowledge that it is too soon to say whether one treatment should be chosen over the other, they suggest that there is a wealth of research opportunity to be had in this space. Moving forward, they propose that clinical trials might prospectively evaluate the effects of lorazepam and alprazolam in the human pancreatic cancer microenvironment.

References

1. Cornwell AC, Tisdale AA, Venkat S, et al. Lorazepam stimulates IL6 production and is associated with poor survival outcomes in pancreatic cancer. Clin Cancer Res. Published online August 17, 2023. doi:10.1158/1078-0432.CCR-23-0547
2. Lorazepam treatment may be linked to worse outcomes for pancreatic cancer patients. News release. American Association for Cancer Research. August 17, 2023. Accessed August 29, 2023. https://www.aacr.org/about-the-aacr/newsroom/news-releases/lorazepam-treatment-may-be-linked-to-worse-outcomes-for-pancreatic-cancer-patients/