Retrospective Study Associates Alprazolam With Improved PFS in Pancreatic Cancer

Michael Feigin, PhD

The benzodiazepines lorazepam (Ativan) and alprazolam (Xanax) had differing effects on progression-free survival (PFS) outcomes among patients with pancreatic cancer, with lorazepam demonstrating an association with decreased PFS and alprazolam prolonging PFS, according to findings from a retrospective study published in Clinical Cancer Research.^1,2

Patients who received alprazolam (n = 27) experienced significantly improved PFS outcomes compared with those who had not received the agent (n = 42; HR, 0.38; 95% CI, 0.16-0.92). However, patients treated with lorazepam (n = 40) experienced significantly worse PFS outcomes compared with those who did not receive the agent (n = 29; HR, 3.83; 95% CI, 1.53-9.57).

“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,” 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.² “We wanted to understand the impact of some of these palliative care drugs on the tumor. We think the mechanism comes down to a difference in structure between different benzodiazepines. Alprazolam has the opposite effect as lorazepam; it has no impact on GPR68, but it potently decreases interleukin [IL]-6, and we think this decreases the inflammatory potential of these tumors.”

The retrospective study included patients with primary cancers of the prostate, pancreas, ovary, kidney, head and neck, corpus uteri, colon, breast, brain, and invasive nevi/melanoma treated at the Roswell Park Comprehensive Cancer Center, and 30.9% of patients had a record of benzodiazepine use when data were acquired on February 3, 2023. Patients with pancreatic cancer were prescribed at least 1 benzodiazepine at a rate of 40.6%—the highest frequency of any population included in the study.

Midazolam (Versed) was the most prescribed benzodiazepine for patients with pancreatic cancer; however, due to its short half-life of 2 to 5 hours, the intermediate-acting lorazepam and alprazolam were examined in the retrospective study, as they have a half-life 6 to 24 hours and are the second- and third-most commonly prescribed benzodiazepines. A combination of in vivo and in vitro models were used to determine the effects of lorazepam and alprazolam on the pancreatic adenocarcinoma tumor microenvironment.

Investigators initiated the pancreatic epidemiology study using the Roswell Park Comprehensive Cancer Center’s web-based tool, nSight, to compare benzodiazepine prescription records for patients with pancreatic cancer treated with chemotherapy from 2004 to 2020. Patients with pancreatic cancer who received benzodiazepines displayed no significant difference in PFS compared with those who did not. However, following covariate-adjusted analyses to account for age, sex, race, clinical stage, additional treatments, and progressive disease, data demonstrated patients experienced a significant improvement in disease-specific survival vs patients who did not have prescription records of benzodiazepine (HR, 0.70; 95% CI, 0.60-0.82).

Findings showed that Kaplan–Meier curves for overall survival (OS) and PFS for melanoma, prostate, and ovarian cancers demonstrated a worse survival for patients prescribed lorazepam compared with those prescribed alprazolam or with no record of benzodiazepine use.¹

Findings showed that alprazolam treatment was rarely associated with significantly different [OS] outcomes. However, lorazepam use correlated with significantly worse OS in patients with prostate, ovarian, head and neck, uterine, colon, and breast cancer, as well as melanoma, with effects ranging from a 25% increased risk to a 116% increased risk.²

The OS outcomes for patients treated with lorazepam compared with those who were not experienced were as follows:¹

• Prostate: HR, 2.160; 95% CI, 1.589-2.936; P < .0001
• Ovarian: HR, 1.521; 95% CI, 1.212-1.907; P = .0003)
• Melanoma: HR, 1.978; 95% CI, 1.519-2.576; P < .0001
• Kidney: HR, 0.898; 95% CI, 0.651-1.240; P = .5132
• Head and Neck: HR, 1.629; 95% CI, 1.304-2.035; P < .0001
• Corpus uteri: HR, 1.376; 95% CI, 1.021-1.854; P = .0362
• Colon: HR, 1.620; 95% CI, 1.317-1.993; P < .0001
• Breast: HR, 1.248; 95% CI, 1.050-1.484; P = .0119
• Brain: HR, 0.779; 95% CI, 0.616-0.986; P = .0381

Patients treated with alprazolam experienced the following OS outcomes vs those who did not receive the agent:

• Prostate: HR, 1.464; 95% CI, 1.038-2.064; P = .0298
• Ovarian: HR, 1.343; 95% CI, 0.901-2.002; P = .1481
• Melanoma: HR, 1.194; 95% CI, 0.791-1.803; P = .3984
• Kidney: HR, 1.153; 95% CI, 0.741-1.795; P = .5268
• Head and Neck: HR, 1.227; 95% CI, 0.907-1.660; P = .1845
• Corpus uteri: HR, 1.497; 95% CI, 0.931-2.405; P = .0956
• Colon: HR, 1.369; 95% CI, 0.988-1.897; P = .0593
• Breast: HR, 1.867; 95% CI, 1.528-2.281; P < .0001
• Brain: HR, 0.661; 95% CI, 0.414-1.055; P = .0829

“To our knowledge, this is the first study to demonstrate that the commonly prescribed benzodiazepine lorazepam modifies the tumor microenvironment and has potential clinical implications when prescribing benzodiazepines to cancer patients,” study authors wrote.¹

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/