Study Suggests Lorazepam May Increase Odds of Pancreatic Cancer Progression, Death

Benzodiazepines are a class of drug that can suppress the central nervous system’s activity, relieving symptoms such as anxiety, seizures, and insomnia. Patients with pancreatic cancer are typically prescribed benzodiazepines to treat symptoms resulting from their disease or treatment (e.g., anticipatory nausea prior to chemotherapy), but there is little information on the adverse effects (AEs) or how benzodiazepine may influence cancer outcomes.^1,2

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“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,” said study author Michael Feigin, PhD, associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center, in a press release. “We wanted to understand the impact of some of these palliative care drugs on the tumor.”²

Investigators had examined the relationship between use of benzodiazepine and survival outcomes of patients with pancreatic cancer. Tests were performed to identify the effects of lorazepam on pancreatic tumors at a cellular level. Although benzodiazepine use was associated with a 30% lower risk of pancreatic cancer-related death, researchers discovered significant differences when looking at specific benzodiazepines.²

Not including short-acting benzodiazepines used as a component of surgical anesthesia, the 2 most common benzodiazepines used were lorazepam (Ativan) (40 patients) and alprazolam (Xanax), used by 40 patients and 27 patients, respectively. Those who were treated with alprazolam had a 62% lower risk of disease progression or related death compared to the patients who did not take alprazolam. Patients who had taken lorazepam had a 3.83-fold higher risk of disease progression or related death.²

The study researchers found that alprazolam was rarely associated with drastically different outcomes in other cancer types when investigating the associations between lorazepam and alprazolam use and patient outcomes; however, lorazepam use was connected to worse overall survival in melanoma, as well as prostate, ovarian, head and neck, uterine, colon, and breast cancers. The effects ranged from an increased risk of 25% to 116%.²

“We think the mechanism comes down to a difference in structure between different benzodiazepines,” Feigin said in the press 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.”²

GPR68, a protein expressed in PDAC cancer-associated fibroblasts (CAFs) that promotes inflammation in pancreatic tumor microenvironment, had appeared to be activated by lorazepam; however, one class of benzodiazepines, n-unsubstituted benzodiazepines (e.g., lorazepam, clonazepam, nordiazepam, and oxazepam) can activate GPR68. These benzodiazepines promote the emission of IL-6 by CAFs in a GPR68-dependent approach. Further, n-substituted benzodiazepines (e.g., alprazolam, diazepam, and temazepam) did not have any effect on GPR68, and they decrease IL-6 emission by CAFs in a GPR68-independent manner.¹

“Some prior studies examined the effect of benzodiazepines on tumor cell growth using models without a microenvironment,” Feigin said in the press release. “Since the tumor microenvironment plays a big role in pancreatic cancer biology, we wanted to know what the benzodiazepines are doing to the microenvironment.”²

Using a syngeneic KPC transplant model, study investigators found that tumors from mice treated with lorazepam had a higher expression of inflammatory signaling pathways and ECM-related genes by RNA sequencing. Tumors treated with lorazepam had increased levels of collagen, alpha-smooth muscle actin staining, and ischemic necrosis found in the centers of the tumors. According to the study authors, these findings indicate that benzodiazepines can modify the PDAC tumor microenvironment, subsequently having the potential to impact chemotherapeutic efficacy and survival in patients with pancreatic cancer.¹

Some limitations of the analysis included differences in optimal benzodiazepine dosing between humans and mice. Additionally, differences in benzodiazepine doses given to human patients for different indications were not accounted for in the study. Some of the experiments on the mice were performed on subcutaneously implanted tumors, and the microenvironment differs than the tumors that develop in the pancreas.²

“I think it’s too early to say patients should stop taking one drug or start taking another drug,” Feigin said in the press release. “There’s a lot more to learn in terms of the clinical implications.” He clarified that this trial was a correlative analysis, and that the next step should be a clinical trial to prospectively examine the effects of lorazepam and alprazolam on pancreatic cancer outcomes and human pancreatic cancer microenvironment.²

References

1. Cornwell A, Alahmari A, Tisdale A, et al. Abstract C048: Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment. Cancer Research. 15 November 2022; 82 (22_Supplement): C048. doi:10.1158/1538-7445.PANCA22-C048
2. American Association for Cancer Research. Lorazepam Treatment May Be Linked to Worse Outcomes for Pancreatic Cancer Patients. News release. August 17, 2023. Accessed August 16, 2023.