Pancreatic cancer has the poorest 5-year survival rate (12.5%) relative to all other cancers. In 2023, about 64,050 people will be diagnosed with pancreatic cancer, and approximately 50,550 will die of the disease.

A retrospective study investigating the impact of palliative care medicine on the tumor microenvironment has found that patients with pancreatic cancer who were prescribed the benzodiazepine lorazepam while undergoing chemotherapy had shorter progression-free survival than those patients who did not receive the benzodiazepine. However, patients receiving alprazolam—which belongs to another class of benzodiazepines—had improved progression-free survival. The study by Cornwell et al was published in Clinical Cancer Research.

Study Methodology

The researchers used multivariate Cox regression modeling to retrospectively measure associations between benzodiazepine use and survival in patients with pancreatic cancer treated at Roswell Park Comprehensive Cancer Center from 2004 to 2020. They also performed mechanistic studies to investigate the effects of lorazepam on pancreatic tumors on a cellular level.

The study assessed the association between benzodiazepine prescriptions (including diazepam, lorazepam, alprazolam, temazepam, clonazepam, nordiazepam, and oxazepam).

Results

When the researchers adjusted for age, race, sex, disease stage and progression, and treatments received, any benzodiazepine use was associated with a 30% lower risk of pancreatic cancer–related death. However, when they studied the relationship between individual benzodiazepines and pancreatic cancer outcomes, they found differences between the two most commonly prescribed benzodiazepines: lorazepam (40 patients) and alprazolam (27 patients). Patients receiving alprazolam had a 62% lower risk of disease progression or death compared with those who did not take the medication (42 patients). Conversely, patients receiving lorazepam had a 3.83-fold higher risk of disease progression or death than patients who did not take the drug (29 patients).

The researchers then investigated the associations between lorazepam and alprazolam use and survival outcomes in other cancer types; they found that use of alprazolam was rarely associated with significantly different outcomes. However, lorazepam use was correlated with significantly worse overall survival in patients with prostate, ovarian, head and neck, uterine, colon, and breast cancers, as well as melanoma, with effects ranging from a 25% increased risk to a 116% increased risk.

To learn why, the researchers then conducted a mechanistic study, which showed that lorazepam may activate the protein GPR68, which is highly expressed on fibroblasts that support the tumor. The protein boosts expression of the cytokine interleukin-6 (IL-6), which promotes inflammation in the pancreatic tumor microenvironment, leading to tumor growth. However, the researchers found that only one class of benzodiazepines, called n-unsubstituted benzodiazepines, which include lorazepam, clonazepam, nordiazepam, and oxazepam, could activate GPR68. N-substituted benzodiazepines, including alprazolam, diazepam, and temazepam, had no effect on GPR68 activation.

“We demonstrate that [lorazepam] stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival,” concluded the study authors.

Clinical Relevance

“We think the mechanism comes down to a difference in structure between different benzodiazepines,” said Michael Feigin, PhD, Associate Professor of Pharmacology and Therapeutics at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and senior author of this study, in a statement. Compared with lorazepam, he continued, “alprazolam has the opposite effect…. It has no impact on GPR68, but it potentially decreases IL-6, and we think this decreases the inflammatory potential of these tumors.”

The next step, said Dr. Feigin, would be a clinical trial to prospectively evaluate the effects of lorazepam and alprazolam on pancreatic outcomes and the human pancreatic cancer microenvironment.

Disclosure: Funding for this study was provided by the National Cancer Institute, the Roswell Park Alliance Foundation, and the Fifth District AHEPA Cancer Research Foundation. For full disclosures of the study authors, visit aacrjournals.org/clincancerres.