pancreas

Benzodiazepines are a class of drugs (anxiolytics) that suppress the activity of the central nervous system, which can relieve symptoms of anxiety, insomnia and seizures. Cancer patients are often prescribed benzodiazepines to help with such problems resulting from the disease or treatment.

Currently, there is little comprehensive research on how benzodiazepine use may affect cancer outcomes, says Michael Feigin, associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center and lead author of the study.

“When we study response to therapy, we think of treatments like chemotherapy or immunotherapy, but patients are also given a lot of drugs for anxiety and pain,” Prof. Feigin said.

The team set out to understand the impact of some of these palliative care drugs on tumors.

Prof. Feigin and his colleagues first assessed how many patients take benzodiazepines during cancer treatment.

Among patients treated at Roswell Park for prostate, pancreatic, ovarian, kidney, head and neck, endometrial, colon, breast, brain, or melanoma cancer, 30.9% had received benzodiazepines.

Pancreatic cancer patients had the highest rate of benzodiazepine use, 40.6%.

The researchers then examined the relationship between benzodiazepine use and survival in pancreatic cancer patients.

When they adjusted for factors such as age, race, sex, disease stage and progression, and treatments received, any benzodiazepine use was associated with a 30% lower risk of death from pancreatic cancer.

However, when the team studied the relationship between benzodiazepines and individual pancreatic cancer outcomes, they found stark differences.

Apart from short-acting benzodiazepines used in surgical anesthesia, the two most frequently used benzodiazepines were lorazepam (40 patients) and alprazolam (27 patients).

Patients who took alprazolam had a 62% lower risk of disease progression or death compared to those who did not take alprazolam (42 patients).

In contrast, patients who took lorazepam had a 3.83 times greater risk of disease progression or death than patients who did not take lorazepam (29 patients).

When researchers investigated associations between lorazepam and alprazolam use and patient outcomes in other types of cancer, they found that alprazolam was rarely associated with significantly different outcomes.

However, lorazepam use was also associated with significantly worse overall survival in prostate, ovarian, head and neck, uterine, colon, and breast cancers, as well as melanoma, with effects ranging from an increased risk by 25% at a risk increased by 116%.

“Some previous studies have examined the effect of benzodiazepines on tumor cell growth using models without a microenvironment,” explained Feigin.

“Since the tumor microenvironment plays an important role in the biology of pancreatic cancer, we wanted to know what benzodiazepines do to the microenvironment.”

Findings from this study show that lorazepam can activate a protein called GPR68, which is highly expressed on tumor-supporting fibroblasts.

GPR68 stimulates the expression of the cytokine IL-6, which promotes inflammation in the pancreatic tumor microenvironment, leading to increased tumor growth.

The team found that only one class of benzodiazepines, called n-unsubstituted benzodiazepines (including lorazepam, clonazepam, nordiazepam and oxazepam), could activate GPR68.

N-substituted benzodiazepines (including alprazolam, diazepam and temazepam) had no effect on GPR68 activation.

“We believe that the mechanism comes down to a difference in structure between the different benzodiazepines,” says Prof. Feigin.

“Alprazolam has an opposite effect to lorazepam; it has no impact on GPR68, but strongly decreases IL-6, and we believe that this decreases the inflammatory potential of these tumors,” he explained.

“I think it’s too early to say that patients should stop taking one drug or start taking another drug,” warns Prof. Feigin, noting that the study was a correlative analysis, with the next step being a clinical trial. to prospectively evaluate the effects of lorazepam and alprazolam on pancreatic cancer outcomes and on the human pancreatic cancer microenvironment.

“There is still much to learn in terms of clinical implications.”

Limitations of this study include differences in the optimal dose of benzodiazepines between mice and humans, as well as differences in the doses of benzodiazepines administered to human patients for different indications, which were not considered in this study.

Moreover, some of the mouse experiments were performed on tumors implanted subcutaneously, which have a different microenvironment than tumors that develop in the pancreas.

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2023-08-20 09:32:40
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