Lorazepam Drug Bad For Pancreatic Cancer Patients

According to findings published in Clinical Cancer Research, individuals with pancreatic cancer who took the benzodiazepine lorazepam (Ativan), frequently given to manage anxiety during cancer therapy, had shorter progression-free survival than patients who did not.

The progression-free survival was considerably longer for patients who took the benzodiazepine alprazolam (Xanax) compared to those who did not.

A group of medications known as benzodiazepines reduce the activity of the central nervous system, which can alleviate the symptoms of seizures, sleeplessness, and anxiety. Benzodiazepines are routinely provided to cancer patients to cope with these problems brought on by their disease or treatment. However, thorough research on the potential effects of benzodiazepine use on cancer outcomes is lacking, according to Michael Feigin, Ph.D., senior author of the study and associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center.

“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.”

Feigin and associates first assessed the proportion of cancer patients who use benzodiazepines. Patients with pancreatic cancer had the greatest rate of benzodiazepine use, at 40.6%, among those treated at Roswell Park for cancers of the prostate, pancreas, ovary, kidney, head and neck, endometrium, colon, breast, brain, or melanoma.

The use of benzodiazepines and survival in people with pancreatic cancer were then investigated by the researchers. Any benzodiazepine use was linked to a 30% decreased risk of pancreatic cancer-related death after adjusting for age, race, sex, illness stage and progression, and therapies used.

Feigin and colleagues discovered significant variations when they examined the connection between certain benzodiazepines and pancreatic cancer outcomes. The two most often utilized benzodiazepines, aside from those used as part of surgical anesthetic, were lorazepam (40 patients) and alprazolam (27 patients). Comparing patients who took alprazolam to those who did not (42 individuals), those who did had a 62% lower risk of mortality or disease progression. On the other hand, lorazepam users (29 patients) had a 3.83-fold increased probability of either the disease progressing or dying.

Alprazolam was infrequently linked to significantly different results when the researchers looked into the relationships between lorazepam and alprazolam use and patient outcomes in other cancer types. However, lorazepam usage was associated with significantly lower overall survival in cases of prostate, ovarian, head & neck, uterine, colon, breast, and melanoma, with risks ranging from 25% to 116% higher.

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

Mechanistic experiments done by Abigail Cornwell, the study’s first author and a graduate student in Feigin’s lab, revealed that lorazepam may activate a protein called GPR68, which is highly expressed on fibroblasts supporting the tumor. In the pancreatic tumor microenvironment, GPR68 increases the expression of the cytokine IL-6, which fosters inflammation and accelerates tumor growth.

The n-unsubstituted benzodiazepines, which include lorazepam, clonazepam, nordiazepam, and oxazepam, were the only class of benzodiazepines that could activate GPR68. Alprazolam, diazepam, and temazepam are examples of N-substituted benzodiazepines that had no impact on GPR68 activation.

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

“I think it’s too early to say patients should stop taking one drug or start taking another drug,” Feigin said, clarifying that this was a correlative analysis. “There’s a lot more to learn in terms of the clinical implications.”

The next stage, according to Feigin, would be a clinical trial to investigate lorazepam and alprazolam’s effects on pancreatic cancer outcomes and the microenvironment of human pancreatic cancer.

This study’s limitations include the fact that it did not account for variations in benzodiazepine doses administered to human patients for various purposes as well as changes in the optimal benzodiazepine dosing between mice and humans. Additionally, several of the mouse studies used subcutaneously implanted tumors, which have a different microenvironment from pancreatic tumors.

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