Sometimes patients with pancreatic cancer are prescribed the benzodiazepine lorazepam (Ativan) for anxiety, but that may be harming their health.

A new study found this treatment was linked to worse outcomes, with shorter survival times and faster disease progression.

Alternatively, those who took alprazolam (Xanax) had a significantly longer progression-free survival than patients who did not.

“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,” explained senior study author Michael Feigin, an associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center, in New York. “We wanted to understand the impact of some of these palliative care drugs on the tumor.”

Benzodiazepines relieve anxiety, insomnia and seizures by suppressing the central nervous system. Cancer patients are often prescribed these drugs to help deal with issues stemming from their disease or treatment.

To study the impact of that, the researchers first evaluated 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 or brain cancer, as well as melanoma, nearly 31% received benzodiazepines. About 41% of patients with pancreatic cancer received the drugs, the highest rate seen in the study.

After adjusting for other factors, benzodiazepine use was associated with a 30% lower risk of pancreatic cancer-related death.

However, the picture changed when they looked at specific benzodiazepines and pancreatic cancer outcomes.

Apart from short-acting benzodiazepines used as part of surgical anesthesia, the two most commonly used benzodiazepines were lorazepam (Ativan), which 40 of these patients were prescribed, and alprazolam (Xanax), which 27 patients were taking.

Those who took Xanax had a 62% lower risk of disease progression or death compared with those who did not take the drug. Meanwhile, patients taking Ativan had a nearly fourfold higher risk of disease progression or death than patients who did not take lorazepam.

Xanax was rarely associated with significantly different outcomes in other cancer types. Yet, Ativan was correlated with significantly worse overall survival in prostate, ovarian, head and neck, uterine, colon and breast cancer, as well as melanoma. Effects ranged from a 25% increased risk to a 116% increased risk.

“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.”

To try to figure that out, the investigators turned to tests in mice.

What did they find? Lorazepam may activate a protein called GPR68, which is highly expressed on fibroblasts that support the tumor, said study first author Abigail Cornwell, a graduate student in Feigin’s lab. GPR68 boosts expression of the cytokine IL-6, which promotes inflammation in the pancreatic tumor microenvironment, leading to increased tumor growth, according to the research.

However, only one class of benzodiazepines, called n-unsubstituted benzodiazepines — including lorazepam, clonazepam (Klonopin), nordiazepam (Nordaz) and oxazepam (Serax) — could activate GPR68. N-substituted benzodiazepines — such as alprazolam, diazepam (Valium) and temazepam (Restoril) — had no effect on GPR68 activation.

The findings were published Aug. 17 in the journal Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR). This study was funded in part by the National Cancer Institute and the Roswell Park Alliance Foundation.

“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 IL-6, and we think this decreases the inflammatory potential of these tumors,” Feigin explained in an AACR news release.

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

The next step would be a clinical trial to evaluate this further. One limitation of the study was that tests done in mice don’t always pan out in humans.

More information

The U.S. National Cancer Institute has more on anxiety and distress in cancer.

SOURCE: American Association for Cancer Research, news release, Aug. 17, 2023