PHILADELPHIA — Cancer patients often take benzodiazepines to help cope with the stress of their diagnosis and treatments. These anti-anxiety medications include Ativan (Lorazepam) and Xanax (Alprazolam). However, a new study suggests doctors should avoid prescribing pancreatic cancer patients Lorazepam. Scientists with the American Association for Cancer Research found that patients taking the benzodiazepine Ativan had a shorter progression-free survival rate than patients not using the medication.
Surprisingly, researchers discovered the opposite was actually true for cancer patients taking Xanax. Those prescribed alprazolam had a significantly longer progression-free survival than other patients.
What are benzos?
Benzodiazepines are a class of anti-anxiety drugs that produce their effects by suppressing the activity of the central nervous system, subsequently relieving symptoms including anxiety, insomnia, and seizures. While it’s been common practice for cancer patients to take these drugs for quite some time, there has always been a concerning dearth of comprehensive research regarding how exactly benzodiazepine use may impact cancer outcomes. So, Michael Feigin, PhD, an associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center and senior author of the study, set out to better understand this relationship.
“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,” Prof. Feigin says in a media release. “We wanted to understand the impact of some of these palliative care drugs on the tumor.”
The research team started by evaluating how many patients were taking benzodiazepines during cancer treatment. More specifically, among patients receiving treatment at Roswell Park for prostate, pancreatic, ovarian, kidney, head and neck, endometrial, colon, breast, or brain cancer or melanoma, 30.9 percent received a prescription for benzodiazepines. Notably, pancreatic cancer patients had the highest rate of benzodiazepine use (40.6%).
Next, the study authors examined the relationship between benzodiazepine use and survival in pancreatic cancer patients. After adjusting for various factors like age, race, sex, disease stage and progression, and treatments received, they determined that the use of any benzodiazepine was associated with a 30-percent lower risk of pancreatic cancer-related mortality.
However, when Prof. Feigin and the team assessed the relationship between individual benzodiazepines and pancreatic cancer outcomes, a number of stark differences emerged. Besides short-acting benzodiazepines used as part of surgical anesthesia, the two most commonly used benzodiazepines were lorazepam (40 patients) and alprazolam (27 patients). Patients taking alprazolam had a 62-percent lower risk of disease progression or death in comparison to those who did not take alprazolam (42 patients). Conversely, those taking lorazepam had a 3.83-fold higher risk of disease progression or death than others not taking lorazepam (29 patients).
After the research team investigated the associations between lorazepam and alprazolam use and patient outcomes in other cancer types, they discovered that Xanax rarely displayed an association with significantly different outcomes. However, Ativan use did correlate with notably worse overall survival in prostate, ovarian, head and neck, uterine, colon, and breast cancer, as well as melanoma – with the effects ranging widely from a 25 percent higher risk to a 116 percent higher risk.
“Some prior studies examined the effect of benzodiazepines on tumor cell growth using models without a microenvironment,” Prof. Feigin notes. “Since the tumor microenvironment plays a big role in pancreatic cancer biology, we wanted to know what the benzodiazepines are doing to the microenvironment.”
Abigail Cornwell, the first author of the study and a graduate student in Feigin’s lab, led a series of mechanistic studies that revealed lorazepam may activate a protein called GPR68, which is highly expressed on fibroblasts that support the tumor. GPR68 boosts expression of the cytokine IL-6, subsequently promoting inflammation in the pancreatic tumor microenvironment, ultimately fostering increased tumor growth.
To be clear, only one class of benzodiazepines, called n-unsubstituted benzodiazepines (including lorazepam, clonazepam, nordiazepam, and oxazepam), showed the capability of activating GPR68. N-substituted benzodiazepines, on the other hand, (alprazolam, diazepam, and temazepam) had no effect on GPR68 activation.
“We think the mechanism comes down to a difference in structure between different benzodiazepines,” Prof. Feigin adds. “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 concludes. “There’s a lot more to learn in terms of the clinical implications.”
Moving forward, researchers say the next step is to perform a clinical trial that will prospectively evaluate the effects of lorazepam and alprazolam on pancreatic cancer outcomes, as well as the human pancreatic cancer microenvironment.
This project was limited by differences in optimal benzodiazepine dosing between mice and humans, in addition to differences in benzodiazepine doses given to human patients for different indications. Both of those elements were not factored into this study. Furthermore, some mouse experiments were conducted on subcutaneously implanted tumors – which are known to have a different microenvironment than tumors that take root in the pancreas.
The study is published in the journal Clinical Cancer Research.
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