A cancer diagnosis and subsequent treatment rightly triggers anxiety in most patients.
Managing those symptoms plays an important role in quality of life. Many patients may benefit from anti-anxiety medications, and they are often prescribed a class of drugs called benzodiazepines.
Now, in a new study published in the American Association for Cancer Research (AACR) journal Clinical Cancer Research, investigators found patients who used any of the benzodiazepine drugs exhibited a 30 percent lower risk for pancreatic cancer-related death. But the researchers also found significant differences in outcomes depending on which benzodiazepine a patient used.
According to the study, patients with pancreatic cancer who took the benzodiazepine lorazepam (brand name Ativan) had shorter progression-free survival than patients who did not. However, patients who took the benzodiazepine alprazolam (brand name Xanax) had significantly longer progression-free survival than patients who did not.
The study was retrospective—meaning it used preexisting data—and although results were “surprising, the results are absolutely not a call for patients to stop taking lorazepam and switch to alprazolam,” says Michael Feigin, Ph.D., Director of the Experimental Therapeutics Graduate Program at Roswell Park Comprehensive Cancer Center (Buffalo, New York), and senior author of the study. “This is just one retrospective study, and patients should talk to their oncologists.”
However, the study is “definitely a call for more research,” he adds. “There’s a real lack of comprehensive studies about how benzodiazepine use may influence cancer outcomes. Most research focuses on response to therapies like immunotherapy or chemotherapy. But cancer patients are also given drugs to help with anxiety and pain. We need to understand just how these drugs can affect the tumor and the tumor microenvironment.”
Using Anti-Anxiety Medications
Benzodiazepines are a class of medications that slow down activity in your brain and nervous system. They’re most often used for treating anxiety and related mental health conditions, as well as brain-related conditions like seizures. Cancer patients are frequently prescribed benzodiazepines to help with such issues resulting from their disease or treatment. Benzodiazepines— which are known as anxiolytic, or anxiety-reducing, drugs—tell your brain to release a neurotransmitter called gamma-aminobutyric acid (GABA). This neurotransmitter has a specific job: It makes your nervous system less active. This has many effects, including a loosening of anxiety. These agents also have a kind of sedative or calming effect on the nervous system.
Feigin credits Abigail C. Cornwell, first author of the study, who at the time of the study was a predoctoral trainee at Roswell Park Comprehensive Cancer Center and is now a postdoctoral fellow at Johns Hopkins Medicine (Baltimore, Maryland). “She came up with the idea during qualifying exams,” Feigin says. “It was pretty amazing. We know drugs like these bind to receptors on the tumor. One of the things these receptors can do is to affect the tumor’s characteristics.
“So the question became do these drugs that bind to receptors affect patient survival. And do they do it in a positive or a negative way.”
He thinks the results of the study were “fascinating,” mostly due to the fact that lorazepam and alprazolam are quite similar. “There are small changes in structure but very different outcomes,” he says. “And that needs to be looked at more.”
The Study Results
The investigators used prescription records to retrospectively assess the association between benzodiazepines and survival outcomes among patients with pancreatic cancer treated at Roswell Park Comprehensive Cancer Center from 2004 to 2020. They also performed mechanistic studies—studies designed to understand biological or behavioral processes—to investigate the effects of lorazepam on pancreatic tumors on a cellular level.
Overall, analyses adjusted for race, age, sex, disease stage and progression, and treatment received showed use of any benzodiazepine appeared linked to a 30 percent reduced risk for pancreatic cancer-related death.
But outcomes varied based on the specific drug used. The two most frequently used benzodiazepines were lorazepam (40 patients) and alprazolam (27 patients). Patients who took alprazolam exhibited a 62 percent reduced risk for disease progression or death, compared with those who did not take alprazolam (42 patients). However, those who took lorazepam exhibited a 3.83-fold higher risk for disease progression or death compared with those who did not take the agent (29 patients).
The investigators also examined the association between lorazepam or alprazolam use and outcomes among individuals with other types of cancer. Alprazolam did not appear to be associated with significant differences in outcomes. But lorazepam seemed to be associated with poor survival among individuals with ovarian, prostate, head and neck, colon, uterine or breast cancers, and melanoma, with elevated risk ranging from 25 percent to 116 percent depending on cancer type.
What Causes the Differences?
The investigators also conducted mouse studies to try to determine lorazepam’s effects on pancreas tumors at the cellular level. Results revealed lorazepam may activate GPR68, a protein that is highly expressed on fibroblasts—a type of cell that contributes to the formation of connective tissue—that support the tumor. GPR68 increases expression of IL-6, which promotes inflammation in the pancreatic tumor microenvironment, resulting in tumor growth.
“Even though the structural changes can be small among benzodiazepines, we think those changes can have a big effect,” explains Feigin. “Lorazepam affected GPR68. But alprazolam had no impact on GPR68. It [alprazolam] also seems to decrease IL-6. So if IL-6 is decreased then inflammation is decreased and tumor growth is impaired.”
Limitations of the Study
The study’s limitations include differences in optimal dosing of benzodiazepines between humans and mice. The researchers did not have access to information about differences in benzodiazepine doses administered to patients. And the mouse experiments were performed on subcutaneously implanted tumors, which have different microenvironments than tumors that develop within the pancreas.
Lorazepam and alprazolam are similar but have some differences. For example, alprazolam works more quickly, but lorazepam lasts longer and leaves the body more quickly, giving it a better safety profile, explains gastrointestinal oncologist Allyson Ocean, M.D., professor of clinical medicine at Weill Cornell Medicine (New York) and chair of the Let’s Win Scientific Advisory Board.
As to the study, Ocean says the study sample size is too small to draw any conclusions. But, she adds, “the study is intriguing. We need more research, since the more we learn about pancreatic cancer the more we can improve the lives of our pancreatic cancer patients.” She also emphasizes the need to talk to your oncology team if you have any questions or concerns.