Medication Used in Cancer Care may be Linked to Worse Outcomes
Lorazepam used to relieve stress may cause inflammation that promotes tumor growth and shortens progression-free survival, study says.
A medication commonly used to ease the stress caused by cancer diagnosis and treatment may be linked to worse outcomes, scientists say.
In a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research, patients who took the medication lorazepam (Ativan) during cancer treatment had a shorter progression-free survival time than patients who didn’t, the study found. Progression-free survival is the time the patient lives with the disease without the cancer getting worse.
In contrast, patients who took a similar medication called alprazolam (Xanax) had a significantly longer progression-free survival than patients who did not, the study reported.
“I think it’s too early to say patients should stop taking one drug or start taking another drug,” said Michael Feigin, PhD, an associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and senior author of the study. “There’s a lot more to learn in terms of the clinical implications.”
Lorazepam and alprazolam are both in the class of drugs called benzodiazepines, which suppress the activity of the central nervous system to relieve symptoms of anxiety, insomnia, and seizures. Cancer patients are frequently prescribed benzodiazepines to help with such problems resulting from their disease or treatment.
“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 colleagues determined that, among patients treated at Roswell Park for prostate cancer, pancreatic cancer, ovarian cancer, kidney cancer, head and neck cancer, endometrial cancer, colon cancer, breast cancer, brain cancer, or melanoma, 30.9% had received benzodiazepines; patients with pancreatic cancer had the highest rate of benzodiazepine use at 40.6%.
The researchers then examined the relationship between benzodiazepine use and survival in patients with pancreatic cancer. When they adjusted for age, race, sex, disease stage and progression, and treatments received, any benzodiazepine use was associated with a 30% lower risk of pancreatic cancer-related death.
However, when Feigin and colleagues studied the relationship between individual benzodiazepines and pancreatic cancer outcomes, they found stark differences.
Apart from short-acting benzodiazepines used as part of surgical anesthesia, the two most commonly 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 with those who did not take alprazolam (42 patients). Conversely, patients taking lorazepam had a 3.83-fold higher risk of disease progression or death than patients who did not take lorazepam (29 patients).
When the researchers investigated the associations between lorazepam and alprazolam use and patient outcomes in other cancer types, they found that alprazolam was rarely associated with significantly different outcomes. However, lorazepam use correlated with significantly worse overall survival in prostate, ovarian, head and neck, uterine, colon, and breast cancer, as well as melanoma, with effects ranging from a 25% increased risk to a 116% increased risk. 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.”
Abigail Cornwell, first author of the study and a graduate student in Feigin’s lab, led studies showing that 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, which promotes inflammation in the pancreatic tumor microenvironment, leading to increased tumor growth.
But some drugs in the benzodiazepine category could activate the protein, and some had no effect on it.
“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.”
This study was funded by the National Cancer Institute of the National Institutes of Health, the Roswell Park Alliance Foundation, and the Fifth District AHEPA Cancer Research Foundation, Inc. Feigin declares no conflicts of interest.