By Heather Lindsey
Retrospective studies in women with advanced ovarian cancer have shown improved survival in those who are current and past users of nonselective beta-blockers.
In a recent feasibility trial, researchers determined that adding nonselective beta-blockers to intraperitoneal (IP) or IV chemotherapy in women with primary peritoneal (EOC) cancer is safe (Gynecol Oncol 2017; http://dx.doi.org/10.1016/j.ygyno.2017.03.058).
The combination could also benefit patients, although more research is needed, said lead study author Premal H. Thaker, MD, MS, Associate Professor of Obstetrics and Gynecology in the Division of Gynecologic Oncology at Washington University School of Medicine in St. Louis. She and her colleagues observed recurrence and mortality rates that were "encouraging based on the typical recurrence and mortality rates for this disease."
Based on this study, nonselective beta-blockers appear safe during primary chemotherapy, commented Kevin Holcomb, MD, Director of Gynecologic Oncology at Weill Cornell Medicine and NewYork-Presbyterian Hospital.
Thaker and her colleagues conducted a prospective study of patients who were started on 40 mg twice daily of oral propranolol 2-3 days before surgery. After intraoperative confirmation of disease, patients were again started on propranolol. It was given with the treating oncologist's choice of standard chemotherapy for 6 cycles. Patients were weaned off the study drug after completion of chemotherapy.
Of 84 enrolled patients, 35 had confirmed EOC and continued taking propranolol.
"Of the 25 evaluable patients, 22 could tolerate the dose that we started them on," said Thaker. Three patients needed a reduced dose of propranolol after the first round of chemotherapy because of hypotension.
Twenty-five women completed propranolol along with 6 cycles of IP (n = 13), dose-dense IV (n= 7), and every 3-week IV chemotherapy (n = 5). Four patients received bevacizumab. One patient was only able to complete 4 cycles of IV chemotherapy
During a 5-year follow-up period, seven patients did not experience a cancer recurrence, 10 have recurrent disease, and eight have died, Thaker reported.
The researchers also conducted a multiplex analysis of 23 cytokines. Compared to baseline blood samples, they observed substantial reductions in circulating proangiogenic molecules, for example, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), interleukin 8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1).
A Well-Tolerated Drug
Propranolol, which is commonly given for blood pressure, problems with heart rate, and migraine, is typically well-tolerated, although rebound tachycardia and hypotension can be side effects, noted Thaker.
In the study, fatigue was common in patients, although whether this side effect was because of the propranolol, the chemotherapy, or having recently undergone surgery is unknown, she explained. Other potential side effects of propranolol include nausea, vomiting, diarrhea, constipation, and stomach cramps, according to Holcomb.
What propranolol mechanisms are benefiting patients "is the million-dollar question," said Thaker. She and her colleagues are still sifting through data from blood and tumor samples taken at several time points during the study; however, she theorizes that the drug may work through antiangiogenic and anti-inflammatory pathways. Specifically, VEGF and IL-6 and IL-8 may play a role in deterring cancer growth.
Holcomb noted that psychosocial stress results in the release of catecholamines from the adrenal gland, including noradrenaline and adrenaline. "These substances have been shown to impede the host immune response, increase tumor cell migration and invasion, and increase the release of proangiogenic factors," he said. "Non-selective beta-blockers have been shown to block these negative effects of the stress response in preclinical models."
Strengths & Limitations
One study strength is that it was a prospective trial with various chemotherapy routes, noted Thaker. Researchers observed tolerability across IP as well as IV chemotherapy, weekly or every 3 weeks. "We also have strong translational correlates," she said, referring to the blood and tumor samples that are giving researchers insight into the tumor microenvironment.
However, one limitation of the study is that it included a small number of patients from a single institution, Holcomb said.
Thaker would like to see studies exploring whether propranolol is an economical and practical drug to give patients. She would also like to see randomized trials of the drug with chemotherapy and potentially as a maintenance therapy.
Other research has shown that propranolol may deter other cancer types such as sarcoma, melanoma, and breast cancer, "So this may be something that is pertinent not just to ovarian cancer patients, but can also work in other disease sites," she said.
"A prospective randomized evaluation of non-selective beta-blockers in women with advanced ovarian cancer with survival as the primary endpoint will be required to definitively determine the impact of this intervention," concluded Holcomb. In keeping with the goal of individualized cancer treatment, future studies need to stratify the various histologic and molecular types of ovarian cancer, he added.
Heather Lindsey is a contributing writer.