Recurrence after surgery for colorectal cancer (CRC) declined by almost two-thirds in patients who received a short course of a COX2 inhibitor and a beta blocker, a small randomized trial showed.
Patients who received the drugs for 20 days, beginning 5 days before surgery, had 3-year disease recurrence rate of 12.5% as compared with 33.3% of placebo-treated patients. An analysis limited to protocol-compliant patients showed no recurrences in the treated group versus 29.4% for the placebo group.
The favorable outcomes in patients who received the COX2 inhibitor and the beta blocker were associated with significant reductions in levels of several biomarkers of malignant and metastatic potential, reported Shamgar Ben-Eliyahu, PhD, of Tel-Aviv University, and colleagues in Cancer.
“Our study shows that inexpensive, accessible medication treatment could be used in order to reduce body stress responses and inflammation associated with surgery, which affects that tumor, significantly reducing the risk of metastases that might be detected months or years after surgery,” Ben-Eliyahu said in a statement.
The study added to a growing body of evidence suggesting that reducing systemic stress and inflammation with simple medications may improve clinical outcomes after cancer therapy.
“What’s really interesting about this study is not necessarily that they were able to see these changes, but that it was such a relatively short duration of therapy that induced the changes,” Anurag Singh, MD, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, told MedPage Today.
A limitation of the study, which the authors acknowledged, is that the use of two drugs together complicated efforts to determine which effects might be attributed to which drug, Singh continued. Additionally, certain genetic mutations in colorectal cancer may increase responsiveness to nonsteroidal anti-inflammatory drugs (NSAIDs). The magnitude of benefit observed in the study is similar to what has been reported with the use of aspirin alone.
“That leaves the question of whether it was the etodolac (NSAID) or the propranolol (beta blocker) or the combination,” said Singh. “But as a preliminary, pilot study, the results are very, very exciting.”
Earlier this year, Singh and colleagues reported preclinical evidence that treatment with propranolol reduced adrenergic stress, which was associated with reduced tumor growth following radiation therapy. They subsequently reported data from a retrospective cohort study showing that NSAID use was associated with improved survival following chemoradiation for head and neck squamous cell carcinoma.
Ben-Eliyahu and colleagues reported findings from a randomized trial involving 34 patients with nonmetastatic, operable CRC. The patients were randomized to receive etodolac and propranolol or placebos, beginning 5 days before surgery and continuing for 15 days afterward. The primary clinical outcomes were safety and disease recurrence. Investigators also performed gene profiling of tumor specimens and bioinformatics analyses.
The tumor analyses showed that treatment with the NSAID and the beta blocker was associated with statistically significant (P<0.05) changes in molecular markers related to malignant transformation and metastasis: reduced epithelial-to-mesenchymal transition, reduced tumor infiltrating CD14+ monocytes and CD19+ B cells, and increased tumor infiltrating CD56+ natural killer cells. Transcription analyses suggested a favorable impact on multiple hypothesized CRC-related transcription factors associated with beta-adrenergic and prostaglandin signaling.
“Alterations observed in these transcriptional activities were previously associated with improved long-term clinical outcomes,” the authors noted.
By intention-to-treat (ITT) analysis, two of 16 patients treated with etodolac and propranolol had disease recurrence at 3 years as compared with six of 18 randomized to placebo (P=0.239). Per-protocol analysis showed no recurrences in 11 patients who received the active drugs versus five of 17 in the placebo arm (P=0.054).
The ITT and per-protocol analyses showed similar rates of drug-related and postoperative adverse events in the two treatment groups.
“In general, these data add to the growing body of literature supporting the use of beta-blockers and anti-inflammatory drugs in the treatment of cancer,” stated Vikas P. Sukhatme, MD, ScD, of Emory University in Atlanta, and colleagues in an accompanying editorial. “More specifically, this study demonstrates a legitimate signal that justifies a larger trial evaluating the efficacy of the combination of propranolol and etodolac.”
They also called for more detailed analyses of molecular changes associated with the treatment, nothing that “demonstration of significant changes in the transcription profiles of treated tumors compared with untreated ones does not necessarily prove a change in the actual immune profile in the tumor or the blood.”
The study was supported by the Israel Science Foundation.
Ben-Eliyahu and co-authors disclosed no relevant relationships with industry.
Sukhatme disclosed relevant relationships with Berg Pharma and HiFiBiO, as well as being the founder of Victa Biotherapeutics, co-founder of Morningside Center for Innovative and Affordable Medicine, and co-founder of GlobalCures.