Effect of coadministered beta blocker and COX-2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) paclitaxel.

Abstract

302 Background: Paclitaxel protein-bound particles nab-paclitaxel plus gemcitabine is rapidly becoming the standard of care for patients with metastatic adenocarcinoma of the pancreas (mPCa). Preclinical and clinical studies of beta-blockers and NSAIDs show a benefit of these drugs in pancreatic cancer. The aim of this study was to evaluate the impact of the co-administration of the beta blocker propranolol (P) and the selective COX-2 inhibitor etodolac (E) on survival of patients with mPCa receiving GemNab as standard of care. PE is presumed to target the adrenergic and prostaglandin stress systems activated in cancer that induce changes in tumor microenvironment, immune system, and HPA axis leading to tumor promotion and immune tolerance. Data on the use of nab-paclitaxel plus gemcitabine (GemNab) with a beta blocker and NSAID in the clinical setting is lacking. Methods: Patients with mPCa were eligible for this randomized investigator initiated trial. Patients received PE daily for one week prior to starting GemNab. PE was administered in a chronodosed regimen to maximize the therapeutic benefit and minimize side effects. The primary endpoint was survival. Twenty-three patients were randomized to either GemNab or GemNab after one week of propranolol and etodolac (PEGemNab). The median age was 62.8 years; 68.2% male. Pain at time of diagnosis as reported in 80% of the patients in the GemNab arm and in 76.9% of the PEGemNab arm and jaundice was observed in 40% and 23% of the GemNab and PEGemNab arms, respectively. Results: Progression free survival was 7.2 and 11.8 months in the GemNab and PEGemNab arms, respectively. Overall survival was 10.5 months for the GemNab arm and 15.9 months for the PEGemNab arm. The treatment was well-tolerated with no unexpected adverse events. Conclusions: Administration of PE one week prior to Paclitaxel protein-bound particles with gemcitabine significantly increased progression free and overall survival. No unexpected adverse reactions were seen. Additional data on cytokine and cancer markers will be presented.

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

“…The same group also reported on a small (n = 37) single centre open-label trial of gemcitabine and nab-paclitxel (GemNab) with and without VT-122 in patients with locally advanced or metastatic pancreatic cancer [85]. Patients in the GemNab + VT-122 arm (n = 20) were treated with VT-122 for one week prior to commencement of GemNab, and then continuously with GemNab.…”

Immunological and pleiotropic effects of individual β-blockers and their relevance in cancer therapies

“…Most importantly, a randomized investigator-initiated and prospective study on metastatic adenocarcinoma of pancreas reported that administration of propranolol and COX-2 inhibitor etodolac (PE) 1 week prior to the start of chemotherapy with nab-paclitaxel and gemcitabine (GemNab) improved progression-free survival (7.2 vs. 11.8) and overall survival (10.5 vs. 15.9 months) in comparison to GemNab treatment alone. [13] Of an interesting note, the largest retrospective cohort study on a single β-blocker that compared the effects of long-term carvedilol use (n = 6771) against nonuse (n = 6771) was recently published with median follow-up of 5.17 years, which reported significant reduction of cancer risk across all cancer sites (HR 0.74: 95% CI = 0.63-0.87, p < 0.001), with maximum risk reduction in stomach (HR 0.30: 0.14-0.63, p < 0.05) and lung (HR 0.59: 95%CI = 0.37-0.94, p < 0.05) cancers [14] (Table 2). Interestingly, it also reported insignificantly reduced risk of hematological malignancy (HR 0.67: 95%CI = 0.27-1.63), head and neck (HR 0.68: 95%CI = 0.38- Chemopotentiating effects of the β-blockers aforementioned have been also reported in numerous preclinical studies concerning conventional cytotoxins and cancer immunotherapeutics.…”

“…These studies rarely assessed the effects of individual β-blockers, and the number of patients on each agent was often too small for a reliable analysis. Thus far, propranolol is the only β-blocker with individually reported clinical therapeutic utility in cancer treatment through both retrospective and randomized-prospective investigations, [12,13] although replicating studies have not been reported yet. Meanwhile, preclinical study findings thus far suggest carvedilol, nebivolol, and propranolol as promising candidate β-blockers with therapeutic effects as adjuvants to cytotoxins or immunotherapeutic treatments.…”

Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention

“…The preclinical studies presented here suggest that β-blockers could be used to complement existing chemotherapeutic strategies to improve cancer outcome in patients with pancreatic cancer [ 44 , 77 , 86 ]. While a small retrospective study did not support this concept [ 123 ], positive results were obtained in a recent prospective trial [ 124 ]. The study was a randomized, open-label, single-center clinical trial to compare the effectiveness of propranolol plus etodolac, a COX-2 inhibitor, in combination with gemcitabine plus nab- paclitaxel [ 124 ].…”