Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection.

BACKGROUND: Repurposing existing drugs for use in oncology is more efficient, cost-effective and safe than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance. This study assessed the impact of calcium channel blockers (CCB) in pancreatic cancer. METHODS: Retrospective population study of patients undergoing resection (curative intent) of pancreatic ductal adenocarcinoma (SEER-Medicare, 2007-2017). Cox models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, the impact of CCB was assessed separately in patients receiving neoadjuvant chemotherapy. RESULTS: 6,223 patients were included, of whom 660 were prescribed CCB. In total, 591 received neoadjuvant chemotherapy; in this cohort CCB prescription was associated with improved overall survival when adjusting for multiple prognostic factors (aHR = 0.715, 0.514-0.996, P = 0.047). This effect was not observed in patients not receiving neoadjuvant chemotherapy (aHR = 1.082, 0.982-1.191, P = 0.112). CONCLUSION: CCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy, mirroring the chemosensitising effect in laboratory studies. This defines patients receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.

Calcium channel blockers in pancreatic cancer: increased overall survival in a retrospective cohort study.

Repurposing commonly prescribed noncancer medications for use in oncology has substantial advantages over de-novo development of anticancer drugs. Calcium signalling has been implicated in many of the hallmarks of cancer. Previous in-vitro and in-vivo studies have shown that calcium channel blockers (CCBs) are able to promote apoptosis, inhibit proliferation and prevent invasion and metastasis in a variety of cancer types. This retrospective cohort study aimed to translate this into the clinic by investigating the effect of CCBs on survival in pancreatic cancer. One hundred sixty-four patients with unresectable pancreatic ductal adenocarcinoma were included. Data were collected on CCB prescription, and for a range of other potentially important prognostic factors: ECOG performance status, AJCC cancer stage, chemotherapy regimen, radiotherapy, age, hypertension and sex. Participants prescribed CCB (n = 30) were more likely to be older (P = 0.004) and have hypertension (P < 0.0005); baseline demographics were otherwise similar between groups. On adjusted cox regression patients prescribed CCBs demonstrated significantly improved overall survival; hazard ratio -0.496 (0.297-0.827; P = 0.007). Performance status (P < 0.0005), tumour stage (P < 0.0005), chemotherapy regimen (P < 0.0005), radiotherapy (0.002) and age (P = 0.012) were also independent predictors of survival. The Kaplan-Meier estimated median survival was 15.3 months for patients prescribed CCBs versus 10.1 months for patients not prescribed CCBs (P = 0.131). This study supports previous work suggesting CCBs may be beneficial in pancreatic cancer. Further work on larger datasets will allow for subgroup analysis delineating the effects of specific CCBs in combination with different forms of chemotherapy, paving the way for future prospective studies.

NARCA: A novel prognostic scoring system using neutrophil-albumin ratio and Ca19-9 to predict overall survival in palliative pancreatic cancer.

BACKGROUND AND OBJECTIVES: Several serum based-markers and ratios have been investigated for their prognostic value in pancreatic ductal adenocarcinoma (PDAC). This cohort study aimed to combine these into a novel prognostic scoring system. METHODS: A retrospective cohort study was performed on 145 patients with unresectable histologically-confirmed PDAC. Based on the existing literature the following markers were investigated: neutrophil-lymphocyte ratio (NLR), neutrophil-albumin ratio (NAR), platelet-lymphocyte ratio (PLR), fibrinogen, and Ca19-9. These values were dichotomized about their medians for Kaplan-Meier and Cox regression analysis. RESULTS: Univariate Cox regression revealed statistically significant prognostic value for: NLR, NAR, PLR, fibrinogen, and Ca19-9. When combining these using Cox regression analysis adjusting for other prognostic indicators, only NAR (hazard ratios [HR] = 3.174, P = 0.022) and Ca19-9 (HR = 2.697, P = 0.031) were independent predictors of survival. Combining NAR and Ca19-9 we split the cohort into three "NARCA" groups: NARCA0 = NAR ≤ 0.13 and Ca19-9 ≤ 770, NARCA1 = either NAR > 0.13 or Ca19-9 >770, NARCA2 = NAR > 0.13 and Ca19-9 > 770. Median survival was 20.5, 9.7 and 4.1 months in NARCA0, 1, and 2 respectively ( P < 0.0005, log-rank test). A separate validation cohort confirmed the prognostic significance of the score ( P = 0.048). CONCLUSIONS: Combining NAR and Ca19-9 into a prognostic score allows stratification of unresectable PDAC patients into groups with significantly different overall survival.