This retrospective study is the first report to clarify the clinical impact of the use of ACEIs or ARBs in pancreatic cancer. The use of ACEIs or ARBs was associated with longer PFS and OS in patients with advanced pancreatic cancer receiving gemcitabine monotherapy. These data suggest that inhibition of the RAS in human pancreatic cancer may inhibit tumour growth and improve survival, in accordance with previous in vitro studies and in vivo animal studies.
ACEIs and ARBs are widely used as antihypertensive drugs, and the reports of organ protective effects (Grandi and Maresca, 2006
) by ACEIs are increasing, including inhibition of cardiac hypertrophy, diabetic nephropathy, and diabetic retinopathy. With respect to anticancer effects, Lever et al (1998
) reported that the long-term use of ACEIs reduced the incidence of cancer in a prospective cohort study, though they did not explore the underlying mechanisms. Since then, in addition to cardiovascular homostasis by the systemic RAS, increasing evidence indicates a role of the local RAS in various aspects of carcinogenesis, including angiogenesis, cell proliferation, apoptosis, and inflammation (Ager et al, 2008
; Khakoo et al, 2008
). On the other hand, a meta-analysis denied the reduced cancer incidence with ACEIs (Coleman et al, 2008
) and the increased risk of cancer incidence was also reported with ARBs (Sipahi et al, 2010
). Both the clinical impact of inhibition of RAS on cancer incidence and its underlying mechanism remains unclear.
The existence of the local RAS was first reported in the canine pancreas in 1991 (Chappell et al, 1991
) and in the human pancreas in 1999 (Tahmasebi et al, 1999
). The local pancreatic RAS has been implicated in various physiological conditions including pancreatitis, fibrosis, and diabetes mellitus (Leung, 2007
). The involvement of the local RAS in pancreatic cancer was suggested because of the expression of angiotensin II (Ohta et al, 2003
) and the angiotensin II type-1 receptor (Fujimoto et al, 2001
) in human pancreatic cancer. The ACEIs and ARBs inhibit pancreatic cancer cell proliferation in vitro
(Arafat et al, 2007
) and also slow murine pancreatic cancer progression in vivo
via down-regulation of VEGF expression (Noguchi et al, 2009
; Fendrich et al, 2010
). Inhibition of RAS is also reported to induce apoptosis in pancreatic cancer cells (Amaya et al, 2004
; Gong et al, 2010
). Accordingly, these drugs were suggested to be potential treatments for pancreatic cancer or for the prevention of pancreatic cancer. However, the clinical impact of ACEIs and ARBs in pancreatic cancer treatment has not been fully clarified. With respect to other cancer types, a pilot study reported that ARBs had cytostatic activity in hormone-refractory prostate cancer, as indicated by decreased prostate-specific antigen levels (Uemura et al, 2005
), and the addition of ACEIs/ARBs to platinum-based chemotherapy was associated with prolonged survival in patients with advanced non-small cell lung cancer in a retrospective study (Wilop et al, 2009
). ACEIs in combination with vitamin K were also reported to suppress the recurrence of hepatocellular carcinoma in a prospective study (Yoshiji et al, 2009
It is possible that ACEIs and ARBs have different influences on cancer because ACEIs block both angiotensin II type-1 and type-2 receptors, whereas ARBs block only type-1 receptor. The role of angiotensin II type-2 receptor is less investigated than angiotensin II type-1 receptor, which is shown to induce angiogenesis, proliferation, and inflammation. Angiotensin II type-2 receptor is reported to be both anti- and pro-angiogenetic (Ager et al, 2008
). In this study, there were no significant differences in survival between patients taking ACEIs and ARBs. Our study population was too small to analyze the differences between these two types of drugs.
The disappointing results of combination therapy with gemcitabine and cytotoxic drugs have led to intense investigation of molecular target drugs for pancreatic cancer (Burris and Rocha-Lima, 2008
). Inhibition of VEGF or EGFR failed to demonstrate significant survival prolongation except one trial with erlotinib (Moore et al, 2007
). The inhibition of RAS by ACEI or ARB reportedly influences multiple pathways including angiogenesis, proliferation, and apoptosis, and can be a safe and inexpensive strategy against pancreatic cancer, but a prospective study is warranted to evaluate antitumour effects by the inhibition of RAS.
This study had some limitations. As this was a retrospective study in a single institution and the sample size of the ACEI/ARB group was small, unknown sources of bias may exist in the findings. However, other than age and HT medications, no significant differences were detected in patient characteristics among groups, and the multivariate analysis revealed that ACEI/ARB use remained a significant prognostic factor for both PFS and OS, though we cannot fully correct the bias that patients with HT were much older than patients without HT. Gemcitabine dose intensity and the induction rate of second-line chemotherapy were also similar in the three groups. The results of the non-ACEI/ARB with HT group also excluded the possibility that patients who did not receive antihypertensive drugs had a poorer prognosis. However, a prospective study with a larger population is warranted to confirm our hypothesis.
In conclusion, our retrospective analysis suggests that ACEIs or ARBs in combination with gemcitabine may improve clinical outcomes in patients with advanced pancreatic cancer. We have started a phase I trial of candesartan in combination with gemcitabine, which is currently ongoing (UMIN registration number 000002152).