Sage Journals: Discover world-class research

Abstract

Background

Inhibition of the renin–angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies.

Objective

The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC).

Methods

Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survival (OS) was evaluated in univariate and multivariate analyses.

Results

In the Vienna cohort, 43 of 156 patients received RASi for hypertension. RASi treatment was associated with longer OS (11.9 vs. 6.8 months (mo); p = 0.014) and remained a significant prognostic factor upon multivariate analysis (HR = 0.6; 95% CI 0.4–0.9; p = 0.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5 mo) compared to those treated with either sorafenib (10.9 mo) or RASi (9.7 mo) alone (p = 0.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (n = 76).

Conclusion

RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A.

Keywords

Hepatocellular carcinoma renin–angiotensin system angiotensin-converting enzyme inhibitor angiotensin II receptor blocker sorafenib

Introduction

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality globally.¹ HCC usually develops in patients with underlying liver cirrhosis, predominantly caused by chronic viral hepatitis or alcohol consumption,^2–4 and nonalcoholic steatohepatitis (NASH) as rapidly growing cause in Western countries.⁵ Treatment of HCC depends on tumor stage, liver function, and general condition of the patient.³ Potential curative treatment options are reserved for patients with small tumors and well-preserved liver function.³ As patients who develop HCC are usually asymptomatic, about 50% of all patients are diagnosed at advanced tumor stages, where only systemic medical treatment is available.³ The oral multikinase inhibitor sorafenib, a pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI), remains the only efficacious treatment in first-line, and provides a modest prolongation of median overall survival (OS) (2.8 months).⁶ A closely related TKI drug (regorafenib) recently showed increased OS in second-line (after sorafenib failure).⁷ None of the other agents tested in the first-line or second-line setting in advanced HCC showed a survival benefit versus sorafenib or placebo.⁸ Thus, there is still an urgent need for further improvements in the treatment of this deadly disease.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are widely prescribed antihypertensive drugs, and may also have beneficial effects in cancer patients. ACEi/ARB use was associated with reduced risk of breast cancer recurrence,⁹ increased tumor response in rectal cancer,¹⁰ and longer OS in patients with pancreatic, renal cell (RCC), lung, and brain cancer.^11–16 However, it was recently reported that the use of renin–angiotensin system inhibitors (RASi) at baseline was not a significant independent prognostic factor for improved survival in a pooled analysis of metastatic RCC patients treated with pazopanib or sunitinib.¹⁷

There is some evidence that these drugs could have beneficial effects in patients with HCC.^18–21

Here, we assessed the association between RASi and survival in a cohort of 156 patients with HCC and Child-Pugh class A treated with sorafenib or experimental/supportive therapy, and confirmed the results in an independent cohort of 76 Child-Pugh A patients treated with sorafenib.

Materials and methods

Patients

Vienna cohort

Patients ≥ 18 years diagnosed with HCC at the Division of Gastroenterology & Hepatology, Medical University of Vienna between December 1992 and January 2013 who received sorafenib or – especially before the sorafenib era – experimental therapy (not standard according to current guidelines,³ e.g. rapamycin, octreotide, thalidomide, etc.) or best supportive care (BSC) as first-line therapy were eligible for this study. Patients treated with surgery or local ablative treatment (i.e. percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization (TACE)) were excluded from this analysis. Treatment decision was based on an interdisciplinary approach involving hepatologists, interventional radiologists, and surgeons. According to current recommendations for HCC trials,²² and due to the potential severe side effects (hypotension, renal insufficiency/failure) of RAS inhibitors in advanced cirrhosis,²³ representing a potential source of bias, only patients with Child-Pugh class A were included into this study. We then identified HCC patients that received ACEi or ARB for treatment of arterial hypertension and investigated the effect of RASi on survival. The retrospective analysis of these data was approved by the Ethics Committee of the Medical University of Vienna.

Mainz cohort

Patients ≥ 18 years with HCC who received sorafenib treatment at the University Medical Center, Johannes Gutenberg University Mainz between January 2007 and April 2016 were eligible. These patients were screened for ACEi and ARB therapy for arterial hypertension. Similar to the Vienna cohort, only patients with Child-Pugh class A were included and treatment decision was based on an interdisciplinary consensus. The retrospective analysis of the data was approved by the local Ethics Committee.

Data collection

Data were collected retrospectively and entered into a database in both cohorts. The date of HCC diagnosis (Vienna cohort) and the date of sorafenib start (Mainz cohort) were considered the baseline of this study.

Statistical analysis

Baseline characteristics were summarized using descriptive statistics. A chi-square test or Fisher’s exact test were used to compare nominal data. A t-test was used to compare metric data. The median duration of RASi treatment was calculated from the date of RASi start or date of HCC diagnosis (if RASi was started before diagnosis) until the date of discontinuation or last follow-up visit where RASi intake was confirmed. In patients whose last follow-up visit took place within one month prior to death, we assumed that RASi were taken until death. OS was defined as time from date of diagnosis (date of biopsy if available or diagnostic imaging; Vienna cohort)/sorafenib start (Mainz cohort) until date of death or last contact. Survival curves were calculated using the Kaplan–Meier method and compared by log rank test (univariate analysis). Variables that reached a p-value of < 0.1 were entered into a multivariate analysis. The multivariate analysis was performed using Cox proportional hazard regression. Statistical tests were two-sided and a p-value < 0.05 was considered significant. All statistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL).

Results

Patient characteristics

Of 1050 patients diagnosed with HCC at the Division of Gastroenterology & Hepatology, Medical University of Vienna between December 1992 and January 2013, 447 subjects received sorafenib, experimental therapy, or BSC. Of these, 156 individuals had Child-Pugh class A and were therefore eligible (Figure 1). Forty-three (28%) of these patients already received RASi treatment (ACEi, n = 40; ARB, n = 3) at the time of HCC diagnosis. Patients who received RASi were older (mean age, 69 vs. 64 years) and included more sorafenib-treated subjects (33% vs. 17%) compared to those who were not treated with RASi. All other baseline characteristics were equally distributed and are shown in Table 1. Median follow-up time was 96.6 months and 147 (94%) patients died during follow-up. Median duration of RASi treatment was 12.7 months (95% confidence interval (CI) 2.7–22.6 months).

Figure 1.

Flow chart of patient selection.

Table 1.

Patient characteristics (Vienna cohort).

		RAS inhibitor			Total
		Yes (n = 43)^a	No (n = 113)		n = 156
		n (%)	n (%)	p-value	n (%)
Age (years)	Mean ± SD	69 ± 8.9	64 ± 10.6		65 ± 10.4
	Range	46–86	32–87	0.010	32–87
Sex	Male	32 (74)	94 (83)		126 (81)
	Female	11 (26)	19 (17)	0.214	30 (19)
Etiology	Viral	15 (35)	47 (42)		62 (40)
	Others	28 (65)	66 (58)	0.444	94 (60)
ECOG PS	0	28 (65)	59 (52)		87 (56)
	≥1	15 (35)	54 (48)	0.147	69 (44)
Macrovascular	No	28 (65)	71 (63)		99 (64)
invasion	Yes	15 (35)	42 (37)	0.791	57 (37)
Extrahepatic	No	36 (84)	85 (75)		121 (78)
Metastases	Yes	7 (16)	28 (25)	0.255	35 (22)
BCLC stage	A	6 (14)	6 (5)		12 (8)
	B	12 (28)	24 (21)		36 (23)
	C	25 (58)	83 (74)	0.096	108 (69)
Sorafenib	No	29 (67)	94 (83)		123 (79)
	Yes	14 (33)	19 (17)	0.031	33 (21)
AST (U/L)^b	Mean±SD	71 ± 73.6	74 ± 100.1	0.834	73 ± 93.3
Creatinine (mg/dL)	Mean ± SD	1.11 ± 0.3	1.06 ± 0.5	0.504	1.07 ± 0.5

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperation Oncology Group performance status; RAS, renin–angiotensin system.

ACEi, n = 40; ARB, n = 3.

Missing, n = 1 for RAS inhibitor ‘No’ group.

Of 213 patients treated with sorafenib at the University Medical Center, Johannes Gutenberg University Mainz between January 2007 and April 2016, 76 patients were eligible (Mainz cohort) (Figure 1). Thirty-eight (50%) of these received RASi (ACEi, n = 27; ARB, n = 10; both, n = 1). Nine of the 38 patients (24%) were put on RASi treatment after the start of sorafenib. Patients who received no RASi had higher mean aspartate aminotransferase (AST) levels (111 U/L vs. 69 U/L) and macrovascular invasion (MVI) was seen more frequently compared to those who received RASi (47% vs. 16%). All other variables were evenly distributed between both groups (Table 2). Median follow-up was 48.9 months and 56 (74%) patients died during the observation period. Median duration of RASi treatment was 12.9 months (95% CI 6.1–19.7 months).

Table 2.

Patient characteristics (Mainz cohort).

		RAS inhibitor			Total
		Yes (n = 38)^a	No (n = 38)		n = 76
		n (%)	n (%)	p-value	n (%)
Age (years)	Mean ± SD	69 ± 7.4	67 ± 10.1		68 ± 8.8
	Range	52–82	38–81	0.353	38–82
Sex	Male	34 (89)	29 (76)		63 (83)
	Female	4 (11)	9 (24)	0.128	13 (17)
Etiology	Viral	19 (50)	13 (34)		32 (42)
	Others	19 (50)	25 (66)	0.163	44 (58)
ECOG PS^b	0	15 (39)	16 (42)		31 (41)
	≥1	21 (55)	21 (55)	0.892	42 (55)
Macrovascular	No	32 (84)	20 (53)		52 (68)
invasion	Yes	6 (16)	18 (47)	0.003	24 (32)
Extrahepatic	No	15 (39)	17 (45)		32 (42)
Metastases^c	Yes	21 (55)	20 (53)	0.713	41 (54)
BCLC stage^d	A	2 (5)	1 (3)		3 (4)
	B	4 (11)	4 (11)		8 (11)
	C	30 (79)	32 (84)	0.888	62 (82)
Prior therapy	None	9 (24)	17 (45)		26 (34)
	Surgery	6 (16)	6 (16)		12 (16)
	Local ablative	14 (37)	9 (24)		23 (30)
	Surgery+local ablative	9 (24)	6 (16)	0.246	15 (20)
AST (U/L)^e	Mean±SD	69 ± 38.5	111 ± 92.6	0.014	90 ± 73.2
Creatinine (mg/dL)^f	Mean ± SD	1.17 ± 0.7	1.00 ± 0.3	0.180	1.09 ± 0.5

ACEi, n = 27; ARB, n = 10; both, n = 1.

b–d

Missing, n = 2 for RAS inhibitor ‘Yes’ group and n = 1 for RAS inhibitor ‘No’ group.

Missing, n = 1 for RAS inhibitor ‘No’ group.

Missing, n = 4 for RAS inhibitor ‘No’ group.

Univariate and multivariate analyses of prognostic factors

Median OS of the Vienna cohort (n = 156) was 8.3 months (95% CI 6.3–10.2 months). The 1-, 3-, and 5-year survival rates were 36%, 11%, and 4%, respectively.

Treatment with RASi was significantly associated with OS (median OS, 11.9 vs. 6.8 months; 95% CI 6.2–17.6 vs. 5.1–8.5 months; p = 0.014) (Table 3; Figure 2(a)). Eastern Cooperative Oncology Group (ECOG) performance status (PS), extrahepatic spread, AST, and serum creatinine were also significantly associated with OS (p < 0.05 for all variables; Table 3) and therefore included into multivariate analysis. Finally, sorafenib treatment achieved a p-value of < 0.1 and thus was also included (Table 3).

Figure 2.

Kaplan–Meier survival curves. Survival according to renin–angiotensin system inhibitor (RASi) treatment in the Vienna (a) and Mainz cohort (b) and according to treatment with sorafenib (SOR) alone, neither SOR nor RASi, SOR+RASi, and RASi alone in the Vienna cohort (c).

Table 3.

Univariate analysis of prognostic factors (Vienna cohort).

			Overall survival (months)		p-value
		n	Median	95% CI	(log rank)
Etiology	Viral	62	7.4	4.5–10.4
	Others	94	8.8	6.8–10.9	0.622
ECOG PS	0	87	11.5	6.2–16.9
	≥1	69	6.3	5.0–7.6	<0.001
Macrovascular	Absent	99	9.3	7.4–11.3
invasion	Present	57	6.4	5.4–7.4	0.126
Extrahepatic spread	Absent	121	9.6	6.8–12.4
	Present	35	6.8	5.1–8.5	0.026
RAS inhibitor	No	113	6.8	5.1–8.5
	Yes	43	11.9	6.2–17.6	0.014
Sorafenib	No	123	7.3	5.4–9.2
	Yes	33	13.8	9.4–18.3	0.061
AST (U/L)^a	<100	129	9.6	7.2–11.9
	≥100	26	5.1	1.8–8.3	<0.001
Creatinine (mg/dL)^b		156			<0.001

AST, aspartate aminotransferase; ECOG PS, Eastern Cooperation Oncology Group performance status; RAS, renin–angiotensin system.

Missing, n = 1.

Continuous variable.

In multivariate analysis, treatment with RASi (HR, 0.6; 95% CI 0.4–0.9; p = 0.011) as well as ECOG PS, extrahepatic spread, sorafenib treatment, AST, and creatinine remained independent predictors of OS (Table 4).

Table 4.

Multivariate analysis of prognostic factors (Vienna cohort).

		Overall survival		p-value
		HR	95% CI	(Cox regression)
ECOG PS	0	1
	≥1	1.8	1.3–2.5	0.001
Extrahepatic spread	Absent	1
	Present	1.5	1.0–2.2	0.047
RAS inhibitor	No	1
	Yes	0.6	0.4–0.9	0.011
Sorafenib	No	1
	Yes	0.6	0.4–1.0	0.032
AST (U/L)^a	<100	1	1
	≥100	2.9	1.8–4.8	<0.001
Creatinine (mg/dL)^b		1.5	1.0–2.0	0.032

AST, aspartate aminotransferase; ECOG PS, Eastern Cooperation Oncology Group performance status; RAS, renin–angiotensin system.

Missing, n = 1.

Continuous variable.

Median survival of the Mainz cohort (n = 76) was 11.6 months (95%CI 9.1–14.2 months) with 1-, 3-, and 5-year survival rates of 47%, 9%, and 3%, respectively. Similar to the Vienna cohort, patients who received RASi had a significantly longer OS (median OS, 13.2 months; 95% CI 10.5–16.0 months) than those who did not receive RASi (median OS, 8.0 months; 95% CI 5.8–10.2; p = 0.005) (see Supplemental table 1 online and Figure 2(b)). ECOG performance status and creatinine were also associated with OS in univariate analysis (Supplemental table 1) and were therefore included in the multivariate Cox regression model. MVI, even though not significantly associated with OS in univariate analysis, was also entered, since MVI was unequally distributed between patients with and without RASi treatment (Table 2). In multivariate analysis, only RASi treatment remained independently associated with OS (HR 0.5; 95% CI 0.3–1.0; p = 0.038) (Table 5).

Table 5.

Multivariate analysis of prognostic factors (Mainz cohort).

		Overall survival		p-value
		HR	95% CI	(Cox regression)
ECOG PS^a	0	1
	≥1	1.8	1.0–3.1	0.055
RAS inhibitor	No	1
	Yes	0.5	0.3–1.0	0.038
Creatinine (mg/dL)^b		1.1	0.6–1.7	0.838
Macrovascular	Absent	1
invasion	Present	1.3	0.6–2.5	0.489

ECOG PS, Eastern Cooperation Oncology Group performance status; RAS, renin–angiotensin system.

Missing, n = 3.

Continuous variable; missing, n = 4.

Association between survival and RASi treatment stratified by sorafenib therapy

In the Vienna cohort, subgroup analysis showed that patients treated with sorafenib plus RASi (n = 14) had a median OS of 19.5 months (95% CI 5.8–33.1 months), subjects receiving sorafenib but no RASi (n = 19) had a median OS of 10.9 months (95% CI 6.0–15.8 months), patients who received RASi but not sorafenib (n = 29) had a median OS of 9.7 months (95% CI 6.6–12.7 months), and those who received neither sorafenib nor RASi (n = 94) had the worst survival of 6.0 months (95% CI 4.7–7.4 months; p = 0.043) (Figure 2(c)). Since all patients in the Mainz cohort received sorafenib treatment we could not perform similar subgroup analysis.

Discussion

We found that RASi treatment was an independent prognostic factor in a cohort of 156 HCC patients with Child-Pugh class A not amenable to surgical or local ablative therapy. We confirmed the association between RASi and OS in an independent cohort of 76 HCC patients treated with sorafenib.

A recently published retrospective study involving 153 HCC patients reported that treatment with ARB was associated with longer OS and time to recurrence after radiofrequency ablation.¹⁸ However, these results have not been validated so far.

The RAS is involved in several tumor-promoting biological processes, such as cell proliferation, metastasis, resisting apoptosis, tumor inflammation, and immunosuppression.^24,25 HCC is a complex disease as it usually develops in patients with liver cirrhosis and is then associated with portal hypertension (PHT) in the majority of cases.^2,3,26 Thus, several other mechanisms may also contribute to the potentially beneficial effects of RASi on HCC survival.

First, RAS inhibition reduces tumor fibrosis/desmoplasia by blocking extracellular matrix (ECM) deposition via inhibition of both myofibroblast activation and expression of the profibrotic cytokine transforming growth factor beta (TGF-β).^27–31 The desmoplastic stroma can act as a barrier to immune cells,³² and cancer-associated fibroblasts can influence the immune system directly by inhibiting T and natural killer cells and by promoting an inflammatory pro-tumorigenic milieu.³³ Hence, the desmoplastic milieu can promote resistance to immunotherapy.^34,35 Additionally, tumor desmoplasia contributes to blood vessel compression by increasing tissue stiffness and solid stress. The reduced tumor perfusion and the resulting hypoxia further support the immunosuppressive microenvironment, promote the selection of more invasive tumor cells, and lower the efficacy of certain treatment modalities.^30,36,37 In several solid malignancies including cholangiocarcinoma, tumor desmoplasia occurs as a secondary event in response to tumor growth, wherein malignant cells drive stromal fibroblasts to produce and deposit ECM.^27,30,38

In contrast, liver fibrosis and cirrhosis represent a procarcinogenic microenvironment that promotes development and progression of HCC, a tumor type not considered to be highly desmoplastic.³⁸

However, it was recently shown that blocking the activation of hepatic stellate cells and their transformation to myofibroblasts can attenuate tumor desmoplasia in HCC.³⁹ Sorafenib increased tumor desmoplasia by intensifying tumor hypoxia which led to increased myofibroblast infiltration and differentiation via upregulation of the stromal-derived factor 1 alpha (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR-4) pathway and increased Gr-1(+) myeloid cell infiltration. Inhibition of the SDF-1α/CXCR-4 pathway or Gr-1(+) myeloid cell infiltration reduced hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.³⁹

Second, the antifibrotic effects of RASi do not only reduce tumor desmoplasia but also inhibit the progression of liver fibrosis, as shown by several preclinical and clinical studies.^40–46 Given the facts that most HCC patients suffer from concomitant liver fibrosis/cirrhosis,^2,3 and that the non-tumoral surrounding liver tissue and the degree of liver dysfunction represent the main prognostic factors in HCC patients,^4,47–50 the attenuation of liver fibrosis progression might also contribute to the improved survival associated with RASi treatment.

Third, the inhibition of angiotensin II type 1 receptor (AT₁R)-mediated angiogenesis (via reducing VEGF production) represents another important mechanism.^51–55 Notably, the combination of sorafenib and losartan attenuated the development of preneoplastic lesions in a non-diabetic rat model of steatohepatitis along with a reduction of hepatic neovascularization and VEGF.²¹ Other preclinical studies investigated ACEi/ARB in the preventive setting,^56–58 or in established tumors,^59–61 in different rodent models of HCC and found that these drugs, alone or in combination with other treatments, were able to inhibit HCC development and growth, respectively. These studies proposed the downregulation of VEGF expression and the consecutive reduction of angiogenesis as potential mechanism of action.^56–61 The combinations of the ACEi perindopril with vitamin K,²⁰ and with branched-chain amino acids,¹⁹ were investigated prospectively in patients who underwent curative treatment for HCC, based on preclinical efficacy data on HCC prevention and tumor growth delay.^62–64 Both clinical studies reported that the combination treatment but not perindopril monotherapy was able to significantly reduce tumor recurrence. This effect was associated with a downregulation of circulating VEGF and soluble VEGF receptor 2 levels in blood.^19,20

Finally, patients with HCC often suffer from portal hypertension (PHT),^3,26 and complications of PHT (i.e. variceal bleeding) represent a common cause of death in patients with HCC. The RAS is implicated in the pathogenesis of PHT since it increases intrahepatic resistance by inducing proliferation and contraction of hepatic stellate cells, profibrogenic TGF-β signaling, and ECM deposition.^23,28,29,31 Moreover, as discussed above, angiotensin is also involved in angiogenesis,⁵¹ which is not only a hallmark of cancer but also of PHT.^65,66 Indeed, several studies of RASi for PHT showed promising results.^67–70 In a meta-analysis²³ of 19 controlled trials, ACEi/ARB treatment reduced portal pressure in Child-Pugh A patients (−17%; 95% CI: −28 to −6) without adverse events. The authors concluded that the efficacy and safety of this group may be owed to a targeted effect on the local hepatic renin–angiotensin–aldosterone (RAAS) system while patients with more advanced/decompensated cirrhosis risk hypotension and renal insufficiency due to activation of the systemic RAAS.²³

This study has several limitations including the small number of patients in some subgroups and the retrospective nature of this study with all its possible shortcomings (e.g., potential impact of unmeasured confounders). However, the well-balanced baseline characteristics between the RAS inhibitors “yes” and “no” groups, the alignment of the survival of sorafenib-treated HCC patients with the survival reported in the SHARP phase III trial,⁶ and the confirmation of the data in an independent cohort support the validity of our data.

In conclusion, RASi were associated with improved survival in HCC patients treated with sorafenib. Several mechanisms may contribute to the beneficial effects of RASi on survival including reduction of tumor desmoplasia and liver fibrosis, improvement of anti-tumor immunity, decrease of portal pressure, and inhibition of angiogenesis. Thus, RASi might be most effective in patients with HCC and early-stage liver cirrhosis when combined with treatment modalities that induce hypoxia and consequently desmoplasia, immunosuppression, and VEGF expression (e.g., sorafenib, TACE). ACEi/ARB might also be a reasonable combination partner for immunotherapy. These promising results should encourage prospective evaluation.

Footnotes

Declaration of conflicting interests

M.P. received travel support and speaking fees from Bayer; A.W. received lecture and travel fees from Bayer Vital; M.A.W. received consulting and lecture fees from Bayer HealthCare; F.H. received travel support from Bayer; S.B. received travel support from Bayer; J.U.M. has no conflicts of interest; D.G.D. received research grants from Merrimack, Bayer and HealthCare Pharma; R.K.J. received consultant fees from Ophthotech, SPARC, SynDevRx, XTuit, owns equity in Enlight, Ophthotech, SynDevRx, XTuit, and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund; P.R.G. is consultant and speakers bureau member of Bayer Healthcare; P.R.G. received consulting and lecture fees from Bayer HealthCare, Lilly, BMS, MSD, Sillajen, Arqule, Sirtex, Blueprint; M.T. serves as a consultant for Albireo, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and is a member of the speakers' bureau of Falk, Gilead, MSD, Roche. He received travel grants from Falk, Roche, Gilead and unrestricted research grants from Albireo, Falk, Intercept, MSD. He is also co-inventor of a patent on the medical use of norUDCA. M.P.R. is an investigator for AbbVie, Arqle-Daiichi, Bayer, BMS, Boehringer-Ingelheim, Imclone, Lilly, Novartis, Roche, a speaker and advisor for Abbott, Bayer, BMS, Boehringer-Ingelheim, Lilly, Novartis, Roche, and received grant support from AbbVie, Arqle-Daiichi, Bayer, Roche; W.S. received travel support and speaking fees from Bayer.

Funding

MP is supported by an Erwin-Schroedinger Fellowship by the Austrian Science Fund (FWF; project number J 3747-B28). JUM is supported by grants from the German Cancer Aid (DKH 110989) and the Volkswagen Foundation (Lichtenberg program). DGD and RKJ are supported by NIH grant P01-CA080124.

References

Torre

Bray

Siegel

et al.

Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.

Hucke

Sieghart

Schoniger-Hekele

et al.

Clinical characteristics of patients with hepatocellular carcinoma in Austria – is there a need for a structured screening program?

Wien Klin Wochenschr 2011; 123: 542–551.

European Association for the Study of the Liver. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–943.

Pinter

Trauner

Peck-Radosavljevic

et al.

Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open 2016; 1: e000042–e000042.

Dyson

Jaques

Chattopadyhay

et al.

Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60: 110–117.

Llovet

Ricci

Mazzaferro

et al.

Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–390.

Bruix

Merle

Granito

et al.

Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Ann Oncol 2016; 27(Suppl 2): ii140–ii140.

Llovet

Hernandez-Gea

. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res 2014; 20: 2072–2079.

Chae

Valsecchi

Kim

et al.

Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Invest 2011; 29: 585–593.

10.

Morris

Saha

Magnuson

et al.

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Cancer 2016; 122: 2487–2495.

11.

Keizman

Huang

Eisenberger

et al.

Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer 2011; 47: 1955–1961.

12.

Nakai

Isayama

Ijichi

et al.

Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine. Br J Cancer 2010; 103: 1644–1648.

13.

Wilop

von Hobe

Crysandt

et al.

Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J Cancer Res Clin Oncol 2009; 135: 1429–1435.

14.

Izzedine

Derosa

Le Teuff

et al.

Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma. Ann Oncol 2015; 26: 1128–1133.

15.

Januel

Ursu

Alkhafaji

et al.

Impact of renin–angiotensin system blockade on clinical outcome in glioblastoma. Eur J Neurol 2015; 22: 1304–1309.

16.

Menter

Carroll

Sakoda

et al.

Effect of angiotensin system inhibitors on survival in patients receiving chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer. Epub ahead of print 20 August 2016. DOI: 10.1016/j.cllc.2016.07.008.

17.

Sorich

Kichenadasse

Rowland

et al.

Angiotensin system inhibitors and survival in patients with metastatic renal cell carcinoma treated with VEGF-targeted therapy: a pooled secondary analysis of clinical trials. Int J Cancer 2016; 138: 2293–2299.

18.

Facciorusso

Del Prete

Crucinio

et al.

Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients. J Gastroenterol Hepatol 2015; 30: 1643–1650.

19.

Yoshiji

Noguchi

Ikenaka

et al.

Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial. Oncol Rep 2011; 26: 1547–1553.

20.

Yoshiji

Noguchi

Toyohara

et al.

Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009; 51: 315–321.

21.

Yoshiji

Noguchi

Namisaki

et al.

Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic lesion development in a non-diabetic rat model of steatohepatitis. J Gastroenterol 2014; 49: 1421–1429.

22.

Llovet

Di Bisceglie

Bruix

et al.

Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698–711.

23.

Tandon

Abraldes

Berzigotti

et al.

Renin–angiotensin–aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010; 53: 273–282.

24.

Ager

Neo

Christophi

. The renin–angiotensin system and malignancy. Carcinogenesis 2008; 29: 1675–1684.

25.

George

Thomas

Hannan

. The renin–angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 2010; 10: 745–759.

26.

Pinter

Sieghart

Reiberger

et al.

The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma: a pilot study. Aliment Pharmacol Ther 2012; 35: 83–91.

27.

Chauhan

Martin

Liu

et al.

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 2013; 4: 2516–2516.

28.

Bataller

Gines

Nicolas

et al.

Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000; 118: 1149–1156.

29.

Gressner

Weiskirchen

Breitkopf

et al.

Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002; 7: d793–d807.

30.

Jain

. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 2013; 31: 2205–2218.

31.

Yoshiji

Kuriyama

Yoshii

et al.

Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001; 34: 745–750.

32.

Watt

Kocher

. The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration. Oncoimmunology 2013; 2: e26788–e26788.

33.

Ohlund

Elyada

Tuveson

. Fibroblast heterogeneity in the cancer wound. J Exp Med 2014; 211: 1503–1523.

34.

Feig

Jones

Kraman

et al.

Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 2013; 110: 20212–20217.

35.

Pure

. Can targeting stroma pave the way to enhanced antitumor immunity and immunotherapy of solid tumors? Cancer Immunol Res 2016; 4: 269–278.

36.

Jain

Martin

Stylianopoulos

. The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng 2014; 16: 321–346.

37.

Jain

. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 2014; 26: 605–622.

38.

Lee

Campbell

. Role of desmoplasia in cholangiocarcinoma and hepatocellular carcinoma. J Hepatol 2014; 61: 432–434.

39.

Chen

Huang

Reiberger

et al.

Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 2014; 59: 1435–1447.

40.

Moreno

Gonzalo

Kok

et al.

Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010; 51: 942–952.

41.

Jonsson

Clouston

Ando

et al.

Angiotensin–converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001; 121: 148–155.

42.

Paizis

Gilbert

Cooper

et al.

Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol 2001; 35: 376–385.

43.

Yoshiji

Yoshii

Ikenaka

et al.

Inhibition of renin–angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats. J Hepatol 2002; 37: 22–30.

44.

Corey

Shah

Misdraji

et al.

The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int 2009; 29: 748–753.

45.

Rimola

Londono

Guevara

et al.

Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation 2004; 78: 686–691.

46.

Terui

Saito

Watanabe

et al.

Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology 2002; 36: 1022–1022.

47.

Hoshida

Villanueva

Kobayashi

et al.

Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359: 1995–2004.

48.

Hollebecque

Cattan

Romano

et al.

Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Ther 2011; 34: 1193–1201.

49.

Pinter

Sieghart

Hucke

et al.

Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib. Aliment Pharmacol Ther 2011; 34: 949–959.

50.

Sohn

Paik

Cho

et al.

Sorafenib therapy for hepatocellular carcinoma with extrahepatic spread: treatment outcome and prognostic factors. J Hepatol 2015; 62: 1112–1121.

51.

Okwan-Duodu

Landry

Shen

et al.

Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis. Am J Physiol Regul Integr Comp Physiol 2013; 305: R205–R215.

52.

Egami

Murohara

Shimada

et al.

Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clini Invest 2003; 112: 67–75.

53.

Fujita

Hayashi

Yamashina

et al.

Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth. Carcinogenesis 2005; 26: 271–279.

54.

Ohnuma

Toda

Fujita

et al.

Blockade of an angiotensin type I receptor enhances effects of radiation on tumor growth and tumor-associated angiogenesis by reducing vascular endothelial growth factor expression. Biomed Pharmacother 2009; 63: 136–145.

55.

Otake

Mattar

Freitas

et al.

Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma. Cancer Chemother Pharmacol 2010; 66: 79–87.

56.

Noguchi

Yoshiji

Kuriyama

et al.

Combination of interferon-beta and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis. Clin Cancer Res 2003; 9: 6038–6045.

57.

Yoshiji

Noguchi

Kuriyama

et al.

Combination of interferon and angiotensin-converting enzyme inhibitor, perindopril, suppresses liver carcinogenesis and angiogenesis in mice. Oncol Rep 2005; 13: 491–495.

58.

Tamaki

Nakade

Yamauchi

et al.

Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis. J Gastroenterol 2013; 48: 491–503.

59.

Yanase

Yoshiji

Ikenaka

et al.

Synergistic inhibition of hepatocellular carcinoma growth and hepatocarcinogenesis by combination of 5–fluorouracil and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. Oncol Rep 2007; 17: 441–446.

60.

Nasr

Selima

Hamed

et al.

Targeting different angiogenic pathways with combination of curcumin, leflunomide and perindopril inhibits diethylnitrosamine-induced hepatocellular carcinoma in mice. Eur J Pharmacol 2014; 723: 267–275.

61.

Yoshiji

Kuriyama

Kawata

et al.

The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res 2001; 7: 1073–1078.

62.

Yoshiji

Kuriyama

Noguchi

et al.

Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression. J Hepatol 2005; 42: 687–693.

63.

Yoshiji

Kuriyama

Noguchi

et al.

Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. Oncol Rep 2006; 15: 155–159.

64.

Yoshiji

Noguchi

Kaji

et al.

Attenuation of insulin-resistance-based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats. J Gastroenterol 2010; 45: 443–450.

65.

Hanahan

Weinberg

. The hallmarks of cancer. Cell 2000; 100: 57–70.

66.

Fernandez

Semela

Bruix

et al.

Angiogenesis in liver disease. J Hepatol 2009; 50: 604–620.

67.

Bandyopadhyay

Das

et al.

Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol 2003; 98: 1371–1376.

68.

Debernardi-Venon

Martini

Biasi

et al.

AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol 2007; 46: 1026–1033.

69.

Gonzalez-Abraldes

Albillos

Banares

et al.

Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology 2001; 121: 382–388.

70.

Schneider

Kalk

Klein

. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology 1999; 29: 334–339.

Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma

Abstract

Background

Objective

Methods

Results

Conclusion

Keywords

Introduction

Materials and methods

Patients

Vienna cohort

Mainz cohort

Data collection

Statistical analysis

Results

Patient characteristics

Univariate and multivariate analyses of prognostic factors

Association between survival and RASi treatment stratified by sorafenib therapy

Discussion

Footnotes

Declaration of conflicting interests

Funding

References