Abstract
Aim: The renin–angiotensin system (RAS) was investigated as a target for cancer treatment. Patients and Methods: A total of 287 patients with biliary tract cancer (BTC) receiving chemotherapy were retrospectively studied to evaluate the role of inhibition of RAS by angiotensin system inhibitors (ASIs). Progression-free survival (PFS) and overall survival (OS) were compared between 74 patients with hypertension, on ASIs (ASI group), 50 patients with hypertension not on ASIs (non-ASI with HT group) and 163 patients without hypertension (non-HT group). Interactions between the use of ASIs and various subgroups were explored. Results: The median PFS was 3.6, 3.9 and 4.6 months (p=0.495) and the median OS was 11.6, 10.9 and 13.1 months (p=0.668), respectively. The use of ASIs was not associated with OS (hazard ratio 1.00, p=0.975) and no subgroups with better survival were identified. Conclusion: No survival benefit from ASIs was observed in BTC.
The local renin–angiotensin system (RAS) in association with angiogenesis, cell proliferation, or fibrosis has been intensively investigated as a potential target for cancer treatment (1, 2). Increasing evidence has been reported regarding better clinical outcomes in various cancer types from the use of angiotensin system inhibitors (ASIs) (3-7). We previously reported the use of ASIs was associated with better survival in patients with advanced pancreatic cancer (8).
Although in biliary tract cancer (BTC) limited evidence is available on the role of RAS, it is reportedly associated with fibrosis, cancer incidence and survival in chronic liver disease and hepatocellular carcinoma (9-11). The association of RAS and intra- or extra-hepatic BTC was also suggested (12-14). Therefore, we conducted this retrospective analysis of 287 patients with advanced or recurrent BTC receiving systemic chemotherapy in order to evaluate the role of inhibition of RAS in BTC.
Patients and Methods
Patients. Consecutive patients receiving first-line systemic chemotherapy for advanced or recurrent BTC between February 2002 and May 2015 at the University of Tokyo Hospital were retrospectively studied. Data on the use of ASIs, including angiotensin I-converting enzyme inhibitors (ACEIs) or angiotensin II type-1 receptor blockers (ARBs), and other medications were retrospectively retrieved from the medical records. This study was approved by the local Ethics Committee (no.1804).
Treatment outcomes. Tumor response was assessed by computed tomography (CT) using Response Evaluation Criteria In Solid Tumors (RECIST) criteria (15). The evaluation was repeated every two courses (every 6 to 12 weeks depending on the regimens), or more frequently in patients with clinically suspected progression. Tumor response, progression-free survival (PFS) and overall survival (OS) were compared among patients with hypertension on ASIs (the ASI group), patients with hypertension not on ASIs (the non-ASI with HT group), and patients without hypertension (the non-HT group).
Statistical methods. PFS and OS were estimated using the Kaplan–Meier method and compared using the log-rank test. The Chi-square test or Fisher's exact test was used to compare categorical variables. The independent t-test or Mann–Whitney U-test was used to compare continuous variables as appropriate.
The univariate and multivariate Cox proportional hazard model was performed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of prognostic factors for OS. In addition, interactions between the use of ASIs for each subgroup were tested with p<0.10 suggesting heterogeneity across subgroups for each factor. Potential prognostic factors and subgroups for interaction included age (<69 or ≥69 years old); gender (male or female); performance status (PS, 0 or ≥1); tumor status (locally advanced, metastatic or recurrent disease), tumor location (intrahepatic or non-intrahepatic); the presence of metastasis in the liver, lung, peritoneum and lymph nodes (yes or no); smoking (ever or never smokers); alcohol intake (<50 g/day or ≥50 g/day); carcinoembryonic antigen (CEA) (<5.8 or ≥5.8 ng/dl); carbohydrate antigen 19-9 (CA19-9) (<205 or ≥205 IU/l); the use of calcium channel blockers (yes or no) and beta blockers (yes or no); diabetes (yes or no), hyperlipidemia (yes or no); chronic liver disease (yes or no); the use of statins (yes or no) and aspirin (yes or no); and treatment protocol (monotherapy or combination therapy). Age, CEA and CA19-9 were dichotomized by the median value of each parameter. All reported p-values, other than p for interaction described below, were the results of two-sided tests, with p<0.05 considered statistically significant. JMP software version 11.0 (SAS Institute, Inc, Cary, NC, USA) was used for all statistical analyses.
Patient characteristics.
Results
Patients. In total, 287 patients received first-line chemotherapy for advanced or recurrent BTC between March 2002 and May 2015 at The University of Tokyo Hospital, with a median follow-up time of 9.3 months. Administered regimens were gemcitabine monotherapy (n=74), S-1 monotherapy (n=59), gemcitabine and cisplatin (n=57), gemcitabine and S-1 (n=78) and gemcitabine, S-1 and leucovorin (n=19). Among 124 patients with hypertension, 74 patients took ASIs: 61 ARBs and 13 ACEIs. The other antihypertensive medications used in our study population were calcium channel blockers (n=84) and beta blockers (n=17).
Patient characteristics of three groups are shown in Table I. There were significant differences only in age and the prevalence of diabetes and hyperlipidemia between the three groups.
Treatment outcomes. In the total cohort of 287 patients with advanced or recurrent BTC, the response rate was 13.6% (95% CI=10.1-18.0%), and the median PFS and OS were 4.0 (95% CI=3.6-5.0) and 12.3 (95% CI=10.9-14.7) months, respectively.
When three groups categorized by hypertension and the use of ASIs were compared, there were no significant differences in clinical outcomes. Response rates were 10.8% (95% CI=5.6-19.9%), 14.0% (95% CI=7.0-26.2%) and 14.7% (95% CI=10.1-21.0%) in the ASI, non-ASI with HT and non-HT groups (p=0.727), respectively. The median PFS was 3.6 (95% CI=2.8-5.5) months, 3.9 (95% CI=1.9-6.7) months and 4.6 (95% CI=3.6-5.2) months and the median OS was 11.6 (95% CI=8.4-18.0) months, 10.9 (95% CI=9.0-17.9) months and 13.1 (95% CI=10.9-15.6) months in the ASI, non-ASI with HT, and non-HT groups (p=0.668), respectively. Kaplan–Meier curves of PFS and OS are shown in Figure 1.
a: Progression-free survival. The median progression-free survival was 3.6 months, 3.9 months and 4.6 months in the angiotensin system inhibitor (ASI), non-ASI with hypertension (HT) and non-HT groups (p=0.495). b: Overall survival. The median overall survival was 11.6 months, 10.9 months and 13.1 months in the ASI, non-ASI with HT and non-HT groups (p=0.668).
The univariate and multivariate analyses of prognostic factors for OS are shown in Table II. The use of ASIs was not associated with OS (HR=1.00, p=0.975) in univariate analysis. PS, lung metastasis and peritoneal dissemination were found to be significant prognostic factors in the multivariate analysis. The association of ASI use with OS was not significant even after matching with those patient characteristics related to ASI use (age, diabetes and hyperlipidemia), with an HR of 1.08 (p=0.647).
Univariate and multivariate analyses of prognostic factors for overall survival.
Cox proportional hazard analyses were then performed to explore subgroups with better survival according to the use of ASIs, but no subgroups associated with better survival were identified (Table III).
Discussion
There have been increasing reports on the association of RAS with prognosis of patients with cancer, including pancreatic cancer (8). In hepatocellular carcinoma, the inhibition of RAS was also reported to be associated with longer OS and recurrence-free survival after radiofrequency ablation (11). Although the association of RAS with BTC development and progression was suggested, especially in intrahepatic BTC (12, 14), there have been no clinical studies investigating the association of prognosis with the inhibition of RAS. In this retrospective analysis of 287 patients receiving chemotherapy for BTC, the inhibition of RAS was not associated with better tumor response, PFS or OS.
In our previous analysis of patients with advanced pancreatic cancer (16), never-smokers, and those receiving gemcitabine monotherapy were likely to show better outcomes by use of ASIs. However, this exploratory analyses in BTC failed to identify any subgroup which would benefit from the inhibition of RAS. In addition, ex vivo experiments suggested medications such as aspirin (17) and statins (18) might have inhibitive effects on cancer development or progression, but no interaction of aspirin or statins with ASIs was identified. In advanced pancreatic cancer, prospective studies (19, 20) failed to demonstrate additional effects of ARB despite positive results in our retrospective study (8), and it is possible that cancer developing in patients who have been on ASIs might behave differently from cancer in patients who start ASIs after cancer development. Subtyping by gene-expression analysis (21), rather than by clinical factors in our study, might be useful to identify any subgroup which would benefit from the inhibition of RAS.
This study has certain limitations. Firstly, this was a single-center, retrospective analysis. Secondly, our study population was heterogeneous, including patients with various sites of BTC with different disease stages, compared with our previous report on advanced pancreatic cancer (8). Therefore, the number of patients in subgroup analyses was too small, and a large-scale study might identify some subgroups which would benefit from ASIs.
Subgroup analyses for overall survival.
In conclusion, no survival benefits from the use of ASIs were observed in patients receiving chemotherapy for advanced or recurrent BTC in our retrospective analysis.
- Received July 27, 2016.
- Revision received August 9, 2016.
- Accepted August 18, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
