Abstract
Background/Aim: Regorafenib is an oral multikinase inhibitor used in later lines for metastatic colorectal carcinoma (mCRC) treatment, but its efficacy and tolerability are low. To improve the response rates and ameliorate adverse effects, different strategies have been implemented. In our study, we examined the effect of statin usage in patients with mCRC treated with regorafenib. Patients and Methods: This single-center retrospective study included patients with mCRC who were treated with regorafenib between January 2015 and December 2023. The primary outcomes were progression-free survival (PFS) and overall survival (OS), and the secondary outcomes were adverse effects and the tolerability of regorafenib. Results: The data of 105 patients were collected retrospectively. The median age of the patients was 66 years, and 60 patients were male. Seventeen patients (16.1%) were receiving statins. Statin-using patients were significantly older than non-users (72 years vs. 66.5 years, p=0.05). Comorbid diseases were more common in patients using statins. The median PFS was 1.9 months for statin users and 4.2 months for statin non-users (p<0.001), and the median OS was 4.7 vs. 6.7 months (p=0.01). Cox regression revealed that statin usage was significantly associated with a higher hazard ratio (HR) for PFS (2.53) and OS (2.06) (both p<0.01 and p=0.02, respectively). Conclusion: Statins are associated with decreased survival and response rates in patients with mCRC treated with regorafenib. However, further studies are needed to confirm these results.
Regorafenib, an oral multikinase inhibitor, is widely used in later lines for the treatment of metastatic colorectal cancer (mCRC), and the effect and tolerability of regorafenib vary from person to person. In the CORRECT trial, which led to the approval of regorafenib in later treatment lines, the survival improvement was lower than expected, but in responders, regorafenib significantly improved progression-free survival (PFS) and overall survival (OS) (1). The tolerability of regorafenib is low, as almost half of the patients experience grade 3-4 toxicities; to increase tolerability, dosing, adverse effect management, and compatibility with other drugs have been investigated (2, 3).
Regorafenib inhibits multiple pathways, including VEGFR-1, VEGFR-2, FGFR1, PDGFR-β, KIT, RET, and BRAF, and due to its multiple pathway inhibition properties, synergistic effects with other drugs have been evaluated (4, 5). A preclinical study by Yuan et al. suggested that rosuvastatin, an antihyperlipidemic agent, could enhance the antitumor effect of regorafenib on tumor cell lines, but this hypothesis has not yet been proven in the clinical setting (6).
The effects of statins on prevalence and survival, as well as potential drug interactions with agents used for the treatment of mCRC, are actively investigated. Lee et al. suggested that statins lower colorectal cancer risk in Korean patients (7). In the CAIRO2 trial, statin usage was shown not to be associated with prolonged survival in patients with mCRC receiving cetuximab therapy (8). Tsubaki et al. suggested that in mouse models, simvastatin enhances the effect of oxaliplatin on tumors through KRAS phenylation, leading to a better antitumor response (9). Mace et al. suggested that statins could also improve the pathological response rate in patients with rectum cancer receiving neoadjuvant treatment (10).
There is a lack of information about statin usage in combination with regorafenib in patients with mCRC. This study assessed the effect of statin usage on survival and adverse effects.
Patients and Methods
The study was designed as a single-center retrospective cohort study. Patients who received regorafenib for mCRC between January 2015 and December 2023 were screened for eligibility. Patients with mCRC who were treated with regorafenib, and aged ≥18 years were included in the study. Patients who lacked drug usage data, were lost to follow-up just after regorafenib initiation, or had an unknown survival status were excluded from the study. All the patient identity data were removed during the data collection process.
Demographics, such as age at diagnosis, sex, comorbidities, and drug usage; disease and treatment-related characteristics, such as severity, primary pathological type, RAS mutation status, lines of treatment received, regorafenib start date, dosage, best response, adverse effects, and tolerance were collected. The drug usage data were extracted from the patients’ records and confirmed with drug usage reports and prescriptions. The adverse effects were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The survival duration started with the first prescription date of regorafenib and ended at the time of radiological progression or death.
The descriptive statistics presented are means and standard deviations for normally distributed variables, medians and 25th-75th percentiles for nonnormally distributed variables, and counts and percentiles for categorical variables. Hypothesis tests were performed with Student’s t-tests for normally distributed variables, Wilcoxon tests for nonnormally distributed variables, and chi-square tests for categorical variables. Survival analyses was performed using the Kaplan-Meier curve and the log-rank test for comparison. Cox regression was used for calculating adjusted and non-adjusted hazard ratios (HRs) and confidence intervals (CI). The statistical analyses were performed with R 4.3.1 (R Foundation, Vienna, Austria).
The institutional ethics committee approved the study protocol (AUTF-KAEK 2024/201), and the study was performed in compliance with the Helsinki Declaration.
Results
A total of 105 patients were enrolled in the study. Sixty-three patients (60%) were male, and 42 patients (40%) were female. The median age of the patients was 66 years. The diseases originated from the left colon and rectum in 86 patients (81.9%) and from the right colon in 19 patients (18.1%). The majority of patients were metastatic at diagnosis, and 67 patients (63.8%) had stage IV disease at diagnosis. Twenty-three patients (21.9%) had stage III disease, 15 patients (14.3%) had stage II disease at diagnosis, and 40 patients (38.1%) had relapsed disease. The most common metastatic site was the liver with 77 patients (73.3%), followed by the lung with 29 patients (27.6%), peritoneum with 14 patients (13.3%), and other metastatic sites with eight patients (7.6%). Molecular profiling revealed that 59 patients (56.2%) had RAS mutations, and four patients (3.8%) had RAF mutations. Hypertension was the most common comorbid disease; 39 patients (37.1%) had hypertension, 19 patients (18.1%) had diabetes mellitus, 15 patients (14.3%) had coronary arterial disease, and 13 patients (12.4%) had hyperlipidemia. Most patients received regorafenib after two treatment lines: 12 patients (11.4%) after first-line treatment, 47 patients (44.8%) after second-line treatment, and 49 patients (40.9%) after third- and more-lines treatment. Seventeen patients (16.1%) in the study were receiving statins. The demographic and disease-related characteristics of the patients are presented in Table I.
Patient demographics and disease-related properties.
Patients treated with statins and regorafenib were significantly older than non-users (72 vs. 66.5 years, p=0.05). There were more male patients, and the sex distribution did not significantly differ between statin users and non-users (p=0.33). Moreover, there was no significant difference between statin users and non-users in terms of right colon-originated or left colon/rectum-originated tumors (p=0.53). The number of metastatic sites did not vary according to statin usage (p=0.32-0.74). Comorbid diseases were more common in statin users than in non-users (p<0.01-0.04). Among statin users, 13 (76.5%) had hypertension, 11 (64.7%) had hyperlipidemia, eight (47.1%) had coronary arterial disease, and six (35.3%) had diabetes mellitus; however, among statin non-users, 2.3% had hyperlipidemia, 7.9% had coronary arterial disease, 14.8% had diabetes mellitus, and 29.6% had hypertension. Among patients not receiving statins, 12 patients (13.6%) received regorafenib as a second-line treatment, approximately half of the patients received regorafenib as a fourth-line treatment, and the previous lines of treatment did not vary among statin users and non-users (p=0.18). The median regorafenib starting dose was 80 mg, and the median maximum tolerated dose was 80 mg in statin users and non-users; moreover, there was no significant difference between the groups (p=0.57-0.70). The incidence of Grade 3-4 toxicities did not differ between patients who received and patients who did not receive statin therapy (p=0.21). Approximately one-quarter of the patients experienced toxicities leading to drug interruption, and the percentages did not significantly differ (p=0.79). The median durations from admission to metastasis were 16.8 months for statin non-users and 20.8 months for statin users; the difference between the two groups was not significant (p=0.44). A comparison of demographic, disease, and treatment-related characteristics between statin users and non-users is presented in Table II.
Comparison of demographic, disease-related and treatment-related characteristics among statin users and non-users.
Nearly half of the statin non-users responded to regorafenib therapy. There was no partial response in statin users. Stable disease rates in statin non-users and users were 47.0% and 25.0%, and progressive disease rates were 49.4% and 75.0%, respectively. The response rates did not differ significantly between the two groups (p=0.04). The best responses to regorafenib therapy are presented in Table III.
Best response to regorafenib in statin nonusers and users.
The median progression-free survival was 4.2 months in patients not receiving statin therapy and 1.9 months in patients receiving statins; this difference was significant (p<0.001). Overall survival was significantly longer in statin non-users (6.7 months in statin non-users and 4.7 months in statin users) (p=0.01). Survival curves are shown in Figure 1.
Progression-free and overall survival curves for patients receiving and not receiving statins. A) Median progression-free survival (PFS) was 4.2 for statin non-users and 1.7 for statin users (p<0.001); B) Median overall survival (OS), was 6.7 months for statin non-users and 4.7 months for statin users; p-values were calculated with the log-rank test.
For progression-free survival, univariate and multivariate Cox regression analyses revealed that there was no significant difference in risk according to sex. Coronary arterial disease was associated with a significant hazard ratio (HR) of 0.48 (p=0.04) according to multivariate analysis but was not significant according to univariate analysis. The number of metastatic sites was not significantly different according to univariate analysis; however, lung metastasis was shown to have a significant HR of 1.68 (p=0.04). The number of previous treatment lines received was not significantly different according to univariate and multivariate analyses. Both univariate and multivariate analyses revealed increased risk of progression and mortality for statin usage. According to univariate analysis, the HR was 2.53, and according to multivariate analysis, the HR was 3.65; both factors were significant with p values lower than 0.001.
According to univariate and multivariate Cox regression analyses, overall survival did not significantly differ according to sex, comorbid disease, metastatic site, or previous treatment line. Moreover, statin usage had a significant HR of 2.06 (p=0.02) according to univariate analysis and an HR of 1.93 (p=0.05) according to multivariate analysis.
For each one-year increase in age, the calculated HRs for progression-free survival and overall survival were 1.00 and 1.02 (p=0.11), respectively, and for patients ≥65 years, the HRs were 1.19 for progression-free survival (p=0.40) and 1.56 for overall survival (p=0.04). Details of the univariate and multivariate Cox regression analyses for progression-free survival and overall survival are given in Table IV.
Univariate and multivariate Cox regression analyses of progression-free survival and overall survival.
Discussion
In this study, we investigated the effect of statin usage in patients with mCRC receiving regorafenib therapy. The results indicated that statin usage in combination with regorafenib leads to shorter median progression-free survival and decreased overall survival in patients with mCRC. As the median age was higher in statin users, a lower overall survival rate was expected, but age and age-related comorbidities alone cannot explain the shorter progression-free survival. Cox regression analysis revealed that statin usage was associated with an increased risk of progression, whereas multivariate analysis revealed an increased risk for both mortality and progression, with the latter being of a greater statistical significance. Additionally, multivariate analysis revealed that progression-free survival is better in patients with coronary arterial disease regardless of statin usage. In a previous study, we showed that angiotensin-converting enzyme inhibitor usage combined with anti-VEGF therapy is associated with longer survival, which may explain the improved progression-free survival in patients with coronary arterial disease (11). Although not significant, statin usage was found to be associated with poorer response rates, which may have translated into worse progression-free survival. Additionally, we found that overall survival was lower in elderly patients than in younger patients, but there were no significant differences in progression-free survival. Additionally, although there were more RAS-mutant patients in our study than expected, the rates of RAS-mutant patients were similar in statin users and non-users; indicating that this finding is unlikely to have influenced the results.
In the CAIRO2 trial, statin usage did not improve progression-free survival in patients with mCRC receiving cetuximab therapy in either KRAS-mutant or KRAS-wild-type patients (8). Additionally, in the subgroup analyses in a study by Alandağ et al., statin use was not associated with improved outcomes in patients receiving regorafenib (5). Although these studies are consistent with our study, both studies were designed to test other hypotheses; therefore, they should not be readily used to support our findings. However, in another study from our institution, polypharmacy was shown to be associated with worse outcomes in patients receiving regorafenib treatment for mCRC (12). Considering that statins are associated with a relatively higher rate of drug interactions, our findings may partially explain the negative effect of polypharmacy on survival. Since our study was not designed to include polypharmacy data, it is not possible to make a definitive conclusion, and further research is warranted on this issue.
In our study, statin-receiving patients were significantly older than non-receivers, and most patients were elderly. In the phase II REGOLD trial, for patients older than 70 years, regorafenib was associated with progression-free survival of 2.2 months, overall survival (OS) of 7.5 months, and grade 3/4 toxicity (13). The progression-free and overall survival outcomes of the patients in the REGOLD cohort are similar with those in our study, but the incidences of dose-limiting toxicities and adverse effects are lower in our cohort. The lower adverse effects can be explained by the doses administered. In the REGOLD trial, more patients received regorafenib doses ≥120 mg/day, but in our study, more patients received 80 mg/day.
In contrast to our findings, of Yuan et al., showed in preclinical models that rosuvastatin, a statin drug, increased the antitumoral activity of regorafenib (6). Shailes et al. suggested that statins can be used as targeted therapies for adenomatous poliposis coli gene (APC)-mutated colorectal cancer in preclinical models and that the pathways associated with mCRC carcinogenesis could be inhibited (14). Alabraba et al. suggested that statin usage is not associated with any histopathological or radiological response in patients with liver metastasis from colorectal cancer and does not change patient survival (15). Although statins demonstrated some benefit in preclinical models even when used in combination with regorafenib, clinical studies have failed to prove this effect. Additionally, in a large-scale prospective observational study of Japanese patients with mCRC treated with regorafenib, advanced age was not associated with poor outcomes (16).
The main effect of statins is to inhibit 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase to decrease cholesterol levels. The end products include intracellular signaling molecules and modifiers, which can also change molecular signaling pathways that are thought to affect colorectal cancer development; however, whether they are chemopreventive or not is still debated (17-19). Regorafenib also non-selectively alters various molecular mechanisms, and there is a knowledge gap regarding their clinical significance; therefore, many studies examined its potential in mCRC treatment and attempted to identify the responding population (20-22). Additionally, regorafenib has not been shown to significantly interact with any statins in the online drug interactions checking system Lexidrug™ (Lexicomp Corp, Hudson, OH, USA). Our findings warrant further studies for their pharmacodynamic and pharmacokinetic properties regarding concomitant usage of regorafenib and statins.
The main limitations of our study are the retrospective design, the small number of patients treated with statins, and uncertainties about the doses and types of statins used.
Conclusion
Statin usage seems to decrease the progression-free and overall survival of patients with mCRC receiving regorafenib treatment. The incidence of grade 3-4 adverse effects and tolerability did not differ between patients who received statins and those who did not.
However, further studies are needed to examine the effect of concurrent statin and regorafenib usage in clinical trials and preclinical models. According to our study, statins should be used cautiously along with regorafenib.
Acknowledgements
The article has not been written or edited with artificial intelligence. The study was not funded by any organization.
Footnotes
Authors’ Contributions
Efe Cem Erdat: Data collection, writing, formal analysis; Engin Eren Kavak: Data collection, conceptualization; Merih Yalciner: Data collection, editing; Gungor Utkan: Conceptalizuation, editing.
Funding
The study was not funded by any organization or corporation.
Conflicts of Interest
There are no conflicts of interest to report in relation to this study.
- Received May 29, 2024.
- Revision received July 16, 2024.
- Accepted July 17, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
