Abstract
Background
Various experimental studies demonstrated that atorvastatin exerted additive effects with anticancer drugs to impair tumor growth, delay relapse, and prolong survival time in lung cancer. However, it is indistinct whether there are survival benefits of atorvastatin in the treatment of small-cell lung cancer (SCLC) patients with dyslipidemia. Therefore, this study aimed to evaluate the efficacy and safety of atorvastatin plus first-line standard chemotherapy in SCLC combined dyslipidemia.
Methods
This was a retrospective analysis of 91 eligible SCLC patients with dyslipidemia registered at the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine from October 2018 to October 2022. SCLC patients with confirmed dyslipidemia were assigned to the treatment group to receive atorvastatin plus first-line standard chemotherapy (n = 45) or to the control group to accept chemotherapy (n = 46) until disease progression or unmanageable toxicity occurred. The clinicopathological parameters and survival data were collected and analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of SCLC. The median progression-free survival (mPFS) was considered to be the pivotal symbol as the primary endpoint. The second endpoints were recognized as the median overall survival (mOS) and toxicity.
Results
In the total of 91 enrolled patients, the curative effect can be evaluated in all patients. Research results showed that atorvastatin added to first-line standard chemotherapy was associated with a significant improvement in survival (mPFS: 7.4 vs 6.8 months, P = 0.031; mOS: 14.7 vs 13.2 months, P = 0.002).
Conclusion
Atorvastatin added to first-line standard chemotherapy achieved prospective efficacy and manageable safety in SCLC combined dyslipidemia.
Keywords: Atorvastatin, Small-cell lung cancer, Dyslipidemia, Chemotherapy
Introduction
As an invasive neuroendocrine malignant tumor, small-cell lung cancer (SCLC) has the characteristics of short doubling time, early metastasis, and a low 5-year survival rate (Thai et al. 2021). Although the precise causes causing SCLC were still unknown, scientists believed that the body’s carcinogenesis was a systemic disorder. Therefore, the malfunction and abnormalities of metabolism brought on by the pathophysiology and etiology of malignancies received increasing attention. Additionally, mounting evidence revealed that obesity and changed lifestyle were directly related to a higher risk of lung cancer (Hao et al. 2018).
Lipids are essential for maintaining cell structure, providing energy, and participating in cellular signal transduction (Prendeville and Lynch 2022). Lipid metabolism produces a variety of bioactive intermediates, which activate and regulate multiple signal pathways. It plays an important role in regulating cell proliferation, differentiation, survival, apoptosis, and cell membrane homeostasis (Murray et al. 2015). Similarly, lipid metabolism disorder can change the composition and permeability of cell membranes, leading to the occurrence and development of tumors (Dorsch et al. 2021). Abnormal lipid metabolism has been found in colon cancer, breast cancer, lung cancer, and prostate cancer (Jiang et al. 2021). At present, it is believed that the lipids most related to tumor development and chemotherapy are fatty acids, glycerol lipids, glycerol phospholipids, sphingomyelin, and sterols (Mitchell et al. 2018). Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that play important roles in the primary and secondary prevention of cardiovascular events by inhibiting this rate-limiting step in cholesterol biosynthesis (Chou et al. 2016). For the prevention and treatment of cardiovascular disease, atorvastatin is a well-established, economical therapeutic which has a significant role in the prevention of cardiovascular events.
Nevertheless, evidence from experimental and preclinical studies has indicated that atorvastatin inhibited tumor progression and induced apoptosis in several tumor types, including pancreatic carcinoma (Xu et al. 2019), mesothelioma (Tuerdi et al. 2013), breast cancer(Bjarnadottir et al. 2015), and SCLC (Cristea et al. 2020). Atorvastatin not only has lipid-lowering effects but also inhibits the proliferation of tumor cells and promotes apoptosis. Despite initial considerations that long-term use could raise the cancer risk, large-scale meta-analyses of randomized trials have shown no overabundance of cancer incidence or mortality.
At present, it is not clear whether the application of atorvastatin in SCLC patients complicated with lipid abnormalities is beneficial to the prognosis. There are not many published clinical data to show the prognostic significance of atorvastatin in patients with SCLC. The purpose of this study was to investigate the effectiveness and safety of atorvastatin on the prognosis of SCLC with dyslipidemia.
Materials and methods
Study population
This study protocol was approved by the Institutional Review Board of First Teaching Hospital of Tianjin University of Traditional Chinese Medicine. 91 eligible patients registered at our hospital from October 2018 to October 2022 were retrospectively analyzed (Fig. 1). The inclusion criteria were composed of the following: (1) 18–75 years male or female; (2) histologically or cytologically confirmed SCLC (limited or extensive stage); (3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score: 0–2 or Karnofsky Performance Status (KPS) score: ≥ 60; (4) at least one measurable objective lesion, which was evaluated according to the response evaluation criteria in solid tumors (RECIST 1.1); (5) the dyslipidemia level met the Guidelines on Prevention and Treatment of Blood Lipid Abnormality in Chinese Adults (Version 2016). The exclusion criteria were comprised of the following: (1) patients who had mixed cell histology, prior antineoplastic therapy, and history of malignant tumor; (2) patients who had severe arrhythmia, liver damage, and kidney function abnormalities; (3) patients with incomplete clinical history information and patients or their families who do not cooperate and cannot be followed up.
Fig. 1.
Flowchart of the patient recruitment and allocation scheme of this study
Therapeutic regimen
The SCLC patients received standard first-line chemotherapy as follows: cisplatin (75 mg/m2, d1) or carboplatin (area under the concentration–time curve (AUC) 4–5, d1) plus etoposide (100 mg/m2, d1–d3), every 21 days for 4–6 cycles. 45 patients in the treatment group received atorvastatin, while 46 patients in the control group only accepted chemotherapy. All patients maintained a reasonable low-cholesterol diet throughout the treatment period. The dose of atorvastatin was individualized according to baseline low-density lipoprotein cholesterol levels, treatment goals, and patient outcomes. The commonly used starting dose was 10 mg and the maximum dose was 80 mg, which was taken once a day at any time of the day and was not affected by meals.
Endpoint assessments
Progression-free survival (PFS): the period between the time when the beginning of initial treatment and the time when the disease progression or the patients died for any cause. Overall survival (OS): the period between the time when the beginning of initial treatment and the time when the patients died for any reason or at the end of the last follow-up. Evaluation criteria for the efficacy of solid tumor: the efficacy of patients were evaluated every two cycles after treatment until the patient progressed, died, or at the end of follow-up. Through the reexamination of chest computed tomography (CT), abdomen CT and brain CT and comparison with the previous imaging reports, the curative effect was evaluated according to RECIST 1.1. Refer to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0) to evaluate the grade of toxicity and side effects during the treatment. PFS was evaluated when disease progression and OS were evaluated when the patient died or at the end of the last follow-up in this study. AEs were graded at the end of treatment. The deadline for follow-up was October 2022, and the endpoint of follow-up was to observe the disease progression or death. The treatment, disease progression, and time of death were recorded during the whole follow-up period according to the medical records, outpatient revisits medical records and telephone follow-up.
Statistical analysis
All the research data were statistically analyzed by IBM SPSS 25.0 statistical software for Windows. For the baseline data belonging to count data, the Chi-square test is applied; for the measurement data following the normal distribution and uniform variance, the t test is applied; the nonparametric test is applied for the non-normal distribution, and the rank sum test is applied for the rank data. PFS, OS and related factors affecting survival in the two groups were calculated by the Kaplan–Meier method. Survival difference was tested by the log-rank method, and the Cox risk proportion model was used in multivariate analysis. P values less than 0.05 were considered statistically significant.
Results
Patients characteristic
Combined with the relevant literature and the opinions of experts in this field, we systematically collected the general and clinical data. The clinicopathological characteristics are shown in Table 1. A total of 68 (74.7%) males and 23 (25.3%) females with SCLC patients combined with dyslipidemia were enrolled. Among these patients, the survival time and clinical data such as gender, age, disease extent, brain metastasis, chemotherapy regimen, performance status, and lipid profiles [including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)] were obtained. The baseline characteristics of the two groups were comparable.
Table 1.
General data characteristics of 91 SCLC patients
| Characteristic | Treatment group (n = 45) | Control group (n = 46) | P value |
|---|---|---|---|
| Gender | |||
| Male | 33 (73.3%) | 35 (76.1%) | 0.763 |
| Female | 12 (26.7%) | 11 (23.9%) | |
| Age | |||
| < 70 | 24 (53.3%) | 28 (60.9%) | 0.468 |
| ≥ 70 | 21 (46.7%) | 18 (39.1%) | |
| Smoking history | |||
| Yes | 29 (64.4%) | 34 (73.9%) | 0.328 |
| No | 16 (35.6%) | 12 (26.1%) | |
| Tumor site | |||
| Left lung | 19 (42.2%) | 25 (54.3%) | 0.247 |
| Right lung | 26 (57.8%) | 21 (45.7%) | |
| Disease extent | |||
| Limited-stage | 25 (55.6%) | 29 (63.0%) | 0.467 |
| Extensive-stage | 20 (44.4%) | 17 (37.0%) | |
| Brain metastasis | |||
| Yes | 7 (15.6%) | 14 (30.4%) | 0.092 |
| No | 38 (84.4%) | 32 (69.6%) | |
| Brain radiotherapy | |||
| Yes | 4 (8.9%) | 11 (23.9%) | 0.053 |
| No | 41 (91.1%) | 35 (76.1%) | |
| Chemotherapy regimen | |||
| Carboplatin/etoposide | 36 (80.0%) | 34 (73.9%) | 0.491 |
| Cisplatin/etoposide | 9 (20.0%) | 12 (26.1%) | |
| KPS | |||
| ≤ 70 | 37 (82.2%) | 35 (76.1%) | 0.317 |
| > 70 | 8 (17.8%) | 11 (23.9%) | |
| ECOG | |||
| 1 | 37 (82.2%) | 42 (91.3%) | 0.200 |
| 2 | 8 (17.8%) | 4 (8.7%) | |
| Lipid profiles, mmol/L | |||
| TC | |||
| Normal (< 5.2) | 7 (15.6%) | 8 (17.4%) | 0.483 |
| BH (≥ 5.2 and < 6.2) | 9 (20.0%) | 5 (10.9%) | |
| High (≥ 6.2) | 29 (64.4%) | 33 (71.7%) | |
| LDL-C | |||
| Normal (< 3.4) | 4 (8.9%) | 7 (15.2%) | 0.513 |
| BH (≥ 3.4 and < 4.1) | 6 (13.3%) | 8 (17.4%) | |
| High (≥ 4.1) | 35 (77.8%) | 31 (67.4%) | |
| HDL-C | |||
| Low (< 1.0) | 28 (62.2%) | 32 (69.6%) | 0.136 |
| Normal (≥ 1.0 and < 1.5) | 11 (24.4%) | 13 (28.3%) | |
| High (≥ 1.5) | 6 (13.3%) | 1 (2.2%) | |
| TG | |||
| Normal (< 1.7) | 2 (4.4%) | 5 (10.9%) | 0.412 |
| BH (≥ 1.7 and < 2.3) | 5 (11.1%) | 3 (6.5%) | |
| High (≥ 2.3) | 38 (84.4%) | 38 (82.6%) | |
Efficacy
The mPFS of the treatment group and the control group was 7.4 and 6.8 months, respectively. According to the log-rank test in the survival analysis, the mPFS of SCLC patients with hyperlipidemia was extended when atorvastatin was used in conjunction with first-line standard treatment (mPFS: 7.4 vs 6.8 months, P = 0.031, Fig. 2). 45 patients in the treatment group, of whom 18 (40.0%) died, and 46 patients in the control group, of whom 26 (56.5%) died, showed a statistically significant difference. The mOS of SCLC patients with hyperlipidemia was extended when atorvastatin was used in conjunction with first-line conventional treatment (mOS: 14.7 vs 13.2 months, P = 0.002, Fig. 3).
Fig. 2.
The median progression-free survival was significantly better in the treatment group (7.4 vs 6.8 months, P = 0.031)
Fig. 3.
The median overall survival was significantly better in the treatment group (14.7 vs 13.2 months, P = 0.002)
Kaplan–Meier univariate survival analysis showed that gender, age, smoking history, tumor site, chemotherapy regimen, KPS score, ECOG and LDL-C, and HDL-C were not correlated with prognosis (P > 0.05). The main influencing factors of PFS and OS in patients with dyslipidemia (such as disease extent, brain metastasis, brain radiotherapy, TC, TG, and atorvastatin) were included in Cox proportional hazard regression analysis (Table 2). The results showed that the use of atorvastatin was the protective factor affecting the prognosis of PFS (HR 0.348, 95% CI 0.185–0.655, P = 0.001) and OS (HR 0.243, 95% CI 0.123–0.480, P < 0.001). Compared with the patients with the extensive stage, the regression coefficient of the patients with the limited stage was smaller, indicating that the risk of disease progression in the limited stage patients was 0.322 times higher than extensive stage (HR 0.322, 95% CI 0.173–0.598, P < 0.001), which was advantageous to the PFS. Furthermore, the level of TC was an unfavorable factor affecting the prognosis of patients. Compared with the high level of TC (≥ 6.2 mmol/L), the patients with normal level was the protective factors affecting the prognosis of PFS (HR 0.158, 95% CI 0.046–0.536, P = 0.003) and OS (HR 0.203, 95% CI 0.059–0.700, P = 0.012) (Table 3).
Table 2.
The univariate analyses of mPFS and mOS
| Characteristic | mPFS | mOS | ||
|---|---|---|---|---|
| χ2 | P value | χ2 | P value | |
| Gender | 0.572 | 0.450 | 0.499 | 0.480 |
| Age | 0.163 | 0.687 | 0.165 | 0.685 |
| Smoking history | 0.196 | 0.658 | < 0.001 | 0.995 |
| Tumor site | 1.865 | 0.172 | 0.492 | 0.483 |
| Disease extent | 13.725 | < 0.001 | 11.156 | 0.001 |
| Brain metastasis | 11.249 | 0.001 | 15.837 | < 0.001 |
| Brain radiotherapy | 5.458 | 0.019 | 9.377 | 0.002 |
| Chemotherapy regimen | 0.094 | 0.759 | < 0.001 | 0.990 |
| KPS | 0.951 | 0.621 | 1.358 | 0.507 |
| ECOG | 0.016 | 0.898 | 0.505 | 0.477 |
| TC | 14.290 | 0.001 | 10.388 | 0.006 |
| LDL-C | 5.388 | 0.068 | 4.615 | 0.099 |
| HDL-C | 3.364 | 0.186 | 3.806 | 0.149 |
| TG | 5.959 | 0.051 | 6.241 | 0.044 |
| Treatment regimen | 4.929 | 0.026 | 9.676 | 0.002 |
Table 3.
The multivariate analyses of mPFS and mOS
| Characteristic | mPFS | mOS | ||
|---|---|---|---|---|
| Exp (β) (95% CI) | P value | Exp (β) (95%CI) | P value | |
| Disease extent | ||||
| Limited stage vs extensive stage | 0.322 (0.173–0.598) | < 0.001 | 0.368 (0.194–0.698) | 0.002 |
| Brain metastasis | ||||
| Yes vs no | 0.121 | 0.985 | ||
| Brain radiotherapy | ||||
| Yes vs no | 0.058 | 0.390 | ||
| TC | < 0.001 | 0.006 | ||
| Normal vs high | 0.158 (0.046–0.536) | 0.003 | 0.203 (0.059–0.700) | 0.012 |
| BH vs high | 0.299 (0.112–0.802) | 0.016 | 0.440 (0.168–1.150) | 0.094 |
| TG | 0.270 | 0.250 | ||
| Normal vs high | 0.324 | 0.172 | ||
| BH vs high | 0.229 | 0.396 | ||
| Atorvastatin | ||||
| Yes vs no | 0.348 (0.185–0.655) | 0.001 | 0.243 (0.123–0.480) | < 0.001 |
Adverse events
According to data from Table 4, the distribution of common TRAEs was similar between the atorvastatin and control arms. The most common TRAEs were neutropenia (42.2% vs 45.7%), leucopenia (15.6% vs 20.0%), pain (22.2% vs 26.1%), and fatigue (24.4% vs 32.6%), which were no significant statistical difference between the atorvastatin group and the control group. Grade 3 were neutropenia (8.9% vs 4.3%), leucopenia (none vs 2.2%), pain (none vs 4.3%), and so on. It was worth pointing out that no grade 4 TRAEs and no treatment-related deaths occurred in this study. No potential solutions included early preventive measures and education to control the TRAEs. In conclusion, these above outcomings indicated atorvastatin had a tolerable safety in the application of SCLC patients.
Table 4.
The comparison of adverse reactions between the treatment group and control group (cases)
| Adverse events | Groups | Grade 1 | Grade 2 | Grade 3 | Grade 4 | P value |
|---|---|---|---|---|---|---|
| Neutropenia | Treatment | 10 | 5 | 4 | 0 | 0.436 |
| Control | 13 | 6 | 2 | 0 | ||
| Leucopenia | Treatment | 5 | 2 | 0 | 0 | 0.745 |
| Control | 6 | 2 | 1 | 0 | ||
| Pain | Treatment | 7 | 3 | 0 | 0 | 0.688 |
| Control | 8 | 2 | 2 | 0 | ||
| Fatigue | Treatment | 8 | 2 | 1 | 0 | 0.872 |
| Control | 10 | 5 | 0 | 0 | ||
| Dyspnea | Treatment | 5 | 1 | 0 | 0 | 0.317 |
| Control | 6 | 0 | 0 | 0 | ||
| Infection | Treatment | 4 | 2 | 0 | 0 | 0.742 |
| Control | 6 | 2 | 0 | 0 | ||
| Appetite loss | Treatment | 6 | 4 | 0 | 0 | 0.708 |
| Control | 5 | 3 | 1 | 0 | ||
| Weight loss | Treatment | 7 | 2 | 0 | 0 | 0.433 |
| Control | 5 | 2 | 1 | 0 | ||
| Hyponatremia | Treatment | 2 | 0 | 0 | 0 | 0.480 |
| Control | 3 | 1 | 0 | 0 |
Discussion
According to our knowledge, our report investigated the association of atorvastatin use with the prognosis of SCLC patients with dyslipidemia. Our data showed that atorvastatin use improved the survival time of SCLC with dyslipidemia. In terms of safety, the most common treatment-related adverse events were neutropenia (42.2% vs 45.7%), leucopenia (15.6% vs 20.0%), and pain (22.2% vs 26.1%). Further analysis identified that atorvastatin use was a predictive factor for the prognosis of SCLC with dyslipidemia. These novel clinical data contribute further evidence that atorvastatin possesses potential anti-cancer effects.
A prospective study was conducted for the first time to systematically review and meta-analyze the relationship between TC, HDL-C, LDL-C levels and breast cancer risk. It was found that there was a significant negative correlation between TC, HDL-C and the risk of breast cancer, while LDL-C had nothing to do with the risk of breast cancer (Touvier et al. 2015). Besides, Bull et al. found that through the data of 22,249 cases of prostate cancer and 22,133 controls in 22 studies, higher levels of LDL-C and TC increased the risk of aggressive prostate cancer (Bull et al. 2016). A randomized, double-blind, placebo-controlled clinical trial was designed to investigate the efficacy of atorvastatin for prostate cancer before radical prostatectomy (NCT01821404). The result suggested that cholesterol-lowering atorvastatin did not generally reduce prostate cancer proliferation rate compared with placebo while exploratory analyses investigated a benefit from extended exposure (Murtola et al. 2018). There were still various malignant tumors related to the disorder of blood lipid metabolism. In the process of tumor occurrence and development, to meet the needs of tumor rapid growth, tumor cells would thrive their best to obtain and consume nutrients to supply energy. The main biological function of lipids in the body is to store energy, so blood lipids are closely related to the occurrence and development of tumors.
It is reported that tumor cells have the characteristics of abnormal glycolysis pathway, active glutamine metabolism and abnormal lipid metabolism. The researchers named this abnormal metabolic pattern the energy metabolism reprogramming of tumor cells. The increased expression and activity of enzymes involved in lipid metabolism in many tumor cells promote fatty acid biosynthesis in cancer cells. The mechanisms are as follows: (1) increased activation and expression of acetyl-CoA carboxylase 1 (ACC1); (2) fatty acid synthase (FASN) is overexpressed by gene amplification and/or oncogenes. Changes in lipid composition and abundance make it a marker of cancer invasiveness, which may strongly affect the physical properties of the cell membrane, such as lipid filling density, membrane fluidity or surface charge, and conversion into bioactive lipid mediators in the process of signal transduction. Furthermore, it was reported that ACC, cPLA2, FASN, SCD1 and FABP related to fatty acid synthesis were associated with the proliferation of lung cancer cells. B7-H3 regulated lipid metabolism in lung cancer through SREBP-1-mediated FASN expression (Luo et al. 2017). Co-culture of adipocytes with lung adenocarcinoma A549 cells stimulated the invasion and metastasis of lung cancer cells (Li et al. 2018). To sum up, lipids have an important impact on solid tumors from many aspects, such as absorption, transport, and metabolism. Through the detection of lipid metabolism-related signal molecules in the blood of tumor patients, early tumors can be screened. Although lipids are closely related to tumorigenesis and development, we still need to further explore the mechanism of abnormal lipid metabolism in tumors to provide a scientific basis for the clinical application of tumor energy reprogramming theory.
Nevertheless, several limitation factors inevitably emerged in our research. Firstly, it was a retrospective study that the current physical and mental state of the patients would affect the authenticity and accuracy of the reports on past data. Secondly, the sample size was small and the statistical analysis of TRAEs was not comprehensive. Thirdly, the anti-tumor mechanism still needed to be clarified. Therefore, it was urgent to need prospective, randomized controlled, multicenter, large-sample clinical studies. The further development of SCLC first-line therapy requires a more in-depth study of its molecular pathological mechanism and identification of potential therapeutic targets. Research and development of anti-cancer drugs with high efficiency and low toxicity and looking for people who could benefit from therapy were needed due to these above reasons. Furthermore, there are not enough large-scale, multicenter, prospective clinical studies, and it is still unclear whether atorvastatin can act as an independent potentiator. However, only a small number of studies examined the links between dyslipidemia and SCLC. Therefore, effective regulation of lipid metabolism in malignant tumor cells is expected to become a new target for cancer treatment in the future.
Conclusion
In summary, atorvastatin can be very helpful in the treatment of SCLC since it prevents tumor development, recurrence, and metastasis as well as decrease tumor load and lengthen survival. Existing research supported atorvastatin to inhibit tumor growth when used to treat SCLC, and retrospective examination of atorvastatin combinations increased survival times for SCLC patients combined with dyslipidemia. To learn more about the function and pharmacological mechanisms of atorvastatin in the adjuvant treatment of SCLC, it still needs long-term and extensive research and exploration.
Author contributions
Data collection and formal analysis were performed by FK and NW. The first draft of the manuscript was written by NW and all authors commented on previous versions of the manuscript.
Funding
This work was supported by grants from the Seventh Batch of National Traditional Chinese Medicine Experts Academic Experience Inheritance Project and the National Key Research and Development (R&D) Plan (no. 2018YFC1707400).
Data availability
The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.
Declarations
Conflict of interest
There are no conflicts of interest.
Ethics statements
Ethical review and approval were not required for the study of human participants in accordance with the local legislation and institutional requirements.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Fanming Kong and Na Wang contributed equally to this work.
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Associated Data
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Data Availability Statement
The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.