Abstract
Background
Statins, widely prescribed for hypercholesterolemia, have demonstrated potential anti-neoplastic properties in preclinical studies. Despite growing interest in their oncologic effects, the role of statin therapy within curative treatment of esophageal cancer remains unexplored. This study aimed to evaluate the impact of statin use on pathologic complete response (pCR) rate, disease-free survival (DFS), and overall survival (OS) in patients undergoing neoadjuvant chemo(radio)therapy followed by esophagectomy.
Methods
All consecutive patients with esophageal or gastroesophageal junction cancer who underwent esophagectomy following neoadjuvant therapy between March 1994 and September 2013 were retrospectively analyzed using a prospectively maintained database. Baseline demographic and clinical variables were compared between statin users and non-users.
Results
A total of 463 patients were included, of whom 90 (19.4%) were statin users at diagnosis. Neoadjuvant chemotherapy (CT) was administered in 88 patients (19%) and chemoradiotherapy (CRT) in 375 patients (81%). pCR (ypT0N0M0) was achieved in 85 patients (18%), with no statistically significant difference between statin users and non-users (22.2% vs. 17.4%, P=0.29). Median DFS (45 vs. 40 months, P=0.25) and OS (44 vs. 42 months, P=0.28) were also not significantly different between the two groups. However, a non-significant trend toward improved DFS was identified in patients with esophageal adenocarcinoma receiving lipophilic statin therapy.
Conclusions
In this cohort, statin use was not associated with improved pathologic response or survival outcomes following neoadjuvant therapy for esophageal cancer. These findings do not support modification or discontinuation of statin therapy in this patient population.
Keywords: Esophageal cancer, statin, outcomes, neoadjuvant therapy
Highlight box.
Key findings
• Prediagnostic statin use was not associated with higher pathologic complete response rates or improved disease-free or overall survival after neoadjuvant therapy and esophagectomy.
• A non-significant trend toward improved disease-free survival was observed among adenocarcinoma patients using lipophilic statins.
• Statin users were older and more comorbid, which may have attenuated any small survival effect.
What is known and what is new?
• Statins demonstrate anti-inflammatory and antitumor activity in preclinical models, and observational studies in several cancers have suggested potential survival benefits. Evidence in esophageal cancer remains limited and inconsistent.
• This study shows no clear oncologic benefit of statin use in patients undergoing neoadjuvant chemoradiotherapy followed by surgery, providing clinically relevant real-world data.
What is the implication, and what should change now?
• Based on current evidence, statins should not be initiated or modified with the intention of improving oncologic outcomes in esophageal cancer.
• Statin therapy should continue to be guided by cardiovascular indications, as oncologic benefit appears unlikely and highly context-dependent.
• Future studies, preferably prospective and powered for histologic and metabolic subgroups, are needed to determine whether specific patient groups, such as those with adenocarcinoma or metabolic syndrome, might benefit from adjunctive statin therapy.
Introduction
Esophageal cancer is an aggressive malignancy characterized by early regional and distant dissemination, contributing to poor overall survival (OS) rates (1). For patients without distant metastases, the current standard curative approach consists of esophagectomy preceded by neoadjuvant chemoradiotherapy (CRT) (2) or perioperative chemotherapy (CT) (3), depending on tumor location. Pathologic complete response (pCR) rates following neoadjuvant treatment differ widely, ranging from 10% to 40%, with multiple studies demonstrating a substantial survival benefit among patients achieving pCR (4-7).
Over recent decades, the incidence of esophageal adenocarcinoma has sharply increased across Western populations (8), largely attributed to rising obesity rates—a major risk factor for this subtype (9,10). While body mass index (BMI) alone has not been shown to affect 5-year survival following esophagectomy (11), a strong association exists between obesity, metabolic syndrome, and hypercholesterolemia. Consequently, the use of statins—3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors—has surged. Statins are now the most frequently prescribed drugs globally for the treatment of hypercholesterolemia (12).
Beyond their lipid-lowering effects, statins have been shown in preclinical studies to exert anti-neoplastic properties, including cell cycle arrest, induction of apoptosis, and inhibition of angiogenesis and tumor proliferation (13,14). Supporting these mechanisms, observational studies have reported associations between statin use and reduced cancer incidence as well as decreased cancer-related mortality (15,16). Specifically for esophageal carcinoma, in vitro investigations have demonstrated multiple mechanisms by which statins promote apoptosis and suppress tumor growth and metastatic spread (17-19). Population-based studies further support a protective association between statin use and the development of esophageal adenocarcinoma (20,21), with a study by Alexandre et al. extending this inverse relationship to esophageal squamous cell carcinoma (22).
Given these findings, there is increasing attention to the potential therapeutic effects of statins in oncology. Nielsen et al. reported in a large nationwide study a 15% reduction in cancer-related mortality among statin users at the time of cancer diagnosis compared to non-users (15). Furthermore, studies in breast and renal cell carcinoma have suggested improved disease-free survival (DFS) with statin use (23,24), and in rectal cancer, statins have been associated with enhanced response to neoadjuvant CRT (25). Notably, some evidence indicates that the therapeutic benefit of statins may differ based on their pharmacologic class, with lipophilic statins potentially offering superior oncologic effects.
To date, no clinical studies have examined the impact of statins on treatment response in esophageal cancer. Based on in vitro data and findings from other tumor types, we hypothesized that statin use—particularly lipophilic statins—may enhance response to neoadjuvant C(R)T and improve survival outcomes.
The present study aimed to evaluate the association between statin use and pCR rate, DFS, and OS in patients undergoing neoadjuvant treatment followed by esophagectomy for locally advanced esophageal cancer. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1500/rc).
Methods
Patient population
From March 1994 to September 2013, consecutive patients with esophageal or gastroesophageal junction cancer who underwent esophagectomy following neoadjuvant C(R)T at the Department of Surgery, Amsterdam UMC, Location University of Amsterdam (Amsterdam, the Netherlands), were eligible for inclusion. Patients were retrospectively selected from a prospectively maintained institutional database. Inclusion criteria comprised histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus or gastroesophageal junction (defined as tumors involving both the cardia and esophagus on endoscopy).
Statin use
Statin users were defined as patients actively taking statins at the time of the initial outpatient evaluation, irrespective of dose or duration. Patients prescribed exclusively lipophilic statins (simvastatin, fluvastatin, lovastatin) were classified as lipophilic statin users, whereas those receiving weakly lipophilic or hydrophilic statins (atorvastatin, pravastatin, rosuvastatin) were categorized as hydrophilic statin users.
Pretreatment staging and treatment indication
Initial staging comprised endoscopy with biopsy, endoscopic ultrasonography, cervical ultrasonography, and thoracoabdominal computed tomography. Although positron emission tomography (PET) or PET-CT was not routinely included in the standard staging protocol during the study period, these modalities were occasionally performed at referring institutions. CRT was offered to patients with histologically proven, locally advanced, resectable esophageal cancer without distant metastases (cT1N+M0 or cT2-3N0-3M0) or tumors of uncertain resectability (cT4a), provided they were deemed fit for surgery. Neoadjuvant CT alone was administered in cases where the tumor bulk was primarily located in the gastric cardia with extension into the distal esophagus. As perioperative CT for gastroesophageal cancer, the FLOT regimen combines 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel.
Neoadjuvant therapy
Three CRT regimens were used during the study period. The standard regimen consisted of 41.4 Gy of external-beam radiotherapy in 23 fractions of 1.8 Gy, combined with weekly carboplatin [area under the curve (AUC) 2] and paclitaxel (50 mg/m2) as per the CROSS trial protocol (2). In selected patients, CRT was combined with deep loco-regional hyperthermia (26). Additionally, a subgroup of patients enrolled in a phase II trial received panitumumab (a monoclonal antibody targeting EGFR) at 6 mg/kg alongside CRT (27).
Restaging after neoadjuvant therapy was performed using CT, PET, or PET-CT imaging. Patients who developed distant metastases during neoadjuvant treatment were excluded from the study.
Surgery
Surgical resection was performed using transthoracic or transhiatal esophagectomy, with either open or minimally invasive techniques, according to standardized procedures previously described (28-30).
Pathology
Resected specimens were evaluated by an experienced gastrointestinal pathologist using a standardized protocol. Histopathological data included pathological TNM stage after neoadjuvant therapy (ypTNM) stage, tumor differentiation grade, resection margin status, and lymph node assessment (total resected and positive nodes with location). All lymph nodes were fully embedded. In cases where no gross tumor was present, all suspicious tissue was paraffin-embedded to assess for residual malignancy.
Resection margins were classified as R0 in the absence of tumor cells at proximal, distal, or circumferential margins. A microscopically positive margin (R1) was defined by the presence of viable tumor cells at any of these sites. Tumor response to neoadjuvant treatment was graded using the Mandard tumor regression scoring system (5). Hematoxylin and eosin (H&E) staining was routinely performed, and CAM 5.2 immunohistochemistry was used when needed to detect viable tumor cells or micrometastases.
Follow-up
Patients were monitored from surgery until death or a minimum follow-up of 6 months. Follow-up was complete for all patients. Outpatient visits were scheduled every 3–4 months during the first 2 years, every 6 months up to 5 years, and subsequently by telephone contact with the patient or their primary care provider.
Disease recurrence was suspected based on clinical findings and confirmed with additional imaging (CT, PET-CT, MRI, or ultrasound) when indicated.
Statistical analysis
All statistical analyses were conducted using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were compared using the Mann-Whitney U test. Categorical variables were analyzed using the chi-squared or Fisher’s exact test as appropriate. Multivariate Cox proportional hazards regression was performed to identify independent prognostic factors. Variables with a P value <0.25 in univariate analysis were entered into the multivariate model. A two-sided P value <0.05 was considered statistically significant.
Ethical statement
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee of Amsterdam UMC (AMC.W19_097). Data were collected for our institutional database through a retrospective review of individual patient records, including documentation in EPIC and Castor EDC. Written informed consent was obtained from all patients for the use of their clinical data in research.
Results
Patient demographics and clinical characteristics
Between March 1994 and September 2013, 504 patients with esophageal or gastroesophageal junction cancer underwent esophagectomy following neoadjuvant CRT. Six patients (1.2%) underwent palliative resections due to intraoperatively detected metastases, and 14 patients (2.7%) underwent salvage resections following definitive CRT; both groups were excluded. An additional 21 patients (4.2%) died from postoperative complications and were also excluded. The final study population consisted of 463 patients, with a follow-up duration ranging from 6 months to 20 years.
Of these, 90 patients (19.4%) were statin users at initial presentation. Among statin users, 49 patients received lipophilic statins, and 41 received hydrophilic or weakly lipophilic statins. Baseline demographic and clinical characteristics of statin users and non-users are summarized (Table 1). Statin users were significantly older (median age 65.2 vs. 62.8 years; P=0.004) and more often male (88.9% vs. 71.3%; P=0.001). In addition, a higher BMI and a greater comorbidity burden were observed, including cardiovascular disease, peripheral artery disease, cerebrovascular disease, and diabetes mellitus (P<0.001 for all), resulting in higher American Society of Anesthesiologists (ASA) scores (P<0.001). Clinical tumor stage, tumor location, and histology did not differ significantly between groups.
Table 1. Clinical characteristics of 463 patients with esophageal or gastroesophageal junction cancer treated with neoadjuvant therapy.
| Variable | Prediagnostic statin users | No prediagnostic statin users | P value |
|---|---|---|---|
| Total, n (%) | 90 (19.4) | 373 (80.6) | |
| Age, years, median (IQR) | 65.2 (59.9–71.8) | 62.8 (55.5–69.2) | 0.004 |
| Gender, n (%) | 0.001 | ||
| Male | 80 (88.9) | 266 (71.3) | |
| Female | 10 (11.1) | 107 (28.7) | |
| BMI, kg/m2, n (%) | 0.02 | ||
| ≤25 | 36 (40.0) | 203 (54.4) | |
| >25 | 54 (60.0) | 170 (45.6) | |
| Smoking status, n (%) | |||
| Current | 28 (31.1) | 129 (34.6) | 0.31 |
| Former | 27 (30.0) | 85 (22.8) | |
| Never | 30 (33.3) | 147 (39.4) | |
| Unknown | 5 (5.6) | 12 (3.2) | |
| Comorbidities, n (%) | |||
| Prior malignancy | 5 (5.6) | 30 (8.0) | 0.42 |
| Cardiac (MI/DC/arrhythmia) | 40 (44.4) | 35 (9.4) | <0.001 |
| Peripheral arterial disease | 11 (12.2) | 11 (2.9) | <0.001 |
| Cerebrovascular disease | 9 (10.0) | 7 (1.9) | <0.001 |
| Diabetes mellitus | 25 (27.8) | 20 (5.4) | <0.001 |
| COPD | 8 (8.9) | 39 (10.5) | 0.66 |
| ASA physical status, n (%) | <0.001 | ||
| ASA 1 | 3 (3.3) | 88 (23.6) | |
| ASA 2 | 51 (56.7) | 225 (60.3) | |
| ASA 3 | 36 (40.0) | 59 (15.8) | |
| ASA 4 | 0 (0.0) | 1 (0.3) | |
| Medications used, n (%) | <0.001 | ||
| Lipophilic statins | 49 (54.4) | – | |
| Hydrophilic statins | 41 (45.6) | – | |
| Aspirin | 41 (45.6) | 20 (5.4) | |
| Tumor histology, n (%) | 0.08 | ||
| Adenocarcinoma | 70 (77.8) | 247 (66.2) | |
| Squamous cell carcinoma | 20 (22.2) | 121 (32.4) | |
| Other | 0 (0.0) | 5 (1.3) | |
| Tumor location, n (%) | 0.057 | ||
| Proximal esophagus | 0 (0.0) | 1 (0.3) | |
| Mid esophagus | 9 (10.0) | 78 (20.9) | |
| Distal esophagus | 57 (63.3) | 226 (60.6) | |
| Gastro-esophageal junction | 24 (26.7) | 68 (18.2) | |
| Clinical T stage, n (%) | 0.31 | ||
| cT1 | 2 (2.2) | 5 (1.3) | |
| cT2 | 19 (21.1) | 53 (14.2) | |
| cT3 | 64 (71.1) | 296 (79.4) | |
| cT4 | 1 (1.1) | 2 (0.5) | |
| cTx | 4 (4.4) | 17 (4.6) | |
| Clinical N stage, n (%) | 0.63 | ||
| cN0 | 18 (20.0) | 82 (22.0) | |
| cN1 | 46 (51.1) | 160 (42.9) | |
| cN2 | 21 (23.3) | 103 (27.6) | |
| cN3 | 2 (2.2) | 10 (2.7) | |
| cNx | 3 (3.3) | 18 (4.8) |
ASA, American Society of Anaesthesiologists; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DC, decompensatio cordis; IQR, interquartile range; MI, myocardial infarction.
Treatment details are outlined (Table 2). A larger proportion of statin users received neoadjuvant CRT compared to non-users (88.9% vs. 79.1%; P=0.03). Surgical approach was comparable between groups, with similar proportions undergoing transthoracic or transhiatal esophagectomy.
Table 2. Treatment characteristics of 463 patients with esophageal or gastroesophageal junction cancer treated with neoadjuvant therapy.
| Variable | Prediagnostic statin users | No prediagnostic statin users | P value |
|---|---|---|---|
| Total | 90 (19.4) | 373 (80.6) | |
| Neoadjuvant treatment | |||
| Chemotherapy | 10 (11.1) | 78 (20.9) | 0.03 |
| EOX | 4 | 12 | |
| ECC | 3 | 1 | |
| Cisplatin and etoposide | 3 | 56 | |
| Cisplatin and etoposide and hyperthermia | 0 | 7 | |
| Other chemotherapy scheme | 0 | 2 | |
| Chemoradiotherapy | 80 (88.9) | 295 (79.1) | 0.03 |
| Radiotherapy & carboplatin and paclitaxel | 68 | 235 | |
| Radiotherapy & carboplatin, paclitaxel and panitumumab | 8 | 29 | |
| Radiotherapy & carboplatin, paclitaxel and hyperthermia | 4 | 27 | |
| Other chemoradiotherapy scheme | 0 | 4 | |
| Surgical approach | 0.54 | ||
| Transthoracic | 61 (67.8) | 265 (71.0) | |
| Transhiatal | 29 (32.2) | 108 (29.0) |
Data are presented as n (%) or n. ECC, epirubici + cisplatin + capecitabine; EOX, epirubicin + oxaliplatin + capecitabine.
Postoperative (pathologic) outcomes
Postoperative histopathologic findings are summarized (Table 3). There were no significant differences between statin users and non-users with respect to resection margin status, tumor differentiation, or lymph node involvement. A trend toward a higher rate of pCR (ypT0N0M0) was observed in statin users (22.2% vs. 17.4%), though this was not statistically significant (P=0.29) (Table 3).
Table 3. Postoperative outcomes in 463 patients with esophageal or gastroesophageal junction cancer treated with neoadjuvant therapy.
| Variable | Prediagnostic statin users | No prediagnostic statin users | P value |
|---|---|---|---|
| Total, n (%) | 90 (19.4) | 373 (80.6) | |
| Mandard score, n (%) | 0.16 | ||
| TRG 1 | 20 (22.2) | 76 (20.4) | |
| TRG 2 | 13 (14.4) | 54 (14.5) | |
| TRG 3 | 30 (33.3) | 102 (27.3) | |
| TRG 4 | 15 (16.7) | 42 (11.3) | |
| TRG 5 | 4 (4.4) | 33 (8.8) | |
| Unknown/NA | 8 (8.9) | 66 (17.7) | |
| Complete response (ypT0N0M0), n (%) | 0.29 | ||
| Yes | 20 (22.2) | 65(17.4) | |
| No | 70 (77.8) | 308 (82.6) | |
| Radicality, n (%) | 0.43 | ||
| R0 (radical) | 87 (96.7) | 353 (94.6) | |
| R1 (microscopically irradical) | 3 (3.3) | 20 (5.4) | |
| pT stage, n (%) | 0.66 | ||
| pT0 | 20 (22.2) | 76 (20.4) | |
| pT1 | 15 (16.7) | 48 (12.9) | |
| pT2 | 10 (11.1) | 61 (16.4) | |
| pT3 | 45 (50.0) | 187 (50.1) | |
| pT4 | 0 (0.0) | 1 (0.3) | |
| pN stage, n (%) | 0.36 | ||
| pN0 | 58 (64.4) | 206 (55.2) | |
| pN1 | 17 (18.9) | 91 (24.4) | |
| pN2 | 12 (13.3) | 52 (13.9) | |
| pN3 | 3 (3.3) | 24 (6.4) | |
| Number of LN harvested, median (IQR) | 20 (16–26) | 20 (15–28) | 0.90 |
| Number of positive LN, median (IQR) | 0 (0–1) | 0 (0–2) | 0.16 |
| Differentiation, n (%) | |||
| Good | 1 (1.1) | 6 (1.6) | 0.98 |
| Moderate | 20 (22.2) | 81 (21.7) | |
| Poor | 26 (28.9) | 111 (29.8) | |
| Unknown/NA | 43 (47.8) | 175 (46.9) |
IQR, interquartile range; LN, lymph node; NA, not applicable; TRG, tumor regression rate.
Survival outcomes
No statistically significant association was observed between statin use and DFS (P=0.25) or OS (P=0.28). Median DFS was 45.0 months among statin users compared with 40.4 months in non-users (Figure 1). Similarly, median OS was longer in statin users (50.5 months) than in non-users (41.9 months) (Figure 2). A subgroup analysis with adenocarcinoma patients revealed a non-significant trend toward improved DFS in lipophilic statin users compared to non-users and hydrophilic statin users (50.9 vs. 39.5 months; P=0.07) (Figure 3). Lipophilic statin use was therefore included in univariate analyses for both DFS and OS (Table 4).
Figure 1.
Disease-free survival in 463 patients with esophageal or gastroesophageal junction cancer, stratified by statin use (n=90 vs. n=373).
Figure 2.
Overall survival in 463 patients with esophageal or gastroesophageal junction cancer, stratified by statin use (n=90 vs. n=373).
Figure 3.
Disease-free survival in 317 patients with esophageal or gastroesophageal junction adenocarcinoma, stratified by lipophilic statin use (n=42 vs. n=275).
Table 4. Univariable Cox regression analysis of prognostic factors in patients with esophageal or gastroesophageal junction cancer treated with neoadjuvant chemo(radio)therapy followed by surgery.
| Variables | HR (95% CI) | P value |
|---|---|---|
| Disease-free survival | ||
| Age (≥65 vs. <65 years) | 0.942 (0.715–1.242) | 0.67 |
| Gender | 1.147 (0.837–1.573) | 0.39 |
| Histology type | 1.026 (0.815–1.291) | 0.83 |
| Tumor location | 0.933 (0.753–1.156) | 0.53 |
| Neoadjuvant treatment (CRT vs. CT) | 1.011 (0.724–1.412) | 0.95 |
| Surgical approach (transthoracic vs. transhiatal) | 1.115 (0.829–1.501) | 0.47 |
| ypT stage | 1.176 (1.078–1.283) | <0.001 |
| ypN stage | 1.719 (1.499–1.970) | <0.001 |
| Resection margin (R1 vs. R0) | 1.421 (0.793–2.546) | 0.24 |
| Complete pathologic response (ypT0N0M0) | 0.491 (0.323–0.746) | <0.001 |
| Statin use | 0.802 (0.553–1.164) | 0.24 |
| Lipophilic statin use | 0.686 (0.412–1.142) | 0.15 |
| Overall survival | ||
| Age ((≥65 vs. <65 years) | 1.162 (0.889–1.518) | 0.27 |
| Gender (male vs. female) | 1.284 (0.936–1.762) | 0.12 |
| Histology type | 0.949 (0.756–1.192) | 0.66 |
| Tumor location | 0.998 (0.810–1.230) | 0.99 |
| Neoadjuvant treatment (CRT vs. CT) | 0.919 (0.669–1.261) | 0.60 |
| Surgical approach (transthoracic vs. transhiatal) | 0.958 (0.723–1.270) | 0.77 |
| ypT-stage | 1.200 (1.101–1.309) | <0.001 |
| ypN-stage | 1.773 (1.551–2.027) | <0.001 |
| Resection margin (R1 vs. R0) | 1.813 (1.086–3.025) | 0.02 |
| Complete pathologic response (ypT0N0M0) | 0.528 (0.355–0.786) | 0.002 |
| Statin use | 0.816 (0.563–1.184) | 0.29 |
| Lipophilic statin use | 0.740 (0.451–1.215) | 0.23 |
CI, confidence interval; CRT, chemoradiotherapy; CT, chemotherapy; HR, hazard ratio.
In the univariate model, significant predictors of DFS included ypT stage, ypN stage, and pCR. For OS, ypT stage, ypN stage, resection radicality, and pCR were significant predictors (Table 4). These variables were entered into a multivariate Cox regression model (Table 5).
Table 5. Multivariable Cox regression analysis focused on (lipophilic) statin use in patients with esophageal or gastroesophageal junction cancer treated with neoadjuvant chemo(radio)therapy followed by surgery.
| Variables | HR (95% CI) | P value |
|---|---|---|
| Disease-free survival | ||
| Statin use† | 0.787 (0.541–1.144) | 0.21 |
| Lipophilic statin use† | 0.642 (0.385–1.072) | 0.09 |
| Overall survival | ||
| Lipophilic statin use‡ | 0.664 (0.403–1.094) | 0.11 |
Covariates with P<0.25 were entered into multivariable model. †, multivariable models included ypT stage, ypN stage, radicality, and complete pathological response (ypT0N0M0). ‡, multivariable models included sex, ypT stage, ypN stage, radicality, and complete pathological response (ypT0N0M0). CI, confidence interval; HR, hazard ratio.
In multivariate analysis, lipophilic statin use was not independently associated with DFS or OS. The only factor independently predictive of both outcomes was postoperative nodal status (ypN) (Table 5).
Discussion
In this retrospective cohort study, statin use was not associated with higher rates of pCR or enhanced survival outcomes in patients with esophageal cancer receiving neoadjuvant chemo(radio)therapy followed by surgical resection. Nevertheless, a non-significant tendency toward improved DFS was noted among patients with esophageal or gastroesophageal junction adenocarcinoma who were treated with lipophilic statins. This observation aligns with findings from preclinical studies and warrants further investigation.
Experimental data offer plausible biological mechanisms to explain the potential anti-tumor effects of lipophilic statins. Ogunwobi et al. demonstrated that statins induce apoptosis and inhibit proliferation in OE33-verified esophageal adenocarcinoma cells through inhibition of Ras farnesylation and disruption of the ERK and Akt signaling pathways (17). Additional in vitro studies have shown that simvastatin reduces COX-2 production, ICAM-1 expression, and NF-κB activation, ultimately promoting apoptosis and reducing malignant potential in esophageal adenocarcinoma cells (18,19).
Currently, no adjuvant systemic therapies have been approved to reduce the risk of recurrence in patients with esophageal cancer after potentially curative neoadjuvant treatment followed by surgery. Observational studies in other malignancies, including breast and renal cell carcinoma, have suggested that statin use may be associated with improved DFS (23,24). In a large population-based Danish study of nearly 300,000 cancer patients, pre-diagnostic statin use was associated with a 15% reduction in cancer-related mortality overall [hazard ratio (HR) 0.85, 95% confidence interval (CI): 0.82–0.87] (15). In subgroup analyses, statin use was associated with a 19% reduction in mortality among patients with esophageal cancer (HR 0.81, 95% CI: 0.69–0.95), supporting the possibility of a protective effect. In line with the study by Abdelfatah et al. (31) we also explored BMI as a potential modifier of the association between statin use and survival. In our dataset, this interaction was not statistically significant, and no clear survival difference was observed between BMI subgroups, supporting the overall null association.
Evidence suggests that the potential anticancer effects of statins may differ by histologic subtype. Benefits appear most consistent for esophageal adenocarcinoma, which is closely linked to metabolic syndrome and hypercholesterolemia, whereas findings for squamous cell carcinoma are less clear (2). As our cohort mainly comprised adenocarcinoma, the present results primarily reflect this subtype. Larger, histology-specific studies are needed to clarify potential differential effects.
To our knowledge, this is one of the first studies to investigate the potential impact of statin use on disease progression in esophageal cancer patients treated with neoadjuvant C(R)T followed by resection. However, the absence of statistically significant findings in our cohort may reflect insufficient statistical power, particularly given the small number of lipophilic statin users. Moreover, the heterogeneity of the cohort in terms of tumor characteristics and neoadjuvant regimens may have obscured potential associations. The greater proportion of statin users receiving neoadjuvant CRT compared with non-users likely reflects temporal trends in clinical practice. Statin prescriptions have increased markedly over time, coinciding with the broader adoption of neoadjuvant CRT following the CROSS trial (22). To limit cohort heterogeneity, only patients treated with neoadjuvant therapy were included, thereby excluding patients with cT1N0 disease who underwent primary surgery alone. While this decision improved consistency in treatment exposure, it may introduce selection bias; it is conceivable that statin users were less likely to develop advanced tumors requiring multimodal treatment. As such, our findings cannot be generalized to all patients with esophageal cancer. Whereas most patients in this historical cohort received neoadjuvant CRT, adenocarcinoma is now commonly treated with perioperative FLOT CT following the ESOPEC trial results (32). Another important source of potential bias is that statin users in our cohort were, on average, older and had more comorbid conditions than non-users. These baseline differences could have attenuated or masked any modest survival advantage related to statin use, despite statistical adjustment. Additional limitations include the retrospective and observational nature of the study. Statin use was documented at the time of initial outpatient evaluation, and information on duration of therapy, adherence, and post-operative continuation was incomplete. Thus, misclassification of exposure is possible.
Conclusions
While the present findings do not justify modification or discontinuation of statin therapy in patients with esophageal cancer, it is suggested that there is a potential association between lipophilic statin use and improved survival in a selected subgroup, particularly patients with adenocarcinoma. Prospective clinical trials with adequately powered cohorts are warranted to clarify the impact of statin use on oncologic outcomes, and to determine patient subgroups that may benefit from statin initiation as part of multimodal cancer treatment.
Supplementary
The article’s supplementary files as
Acknowledgments
This work partially contained M.C.J.A.’s thesis of the PhD. degree in Location University of Amsterdam.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee of Amsterdam UMC (AMC.W19_097). Written informed consent was obtained from all patients for the use of their clinical data in research.
Footnotes
Provenance and Peer Review: This article was commissioned by the Guest Editor (Misha D. P. Luyer) for the series “Esophageal Surgery: Evolving Concepts and Techniques” published in Journal of Thoracic Disease. The article has undergone external peer review.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1500/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1500/coif). The series “Esophageal Surgery: Evolving Concepts and Techniques” was commissioned by the editorial office without any funding or sponsorship. M.I.V.B.H. reports that he is consulting in an advisory role for Alesi Surgical, BBraun, Johnson and Johnson, Medtronic, and Viatris and that he receives research grants from Stryker outside the submitted work. H.W.M.V.L. reports receiving grants from Amphera, Anocca, Astellas, AstraZeneca, Beigene, Boehringer, BMS, Daiichy-Sankyo, Dragonfly, MSD, MyeloidTx, ORCA, and Servier; honoraria from Astellas, Beigene, Benecke, BMS, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Springer, and Travel Congress Management B.V; meeting support from AstraZeneca; participation in Advisory Boards for Auristone, Incyte, Merck, Myeloid, and Servier ; and a role as a member of the ESMO Faculty for Upper GI cancer (serving as Chair until January 2025). S.S.G. is a consultant for Medicaroid, J&J, and Olympus. The authors have no other conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1500/dss
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