Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis

Introduction

Neuroendocrine neoplasms (NENs) represent a rare entity originating from neuroendocrine cells, accounting for about 0.5% of all newly diagnosed malignancies (1,2). In the last decades, the incidence of NENs has shown a significant upward trend worldwide (3,4), with a large-sample study (64,791 NEN cases) based on the Surveillance, Epidemiology, and End Results (SEER) database finding that the age-adjusted incidence in 2012 (6.98/100,000 people) increased 6.4 times from that in 1973 (1.09/100,000 people) (5). NENs are highly heterogeneous tumors which can be divided into well differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) according to tumor differentiation, with significant differences in their natural course and prognosis (6).

In view of the high complexity, rapidly growing incidence, and relatively longer survival, extensive treatment demands occur in NEN patients, and long-term and personalized health management play a crucial role. Surgery is the cornerstone of NEN therapeutic strategies, but 13–44% of NEN patients are detected with metastatic diseases at the diagnosis (7,8). Systemic therapy remains vital in advanced/metastatic NEN patients to control tumor growth and alleviate symptoms, which have been continuously developed in the past few decades, including biotherapy, chemotherapy, targeted therapy, and radiopharmaceuticals (6,9). With the gradual exploration of molecular pathways in NEN, relatively less toxic and efficient targeted therapies have received promising attention. In this context, the National Comprehensive Cancer Network (NCCN), European Neuroendocrine Tumor Society (ENETS), and Chinese Society of Clinical Oncology (CSCO) guidelines recommended targeted drugs as suitable options for patients with advanced NENs (10-12). Currently, three targeted drugs have been approved in Chinese clinical practice including surufatinib, sunitinib, and everolimus.

NENs are characterized by a highly vascularized microenvironment, in which multiple angiogenic factors drive tumorigenesis and progression (13-15). Surufatinib, developed independently in China, is a novel tyrosine kinase inhibitor (TKI) which simultaneously targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and colony stimulating factor-1 receptor (CSF1 receptor), and has been shown to prolong progression-free survival (PFS) in advanced pancreatic (pNEN) and extrapancreatic NEN (epNEN) through the SANET-p and SANET-ep phase III trials (16,17). At present, surufatinib covers nearly all site-originated NEN, whereas sunitinib has shown survival benefits for advanced pNEN (18) and everolimus, an oral mTOR inhibitor (mTORi), was reported to achieve a significantly longer PFS in advanced gastroenteropancreatic (GEP) or lung NENs through the RADIANT-3 and RADIANT-4 trials (19,20).

While surufatinib, sunitinib and everolimus have shown efficacy for advanced NENs in randomized controlled trials (RCTs), direct comparisons in a real-world setting remain unexplored. Due to the heterogeneity of NEN, the difficulty of diagnosis and treatment in real-world clinical practice appears significantly higher than in strictly-controlled clinical trial environments. The actual benefits of targeted drugs remain unclear, so this gap highlights the clinical need to understand their comparative effectiveness and safety within the diverse Chinese population. Therefore, we conducted an observational study and analyzed real-world data to evaluate the efficacy and safety of surufatinib compared with sunitinib and everolimus for advanced NEN patients in China, in order to provide insights, inform treatment selection and improve patient outcomes into the real-world performance. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-218/rc).

Methods

Study design and patients

This was a retrospective cohort study conducted at Fudan University Shanghai Cancer Center. Patients treated with surufatinib, sunitinib, or everolimus between July 2020 and April 2023 were identified, with the observation period lasting from first administration of targeted agents until disease progression/death, loss to follow-up, or the end of the study. The follow-up was until November 2023. Genomic profiles for pNEN were clearer than epNEN, in which more abundant evidences demonstrated that molecular circuits regulating angiogenesis exerts a critical role throughout the development of pNEN (14,21). Furthermore, considering the differences in disease characteristics and indications, the included patients were divided into pNEN and epNEN patients, among whom the study analysis were made on surufatinib treatment cohort vs. sunitinib or everolimus (sunitinib + everolimus) treatment cohort for pNEN patients and surufatinib treatment cohort vs. everolimus treatment cohort for epNEN patients.

The eligibility criteria were as follows: histological diagnosis of locally advanced unresectable or metastatic NEN (including pheochromocytoma/paraganglioma), having already received at least 1 month of targeted therapy. Patients with incomplete medical records were excluded. During baseline and follow-up period, clinical characteristics, treatment, efficacy and safety pertaining to included patients were collected through the electronic hospital information system (HIS) and telephone, based on International Agency for Research on Cancer (IARC)/World Health Organization (WHO) classification framework and consensus (22). The sample size of the study was determined by the number of patients that could be retrospectively collected from HIS of Fudan University Shanghai Cancer Center. Clinico-pathologic variables were collected and assessed for the propensity score (PS) calculation, including age, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), primary tumor site, functional status, genetic mutations, tumor differentiation, Ki67 index, tumor grade, metastasis site, and previous therapies. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by institutional ethics committee of Fudan University Shanghai Cancer Center (No. 2205254-19) and individual consent for this retrospective analysis was waived.

Treatment

The standard doses were set at 300 mg for surufatinib, 37.5 mg for sunitinib, and 10 mg for everolimus, once daily continuously. Initial dose, dose modification, and dose interruption were made solely at the physician’s discretion, according to disease severity and patient tolerance. Moreover, we imposed no restrictions on treatment lines or combination therapies, leaving this to the judgement of the medical staff.

Evaluation and endpoints

The primary outcome was PFS, defined as the time from first targeted agent administration to disease progression or death. Tumor responses were evaluated routinely every 2–3 months as complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) (23). If disease progression or death had not occurred in a certain patient, the last follow-up time was censored. Secondary outcomes included objective response rate (ORR), defined as the proportion of patients achieving CR and PR; disease control rate (DCR), defined as the proportion of patients with CR, PR, and SD; adverse events (AEs), identified and graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) (24).

Statistics

Descriptive statistical methods were utilized to summarize data. The Pearson’s chi-square test/Fisher’s exact test and the Wilcoxon test/t-test were used to assess differences of categorical variables and continuous variables among groups.

Inverse probability weighting (IPW) with the PS was applied to account for the bias of baseline characteristics, which created a pseudo-population for the following analysis between targeted agent groups. IPW adjusts weights based on PSs to address confounding factors. Compared to PS matching, IPW method does not result in sample size loss and can fully utilize all case data to avoid sample selection bias. Unadjusted and IPW-adjusted Kaplan-Meier curves were drawn, and PFS was compared using Cox proportional hazards model with hazard ratio (HR) and 95% confidence interval (CI). ORR and DCR were compared with the Pearson’s chi-square test method. Univariate and multivariate analyses were performed using Cox proportional hazards model to determine meaningful independent indicators on efficacy outcomes with HR and 95% CI estimation. In addition, exploratory subgroup analyses were performed for PFS between treatment groups.

Statistical analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, NC, USA). A two-sided significance level of P<0.05 on all statistic tests was defined.

Results

Patient characteristics

Out of 267 assessed patients, those eligible were enrolled as follows: 123 in the surufatinib group, 56 in the sunitinib group, and 68 in the everolimus group (Figure 1). Table 1 summarizes the patients’ baseline characteristics. The inferior baseline profile of the surufatinib group, compared to others, created an imbalance between groups, hence all were incorporated into the PS calculation for IPW. Before IPW, for pNEN, the number of patients receiving surufatinib as first-line treatment was slightly less than that in the sunitinib + everolimus group (11.1% vs. 22.1%, P=0.057); for epNEN, there were significant differences in previous somatostatin analogues (SSA), primary tumor site, liver metastasis, treatment line, and treatment regimen between surufatinib and everolimus (P<0.05). After IPW adjustment, all baseline data of the two groups were balanced without significant differences (P>0.05).

Figure 1 Flow chart of patient enrollment. pNEN, pancreatic neuroendocrine neoplasm; epNEN, extrapancreatic neuroendocrine neoplasm; IPW, inverse probability weighting.

Clinical treatment

In the IPW-adjusted cohort, nearly 80% of pNEN and epNEN patients received monotherapy in the two treatment groups, and the remaining patients were treated with combination therapy including SSAs, targeted agents, chemotherapy, and immune checkpoint inhibitors (ICIs).

Figure 2 shows the initial and final dose of the three targeted agents at IPW-adjusted cohort. Less patients received the standard dose initially and throughout the whole treatment course in the surufatinib group with 300 mg/day compared to that in sunitinib group with 37.5 mg/day and everolimus group with 10 mg/day (P<0.001). Through the treatment course, in the pNEN population, surufatinib’s dose of 250 mg increased from 22.4% to 49.5%, whereas that of 200 mg decreased from 66.3% to 45.1%. Sunitinib’s 25 mg dose rose from 19.5% to 34.8%, and that of 37.5 mg fell from 80.5% to 63.8%. Everolimus saw a rise in the 10 mg dose from 35.3% to 59.0%, and a drop in 5 mg from 59.3% to 16.4%. Through the treatment course, surufatinib’s 250 mg dose increased from 2.5% to 9%, and 200 mg decreased from 86.3% to 76.2% in epNEN patients. Everolimus’s 10 mg dose increased from 29.5% to 54.5%, and that of 5 mg decreased from 52.7% to 18.8%.

Figure 2 Initial and final dose of targeted agent during treatment course in (A) pNEN and (B) epNEN patients at IPW-adjusted cohort. pNEN, pancreatic neuroendocrine neoplasm; epNEN, extrapancreatic neuroendocrine neoplasm; IPW, inverse probability weighting.

Efficacy

In the unadjusted and IPW-adjusted cohort, surufatinib showed significantly longer median PFS (mPFS) than did sunitinib + everolimus in pNEN patients with the median follow-up time as 11 and 15 months, respectively (unadjusted cohort: 8.67 vs. 6.37 months, HR 0.587, 95% CI: 0.372–0.927, P=0.02; IPW-adjusted cohort: 8.30 vs. 6.33 months, HR 0.592, 95% CI: 0.436–0.804, P<0.001) (Figure 3A,3B). For epNEN patients, surufatinib showed significantly superior mPFS benefit over everolimus after IPW adjustment with the median follow-up time as 10 and 13 months, respectively (unadjusted cohort: 9.47 vs. 6.70 months, HR 0.728, 95% CI: 0.471–1.126, P=0.15; IPW-adjusted cohort: 8.73 vs. 3.70 months, HR 0.608, 95% CI: 0.456–0.810, P<0.001) (Figure 3C,3D). In addition, ORR and DCR were also found to have significant differences between targeted agent groups in pNEN and epNEN patients (Table 2).

Figure 3 Kaplan-Meier curves for progression-free survival in (A) pNEN patients at unadjusted cohort, (B) pNEN patients at IPW-adjusted cohort, (C) epNEN patients at unadjusted cohort, (D) epNEN patients at IPW-adjusted cohort. CI, confidence interval; pNEN, pancreatic neuroendocrine neoplasm; IPW, inverse probability weighting; epNEN, extrapancreatic neuroendocrine neoplasm.

Subgroup analysis of PFS in the IPW-adjusted cohort is shown in Figure 4 and demonstrated surufatinib’s notable survival benefits over controls. In pNEN, mPFS was 11.3 months with Ki67 3–20%, to 11.87 months for first-line, 12.63 months for initial full dose, and 13.13 months with dose adjustment. In epNEN, Ki67 3–20% had a mPFS of 10.4 months, first-line was 12.63 months, initial full dose was 9.47 months, dose adjustment was 11.1 months, and lung/thymus was 10.4 months.

Figure 4 Forest plot of subgroup analysis for progression-free survival in (A) pNEN and (B) epNEN patients at IPW-adjusted cohort. PFS, progression-free survival; CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status; TNM, tumor, node, metastasis; SSA, somatostatin analogues; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; pNEN, pancreatic neuroendocrine neoplasm; epNEN, extrapancreatic neuroendocrine neoplasm; IPW, inverse probability weighting.

To define whether certain clinical features impacted on PFS in NEN patients with targeted agents, univariate and multivariate analysis were performed (Tables 3,4). Multivariate Cox analysis revealed that male, functional status, Ki67 index >20%, previous SSA and germline mutation, poor differentiation at histopathology, liver metastasis, and multi treatment lines had a negative effect on PFS in pNEN and epNEN patients, respectively, whereas previous mTORi, dose adjustment, and surufatinib correlated with longer PFS.

Safety

Overall, no significant differences were found in the frequency of treatment-related AE with surufatinib, sunitinib, and everolimus in pNEN and epNEN patients (P=0.46 and 0.42) (Tables 5,6). In the pNEN cohort, the reported incidence of grade 3 or higher treatment-related AE were 26.0% for sunitinib, 25% for surufatinib, and 11.1% for everolimus (Table 5). Within the epNEN group, such AEs occurred in 31% of patients treated with surufatinib and 17.1% with everolimus (Table 6). The spectrum of AEs varied between targeted agents. The most frequent AEs were proteinuria, hypertension, increased blood thyroid-stimulating hormone, increased bilirubin, and hyperuricemia with surufatinib; hematologic toxicity (decreased platelet count, deceased white blood cell, decreased neutrophil count, and anemia) with sunitinib; anemia, hyperglycemia, hyperlipemia, stomatitis, and increased liver enzymes (γ-glutamyl transferase, aspartate aminotransferase) with everolimus. Moreover, the most common grade 3 or >3 AE that patients experienced was hypertension with surufatinib, which was typically controlled with medical management; decreased neutrophil count with sunitinib and anemia with everolimus were also effectively managed as per clinical guidelines. Apart from that, diarrhea (P=0.03), hypothyroidism (P=0.02), and occult blood positive (P=0.02) were found more commonly with surufatinib, whereas interstitial pneumonia (P=0.009) was more likely to appear with everolimus.

Discussion

NEN is a neoplasm with extremely high heterogeneity, which in some cases can be mixed with non-neuroendocrine components, resulting in significant differences in biological behavior, malignant potential and prognosis of NEN (25). NENs have been found in multiple organs, of which GEP-NENs are more common and thymic/lung NEN appear relatively rare (6,26). The development and advancement of targeted therapies have revolutionized the treatment landscape for advanced NENs, with endorsement by worldwide national treatment guidelines. To our knowledge, this is the first study to compare the efficacy and safety of surufatinib, sunitinib, and everolimus, all of which have been approved as standard treatment for advanced NENs patients in China. With high heterogeneity of NEN, it is critical to explore whether various clinical subtypes could benefit from current targeted agents in the real world.

Our study demonstrated that surufatinib (pNEN: 8.30 months, epNEN: 8.73 months) showed significantly superior mPFS benefit over sunitinib and everolimus in the overall population. Data on surufatinib, a targeted agent originally researched and launched in China, warrant further explorations currently. In the SANET-p and SANET-ep trials, the mPFS was 10.9 months (95% CI: 7.5–13.8) and 9.2 months (95% CI: 7.4–11.1), respectively, for surufatinib, which were slightly longer than that in our study (16,17). Our approach, unlike clinical trials, did not impose strict entry criteria to better mirror real-world scenarios, accommodating patients with ECOG-PS ≥2, primarily ≥2 lines of treatment, Ki67% ≥20%, advanced pathological grades, poor differentiation, and uncommon/multiple primary tumor sites, potentially contributing to the shorter mPFS than that in previous studies comparing sunitinib and everolimus (27,28). In addition, we did not exclude patients receiving combination therapy with other agents, including SSAs, chemotherapy, and ICIs to meet practical treatment demands, although survival periods showed no statistical differences compared with monotherapy. Combination therapy has become a common medication pattern in the current tumor treatment area. Several RCTs had been developed to explore whether everolimus plus SSA could improve effectiveness in advanced NENs, but the desired results were not achieved with no adequate improvement on PFS and overall survival (OS). The RADIANT-2 trial demonstrated that everolimus plus octreotide long-acting repeatable (LAR) obtained mPFS (16.4 vs. 11.3 months, HR 0.77, 95% CI: 0.59–1.00, one-sided P=0.02) and OS (29.2 vs. 35.2 months, HR 1.17, 95% CI: 0.92–1.49) with no statistical significances in advanced NENs and carcinoid syndrome patients (29,30), whereas just in the colorectal NENs subgroup this combined treatment was associated with a 66% reduction in the estimated risk for disease progression (29.90 vs. 6.57 months, HR 0.34, 95% CI: 0.13–0.89, P=0.01) (31). The COOPERATE-2 trial showed that the addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone (16.8 vs. 16.6 months, HR 0.99, 95% CI: 0.64–1.54, P=0.48) (32). For sunitinib and surufatinib, evidences on combination therapy were limited. A single-arm phase I trial evaluated that the overall ORR and DCR were 23.8% and 76.2% in 21 NEN patients (more than half were NECs) receiving surufatinib combined with toripalimab (a programmed cell death protein-1inhibitor) (33), which provided a potential option for higher malignancy subtypes. With regard to targeted agents, further studies are warranted to confirm whether combination therapy can bring more benefits in advanced NENs.

In this study, some histopathological factors associated with tumor grading/classification/staging (differentiation, Ki67 index, liver metastasis, functional status, germline mutation) were identified as related with mPFS in advanced NEN patients, which had been also validated by numerous studies (34-37). Phase III trials of targeted therapy solely encompassed patients with G1/G2 NENs, while the effectiveness and safety of drugs for high-grade (G3 or Ki67 >20%) NENs and poorly-differentiation NECs remain unexplored. Two prospective phase 2 trials tried to verify everolimus and sunitinib activity in advanced G3/NEC patients and found that efficacy was limited with mPFS of 1.2 and 1.4 months (38,39), respectively, whereas surufatinib achieved a 23% ORR and 4.14 months mPFS in NEC (40). Hence, application of targeted agents needs careful consideration. Liver metastasis was considered a common influencing factor (5,41), while compared to the presence of liver metastasis itself, the liver tumor burden may serve as a more instructive prognostic factor (42,43). A retrospective study found that liver tumor burden ≤25% (HR 0.27, 95% CI: 0.13–0.55, P<0.001) became the significant factors influencing OS in pNENs treated with everolimus (44), which could offer limited proof on availability of therapeutic effect prediction. Apart from that, we also found that functional and germline-mutated NENs, subgroups that clinical trials commonly excluded, were related with worse PFS. A small portion of NENs (approximately 10%) were related to genetic factors, namely those carrying germline gene mutations and occurring hereditary syndromes (45). Nuñez et al. found that everolimus achieved similar efficacy in multiple endocrine neoplasia type 1 (MEN1) and Von-Hippel-Lindau (VHL) compared with sporadic NENs (46). This differed from the conclusion we drew, but considering the small population, more evidences would be needed. Regarding treatment-related factors, previous SSA was considered to increase the risk of disease progression, whereas RADIANT-4 subgroup analysis indicated that everolimus had not significantly improved PFS in any previous SSA subgroup (47). NCCN, European Society for Medical Oncology (ESMO), and ENETS guidelines recommend SSAs as the first-line treatment of patients with somatostatin receptor (SSTR) positivity, G1/2 NENs with relatively low proliferative activity (Ki67 <10%), low tumor burden, and indolent behavior (11,12,48). In the absence of high-level evidences, systemic therapy selection and sequencing in advanced NENs are not fully elucidated, which mainly depends on the biological behavior and malignancy of the tumor, patient characteristics and treatment goals (49). Multiple prior treatment lines tended to be unfavorable factors on PFS in our study, in similarity with conclusions drawn in other investigations (27,28,50), which was probably due to the powerful invasiveness of an uncontrollable tumor.

A considerable portion of patients received surufatinib, sunitinib, and everolimus at reduced doses initially in this study. Although combination therapy possibly induced physicians to further take tolerance into account, more than 60% of patients with monotherapy did not accept standard dose initially. We analyzed that the initial recommended dose for treatment would not affect PFS and dose adjustment may play a positive role on PFS in pNEN patients. It is common that the strategy with lower tolerant initial dose and gradually increased dose is chosen to avoid AEs as far as possible in clinical practice. For small molecule kinase inhibitors, dose escalation is indeed one of the methods to optimize administration strategy. The DESIREE prospective trial reported that the use of a stepwise dose-escalation schedule of everolimus (2.5 mg week 1 increased by 2.5 mg per week to 10 mg) could significantly reduce the incidence of high-grade stomatitis in patients with hormone receptor (HR)⁺/human epidermal growth factor receptor 2 (HER2)^– metastatic breast cancer (51). Escalation of sunitinib dosing (12.5 mg steps) in patients with metastatic renal cell cancer, based on tolerable toxicity, has been shown to be safe and improve outcome (52). Despite lacking related evidences in advanced NENs, dose escalation of targeted agents can be a reasonable attempt in real-world practice. As a result, dose adjustment appeared in nearly one-third of patients in an effort to balance efficacy and tolerance. Berardi et al. reported that cumulative dose >3,000 mg and dose intensity >9 mg/day of everolimus played a prognostic role for patients with advanced pancreatic neuroendocrine tumors (pNETs) (53). Despite that a small sample-size study suggested that median daily dose reduction of sunitinib would probably not alter prognosis and safety for patients with advanced pNENs (54), Lee et al. demonstrated that severe AEs occurred in 63% of patients with sunitinib whose prolonged treatment period was significantly correlated with decreased relative dose intensity (55). Consequently, well-developed patient management with appropriate initial dose selection, dose adjustment, and interruption will provide guarantees for the long-term application of targeted agents.

In general, the safety profile of surufatinib, sunitinib, and everolimus was substantially similar to the reports of RCTs (16-20), which illustrated that under appropriate management, combination therapy would not increase the potential toxicity. Except adverse events of special interest (AESI) for the three drugs, there were differences in common AEs including hematologic toxicity and hepatotoxicity. Hematologic toxicity, which mainly manifested as myelocyte and megakaryocyte suppression, occurred more frequently with sunitinib, whereas everolimus and surufatinib were more likely to cause erythrocytes suppression and hemorrhage, respectively. Hepatotoxicity was also represented as different abnormal liver function indexes among the drugs. Considering that there is currently no clear evidence for position and sequence among targeted agents, it is recommended to match baseline characteristics of patients with drug toxicity for selection in clinical settings.

Our study had some limitations. Firstly, the most important constraint was the retrospective observational design with inherent bias, although we applied statistical methods to balance heterogeneity as far as possible. The relatively small sample size probably expanded the negative impact, so that we collected substantial variables and conducted subgroup analysis in order to explore the outcomes under different clinical features. Moreover, clinical data capture based on medical records system, together with early approval of sunitinib and everolimus in China, may have resulted in patient loss of follow-up and biased survival outcome. What’s more, surufatinib’s approval period was much shorter than everolimus and sunitinib, which resulted in differences on patients’ follow-up time and survival outcome acquiring. Under these circumstances, prospective research is required for further verification and OS data would be reported. Finally, we included NENs originating from any organ and tissue to reflect a real-world setting, yet the intrinsic heterogeneity possibly confused the results considering drug indication and histopathological difference.

Conclusions

This study explored the efficacy and safety of surufatinib, sunitinib, and everolimus in advanced NEN patients in real-world clinical practice in China. We demonstrated that surufatinib significantly prolonged PFS compared to sunitinib and everolimus in patients with advanced NEN treatments with different AE types to provide future perspective in patient management. This finding, together with identified clinical features affecting survival outcome, may lead to implications for selection of targeted agents in Chinese advanced NEN patients. These results should be further validated in well-designed prospective studies, in which specific molecular biomarkers should be explored to facilitate personalized treatment progress for advanced NEN.

Acknowledgments

Funding: This study was supported by the 2022 Shanghai Youth Pharmacy Talent Ability Enhancement Project “Intelligent clinical comprehensive evaluation platform for anti-tumor drugs” (to Q.D.), and the 2022–2023 Shanghai Anticancer Association “Soaring Project” (No. SHAX-QT-202101 to Q.Z.).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-218/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-218/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-218/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-218/coif). The authors have no conflicts of interest to declare.

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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by institutional ethics committee of Fudan University Shanghai Cancer Center (No. 2205254-19) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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