Protocol for Evaluating the Efficacy and Safety of Radiotherapy for Prostate and Oligometastatic Lesions in Patients With Low-Burden Sensitive Oligometastatic Prostate Cancer: An Open,Exploratory Pilot Clinical Trial

Abstract

Introduction

The existing large prospective study demonstrates the benefits of primary radiotherapy in patients with low-volume oligometastatic prostate cancer (OMPC), and there is additional evidence of the benefits of local metastasis-directed therapy (MDT) for metastatic lesions. However, there are no results from a prospective study to demonstrate the efficacy of radiotherapy for prostate and oligometastases. Therefore, the aim of the protocol is to illustrate the efficacy of radiotherapy for prostate and oligometastatic lesions in patients with low-volume de novo hormone-sensitive OMPC.

Methods and analysis

This study involves a prospective, single-center, limited-sample, single-arm exploration of radiotherapy for prostate and oligometastatic lesions in patients diagnosed with low-volume hormone-sensitive OMPC. Eligible participants undergo thorough assessments and treatment involving endocrine therapy alongside radiation targeting metastatic lesions and the pelvic region. The primary site is treated with volumetric modulated arc therapy (VMAT), while metastatic sites are treated with either VMAT or stereotactic body radiation therapy (SBRT) depending on their location. All patients received radiation therapy for both the primary and metastatic lesions combined with endocrine therapy. Endocrine therapy with an antiandrogen (bicalutamide, for 4 weeks) androgen deprivation therapy combined with novel hormonal agents (acetate abiraterone) will be continued for 2 years. The primary objective is to evaluate progression-free survival-2 (PFS-2), while secondary endpoints include androgen deprivation therapy (ADT)-free survival, quality of life (QoL), overall survival, time to castration-resistant prostate cancer (CRPC), radiation-related complications, and endocrine therapy-related adverse events.

Ethics and dissemination

Approval was obtained from the ethics committee of the First Affiliated Hospital of Naval Medical University (CHEC2023-220). This is a single-arm exploration pilot trial evaluating radiotherapy for prostate and oligometastatic lesions in patients with OMPC. It aims to disseminate its findings through peer-reviewed journals and relevant medical conferences, with the intention of publication and presentation at these events.

Trial registration numbers

Clinicaltrials.gov identifier NCT06198387.

Keywords

de novo oligometastatic prostate cancer low-burden radiotherapy

Background

Prostate cancer (PCa) stands as one of the prevailing health concerns among patients. Its incidence among older individuals ranks second highest among the expected cancer cases in the Chinese elderly population in 2022.¹ Domestic patients in particular tend to have irregular monitoring of PSA, resulting in later diagnosis and staging compared to patients in Europe and the United States.² Especially, patients with limited metastases have a desire to alleviate the burden of tumors and enhance their quality of life (QoL). Despite advancements in systemic treatments for hormone-sensitive and castration-resistant diseases, metastatic prostate cancer remains incurable.^3,4

Oligometastatic prostate cancer (OMPC) has been proposed as an intermediate stage of cancer spread between localized disease and widespread metastases.⁵ Current treatment guidelines for OMPC recommend a combination of androgen deprivation therapy (ADT) with innovative hormonal agents like abiraterone and enzalutamide, ADT alongside docetaxel chemotherapy, and ADT in conjunction with radiotherapy targeting the primary site. While these approaches have shown improved survival rates, none of them constitutes a curative treatment modality. And mounting prospective evidence supports the inclusion of radiotherapy in the metastatic paradigm. Large-scale prospective studies, HORRAD and STAMPEDE, indicated that prostate radiation therapy combined with systemic therapy can be beneficial for newly diagnosed patients with de novo limited metastasis.^6-8 Moreover, an increasing body of evidence indicates that local metastasis-directed therapy (MDT) can delay disease progression, postpone the need for systemic treatment, and mitigate its toxicity. Additionally, literature reports underscore the efficacy of utilizing stereotactic body radiation therapy (SBRT) for treating metastatic lesions, leading to improved patient survival outcomes, regardless of hormone sensitivity or resistance.⁹ Patients within this subset of OMPC, distinct from those with widespread metastasis, require a tailored treatment approach. There is an urgent need to explore curative treatment modalities. The proposal involves contemplating localized curative radiotherapy directed at both the prostate and metastatic sites, leveraging the groundwork established by ADT.

However, there is currently limited research focusing on the concurrent radiation therapy of both primary and metastatic lesions in patients with limited metastasis, along with concurrent systemic therapy. The pilot single-center, exploratory pilot study aimed to investigate the efficacy and safety of curative radiotherapy for both local and all metastatic lesions among patients diagnosed with low-burden de novo OMPC.

Methods/Design

Study Design

This exploratory research constitutes a prospective, single-center, limited-sample, single-arm study conducted by investigators affiliated with the First Affiliated Hospital of Naval Medical University. Eligible participants will engage in personal interviews with physicians to receive a comprehensive understanding of the entire study and its related treatments. Prior to commencing this clinical trial, patients are required to furnish written informed consent encompassing treatment programs, potential benefits, foreseeable risks, and treatment procedures, which is mandatory. Subsequently, patients will undergo a series of pretreatment assessments, including, but not limited to, a review of medical history, collection of demographic data, physical examinations, blood routine tests, urine routine tests, liver and renal function evaluations, coagulation function tests, serum prostate-specific antigen (PSA), blood and urine amylase tests, 68Ga-prostate specific membrane antigen (PSMA)-PET/CT scans, and magnetic resonance imaging (MRI) assessments. This protocol strictly adheres to the reporting guidelines outlined in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT).¹⁰

Outcomes and Measurements

Primary Outcome Measures

The primary objective of this study is to assess progression-free survival 2 (PFS2) following the reinitiation of endocrine therapy. PFS2 is defined as the duration from the reinitiation of endocrine therapy until the identification of disease progression again, encompassing local recurrence, metastases, mortality, or the last follow-up. Disease progression is identified by meeting any of the following criteria: radiographic progression, determined by the discovery of new visceral metastases or 2 or more new bone metastases following the criteria specified in the third amendment of the LATITUDE trial protocol¹¹; PSA progression post-radiation therapy according to PCWG3 guidelines, refers to an increase of 2 ng/mL or more from the nadir PSA level¹²; or patient mortality.

Secondary Outcome Measures

Secondary endpoints encompass various aspects: ADT-free survival, self-assessment of QoL and patient-reported satisfaction, prostate cancer-specific survival, overall survival (OS), health economics, time to progression to castration-resistant prostate cancer (CRPC), and evaluations of radiation-related complications and endocrine therapy-related adverse events.

ADT-free survival is defined as the timeframe between the completion of the initial ADT treatment and the onset of the subsequent ADT treatment. Self-assessment of QoL and patient satisfaction is evaluated utilizing FACT-P, EQ-5D-5L, BPI-SF questionnaires every 3 months.¹³ Prostate cancer-specific survival refers to the likelihood or duration of survival specifically attributed to prostate cancer, excluding deaths from other causes. OS is defined as the duration from enrollment until death from any cause or the last follow-up. Radiation-related complications encompass the comprehensive documentation of genitourinary (GU), gastrointestinal (GI), and erectile dysfunction (ED) issues arising from radiation therapy, including both early (≤3 months after radiotherapy completion) and late (>3 months after radiotherapy completion) manifestations. Detailed recording and grading of radiation-related complications adhere to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) scale.¹⁴ Complications linked to endocrine therapy and QoL will be assessed and recorded using the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 scale for statistical analysis.¹⁵

Study Participants

Recruitment

Due to the scarcity of investigations into the administration of radiotherapy to both primary tumor and metastatic lesions in OMPC patients, alongside the potential advantages in terms of survival and biochemical control, this pilot study aims to evaluate the clinical outcomes linked to full-coverage radiotherapy in men diagnosed with low-volume, hormone-sensitive de novo metastatic prostate cancer. Concurrently, eligible patients will be proposed to participate in this study and subsequently enrolled by the responsible physicians in charge of the study.

Inclusion criteria

• Aged 18 years or over at the time of registration.

• Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.

• Histologically confirmed prostate adenocarcinoma via prostate biopsy.

• Assessment conducted via single-photon emission computed tomography (SPECT), MRI, and 68Ga-PSMA-PET/CT, revealing oligometastasis (involving <4 metastatic lesions in non-pelvic lymph nodes and bones) with or without pelvic lymph node involvement.

• Testosterone levels greater than 50 ng/dL at the screening.

• They must have adequate hematological (total neutrophil count ≥1500/μL, platelet count ≥100.000/μL and hemoglobin ≥9 g/dL), liver (serum bilirubin ≤1.5 × ULN, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase ≤1.5 × ULN), and kidney (serum creatinine ≤1.5 × ULN based on the Cockcroft−Gault equation) functions.

• Expected survival duration >2 years.

• The willingness of patients to voluntarily accept the experimental research protocol after being informed of existing treatment options.

Exclusion criteria

• Any previous or ongoing treatment for PCa, including radiotherapy, chemotherapy, focal treatment, etc.

• Pathology indicating small-cell or neuroendocrine tumor components.

• Patients with visceral metastases, or ≥4 metastases.

• Patients with concurrent malignancies or those in an acute infection period or severe infection state; patients positive for Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), and/or syphilis (Treponema pallidum).

• Severe or active systemic comorbidities that, in the investigator’s judgment, might interfere with the treatment, evaluation, and compliance of this trial, including severe conditions affecting respiratory, circulatory, nervous, mental, digestive, endocrine, immune, urological, and other systems.

• Individuals with contraindications related to radiation therapy may present heightened risks of treatment-related complications.

• Patients participating in other clinical trials.

• Patients unsuitable for participation in this clinical trial as per the judgment of the investigator.

Intervention

Upon enrollment, patients will be initiated on endocrine therapy concurrently with the commencement of radiation therapy targeting both prostate and metastatic lesions. Upon completion of a 2-year course of endocrine therapy, its administration will cease. Then subsequent monitoring will include serum PSA, testosterone levels, and imaging examinations. If disease progression is identified during this monitoring phase, resumption of endocrine therapy will be considered. In cases where treatment proves ineffective or disease progression occurs, discussions will be held to explore potential remedial measures tailored to the patient’s specific condition. The detailed flowchart is depicted in Figure 1.

Figure 1.

Treatment schedule in the protocol.

Endocrine Therapy

The treatment protocol involves administering anti-androgen medication such as bicalutamide (50 mg orally once daily) for a 28-day period. Luteinizing hormone-releasing hormone (LHRH) agonists like goserelin acetate, will be initiated 2 weeks after commencing bicalutamide, given via a subcutaneous injection of 3.6 mg monthly or 10.8 mg every 3 months. After the 28-day bicalutamide course, a transition to abiraterone is scheduled. Abiraterone is to be taken on an empty stomach at a dosage of 1,000 mg orally once daily, in combination with prednisone (5 mg orally twice daily). Endocrine therapy will be discontinued after a 2-year application, followed by monitoring through PSA tests and imaging examinations. If disease progression is observed during follow-ups, resuming endocrine therapy will be considered.

Radiation Therapy

Radiotherapy for Primary Prostate and Whole Pelvic

When it comes to radiotherapy for primary prostate lesions and lymph node metastases in the pelvic region, volumetric modulated arc therapy (VMAT) will be administered 5 times per week. Clinical target volume 1 (CTV1) encompasses the following: for high-risk prostate cancer, it includes the prostate gland with an additional 0.5 cm margin of extraprostatic tissue and the seminal vesicles within 2 to 2.5 cm adjacent to the prostate. If the seminal vesicles are involved, the entire seminal vesicles need to be included. Planning clinical target volume 1 (PCTV1) extends 5-10 mm outward in all directions from the CTV1, but in the posterior direction, only 5 mm to minimize rectal exposure, in which 60 Gy/20 fractions or 70 Gy/28 fractions is recommended for it.

Gross tumor volume in lymph nodes (GTVnd) comprises lymph nodes with pelvic metastasis confirmed by imaging. Planning gross tumor volume for lymph nodes (PGTVnd) extends 5 mm outward in all directions from the GTVnd, in which 54-60 Gy/20 fractions or 61.6-70 Gy/28 fractions is recommended for it.

CTV2 is defined as CTV1 plus GTVnd plus the pelvic lymph drainage area. The pelvic lymph drainage area includes the iliac, external iliac, internal iliac lymph nodes, lymph nodes anterior to the sacral vertebrae levels 1-3, and the obturator lymph nodes. PCTV2 extends 5 mm outward in all directions from the CTV2, in which 42 Gy/20 fractions or 50.4 Gy/28 fractions is recommended for it.

Delineation of Normal Tissues and Structures: This encompasses the rectum, bladder, femoral heads, small intestine, colon, anal canal, and penile bulb.

Radiotherapy Strategies for Oligometastasis

The radiation therapy approach and timing for oligometastatic lesions (including bone and non-pelvic lymph nodes, with ≤3 occurrences) vary depending on the specific location of the oligometastatic lesions. It is necessary to match the lesions identified by PET-PSMA with those found in CT scans.

For oligometastatic lesions located in the pelvic region, the recommended radiotherapy approach is VMAT. Gross Tumor Volume (GTV): Targeting metastatic lesions confirmed through imaging studies. Planning Gross Tumor Volume (PGTV): GTV relies on 5 mm uniform expansion. The radiation dosages are either 60 Gy over 20 fractions (60 Gy/20f) or 70 Gy over 28 fractions (70 Gy/28f), depending on the specific location of the target area within the pelvic region. Radiotherapy should be administered concurrently with pelvic radiotherapy to maximize treatment synergy and efficacy.

For oligometastatic lesions beyond the pelvic region, the recommended radiotherapy approach is SBRT technique. GTV: Targeting metastatic lesions confirmed through imaging studies. PGTV: Expanded outward by 3-5 mm from the GTV, forming the basis for treatment planning.

The radiation dosages involve a single dose of 6-10 Gy per fraction (6-10 Gy/f) with a fractionation range of 3-5 fractions (3-5f). The specific single fraction dose and number of fractions are determined based on the lesion’s precise location and size. If oligometastatic lesions manifest noticeable symptoms, their radiation therapy will be prioritized. In instances where these lesions do not cause significant symptoms, pelvic IMRT radiation therapy will be initiated first.

Follow-up

Serum PSA and testosterone levels will be assessed monthly. Additionally, contrast-enhanced CT and MRI scans will be performed every 3 months during follow-up or as advised by the physician. All patients will be evaluated for 68Ga-PSMA-PET/CT, every year after treatment. If the disease progresses during follow-up, reinitiating endocrine therapy will be considered. In instances of treatment failure or disease progression again, discussions will revolve around potential salvage therapies based on the patient’s specific condition.

Determination of Sample Size

According to the design of a single-arm exploratory pilot clinical trial and the limited sample size, our targeted enrollment aims to incorporate a total of 30 cases.

Quality Assurance

The Radiotherapy QA group is comprised of 3 radiation oncologists and 2 physicists to guarantee the quality of radiotherapy.

Data Collection and Monitoring

The schematic diagram for data collection and evaluations of efficacy and safety is shown in Table 1. Healthcare professionals will conduct the initial assessment of treatment baseline data and follow-up details for all patients. Subsequent verification by non-study personnel will ensure accuracy and completeness. Patient demographics, medical records, clinical and laboratory exam results, along with relevant data will be securely stored in our designated database. Strict confidentiality measures will safeguard all patient-related information. Data extraction for treatment and follow-up will be carried out as needed for review by the ethics committee or authorized researchers. Interim findings will be periodically reported to the committee for review.

Table 1.

The Schematic Diagram for Data Collections and Assessment.

Test Items	Screening	Before Radiotherapy	Follow- up
Demographics	●	●	●
Medical history	●	●	●
Physical examination	●	●	●
Concomitant symptoms	●	●	●
PSA	●	●	●
Testosterone		●	●
Blood routine	●	●	●
Ga-68 PSMA PET/CT	●	◯	◯
SPECT	◯	●	◯
Contrast-enhanced CT	◯		◯
Contrast-enhanced MRI	◯		◯
Biopsies of the prostate	●
Blood biochemistry	●	●	◯
Adverse effects		●	●
Combined drug record	●	●	●

Abbreviations: ADT, androgen deprivation therapy; PET, positron emission tomography; PSA, prostate specific antigen; PSMA, prostate-specific membrane antigen; SBRT, stereotactic body radiotherapy;SPECT, single-photon emission computed tomography.

● represents required items; ◯ represents selected items.

Data Analysis

The normally distributed continuous data will be described using means along with ± standard deviations and 95% confidence intervals for normally distributed continuous data. For non-normally distributed continuous data, median and range will be used. Qualitative data will be presented as percentages. We will estimate PFS2, ADT-free survival, OS, and the duration from enrollment to CRPC using the Kaplan-Meier actuarial analyses. Univariate and multivariable hazard ratios will be calculated via the Cox proportional hazards model. Statistical significance will be determined at P < .05. Statistical analyses will be conducted using SPSS 26.0 (IBM Corporation, Armonk, NY, USA). Additionally, we will summarize radiation and endocrine therapy-related toxicity, respectively.

Discussion

Both radical prostatectomy (RP) and radiation therapy are feasible treatment options for patients suspected to have regional lymph node metastasis.¹⁶ However, systemic therapy remains the cornerstone in managing oligometastatic prostate cancer, and the role of localized treatments in men with primary oligometastatic prostate cancer remains contentious.¹⁷ Recent research data have indicated a survival benefit from prostate-directed therapy (PDT) for some newly diagnosed metastatic prostate cancer (mPCa) patients. Extensive prospective investigations suggest that localized radiation therapy targeting the primary tumor in patients with low tumor burden significantly improves overall prognostic outcomes.^6-8

Further research has additionally highlighted that targeting metastatic sites among this specific patient subset can bolster local disease management and extend the duration of progression-free survival. With the development of radiotherapy technology, SBRT has been proven to be effective in locally controlling disease advancement in cases of oligometastatic lesions. Consequently, the concept of metastasis-directed therapy has emerged to reduce the overall tumor burden in patients with oligometastatic prostate cancer. Furthermore, a review summarized the effectiveness of combining localized prostate therapy with radiotherapy for distant lymph node lesions, concurrently with systemic therapy in newly diagnosed M1a PCa. This review demonstrated that radiotherapy for distant lymph node lesions could postpone the necessity for systemic treatment. It further corroborates the efficacy of prostate radiotherapy and radiotherapy for metastatic lesions in M1a prostate cancer patients.¹⁸

Some researchers have coined the term ‘oligometastasis’ in prostate cancer to categorize patients with limited metastatic dissemination, suggesting a relatively favorable prognosis for those with fewer than 4 metastatic sites.¹⁹ According to the CHAARTED study, metastatic disease can be categorized as high volume (4 or more bone metastases, including spinal metastases, or any visceral metastases) or low volume (not meeting the criteria for high volume).^20,21 However, there exists considerable variation in defining the criteria for oligometastatic status across research studies. The quantity of metastatic lesions is partly contingent upon the diagnostic approach utilized. The emergence of 68Ga-PSMA-PET/CT in recent years has enabled the early detection of metastatic lesions with increased precision and sensitivity.²²

Prostate radiotherapy exhibits promising potential in improving the outlook for oligometastatic patients, as emphasized in an extensive review article discussing treatment options for oligometastatic hormone-sensitive prostate cancer (omHSPC).⁷ In the prospective randomized HORRAD trial, 432 patients with primary bone metastatic prostate cancer were divided into groups receiving either ADT alone or a combination of ADT with external beam radiotherapy. Although the trial did not demonstrate a notable disparity in OS, especially among patients with fewer than 5 metastases, it hinted at the potential advantages of employing low-dose radiotherapy in prolonging the time to PSA progression.⁸ Results derived from the STAMPEDE trial reveal that individuals diagnosed with low-volume metastatic prostate cancer exhibited enhanced OS upon receiving a combined treatment of hormone therapy and prostate radiotherapy compared to the control cohort (HR .68, 95% CI .52-.90; P = .007). Notably, the 3-year survival rate for patients subjected to radiotherapy stood at 81%, whereas those undergoing systemic therapy (comprising hormone therapy alone or combined with docetaxel) recorded a rate of 73%.⁶ Local treatment of the primary lesion can reduce tumor burden, alleviate symptoms, and confer survival benefits. The underlying principle lies in targeting the primary tumor as the origin of metastatic cancer cells; actively managing the primary tumor might impede the progression of metastatic lesions and the development of new metastases.²³

Metastatic site radiotherapy significantly enhances survival rates. The ORIOLE Phase 2 study investigated OMPC, involving 54 participants across three U.S. radiotherapy institutions (May 2016 - March 2018). Among the 36 patients treated with stereotactic ablative radiotherapy (SABR), progression occurred in 19% at the 6-month mark, contrasting with 61% in the observation group (P = .005). Notably, SBRT substantially extended the median PFS period (not reached vs 5.8 months in the control; HR .30; 95% CI .11-.81; P = .002). It effectively managed lesions with minimal adverse effects, seemingly without compromising the quality of life.²⁴

Patients diagnosed with OMPC stand to gain considerable benefit from a combined treatment strategy, merging local consolidative treatment (LCT) with systemic therapy. In a retrospective study involving 47 patients with de novo OMPC, a combined approach of prostate and oligometastatic radiation therapy demonstrated promising results with manageable side effects during a 27-month follow-up. Post-treatment, distant metastatic progression rates at 1- and 2-year were 21% and 32% respectively, with OS rates of 90% and 87% respectively. This comprehensive radiotherapeutic strategy displayed favorable clinical outcomes and could lead to extended periods of noncastrate remission in certain cases of de novo OMPC.²⁵ Another retrospective investigation conducted by C. Reverberi et al concentrated on evaluating the effect of LCT on both the primary site and metastatic tumor burden among recently diagnosed patients with OMPC. The 2-year and 5-year bPFS rates were 73.3% and 39.3%, respectively. Moreover, their research unveiled robust local recurrence-free survival rates of 93.9% and 83.7% at 2 years and 5 years, respectively.²⁶

Although prior studies have explored the effectiveness of concurrent radiotherapy for both the prostate and metastatic lesions in managing oligometastatic prostate cancer, it is crucial to acknowledge their reliance on retrospective data. There is a notable deficiency in prospective research dedicated specifically to examining the simultaneous irradiation of all lesions in conjunction with ADT for OMPC.

Conclusion

Consequently, this single-arm exploratory clinical study aims to explore the feasibility and efficacy of employing radiotherapy on both the prostate and oligometastatic sites, combined with extended-term endocrine therapy in patients diagnosed with de novo OMPC. It may signify the preliminary shift from palliative to curative therapeutic approaches. Additionally, the exemption of patients from endocrine therapy has the potential to significantly enhance their QoL. However, several pertinent questions persist, such as identifying clinical features that could indicate tumors are more effective to radiotherapy. The correlation between clinical efficacy and factors such as tumor quantity, location, histopathological type, immune response, and genomic susceptibility characteristics may offer valuable insights.

Strengths and Limitations of This Study

A pilot trial demonstrating the safety and effectiveness of radiotherapy in the treatment of prostate and all the oligometastatic lesions for individuals with low-burden, hormone-sensitive oligometastatic prostate cancers.

In this protocol, before and after treatment, 68Ga prostate-specific membrane antigen PET/CT shall be performed in all patients to determine the most suitable radiotherapy fraction regimen for prostate and oligometastases.

A single-centre study, with a relatively small sample size.

Supplemental Material

Supplemental Material - Protocol for Evaluating the Efficacy and Safety of Radiotherapy for Prostate and Oligometastatic Lesions in Patients with Low-burden Sensitive Oligometastatic Prostate Cancer: An Open, Exploratory Pilot Clinical Trial

Supplemental Material for Protocol for Evaluating the Efficacy and Safety of Radiotherapy for Prostate and Oligometastatic Lesions in Patients with Low-burden Sensitive Oligometastatic Prostate Cancer: An Open, Exploratory Pilot Clinical Trial by Bichun Xu, Xianzhi Zhao, Zhiru Feng, Yiyin Liang, Weiwei Zhang, Liang Chen, Jialun Li, Xianqi Shen, Min Qu, Xu Gao, and Huojun Zhang in Cancer Control

Footnotes

Author Contributions

Study conception: HZ and XG. Initial study design: BX, XZ and JL. Revision of study design and protocol: BX, XZ, HZ, XG, JL, YL, WZ, LC, XS and MQ. Study coordination: all authors. Drafting the manuscript: BX, XZ and ZF. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is sponsored by the First Affiliated Hospital of Navy Medical University “234 Subject Climbing Program” (2019YPT004), Changhai Hospital Guhai Program (GH145-33), the First Affiliated Hospital of Naval Medical University “Youth Development Program”(2021JCQNO3), Shanghai Health Commission Leading Talent Program(2022LJ019) and Shanghai Top Priority Research Center Construction Program (2022ZZ01011). The funding body had no role in the design of the study and will have no role in the collection, analysis or interpretation of the data as well as in writing the manuscript or the decision to submit the report for publication.

Open Access

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: .

Ethical Statement

ORCID iD

Huojun Zhang

Availability of Data and Materials

The materials and methods are available in the .

Supplemental Material

Supplemental material for this article is available online.

Abbreviations

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Supplementary Material

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