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Abstract
Introduction Nowadays, invasive prostate biopsy is the standard diagnostic test for patients with suspected prostate cancer (PCa). However, it has some shortcomings such as perioperative complications, economic and psychological burden on patients, and some patients may undergo repeated prostate biopsy. In this study protocol, our aim is to provide a non-invasive diagnostic strategy we call the ‘prostate-specific membrane antigen (PSMA) combined model’ for the diagnosis of PCa. If patients are diagnosed with PCa using PSMA combined model, we want to prove these patients can receive radical prostatectomy directly without prior prostate biopsies.
Methods The SNOTOB trial adopts a prospective, single-centre, single-arm, open-label study design. The PSMA combined model consists of a diagnostic model based on what we previously reported and 18F-PSMA-1007 positron emission tomography/CT (18F-PSMA-1007 PET/CT) examinations in series. First, patients use the diagnostic model (online address: https://ustcprostatecancerprediction.shinyapps.io/dynnomapp/) to calculate the risk probability of clinically significant PCa (csPCa). When the risk probability of csPCa is equal or greater than 0.60, 18F-PSMA-1007 PET/CT will be applied for further diagnosis. If patients are still considered as csPCa after 18F-PSMA-1007 PET/CT examinations, we define this condition as positive results of PSMA combined model. Subsequently, we will recommend these patients to accept radical prostatectomy without prostate biopsy directly. Finally, the diagnostic performance of PSMA combined model will be verified with the pathological results. Totally, 57 patients need to be enrolled in this clinical trial.
Ethics and dissemination This study was approved by the ethics committee of The First Affiliated Hospital of USTC (No. 2022KY-142). The results of this study will be published in peer-reviewed journals and reported at academic conferences.
Trial registration number NCT05587192.
- prostatic neoplasms
- biopsy
- diagnostic radiology
- protocols & guidelines
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The say no to biopsy (SNOTOB) study is a single-centre, single-arm, open-label trial and is conducted in a tertiary hospital of China.
This study provides a non-invasive diagnostic strategy consists of a diagnostic model based on what we previously reported and 18F-PSMA-1007 positron emission tomography/CT (18F-PSMA-1007 PET/CT) examination in series.
In this protocol, if eligible patients cannot accept the low risk of benign prostatic disease, they can still choose prostate biopsy prior to radical prostatectomy.
The 18F-PSMA-1007 PET/CT examinations in this study are free of charge for all eligible patients and are funded by the research group.
Considering only a few hospitals that have the conditions to perform 18F-PSMA-1007 PET/CT in China, the trial is not conducted in multicentre.
Introduction
Prostate cancer (PCa) is the most common malignant tumour in the male genitourinary system. According to recent data, PCa ranks first and second in terms of morbidity and mortality among male malignancies in western countries.1 In China, with the rapid development of the economy and the application of early diagnosis technologies, the incidence and mortality of PCa are increasing rapidly.2 At present, the main methods recommended by the guidelines for early diagnosis of PCa include digital rectal examination (DRE), serum prostate-specific antigen (PSA) test, transrectal ultrasound and multiparameter magnetic resonance imaging (mpMRI), genetic screening can also be performed for patients with a family history.3 4 But none of these tools is perfect, for example, the serum PSA test has high sensitivity, but the increase in PSA is not specific for PCa.5 mpMRI has been widely used in clinical practice in recent years and its diagnostic accuracy is significantly better than DRE and serum PSA. However, mpMRI has a poor discrimination ability between inflammatory lesions and PCa tissues and the positive predictive value is barely satisfactory for the diagnosis of PCa.6 7
At present, all patients with suspected PCa must undergo prostate biopsy to confirm the final diagnosis. But prostate biopsy has some inherent drawbacks. First, it may cause some complications, such as urinary infection, bleeding, acute urinary retention and so on.8 Second, prostate biopsy is a local anaesthesia operation that will bring certain psychological and economic burden to patients. In addition, after prostate biopsy, patients with definite PCa have to wait a period to receive surgical treatment. Finally, patients with negative prostate biopsy cannot completely exclude the possibility of PCa, repeated prostate biopsy may be unavoidable in the future.9 In summary, there are many shortcomings in the diagnosis of PCa. According to the latest reports, the overdiagnosis caused by false positive examinations and overtreatment of low-grade PCa have become worldwide problems and need to be solved urgently.10 11
In our previous study, we retrospectively analysed the data of 701 patients and created a clinical predictive model based on PSA density (PSAD) and prostate imaging-reporting and data system (PI-RADS) score.12 Meanwhile, in order to avoid the regional differences of the conclusions, we also made external verifications and the results further confirmed the reliability of the diagnostic model. Recently, we made some updates to this model and an online dynamic nomogram was created (https://ustcprostatecancerprediction.shinyapps.io/dynnomapp/).13 We found when the risk probability of the patients reaches 0.60, they are extremely likely to be diagnosed as clinically significant PCa (csPCa). If we set the cut-off value 0.60 as diagnostic criteria for csPCa diagnosis, the specificities and true positive rates are greater than 90% and 80%, respectively.
For the purpose of performing biopsy-free radical prostatectomy, the positive predictive value should be further improved. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein specifically expressed on the cell membrane of PCa, and its expression is much higher than that of normal prostate cells.14 The application of small molecular inhibitors labelled PSMA positron emission tomography/CT (PSMA PET/CT) has excellent diagnostic ability for PCa compare to traditional imaging.15 16 Studies have shown that if PI-RADS score ≥4 and the high maximum standardised uptake value (SUVmax) were used together as the diagnostic criteria, the specificity and the true positive rate of csPCa were 100%. But these studies are limited by retrospective design and small samples.17 18 In this prospective study protocol, we set a high-risk probability of the predictive model to screen patients first, and 18F-PSMA-1007 PET/CT examinations will be performed for patients with risk probability equal or greater than 0.60. Our purpose is to provide a strategy for patients with highly suspected csPCa and confirm the feasibility of directly radical prostatectomy without prior prostate biopsy. Our results will present a novel, non-invasive and safe diagnostic method for PCa.
Methods and analysis
Study design and setting
This single-centre, single-arm, open-label clinical study will be conducted in the First Affiliated Hospital of University of Science and Technology of China (USTC) in China. Patients who have no surgical contraindications and meet the screening criteria will be recruited to the study. Subsequently, we will recommend these patients to accept radical prostatectomy without prostate biopsy directly. Before the operation, patients and their family member will be fully informed of the surgical risks, the necessity to perform a prostate biopsy for pathological confirmation, the possibility of benign prostatic disease and the other alternative therapeutic methods including active surveillance, radiotherapy, and focal therapies and so on. Traditional prostate biopsy can also be performed if patients refuse radical prostatectomy directly. Finally, the diagnostic performance of PSMA combined model will be verified with the pathological results. The study flow chart is presented in figure 1. This trial is reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting guidelines.19
Study flow chart. PSA, prostate-specific antigen; mpMRI, multiparameter magnetic resonance imaging; csPCa, clinically significant prostate cancer; PSMA PET/CT, prostate-specific membrane antigen positron emission tomography/computed tomography; PPV, positive prediction value; hgPCa, high grade prostate cancer.
Recruitment
The schedule of assessing patients’ eligibility for this trial is described in table 1. The PSMA combined model in this study consists of a diagnostic model and 18F-PSMA-1007 PET/CT examination in series. After the patients complete the serum PSA test and mpMRI, we can obtain the information of PSAD and PI-RADS score. Then, patients’ risk probability of csPCa will be calculated by the online diagnostic nomogram (available address: https://ustcprostatecancerprediction.shinyapps.io/dynnomapp/). When the risk probability of csPCa is equal or greater than 0.60, 18F-PSMA-1007 PET/CT will be applied for further diagnosis, two nuclear medicine physicians with more than 10-year experience analysed PET images independently and blinded to all clinical information and outcome. Any disagreements were resolved by consensus. The SUVmax of PCa lesion was automatically acquired by a spheric volume of interest. If patients are still considered as csPCa after 18F-PSMA-1007 PET/CT examinations, we define this condition as positive result of PSMA combined model. Only patients who have positive result of PSMA combined model meet the enrolment criteria. Patients with risk probability less than 0.60 will no longer undergo 18F-PSMA-1007 PET/CT examinations, and patients with risk probability equal or greater than 0.60 but negative 18F-PSMA-1007 PET/CT examinations will not meet the enrolment criteria too. Before any surgical operation is carried out, eligible patients will be requested to give their written informed consent.
Schedule of assessing the eligibility
Inclusion criteria
Male patients with clinically suspected PCa (abnormal DRE or serum PSA).
Finish the detection of serum PSA and mpMRI.
4 ng/mL≤serum PSA<100 ng/mL.
Risk probability of csPCa evaluated by the online diagnostic nomogram ≥0.60.
Finish 18F-PSMA-1007 PET/CT and present positive result.
Patients without contraindications of radical prostatectomy.
Exclusion criteria
Unable to perform PSA test or mpMRI examination.
Serum PSA<4 ng/mL or ≥100 ng/mL.
Risk probability of csPCa evaluated by the online diagnostic nomogram <0.60.
Finish 18F-PSMA-1007 PET/CT but negative result.
Patients who have negative results in the previous prostate biopsy.
Patients refuse radical prostatectomy or still choose prostate biopsy.
Exit criteria
Patients requiring exit (withdrawal/revocation of informed consent).
If there are any clinical adverse events or changes in the physical condition of the patients, it is not in the best interests of the patients to continue participating in the study.
Patients with a poor compliance or unable to truthfully provide relevant information or violate the protocol.
Patients who died.
Other reasons for withdrawing from the study (need to be recorded in detail).
Sample size
This study is designed for a single group of objective performance criteria. With reference to the opinions of many senior clinical and statistical experts, it is considered that the clinically acceptable positive predictive value should not be less than 90%. According to the literature exploration and previous research results, it is expected that the positive predictive value of PSMA combined model is more than 98%. Suppose the significance level is 0.05 (bilateral) and the degree of power is 80%. The required number of eligible samples (positive results in PSMA combined model) is 55. Considering the drop rate of 5%, the study is expected to enrol 57 patients.
Radical prostatectomy
In this study, radical prostatectomy is done with conventional laparoscopy or robotic assistance. After the extraperitoneal space is established, cut the bilateral pelvic fascia close to the pelvic wall and the public prostate ligament, and suture the dorsal deep vein complex of the penis. Then, separation is carried out along the plane between the prostate and the bladder neck. The back lip of the bladder neck can be cut against the prostate to completely break the urethra at the bladder neck. In the posterior of the seminal vesicle blunt separation to both sides, find the vas deferens, clamp and break the vas deferens, and blunt free seminal vesicles along the direction of the vas deferens. Next, bluntly free anterior to the tip of the prostate, exposing the ligaments on both sides of the prostate. If the neurovascular bundle is not preserved, prostate resection can be performed at the ‘extrafascial’ level. If the neurovascular bundle is preserved, it should be performed at the ‘intrafascia’ level. After completely cutting off the ligaments on both sides of the prostate, the distal urethra is severed. Urethral anastomosis uses the ‘sandwich’ reconstruction technique. Lymph node dissection in the external iliac arteriovenous, medial iliac artery and paraobturator lymph nodes will be performed according to perioperative evaluation.
Study period
The schedule of different periods for this trial is described in table 2. The following procedures will be completed during the screening period, perioperative period of radical prostatectomy and evaluation period.
The schedule of the screening period, perioperative period and evaluation period for this trial
Primary endpoints
The detection rate of clinically significant PCa (Gleason score ≥3+4); (positive predictive value of PSMA combined model for clinically significant PCa).
Secondary endpoints
The detection rate of any-grade PCa (Gleason score ≥3+3); (positive predictive value of PSMA combined model for any-grade PCa).
The detection rate of high-grade PCa (Gleason score ≥4+3); (positive predictive value of PSMA combined model for high-grade PCa).
The detection rate of benign prostatic diseases; (misdiagnosis rate of PSMA combined model for any-grade PCa).
Adverse events
The adverse events in this study originated from complications after 18F-PSMA-1007 PET/CT examination and radical prostatectomy . We plan to follow up the patients by telephone after the 1st month, 3rd month, 6th month and 12th month after radical prostatectomy, mainly asking whether the patients have any discomfort such as hematuria, urinary retention, urinary incontinence, urinary extravasation, etc. We will classify and record according to the patient’s symptoms according to the Clavien-Dindo Classification. Once an adverse event occurs, the researcher should ensure that the patients are provided with timely treatment and record in detail.
Statistical analysis
IBM SPSS (V.25.0) statistical software is used for statistical analysis. All statistical tests use two-sided tests, and p<0.05 will be considered as statistically significant. Description statistics for the measurement of continuous variables are means, SD, or median, IQR, categorical variables are described by number and proportion (%). The comparison of the two groups of variables will be analysed by appropriate methods according to the type of variables. T-test or Wilcoxon rank sum test is used for continuous variables. A χ2 test or Fisher’s exact test is used for categorical variables. Positive predictive value means the patients with malignant pathological results accounted for the proportion of all patients with positive PSMA combined model. Misdiagnosis rate means the patients with benign pathological results accounted for the proportion all patients with positive PSMA combined model.
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Monitoring
Key researchers formulate monitoring plans and appoint independent inspectors to conduct regular on-site monitoring visits to experimental hospitals to ensure that all contents of the research programme are strictly observed, and regularly check the database to ensure consistency with the contents of the original materials.
Ethics and dissemination
Our study protocol was approved by the ethics committee of The First Affiliated Hospital of USTC (No. 2022KY-142) and we will conduct this trial according to the principles of the Declaration of Helsinki strictly. All patient data will be processed anonymously. The results of this study will be published in peer-reviewed journals and reported at academic conferences. In addition, any modification to the protocol that has an impact on the study’s conduct, potential benefit to the patient, or patient safety, such as changes in study design, sample sizes or study procedures will necessitate a formal amendment to the protocol. The revised protocol needs to be resubmitted to the ethics committee for approval.
Ethics statements
Patient consent for publication
Footnotes
CW and QD contributed equally.
Contributors JX and TT developed the research question and contributed to the study design, funding support and project administration. XL, MN and QX helped in the registration of the trial and with the attainment of ethical approval. The manuscript was drafted by CW and QD. All authors have read and approved the final manuscript.
Funding This study was supported by the Key Research and Development Program of Anhui Province (202204295107020003), the Distinguished Young Scholars Fund of Anhui Province (2022AH020078) and the Key health Project of Anhui Province (AHWJ2022a037).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.