Editor's note
Science and technology are the primary productive forces, and in the field of prostate cancer treatment, new medical technologies such as prostate-specific membrane antigen (PSMA) nuclide tracers, robot-assisted surgery, and 3D visualization technology have made new achievements in recent years. There are still some questions worth further exploring: Can PSMA-based radioguided surgery help doctors better identify lymph node metastases during surgery? Formulate medication strategies for patients with biochemical recurrence based on more accurate PSMA PET/CT results, and what are the treatment outcomes? Can emerging 3D visualization technologies help more accurate individualized surgery and translate it into patient benefits? Focusing on the 2024 Annual Meeting of the European Urological Association (EAU), Professor Wang Zhirong from Wuxi People's Hospital was specially invited to deeply interpret the new progress in the application of medical technology in the field of prostate cancer diagnosis and treatment, discuss the future development direction of precision treatment of prostate cancer, and share his professional insights.
Expert Profile
Prof. Zhirong Wang
- Chief Physician and Deputy Director of the Department of Urology of Wuxi People's Hospital
- Vice Chairman of the Department of Urology of Wuxi Medical Association
- Business expertise: diagnosis and treatment of urinary tumors, urinary stones, female urinary incontinence and prostate diseases, with solid urological professional knowledge and surgical skills to deal with incurable diseases.
- He has long been committed to minimally invasive surgery in urology: (robot-assisted) laparoscopic radical prostatectomy, kidney cancer surgery, renal cancer with inferior vena cava cancer embolectomy, radical bladder cancer + orthotopic ileal neobladder surgery (started in May 2008), retroperitoneal or inguinal lymph node dissection, percutaneous nephrostomy lithotripsy, flexible ureteroscopic holmium laser lithotripsy, transurethral prostate enucleation (plasma or holmium laser), sling or mesh suspension for the treatment of stress urinary incontinence in men and women, etc.
Abstract A0436 - Detection of lymph node metastases in patients with prostate cancer undergoing robotic-assisted radical prostatectomy (RARP) and expanded pelvic lymph node dissection (ePLND) by prostate-specific membrane antigen radioguided surgery (PSMA-RGS): updated results from a planned interim analysis of a prospective phase II study[1]
Background:
ePLND is the gold standard for lymph node staging for prostate cancer. PSMA-RGS helps physicians identify lymph node invasion (LNI) during RARP. This report updates the interim analysis results of a Phase II, prospective study (NCT04832958) to characterize the feasibility and accuracy of PSMA-RGS.
Research Methods:
A total of 56 patients with intermediate- or high-risk prostate cancer with cN0M0 on traditional imaging and Briganti nomogram predicted a risk of LNI of >5% were included. Thirty-four of these patients received PSMA-RGS between June 2021 and September 2023. All patients underwent preoperative PSMA-PET examination. The patient was injected with 99mTc-PSMA I&S intravenously one day before surgery, followed by SPECT/CT examination. Drop-in gamma probes were used for both in vivo and in vitro detection. All positive lesions were excised (target/background signal ratio ≥2), and ePLND was performed in the obturator, intrailiac, and extrailiac lymph node regions. Side effects, perioperative outcomes, and PSA persistence were assessed, and the effects of different positive uptake definitions (target/background signal ratio ≥2 vs ≥3) in PSMA-RGS were compared for diagnostic accuracy.
Findings:
Fifteen (44%), 11 (32%), and 8 (24%) of all patients had intermediate-risk, high-risk, and locally advanced prostate cancer, respectively, and 10 (29%) patients showed lymph node uptake on PSMA PET. No adverse events were observed after 99mTc-PSMA injection. The median duration of surgery, blood loss, and hospital stay were 222 minutes, 100 mL, and 5 days, respectively. No intraoperative complications were observed. A total of 2 patients developed complications (Clavien-Dindo grade 2 and 3) within 30 days after surgery, as detailed in Table 1.
Table 1. Perioperative outcomes
A total of 7 patients (20%) had positive resection margins, and 6 patients (17%) had persistent PSA after surgery. A total of 174 specimens, including 872 lymph nodes, were removed (median 23 per patient). A total of 12 patients (35%) had LNI (median number of positive lymph nodes was 4). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PSMA-RGS were 73% vs 54%, 89% vs 98%, 48% vs 80%, 96% vs 94%, and 87% vs 92%, respectively, when the target/background ≥≥signal ratio was selected as the positive threshold, as shown in Table 2.
Table 2. Analysis by resection area (n=174 anatomical regions)
When the target/background signal ratio ≥2 vs ≥3 was selected as the positive threshold, the sensitivity, specificity, PPV, and NPV of PSMA-RGS were 82% vs 73%, 78% vs 96%, 64% vs 89%, 90% vs 88%, and 79% vs 88%, respectively, as shown in Table 3.
Table 3. By Patient Analysis (n=34)
PSMA-RGS detected suspicious lesions outside the standard pelvic template in 5 (15%) patients. All 5 patients had positive PSMA PET, and 2 of them were confirmed to have LNI.
Conclusions of the study
The results of this update confirm that the use of 99mTc-PSMA-RGS in RARP is a safe and feasible procedure. Compared with the target/background signal ratio of ≥2 as the positive threshold, the ≥3-fold threshold was more accurate and had a lower false-positive rate, but a greater proportion of positive lymph nodes were missed.
Professor Wang Zhirong commented
Although the benefit of ePLND on oncological outcomes remains to be demonstrated, it is important for determining disease staging and assessing prognosis, and guidelines recommend ePLND in high-risk and intermediate-risk patients predicted to be at high risk of LNI based on nomogram models [2,3]. However, studies have shown that more than 65% of patients who are scheduled to undergo ePLND have negative lymph node final pathology results [4], and ePLND will inevitably prolong the operation time and increase the risk of complications. However, in recent years, great progress has been made in the diagnosis and treatment of PSMA as the target, and there are also studies on the preoperative evaluation of LNI by PSMA PET.
In this study, PSMA and intraoperative imaging guidance technology were combined to enable urologists to detect and remove lymph node metastases in real time during surgery through PSMA imaging and handheld probes, and to find some small or atypical lesions that could not be detected in preoperative in vitro PSMA PET. The results of the study were first published in 2022 for 12 patients [2], and the results reported in this interim report are similar, with 99mTC-PSMA-RGS showing high specificity but low sensitivity, i.e., there are few false positives, especially when the target/background signal ≥3 is used as the threshold for positivity, but there are still many false negative results, which means that there is a possibility of missing positive lesions. Therefore, based on the current evidence, ePLND is still irreplaceable.
However, the pace of new technologies is unstoppable, and in the future, we are looking forward to the potential of new intraoperative guidance technologies such as PSMA-based PET/CT and 99mTc-PSMA-RGS, and on the other hand, we need to understand their limitations in clinical application, and in practice, we will balance the pros and cons according to the specific conditions and the situation and wishes of each patient, and choose the most appropriate treatment plan for them. The study plans to include 100 patients, and we look forward to the publication of the final results, as well as the results of more large-scale studies that will rewrite the standard of care and bring greater benefits to patients."
Abstract A0600-PICHE Study (NCT05022914): PSMA-Guided Treatment in Biochemical Recurrence (BCR) After Radical Prostatectomy (RP)—A Prospective Study[5]
Background:
Salvage radiotherapy (SRT) is one of the main treatments for BCR after RP. However, based on recent studies, next-generation imaging (NGI) technology may significantly influence the treatment pattern of patients with BCR, and [68Ga]Ga-PSMA-11 PET/CT has been widely and routinely used in early staging. However, the correct treatment of patients with BCR after PSMA PET restaging remains controversial, and more prospective evidence is needed. PSICHE (NCT05022914) is a prospective, multicenter trial to explore imaging-based strategies in this setting. This is a first-time report of results for detection rates and early clinical outcomes after treatment.
Research Methods:
All patients developed BCR after RP± postoperative radiotherapy, with prostate-specific antigen (PSA) > 0.2 ng/ml and <1 ng/ml, and underwent [68Ga]Ga-PSMA-11 PET/CT. After restaging, all patients were treated according to the pre-defined treatment plan. SRT of the prostate bed is recommended for all patients with negative stage or only positive prostate bed imaging. All patients with recurrent or oligometastatic pelvic lymph nodes received stereotactic radiosurgery (SBRT). For patients with extensive metastases, androgen deprivation therapy (ADT) ± androgen receptor-targeted drugs such as enzalutamide or apalutamide are given. Observation is recommended for all patients who are PSMA-negative and have received postoperative radiotherapy. If the patient has a positive PSMA in the prostate bed after SRT, it is recommended to re-administer stereotactic therapy for visible recurrent lesions. See Figure 1 for details.
Figure 1.Study design
Findings:
A total of 174 patients were included in this analysis. Among them, 69.5% of patients had negative PSMA PET or only positive prostate bed, 22.4% and 5.7% of patients had pelvic lymph node or oligometastatic recurrence, respectively, and 2.3% had extensive metastases. As a result, SRT, observation, or retreatment was performed in 59.8%, 8.6%, and 1.1% of patients, SBRT in 28.2%, and ADT in 2.3% of patients, respectively. After a median follow-up of 17 months, 50 patients had further biochemical progression after treatment, of which 27 patients had new distant metastases detected by PSMA and 13 patients started ADT therapy. Median BCR-free survival was 25 months (95% CI 20-63), while metastasis-free and ADT-free survival were not reached.
Conclusions of the study
Pelvic or metastatic disease can be detected in a significant proportion of patients with early-stage BCR, which has a significant impact on standard treatment options. The results of this prospective, multicenter study show promise for a PSMA-guided therapy strategy. Under this strategy, most patients remain untreated with ADT, avoiding unnecessary treatment toxicity.
Professor Wang Zhirong commented
BCR will still occur in 15-45% of patients after RP, and re-staging the disease, timely selection and adjustment of treatment strategies will greatly affect the progression and overall survival of subsequent diseases. Traditional imaging has limited efficacy at this stage, but NGI represented by PSMA PET/CT has shown good potential in the staging of patients with BCR, and treatment strategies based on NGI results have also shown some benefit, such as the EMPIRE-1 and OLI-P studies, respectively, which demonstrated that NGI-based treatment strategies can improve treatment outcomes in patients with local or oligometastatic recurrence of BCR [6,7].
Based on the results of PSMA PET/CT, a complete treatment pathway has been developed for patients with different stages including negative/prostate bed positive, lymph node recurrence or oligometastases, and distant metastases, and the results first reported in 2023 show promising potential for PSA response and tolerability at 3 months after treatment. In this report, the results of long-term follow-up with a median of 17 months were reported, and the metastasis-free and ADT-free survival in the overall population were not reached, suggesting that the individualized treatment strategy based on the results of PSMA PET/CT detection enabled patients to receive appropriate treatment after BCR, and the disease was controlled, while avoiding unnecessary side effects caused by treatment.
Of course, there are still limited studies on the long-term outcomes of treatment strategies for patients with BCR based on NGI test results, and we look forward to more studies in the future, and the results of longer follow-up will provide us with more evidence, confidence, and better improvement in the survival of these patients.
Abstract A0953 - A phase III prospective randomized trial to evaluate the effect of the use of augmented reality technology in RARP on the positive rate of postoperative surgical margins[8]
Background:
In RARP, the role of augmented reality (AR) technology in reducing the rate of positive surgical margins (PSM) and intraoperative frozen section (IFS) analysis has not been fully studied, and only retrospective studies and case series analyses are currently available, and prospective studies are necessary.
Research Methods:
This study is a single-center, prospective, double-blind randomized trial (NCT06059859). Patients with EAU low- or intermediate-risk prostate cancer with an international index of erectile function (IIEF) of ≥ 20 and magnetic resonance (mpMRI) showing at least one visible lesion were randomized (1:1) to receive:
●AR RARP: 3D reconstruction based on mpMRI. The model was projected onto the surgical field using TileProTM technology. and the use of mixed reality technologies during IFS. See Figure 2 for details.
● Standard RARP: Neuropreservation and IFS based on mpMRI.
Figure 2. Application of AR technology in RARP
The primary endpoint was PSM rate. Secondary endpoints were nerve preservation of AR RARP versus standard RARP and rate of erectile recovery at 3, 6, and 12 months postoperatively. In addition, subgroup analyses were performed for patients who were particularly candidates for AR RARP. Assuming an expected difference of 10% between groups, the number of patients required for each group is 159 to ensure adequate statistical power (80%). A pre-defined interim analysis will be performed after enrollment of 159 patients.
Findings:
As of September 2023, a total of 115 patients were enrolled. Among them, 58 (50.4%) and 57 (49.6%) patients received AR RARP and standard RARP, respectively. No differences in baseline characteristics were observed between groups. The median operative time for AR RARP versus standard RARP was 212 and 213 minutes, respectively (P=0.9). No difference in nerve preservation was observed between the two groups (P=0.8). Thirteen patients (22.5%) and 18 (31.5%) patients in the AR RARP and standard RARP groups had PSM (P=0.3). However, the rate of positivity for IFS was higher in the AR RARP group (36 vs. 19%, P=0.06). In the final pathologic results, the PSM rate of mpMRI indicator lesions in the AR RARP group was lower than that in the standard RARP group (8.5% vs. 14%). See Table 4 for details.
Table 4. Preliminary results
Conclusions of the study
Compared with conventional RARP, AR RARP and IFS based on AR models appear to reduce PSM rates in patients undergoing neuro-sparing surgery. Final results will be evaluated after completion of this study. Professor Wang Zhirong commented
With the improvement of patients' quality of life requirements and the development of prostate cancer surgical techniques, RP nowadays will choose to preserve more surrounding normal tissues and vascular nerves to protect postoperative function, but on the other hand, this may lead to an increased risk of positive resection margins. With the help of AR technology, the images of preoperative MRI or PET/CT are converted into intraoperative, and doctors can observe the spatial relationship between the lesion and its surrounding structures in real time and intuitively.
Previous studies have reported that AR models reconstructed from preoperative PSMA PET/CT data can accurately assist in the identification of sentinel lymph nodes, thereby achieving accurate lymph node dissection [9]. It has also been shown that the use of fluorescence tracer imaging combined with AR technology in RP can visualize the extent of lymphatic invasion that is difficult to see in the conventional field of view during surgery, further improving the resection accuracy of lesions [10]. In addition, we note that in the summary A0952 of the EAU Congress, a prospective randomized study conducted by Chinese colleagues also showed that the use of holographic image technology combined with IFS analysis can effectively reduce the PSM rate [11]. Compared with traditional RARP, the introduction of emerging visualization technologies such as AR or holograms can help clinicians better balance the relationship between maximizing complete tumor resection and better protecting the patient's urinary continence and sexual function.
In the future, with the continuous development of research in the field of digital medicine, we look forward to greater breakthroughs in related technologies to provide patients with more individualized, precise and minimally invasive surgical solutions, so that patients can not only achieve a longer life, but also live a more quality and dignified life.
brief summary
The innovation of medical technology provides a powerful tool for the precise diagnosis and treatment of prostate cancer. PSMA nuclide tracers, robotic surgery, intraoperative guidance technology, and 3D visualization technology are redefining the diagnosis and treatment of prostate cancer. We have reason to believe that prostate cancer patients will enjoy a more precise and personalized treatment plan. With the further deepening of future research, these technologies may blossom in many places to improve diagnostic accuracy, optimize treatment strategies and improve patient prognosis. We look forward to the wider application of these innovative technologies in clinical practice and the benefit of prostate cancer patients."
Bibliography:
1. Quarta L., et al. Present on EAU24 - 39th Annual EAU Congress. Abstract A0436.
2. P. Cornford, et al. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. 2023
3. Wei Qiang. Guidelines for the diagnosis and treatment of prostate cancer // Huang Jian, et al. Editor-in-chief. Guidelines for the diagnosis and treatment of urological and andrological diseases in China: 2022 edition. Beijing; Science Press. 2022: 130-216.
4. Gandaglia G, Mazzone E, Stabile A, et al. Eur Urol. 2022 Oct; 82(4):411-418.
5. Francolini G., et al. Present on EAU24 - 39th Annual EAU Congress. Abstract A0600.
6. Jani A B, et al. Lancet. 2021, 397(10288): 1895-1904.
7. Hölscher T, et al. Eur Urol Oncol. 2022, 5(1): 44-51.
8. Luzzago S., et al. Present on EAU24 - 39th Annual EAU Congress. Abstract A0953.
9. From Oosterom M N, et al. J Urol. 2018, 199(4): 1061-1068.
10. Mathur P, et al. Int J Comput Assist Radiol Surg. 2019, 14(6): 923-931.
11. Wang X., et al. Present on EAU24 - 39th Annual EAU Congress. Abstract A0952.
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