A New Technique for Treating Low-risk Prostate Cancer—Super Active Surveillance

Prostate cancer is the most common malignant tumor among male urinary system diseases, and with the widespread application of prostate-specific antigen (PSA) screening, the proportion of patients diagnosed with localized low-risk prostate cancer has been increasing year by year¹. The treatment methods for low-risk prostate cancer patients with a life expectancy greater than 10 years primarily include radical prostatectomy, radiotherapy, active surveillance (AS), and focal therapy². Radical prostatectomy and radiotherapy remain the primary methods for treating localized prostate cancer in China; however, the high incidence of postoperative complications leads some patients to refuse treatment due to fear and quality-of-life concerns. Although AS can avoid some complications and decline in quality of life associated with local treatments, patients still face the risks of elevated PSA levels and ongoing progression of Gleason scores, resulting in psychological anxiety³.

Currently, there is a lack of suitable treatment options for low-risk prostate cancer patients who refuse radical surgery and are concerned about the risk of progression after AS. Super-AS is a novel treatment involving the application of ¹⁸F-PSMA PET/MR multimodal medical imaging, combined with real-time fusion of intraoperative transrectal ultrasound images, thereby enabling precise navigation for targeted argon-helium cryoablation therapy. It combines the patient's health status and subjective willingness to implement a more proactive clinical approach to localized therapy. Super-AS not only alleviates the potential side effects associated with radical surgery and radiotherapy for patients but also reduces the psychological stress related to concerns about the risk of tumor progression. According to the pathological characteristics of prostate cancer, "Super-AS" can be considered as a treatment option for localized low-risk prostate cancer⁴. This study provides new ideas and evidence for the establishment of new treatment methods for low-risk prostate cancer by preliminarily exploring the effectiveness and feasibility of this treatment approach.

The study has been reviewed by the Ethics Committee of the Civil Aviation General Hospital. Ethical statement. Written, informed consent was obtained from the patients.

1. Set the following inclusion criteria

1. Include patients following pathological confirmation of prostate adenocarcinoma through prostate system puncture.
2. Include patients with PSA < 10 ng/mL, Gleason score < 7, and cT1N0M0 or T2aN0M0 stage (classified as low risk according to D'Amico risk stratification).
3. Include patients who refuse to undergo radical surgery, radiotherapy, or endocrine therapy.
4. Include patients who refuse to accept AS or watchful waiting.

2. Exclusion criteria

1. Exclude patients with a previous diagnosis of prostate cancer with prior radical surgery, radiotherapy, or endocrine therapy.
2. Exclude patients with a history of mental illness, such as depression or severe anxiety, suspected or diagnosed alcohol or drug addiction.
3. Exclude patients if they have diseases that can lead to systemic immune dysfunction.
4. Exclude patients participating in other clinical trials.
5. Exclude patients with surgical contraindications.

3. Instruments for operation

1. Ensure the availability of a cryotherapy system and real-time image fusion ultrasound.
2. Prepare a USB flash drive containing ¹⁸F-PSMA PET/MR imaging data.
3. Choose the appropriate target framework for the puncture. Select different puncture targets based on prostate volume and tumor location. To ensure the precision of cryotherapy, perform 3D customization of puncture targets for some patients.
4. Prepare a V-shaped variable probe (freezing adjustment range of the probe from 1.5 cm to 5 cm in diameter) and two temperature probes.

4. Preparation for operation

1. Connect the USB flash drive to the integrated ultrasound system.
2. Preoperatively Import the patients' imaging data into ultrasound fusion software for 18F-PSMA PET/MR image target planning and marking (Figure 1).
3. Complete the preoperative planning for cryoablation (Figure 2).

5. Procedure

1. Position the patient in the lithotomy position and infuse Levofloxacin (0.5 g) 30 min before the start of surgery. After the import of Levofloxacin, retain a three-lumen pure silicone catheter.
2. Apply ultrasound and preoperative planning markers in ¹⁸F-PSMA PET/MR imaging for intraoperative registration (Figure 3).
3. Complete the targeted puncture of the cryoprobe (Figure 4).
4. Insert the variable probe into the target lesion based on the image fusion results.
5. Place two temperature probes in the perineal puncture, one located anterior to the rectum on the same side or in the Denonvilliers fascia and the other placed proximally adjacent to the neurovascular bundle on the same side.
6. Use a 50 °C constant-temperature saline solution to irrigate the bladder through the three-lumen urinary catheter to protect the urethra and prevent urethral frostbite.
7. Start the cryotherapy system (Figure 5).
   1. Rapidly lower the probe's front end to below -140 °C.
   2. Use ultrasound for real-time monitoring of the ice ball's edge, ensuring it exceeds the preoperative planned tumor coverage area by 0.5 cm while the temperature probe in the rectal anterior space remains above 0 °C.
8. Gradually reduce the freezing power while maintaining the ice ball range for 5 min.
9. Apply helium gas for rapid warming to reach above 15 °C and maintain for 5 min.
10. Repeat the low temperature and rewarming melting cycle.
11. Remove all probes, apply pressure to the puncture site to stop bleeding, and secure with a dressing.
12. Observe the color of the urinary catheter's contents. If the urine is clear, bladder irrigation is unnecessary; if blood is visible in the urine, perform bladder irrigation and transfer the patient to the anesthesia recovery room.
13. Discharge the patient from the hospital 2-3 days after the removal of the urinary catheter post surgery.

6. Evaluation

1. Oncology evaluation
   1. Recheck PSA at 1 and 3 months post surgery, then recheck once every 3 months.
   2. Imaging examination: Recheck ¹⁸F-PSMA PET/MRI at 6 months post surgery; T2WI indicates the disappearance of radioactive concentration in the original right peripheral zone.
2. Functional evaluation (followed by re-examination every month):
   1. Measure the International Prostate Symptom Score (IPSS), which is currently internationally recognized as the best means to judge the severity of lower urinary tract symptoms (LUTS).
   2. Measure the Quality-of-life score (Qol score) to understand patients' subjective feelings about the current level of LUTS.
   3. Measure the maximum urinary flow rate (Qmax) to understand patients' concise objective indicators of current LUTS levels.
   4. Use the International Consultation on Incontinence Questionnaire-Short Form (ICI-Q-SF) to evaluate whether there is urethral sphincter injury after cryoablation.
   5. Measure the International Index of erectile function-5 (IIEF-5) to evaluate whether there is neurovascular bundle damage after cryoablation.

Nine patients underwent surgery successfully, with no intraoperative complications. All 12 lesions were subjected to cryoablation, with a median ablation time of 46 min (ranging from 34 to 65 min). The urinary catheters were successfully removed in all cases 2-3 days postoperatively. The median follow-up time was 37 months (ranging from 14 to 61 months), and the postoperative PSA levels significantly decreased compared to preoperative levels. As of now, the follow-up evaluations for the six patients have shown no oncological progression, and the functional assessments are satisfactory (Table 1 and Table 2).

Figure 1: Preoperative ultrasound fusion software for 18F-PSMA PET/MRI target planning and marking. The figure shows the fused image of 18F-PSMA PET/MR with real-time fusion ultrasound, serving as the preoperative planning image and the basis for precise calculations. Please click here to view a larger version of this figure.

Figure 2: Target planning marker and three-dimensional reconstruction. Red outline: tumor ablation target; green outline: urethra; yellow outline: prostate gland area. Along with Figure 3, this figure displays the images obtained after the placement of the finger puncture frame-the preoperative puncture images that are precisely calculated based on Figure 1. They further emphasize that one cannot rely solely on computer-fused images because there are instances where computer-fused images do not align with the intraoperative target lesions. Please click here to view a larger version of this figure.

Figure 3: Application of ultrasound and preoperative planning markers in 18F-PSMA PET/MRI for intraoperative registration. Please click here to view a larger version of this figure.

Figure 4: Completion of the targeted puncture of the cryoprobe. Please click here to view a larger version of this figure.

Figure 5: Starting the cryotherapy system. Please click here to view a larger version of this figure.

Table 1: Preoperative baseline data of patients. Please click here to download this Table.

Table 2: Median values of patients with no duplicate data. Please click here to download this Table.

Radical prostatectomy and radiotherapy remain the primary treatment modalities for localized prostate cancer². However, the relatively high incidence of postoperative complications-such as urinary incontinence and erectile dysfunction after surgery, as well as radiation cystitis and radiation proctitis associated with radiotherapy-leads some patients to refuse these treatments. This refusal is often driven by their fear of postoperative complications and higher demands for quality of life. To avoid the adverse reactions of local treatment and its impact on quality of life for clinically low-risk and a small number of intermediate-risk prostate cancer patients with good prognosis, a treatment method has emerged that actively chooses not to immediately implement local treatment but to conduct close follow-up. Although the treatment method of AS can avoid some complications and decline in quality of life caused by local treatment, patients need to bear the risks of PSA elevation and progression of Gleason scores, resulting in psychological anxiety. Currently, there is a lack of appropriate treatment options for clinically low-risk prostate cancer patients who refuse radical surgery and are concerned about the risk of progression after active surveillance.

Research has shown that in specimens of radical prostate cancer, unifocal prostate cancer accounts for 13% to 18%. Although most cases are sporadic and multifocal, they are biologically unifocal. The proposal of the index lesion indicates that the metastasis of prostate cancer has a common origin, which arises from the same clone⁵. If it is possible to accurately identify and locate individual lesions containing this metastatic clone, it is likely that the side effects of prostate cancer treatment will be reduced. The proposal of multifocality in prostate cancer pathology and the index lesion provides theoretical feasibility for focal ablation of prostate-specific cancer lesions, indicating that targeted treatment of unifocal or multifocal prostate cancer can achieve good therapeutic outcomes.

The methods of targeted therapy are diverse, including cryoablation, high-intensity focused ultrasound, photodynamic therapy, and local radiotherapy, all of which have achieved good therapeutic effects⁶. Among the various focal treatment methods, cryoablation therapy has become a research hotspot both domestically and internationally in recent years, including whole-gland cryoablation and focal cryoablation. Several investigators have reported satisfactory results of targeted cryoablation in the treatment of localized low-risk prostate cancer^7,8.

The imaging method most commonly used in clinical practice for the diagnosis of prostate cancer is mpMRI, which has the characteristic of high sensitivity but relatively low specificity. However, it is somewhat limited in detecting distant metastases and biochemical recurrence. In recent years, prostate-specific membrane antigen (PSMA) has received widespread attention⁹. Eiber found that the imaging method of PSMA PET/MR labeled with radioactive nuclides is more accurate in locating and detecting lesions located within the prostate than the application of PET or multiparametric MRI alone¹⁰. Different radionuclide labels exhibit distinct characteristics, among which ¹⁸F has a higher affinity for PSMA, making it more advantageous in detecting low-grade and smaller-volume primary prostate cancer lesions. Previous studies on Super-AS primarily focused on targeting localization methods that combine MR or CT with intraoperative transrectal ultrasound-assisted cognitive fusion to locate tumor positions and freezing ranges. There is a lack of relevant reports on the use of the novel multimodal ¹⁸F-PSMA-PET/MR medical imaging technology for assisted localization.

Therefore, our center proposes the "Super-active surveillance" treatment technology, exploring the precise navigation of cryoablation therapy for localized low-risk prostate cancer through the real-time fusion of multimodal nuclear medicine imaging with ¹⁸F-PSMA PET/MR and preoperative planning combined with intraoperative transrectal ultrasound imaging. Intraoperative image fusion technology is key to accurately locating prostate cancer lesions. Intraoperative ultrasound has the advantages of being done in real time, simple, and cost-effective. The fusion imaging technology combines preoperative images (such as MRI or CT) with intraoperative ultrasound, complementing each other's strengths and combining the high resolution of MR or CT imaging with the real-time, economical, and straightforward nature of ultrasound imaging, thereby playing a crucial role in accurately locating lesions during surgery. Does the failure of focal treatment affect subsequent radical treatment? This is a clinical issue of great concern to urologists. Several studies have demonstrated that the outcomes of radical treatment after the failure of focal treatment do not significantly differ in terms of overall oncological control, functionality (urinary and sexual function), and postoperative complications^11,12.

In summary, "Super-AS" is a more proactive focal treatment clinical method implemented based on a reasonable stratification of risk, combined with the patient's health status and subjective willingness, which can achieve a relatively ideal organ function preservation effect, significantly improve the patient's postoperative quality of life, and is a safe and feasible treatment approach. However, due to the small sample size and short follow-up period of this study, the conclusions require further validation through an expanded sample and extended follow-up time.