Detection and treatment of lymph node metastases in prostate cancer

Assessment of Lymph Node Involvement in Prostate Cancer Extended pelvic lymph node dissection (ePLND) remains the standard for assessing nodal involvement in prostate cancer (PCa), yet its invasiveness requires selective application. In Chapter 1, we explored whether ePLND could be omitted for PSMA PET/CT node-negative (miN0) patients undergoing robot-assisted radical prostatectomy (RARP). The results suggested that intermediate-risk, prostate-confined miN0 PCa patients might forego ePLND, though further validation is needed. Cribriform carcinoma and/or intraductal carcinoma (CR/IDC), which are adverse histopathological indicators, correlate strongly with nodal metastases and poorer outcomes in PCa. In Chapter 2, we assessed CR/IDC’s prevalence and prognostic value in intermediate-risk PCa patients with ISUP GG2 undergoing radical prostatectomy (RP). Results showed a high association between CR/IDC and nodal metastases, yet no significant link between CR/IDC and outcomes in patients without nodal metastases. Further, adding CR/IDC data to preoperative nomograms did not improve their predictive accuracy for nodal invasion in our study cohort. Overall, combining miN0 PSMA PET/CT, MRI-confirmed organ confinement, and CR/IDC-negative biopsies could indicate which patients may omit ePLND, pending prospective confirmation. Sentinel Node Procedure in Localized Prostate Cancer Sentinel lymph node biopsy (SLNB) offers a promising alternative to ePLND for nodal staging, with less associated toxicity. At the Netherlands Cancer Institute, SLNB guides radiotherapy field adjustments in cN0 PCa patients. In Chapter 4, we analyzed 528 cN0 PCa patients with >5% risk of nodal metastasis, comparing those who underwent SLNB-guided field adjustments to those with imaging-based prostate-only radiotherapy (PORT). SLNB identified occult metastases in 37% of patients, and those receiving SLNB-based radiotherapy showed improved biochemical and radiological recurrence-free survival over PORT, especially in avoiding whole-pelvis radiotherapy (WPRT) in node-negative cases. Despite increased PSMA PET/CT use, SLNB remained effective for staging in patients without PSMA PET-detected nodes. In Chapter 5, SLNB’s diagnostic value was tested in PSMA PET-staged node-negative patients. Results showed a constant rate of pN1 patients (35%) between conventional and PSMA PET-staged groups, suggesting SLNB's utility even when PSMA PET/CT shows only localized disease. A randomized trial is recommended to further validate SLNB-based radiotherapy for localized high-risk PCa. PSMA-Targeted Image-Guided Surgery Real-time identification of prostate cancer lesions during surgery is challenging but crucial for complete resection. In Chapter 6, we explored PSMA-targeted radioguided surgery (PSMA-RGS) with a miniaturized DROP-IN gamma probe in robot-assisted settings. Among 20 patients with pelvic PCa recurrences, 90% of pre-detected lesions were located and resected. This approach showed potential for accurately guiding surgeries for recurrent PCa, with further investigation underway in the TRACE-II trial. PSMA-RGS combined with androgen deprivation therapy (ADT) may improve survival in recurrent PCa, as indicated by retrospective studies. Chapter 7 further examined fluorescence-guided surgery with PSMA-targeted near-infrared (NIR) imaging agent OTL78 in primary PCa. Among patients undergoing RARP, those receiving OTL78 showed high specificity for tumor visualization and detected nodal metastases not visible on PSMA PET/CT. This method was effective for identifying positive margins and residual tumors, supporting its potential for enhancing surgical outcomes without serious side effects. In Chapter 8, a hybrid approach using radioactive and fluorescent signals was tested to enhance lesion detection. By integrating indocyanine green (ICG) fluorescence with PSMA-RGS, we successfully identified macro- and micrometastatic lymph nodes, showcasing the combined approach's utility in guiding precise nodal dissections during PCa surgery. In conclusion, enhanced perioperative visualization of PCa by PSMA-targeting has promising value in the surgical treatment of PCa and warrants further validation in a larger cohort of PCa patients.