The role of androgen deprivation therapy prior to radical prostatectomy in high-risk prostate cancer: a systematic review.

INTRODUCTION: Patients with high-risk prostate cancer (HRPCa) are prone to have worse pathological features, resulting in early biochemical recurrence after radical prostatectomy (RP). There is an urgent need to develop novel treatment strategies for this group of patients to optimize their outcomes. The purpose of this study is to perform a systematic review of the role of neoadjuvant hormonal therapy (NHT) followed by RP in HRPCa patients. EVIDENCE ACQUISITION: We performed a systematic review of the following databases, MEDLINE (PubMed), EMBASE, Cochrane Library, and clinical Trial.gov; between January 2007 and August 2023, following the PRISMA guidelines. EVIDENCE SYNTHESIS: After screening and deduplication, we included ten studies from an initial pool of 1275. The risk of bias was low in observational studies but ranged from moderate to low in controlled trials. Five studies utilized traditional androgen deprivation treatments (ADT), revealing favorable pathological outcomes but inconsistency in evaluating oncological results. Additionally, four studies focused on RP combined with androgen receptor pathway inhibitors (ARPIs) in the NHT setting, all showing primarily positive pathological outcome, with no clear evidence of an oncological benefit. Limited long-term follow-up data and a shortage of randomized controlled trials were evident among all the studies included in this review, regardless of the type of hormonal treatment used. CONCLUSIONS: Different hormonal treatments, including traditional ADT and ARPIs, yield positive pathology outcomes. Oncological evidence remains limited, echoing older findings predating ARPIs. Definitive conclusions require longer follow-ups and precise patient selection. Currently, insufficient evidence support ARPIs' superiority over conventional therapy before RP.

Neglected lymph nodal metastases in patients with renal cancer: when to extend the anatomical template of lymph node dissection during nephrectomy.

BACKGROUND: The role of lymph node dissection (LND) in patients with renal cell carcinoma (RCC) is still controversial. However, detecting lymph node invasion (LNI) is key due to prognostic implications and to identify patients who might benefit from adjuvant therapies such as adjuvant pembrolizumab. MATERIALS AND METHODS: Out of 796 patients, 261 (33%) received eLND, of whom 62 (8%) for suspicious lymph node (LN) metastases at preoperative staging (cN1). eLND was divided in 3 anatomical areas: (1) hilar, (2) side-specific (pre-/para-aortic or pre-/para-caval) and (3) inter-aorto-caval nodes. Overall maximum LN diameter was measured by a dedicated radiologist for each patient. Multivariable logistic regression models (MVA) were tested for the effect of maximum LN diameter in predicting the presence of nodal metastases outside the anatomical area of cN1. RESULTS: LNI was confirmed in 50% of cN1, whilst only 13 out of 199 cN0 patients were pN1 at final histology (6.5%; p < 0.001). In a per-patient analysis, of 62 cN1 patients, 24% vs. 18% vs. 8% harboured pN1 disease only inside vs. in-outside vs. only outside the suspicious anatomical field of cN1 at preoperative CT/MRI scan. At MVA, increasing diameter of suspicious LNs was independently associated with risk of finding positive LNs outside the suspicious anatomical field (OR 1.05, 95%CI 1.02-1.11; p = 0.02). CONCLUSIONS: Roughly 50% of cN1 patients undergoing eLND will harbour LN metastases, also outside the suspicious radiological area, and maximum LNs diameter at preoperative imaging correlates with such risk. Thus, an eLND might be justified in patients with large suspicious LN metastases, to better stage this patient population and to improve postoperative treatment management.

Diagnostic accuracy and clinical utility of micro-ultrasound guided biopsies in patients with suspected prostate cancer.

Introduction: New technologies to improve quality of prostate biopsies are appearing in clinical practice.We evaluate the performance of a micro-ultrasound device and the Prostate Risk Identification using MicroUltraSound (PRI-MUS) score in detecting clinically significant prostate cancer (csPCa). Material and methods: We retrospectively reviewed data of 139 biopsy- naïve patients with suspicion of prostate cancer, who underwent diagnostic MRI and micro-ultrasonography (microUS), followed by transrectal prostatic biopsy (systematic ±targeted) under local anesthetic. The main objective was to evaluate the performance of the Prostate Risk Identification using MicroUltraSound (PRI-MUS) score in detecting csPCa, defined as International Society of Urological Pathology (ISUP) ≥2. Results: Of all patients, 97 (70%) were found to have PCa, and 62 (45%) having csPCa.Among 100 patients with positive microUS (PRI-MUS score ≥3), 23 (23%) had ncsPCa and 57 (57%) were diagnosed with csPCa (ISUP ≥2); and in 39 patients with negative microUS, 12 (31%) were diagnosed with ncsPCa and 5 (13%) with csPCa.A PRI-MUS score ≥3 presented a sensitivity, specificity, positive predictive value and negative predictive value of 92%, 44%, 57% and 95%, respectively, for the detection of csPCa.The PRI-MUS score had higher areas under the curve than Prostate Imaging Reporting & Data System (PI-RADS) both for targeted (AUC 0.801 vs 0.733) and systematic + targeted (AUC 0.776 vs 0.694) biopsies for csPCa detection. Conclusions: In our cohort, microUS performed well as a diagnostic tool through an easily implementable scale. MicroUS presented similar sensitivity and higher specificity than MRI in detecting csPCa. Further multicenter prospective studies may clarify its role in prostate cancer diagnosis.

Holmium Laser Enucleation of the Prostate Is Associated with Complications and Sequelae Even in the Hands of an Experienced Surgeon Following Completion of the Learning Curve.

BACKGROUND: Holmium laser enucleation of the prostate (HoLEP) is considered a challenging procedure even for surgeons who have completed the learning curve. OBJECTIVES: To assess outcomes and complications following HoLEP performed by a highly experienced surgeon. DESIGN, SETTING, AND PARTICIPANTS: This was a single-institution prospective study (NCT03583034) performed at a tertiary referral centre that included 243 consecutive patients with lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE) treated with HoLEP by a single experienced surgeon (>1600 cases). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were assessed using validated questionnaires and uroflowmetry at baseline and several follow-up dates. Intraoperative and postoperative complications were recorded. Kaplan-Meier analysis was used to estimate recovery rates for urinary continence and erectile function. Logistic regression models were constructed to assess predictors of postoperative complications. RESULTS AND LIMITATIONS: Of the 243 patients, 78 (32.1%) had an indwelling urethral catheter. The median prostate volume (PV) was 87 cm3 (interquartile range 60-115) and 146 patients (59.8%) had PV >80 cm3. At 3-mo follow-up, 219 patients (90.1%) had a peak flow rate >20 ml/s and 182 (74.9%) had no postvoid residual urine. The improvement in subjective symptoms was significant at 1-mo follow-up and was maintained until 12 mo after surgery. Urinary continence recovery was slow, with an estimated rate of 68% (95% confidence interval [CI] 62-74%) at 1 mo and 94% (95% CI 91-97%) at 12 mo after HoLEP. The recovery rate for erectile function was 53% (95% CI 46-61%) at 1 mo and 85% (95% CI 77-90%) at 12 mo. Postoperative complications occurred in 36 patients (14.8%) during their hospital stay, in 34 (14%) within 1 mo following discharge from hospital, and in ten (4.1%) at later follow-up dates. Clinically significant complications (Clavien-Dindo ≥2) were observed in 44 cases (18%) and were more common for patients with an indwelling catheter at baseline (odds ratio 5.05; p = 0.006). CONCLUSIONS: HoLEP is an effective procedure for treating LUTS due to BPE, although it is not devoid of complications and sequelae, even in the hands of a highly experienced surgeon. PATIENT SUMMARY: Holmium laser treatment of the prostate to reduce its size has positive results for urinary function when performed by an experienced surgeon, even in complex cases, although there can be complications.

Differential Prognostic Value of Extrarenal Involvement in Patients With Non-Metastatic Renal Cell Cancer.

INTRODUCTION: A better definition of the prognostic significance of non-metastatic pT3a stage RCC subcategories is crucial to select the best candidate for adjuvant treatment. The aim of the study is to investigate the differential prognosis of extrarenal involvement in patients with non-metastatic pT3a RCC. MATERIALSAND METHODS: From a single institutional prospective database, 451 consecutive patients treated for pT3aN0/NxM0 RCC were selected and stratified according to pT3a subtypes (perirenal fat invasion, sinus fat invasion, segmental/renal vein thrombus, ≥ 2 features). Cancer specific survival (CSS), metastasis free survival (MFS) and relapse free survival (RFS) were primary endpoints of multivariable Cox regression models. RESULTS: Overall, 67 (15%) patients presented with renal/segmental vein thrombus only, 185 (41%) with perirenal fat invasion, 101 (22%) with sinus fat invasion and 98 (22%) with ≥ 2 features. The presence of ≥ 2 pT3a features was associated with a higher risk of metastasis (HR=2.36; 95%CI 1.30-4.27; P value = .005), recurrence (HR=2.41; 95%CI 1.36-4.28; P value=.003) and cancer specific mortality (HR=3.54; 95%CI 1.45-8.63; P value = .005) compared to only 1 pT3a feature. Moreover, the presence of perirenal fat invasion was associated with lower CSS (HR=2.82; 95% CI 1.19-6.69; P value = .02) compared to sinus fat invasion or tumoral thrombus only. CONCLUSION: The concurrent presence of ≥ 2 pT3a features is associated to a higher risk of distant progression, relapse and cancer specific mortality, implying potential role for adjuvant therapy or a more stringent follow-up. Moreover, perirenal fat invasion is associated with worse CSS compared to other pT3a patterns taken alone.

Accuracy of PET-choline in nodal staging of localized very high-risk prostate cancer.

OBJECTIVES: Localized very high-risk prostate cancer (VHR PCa) has long suffered from the inex-istence of good lymph node staging methods other than invasive surgery, as computed tomogra-phy has low sensitivity for nodal disease. With the rising use of positron emission tomography (PET), it is clinically meaningful to know its value for these patients. Our goal was to evaluate the real-life diagnostic accuracy of PET Choline in nodal staging, comparing it with the gold standard of extended pelvic lymph node dissection (ePLND). MATERIALS AND METHODS: We reviewed data from a high-volume center, including patients with VHR PCa according to current NCCN guidelines who underwent community 18F-fluorocholine PET/CT; followed by ro-botic assisted laparoscopic prostatectomy (RALP) and ePLND between 2010 and 2021. RESULTS: We included 44 patients and 88 lymph node regions. Among those, 14/44 (31.8%) patients and 20/88 (22.7%) regions had nodal disease present on definitive pathology. In comparison with ePLND, we found a sensitivity of 64.3% (95% CI, 39.2-89.4%), specificity of 83.3% (95% CI, 70.0- 96.7%), PPV of 64.3% (95% CI, 39.2-89.4%), and NPV of 83.3% (95% CI, 70.0-96.7%) for nodal disease on a patient-based analysis; and sensitivity of 35.0% (95% CI, 14.1-60.0%), specificity of 88.2% (95% CI, 80.6-95.9%), PPV of 46.7% (95% CI, 21.4-71.9%), and NPV of 82.2% (95% CI, 73.4-91.0%) on a region-based analysis. CONCLUSIONS: In our view 18F-fluorocholine PET/CT doesn't meet the criteria to be a standard exam for pre-operative staging for patients with VHR PCa, mostly due to its low sensitivity. However, other radiotracers should continue to be investigated in this setting.

Medium-term oncological outcomes of intermediate-risk prostate cancer treated with HIFU or cryotherapy. A single center 10-year experience.

OBJECTIVES: Focal therapies (FTs) are promising techniques for the treatment of localized prostate cancer. We assessed the medium-term oncological outcomes of intermediate-risk prostate cancer (PCa) treated with HIFU or cryotherapy. MATERIALS AND METHODS: One-hundred and fifty consecutive patients with intermediate-risk PCa, treated between 2009 and 2018 at a single center were included. Primary study outcome was failure-free survival (FFS), defined as absence of additional treatment, systemic progression or prostate cancer related death. RESULTS: Thirty-seven (25%) patients underwent cryotherapy and 113 (75%) HIFU. Median age was 69 (IQR 62-72) years, with 36 (24%) presenting palpable disease on rectal examination, and median total PSA of 7.85 (IQR 5.75-10.62) ng/mL. Patients were followed for a median of 61 (IQR 48-82) months. FFS at 2 and 4 years was of 75.6% and 53.6%, respectively. Survival from whole gland or systematic treatment at 2 and 4 years was of 78.9% and 53.9%, respectively. Patients with FFS presented lower total PSA nadir (1.89 vs 3.25 ng/mL, p < 0.001), higher % PSA reduction at 3 months (66.1% vs 49.3%, p < 0.001), and at nadir (75.5% vs 55.8%, p < 0.001). Other characteristics such has the treatment modality, age, prostate size, initial total PSA, cT stage, International Society of Urological Pathology (ISUP), tumor location and biopsy results by region did not differ between patients failing and not failing FT. Complications were uncommon (13%), with only onr (1%) patient having Clavien-Dindo grade > II. No deaths due to treatment were registered. CONCLUSIONS: At medium-term, FTs for intermediate-risk PCa presented good oncological results, with an excellent safety profile.

How to optimize the use of adjuvant pembrolizumab in renal cell carcinoma: which patients benefit the most?

PURPOSE: The KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab. METHODS: Within a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery. RESULTS: In the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21-35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6-69.2) as compared to 76.2% (95% CI 72.2-79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2-40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9-68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1-88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence. CONCLUSIONS: Patients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab.

Pancreatic metastases after surgery for renal cell carcinoma: survival and pathways of progression.

PURPOSE: Metastatic ccRCC has peculiar tropism in the pancreas. We describe the characteristics and pathways of progression of patients with PM in a large multi-institutional consortium and compare them to patients with metastases from ccRCC at other sites. METHODS: Detailed clinical and histopathological data were collected. To account for differences in baseline characteristics between the two groups, IPTW was used to compare the two groups in terms of PFS and OS. RESULTS: Of the 182 patients, 33 (18%) had pancreatic, 94 (52%) pulmonary, 30 (16%) bone, 13 (7%) hepatic, and 12 (7%) brain metastases. Patients with PM had less aggressive ccRCC at baseline compared to those with progression at other sites in terms of tumour stage and grade. Median time from ccRCC surgery to PM was 8 (95%CI 5-10) vs. 1 year (95%CI 1-2) for progression to other sites (p < 0.001). Median IPTW-weighted time to second progression was 4.3 years (95%CI 2.4-not reached) for patients with PM vs 1.1 year (95%CI 0.8-2.3) for those with progression in other sites (p < 0.001). The most frequent second progression sites were pancreas (24%) and liver (15%) in patients with PM, while progression to the pancreas was rare (4%) in those with a different first progression site. Surgery alone (55%) or in combination with medical therapy (30%) was more frequent in the PM group than in other sites (p < 0.001). Median IPTW-OS time was longer for patients with PM [8.8 years (95%CI 6.5-not reached)] compared to those with first progression in other sites [2.8 years (95%CI 1.9-4.3), p < 0.001]. CONCLUSION: Pancreatic tropism is typical of ccRCC tumours with more indolent behaviour than those progressing to other sites. A long follow-up period is necessary to distinguish PM from ccRCC.

The impact of intraoperative bleeding on the risk of chronic kidney disease after nephron-sparing surgery.

PURPOSE: The current literature regarding the effect of blood loss (eBL) after nephron-sparing surgery (NSS) on long-term renal function is scarce. We tested the effect of eBL on the risk of developing chronic kidney disease (CKD) after NSS. METHODS: Within an institutional prospectively maintained database, we identified 215 patients treated with NSS for cT1N0M0 renal mass at one European high-volume center. Multivariable logistic regression models tested the effect of eBL on the risk of developing CKD, after accounting for surgical complexity, individual clinical characteristics, and surgical experience. Multivariable linear regression models identified predictors of eBL. RESULTS: After a median follow-up of 36 months, 55 (25.6%) patients experienced CKD after surgery. At multivariable analyses, eBL independently predicted higher risk of CKD after NSS (odds ratio [OR]: 1.16; 95% confidence intervals [CI] 1.04-1.30; p < 0.01). Specifically, the relationship between eBL and probability of CKD emerged as nonlinear, with a plateau from 0 to 500 mL of eBL and an increase afterward. When multivariable linear regression analyses investigated predictors of eBL, hypertension (Est: 127, 95% CI 12-242; p = 0.03), clinical size (Est: 47, 95% CI 7-87; p = 0.02), and PADUA score (Est: 42; 95% CI 4-80 p = 0.03) achieved independent predictor status for higher intraoperative eBL. Conversely, surgical experience was associated with lower eBL (p = 0.01). CONCLUSIONS: Intraoperative bleeding is independently associated with the risk of developing CKD after surgery, even after adjustment for well-known predictors of renal failure and tumor complexity. Hence, strategies aimed at maximally reducing such adverse events deserve special consideration.

Cytoreductive Nephrectomy in Metastatic Patients with Signs or Symptoms: Implications for Renal Cell Carcinoma Guidelines.

The role of cytoreductive nephrectomy (CN) patients with metastatic renal cell carcinoma (mRCC) is unclear. To define the proportion of symptomatic mRCC, to investigate the impact of CN on symptomatic improvement and perioperative morbidity, and to elucidate the trade-off between such benefit and harm, an observational study of 317 mRCC patients treated with CN was performed. Symptomatic mRCC was defined as the presence of any sign or symptom causally related to the disease. Sign or symptom resolution and improvement were defined as the absence of all the signs and symptoms recorded at baseline, and the absence of at least one sign or symptom recorded at baseline, respectively. Perioperative morbidity was assessed using the Clavien-Dindo classification. Response to CN was classified as beneficial, mixed, or harmful according to the trade-off between symptomatic improvement and perioperative morbidity. The proportions of local, metastasis-specific, and general signs or symptoms were 37%, 23%, and 27%, respectively. The proportions of any sign or symptom resolution and improvement after CN were 43% and 71%, respectively. The proportions of local sign or symptom resolution and improvement after CN were 91% and 95%, respectively. The risks of any complication and major complication were 37% and 10%, respectively. At regression analysis, symptomatic status was not associated with perioperative morbidity. The proportion of beneficial response was invariably higher than the proportion of harmful response. At mRCC diagnosis, two out of three patients suffer from any sign or symptom, and one out of three suffers from local signs or symptoms. CN has a positive impact on symptomatic status. PATIENT SUMMARY: Most metastatic renal cell carcinoma patients are symptomatic, and they should be aware that cytoreductive nephrectomy has a positive impact on symptomatic status.