Pembrolizumab for the treatment of renal cell carcinoma.

INTRODUCTION: The acquisition of resistance to VEGF-inhibiting therapies has prompted research toward immunotherapy for the treatment of metastatic renal cell carcinoma (mRCC). Among several, checkpoint inhibitors including PD-1 and PD-L1 inhibitors are the most promising approach. AREAS COVERED: This review addresses the clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab in first- and second-line treatment for mRCC regarding the most recent and significant published and ongoing studies. Attention is also given to its pharmacological characteristics as well as adverse events and its impact on patients' quality of life. EXPERT OPINION: Immunotherapy has become the backbone for the treatment of advanced RCC. With the approval of several therapeutic options, research needs now to focus on defining the appropriate therapy for each patient. Axitinib plus pembrolizumab belongs to the combinations of tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors for the first-line treatment of metastatic RCC. New combinations of pembrolizumab plus TKI for the evaluation in first- and second-line treatment of mRCC available. However, studies directly comparing the various treatment regimens using predictive biomarkers and long-term endpoints, including treatment-free survival, are lacking.

Prediction of the Need for an Extended Lymphadenectomy at the Time of Radical Cystectomy in Patients with Bladder Cancer.

BACKGROUND: A prospective randomized trial (LEA AUO AB 25/02) found no survival benefit in extended compared with limited pelvic lymph node dissection (PLND) templates in bladder cancer (BCa) patients treated with radical cystectomy (RC). However, the rate of lymph node invasion (LNI) in the standard and extended templates was lower than estimated. OBJECTIVE: To assess the accuracy of preoperative clinical and pathological parameters to predict LNI and to develop a model to preoperatively select candidates for the extended PLND templates. DESIGN, SETTING, AND PARTICIPANTS: A total of 903 BCa patients treated at a single institution were retrospectively identified. The primary outcome was to identify preoperatively the risk of LNI to tailor the type of PLND. The extended PLND templates consisted in the removal of pelvic lymph nodes together with the common iliac, presacral, para-aortocaval, interaortocaval, and paracaval sites up to the inferior mesenteric artery. INTERVENTION: A total of 903 BCa patients were treated with RC and bilateral extended PLND templates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Several models predicting LNI were evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analyses. A nomogram predicting LNI in the extended pattern was developed and validated internally. RESULTS AND LIMITATIONS: Overall, 55 patients (6.1%) had LNI in the extended PLND templates at RC. The median number of nodes removed was 19 (interquartile range: 13-26). A model including age, clinical T stage, clinical node stage, lymphovascular invasion, and presence of carcinoma in situ at the last transurethral resection before RC was developed. The AUC of this model is 73%. Using a cutoff of 3%, 108 extended PLNDs (12%) would be spared and only two LNIs (3%) would be missed. The main limitations of our model are the retrospective nature of the data, lack of external validation, and low rate of LNI. CONCLUSIONS: This is the first proposed model to predict LNI in the extended PLND templates. This model might help urologists identify which patients might benefit from an extended PLND at the time of RC, reserving a standard PLND for all the others. PATIENT SUMMARY: We developed the first nomogram to predict lymph node invasion (LNI) in the extended pelvic lymph node dissection templates in bladder cancer patients treated with radical cystectomy. The adoption of our model to identify candidates for the extended pelvic lymph node dissection templates could avoid up to 12% of these procedures at the cost of missing only 3% of patients with LNI.

Comparing oncological outcomes of laparoscopic vs open radical nephroureterectomy for the treatment of upper tract urothelial carcinoma: A propensity score-matched analysis.

OBJECTIVES: To compare oncological outcomes of open (ORNU) and laparoscopic radical nephroureterectomy (LRNU) after controlling for preoperative patient-derived factors. PATIENTS AND METHODS: We evaluated a multi-institutional collaborative database composed of 3984 patients diagnosed with upper tract urothelial carcinoma (UTUC) treated with RNU between 2006 and 2018. To adjust for potential selection bias, propensity score matching adjusted for age, gender and American society Anesthesiology (ASA) score was performed with one ORNU patient matched to one LRNU patient. Uni- and multivariable Cox regression evaluating the risk of overall recurrence, cancer-specific mortality (CSM) and overall mortality (OM) in the overall population and after propensity matching were performed. RESULTS: In total, 3984 patients underwent RNU, of these 3227 (81%) patients were treated with ORNU and 757 (19%) patients with LRNU. Within a median follow-up of 62 months, 1276 recurrences, 844 CSMs and 1128 OMs were recorded. On multivariable analyses, the LRNU approach was associated with an increased risk of overall recurrence (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.03-1.54; P = 0.02), but on the other hand LRNU was associated with a protective effect on CSM (HR 0.74, 95% CI 0.56-0.98; P = 0.04). After propensity matching analyses adjusted for age, gender and ASA score, 757 patients treated with LRNU and 757 patients treated with ORNU were available for the analyses. On multivariable Cox regression, LRNU vs ORNU was not associated with any difference in overall recurrence (P = 0.08), CSM (P = 0.1) or OM (P = 0.9). CONCLUSION: Our present data suggest that even if the type of approach to RNU was associated with different survival outcomes considering the overall population, this difference vanished when adjusted for potential confounders in propensity matching analyses. Therefore, we found that LRNU is not inferior to the ORNU approach for the treatment of UTUC. ABBREVIATIONS: ASA: American Society of Anesthesiology; CIS: carcinoma in situ; CSM: cancer-specific mortality; HR: hazard ratio; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; LVI: lymphovascular invasion; OM: overall mortality; pT: pathological tumour stage; RCT: randomised controlled trial; (L)(O)RNU: (laparoscopic) (open) radical nephroureterectomy; UTUC: upper tract urothelial carcinoma.

Evaluation of Cause of Death After Radical Cystectomy for Patients With Bladder Cancer: The Impact of Age at the Time of Surgery.

INTRODUCTION: Patients with bladder cancer treated with radical cystectomy (RC) have heterogeneous results in term of cancer-specific (CSM) and other cause mortality (OCM). Our aim is to assess the impact of age on cause of death after RC. PATIENTS AND METHODS: We retrospectively analyzed the data of 1222 patients treated with RC and bilateral pelvic lymph node dissection owing to nonmetastatic bladder cancer between 1990 and 2013. Patients were stratified according to age (< 59 vs. 60-69 vs. 70-79 vs. ≥ 80 years), tumor T stage at RC (pT0-T2 vs. pT3-T4), and tumor N stage at RC (pN+ vs. pN0). Competing-risks survival analyses were used to estimate CSM and OCM rates. RESULTS: With a median follow up of 6 years, 92 (7.5%) and 385 (31.5%) OCM and CSM were recorded. The 5-year CSM and OCM rates were 40% and 8.8%, respectively. After stratification according to disease stage and patient age, CSM emerged as the main cause of mortality in all patient subgroups. The 5-year OCM was 4.6%, 4.8%, 11%, and 32% for patients aged < 60 years versus 60 to 69 years versus 70 to 79 years versus ≥ 80 years, respectively. The 5-years CSM was 34%, 45%, 35%, and 56% for patients aged < 60 years versus 60 to 69 years versus 70 to 79 years versus ≥ 80 years, respectively. Similar findings were observed stratifying the population according to pathologic T and N stage. CONCLUSION: CSM is the preponderant cause of death for all the patients, regardless of age or stage. In this regard, RC also seems to be a reasonable approach for octogenarians.

Incidence and survival outcomes in patients with upper urinary tract urothelial carcinoma diagnosed with variant histology and treated with nephroureterectomy.

OBJECTIVE: To evaluate the incidence and survival outcomes of histological variants of upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analysed data from 1610 patients treated with RNU for clinically non-metastatic UTUC between 1990 and 2016 in several centres participating in the UTUC Collaboration. Histological variants were classified as micropapillary, squamous, sarcomatoid and other, including other rare variants (<10 cases for each). Multivariable competing risk analyses were conducted to assess the effect of variant histology on overall recurrence and cancer-specific mortality (CSM). RESULTS: Overall, 1460 patients (91%) had pure urothelial carcinoma (PUC), whereas 150 (9%) were diagnosed with a variant histology, including 89 (5.0%), 41 (2.0%), 10 (1.0%) and 10 (1.0%) cases of micropapillary, squamous, sarcomatoid and other tumours, respectively. Variant histology was associated with the presence of adverse pathological features compared with PUC, including non-organ-confined disease (59% vs 38%; P < 0.001), lymph node invasion (28% vs 24%; P = 0.02), high-grade disease (88% vs 71%; P < 0.001), tumour necrosis (28% vs 16%; P = 0.001) and positive surgical margins (15% vs 8%; P = 0.01). In competing risk analysis, micropapillary variant was the only factor associated with worse recurrence (sub-hazard ratio [SHR] 2.27, 95% confidence interval [CI] 1.25-4.79; P = 0.02) whereas sarcomatoid variant was associated with worse CSM (SHR 16.8, 95% CI 6.86-41.17; P < 0.001). CONCLUSION: We found that one out of 10 patients with UTUC treated with RNU had variant histology. Only micropapillary and sarcomatoid variants were associated with poorer oncological outcomes after adjusting for available confounding factors.

Radical Cystectomy in Pathological T4a and T4b Bladder Cancer Patients: Is There Any Space for Sub Stratification?

INTRODUCTION: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion. MATERIALS AND METHODS: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival. RESULTS: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM. CONCLUSIONS: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.

80-W GreenLight Laser Vaporization Versus Transurethral Resection of the Prostate for Treatment of Benign Prostatic Obstruction: 5-Year Outcomes of a Single-center Prospective Randomized Trial.

OBJECTIVE: To assess long term functional and safety follow-up data after 80-W GreenLight photoselective vaporization (GL PV) of the prostate and transurethral resection of the prostate (TURP). MATERIALS AND METHODS: Prospective randomized trial at a single tertiary referral center (Geneva, Switzerland). Patients were recruited in the outpatient clinic if they met the criteria for surgical treatment of benign prostatic obstruction. At baseline, 238 patients were treated either with the 80-W GL PV or monopolar TURP. After 5 years, data were available from 105 patients: 44 GL PV patients and 61 TURP patients. The primary outcome measure was the International Prostate Symptom Score (IPSS). Secondary outcome measures included maximum urinary flow rate (Qmax), postvoidal residual (PVR) and reoperation rate. Statistical analyses were performed using Stata 14 (StataCorp). RESULTS: After 5 years of follow-up, mean improvements in International Prostate Symptom Score, postvoidal residual and maximum urinary flow rate were similar in both groups. The re-treatment rate was 14.3% in the GL PV group vs 11.9% in the TURP group (P = .9). CONCLUSION: Noninferiority of the GL PV to TURP was confirmed in all functional and safety outcomes at 5-year follow-up. GL-PV could be a safe surgical alternative for patients suffering from benign prostatic obstruction.