Development and Internal Validation of a Novel Nomogram Predicting the Outcome of Salvage Radiation Therapy for Biochemical Recurrence after Radical Prostatectomy in Patients without Metastases on Restaging Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography.

Background and objective: Owing to the greater use of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after robot-assisted radical prostatectomy (RARP), patient selection for local salvage radiation therapy (sRT) has changed. Our objective was to determine the short-term efficacy of sRT in patients with BCR after RARP, and to develop a novel nomogram predicting BCR-free survival after sRT in a nationwide contemporary cohort of patients who underwent PSMA PET/CT before sRT for BCR of PCa, without evidence of metastatic disease. Methods: All 302 eligible patients undergoing PCa sRT in four reference centers between September 2015 and August 2020 were included. We conducted multivariable logistic regression analysis using a backward elimination procedure to develop a nomogram for predicting biochemical progression of PCa, defined as prostate-specific antigen (PSA) ≥0.2 ng/ml above the post-sRT nadir within 1 yr after sRT. Key findings and limitations: Biochemical progression of disease within 1 yr after sRT was observed for 56/302 (19%) of the study patients. The final predictive model included PSA at sRT initiation, pathological grade group, surgical margin status, PSA doubling time, presence of local recurrence on PSMA PET/CT, and the presence of biochemical persistence (first PSA result ≥0.1 ng/ml) after RARP. The area under the receiver operating characteristic curve for this model was 0.72 (95% confidence interval 0.64-0.79). Using our nomogram, patients with a predicted risk of >20% had a 30.8% chance of developing biochemical progression within 1 yr after sRT. Conclusions: Our novel nomogram may facilitate better patient counseling regarding early oncological outcome after sRT. Patients with high risk of biochemical progression may be candidates for more extensive treatment. Patient summary: We developed a new tool for predicting cancer control outcomes of radiotherapy for patients with recurrence of prostate cancer after surgical removal of their prostate. This tool may help in better counseling of these patients with recurrent cancer regarding their early expected outcome after radiotherapy.

Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Is Associated with Improved Oncological Outcome in Men Treated with Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer.

BACKGROUND: Radiolabeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has shown superior diagnostic accuracy to conventional imaging for the detection of prostate cancer deposits . Consequently, clinical management changes have been reported in patients with biochemical recurrence (BCR) of disease after robot-assisted radical prostatectomy (RARP). We hypothesized that, due to the exclusion of patients with metastatic disease on PSMA-PET/CT, those who underwent local salvage radiation therapy (SRT) after restaging PSMA-PET/CT for BCR may have better oncological outcomes than patients who underwent "blind" SRT. OBJECTIVE: To compare the oncological outcome of a patient cohort that underwent PSMA-PET imaging prior to SRT with that of a patient cohort that did not have PSMA-PET imaging before SRT. DESIGN, SETTING, AND PARTICIPANTS: We included 610 patients who underwent SRT, of whom 298 underwent PSMA-PET/CT prior to SRT and 312 did not. No additional hormonal therapy was prescribed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To compare both cohorts, case-control matching was performed, using the prostate-specific antigen (PSA) value at the initiation of SRT, pathological grade group, pathological T stage, surgical margin status, and biochemical persistence after RARP as matching variables. The outcome variable was biochemical progression at 1 yr after SRT, defined as either a rise of PSA ≥0.2 ng/ml above the nadir after SRT or the start of additional treatment. RESULTS AND LIMITATIONS: After case-control matching, 216 patients were matched in both cohorts (108 patients per cohort). In the patient cohort without PSMA-PET/CT prior to SRT, of 108 patients, 23 (21%) had biochemical progression of disease at 1 yr after SRT, compared with nine (8%) who underwent restaging PSMA-PET/CT prior to SRT (p = 0.007). CONCLUSIONS: PSMA-PET/CT is found to be associated with an improved oncological outcome in patients who undergo SRT for BCR after RARP. PATIENT SUMMARY: Performing prostate-specific membrane antigen positron emission tomography/computed tomography imaging in patients with biochemical recurrence of disease after robot-assisted radical prostatectomy, before initiating salvage radiation therapy, resulted in improved short-term oncological outcomes.

Adding multiparametric MRI to the MSKCC and Partin nomograms for primary prostate cancer: Improving local tumor staging?

INTRODUCTION AND OBJECTIVES: As a single diagnostic modality, multiparametric MRI (mpMRI) has imperfect accuracy to detect locally advanced prostate cancer (T-stages 3-4). In this study we evaluate if combining mpMRI with preoperative nomograms (Memorial Sloan Kettering Cancer Center [MSKCC] and Partin) improves the prediction of locally advanced tumors. MATERIALS AND METHODS: Preoperative mpMRI results of 430 robot-assisted radical prostatectomy patients were analyzed. MSKCC and Partin nomogram scores predicting extraprostatic growth were calculated. Logistic regression analysis was performed, combining the nomogram prediction scores with mpMRI results. The diagnostic value of the combined models was evaluated by creating receiver operator characteristics curves and comparing the area under the curve (AUC). RESULTS: mpMRI was a significant predictor of locally advanced disease in addition to both the MSKCC and Partin nomogram, despite its low sensitivity (45.3%). However, overall predictive accuracy increased by only 1% when mpMRI was added to the MSKCC nomogram (AUC MSKCC 0.73 vs MSKCC + mpMRI 0.74). Predictive accuracy for the Partin Tables increased 4% (AUC Partin 0.62 vs Partin + mpMRI 0.66). CONCLUSION: The addition of mpMRI to the preoperative MSKCC and Partin nomograms did not increase diagnostic accuracy for the prediction of locally advanced prostate cancer.

Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival.

PURPOSE: We identified pathological parameters of inguinal lymph node involvement with the aim of predicting pelvic lymph node involvement and survival. MATERIALS AND METHODS: A total of 308 patients with penile carcinoma and adequate followup were included in this study. The outcome of 102 patients who underwent lymphadenectomy for lymph node metastases was analyzed further. Histopathological characteristics of the regional lymph nodes were reviewed including unilateral or bilateral involvement, the number of involved nodes, pathological tumor grade of the involved nodes, and the presence of extracapsular growth. RESULTS: Tumor grade of the involved inguinal lymph nodes (OR 6.0, 95% CI 1.2-30.3) and the number of involved nodes (2 or less vs more than 2) (OR 12.1, 95% CI 3.0-48.1) were independent prognostic factors for pelvic lymph node involvement. Extracapsular growth (OR 2.3, 95% CI 1.1-4.8), bilateral inguinal involvement OR 3.4, 95% CI 1.2-9.4) and pelvic lymph node involvement (OR 3.1, 95% CI 1.4-6.6) were independent prognostic factors for disease specific survival. CONCLUSIONS: Patients with only 1 or 2 inguinal lymph nodes involved without extracapsular growth and no poorly differentiated tumor within these nodes are at low risk of pelvic lymph node involvement and have a good prognosis with a 5-year survival rate of approximately 90%. Pelvic lymph node dissection seems to be unnecessary in these cases.

Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival.

There is evidence that a subset of penile carcinomas is caused by infection with high-risk human papillomavirus (HPV). However, extensive studies on the possible influence of HPV infection on clinical outcome of penile cancer are lacking. This investigation is aimed to examine the prevalence of high-risk HPV in a large series of penile squamous-cell carcinomas (SCCs) and to determine the relationship between HPV and survival. Formalin-fixed, paraffin-embedded tumor specimens of 171 patients with penile carcinoma were tested for high-risk HPV DNA presence by GP5+/6+-PCR. The clinical course of the patients and the histopathological characteristics of the primary tumors were reviewed. High-risk HPV DNA was detected in 29% of the tumors, with HPV 16 being the predominant type, accounting for 76% of high-risk HPV containing SCCs. Disease-specific 5-year survival in the high-risk HPV-negative group and high-risk HPV-positive group was 78% and 93%, respectively (log rank test p = 0.03). In multivariate analysis, the HPV status was an independent predictor for disease-specific mortality (p = 0.01) with a hazard ratio of 0.14 (95% CI: 0.03-0.63). Our results indicate that the presence of high-risk HPV (29%) confers a survival advantage in patients with penile carcinoma.

Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus.

A comprehensive analysis of 53 penile carcinomas was performed to determine which mechanisms might be involved in the disruption of the p16(INK4A)/cyclin D/Rb pathway. To that end, human papillomavirus (HPV) presence, p16(INK4A) expression and promoter methylation, and expression of the BMI-1 polycomb gene product were studied. Sixteen (30%) of the carcinomas were found to harbour high-risk HPV DNA, 15 of which contained HPV 16. HPV 16 E6/E7 oncogene transcripts were detected in 13 (87%) of the carcinomas that contained HPV 16. Strong immunostaining for p16(INK4A) was significantly more frequent in carcinomas that contained high-risk HPV DNA (p < 0.001) and amongst those with HPV 16 DNA, it was more frequent in lesions in which E6/E7 transcripts were detectable (p = 0.029). This supports an active role for HPV E7 in interfering with the p16(INK4A)/cyclin D/Rb pathway. Methylation of the p16(INK4A) promoter or overexpression of the BMI-1 polycomb gene product may provide alternative modes of interference with this pathway. These phenomena were mutually exclusive and found in the absence of HPV in 15% and 10% of the penile carcinomas, respectively. These data indicate that there are at least three plausible mechanisms by which the p16(INK4A)/cyclin D/Rb pathway can become disrupted during penile carcinogenesis.