Concomitant vs Staged Therapeutic Inguinal Lymphadenectomy in Clinically Node Positive Penile Squamous Cell Carcinoma: Does It Make a Difference?

PURPOSE: Inguinal lymph node dissection within 3 months of primary tumor resection in penile cancer has been associated with longer recurrence-free and cancer-specific survival. However, the optimal timing and effect of lymphadenectomy performed concurrently at the time of primary lesion management on oncologic outcomes in clinically lymph node positive penile squamous cell carcinoma remains unknown. MATERIALS AND METHODS: An international, multicenter cohort of 966 penile cancer cases was queried for penile squamous cell carcinoma management after the year 2000, clinically lymph node positive status, and performance of penile surgery and inguinal lymph node dissection. Cohorts were stratified as concomitant if inguinal lymph node dissection and penile surgery occurred on the same date or staged when inguinal lymph node dissection was performed after penile resection. Rates and patterns of penile squamous cell carcinoma recurrence were reported. Distant recurrence-free, cancer-specific, and overall survival were estimated using Kaplan-Meier analyses and groups compared with log-rank testing. RESULTS: Of 253 contemporary men with clinically lymph node positive penile squamous cell carcinoma, 96 (38%) underwent concomitant inguinal lymph node dissection and 157 (62%) had inguinal lymph node dissection performed in a staged manner. Penile cancer was most likely to recur distantly (19%) followed by in the groin (14%) or pelvis (5%). There were no differences in distant recurrence-free, cancer-specific, or overall survival between management strategies. Multivariable analysis adjusting for stage, treatment center, and perioperative chemoradiation also demonstrated no recurrence-free, cancer-specific, or overall survival benefit between management strategies. CONCLUSIONS: Inguinal lymph node dissection performed concurrently with excision of the penile tumor for clinically node positive penile squamous cell carcinoma is not associated with differences in recurrence-free, cancer-specific, or overall survival compared to staged lymph node dissection.

Association of patients' sex with treatment outcomes after intravesical bacillus Calmette-Guérin immunotherapy for T1G3/HG bladder cancer.

PURPOSE: To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC). MATERIALS AND METHODS: We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression. RESULTS: A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78-1.60, p = 0.55). CONCLUSION: Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.

A risk calculator predicting recurrence in lymph node metastatic penile cancer.

OBJECTIVES: To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM. PATIENTS AND METHODS: The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts. RESULTS: Positive surgical margins, pN3 , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low (<19%) 24m-R risk of recurrence, for both the development (43% and 58% vs 83%, P < 0.001) and validation cohort (44% and 50% vs 85%, P < 0.001). Results were confirmed in the subgroup of patients who did not receive adjuvant treatment (P < 0.001), but not in patients who did receive adjuvant treatments in both the development and validation cohorts (P > 0.1). CONCLUSION: Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments.

Complication rate after cystectomy following pelvic radiotherapy: an international, multicenter, retrospective series of 682 cases.

PURPOSE: Conflicting evidence exists on the complication rates after cystectomy following previous radiation (pRTC) with only a few available series. We aim to assess the complication rate of pRTC for abdominal-pelvic malignancies. METHODS: Patients treated with radical cystectomy following any previous history of RT and with available information on complications for a minimum of 1 year were included. Univariable and multivariable logistic regression models were used to assess the relationship between the variable parameters and the risk of any complication. RESULTS: 682 patients underwent pRTC after a previous RT (80.5% EBRT) for prostate, bladder (BC), gynecological or other cancers in 49.1%, 27.4%, 9.8% and 12.9%, respectively. Overall, 512 (75.1%) had at least one post-surgical complication, classified as Clavien ≥ 3 in 29.6% and Clavien V in 2.9%. At least one surgical complication occurred in 350 (51.3%), including bowel leakage in 6.2% and ureteric stricture in 9.4%. A medical complication was observed in 359 (52.6%) patients, with UTI/pyelonephritis being the most common (19%), followed by renal failure (12%). The majority of patients (86%) received an incontinent urinary diversion. In multivariable analysis adjusted for age, gender and type of RT, patients treated with RT for bladder cancer had a 1.7 times increased relative risk of experiencing any complication after RC compared to those with RT for prostate cancer (p = 0.023). The type of diversion (continent vs non-continent) did not influence the risk of complications. CONCLUSION: pRTC carries a high rate of major complications that dramatically exceeds the rates reported in RT-naïve RCs.

The Microbiome, Intestinal Function, and Arginine Metabolism of Healthy Indian Women Are Different from Those of American and Jamaican Women.

BACKGROUND: Indian women have slower arginine flux during pregnancy compared with American and Jamaican women. Arginine is a semi-essential amino acid that becomes essential during periods of rapid lean tissue deposition. It is synthesized only from citrulline, a nondietary amino acid produced mainly in the gut. The gut is therefore a key site of arginine and citrulline metabolism, and gut microbiota may affect their metabolism. OBJECTIVE: The objective of this study was to identify differences in the gut microbiota of nonpregnant American, Indian, and Jamaican women and characterize the relations between the gut microbiota, gut function, and citrulline and arginine metabolism. METHODS: Thirty healthy American, Indian, and Jamaican women (n = 10/group), aged 28.3 ± 0.8 y, were infused intravenously with [guanidino-15N2]arginine, [5,5-2H2]citrulline, and [15N2]ornithine and given oral [U-13C6]arginine in the fasting and postprandial states. Fecal bacterial communities were characterized by 16S rRNA gene sequencing. RESULTS: In the fasting state, Indian women had lower citrulline flux than did American and Jamaican women [7.0 ± 0.4 compared with 9.1 ± 0.4 and 8.9 ± 0.2 µmol ⋅ kg fat-free mass (FFM)-1 ⋅ h-1, P = 0.01] and greater enteral arginine conversion to ornithine than did American women (1.4 ± 0.11 compared with 1.0 ± 0.08 µmol ⋅ kg FFM-1 ⋅ h-1, P = 0.04). They also had lower mannitol excretion than American and Jamaican women (154 ± 37.1 compared with 372 ± 51.8 and 410 ± 39.6 mg/6 h, P < 0.01). Three dominant stool community types characterized by increased abundances of the genera Prevotella, Bacteroides, and Bacteroides with Clostridium were identified. Indian women had increased mean relative abundances of Prevotella (42%) compared to American and Jamaican women (7% and < 1%, P = 0.03) which were associated with diet, impaired intestinal absorptive capacity, and arginine flux. CONCLUSIONS: These findings suggest that dysregulated intestinal function and a unique gut microbiome may contribute to altered arginine metabolism in Indian women.

Indian women of childbearing age do not metabolically conserve arginine as do American and Jamaican women.

BACKGROUND: In a previous study in pregnant American women, we reported that arginine flux and nitric oxide synthesis increased in trimester 2. More recently, we reported that Indian women do not increase arginine flux during pregnancy as their American or Jamaican counterparts do. OBJECTIVE: The purpose of this study was to determine whether Indian women of childbearing age are producing less arginine and/or catabolizing more arginine and therefore have less available for anabolic pathways than do Jamaican and American women. METHODS: Thirty healthy women aged 28.3 ± 0.8 y from the United States, India, and Jamaica (n = 10/group) were given 6 h primed, constant intravenous infusions of guanidino-¹5N2-arginine, 5,5-²H2-citrulline, ¹5N2-ornithine, and ring-²H5-phenylalanine, in addition to primed, oral doses of U-¹³C6-arginine in both the fasting and postprandial states. An oral dose of deuterium oxide was also given to determine fat-free mass (FFM). RESULTS: Compared with American women, Indian and Jamaican women had greater ornithine fluxes (µmol · kg fat FFM⁻¹ · h⁻¹) in the fasting and postprandial states (27.3 ± 2.5 vs. 39.6 ± 3.7 and 37.2 ± 2.0, respectively, P = 0.01), indicating greater arginine catabolism. However, Jamaican women had a higher endogenous arginine flux than did Indian and American women in the fasting (66.1 ± 3.1 vs. 54.2 ± 3.1 and 56.1 ± 2.1, respectively, P = 0.01) and postprandial (53.8 ± 2.2 vs. 43.7 ± 4.9 and 42.8 ± 3.1, respectively, P = 0.06) states. As a consequence, Indian women had lower arginine bioavailability (µmol · kg FFM⁻¹ · h⁻¹) in the fasting state (42.0 ± 2.6) than did American (49.9 ± 1.3, P = 0.045) and Jamaican (55.5 ± 3.5, P = 0.004) women, as well as in the postprandial state (40.7 ± 3.5 vs. 51.8 ± 1.2 and 57.5 ± 3.2, respectively, P = 0.001). CONCLUSION: Compared with American and Jamaican women, Indian women of childbearing age have a decreased arginine supply because of increased arginine catabolism without an increase in arginine flux.

Early localization of recurrent prostate cancer after prostatectomy by endorectal coil magnetic resonance imaging.

INTRODUCTION: To evaluate the ability of endorectal coil (e-coil) magnetic resonance imaging (MRI) to identify early prostatic fossa recurrence after radical prostatectomy. MATERIALS AND METHODS: We identified 187 patients from 2005-2011 who underwent e-coil MRI with dynamic gadolinium-contrast enhancement followed by transrectal ultrasound (TRUS) guided prostatic fossa biopsy for possible local prostate cancer recurrence. For analysis, local recurrence was defined as a negative evaluation for distant metastatic disease with a positive prostatic fossa biopsy, decreased prostate-specific antigen (PSA) following salvage radiation therapy, or increased lesion size on serial imaging. RESULTS: Local recurrence was identified in 132 patients, with 124 (94%) detected on e-coil MRI. The median PSA was 0.59 ng/mL (range < 0.1-13.1), and median lesion size on MRI was 1 cm. The sensitivity of MRI was 91%, with a specificity of 45%. The positive predictive value was 85%, with a negative predictive value of 60%. For patients with a PSA < 0.4 ng/mL the sensitivity of e-coil MRI was 86%. When a lesion was identified on MRI, the positive biopsy rate was 65% and lesion size was a significant predictor of positive biopsies. The positive biopsy rates were 51%, 74%, and 88% when the lesion was < 1 cm, 1 cm-2 cm, or > 2 cm, respectively (p = 0.0006). CONCLUSIONS: E-coil MRI has a high level of sensitivity in identifying local recurrence of prostate cancer following radical prostatectomy, even at low PSA levels. E-coil MRI should be considered as the first imaging evaluation for biochemical recurrence for identifying patients suitable for localized salvage therapy.

Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer.

Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies. SIGNIFICANCE: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489.

Outcome predictors of radical prostatectomy followed by adjuvant androgen deprivation in patients with clinical high risk prostate cancer and pT3 surgical margin positive disease.

PURPOSE: Patients with high risk prostate cancer with pT3 tumor and positive surgical margins have a high risk of biochemical failure after radical prostatectomy and adjuvant androgen deprivation therapy. Predictors of cancer related death in this patient group are necessary. MATERIALS AND METHODS: We performed subset analysis of a prospective trial including 550 consecutive patients with preoperative high risk prostate cancer (prostate specific antigen greater than 20 ng/ml ± cT3/4 ± biopsy Gleason 8-10). Men who underwent radical prostatectomy and received continuous adjuvant androgen deprivation therapy for pT3a/b N0-1 positive surgical margin disease were included in the analysis, and none of the patients received neoadjuvant androgen deprivation therapy or adjuvant radiation therapy. RESULTS: Overall 173 of 550 patients (31.5%) with a median followup of 67 months met the study inclusion criteria. For these men the estimated 8-year prostate cancer specific and overall survival rates were 86.3% and 77.0%, respectively. Tumor stage and positive surgical margin at the bladder neck were independent predictors of prostate cancer specific survival and overall survival, and were used to substratify cases. Those with pT3b disease with positive surgical margins at the bladder neck had the highest risk of death (5-year cancer specific survival 60.0% and overall survival 52.3%), while pT3a disease (regardless of positive surgical margin location and lymph node invasion) and pT3b tumors with negative bladder neck margins had 8-year prostate cancer specific survival and overall survival rates of 92.0% and 84.9%, respectively. CONCLUSIONS: The results of this trial demonstrated the heterogeneity of high risk prostate cancer cases with T3 tumors and positive surgical margins. The presented substratification by tumor stage and positive surgical margin location identifies men at high risk for prostate cancer related death and might help in the design of adjuvant therapy trials.

Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases.

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

Prognostic value of the SPOP mutant genomic subclass in prostate cancer.

BACKGROUND: Speckle-type POZ protein (SPOP) mutation defines one of the dominant prostate cancer genomic subtypes, yet the impact of this mutation on clinical prognosis is unknown. METHODS: We defined SPOP mutation status either by DNA sequencing or by transcriptional signature in a pooled retrospective multi-institutional cohort, the Decipher retrospective cohort, the Decipher Genomics Resource Information Database prospective cohort, and The Cancer Genome Atlas. Kaplan-Meier survival analysis and multivariable Cox models were used to assess the independent impact of SPOP mutation on survival, biochemical recurrence and time to metastasis. The Decipher retrospective cohort was also used to assess the impact of the addition of SPOP mutation status to a model predicting adverse pathology at prostatectomy which was then validated in the Decipher prospective cohort. RESULTS: A fixed-effect model incorporating results from multivariable Cox regression including 5,811 subjects demonstrated that SPOP mutation was associated with a lower rate of adverse pathology at radical prostatectomy (odds ratios 0.57, 95% confidence interval 0.34-0.93), independent of preoperative prostate-specific antigen, age, and pathologic Gleason score. SPOP was not associated with biochemical recurrence, metastasis-free survival, or cancer-specific survival independent of pathologic information. The addition of SPOP status to prognostic models reclassified a large proportion of patients with the mutation (55%) into a favorable risk group when used to predict adverse pathology. CONCLUSION: While the clinical utility of delineating any single molecular alteration in prostate cancer remains unclear, these results illustrates the importance of genomic subtypes in prostate cancer behavior and potential role in prognostic tools.

18F-FDG PET/CT and Urothelial Carcinoma: Impact on Management and Prognosis-A Multicenter Retrospective Study.

Objectives: To evaluate the ability of 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to predict survivorship of patients with bladder cancer (BC) and/or upper urinary tract carcinoma (UUTC). Materials: Data from patients who underwent FDG PET/CT for suspicion of recurrent urothelial carcinoma (UC) between 2007 and 2015 were retrospectively collected in a multicenter study. Disease management after the introduction of FDG PET/CT in the diagnostic algorithm was assessed in all patients. Kaplan-Meier and log-rank analysis were computed for survival assessment. A Cox regression analysis was used to identify predictors of recurrence and death, for BC, UUTC, and concomitant BC and UUTC. Results: Data from 286 patients were collected. Of these, 212 had a history of BC, 38 of UUTC and 36 of concomitant BC and UUTC. Patient management was changed in 114/286 (40%) UC patients with the inclusion of FDG PET/CT, particularly in those with BC, reaching 74% (n = 90/122). After a mean follow-up period of 21 months (Interquartile range: 4-28 mo.), 136 patients (47.4%) had recurrence/progression of disease. Moreover, 131 subjects (45.6%) died. At Kaplan-Meier analyses, patients with BC and positive PET/CT had a worse overall survival than those with a negative scan (log-rank < 0.001). Furthermore, a negative PET/CT scan was associated with a lower recurrence rate than a positive examination, independently from the primary tumor site. At multivariate analysis, in patients with BC and UUTC, a positive FDG PET/CT resulted an independent predictor of disease-free and overall survival (p < 0,01). Conclusions: FDG PET/CT has the potential to change patient management, particularly for patients with BC. Furthermore, it can be considered a valid survival prediction tool after primary treatment in patients with recurrent UC. However, a firm recommendation cannot be made yet. Further prospective studies are necessary to confirm our findings.

Comparison between the diagnostic accuracies of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and conventional imaging in recurrent urothelial carcinomas: a retrospective, multicenter study.

PURPOSE: To determine the performance accuracy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) after primary tumor treatment for both bladder cancer (BC) and upper tract urothelial cancer (UTUC). To compare the accuracy of FDG PET/CT with that of contrast-enhanced-ceCT and magnetic resonance imaging (MRI). METHODS: Data of patients with recurrent urothelial carcinomas (UC) after primary treatment were collected in a retrospective, international multicenter study. Inclusion criteria were (1) patients with a known history of UC in the BC and/or in the UTUC; (2) PET/CT images after curative intent treatment of the primary tumor; (3) conventional imaging modalities (abdominal ceCT or MRI, or total body ceCT, and chest X-ray: called C.I.) performed no more than 3 months from PET/CT; (4) available standard of reference (e.g., histological data or follow-up imaging modalities) for the validation of PET/CT findings. Exclusion criteria were other abdominal tumors, chemotherapy administration prior to and/or concomitant to imaging, and non-urothelial histologic variants. Sensitivities, specificities, positive, and negative predictive values were evaluated for all patients and separately for bladder and UTUC. RESULTS: Overall, 287 patients were enrolled. Two-hundred thirteen patients underwent cystectomy (74.2%), 35 nephroureterectomy (12.2%), 31 both cystectomy + nephroureterectomy (10.8%), 5 both cystectomy + conservative treatment for UTUC (1.4%), and 3 (1%) other types of nephron-sparing treatments for UTUC. Neoadjuvant and adjuvant treatments were performed in 36 (12.5%) and 111 (38.7%) patients, respectively. Sensitivity and specificity (95% confidence intervals) of PET/CT for the detection of recurrent UC were 94% (91% to 96%) and 79% (68% to 88%), respectively. However, sensitivity was higher for BC than UTUC (95% vs. 85%) while specificity was lower in BC (78% vs. 85% for BC and UTUC, respectively). PET/CT and C.I. findings were available in 198 patients. The results were positively concordant in 137 patients, negatively concordant in 23 patients, and discordant in 38 patients (20 negative at C.I. vs. positive at PET/CT and 18 positives at ceCT/MRI vs. negative at PET/CT) (K Cohen = 0.426; p < 0.001). Sensitivities, specificities, and accuracies (95% confidence intervals) of PET/CT vs. C.I. for the detection of recurrent BC and UTUC were 94% (90% to 97%) vs. 86% (81% to 92%), 79% (67% to 92%) vs. 59% (44% to 74%), and 91% (87% to 95%) vs. 81% (75% to 86%), respectively. CONCLUSIONS: FDG PET/CT has a high diagnostic accuracy for the identification of recurrent UC, particularly in patients with BC. Moreover, its accuracy outperforms C.I. for both BC and UTUC.

A Multi-institutional Analysis of Perioperative Outcomes in 106 Men Who Underwent Radical Prostatectomy for Distant Metastatic Prostate Cancer at Presentation.

BACKGROUND: Current trials are investigating radical intervention in men with metastatic prostate cancer. However, there is a lack of safety data for radical prostatectomy as therapy in this setting. OBJECTIVE: To examine perioperative outcomes and short-term complications after radical prostatectomy for locally resectable, distant metastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case series from 2007 to 2014 comprising 106 patients with newly diagnosed metastatic (M1) prostate cancer from the USA, Germany, Italy, and Sweden. INTERVENTION: Radical prostatectomy and extended pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were used to present margin status, continence, and readmission, reoperation, and overall complication rates at 90 d, as well as for 21 specific complications. Kaplan-Meier plots were used to estimate survival function. Intercenter variability and M1a/ M1b subgroups were examined. RESULTS AND LIMITATIONS: Some 79.2% of patients did not suffer any complications; positive-margin (53.8%), lymphocele (8.5%), and wound infection (4.7%) rates were higher in our cohort than in a meta-analysis of open radical prostatectomy performed for standard indications. At a median follow-up of 22.8 mo, 94/106 (88.7%) men were still alive. The study is limited by its retrospective design, differing selection criteria, and short follow-up. CONCLUSIONS: Radical prostatectomy for men with locally resectable, distant metastatic prostate cancer appears safe in expert hands for meticulously selected patients. Overall and specific complication rates related to the surgical extirpation are not more frequent than when radical prostatectomy is performed for standard indications, and the use of extended pelvic lymphadenectomy in all of this cohort compared to its selective use in localized/locally advanced prostate cancer accounts for any extra morbidity. PATIENT SUMMARY: Men presenting with advanced prostate cancer that has spread beyond the prostate are increasingly being considered for treatments directed at the prostate itself. On the basis of results for our international series of 106 men, surgery appears reasonably safe in this setting for certain patients.

A systematic review of randomised controlled trials of radiotherapy for localised prostate cancer.

BACKGROUND: Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males. A systematic review of randomised controlled trials (RCTs) of radiotherapy and other non-pharmacological management options for localised prostate cancer was undertaken. METHODS: A search of thirteen databases was carried out until March 2014. RCTs comparing radiotherapy (brachytherapy (BT) or external beam radiotherapy (EBRT)) to other management options i.e. radical prostatectomy (RP), active surveillance, watchful waiting, high intensity focused ultrasound (HIFU), or cryotherapy; each alone or in combination, e.g. with adjuvant hormone therapy (HT), were included. Methods followed guidance by the Centre for Reviews and Dissemination and the Cochrane Collaboration. Indirect comparisons were calculated using the Bucher method. RESULTS: Thirty-six randomised controlled trials (RCTs, 134 references) were included. EBRT, BT and RP were found to be effective in the management of localised prostate cancer. While higher doses of EBRT seem to be related to favourable survival-related outcomes they might, depending on technique, involve more adverse events, e.g. gastrointestinal and genitourinary toxicity. Combining EBRT with hormone therapy shows a statistically significant advantage regarding overall survival when compared to EBRT alone (Relative risk 1.21, 95% confidence interval 1.12-1.30). Aside from mixed findings regarding urinary function, BT and radical prostatectomy were comparable in terms of quality of life and biochemical progression-free survival while favouring BT regarding patient satisfaction and sexual function. There might be advantages of EBRT (with/without HT) compared to cryoablation (with/without HT). No studies on HIFU were identified. CONCLUSIONS: Based on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices.

Pelvic lymph node dissection in prostate cancer.

CONTEXT: Pelvic lymph node dissection (PLND) is considered the most reliable procedure for the detection of lymph node metastases in prostate cancer (PCa); however, the therapeutic benefit of PLND in PCa management is currently under debate. OBJECTIVE: To systematically review the available literature concerning the role of PLND and its extent in PCa staging and outcome. All of the existing recommendations and staging tools determining the need for PLND were also assessed. Moreover, a systematic review was performed of the long-term outcome of node-positive patients stratified according to the extent of nodal invasion. EVIDENCE ACQUISITION: A Medline search was conducted to identify original and review articles as well as editorials addressing the significance of PLND in PCa. Keywords included prostate cancer, pelvic lymph node dissection, radical prostatectomy, imaging, and complications. Data from the selected studies focussing on the role of PLND in PCa staging and outcome were reviewed and discussed by all of the contributing authors. EVIDENCE SYNTHESIS: Despite recent advances in imaging techniques, PLND remains the most accurate staging procedure for the detection of lymph node invasion (LNI) in PCa. The rate of LNI increases with the extent of PLND. Extended PLND (ePLND; ie, removal of obturator, external iliac, hypogastric with or without presacral and common iliac nodes) significantly improves the detection of lymph node metastases compared with limited PLND (lPLND; ie, removal of obturator with or without external iliac nodes), which is associated with poor staging accuracy. Because not all patients with PCa are at the same risk of harbouring nodal metastases, several nomograms and tables have been developed and validated to identify candidates for PLND. These tools, however, are based mostly on findings derived from lPLND dissections performed in older patient series. According to these prediction models, a staging PLND might be omitted in low-risk PCa patients because of the low rate of lymph node metastases found, even after extended dissections (<8%). The outcome for patients with positive nodes is not necessarily poor. Indeed, patients with low-volume nodal metastases experience excellent survival rates, regardless of adjuvant treatment. But despite few retrospective studies reporting an association between PLND and PCa progression and survival, the exact impact of PLND on patient outcomes has not yet been clearly proven because of the lack of prospective randomised trials. CONCLUSIONS: On the basis of current data, we suggest that if a PLND is indicated, then it should be extended. Conversely, in view of the low rate of LNI among patients with low-risk PCa, a staging ePLND might be spared in this patient category. Whether this approach is also safe from oncologic perspectives is still unknown. Patients with low-volume nodal metastases have a good long-term prognosis; to what extent this prognosis is the result of a positive impact of PLND on PCa outcomes is still to be determined.

Two positive nodes represent a significant cut-off value for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy.

BACKGROUND: Currently, the 2002 American Joint Committee on Cancer (AJCC) staging system of prostate cancer does not include any stratification of patients according to the number of positive nodes. However, node positive (N+) patients share heterogeneous outcomes according to the extent of lymph node invasion (LNI). OBJECTIVE: To test whether the accuracy of cancer specific survival (CSS) predictions may be improved if node positive patients are stratified according to the number of positive nodes. DESIGN, SETTING, AND PARTICIPANTS: The study cohort included 703 N+ M0 patients treated with radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND) between September 1988 and January 2003 at two large Academic Institutions. Number of positive nodes was dichotomized according to the most informative cut-off predicting CSS. Kaplan-Meier curves assessed cancer specific survival rates. Predictive accuracy of the current N stage and of the new N classification in predicting CSS was quantified with Harrell's concordance index after adjusting for pathological (T) stage and internally validated with 200 boostraps resamples. Differences in predictive accuracy were compared with the Mantel-Haentzel test. RESULTS AND LIMITATIONS: Mean follow-up was 113.7 months (median: 112.5, range 3.5-243). The mean number of nodes removed was 13.9 (range: 2-52). The mean number of positive nodes was 2.3 (range: 1-31). The most informative cut-off of positive nodes in predicting CSS was 2. Of all, 532 (75.7%) patients had 2 or less positive nodes, while 171 (24.3%) had more than 2 positive nodes. Patients with 2 or less positive nodes had significantly better CSS outcome at 15 year follow-up compared to patients with more than 2 positive nodes (84% vs 62%; p<0.001). After adjusting for pathological stage, multivariable predictive accuracy of the new N staging (2 positive nodes) was 65.0% vs 60.1% when the number of positive nodes was not considered (4.9% gain; p<0.001). CONCLUSIONS: We demonstrated that patients with up to 2 positive nodes experienced excellent CSS, which was significantly higher compared to patients with more than 2 positive nodes. Moreover, a significant improvement in CSS prediction was reached when the number of positive nodes was considered. Thus, our results reinforce the need for a stratification of node positive patients according to the number of positive nodes and may warrant consideration in the next revision of the pathologic TNM classification.