Dynamic assessment of serum chromogranin A and treatment response with abiraterone acetate in metastatic castration-resistant prostate cancer.

OBJECTIVE: Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy. METHODS: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival. RESULTS: An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001). CONCLUSIONS: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).

BACKGROUND: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer. METHODS: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960. FINDINGS: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug. INTERPRETATION: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination. FUNDING: Exelixis.

Radiographic paradoxical response in metastatic castrate-resistant prostate cancer (mCRPC) managed with new generation anti-androgens: a retrospective analysis.

BACKGROUND: Prostatic specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration-resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti-androgens (SGA) post-chemotherapy using combined conventional imaging, and new generation imaging in the form of C-11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan. METHODS: We retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3-6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C-11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging. RESULTS: We identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75-21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group-A), whereas 39.6% displayed a paradoxical response (PR) (Group-B), defined as increased choline avidity combined with stable or down-trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group-A, 4.6 for Group-B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group-A versus Group-B, respectively (Log-Rank = 0.0063). CONCLUSION: Nearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C-11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

Comparative cost-effectiveness of neoadjuvant chemotherapy regimens for muscle-invasive bladder cancer: Results according to VESPER data.

BACKGROUND: The VESPER trial demonstrated improved progression-free (PFS) and (preliminarily) overall survival (OS) with six cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVACx6) versus four cycles of gemcitabine and cisplatin (GCx4) before radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), but with increased toxicity. This study compares the cost-effectiveness of these regimens. METHODS: A cost-effectiveness analysis of neoadjuvant ddMVACx6 and GCx4 was performed using a decision-analytic Markov model with 5-year, 10-year, and lifetime horizons. Probabilities were derived from reported VESPER data. Utility values were obtained from the literature. Primary outcomes were effectiveness measured in quality-adjusted life years (QALY) and incremental cost-effectiveness ratio (ICER) with a willingness to pay threshold of $100,000 per QALY. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model. RESULTS: At 5 years, ddMVACx6 improved QALYs by 0.30 at an additional cost of $16,100, rendering it cost-effective relative to GCx4 (ICER: $53,284/QALY). Additionally, probabilistic sensitivity analysis found ddMVACx6 to be cost-effective in 79% and 81% of microsimulations at10-year and lifetime horizons, respectively. One-way sensitivity analysis demonstrated a minimum difference in 5-year progression of 0.9% and progression mortality of 0.7% between ddMVACx6 and GCx4 was necessary for ddMVACx6 to remain cost-effective. CONCLUSIONS: Neoadjuvant ddMVACx6 was more cost-effective than GCx4 for MIBC. These data, together with the improved PFS and (albeit preliminary) OS noted in VESPER, support use of this regimen in appropriate candidates for neoadjuvant chemotherapy before RC. LAY SUMMARY: We performed a benefit-to-cost analysis using evidence from a randomized controlled trial that compared two different chemotherapy treatments before bladder removal for bladder cancer that had invaded into the bladder muscle. Despite being more expensive and having a greater likelihood of toxicity, six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin was more cost-effective (or had higher value) than four cycles of gemcitabine and cisplatin.

Rational Second-Generation Antiandrogen Use in Prostate Cancer.

The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data.

NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

Chemotherapy with atezolizumab for small cell or neuroendocrine carcinoma of the prostate: A single institution experience.

INTRODUCTION: Chemotherapy in combination with immunotherapy has a proven survival benefit compared to chemotherapy alone in extensive stage small cell lung cancer (SCLC) and is the new standard of care. Since extrapulmonary small cell carcinomas (SCCs) are less common, treatment paradigms are reasonably extrapolated from SCLC regimens. We examined our institution's experience utilizing the combination of chemotherapy and immunotherapy (as used in SCLC) for SCC and neuroendocrine carcinoma of the prostate. METHODS: Utilizing an institutional database search tool, we queried the electronic medical record to identify patients with SCC or neuroendocrine carcinoma of the prostate who had been treated with atezolizumab and chemotherapy. We recorded patient characteristics, including age, pathology, and disease extent. Treatment characteristics included number of prior treatments, use of concominant androgen deprivation, number of cycles of immunotherapy, and prior systemic therapies (including those for adenocarcinoma of the prostate). Progression free survival (PFS) and overall survival (OS) were the primary outcomes. RESULTS: We identified seven men who received atezolizumab for metastatic prostate cancer with a small cell or neuroendocrine component. In six of the seven patients, the combination of carboplatin, etoposide, and atezolizumab was the first-line of treatment after diagnosis of small cell or neuroendocrine carcinoma. Two of the seven patients had de novo small cell/neuroendocrine pathology, while the other five had transformation from a preexisting adenocarcinoma. In the patients who received chemotherapy plus immunotherapy in the first-line setting, at a median follow-up of 6.5 months (range: 1.5-15.1) the median PFS was 3.4 months and median OS was 8.4 months. CONCLUSION: Small cell or neuroendocrine carcinoma of the prostate was associated with poor survival outcomes despite adding immunotherapy (atezolizumab) to chemotherapy (carboplatin and etoposide). To our knowledge, there has been no demonstrable benefit of adding immunotherapy to chemotherapy in this setting.

Cost-Effectiveness Analysis of Pembrolizumab for Bacillus Calmette-Guérin-Unresponsive Carcinoma In Situ of the Bladder.

PURPOSE: Patients with bacillus Calmette-Guérin-unresponsive carcinoma in situ are treated with radical cystectomy or salvage intravesical chemotherapy. Recently, pembrolizumab was approved for bacillus Calmette-Guérin-unresponsive carcinoma in situ. MATERIALS AND METHODS: We used a decision-analytic Markov model to compare pembrolizumab, salvage intravesical chemotherapy (with gemcitabine-docetaxel induction+monthly maintenance) and radical cystectomy for patients with bacillus Calmette-Guérin-unresponsive carcinoma in situ who are radical cystectomy candidates (index patient 1) or are unwilling/unable to undergo radical cystectomy (index patient 2). The model used a U.S. Medicare perspective with a 5-year time horizon. One-way and probabilistic sensitivity analyses were performed. Incremental cost-effectiveness ratios were compared using a willingness to pay threshold of $100,000/quality-adjusted life year. RESULTS: For index patient 1, pembrolizumab was not cost-effective relative to radical cystectomy (incremental cost-effectiveness ratios $1,403,008/quality-adjusted life year) or salvage intravesical chemotherapy (incremental cost-effectiveness ratios $2,011,923/quality-adjusted life year). One-way sensitivity analysis revealed that pembrolizumab only became cost-effective relative to radical cystectomy with a >93% price reduction. Relative to radical cystectomy, salvage intravesical chemotherapy was cost-effective for time horizons <5 years and nearly cost-effective at 5 years (incremental cost-effectiveness ratios $118,324/quality-adjusted life year). One-way sensitivity analysis revealed that salvage intravesical chemotherapy became cost-effective relative to radical cystectomy if risk of recurrence or metastasis at 2 years was less than 55% or 5.9%, respectively. For index patient 2, pembrolizumab required >90% price reduction to be cost-effective (incremental cost-effectiveness ratios $1,073,240/quality-adjusted life year). Pembrolizumab was cost-effective in 0% of 100,000 microsimulations in probabilistic sensitivity analyses for both index patients. CONCLUSIONS: At its current price, pembrolizumab is not cost-effective for bacillus Calmette-Guérin-unresponsive carcinoma in situ relative to radical cystectomy or salvage intravesical chemotherapy. Although gemcitabine-docetaxel is not cost-effective relative to radical cystectomy at 5 years, further studies may validate its cost-effectiveness if recurrence and metastasis thresholds are met.

Chemoimmunotherapy after progression on single-agent pembrolizumab for metastatic urothelial carcinoma: a case series.

Those with metastatic urothelial carcinoma generally respond more poorly to chemotherapy after they have progression on a checkpoint inhibitor (CPI). There is interest in combining CPIs with conventional cytotoxic chemotherapies as a strategy to exploit the efficacy and immunomodulatory effects of chemotherapy. We conducted a single institution, retrospective analysis including all patients treated between May 2018 and May 2020 with carboplatin and paclitaxel, concurrently or sequential with pembrolizumab, after having progression on a CPI alone. Clinical characteristics, response by RECIST 1.1, progression-free survival, and safety/tolerance of the treatment are reported. Median age was 80 years (64-85). Five patients (100%) had visceral metastases when starting carboplatin and paclitaxel. Chemotherapy was given with concurrent pembrolizumab (four patients) or following pembrolizumab (one patient) and continued until maximum response, significant toxicity, or progression. Two patients subsequently remained on maintenance pembrolizumab. There were four partial responses and one patient with stable disease. All patients on follow-up have progressed with median time to progression of 47 weeks (18-75). Two patients died from disease progression. This case series suggests that the combination of carboplatin, paclitaxel, and pembrolizumab leads to durable freedom from progression in some with metastatic urothelial cancer, who have progressed on a CPI alone. Larger studies of chemoimmunotherapy for metastatic urothelial carcinoma are warranted.

Systematic Review and Meta-Analysis-Is there a Benefit in Using Neoadjuvant Systemic Chemotherapy for Locally Advanced Penile Squamous Cell Carcinoma?

PURPOSE: Neoadjuvant chemotherapy is a recommended treatment for patients with penile cancer with bulky inguinal lymphadenopathy or unresectable primary tumors, although there is no evidence of its benefit from randomized trials. MATERIALS AND METHODS: We conducted a systematic search in Embase® and MEDLINE® for studies reporting on patients who received preoperative neoadjuvant chemotherapy for locally advanced penile squamous cell carcinoma. Objective response rate, pathological complete response, grade 3 or greater toxicity and overall mortality were evaluated in terms of neoadjuvant chemotherapy type, which was dichotomized as nontaxane-platinum and taxane-platinum regimens. RESULTS: Overall 10 studies met the inclusion criteria, enrolling a total of 182 patients, with 66 (36.3%) and 116 (63.7%) treated with nontaxane-platinum and taxane-platinum regimens, respectively. The pooled results demonstrated an objective response rate of 53% (95% CI 42-64), pathological complete response rate of 16%, grade 3 or greater toxicity rate of 40% (95% CI 19-64) and overall mortality of 55% (95% CI 40-70) in patients treated with neoadjuvant chemotherapy. Stratified subanalysis revealed an objective response rate of 55% and 49%, a pathological complete response of 9% and 20%, a toxicity rate of 26% and 49%, and an overall mortality of 54% and 58% for nontaxane-platinum vs taxane-platinum regimens, respectively. CONCLUSIONS: The pooled findings in this study suggest that approximately 50% of the patients with bulky regional lymph node metastases from penile cancer respond to platinum based neoadjuvant chemotherapy and approximately 16% of patients achieve a pathological complete response. Nontaxane based regimens appear to be better tolerated than taxane regimens based on reported grade 3 or greater adverse events (26% vs 49%). Ultimately the robustness of these observations should be interpreted with an awareness of the inherent limitations of deriving data from a collection of small, heterogeneous series.

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Outcomes and Prognostic Factors in Men Receiving Androgen Deprivation Therapy for Prostate Cancer Recurrence after Radical Prostatectomy.

PURPOSE: We sought to determine clinicopathological factors associated with early progression in men on androgen deprivation therapy as well as cancer specific and overall survival. We also assessed whether certain prostate specific antigen thresholds at androgen deprivation therapy initiation are associated with poorer outcomes. MATERIALS AND METHODS: We identified 2,418 men with rising prostate specific antigen after undergoing radical prostatectomy at a single institution between 1987 and 2007 in a prospectively maintained registry. Early progression was defined as clinical progression within 2 years of initiating androgen deprivation therapy. The primary study outcome was cancer specific and overall survival. RESULTS: The risk of early progression while on androgen deprivation therapy was lower for prostate specific antigen doubling time 3 to less than 9 months (OR 0.19) and less than 9 months or longer (OR 0.10, each p <0.001) prior to androgen deprivation therapy. Independent predictors of cancer specific survival were metastatic disease at androgen deprivation therapy initiation (HR 2.60), prostate specific antigen 5 to 50 ng/ml (HR 2.68) and 50 ng/ml or greater (HR 4.33), and doubling time 3 to less than 9 months (HR 0.54) and 9 months or longer (HR 0.45, all p <0.001). Independent predictors of overall survival were prostate specific antigen 5 to 50 ng/ml (HR 3.10) and 50 ng/ml or greater (HR 5.20, each p <0.001). CONCLUSIONS: In men in whom androgen deprivation therapy was initiated for relapse after radical prostatectomy prostate specific antigen doubling time less than 3 months and prostate specific antigen 5 ng/ml or greater were adverse prognostic factors for early progression and cancer specific survival. Prostate specific antigen 5 ng/ml or greater also predicted shorter overall survival. Longer doubling time and prostate specific antigen less than 5 ng/ml were associated with lower risk and these men may not require immediate androgen deprivation therapy.

Comparative Survival following Initial Cytoreductive Nephrectomy versus Initial Targeted Therapy for Metastatic Renal Cell Carcinoma.

PURPOSE: The optimal sequence of cytoreductive nephrectomy and targeted therapy of metastatic renal cell carcinoma is unclear. We compared overall survival between patients with metastatic renal cell carcinoma treated with initial cytoreductive nephrectomy with or without subsequent targeted therapy vs initial targeted therapy with or without subsequent cytoreductive nephrectomy. MATERIALS AND METHODS: We evaluated the records of cases in the National Cancer Database diagnosed with metastatic renal cell carcinoma between 2006 and 2013 who were treated with cytoreductive nephrectomy and/or targeted therapy. Receipt of targeted therapy after initial cytoreductive nephrectomy and cytoreductive nephrectomy after initial targeted therapy were evaluated on competing risks analyses. To account for treatment selection bias, inverse probability of treatment weighting was performed based on the propensity to receive initial cytoreductive nephrectomy or initial targeted therapy. Overall survival was compared between the groups by Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: Of the 15,068 patients included in study 6,731 underwent initial cytoreductive nephrectomy and 8,337 received initial targeted therapy. Six months after initial cytoreductive nephrectomy 48.0% of patients received targeted therapy, of whom 15.3% died after initial cytoreductive nephrectomy prior to targeted therapy. Six months after initial targeted therapy 4.7% of patients underwent cytoreductive nephrectomy, of whom 44.9% died after initial targeted therapy prior to cytoreductive nephrectomy. Initial cytoreductive nephrectomy (OR 2.02, 95% CI 1.69-2.43, p <0.001) and cytoreductive nephrectomy after initial targeted therapy (HR 2.6, 95% CI 1.69-4.01, p <0.001) were more likely to be performed at academic vs community institutions. On inverse probability of treatment weighting analysis initial cytoreductive nephrectomy was associated with improved overall survival compared to initial targeted therapy (median 16.5 vs 9.2 months, HR 0.61, 95% CI 0.59-0.64, p <0.001). CONCLUSIONS: Given the greater likelihood of receiving multimodal therapy and the associated overall survival benefit, these data support cytoreductive nephrectomy as the initial approach to metastatic renal cell carcinoma in appropriate surgical candidates. Continued efforts are warranted to establish the optimal multimodal approach in these patients.

NCCN Guidelines Insights: Bladder Cancer, Version 5.2018.

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease.

Factors associated with regional recurrence after lymph node dissection for penile squamous cell carcinoma.

OBJECTIVE: To identify factors associated with regional recurrence after lymph node dissection (LND) for squamous cell carcinoma (SCC) to determine which patients might benefit from adjuvant therapy. PATIENTS AND METHODS: Men who underwent LND for penile SCC from 1977 to 2014 were identified from an institutional database. Kaplan-Meier curves estimated recurrence-free survival (RFS) calculated from the date of LND. Cox regression models evaluated the association between RFS and patient and tumour characteristics. RESULTS: In all, 182 men who underwent LND for penile SCC were identified. The median patient age was 62 years and the median follow-up was 4.2 years. After LND 34 men had regional recurrence, of which 24 developed isolated regional recurrences without distant metastasis. The median RFS was 5.7 months, and the 3-year RFS rate was 70%. On univariate analysis, lymphovascular invasion, clinical and pathological nodal stage, pathological inguinal laterality, pelvic nodal involvement, lymph node density ≥5.2%, ≥3 pathologically involved lymph nodes, and extranodal extension (ENE) were associated with worse RFS (all P < 0.05). On multivariate analysis, clinical N3 disease [adjusted hazard ratio (AHR)] 3.53, 95% confidence interval (CI) 1.68-7.45; P = 0.001), ≥3 pathologically involved lymph nodes (AHR 3.78, 95% CI 2.12-6.65; P < 0.001), and ENE (AHR 3.32, 95% CI 1.93-5.76; P < 0.001) were associated with worse RFS. The 3-year RFS for patients with cN0, cN1, cN2, and cN3 disease was 91.7%, 64.5%, 54.7%, and 38.3%, respectively. For men with ≥3 involved nodes, the 3-year RFS was 17% vs 82.4% in men with <3 involved nodes. The 3-year RFS was 29.7% in men with ENE and 85.7% in men without ENE. CONCLUSION: The presence of clinical N3 disease, ≥3 pathologically involved lymph nodes, and ENE was associated with worse RFS. As regional recurrence portends a dismal prognosis with few salvage options, adjuvant therapies should be developed for men with the aforementioned adverse factors.

Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.

Low hypoxia inducible factor-1α (HIF-1α) expression in testicular germ cell tumors - a major reason for enhanced chemosensitivity?

The molecular basis for enhanced chemosensitivity of testicular germ cell tumors (GCT) has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of GCT has been variously attributed to multiple factors - an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-1α (HIF-1α) expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

BACKGROUND: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy.

OBJECTIVE: To describe both clinical and pathological response rates, survival, and predictors of survival when using contemporary perioperative chemotherapy and surgical resection for patients with regionally advanced squamous cell carcinoma (SCC) of the penis. PATIENTS AND METHODS: Retrospective review of all patients diagnosed with SCC of the penis and regional lymph node metastases that were treated with chemotherapy with the intent to undergo lymphadenectomy. Clinical and pathological responses were reported. Recurrence-free and overall survival was estimated using Kaplan-Meier analysis. Cox proportional hazards regression was used to assess factors for survival. RESULTS: In all, 61 patients were identified, of which 54 (90%) received chemotherapy with paclitaxel/ifosfamide/cisplatin. In all, 39 patients (65%) had either a partial (PR) or complete response (CR) to chemotherapy. The 5-year survival varied significantly (P = 0.045-0.001) among patients achieving a CR/PR (50%), stable disease (25%), and progression (7.7%). In all, 10 patients (16.4%) were rendered pN0 with combined therapy and 20 patients (33%) were alive and disease free at a median follow-up of 67 months, while 32 (52%) died from disease. Long-term survival was associated with response to chemotherapy and favourable pathological findings after resection. CONCLUSION: Contemporary chemotherapy resulted in clinically significant responses among patients with regionally advanced penile cancer. About 50% of such patients with an objective response to chemotherapy who undergo consolidative lymphadenectomy will remain alive at 5 years.

NCCN Guidelines Insights: Bladder Cancer, Version 2.2016.

These NCCN Guidelines Insights discuss the major recent updates to the NCCN Guidelines for Bladder Cancer based on the review of the evidence in conjunction with the expert opinion of the panel. Recent updates include (1) refining the recommendation of intravesical bacillus Calmette-Guérin, (2) strengthening the recommendations for perioperative systemic chemotherapy, and (3) incorporating immunotherapy into second-line therapy for locally advanced or metastatic disease. These NCCN Guidelines Insights further discuss factors that affect integration of these recommendations into clinical practice.