David D’Andrea

Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer

ObjectivesA small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients.Methods and materialsA systematic medline/pubmed© literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC.ResultsTumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers.ConclusionsPP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.

An up-to-date catalog of available urinary biomarkers for the surveillance of non-muscle invasive bladder cancer

ObjectivesWith the advent of novel genomic and transcriptomic technologies, new urinary biomarkers have been identified and tested for bladder cancer (BCa) surveillance. To summarize the current status of urinary biomarkers for the detection of recurrence and/or progression in the follow-up of non-muscle invasive BCa patients, and to assess the value of urinary biomarkers in predicting response to intravesical Bacillus Calmette–Guerin (BCG) therapy.Methods and materialsA medline/pubmed© literature search was performed. The performance of commercially available and investigational biomarkers has been reviewed. End points were cancer detection (recurrence), cancer progression, and response to BCG therapy.ResultsThe performance requirements for biomarkers are variable according to the clinical scenario. The clinical role of urinary biomarkers in the follow-up of non-muscle invasive BCa patients remains undefined. The FDA-approved tests provide unsatisfactory sensitivity and specificity levels and their use is limited. Fluorescence in situ hybridization (FISH) has been shown to be useful in specific scenarios, mostly as a reflex test and in the setting of equivocal urinary cytology. FISH and immunocytology could conceivably be used to assess BCG response. Recently developed biomarkers have shown promising results; upcoming large trials will test their utility in specific clinical scenarios in a manner similar to a phased drug development strategy.ConclusionsCurrent commercially available urinary biomarker-based tests are not sufficiently validated to be widely used in clinical practice. Several novel biomarkers are currently under investigation. Prospective multicenter analyses will be needed to establish their clinical relevance and value.

Accuracy and prognostic value of variant histology and lymphovascular invasion at transurethral resection of bladder

ObjectivesTo evaluate the concordance rate of lymphovascular invasion (LVI) and variant histology (VH) of transurethral resection (TUR) with radical cystectomy (RC) specimens. Furthermore, to evaluate the value of LVI and VH at TUR for predicting non-organ confined (NOC) disease, lymph node metastasis, and survival outcomes.Patients and methodsTwo hundred and sixty-eight patients who underwent TUR and subsequent RC were reviewed. Logistic regression analyses were performed to evaluate the association of LVI and VH with NOC and lymph node metastasis at RC. Cox regression analyses were used to estimate recurrence-free survival (RFS) and cancer-specific survival (CSS).ResultsLVI and VH were detected in 13.8 and 11.2% of TUR specimens, and in 30.2 and 25.4% of RC specimens, respectively. The concordance rate between LVI and VH at TUR and subsequent RC was 69.8 and 83.6%, respectively. They were both associated with adverse pathological features such as lymph node metastasis and advanced stage. TUR LVI and VH were both independently associated with lymph node metastasis and TUR VH was independently associated with NOC. On univariable Cox regression analyses, TUR LVI was associated with RFS and CSS while TUR VH was only associated with RFS. Only TUR LVI was independently associated with RFS.ConclusionDetection of LVI is missed in a third of TUR specimens while VH seems more accurately identified. TUR LVI and VH are associated with more advanced disease and LVI predicts disease recurrence. Assessment and reporting of LVI and VH on TUR specimen are important for risk stratification and decision-making.

Association of Smoking Status With Recurrence, Metastasis, and Mortality Among Patients With Localized Prostate Cancer Undergoing Prostatectomy or Radiotherapy: A Systematic Review and Meta-analysis

Importance Studies investigating the association of cigarette smoking with prostate cancer incidence and outcomes have revealed controversial results. Objective To systematically review and analyze the association of smoking status with biochemical recurrence, metastasis, and cancer-specific mortality among patients with localized prostate cancer undergoing primary radical prostatectomy or radiotherapy. Data Sources A systematic search of original articles published between January 2000 and March 2017 was performed using PubMed, MEDLINE, Embase, and Cochrane Library databases in March 2017. Study Selection Observational studies reporting Cox proportional hazards regression or logistic regression analyses were independently screened. Data Extraction and Synthesis This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. Available multivariable hazard ratios (HRs) and corresponding 95% CIs were included in quantitative analysis. A risk-of-bias assessment was completed for nonrandomized studies. Main Outcomes and Measures Prespecified outcomes of interest were biochemical recurrence, metastasis, and cancer-specific mortality. Results A total of 5157 reports were identified, of which 16 articles were selected for qualitative analysis and 11 articles were selected for quantitative analysis. All included studies were observational and nonrandomized and comprised a total of 22 549 patients. Overall, 4202 patients (18.6%) were current smokers. The overall median follow-up was 72 months. Current smokers had a statistically significantly higher risk of biochemical recurrence (HR, 1.40; 95% CI, 1.18-1.66; P < .001 [10 studies]), as did former smokers (HR, 1.19; 95% CI, 1.09-1.30; P < .001 [7 studies]). Current smokers were also at a higher risk of metastasis (HR, 2.51; 95% CI, 1.80-3.51; P < .001 [3 studies]) and cancer-specific mortality (HR, 1.89; 95% CI, 1.37-2.60; P < .001 [5 studies]), whereas former smokers were not (metastasis: HR, 1.61; 95% CI, 0.65-3.97; P = .31 [2 studies]; cancer-specific mortality: HR, 1.05; 95% CI, 0.81-1.37; P = .70 [4 studies]). Conclusions and Relevance Current smokers at the time of primary curative treatment for localized prostate cancer are at higher risk of experiencing biochemical recurrence, metastasis, and cancer-specific mortality.

Is transurethral resection alone enough for the diagnosis of histological variants? A single-center study

INTRODUCTION To evaluate incidence of histological variants and grade agreement between transurethral resection (TUR) and radical cystectomy (RC) in patients with bladder cancer. METHODS A total of 779 patients treated with TUR and subsequently with RC between 1990 and 2013 at a single center were analyzed retrospectively. Variant histology classifications used in our analyses were sarcomatoid, small cell, squamous, or micropapillary. Grade agreement was calculated using the Cohen kappa coefficient. Logistic regression analyses were built to predict adverse pathologic features from histological variants at TUR. RESULTS Considering TUR, 213 (27.3%) patients were diagnosed with histological variants. Of these, 2.1% (n = 16) were found with sarcomatoid variant, 1.7% (n = 13) with small cell, 7.1% (n = 55) with squamous, 12.5% (n = 97) with micropapillary. Considering RC, 212 (27.2%) patients were diagnosed with histological variants. Poor agreement was found considering micropapillary variant and the presence of a histological variant in general (0.11 and 0.27, respectively). Intermediate agreement was found analyzing the presence of sarcomatoid, small cell, and squamous variants (0.43, 0.61, and 0.61, respectively). Small cell carcinoma at TUR was found associated with an increased risk of harboring positive soft tissue surgical margin (odds ratio = 2.08; CI: 1.27-3.41; P = 0.03). CONCLUSIONS One out of our patients with bladder cancer was diagnosed with a histological variant either at TUR and RC. We found poor agreement between TUR and RC. Our findings highlight that TUR alone is not sufficient to accurately evaluate the presence of histological variants that may have an effect on treatment and survival outcomes.

Development of a tool for prediction of ovarian cancer in patients with adnexal masses: Value of plasma fibrinogen

Objective To develop a tool for individualized risk estimation of presence of cancer in women with adnexal masses, and to assess the added value of plasma fibrinogen. Study design We performed a retrospective analysis of a prospectively maintained database of 906 patients with adnexal masses who underwent cystectomy or oophorectomy. Uni- and multivariate logistic regression analyses including pre-operative plasma fibrinogen levels and established predictors were performed. A nomogram was generated to predict the probability of ovarian cancer. Internal validation with split-sample analysis was performed. Decision curve analysis (DCA) was then used to evaluate the clinical net benefit of the prediction model. Results Ovarian cancer including borderline tumours was found in 241 (26.6%) patients. In multivariate analysis, elevated plasma fibrinogen, elevated CA-125, suspicion for malignancy on ultrasound, and postmenopausal status were associated with ovarian cancer and formed the basis for the nomogram. The overall predictive accuracy of the model, as measured by AUC, was 0.91 (95% CI 0.87–0.94). DCA revealed a net benefit for using this model for predicting ovarian cancer presence compared to a strategy of treat all or treat none. Conclusion We confirmed the value of plasma fibrinogen as a strong predictor for ovarian cancer in a large cohort of patients with adnexal masses. We developed a highly accurate multivariable model to help in the clinical decision-making regarding the presence of ovarian cancer. This model provided net benefit for a wide range of threshold probabilities. External validation is needed before a recommendation for its use in routine practice can be given.

Accurate prediction of progression to muscle-invasive disease in patients with pT1G3 bladder cancer: A clinical decision-making tool

PURPOSE To improve current prognostic models for the selection of patients with T1G3 urothelial bladder cancer who are more likely to fail intravesical therapy and progress to muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS We performed a retrospective analysis of 1,289 patients with pT1G3 urothelial bladder cancer who were treated with transurethral resection of the bladder (TURB) and adjuvant intravesical bacillus-Calmette-Guérin (BCG). Random-split sample data and competing-risk regression were used to identify the independent impact of lymphovascular invasion (LVI) and variant histology (VH) on progression to MIBC. We developed a nomogram for predicting patient-specific probability of disease progression at 2 and 5 years after TURB. Decision curve analysis (DCA) was performed to evaluate the clinical benefit associated with the use of our nomogram. RESULTS In the development cohort, within a median follow-up of 51.6 months (IQR: 19.3-92.5), disease progression occurred in 89 patients (13.8%). A total of 84 (13%) patients were found to have VH and 57 (8.8%) with LVI at TURB. Both factors were independently associated with disease progression on multivariable competing-risk analysis (HR: 4.4; 95% CI: 2.8-6.9; P<0.001 and HR: 3.5; 95% CI: 2.1-5.8; P<0.001, respectively). DCA showed superior net benefits for the nomogram within a threshold probability of progression between 5% and 55%. Limitations are inherent to the retrospective design. CONCLUSIONS We demonstrated the clinical value of the integration of LVI and VH in a prognostic model for the prediction of MIBC. Indeed, our tool provides superior individualized risk estimation of progression facilitating decision-making regarding early RC.

Waiting in the wings: the emerging role of molecular biomarkers in bladder cancer

ABSTRACT Introduction: Bladder cancer (BCa) is the fifth most frequently diagnosed cancer worldwide and is, in fact, the most expensive cancer on a per-patient to treat basis. There is a critical need to implement new tests into clinical practice to improve the quality of clinical care, decrease unnecessary invasive therapies and ultimately save costs. Currently, no molecular or genetic biomarker has been widely integrated into daily clinical practice. However, major milestones have been achieved in our understanding of the molecular alterations in BCa that will provide the basis for integrating molecular and genetic biomarkers into clinical decision making to guide management. Clinical implementation of such novel molecular and genetic concepts is the cornerstone in an effort to usher the age of precision medicine into patient care. Areas covered: In this review, the authors discuss the emerging role of molecular biomarkers in patients receiving BCG immunotherapy as well as neoadjuvant and adjuvant chemotherapy in BCa. Expert commentary: Molecular predictive and prognostic biomarkers in BCa are promising diagnostic options that will pave the way for molecular-based personalized medicine.

Predicting local failure after radical cystectomy in patients with bladder cancer: Implications for the selection of candidates at adjuvant radiation therapy

OBJECTIVE To evaluate incidence and predictors of local failure (LF) after radical cystectomy (RC) due to bladder cancer. METHODS We focused on 1,112 patients treated with RC, between 1990 and 2012, at a single center. LF was defined as imaging evidence of recurrence in the pelvic soft tissues or nodes below the aortic bifurcation at least 3 months before the detection of distant metastases. Competing risk analyses tested the relationship between clinical and pathological factors and the risk to develop LF. Regression tree analysis stratified patients into risk-groups based on their characteristics and the corresponding LF rate. RESULTS Overall, 50 (4.5%) patients developed LF during a median follow-up period of 62 (35-92) months. On univariable competing risk regression analyses, pathological T stage (pT4 vs. pT3; hazard ratio [HR] = 2.55, P = 0.003), soft tissue surgical margin (STSM; HR = 2.95, P = 0.005), and variant histology (HR = 1.79, P = 0.03) were associated with an increased risk of developing LF. The cohort was stratified into 4 risk groups: very low (≤pT3a disease and pure urothelial histology), low (≤pT3a disease and variant histology), intermediate (pT4 disease), and high (positive STSM). CONCLUSIONS LF is an important event in RC patients. We developed a new risk model based on bladder cancer characteristics. Our findings could help with the identification of the best candidate for consideration of adjuvant radiotherapy.

Tertiary Gleason pattern in radical prostatectomy specimens is associated with worse outcomes than the next higher Gleason score group in localized prostate cancer

AIM To assess the predictive value of TGP on biochemical recurrence (BCR) and its association with clinicopathological outcomes in a large, multicenter cohort of patients with localized prostate cancer (PCa) treated with radical prostatectomy (RP). MATERIALS AND METHODS Records of 6,041 patients who were treated with RP between 2000 and 2011 for clinically nonmetastatic PCa were, retrospectively, analyzed from prospectively collected datasets. BCR-free survival rates were assessed using univariable and multivariable cox-regression analyses. RESULTS Median patient age was 61 years (interquartile range [IQR]: 57-66) with a median preoperative prostrate specific antigen of 6ng/ml (IQR: 4-9). Overall, 28% of patients had Gleason score (GS) 6, 0.3% GS 6 + TGP, 33% GS 7 (3 + 4), 0.2% GS 7 (3 + 4) + TGP, 22% GS 7 (4 + 3), 0.2% GS 7 (4 + 3) + TGP, 0.1% GS 8 and 0.4% GS 9 or 10. Median follow-up was 45 months (IQR: 31-57). Harboring a TGP was associated with higher rates of positive surgical margins, lymphovascular invasion, extraprostatic extension, and seminal vesicle invasion than their counterparts within the same GS group as well as in the next higher GS group (all P ≤ 0.05). At 5 years post-RP, BCR estimates were 5% for patients with GS 6, 13% for patients with GS 6 + TGP, 6% for patients with GS 7 (3 + 4), 22% for patients with GS 7 (3 + 4) + TGP, 16% for patients with GS 7 (4 + 3), 41% for patients with GS 7 (4 + 3) + TGP, 38% for patients with GS 8 (4 + 4) and 46% for patients with GS 9 or 10. Patients harboring a TGP had higher BCR rates than the patients in the next higher GS group: GS 6 + TGP vs. GS 7 (3 + 4), HR = 1.6, P = 0.02 and GS 7 (3 + 4)+TGP vs. GS 7 (4 + 3), HR = 1.4, P = 0.03. Patients with a TGP in the GS 7 (4 + 3) group had comparable BCR rates as patients with GS = 8 (P = 0.4) and GS 9 to 10 (P = 0.2). On multivariable analysis that adjusted for the effects of preoperative prostrate specific antigen, nodal involvement, positive surgical margin, extraprostatic disease (pT3a), seminal vesicle invasion (pT3b) and different institution, harboring a TGP showed higher risk of developing BCR within the same GS group and comparable risk of developing BCR with the next higher GS group. CONCLUSION Patients with TGP at RP have adverse clinicopathological features when compared to their counterparts in the same and the next higher GS group without TGP. Risk of developing BCR increases with the presence of TGP within the same GS group. This risk seems to be comparable between patients with TGP and their counterparts in the next higher GS group without TGP. Knowledge of TGP in RP specimens is likely to improve risk stratification, patient counseling and follow-up scheduling. Further prospective studies that control significant clinical endpoints such as metastasis and mortality are necessary for more significant predictions.