Testicular Cancer, Version 2.2015.

Germ cell tumors (GCTs) account for 95% of testicular cancers. Testicular GCTs constitute the most common solid tumor in men between the ages of 20 and 34 years, and the incidence of testicular GCTs has been increasing in the past 2 decades. Testicular GCTs are classified into 2 broad groups--pure seminoma and nonseminoma--which are treated differently. Pure seminomas, unlike nonseminomas, are more likely to be localized to the testis at presentation. Nonseminoma is the more clinically aggressive tumor associated with elevated serum concentrations of alphafetoprotein (AFP). The diagnosis of a seminoma is restricted to pure seminoma histology and a normal serum concentration of AFP. When both seminoma and elements of a nonseminoma are present, management follows that for a nonseminoma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer outline the diagnosis, workup, risk assessment, treatment, and follow-up schedules for patients with both pure seminoma and nonseminoma.

Kidney cancer, version 3.2015.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma.

Small renal mass biopsy--how, what and when: report from an international consensus panel.

To discuss the use of renal mass biopsy (RMB) for small renal masses (SRMs), formulate technical aspects, outline potential pitfalls and provide recommendations for the practicing clinician. The meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics. A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point. A consensus was established and lack of agreement to topics or specific items was noted at this point. Recommended biopsy technique: at least two cores, sampling different tumour regions with ultrasonography being the preferred method of image guidance. Pathological interpretation: 'non-diagnostic samples' should refer to insufficient material, inconclusive and normal renal parenchyma. For non-diagnostic samples, a repeat biopsy is recommended. Fine-needle aspiration may provide additional information but cannot substitute for core biopsy. Indications for RMB: biopsy is recommended in most cases except in patients with imaging or clinical characteristics indicative of pathology (syndromes, imaging characteristics) and cases whereby conservative management is not contemplated. RMB is recommended for active surveillance but not for watchful-waiting candidates. We report the results of an international consensus meeting on the use of RMB for SRMs, defining the technique, pathological interpretation and indications.

Kidney cancer, version 2.2014.

These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.

Perioperative intravesical chemotherapy in non-muscle-invasive bladder cancer: a systematic review and meta-analysis.

The role for a single dose of intravesical chemotherapy (IVC) after transurethral resection (TUR) remains unclear in patients with non-muscle-invasive bladder cancer (NMIBC). Several recent randomized clinical trials (RCTs) have evaluated its effect on recurrence, prompting this systematic review of RCTs comparing a single immediate postoperative dose of IVC versus placebo within 24 hours of TUR of NMIBC, and this meta-analysis using a random-effects model to predict the pooled relative risk (RR) of tumor recurrence. Subanalyses pooled studies by drug type and a meta-regression was performed to determine the effect of underlying patient risk factors on the efficacy of a single dose of IVC. A total of 3103 patients were randomized in the 18 RCTs that met inclusion criteria. The recurrence rate in patients receiving perioperative IVC and TUR was 37% versus 50% in the TUR-alone group. The pooled RR of recurrence for IVC and TUR was 0.67 (95% CI, 0.56-0.79), corresponding to a 13% absolute reduction and a number needed to treat of 7.2 patients to avoid 1 recurrence. The proportions of patients with tumor risk factors (T1, high-grade, multifocal, or recurrent) were not associated with IVC efficacy. A single dose of IVC administered within 24 hours of TUR of NMIBC was found to result in a reduction in tumor recurrence (RR, 0.67; 95% CI, 0.56-0.79). Patients with higher-risk tumor features seem to benefit at a similar rate.

Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival.

BACKGROUND: Tobacco use is a leading cause of premature death, yet few studies have investigated the effect of tobacco exposure on the outcome of patients with renal cell carcinoma (RCC). The authors of this report retrospectively studied the impact of smoking on clinicopathologic factors, survival outcomes, and p53 expression status in a large cohort of patients with RCC. METHODS: Eight hundred-two patients (457 nonsmokers and 345 smokers) who had up to 232 months of follow-up were compared for differences in their clinicopathologic features and survival outcomes. Immunohistochemical differences in p53 expression were correlated with smoking status. RESULTS: Smokers presented more commonly with pulmonary comorbidities (P < .0001) and cardiac comorbidities (P = .014) and with a worse performance status (P = .031) than nonsmokers. Smoking was associated significantly with tumor multifocality (P = .022), higher pathologic tumor classification (P = .037), an increased risk of bulky lymph node metastases (P = .031), and the presence of distant metastases (P < .0001), especially lung metastases (P < .0001). Both overall survival (OS) (62.37 months vs 43.64 months; P = .001) and cancer-specific survival (CSS) (87.43 months vs 56.57 months; P = .005) were significantly worse in patients who smoked. The number of pack-years was retained as an independent predictor of CSS and OS in patients with nonmetastatic disease. Mean expression levels of p53 were significantly higher in current smokers compared with former smokers and nonsmokers (P = .012). CONCLUSIONS: In patients with RCC, a history of smoking was associated with worse pathologic features and survival outcomes and with an increased risk of having mutated p53. Further investigation of the genetic and molecular mechanisms associated with decreased CSS in patients with RCC who have a history of smoking is indicated.

Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma.

BACKGROUND: The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease-specific survival (DSS). METHODS: The tumor karyotypes of 336 consecutive patients with CCRCC were prospectively evaluated with classical cytogenetic analysis. Chromosome 8q status was correlated with clinicopathological variables, and its impact on DSS was evaluated. RESULTS: Gain of 8q occurred in 28 tumors (8.3%). Gain of 8q was associated with a higher risk of regional lymph node (21.4% vs 6.2%, P = .011) and distant metastases (50.0% vs 24.4%, P = .006), and greater tumor sizes (P = .030). Patients with gain of 8q had a 3.22-fold increased risk of death from CCRCC (P < .001). In multivariable analysis, gain of 8q was identified as an independent prognostic factor (hazard ratio, 2.37; P = .006). The concordance index of a multivariable base model increased significantly following inclusion of 8q gain (P = .0015). CONCLUSIONS: Gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto-oncogene c-MYC is among the list of candidate genes located on 8q, our data suggest that these tumors may have unique pathways activated, which are associated with an aggressive tumor phenotype. If confirmed, defining tumors with gain of 8q may assist in identifying patients who would benefit for specific c-MYC inhibitors or agents that target the MAPK/ERK (mitogen-activated protein kinase) pathway.

Prognostic value of microvascular invasion in predicting the cancer specific survival and risk of metastatic disease in renal cell carcinoma: a multicenter investigation.

PURPOSE: While microvascular invasion is an accepted risk factor in various cancers, its prognostic role in renal cell carcinoma is still unclear. Therefore, a large multicenter study examining the experience of 5 international institutions was performed to evaluate the prognostic value of microvascular invasion in the occurrence of metastases and cancer specific survival. MATERIALS AND METHODS: A total of 2,596 patients (475 with microvascular invasion and 2,121 without microvascular invasion) having up to 212 (median 22.4) months of followup were compared for differences in clinicopathological features, occurrence of metastases and cancer specific survival. RESULTS: Patients with microvascular invasion presented with higher age (p = 0.001) and a worse Eastern Cooperative Oncology Group performance status (p <0.0001). Microvascular invasion was associated with larger tumor diameter (p <0.0001), higher Fuhrman grade (p <0.0001), more advanced pT stage (p <0.0001), and the presence of lymph node and distant metastases (p <0.0001). In particular, in nonmetastatic cases worse survival was associated with microvascular invasion (p <0.0001, HR 2.38). Univariate analysis demonstrated a strong correlation between microvascular invasion and cancer specific survival (p <0.0001). However, after controlling for gender, Eastern Cooperative Oncology Group performance status, Fuhrman grade and TNM stage statistical significance was lost. Of interest, low stage tumors with microvascular invasion were strongly correlated with the occurrence of metastases (p <0.0001). CONCLUSIONS: Microvascular invasion occurs in nearly 1 of 5 patients with renal cell carcinoma, is tightly correlated with adverse clinicopathological features and is an independent predictor of metastatic spread including in those presenting with low stage tumors.

Hyperthermia as a treatment for bladder cancer.

Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non-muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.

Impact of an enhanced recovery pathway on length of stay and complications in elective radical cystectomy: a before and after cohort study.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways aim to standardize and integrate perioperative care, incorporating the best available evidence-based practice throughout the perioperative period targeted at attenuating the surgical stress response while optimizing physiologic function, with the goal of facilitating recovery. Radical cystectomy is associated with significant postoperative morbidity, but comprehensive ERAS pathways have not been well studied in this population. METHODS: This is a before and after cohort study of an ERAS pathway for radical cystectomy at a large academic medical center. Following introduction of the ERAS pathway and a wash in period, we prospectively collected data from the next 100 consecutive subjects undergoing radical cystectomy with the ERAS pathway. This cohort was compared to a retrospective cohort of 100 consecutive patients undergoing radical cystectomy with traditional care. The primary outcome was hospital length of stay. Secondary outcomes included perioperative management, time to recovery milestones, complications, and costs. RESULTS: Implementation of an ERAS pathway for radical cystectomy was associated with reduced hospital length of stay (median LOS 10 days (IQR = 8-18) vs 7 days (IQR = 6-11); p < 0.0001), reduced time to key recovery milestones, including days to first stool (5.83 vs 3.99; p < 0.001) and days to first solid food (9.68 vs 3.2; p < 0.001), reductions in some complications, and a 26.6% reduction in overall costs (p < 0.001). CONCLUSIONS: Our data support the use of an ERAS pathway for radical cystectomy and add to the increasing body of literature supporting enhanced recovery over a wide variety of procedures. TRIAL REGISTRATION: Not applicable.

Percent tumor involvement and risk of biochemical progression after radical prostatectomy.

PURPOSE: Percent tumor involvement has been associated with biochemical progression in organ confined disease, although its role in predicting outcome in men with more advanced disease pathology is unclear. We hypothesized percent tumor involvement may be a good correlate of outcome in all stages of prostate cancer. MATERIALS AND METHODS: We examined the association between percent tumor involvement in the radical prostatectomy specimen and the outcome measures of pathological stage and biochemical progression using multivariate logistic regression and Cox proportional hazards analysis, respectively, in 2,220 patients from the Duke Prostate Center radical prostatectomy database. RESULTS: On multivariate analysis, percent tumor involvement significantly predicted the risk of positive margins (p <0.001), extracapsular extension (p <0.001), seminal vesicle invasion (p <0.001) and biochemical progression (HR 1.16, 95% CI 1.01-1.33, p = 0.035). The percent tumor involvement cut points of 5% or less, 6% to 20%, 21% to 50% and greater than 50% significantly separated men in groups with differing biochemical progression risk (p <0.001). In addition, these cut points were further able to stratify men among those with organ confined margin negative disease (p <0.001), either positive margins or extracapsular extension (p <0.001), and those with seminal vesicle invasion (p = 0.02). CONCLUSIONS: Percent tumor involvement was a significant predictor of biochemical progression and was able to further stratify men who were already assigned to narrowly defined pathological groups. If confirmed in other studies, percent tumor involvement may enable the clinician to identify the high risk patient who stands to benefit the most from adjuvant therapy.

Effect of blood transfusions on oncological outcomes of surgically treated localized renal cell carcinoma.

OBJECTIVE: To assess the associations between perioperative allogeneic blood transfusions (ABTs) and recurrence, overall and renal cell carcinoma (RCC)-specific survival in patients undergoing surgical treatment for clinically localized disease. MATERIALS AND METHODS: We performed a retrospective review of 1,056 consecutive patients undergoing surgical treatment (radical or partial nephrectomy) for clinically localized RCC between 2000 to 2010. Demographic (age, race, and sex) clinical (preoperative hemoglobin and hematocrit, type of surgery [partial or radical nephrectomy]), and pathological (T and N stages, RCC histotype, grade) data were compared between patients receiving perioperative (intraoperative or postoperative) blood transfusions and those who are not. Distant and local recurrence-free survival, overall survival, RCC-specific survival were recorded and Kaplan-Meier survival curves as well as multivariable proportional regression models adjusted for clinical and pathological characteristics were produced. RESULTS: On multivariable analyses adjusted for clinical and pathological characteristics, the receipt of ABTs was associated with lower recurrence-free (HR = 1.86, P = 0.002), overall (HR = 1.83, P = 0.016), and RCC-specific survival (HR = 2.12, P = 0.031). The negative effect of ABTs was apparent for distant (HR = 2.24, P<0.001) but not local recurrences (HR = 0.78, P = 0.643). Limitations include retrospective nature and lack of uniform criteria for blood transfusion during the study period. CONCLUSIONS: In this study, perioperative ABTs were independently associated with worse oncological outcomes in patients with clinically localized RCC. Receipt of ABT was associated with roughly a 2-fold increase in the hazard of metastatic progression, all-cause and RCC-specific mortality. Further research is needed on the mechanisms of transfusion-induced immunomodulation, alternative transfusion protocols and methods for autologous blood transfusion and recovery.

The effect of gender and age on kidney cancer survival: younger age is an independent prognostic factor in women with renal cell carcinoma.

OBJECTIVE: Gender-specific differences in incidence of renal cell carcinoma (RCC) and its outcome have previously been reported. We used age as a surrogate to test whether this might be hormone-related in a large international RCC cohort. METHODS AND MATERIALS: This study included patients treated by nephrectomy at 10 international academic centers. Clinicopathologic features were assessed using chi-square and the Student t-tests. Kaplan-Meier survival estimates and Cox proportional hazards models addressed the effect of gender and age on disease-specific survival. RESULTS: Of the 5,654 patients, 3,777 (67%) were men and 1,877 (33%) were women. Generally, women presented at lower T stages (P<0.001), had fewer metastases (P<0.001), and had lower-grade tumors (P<0.001). Women more frequently had clear-cell (87% vs. 82%) and less frequently had papillary RCC (7% vs. 12%) than men (P<0.001). Women had a 19% reduced risk of death from RCC than men (hazard ratio 0.81, 95% confidence interval 0.73-0.90, P<0.001). The survival advantage for women was present to the greatest degree in the age group<42 years (P = 0.0136) and in women aged 42 to 58 years (P<0.001), but was not apparent in patients aged 59 years and older (P = 0.248). Age was an independent predictor of disease-specific survival in women (hazard ratio 1.011, 95% confidence interval 1.004-1.019, P = 0.004), but not in men. CONCLUSIONS: As a group, women present with less advanced tumors, leading to a 19% reduced risk of RCC-specific death compared with men. This survival difference is present only in patients aged<59 years. Because this gender-based survival difference is not related to pathologic features, the role of hormonal effects on the development and progression of RCC needs to be investigated.

Salvage-targeted kidney cancer therapy in patients progressing on high-dose interleukin-2 immunotherapy: the UCLA experience.

PURPOSE: To analyze the outcomes of patients with metastatic renal cell carcinoma treated with salvage-targeted therapy after progressing on high-dose interleukin (IL)-2 immunotherapy in a tertiary referral center. MATERIALS AND METHODS: A retrospective nonrandomized cohort consisting of 286 patients with metastatic renal cell carcinoma treated from 2003 to 2010 was analyzed from the University of California, Los Angeles (UCLA) Kidney Cancer database. All patients underwent cytoreductive nephrectomy, and 21 patients received salvage-targeted therapy after progression on high-dose IL-2, whereas 111 patients received targeted therapy alone. The remaining 154 patients had other treatment combinations or experimental targeted therapy agents only. Since 2003, selection of patients for high-dose IL-2 was increasingly based on clinical, pathologic, and molecular criteria (UCLA CPM criteria). Disease-specific survival was calculated from diagnosis of metastatic renal cell carcinoma. RESULTS: Patients selected according to UCLA CPM criteria and treated with salvage-targeted therapy after progressing on high-dose IL-2 experienced a significantly greater disease-specific survival (median not reached) than those treated with targeted therapy alone (30 months; P = 0.004). Since 2006, all high-dose IL-2 patients met the UCLA CPM criteria and were able to receive salvage-targeted therapy upon progression. Disease-specific survival calculated from initiation of targeted therapy was comparable for patients treated with salvage-targeted therapy after progression on high-dose IL-2 (34 months) versus first-line targeted therapy (26 months; P = 0.175). DISCUSSION: Patients selected for high-dose IL-2 based on UCLA CPM criteria and treated with salvage-targeted therapy upon progression have achieved outstanding disease-specific survival. Our data suggest a new algorithm for carefully selected patients with metastatic renal cell carcinoma based on UCLA CPM criteria to receive first-line high-dose IL-2 while reserving their option for salvage-targeted therapy with uncompromised efficacy upon progression.

Dendritic cell-based immunotherapy in prevention and treatment of renal cell carcinoma: efficacy, safety, and activity of Ad-GM·CAIX in immunocompetent mouse models.

The dendritic cell vaccine DC-Ad-GM·CAIX is an active, specific immunotherapy with the potential of providing a safe and effective therapy against renal cell carcinoma (RCC). Using immunocompetent Balb/c mouse models we tested the efficacy and mechanism of the vaccine to prevent and treat the growth of a syngeneic RCC (RENCA) engineered to overexpress the human TAA carbonic anhydrase IX (NPR-IX). In a prevention model, NPR-IX tumor development was specifically and significantly delayed by 13 days in DC-Ad-GM·CAIX-treated mice (P < 0.001), tumor volumes were 79% smaller (day 24, P < 0.007), and body weight was maintained at study termination compared with the controls. Six of these mice remained tumor-free for > 1 year. In a treatment model, NPR-IX tumors remained smaller in DC-Ad-GM·CAIX-treated mice for 8 days (P < 0.002), achieving a 60% growth inhibition at termination. No vaccine-related organ toxicity was observed in either model. The critical mechanistic parameter separating responsive from nonresponsive tumors was hCAIX protein expression, demonstrated by aggressive growth of tumors that did not express hCAIX protein and in sham-treated mice (DC-Ad-Null). No murine serum anti-hCAIX antibodies were detected. Moreover, altered mechanisms of immunoediting as a means for immune evasion were suggested by differential gene expression (Ccl1, Hmgb1, Fgl2, Cd209a, and Klra2) and therapy evasion miRNAs (miR-1186, miR-98, miR-5097, miR-1942, and miR-708) in tumors that evaded DC-Ad-GM·CAIX immunotherapy. This is the first study in immunocompetent mice that provides a proof of concept for the specificity, efficacy, safety, and activity of the DC-Ad-GM·CAIX immunotherapy, forming the basis for a first-in-human phase I trial in RCC patients.

Systemic therapy for metastatic renal cell carcinoma: a review and update.

An in-depth understanding of metastatic renal cell carcinoma (mRCC) is important so that practitioners can make informed evidenced-based decisions with patients to optimize not only quantity of life but quality of life as well. Therefore, this review focuses on the biology of mRCC as it relates to targets for therapy, as well as on the small molecules rationally designed with these targets in mind. In addition, anticipated emerging therapies are highlighted, including the new tyrosine kinase inhibitors axitinib and tivozanib, as well as new immune-based therapies such as dendritic cell-based vaccines and antibodies. We also briefly review recent reports from the emerging field of predicting drug response based on molecular markers. And finally, management of metastatic non-clear cell RCC histologies are discussed focusing on available evidence to direct decision making when assessing therapeutic options.

Clinical, molecular, and genetic correlates of lymphatic spread in clear cell renal cell carcinoma.

BACKGROUND: While it is well known that clear cell renal cell carcinoma (ccRCC) that presents with lymphatic spread is associated with an extremely poor prognosis, its molecular and genetic biology is poorly understood. OBJECTIVE: Define the clinicopathologic, molecular, and genetic biological characteristics of these tumors in comparison to nonmetastatic (N0M0) renal cell carcinomas. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study defined clinicopathologic features, expression of 28 molecular markers, and occurrence of chromosomal aberrations for their correlation with lymphatic spread in three cohorts of 502, 196, and 272 patients, respectively. MEASUREMENTS: Fisher exact test or the χ(2) test were used to compare categorical variables; continuous variables were compared with the Mann-Whitney U test or student t test. Cut-off values were calculated based on receiver operating characteristic curves and the Youden Index. Uni- and multivariate regression analyses were used to investigate the correlation with lymphatic spread. RESULTS AND LIMITATIONS: In clinical analyses, a predictive model consisting of smoking history (p=0.040), T stage (p<0.0001), Fuhrman grade (p<0.0001), Eastern Cooperative Oncology Group performance status (p<0.0001), and microvascular invasion (p<0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p=0.043) and high epithelial vascular endothelial growth factor receptor 2 (p=0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p<0.0001) with a lower risk. The current study is limited by its retrospective design, small sample size, and single-center experience. CONCLUSIONS: The low rates of CAIX expression and loss of chromosome 3p suggest that lymphatic spread in ccRCC occurs independently of von Hippel-Lindau tumor suppressor inactivation.