EAU Guidelines on Renal Cell Carcinoma: The 2010 Update

Context and objectives

The European Association of Urology Guideline Group for renal cell carcinoma (RCC) has prepared these guidelines to help clinicians assess the current evidence-based management of RCC and to incorporate the present recommendations into daily clinical practice.

Evidence acquisition

The recommendations provided in the current updated guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials.

Evidence synthesis

A number of recent prospective randomised studies concerning RCC are now available with a high level of evidence, whereas earlier publications were based on retrospective analyses, including some larger multicentre validation studies, meta-analyses, and well-designed controlled studies.

Conclusions

These guidelines contain information for the treatment of an individual patient according to a current standardised general approach. Updated recommendations concerning diagnosis, treatment, and follow-up can improve the clinical handling of patients with RCC.     

Carbonic Anhydrase IX in Renal Cell Carcinoma: Implications for Prognosis,Diagnosis, and Therapy

Context

The clinical management of patients with renal cell carcinoma (RCC) remains difficult, and the development of new diagnostic, prognostic, and therapeutic tools is still required.

Objective

To review the current knowledge on the RCC-associated antigen carbonic anhydrase IX (CAIX) and provide evidence for how this antigen may aid in the clinical management of RCC.

Evidence acquisition

Clinical papers describing diagnostic, prognostic, and/or therapeutic applications of CAIX in RCC were selected from the Pubmed database. The search was manually augmented by reviewing the reference lists of articles.

Evidence synthesis

Expression of CAIX is regulated by the Von Hippel Lindau (VHL) protein (pVHL). Because of the invariable VHL mutational loss in clear-cell RCC (ccRCC) patients, CAIX expression is ubiquitous in ccRCC. Determination of CAIX expression in nephrectomy specimens of RCC patients improves prognostic accuracy; high CAIX expression appears to correlate with a favourable prognosis and a greater likelihood of response to systemic treatment for metastatic disease. Therefore, CAIX expression might be used to stratify metastatic ccRCC (mRCC) patients for systemic treatment. When incorporated into the RCC nomogram, CAIX expression seems to improve diagnostic accuracy for primary RCC as well as mRCC patients, but further evidence is required. Clinical studies with the CAIX-specific monoclonal antibody (mAb) cG250 have provided unequivocal evidence that ccRCC lesions can be imaged with radiolabeled cG250. Results are awaited of a large, randomised trial that aims to establish the value of cG250 imaging for primary RCC. The outcome of another large, placebo-controlled study is awaited to establish the usefulness of CAIX-targeted therapy in the adjuvant setting. Therapeutic trials with high-dose radiolabeled cG250 and CAIX-loaded dendritic cells in mRCC patients are still in phase 1 or 2.

Conclusions

CAIX improves diagnostic accuracy and is an attractive target for imaging of and therapy for ccRCC.     

Diagnostic and Prognostic Molecular Markers for Renal Cell Carcinoma: A Critical Appraisal of the Current State of Research and Clinical Applicability

Context

Earlier detection of renal cell carcinoma (RCC) and the recent expansion of treatment possibilities have positively influenced the outlook for patients with this disease. However, progression and treatment response are still not sufficiently predictable. Molecular markers could help to refine individual risk stratification and treatment planning, although they have not yet become clinically routine.

Objective

This review presents an overview of diagnostic and prognostic molecular markers for RCC and a subgrouping of these markers for different clinical issues.

Evidence acquisition

Literature and recent meeting abstracts were searched using these terms: renal (cell) carcinoma, molecular/tumor markers, biopsy, blood, urine, disease progression/prognosis, immunohistochemistry, risk factors, and survival.Due to the resulting large number of articles, studies were subjectively selected according to the importance of a study on the field, number of investigated patients, originality, multivariate analyses performed, contrast with previously published data, actuality, and assumed clinical applicability of the described results. More then 90% of the selected studies originated from the past 10 yr; >50% of the articles were written in 2006 or later.

Evidence synthesis

These data were predominantly obtained via nonrandomized, retrospective, but often controlled studies. Thereby, the resulting level of evidence is 2A/2B. The broad spectrum of described molecular markers (MMs) for RCC consists of markers already extensively studied in other malignancies (eg, p53), as well as MMs typically associated with specific RCC-altered gene functions and pathways (eg, von Hippel–Lindau [VHL]). The main goal of using MMs is to refine the prediction of clinical end points like tumor progression, treatment response, and cancer-specific and/or overall survival. Further, MMs might facilitate the clinical work-up of undefined renal masses and prove to be more convenient tools for screening and follow-up in blood and urine.

Conclusions

Presently, there are a number of promising MMs for diverse clinical questions, but the available data are not yet valid enough for routine, clinical application. We should comply with the demand for large multicenter prospective investigations, stratified for RCC type and treatment modalities, to lift the use of molecular markers in RCC to a practical level, thereby providing a better consultation for our patients regarding diagnosis, treatment, and follow-up.     

Vaccine Therapy in Patients with Renal Cell Carcinoma

Context

Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans. Although immunotherapy is currently much less used than in the past, it remains an important option that warrants further exploration.

Objective

To examine the current status of vaccine therapy for RCC and to provide information on relevant clinical studies.

Evidence acquisition

We reviewed recent literature on Medline (2003–2008, using the keywords renal cell carcinoma, cancer vaccines, active immunotherapy, and dendritic cells). Subsequent references were identified from reference list of retrieved articles. Quality assessment included prospective phase 1–3 trials and critical evaluations with low numbers of patients.

Evidence synthesis

Therapeutic vaccines can be divided in autologous tumour cell–based vaccines, genetically modified tumour cell–based and dendritic cell (DC)–based vaccines, and peptide-based vaccines. To date, only two randomised, adjuvant, phase 3 studies investigating RCC vaccines have been published. Autologous tumour cell vaccine (Reniale) improved the 5-yr progression-free survival (PFS) for high-risk nonmetastatic RCC patients at all tumour stages when administered after nephrectomy. The benefit was clearer in the T3 group. A per-protocol analysis revealed a statistically significant PFS and overall survival (OS) in favour of the vaccine. Autologous tumour-derived heat shock protein peptide complex (HSPPC-96; vitespen) could not significantly improve recurrence-free survival in RCC patients at high risk for recurrence after nephrectomy, but did so in intermediate risk patients. DC vaccination in metastatic RCC (mRCC) patients is safe and can induce antigen-specific immune response and obtain tumour regression in a subset of patients.

Conclusions

RCC vaccines have much less toxicity than other current therapies and remain an important area for further research. Reniale has shown significant benefit as an adjuvant RCC vaccine. Vitespen seems promising as an adjuvant treatment in earlier stage disease. A possible area of research is the use of RCC vaccines with immune-enhancing or antiangiogenic agents in the adjuvant setting.     

Systematic Review of Adrenalectomy and Lymph Node Dissection in Locally Advanced Renal Cell Carcinoma

Context

Controversy remains over whether adrenalectomy and lymph node dissection (LND) should be performed concomitantly with radical nephrectomy (RN) for locally advanced renal cell carcinoma (RCC) cT3–T4N0M0.

Objective

To systematically review all relevant literature comparing oncologic, perioperative, and quality-of-life (QoL) outcomes for locally advanced RCC managed with RN with or without concomitant adrenalectomy or LND.

Evidence acquisition

Relevant databases were searched up to August 2012. Randomised controlled trials (RCTs) and comparative studies were included. Outcome measures were overall survival, QoL, and perioperative adverse effects. Risks of bias (RoB) were assessed using Cochrane RoB tools. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.

Evidence synthesis

A total of 3658 abstracts and 252 full-text articles were screened. Eight studies met the inclusion criteria: six LNDs (one RCT and five nonrandomised studies [NRSs]) and two adrenalectomies (two NRSs). RoB was high across the evidence base, and the quality of evidence from outcomes ranged from moderate to very low. Meta-analyses were not undertaken because of diverse study designs and data heterogeneity. There was no significant difference in survival between the groups, even though 5-yr overall survival appears better for the RN plus LND group compared with the no-LND group in one randomised study. There was no evidence of a difference in adverse events between the RN plus LND and no-LND groups. No studies reported QoL outcomes. There was no evidence of an oncologic difference between the RN with adrenalectomy and RN without adrenalectomy groups. No studies reported adverse events or QoL outcomes.

Conclusions

There is insufficient evidence to draw any conclusions on oncologic outcomes for patients having concomitant LND or ipsilateral adrenalectomy compared with patients having RN alone for cT3–T4N0M0 RCC. The quality of evidence is generally low and the results potentially biased. Further research in adequately powered trials is needed to answer these questions.     

Potential Role of Genetic Markers in the Management of Kidney Cancer

Context

Kidney cancer is not a single entity but comprises a number of different types of cancer that occur in the kidney including renal cell tumours as the most common type. Four major renal cell tumour subtypes can be distinguished based on morphologic and genetic characteristics. To individualise therapy and to improve the prognosis in patients with renal cell tumours, accurate subtyping, definition of individual course of disease, and the prediction of therapy response are necessary.

Objective

To discuss the potential role of genetic markers in the management of kidney cancer.

Evidence acquisition

A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of genetic alterations in kidney cancer management. Keywords included kidney neoplasms, genetics, SNP, gene expression, miRNA, classification, diagnosis, drug therapy, prognosis, and therapy. The articles with the highest level of evidence were identified and critically reviewed. This review is the result of an interactive peer-reviewing process by an expert panel of co-authors.

Evidence synthesis

Each subtype is characterised by specific genetic, epigenetic, and expression patterns that potentially can be used to subclassify renal cell tumours in cases of ambivalent histopathology. Molecular signatures and single alterations in primary tumours are associated with aggressiveness and prognosis. Germline polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets seem to be associated with toxicity and response in patients receiving targeted therapy.

Conclusions

Significant advances have been achieved in the molecular analysis of renal cancer. Validation of findings is greatly needed to implement genetic markers in the management of renal cancer. This should lead to improved diagnosis, prognosis, and personalised therapy in this heterogeneous disease.     

Salvage cryoablation for locally recurrent prostate cancer following primary radiotherapy

Context

The purpose of this paper is to review current salvage cryoablation (SCA) outcomes in patients with locally recurrent prostate cancer (PCa) following primary radiation therapy.

Objective

The objectives of this review are (1) to analyze the eligibility criteria for careful patient selection for these salvage modalities and (2) to evaluate the oncologic results and reported complication rates for these respective modalities.

Evidence acquisition

A Medline/PubMed literature search was performed of peer-reviewed scientific articles published from 1991 to 2012 regarding salvage therapy for radiorecurrent PCa. The following search terms and various permutations were used: radiorecurrent prostate cancer, local salvage treatment, salvage radical prostatectomy, salvage cryoablation, salvage brachytherapy, and salvage high-intensity focused ultrasound. Only articles written in English were included.

Evidence synthesis

SCA is a feasible and efficacious treatment modality, especially using third-generation technology, whereby the biochemical disease-free survival is estimated to be between 50% and 70% at 5-yr follow-up in properly selected patients. Severe complications such as rectourethral fistulas are significantly less common over the last decade than was reported in the past. Because there are no prospective, randomized studies and the definitions of PSA failure vary among many studies, comparisons between these different salvage modalities are limited in terms of cancer-specific outcomes. Nevertheless, in recent years, tertiary care referral centers for prostate cryotherapy have reported their treatment outcomes using rigorous treatment end points and morbidity grading systems, dramatically improving the quality of reported clinical data. Consequently, favorable predictors of treatment outcomes have been identified.

Conclusions

The inability to effectively salvage patients with locally recurrent PCa following radiation therapy has in large part resulted from the lack of sufficiently sensitive and specific diagnostic tools to detect local recurrences at an early, potentially curable stage. Consequently, a more stringent definition of biochemical failure, improved imaging techniques, and accurate PCa mapping imaging technology is greatly needed within our diagnostic armamentarium. Additional research and randomized clinical trials are required to determine which salvage modality is superior in terms of oncologic efficacy and reduced morbidity.     

Rationale for percutaneous biopsy and histologic characterisation of renal tumours

Context

The use of percutaneous biopsy of renal tumours has been traditionally reserved for selected cases because of uncertainties regarding its safety, accuracy, and clinical utility. With the adoption of modern biopsy techniques and increasing expertise in interpreting biopsy specimens, renal tumour biopsy today has limited morbidity and allows histologic diagnosis in the majority of cases in centres with expertise.

Objective

To review the current rationale, indications, and outcomes of percutaneous biopsies and histologic characterisation of renal tumours.

Evidence acquisition

We conducted a systematic review of English-language articles on percutaneous biopsies of renal tumours published between January 1999 and December 2011 using the Medline, Embase, and Web of Science databases. One hundred twelve articles were selected with the consensus of all authors and analysed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria.

Evidence synthesis

In recent years, the increasing incidence of incidental small renal masses (SRMs), the development of conservative and minimally invasive treatments for low-risk renal cell carcinoma (RCC), and the discovery of novel targeted treatments for metastatic disease have provided the rationale for expanding the indications for renal tumour biopsy. Percutaneous biopsy for diagnostic assessment of SRMs can avoid unnecessary surgeries and support treatment decisions, especially in patients at high surgical risk. Biopsies can confirm histologic success after thermal ablation of SRMs and support the selection of the appropriate systemic therapy for metastatic RCC. There is increasing evidence that further diagnostic and prognostic information can be obtained from renal tumour biopsies with the use of immunohistochemistry, cytogenetic and molecular analysis, and high-throughput gene expression profiling.

Conclusions

Percutaneous biopsies have increasing indications and can significantly contribute to clinical management of renal tumours but are still underutilised in clinical practice. Further research is needed to define optimal and standardised patterns of biopsy and improve the accuracy of biopsies to determine tumour histology. Molecular and genetic analysis of biopsy specimens can provide additional information to support patient counselling and treatment decision making.     

Postprostatectomy incontinence: all about diagnosis and management

Context

The ever-increasing number of radical prostatectomies entails an increasing number of patients suffering from postprostatectomy stress incontinence despite improved surgical techniques. We provide an overview of the current diagnosis and treatment of postprostatectomy stress incontinence.

Objective

To review previous and recent literature on this subject and to assess the current standards of diagnosis and management of postprostatectomy incontinence.

Evidence acquisition

The PubMed database was searched, and all articles published since 2000 were evaluated.

Evidence synthesis

This review presents the current recommended diagnostic tools and available noninvasive and invasive treatment options.

Conclusions

The European Association of Urology (EAU) recommends a two-stage assessment for diagnosis of postprostatectomy incontinence. Noninvasive therapy, pelvic floor-muscle training and biofeedback, is recommended in early postoperative and mild incontinence. Pharmacological treatment with duloxetine is especially effective in combination with physiotherapy, where it synergistically improves the continence rate. For surgical treatment, the insertion of an artificial urinary sphincter, AS-800, is still the gold standard. In recent years, several minimal invasive treatment options have been introduced with different rates of success, but they have not yet surpassed the results of the artificial sphincter.     

Prognostic and Therapeutic Impact of the Histopathologic Definition of Parenchymal Epithelial Renal Tumors

Context

In the last few years, the treatment of renal cell carcinoma (RCC) has progressed significantly, and some histopathologic issues have become important for selection and follow-up after medical and surgical therapies.

Objective

The aim of this collaborative article is to review the most recent literature on the role of traditional histopathologic features obtained from renal core biopsy or nephrectomy specimens in the management of confined, locally advanced, and metastatic RCC.

Evidence acquisition

A nonsystematic review of the literature was performed in April 2010 using the Medline database. Multiple free-text searches were performed for the following items: renal cell carcinoma, clear cell, papillary, chromophobe, histologic* subtype*, histotype*, nuclear grade*, necrosis, sarcomatoid differentiation, biopsy, molecular marker*, and cytogenetic marker*. A total of 2369 records were retrieved from Medline, and 263 full-text studies were considered and partially included in the present review. A panel of experts reached consensus on the main subheadings of this paper.

Evidence synthesis

Core needle biopsies can provide important information that is useful to avoid the overtreatment of benign tumors and to help plan watchful waiting or minimally invasive treatments in selected patients. Tumor histotype is fundamental in the pathologic report. In the context of integrated prognostic systems, the combination of the most important clinical and pathologic factors (TNM stage, Fuhrman nuclear grade, presence of necrosis, microvascular invasion, and sarcomatoid dedifferentiation) allows us to reach a high prognostic accuracy. These models can be used to select patients suitable for adjuvant protocols, to design an appropriate follow-up schedule, and to provide careful patient counseling. Molecular and cytogenetic markers should be further evaluated.

Conclusions

The histopathologic definition of parenchymal epithelial renal tumors is fundamental to plan the management and follow-up of patients with locally confined, locally advanced, and metastatic RCC.     

Reassessing the Current UICC/AJCC TNM Staging for Renal Cell Carcinoma

Context

The outcome prediction for renal cell cancer (RCC) remains controversial, and although many parameters have been tested for prognostic significance, only a few have achieved widespread acceptance in clinical practice. The TNM staging system defines local extension of the primary tumour (T), involvement of regional lymph nodes (N), and presence of distant metastases (M).

Objective

This review focuses on reassessing the current TNM staging system for RCC.

Evidence acquisition

A literature search in English was performed using the National Library of Medicine database and the following keywords: renal cell cancer, kidney neoplasm, and staging. We scrutinized 1952 references, and 62 were selected for review based on their pertinence, study size, and overall contribution to the field.

Evidence synthesis

The prognostic significance of tumour size for localized RCC has been investigated in a large number of studies. As a consequence, many modifications of the TNM staging system were primarily made to the size cut points between stage I and II tumours. The latest three revisions of the TNM system are systematically reviewed. For the heterogeneous group of locally advanced RCCs, involving different anatomic structures surrounding the kidney, the situation is still the subject of controversial scientific dispute. In detail, perirenal fat invasion, direct infiltration of the ipsilateral adrenal gland, invasion of the urinary collecting system, infiltration of renal sinus fat, and vena cava and renal vein thrombosis are disputed. Finally, staging of lymph node metastases and distant metastatic disease is discussed.

Conclusions

Special emphasis should be put on renal sinus invasion for stage evaluation. Retrospective studies relying on material collected at a time when no emphasis was placed on adequate sampling of the renal sinus should be treated with caution. In view of new treatment opportunities, the current TNM staging system of RCC and any other staging system must be dynamic.     

A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer

Context

Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC.

Objective

To review the data supporting perioperative chemotherapy and emerging regimens for MIBC.

Evidence acquisition

Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included.

Evidence synthesis

The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.

Conclusions

Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.     

Contemporary management of postprostatectomy incontinence

Context

In recent years, despite improvement in the surgical technique, the prevalence of postprostatectomy incontinence has increased due to a rise in the number of radical prostatectomies performed annually.

Objective

The aim of this review is to evaluate contemporary noninvasive and invasive treatment options for postprostatectomy incontinence.

Evidence acquisition

In August 2010, a review of the literature was performed using the Medline database.

Evidence synthesis

All articles concerning noninvasive and invasive treatment for postprostatectomy incontinence were included.

Conclusions

No randomised controlled trials exist to compare currently used noninvasive and invasive treatments for postprostatectomy incontinence. Pelvic floor muscle training is recommended for the initial treatment of stress urinary incontinence (SUI). Additionally, antimuscarinic therapy should be applied for urgency or urge incontinence. For decades, the artificial urinary sphincter was the reference standard for persistent SUI. Nowadays, male slings are an alternative for men with mild to moderate postprostatectomy SUI.     

Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks

Context

Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality.

Objective

To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects.

Evidence acquisition

A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed.

Evidence synthesis

Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown.

Conclusions

ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk–benefit ratio, to alleviate comorbidities.     

The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature

Context

Sipuleucel-T, an autologous antigen-presenting cell vaccine loaded with prostate acid phosphatase conjugated with granulocyte-macrophage colony-stimulating factor (GM-CSF), yielded a survival advantage in men with metastatic castration-resistant prostate cancer (mCRPC).

Objective

Critically analyze the role of sipuleucel-T in therapy for mCRPC.

Evidence acquisition

A systematic review of the literature was performed in June 2011 using Medline and an abstract search of major cancer conferences. The search strategy included the terms sipuleucel-T, APC-8015, castration-resistant, prostate cancer, and immunotherapy.

Evidence synthesis

The era of targeted immunotherapy was initiated with the regulatory approval in 2010 of sipuleucel-T for asymptomatic and minimally symptomatic mCRPC. The median survival was prolonged by 4.1 mo (25.8 vs 21.7 mo; hazard ratio: 0.78; 95% confidence interval, 0.61–0.98; p = 0.03), coupled with an improvement in 3-yr survival (31.7% vs 23.0%). Outcomes were characterized by the lack of tumor regression or delay in progression. Further development is proceeding in earlier stages of prostate cancer and in the context of a host of emerging agents.

Conclusions

The addition of sipuleucel-T, an immunotherapeutic agent, to the armamentarium represents a paradigm shift in therapy for mCRPC. The rational combination and proper sequencing of sipuleucel-T with other newly approved agents (abiraterone acetate, cabazitaxel) and emerging agents (MDV3100, TAK-700, ipilimumab) will be important to evaluate.     

ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for Urothelial Carcinoma—Neoadjuvant and Adjuvant Settings

Context

We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy.

Objective

To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings.

Evidence acquisition

Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included.

Evidence synthesis

The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed.

Conclusions

Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin-ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking.     

Hereditary Renal Cancer Syndromes: An Update of a Systematic Review

Context

Hereditary renal cancers (HRCs) comprise approximately 3–5% of renal cell carcinomas (RCCs).

Objective

Our aim was to provide an overview of the currently known HRC syndromes in adults.

Evidence acquisition

Data on HRC syndromes were analysed using PubMed and Online Mendelian Inheritance in Man with an emphasis on kidney cancer, clinical criteria, management, treatment, and genetic counselling and screening.

Evidence synthesis

Ten HRC syndromes have been described that are inherited with an autosomal dominant trait. Eight genes have already been identified (VHL, MET, FH, FLCN, TSC1, TSC2, CDC73, and SDHB). These HRC syndromes involve one or more RCC histologic subtypes and are generally bilateral and multiple. Computed tomography and magnetic resonance imaging are the best imaging techniques for surveillance and assessment of renal lesions, but there are no established guidelines for follow-up after imaging. Except for hereditary leiomyomatosis RCC tumours, conservative treatments favour both an oncologically effective therapeutic procedure and a better preservation of renal function.

Conclusions

HRC involves multiple clinical manifestations, histologic subtypes, genetic alterations, and molecular pathways. Urologists should know about HRC syndromes in the interest of their patients and families.     

Novel Immunotherapeutic Strategies in Development for Renal Cell Carcinoma

Context

The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase.

Objective

To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm.

Evidence acquisition

A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy.

Evidence synthesis

Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host–tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies.

Conclusions

It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.