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.     

Neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer

Context

The use of neoadjuvant and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer is still controversial.

Objective

To determine the optimal use of chemotherapy in the neoadjuvant and adjuvant settings in patients with advanced urothelial cell carcinoma. Bladder preservation is also discussed.

Evidence acquisition

A critical review of the published literature on chemotherapy for patients with locally advanced bladder cancer was performed.

Evidence synthesis

The presence of occult micrometastases at the time of radical cystectomy leads to both distant and local failure in patients with locally advanced transitional cell carcinoma of the bladder. Both neoadjuvant and adjuvant therapies have been evaluated in patients with locally advanced bladder cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power to detect meaningful clinical answers as well as by experimental arms utilizing inadequate chemotherapy.

Conclusions

The aggregate of available evidence suggests that neoadjuvant cisplatin-based combination chemotherapy should be considered as a standard of care for patients with muscle-invasive or locally advanced operable bladder cancer. In patients who are either unfit for or refuse radical cystectomy, neoadjuvant chemotherapy with or without radiation can render bladder preservation possible for patients who attain an excellent clinical response. With the introduction of new cytotoxic drugs, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.     

The Effect of Neoadjuvant Chemotherapy on Perioperative Outcomes in Patients Who Have Bladder Cancer Treated with Radical Cystectomy: A Population-based Study

Background

Although therapeutic guidelines recommend the use of neoadjuvant chemotherapy before radical cystectomy (RC) in patients who have muscle-invasive bladder cancer (MIBC), this approach remains largely underused. One of the main reasons for this phenomenon might reside in concerns regarding the risk of morbidity and mortality associated with neoadjuvant chemotherapy.

Objective

To compare perioperative outcomes between patients receiving neoadjuvant chemotherapy and those treated with RC alone.

Design, setting, and participants

Relying on the Surveillance Epidemiology and End Results–Medicare-linked database, 3760 patients diagnosed with MIBC between 2000 and 2009 were evaluated.

Intervention

RC alone or RC plus neoadjuvant chemotherapy.

Outcome measurements and statistical analysis

Complications occurred within 30 and 90 d after surgery. Heterologous blood transfusions (HBTs), length of stay (LoS), readmission, and perioperative mortality were compared. To decrease the effect of unmeasured confounders associated with treatment selection, propensity score–matched analyses were performed.

Results and limitations

Overall, 416 (11.1%) of patients received neoadjuvant chemotherapy. Following propensity score matching, 416 (20%) and 1664 (80%) patients treated with RC plus neoadjuvant chemotherapy and RC alone remained, respectively. The 30-d complication, readmission, and mortality rates were 66.0%, 32.2%, and 5.3%, respectively. The 90-d complication, readmission, and mortality rates were 72.5%, 46.6%, and 8.2%, respectively. When patients were stratified according to neoadjuvant chemotherapy status, no significant differences were observed in the rates of complications, HBT, prolonged LoS, readmission, and mortality between the two groups (all p ≥ 0.1). These results were confirmed in multivariate analyses, where the use of neoadjuvant chemotherapy was not associated with higher risk of 30- and 90-d complications, HBT, prolonged LoS, readmission, and mortality (all p ≥ 0.1). Our study is limited by its retrospective nature.

Conclusions

The use of neoadjuvant chemotherapy is not associated with higher perioperative morbidity or mortality. These results should encourage wider use of neoadjuvant chemotherapy when clinically indicated.

Patient summary

Chemotherapy before radical cystectomy in patients with muscle-invasive bladder cancer does not increase the risk of complications or death. The use of chemotherapy should be strongly encouraged, as recommended by clinical guidelines, given its benefits.     

Maximizing cure for muscle-invasive bladder cancer: integration of surgery and chemotherapy

Context

The optimal treatment strategy for muscle-invasive bladder cancer remains controversial.

Objective

To determine optimal combination of chemotherapy and surgery aimed at preserving survival of patients with locally advanced bladder cancer.

Evidence acquisition

We performed a critical review of the published abstract and presentation literature on combined modality therapy for muscle-invasive bladder cancer. We emphasized articles of the highest scientific level, combining radical cystectomy and perioperative chemotherapy with curative intent to affect overall and disease-specific survival.

Evidence synthesis

Locally invasive, regional, and occult micrometastases at the time of radical cystectomy lead to both distant and local failure, causing bladder cancer deaths. Neoadjuvant and adjuvant chemotherapy regimens have been evaluated, as well as the quality of cystectomy and pelvic lymph node dissection.

Conclusions

Prospective, randomized clinical trials argue strongly for neoadjuvant cisplatin-based chemotherapy followed by high-quality cystectomy performed by an experienced surgeon operating in a high-volume center. Adjuvant chemotherapy after surgery is also effective when therapeutic doses can be given in a timely fashion. Both contribute to improved overall survival; however, many patients receive only one or none of these options, and the barriers to receiving optimal, combined, systemic therapy and surgery remain to be defined. An aging, comorbid, and often unfit population increasingly affected by bladder cancer poses significant challenges in management of individual patients.     

Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and Meta-Analysis of Randomized Trials

Context

The role of adjuvant chemotherapy remains poorly defined for the management of muscle-invasive bladder cancer (MIBC). The last meta-analysis evaluating adjuvant chemotherapy, conducted in 2005, had limited power to fully support its use.

Objective

To update the current evidence of the benefit of postoperative adjuvant cisplatin-based chemotherapy compared with control (ie, surgery alone) in patients with MIBC.

Evidence acquisition

A comprehensive literature review was performed to identify all randomized controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy with control for patients with MIBC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to May 2013. An updated systematic review and meta-analysis was performed.

Evidence synthesis

A total of 945 patients included in nine RCTs (five previously analyzed, one updated, and three new) were examined. For overall survival, the pooled hazard ratio (HR) across all nine trials was 0.77 (95% confidence interval [CI], 0.59–0.99; p = 0.049). For disease-free survival, the pooled HR across seven trials reporting this outcome was 0.66 (95% CI, 0.45–0.91; p = 0.014). This disease-free survival benefit was more apparent among those with positive nodal involvement (p = 0.010).

Conclusions

This updated and improved meta-analysis of randomized trials provides further evidence of an overall survival and disease-free survival benefit in patients with MIBC receiving adjuvant cisplatin-based chemotherapy after radical cystectomy.     

Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines

Context

New data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC.

Objective

To review the new EAU guidelines for MiM-BC with a specific focus on treatment.

Evidence acquisition

New literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence.

Evidence synthesis

Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available.

Conclusions

In the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.     

Critical Analysis of Bladder Sparing with Trimodal Therapy in Muscle-invasive Bladder Cancer: A Systematic Review

Context

Aims of bladder preservation in muscle-invasive bladder cancer (MIBC) are to offer a quality-of-life advantage and avoid potential morbidity or mortality of radical cystectomy (RC) without compromising oncologic outcomes. Because of the lack of a completed randomised controlled trial, oncologic equivalence of bladder preservation modality treatments compared with RC remains unknown.

Objective

This systematic review sought to assess the modern bladder-preservation treatment modalities, focusing on trimodal therapy (TMT) in MIBC.

Evidence acquisition

A systematic literature search in the PubMed and Cochrane databases was performed from 1980 to July 2013.

Evidence synthesis

Optimal bladder-preservation treatment includes a safe transurethral resection of the bladder tumour as complete as possible followed by radiation therapy (RT) with concurrent radiosensitising chemotherapy. A standard radiation schedule includes external-beam RT to the bladder and limited pelvic lymph nodes to an initial dose of 40 Gy, with a boost to the whole bladder to 54 Gy and a further tumour boost to a total dose of 64–65 Gy. Radiosensitising chemotherapy with phase 3 trial evidence in support exists for cisplatin and mitomycin C plus 5-fluorouracil. A cystoscopic assessment with systematic rebiopsy should be performed at TMT completion or early after TMT induction. Thus, nonresponders are identified early to promptly offer salvage RC. The 5-yr cancer-specific survival and overall survival rates range from 50% to 82% and from 36% to 74%, respectively, with salvage cystectomy rates of 25–30%. There are no definitive data to support the benefit of using of neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is proper patient selection. The best cancers eligible for bladder preservation are those with low-volume T2 disease without hydronephrosis or extensive carcinoma in situ.

Conclusions

A growing body of accumulated data suggests that bladder preservation with TMT leads to acceptable outcomes and therefore may be considered a reasonable treatment option in well-selected patients.

Patient summary

Treatment based on a combination of resection, chemotherapy, and radiotherapy as bladder-sparing strategies may be considered as a reasonable treatment option in properly selected patients.     

ICUD-EAU International Consultation on Bladder Cancer 2012: Radical Cystectomy and Bladder Preservation for Muscle-Invasive Urothelial Carcinoma of the Bladder

Context

New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published.

Objective

To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC.

Evidence acquisition

A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder-preserving strategies.

Evidence synthesis

The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data.

Conclusions

Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC.     

The Impact of the Extent of Lymphadenectomy on Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer: A Systematic Review

Context

Controversy exists regarding the therapeutic value of lymphadenectomy (LND) in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC).

Objective

To systematically review the relevant literature assessing the impact of LND on oncologic and perioperative outcomes in patients undergoing RC for MIBC.

Evidence acquisition

Medline, Medline In-Process, Embase, the Cochrane Central Register of Controlled Trials, and the Latin American and Caribbean Center on Health Sciences Information (LILACS) were searched up to December 2013. Comparative studies reporting on no LND, limited LND (L-LND), standard LND (S-LND), extended LND (E-LND), superextended LND (SE-LND), and oncologic and perioperative outcomes were included. Risk-of-bias and confounding assessments were performed.

Evidence synthesis

Twenty-three studies reporting on 19 793 patients were included. All but one study were retrospective. Planned meta-analyses were not possible because of study heterogeneity; therefore, data were synthesized narratively. There were high risks of bias and confounding across most studies as well as extreme heterogeneity in the definition of the anatomic boundaries of LND templates. All seven studies comparing LND with no LND favored LND in terms of better oncologic outcomes. Seven of 14 studies comparing (super)extended LND with L-LND or S-LND reported a beneficial outcome for (super)extended LND in at least a subset of patients. No difference in outcome was reported in two studies comparing E-LND and S-LND. The comparative harms of different extents of LND remain unclear.

Conclusions

Although the quality of the data was poor, the available evidence indicates that any kind of LND is advantageous over no LND. Similarly, E-LND appears to be superior to lesser degrees of dissection, while SE-LND offered no additional benefits. It is hoped that data from ongoing randomized clinical trials will clarify remaining uncertainties.

Patient summary

The current literature suggests that removal of lymph nodes in bladder cancer surgery is beneficial and might result in better outcomes in terms of prolonging survival; however, the quality of the available studies is poor, and high-quality studies are needed.     

Outcome of Patients Who Refuse Cystectomy after Receiving Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer

Objectives

To determine the outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer.

Methods

Between 1995 and 2001, 63 patients were evaluated who declined to undergo a planned cystectomy, because they achieved a complete clinical response to neoadjuvant cisplatin-based chemotherapy. Patient, tumor, and treatment features were assessed prospectively, and correlated in univariate and multivariate analyses with overall survival. The median follow-up was 86 mo and all patients were followed for more than 5 yr.

Results

Forty patients (64%) survived, with 54% of them having an intact functioning bladder. The number and size of invasive tumors were strongly associated with overall survival. The most significant treatment variable predicting better survival was complete resection of the invasive tumor on re-staging transurethral resection before starting chemotherapy. Of 23 patients (36%) who subsequently died of disease, 19 (30%) relapsed with invasive cancer in the bladder. Over 90% of surviving patients had solitary, small, and low-stage invasive tumors completely resected, and 83% survived without relapses in the bladder.

Conclusions

Selected patients with muscle-invasive bladder cancers may survive after transurethral resection and neoadjuvant chemotherapy, and tumor features can identify which patients responding completely to chemotherapy may survive without cystectomy.     

Treatment Options Available for Bacillus Calmette-Guérin Failure in Non–muscle-invasive Bladder Cancer

Context

Intravesical bacillus Calmette-Guérin (BCG) is a standard conservative treatment for patients with high-risk non–muscle-invasive bladder cancer (NMIBC). Many patients will experience recurrence or progression following BCG and are termed BCG failures.

Objective

To summarise the current treatment options available for patients with high-risk NMIBC who experience BCG failure.

Evidence acquisition

We searched the Medline, Embase, and Cochrane Trials databases for studies of BCG failure using predetermined relevant Medical Subject Heading terms and free text terms.

Evidence synthesis

Radical cystectomy (RC) should be strongly recommended when a patient has been deemed to fail BCG, if the patient is fit and fully informed of the risks, benefits, and quality-of-life issues. RC achieves long-term survival in excess of 90% with ongoing improvements in morbidity. While other salvage intravesical therapies have to be considered oncologically inferior to RC, several options are now available if bladder preservation is the objective. The options can be categorised as immunotherapy, chemotherapy, device-assisted therapy, and sequential combinations of these newer modalities with conventional therapy. Some agents have shown specific promise in BCG-failure patients (eg, gemcitabine, thermochemotherapy, taxane chemotherapy), and some modalities have been shown to be effective only in non–BCG-failure cohorts (eg, electromotive mitomycin).

Conclusions

The definition, prediction, and treatment of BCG failure remain unclear secondary to inconsistent studies and the heterogeneous entity of patients with NMIBC. RC should be the default position upon failing BCG, but if bladder preservation is sought, then several promising intravesical salvage options are available. It will be necessary to individually tailor the management of such patients based on tumour risk and medical profiles. Currently data are still inadequate to formulate definitive recommendations, and larger studies of salvage intravesical agents are urgently required.     

The Economics of Bladder Cancer: Costs and Considerations of Caring for This Disease

Context

Due to high recurrence rates, intensive surveillance strategies, and expensive treatment costs, the management of bladder cancer contributes significantly to medical costs.

Objective

To provide a concise evaluation of contemporary cost-related challenges in the care of patients with bladder cancer. An emphasis is placed on the initial diagnosis of bladder cancer and therapy considerations for both non–muscle-invasive bladder cancer (NMIBC) and more advanced disease.

Evidence acquisition

A systematic review of the literature was performed using Medline (1966 to February 2011). Medical Subject Headings (MeSH) terms for search criteria included “bladder cancer, neoplasms” OR “carcinoma, transitional cell” AND all cost-related MeSH search terms. Studies evaluating the costs associated with of various diagnostic or treatment approaches were reviewed.

Evidence synthesis

Routine use of perioperative chemotherapy following complete transurethral resection of bladder tumor has been estimated to provide a cost savings. Routine office-based fulguration of small low-grade recurrences could decrease costs. Another potential important target for decreasing variation and cost lies in risk-modified surveillance strategies after initial bladder tumor removal to reduce the cost associated with frequent cystoscopic and radiographic procedures. Optimizing postoperative care after radical cystectomy has the potential to decrease length of stay and perioperative morbidity with substantial decreases in perioperative care expenses. The gemcitabine-cisplatin regimen has been estimated to result in a modest increase in cost effectiveness over methotrexate, vinblastine, doxorubicin, and cisplatin. Additional costs of therapies need to be balanced with effectiveness, and there are significant gaps in knowledge regarding optimal surveillance and treatment of both early and advanced bladder cancer.

Conclusions

Regardless of disease severity, improvements in the efficiency of bladder cancer care to limit unnecessary interventions and optimize effective cancer treatment can reduce overall health care costs. Two scenarios where economic and comparative-effectiveness research is limited but would be most beneficial are (1) the management of NMIBC patients where excessive costs are due to vigilant surveillance strategies and (2) in patients with metastatic disease due to the enormous cost associated with late-stage and end-of-life care.     

European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update

Context

The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice.

Objective

This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice.

Evidence acquisition

The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references.

Evidence synthesis

There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options.

Conclusions

These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patient's specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status.     

A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma

Context

The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit.

Objective

To update the current evidence on the role of NC and AC for UTUC patients.

Evidence acquisition

We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed.

Evidence synthesis

No randomized trials investigated the role of AC for UTUC. There was one prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; p = 0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24–0.99; p = 0.048). Benefit was not seen for non-cisplatin–based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22–0.76; p = 0.005).

Conclusions

There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility.

Patient summary

After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.     

ICUD-EAU International Consultation on Bladder Cancer 2012: Non–Muscle-Invasive Urothelial Carcinoma of the Bladder

Context

Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non–muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach.

Objective

To critically review the recent data on the management of NMIBC to arrive at a general consensus.

Evidence acquisition

A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched.

Evidence synthesis

The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies.

Conclusions

Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.     

Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review

Context

Some studies report that tumour progression in patients with non-muscle-invasive bladder cancer (NMIBC) is associated with a poor prognosis. However, no systematic evidence is available.

Objective

The aim of the study was to systematically review literature to determine the long-term cancer-specific survival in patients with high-risk NMIBC (T1G3, multifocal, highly recurrent, or carcinoma in situ) having tumour progression.

Evidence acquisition

A systematic review was conducted by searching PubMed and the Cochrane library for studies published between 2006 and 2011. Additional studies were identified by scanning reference lists of relevant papers. We attempted to retrieve missing data by contacting the corresponding author. Keywords used included bladder cancer, high-risk, high grade, carcinoma in situ, non-muscle invasive bladder cancer, progression, and survival. Studies were included when they met the following criteria: inclusion of at least 75 patients having high-risk NMIBC, patients were initially treated conservatively with transurethral resection of the bladder tumour and intravesical instillations, a median follow-up of at least 48 mo, and reporting data on progression to muscle-invasive bladder cancer (MIBC) and death resulting from bladder cancer (BCa).

Evidence synthesis

Literature was systematically reviewed, and 19 trials were included, producing a total of 3088 patients, of which 659 (21%) showed progression to MIBC and 428 (14%) died as a result of BCa after a median follow-up of 48-123 mo. Survival after progression from high-risk NMIBC to MIBC was 35%. Progression to MIBC and BCa-related death in high-risk NMIBC were found to be relatively early events, occurring mainly within 48 mo. Finally, even in cases of early cystectomy in patients with high-risk NMIBC, a relevant proportion of these patients appear not be cured of their disease.

Conclusions

This study provides systematically gathered evidence showing a poor prognosis for patients with high-risk NMIBC and tumour progression.     

European Guidelines on Upper Tract Urothelial Carcinomas: 2013 Update

Context

The European Association of Urology (EAU) guideline group for upper tract urothelial carcinoma (UTUC) has prepared updated guidelines to aid clinicians in assessing the current evidence-based management of UTUC and to incorporate present recommendations into daily clinical practice.

Objective

To provide a brief overview of the EAU guidelines on UTUC as an aid to clinicians in their daily clinical practice.

Evidence acquisition

The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified using a systematic search of Medline. Data on urothelial malignancies and UTUCs in the literature were searched using Medline with the following keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; instillation; neoadjuvant treatment; recurrence; risk factors; nomogram; and survival. References were weighted by a panel of experts.

Evidence synthesis

There is a lack of data in the current literature to provide strong recommendations (ie, grade A) due to the rarity of the disease. A number of recent multicentre studies are now available, and there is a growing interest in UTUC in the recent literature. Overall, 135 references have been included here, but most of these studies are still retrospective analyses. The TNM 2009 classification is recommended. Recommendations are given for diagnosis as well as radical and conservative treatment (ie, imperative and elective cases); additionally, prognostic factors are discussed. Recommendations are also provided for patient follow-up after different therapeutic options.

Conclusions

These guidelines contain information for the management of individual patients according to a current standardised approach. Physicians must take into account the specific clinical characteristics of each individual patient when determining the optimal treatment regimen including tumour location, grade, and stage; renal function; molecular marker status; and medical comorbidities.     

Use of Potentially Curative Therapies for Muscle-invasive Bladder Cancer in the United States: Results from the National Cancer Data Base

Background

Despite its lethal potential, many patients with muscle-invasive bladder cancer (MIBC) do not receive aggressive, potentially curative therapy consistent with established practice standards.

Objective

To characterize the treatments received by patients with MIBC and analyze their use according to sociodemographic, clinical, pathologic, and facility measures.

Design, setting, and participants

Using the National Cancer Data Base, we analyzed 28 691 patients with MIBC (stages II–IV) treated between 2004 and 2008, excluding those with cT4b tumors or distant metastases. Treatments included radical or partial cystectomy with or without chemotherapy (CT), chemoradiotherapy (CRT), radiation therapy (RT), or CT alone and observation following biopsy. Aggressive therapy (AT) was defined as radical or partial cystectomy or definitive RT/CRT (total dose ≥50 Gy).

Outcome measurements and statistical analysis

AT use and correlating variables were assessed by multivariable, generalized estimating equation models adjusted for facility clustering.

Results and limitations

According to the database, 52.5% of patients received AT; 44.9% were treated surgically, 7.6% received definitive CRT or RT, and 25.9% of patients received observation only. AT use decreased with advancing age (odds ratio [OR]: 0.34 for age 81–90 yr vs ≤50 yr; p < 0.001). AT use was also lower in racial minorities (OR: 0.74 for black race; p < 0.001), the uninsured (OR: 0.73; p < 0.001), Medicaid-insured patients (OR: 0.81; p = 0.01), and at low-volume centers (OR: 0.64 vs high-volume centers; p < 0.001). Use of AT was higher with increasing tumor stage (OR: 2.23 for T3/T4a vs T2; p < 0.001) and nonurothelial histology (OR: 1.25 and 1.43 for squamous and adenocarcinoma, respectively; p < 0.001). Study limitations include retrospective design and lack of information about patient and provider motivations regarding therapy selection.

Conclusions

AT for MIBC appears underused, especially in the elderly and in groups with poor socioeconomic status. These data point to a significant unmet need to inform policy makers, payers, and physicians regarding appropriate therapies for MIBC.     

ICUD-EAU International Consultation on Bladder Cancer 2012: Screening,Diagnosis, and Molecular Markers

Context and objective

To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the screening, diagnosis, and markers of bladder cancer using an evidence-based strategy.

Evidence acquisition

A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to screening, diagnosis, markers, and pathology. Proceedings from the last 5 yr of major conferences were also searched.

Evidence synthesis

The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed.

Conclusions

Cystoscopy alone is the most cost-effective method to detect recurrence of bladder cancer. White-light cystoscopy is the gold standard for evaluation of the lower urinary tract; however, technology like fluorescence-aided cystoscopy and narrow-band imaging can aid in improving evaluations. Urine cytology is useful for the diagnosis of high-grade tumor recurrence. Molecular medicine holds the promise that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patient's tumor. The challenge remains to optimize measurement of these targets, evaluate the impact of such targets for therapeutic drug development, and translate molecular markers into the improved clinical management of bladder cancer patients. Physicians and researchers eventually will have a robust set of molecular markers to guide prevention, diagnosis, and treatment decisions for bladder cancer.