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.     

Predictors of oncological outcomes in T1G3 patients treated with BCG who undergo radical cystectomy

Purpose

To evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG.

Methods

According to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups.

Results

Of 2451 patients, 509 (20.8%) underwent RC. Patients with tumors?>?3 cm or with CIS had earlier cystectomies (HR?=?1.79, p?=?0.001 and HR?=?1.53, p?=?0.02, respectively). Patients with tumors?>?3 cm, multiple tumors or CIS had earlier T3/T4 or N?+?cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N?+?disease at RC. Patients with T3/T4 or N?+?disease at RC had a shorter disease-specific survival (HR?=?4.38, p?<?0.001), as did patients with CIS at cystectomy (HR?=?2.39, p?<?0.001). Patients who progressed prior to cystectomy had a shorter disease-specific survival than patients for whom progression was only detected at cystectomy (HR?=?0.58, p?=?0.024)

Conclusions

Patients treated with RC before experiencing progression to muscle-invasive disease harbor better oncological and survival outcomes compared to those who progressed before RC and to those upstaged at surgery. Tumor size and concomitant CIS at diagnosis are the main predictors of surgical treatment while tumor size, CIS and tumor multiplicity are associated with extravesical disease at surgery.

     

Pathologic Nodal Staging Score for Bladder Cancer: A Decision Tool for Adjuvant Therapy After Radical Cystectomy

Background

Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard of care for high-risk non–muscle-invasive and muscle-invasive bladder cancer (BCa).

Objective

To develop a model that allows quantification of the likelihood that a pathologically node-negative patient has, indeed, no positive nodes.

Design, setting, and participants

We analyzed data from 4335 patients treated with RC and PLND without neoadjuvant chemotherapy at 12 international academic centers.

Interventions

Patients underwent RC and PLND.

Outcome measurements and statistical analysis

We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative as a function of the number of examined nodes.

Results and limitations

Overall, the probability of missing a positive node decreases with the increasing number of nodes examined (52% if 3 nodes are examined, 40% if 5 are examined, and 26% if 10 are examined). The proportion of having a positive node increased proportionally with advancing pathologic T stage and lymphovascular invasion (LVI). Patients with LVI who had 25 examined nodes would have a pNSS of 80% (pT1), 88% (pT2), and 66% (pT3–T4), whereas 10 examined nodes were sufficient for pNSS exceeding 90% in patients without LVI and pT0–T2 tumors. This study is limited because of its retrospective design and multicenter nature.

Conclusions

We developed a tool that estimates the likelihood of lymph node (LN) metastasis in BCa patients treated with RC by evaluating the number of examined nodes, the pathologic T stage, and LVI. The pNSS indicates the adequacy of nodal staging in LN-negative patients. This tool could help to refine clinical decision making regarding adjuvant chemotherapy, follow-up scheduling, and inclusion in clinical trials.     

High expression of karyopherin-α2 defines poor prognosis in non-muscle-invasive bladder cancer and in patients with invasive bladder cancer undergoing radical cystectomy

Background

Conventional clinicopathologic risk factors have failed to accurately predict the prognosis of patients with bladder cancer (BC).

Objective

To evaluate karyopherin-α2 (KPNA2) expression as a progression marker in patients with non–muscle-invasive BC (NMIBC) treated by conservative methods and as a prognostic marker in patients with invasive BC undergoing radical cystectomy (RC).

Design, setting, and participants

Two different tissue microarrays were constructed, one with 234 primary Ta/T1 tumours from patients treated by transurethral resection of the bladder and one with 377 tumours from RC patients.

Intervention

KPNA2 expression based on immunohistochemistry.

Measurements

Risk of progression of Ta/T1 patients to muscle-invasive BC was estimated in clinical follow-up to progression or a minimum of 53 mo. Risk of recurrent disease and death following RC was estimated in clinical follow-up of a minimum of 24 mo in patients alive.

Results and limitations

A high KPNA2 expression in Ta/T1 patients was significantly correlated with a higher risk of progression that was independent of conventional risk factors in multivariate analysis. In patients undergoing RC, a high KPNA2 expression was an independent predictor of poor prognosis. A high KPNA2 expression was correlated with a higher risk of visceral metastasis rather than lymphatic spread.

Conclusions

KPNA2 expression is a marker for progression of NMIBC and a prognostic marker in patients undergoing RC.     

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.     

Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience

Background

Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown.

Objective

Report long-term outcomes of patients with muscle-invasive BCa treated by CMT.

Design, setting, and participants

We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2–4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr.

Interventions

Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC—60 for less than CR and 42 for recurrent invasive tumors.

Measurements

Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method.

Results and limitations

Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2 = 74%, 67%, and 63%; T3–4 = 53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3–4 = 41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p < 0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity.

Conclusions

CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients.     

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.     

Clinical Outcome in a Contemporary Series of Restaged Patients with Clinical T1 Bladder Cancer

Objectives

To evaluate the indications for early and deferred cystectomy and to report the impact of this tailored approach on survival.

Design, setting, and participants

We retrospectively studied 523 patients seen at our institution who were initially diagnosed with T1 disease between 1990 and 2007.

Measurements

Variables analyzed included age, gender, multifocality, multifocal T1 disease, carcinoma in situ, grade, recurrence rate, and restaging status. End points were overall and disease-specific survival.

Results and limitations

A restaging transurethral resection (TUR) was performed in 523 patients. Of the patients who underwent restaging, 106 (20%) were upstaged to muscle-invasive disease and 417 patients were considered true clinical T1 (cT1); 84 of the latter group underwent immediate cystectomy. The median follow-up for survivors was 4.3 yr. The cumulative incidence of disease-specific death at 5 yr was 8% (95% confidence interval [CI], 5–13%), 10% (95% CI, 5–17%), and 44% (95% CI, 35–56%) for those restaged with lower than T1, T1, and T2 disease, respectively. Immediate cystectomy was more likely in patients with cT1 disease at restaging than in those with disease lower than cT1, but there were no other obvious differences in clinical characteristics between those with and without immediate cystectomy. Survival was not statistically different for patients who underwent an immediate cystectomy versus those who were maintained on surveillance with deferred cystectomy if deemed appropriate. Of 333 patients who did not undergo immediate cystectomy, 59 had a deferred cystectomy, and the likelihood of deferred cystectomy was greater in those with T1 disease on restaging TUR (hazard ratio: 2.40; 95% CI, 1.43–4.01; p = 0.001).

Conclusions

Restaging TUR should be performed in patients diagnosed with cT1 bladder cancer to improve staging accuracy. Patients with T1 disease on restaging are at higher risk of progression and should be considered for early cystectomy.     

Comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder

Background

Comorbidity and performance indices allow assessment of preoperative health status. However, the optimal tool for use in patients with urothelial carcinoma of the bladder (UCB) who are undergoing radical cystectomy (RC) has not yet been established.

Objective

To evaluate correlation of Adult Comorbidity Evaluation-27 (ACE27), Charlson Comorbidity Index, Age-Adjusted Charlson Comorbidity Index, Eastern Cooperative Oncology Group performance status, and American Society of Anesthesiologists (ASA) score with survival.

Design, setting, and participants

A retrospective multicenter study was carried out on 555 unselected consecutive patients who underwent RC for UCB from 2000 to 2010.

Intervention

RC with pelvic lymph node dissection in patients with UCB without neoadjuvant chemotherapy.

Outcome measurements and statistical analysis

Cox regression models were calculated with established variables to assess predictive capacity for cancer-specific mortality (CSM) and cancer-independent mortality (CIM).

Results and limitations

All indices were independent predictors for CIM but not for CSM. The ASA score was the only index that significantly increased the predictive accuracy of the predefined CIM model (+2.3%; p = 0.045). To create a clinically valuable tool, we devised a weighted prognostic model including age and the best prognosticators within the performance and comorbidity scores (ASA/ACE27 0–1/2–3). A 3-yr CIM rate of 8%, 26%, and 47% was calculated for the low-, intermediate-, and high-risk groups, respectively. Patients >75 yr of age with ASA 3/4 and ACE27 >1 exhibited a CIM risk seven times greater than patients ≤75 yr with ASA 1/2 and ACE27 0/1. This study is limited by the short follow-up and its retrospective nature.

Conclusions

Comorbidity and performance assessment is mandatory in the preoperative prediction of CIM for patients undergoing RC for UCB. The present results indicate that the ASA score is the tool of choice. External and prospective validation is warranted.     

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.     

Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients

Background

The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.

Objective

To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).

Design, setting, and participants

Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.

Outcome measurements and statistical analysis

Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).

Results and limitations

Female patients were older at the time of RC (p = 0.033) and had higher rates of pathologic stage T3/T4 disease (p < 0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p = 0.022 and p = 0.11, respectively). Female gender was an independent predictor for CSM (p = 0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).

Conclusions

We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.     

Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study

Background

Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB).

Objective

Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB.

Design, setting, and participants

Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization.

Intervention

Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy.

Measurements

Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis.

Results and limitations

CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1–100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size.

Conclusions

Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials.     

Lymphadenectomy for Bladder Cancer at the Time of Radical Cystectomy

Context

Although the importance of lymphadenectomy during radical cystectomy (RC) in high-risk non–muscle-invasive and muscle-invasive bladder cancer (BCa) is well accepted, the optimal extent of lymphadenectomy, number of lymph nodes (LNs) to be retrieved, and prognostic and therapeutic role of lymphadenectomy remain debated issues.

Objective

In this review, we summarize the existing data on the value of lymphadenectomy for staging and outcome of BCa patients undergoing RC and lymphadenectomy.

Evidence acquisition

A systematic Medline/PubMed literature search of peer-reviewed scientific articles published from 1998 and 2012, concerning the role of lymphadenectomy in BCa patients, was carried out. The terms and permutations used were lymphadenectomy, bladder cancer/carcinoma, urothelial carcinomas, radical cystectomy, lymph node metastasis, lymph node dissection, bladder, recurrence, and survival. Selective older articles were included.

Evidence synthesis

Bilateral pelvic lymphadenectomy is an integral part of RC for BCa. The literature regarding the role of lymphadenectomy in BCa patients in general is retrospective, nonstandardized, and of low-level quality in regard to evidence. Prospective randomized trials designed to define the optimal template of lymphadenectomy and its impact on oncologic outcome are advocated. Some of these studies are ongoing, and their completion and analyses are necessary to resolve controversies.

Conclusions

Many consistent and concordant observations, although of low level of evidence, document that the extent of lymphadenectomy may influence disease-free survival after RC independent of the status of LNs and the pathologic stage of BCa. Lymphadenectomy standardization at the time of RC to create evidence-based guidelines is essential for further improvement of surgical quality and BCa patient survival.     

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.     

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.     

An Updated Critical Analysis of the Treatment Strategy for Newly Diagnosed High-grade T1 (Previously T1G3) Bladder Cancer

Context

High-grade T1 (formerly T1G3) bladder cancer (BCa) has a high propensity to recur and progress. As a result, decisions pertaining to its treatment are difficult. Treatment with bacillus Calmette-Guérin (BCG) risks progression and metastases but may preserve the bladder. Cystectomy may offer the best opportunity for cure but is associated with morbidity and a risk of mortality, and it may constitute potential overtreatment for many cases of T1G3 tumours. For purposes of this review, we continue to refer to high-grade T1 lesions as “T1G3.”

Objective

To review the current literature on the management of T1G3 BCa and to provide recommendations for its treatment.

Evidence acquisition

A National Center for Biotechnology Information (NCBI) PubMed search for relevant articles published between 1996 and 9 January 2009 was performed using the Medical Subject Headings “T1G3” or “T1” and “Bladder cancer.” Articles relevant to the treatment of T1G3 BCa were retained.

Evidence synthesis

The diagnosis of T1G3 disease is difficult because pathologic staging is often unreliable and because of the risk of significant understaging at initial transurethral resection (TUR) of bladder tumour. A secondary restaging TUR is recommended for all cases of T1G3. A single dose of immediate post-TUR chemotherapy is recommended. For a bladder-sparing approach, intravesical BCG should be given as induction with maintenance dosing. Immediate or early radical cystectomy (RC) should be offered to all patients with recurrent or multifocal T1G3 disease, those who are at high risk of progression, and those failing BCG treatment.

Conclusions

Both bladder preservation and RC are appropriate options for T1G3 BCa. Risk stratification of patients based on pathologic features at initial TUR or at recurrence can select those most appropriate for bladder preservation compared to those for whom cystectomy should be strongly considered.     

Validation of the AJCC TNM Substaging of pT2 Bladder Cancer: Deep Muscle Invasion Is Associated with Significantly Worse Outcome

Background

The current TNM bladder cancer staging system stratifies bladder muscle invasion into superficial (pT2a) and deep (pT2b). Controversy exists regarding the significance of the extent of muscle invasion on clinical outcome.

Objective

Our aim was to compare the cancer-specific outcomes of patients with pT2 urothelial carcinoma of the bladder (UCB) at radical cystectomy (RC) in a large international cohort of patients.

Design, setting, and participants

The records of patients treated with RC for UCB at six centers were reviewed. Of the 2605 reviewed patients, 565 (21.7%) had pT2 disease. None of the patients received preoperative systemic chemotherapy or radiotherapy.

Measurements

Patients’ characteristics and outcome were evaluated.

Results and limitations

The median patient age in the entire group was 66.2 yr. Of the 565 patients with pT2 UCB, 249 patients (44.1%) had substage pT2a; 316 patients (55.9%) had pT2b. One hundred and eleven patients (19.6%) had metastases to regional lymph nodes. Median follow-up was 50.5 mo. Recurrence-free survival (73.2% vs 58.7%) and cancer-specific survival (78.0% vs 65.1%) estimates were significantly better for pT2a patients compared with those with pT2b (p = 0.002 and p = 0.001, respectively). Pathologic T2 substaging was associated with worse recurrence-free and cancer-specific survival after adjusting for the effects of standard pathologic features (p = 0.011 and p = 0.006, respectively). The statistical significance of these associations was reconfirmed in subgroup analysis limited to those patients with pathologically negative lymph nodes.

Conclusions

In this large international cohort, pathologic substaging helped to stratify patients with lymph node–negative pT2 UCB into statistically significantly different risk groups. These data support the value of the current American Joint Committee on Cancer TNM staging.     

Pretreatment Neutrophil-to-Lymphocyte Ratio Is Associated with Advanced Pathologic Tumor Stage and Increased Cancer-specific Mortality Among Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

Background

Pretreatment neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been associated with adverse survival in a variety of malignancies. However, the relationship between NLR and oncologic outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) has not been well studied.

Objective

To evaluate the association of preoperative NLR with clinicopathologic outcomes following RC.

Design, setting, and participants

We identified 899 patients who underwent RC without neoadjuvant therapy at our institution between 1994 and 2005 and who had a pretreatment NLR.

Outcome measurements and statistical analysis

Preoperative NLR (within 90 d prior to RC) was recorded. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazard and logistic regression models were used to analyze the association of NLR with clinicopathologic outcomes.

Results and limitations

Median postoperative follow-up was 10.9 yr (interquartile range: 8.3–13.9 yr). Higher preoperative NLR was associated with significantly increased risks of pathologic, extravesical tumor extension (odds ratio [OR]: 1.07; p = 0.03) and lymph node involvement (OR: 1.09; p = 0.02). Univariately, 10-yr cancer-specific survival was significantly worse among patients with a preoperative NLR (≥2.7 [51%] vs <2.7 [64%]; p < 0.001). Moreover, on multivariate analysis, increased preoperative NLR was independently associated with greater risks of disease recurrence (hazard ratio [HR]: 1.04; p = 0.02), death from bladder cancer (HR: 1.04; p = 0.01), and all-cause mortality (HR: 1.03; p = 0.01).

Conclusions

Elevated preoperative NLR among patients undergoing RC is associated with significantly increased risk for locally advanced disease as well as subsequent disease recurrence, and cancer-specific and all-cause mortality. These data suggest that serum NLR may be a useful prognostic marker for preoperative patient risk stratification, including consideration for neoadjuvant therapy and clinical trial enrollment.     

Laparoscopic Radical Cystectomy with Orthotopic Ileal Neobladder for Bladder Cancer: Oncologic Results of 171 Cases With a Median 3-Year Follow-up

Background

Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard treatment for muscle-invasive and high-risk non–muscle-invasive bladder cancer (BCa). Large series with long-term oncologic data after laparoscopic RC (LRC) are rare.

Objective

To report oncologic outcomes of LRC for 171 cases with a median 3-yr follow-up.

Design, setting, and participants

From December 2002 to June 2009, 171 consecutive patients with BCa who underwent LRC with orthotopic ileal neobladder (OIN) at our institution were enrolled in this retrospective study.

Intervention

All patients underwent LRC OIN. Adjuvant chemotherapy was administered to patients with non–organ-confined disease or positive lymph nodes.

Measurements

The demographic, perioperative, complication, pathologic, and survival data were collected and analysed.

Results and limitations

Most tumours were transitional cell carcinoma (TCC; 160, 93.6%). Tumours were organ confined in 113 patients (pT1–T2; 66.1%) and non–organ confined in 58 patients (pT3–T4a; 33.9%). There was involvement of the lymph nodes in 38 patients (22.2%). Surgical margins were all tumour free. The mean number of removed lymph nodes was 16 (5–46). Follow-up ranged from 3 to 83 mo, and 54 (31.6%) patients completed 5-yr follow-up. Two patients (1.2%) had local recurrence and distant metastasis, 9 patients (5.3%) had local recurrence alone, and 23 patients (13.5%) had distant metastasis. One patient (0.6%) had port-site seeding. One hundred twenty-four patients (72.5%) were alive with no evidence of recurrence; 28 patients (16.4%) died, 20 from metastasis and 8 from tumour-unrelated causes. The estimated 5-yr overall survival, cancer-specific survival, and recurrence-free survival rates were 73.7%, 81.3%, and 72.6%, respectively. The relatively low percentage of patients reaching 5-yr follow-up is a limitation of this retrospective study.

Conclusions

Surgical technique of LRC with OIN can achieve the established oncologic criteria of open surgery, and our oncologic outcome is encouraging. Long-term follow-up is needed for further confirmation.     

Bladder Preservation in Selected Patients with Muscle-Invasive Bladder Cancer by Complete Transurethral Resection of the Bladder Plus Systemic Chemotherapy: Long-Term Follow-up of a Phase 2 Nonrandomized Comparative Trial with Radical Cystectomy

Background

Many phase 2 bladder-sparing programmes using transurethral resection of the bladder (TURB) plus chemotherapy or radio-chemotherapy have been undertaken, but some controversies remain.

Objective

To determine the efficacy of complete TURB plus three cycles of cisplatin-based chemotherapy in selected patients with muscle-invasive bladder cancer (MIBC).

Design, setting, and participants

A phase 2 nonrandomized trial was designed that included patients with MIBC who underwent complete TURB with positive biopsies of the tumour bed. Patients with negative biopsies of the tumour bed, with macroscopically residual tumour, with hydronephrosis, or with distant metastasis were excluded from this trial. Patients included in this trial were offered three cycles of systemic chemotherapy or radical cystectomy (RC). Clinical response (cR) was denoted by either no tumour or the presence of Ta1–Tis bladder tumour at 3-mo evaluation; clinical non-response (cNR) was denoted by cases of muscle-invasive tumour or distant metastasis. Of 146 patients who entered this trial, 75 choose the bladder-sparing programme and 71 chose RC.

Measurements

At 5 yr and 10 yr, the cancer-specific survival (CSS) rate was 64.5% and 59.8%, respectively, with no significant difference compared to the RC arm (p = 0.544). The progression-free survival with bladder preserved was 52.6% and 34.5%, respectively. In multivariate analysis, cR was the only predictive factor for survival (p = 0.001) and bladder preservation (p = 0.000).

Results and limitations

This was not a randomized trial, and patients were included over 16 yr. However, no modifications were made to the therapy schedule except from chemotherapy schemes considered standard at the time.

Conclusions

Patients with microscopic residual cancer after complete TURB seem to be good candidates for the bladder-sparing programme using three cycles of systemic chemotherapy, with CSS comparable to RC.