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Prof Arnulf Stenzl, MD
Chairman of the European Association of Urology (EAU) Guideline Panel for Muscle-invasive and Metastatic Bladder Cancer
Department of Urology, University Hospital Tübingen, Germany
Georgios Gakis, MD
Department of Urology, University Hospital Tübingen, Germany
Nigel C Cowan, MD
Department of Radiology, The Churchill Hospital, Oxford, UK
Maria De Santis, MD
3rd Medical Department and ACR-ITR/CEADDP and LBI-ACR Vienna-CTO, Kaiser Franz Josef Spital, Vienna, Austria
Markus Kuczyk, MD
Department of Urology and Urologic Oncology, Hannover Medical School (MHH), Hannover, Germany
Axel S Merserburger, MD
Department of Urology and Urologic Oncology, Hannover Medical School (MHH), Hannover, Germany
Maria J Ribal, MD
Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain
Amir Sherif, MD
Department of Urology, Karolinska University Hospital, Stockholm, Sweden
Alfred J Witjes, MD
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
In 2010, the European Association of Urology (EAU) updated its guidelines on the treatment of muscle-invasive and metastatic bladder cancer based on the available clinical evidence in order to guide clinicians in treatment decision-making and improving outcomes.
The recommendations given are graded according to the type of clinical evidence (see Table 1 and Table 2) obtained from extensive literature search, including large database platforms such as the Cochrane Libraries, Medline, Scottish Intercollegiate Guidelines Network (SIGN), Modified McMaster/Health Information Research Unit (HIRU), OVID and Embase.
The first EAU guidelines in this area were published in 2000, covering recommendations on both non-muscle invasive and muscle-invasive bladder cancer (MIBC). As a consequence of growing evidence in the field of bladder cancer, both issues were split up, which led to the first guideline on MIBC in 2004 and subsequent revisions in 2007 and 20091 and with an updated version in 2010.
This review will particularly focus on treatment recommendations of the 2010 guidelines for MIBC and metastatic bladder cancer based on the current evidence, including the role of radical cystectomy, neoadjuvant and adjuvant strategies as well as bladder-sparing modalities.
The role of neoadjuvant modalities in MIBC
Neoadjuvant chemotherapy
Radical cystectomy (RC) is the treatment of choice for patients with MIBC with cancer-specific survival rates ranging between 50% and 60%.2 Therefore, the use of neoadjuvant cisplatin-containing chemotherapy has been investigated in different prospective randomised trials and meta-analyses which suggest an increase in overall survival by 5–7% at five years (Level 1a).3,4
The rationale of providing neoadjuvant chemotherapy to patients with MIBC at the earliest time-point is that the micrometastatic burden is expected to be low at that stage. By contrast to the adjuvant setting, the in-vivo chemosensitivity can be assessed and toxic side-effects are expected to be less pronounced than after radical surgery with urinary diversion.
When considering a neoadjuvant approach in cystectomy candidates, possible disadvantages have to be borne in mind. Clinical staging errors can result in overtreatment, since current staging modalities with computed tomography (CT) or magnetic resonance imaging (MRI) show accuracy rates of only 70% (Level 3).
In addition, a delay of radical cystectomy more than 12 weeks in patients with MIBC is associated with a significantly reduced cancer-specific survival (Level 3).5 Therefore, the number of treatment cycles given with continuous evaluation of treatment response is crucial to identify timely those patients who will only profit from radical surgery.
According to the current 2010 guideline, neoadjuvant cisplatin-containing combination chemotherapy should be considered in MIBC, independently of definitive treatment (Grade A). With regard to patient selection, the neoadjuvant approach should not be offered to those with an Eastern Co-operative Oncology Group (ECOG) Performance Status of ≥2 or impaired renal function (Grade B).
Neoadjuvant radiotherapy
There is substantial evidence for the role of neoadjuvant radiotherapy in MIBC based on five randomised prospective trials and one resulting meta-analysis (Level 1a). While pre-operative radiotherapy in localised MIBC using cumulative doses between 45 and 50Gy fractionated in single doses of 1.8Gy–2Gy resulted in tumour downstaging after 4–6 weeks with no reported increase in toxicity, none of these studies was able to demonstrate significant improvement in overall survival compared to radical cystectomy alone.
Moreover, some of these analyses were hampered by the exclusion of a significant proportion of patients who did not obtain the intended treatment, different radiotherapeutic schedules and relatively small patient collectives. In spite of the positive effects on tumour downstaging, there is currently no evident overall survival benefit of neoadjuvant radiotherapy in localised T2-T4a MIBC (Grade A).
Indication, techniques and extent of radical cystectomy
RC is the gold standard treatment in patients with MIBC, including the removal of the bladder, prostate and seminal vesicles in men and bladder, uterus and adnexa in women. Female patients undergoing cystectomy for bladder cancer have a worse prognosis regarding outcome compared to male patients.6
RC with curative intent is indicated in patients with localised disease (T2-T4a, N0-NX and M0). Further indications for RC are bladder cancer that is bacillus Calmette-Guerin treatment-resistant, high-risk and non-muscle invasive (Tis, T1) and extensive papillary disease (Ta) that is not amenable to transurethral resection (Grade B, see Figure 1).
Salvage cystectomy is optional in patients in whom conservative treatment has failed, but also in patients with recurrence after bladder-sparing treatment or in non-urothelial carcinomas which are generally characterised by poor chemo- and radio-sensitivity. Patients with abdominal or pelvic wall infiltration (T4b) at preoperative staging can be offered palliative cystectomy to prevent local complications i.e. pain, fistulae and gross hematuria (Grade B).
The expertise of the treating surgeon has been demonstrated to be associated with the rate of postoperative morbidity and mortality in cystectomy patients. Even in experienced hands, the rate of ‘major’ perioperative complications is approximately 25%.7
To improve functional outcomes in terms of continence and potency in male patients, different techniques of prostate-sparing cystectomy have been described. In a highly-selected, small patient collective, there was a low risk of tumour progression after sparing the seminal vesicles and the prostatic capsule, while postoperative potency rate remained high.8
Despite this, a considerable range of prevalence (23–54%) of prostate cancer found incidentally in cystoprostatectomy specimens has been reported.9,10 Almost a quarter of these prostate cancers represent clinically significant ones, according to the Epstein criteria.11 With regard to the lack of sufficient long-term data, a prostate-sparing approach aiming to reduce functional impairments of conventional RC has still to be considered investigational.
RC should also be accompanied by bilateral pelvic lymphadenectomy (Grade B). However, the extent of lymphadenectomy has been addressed only in retrospective studies. In these studies, a threshold number of 16 pelvic lymph nodes was useful for diagnostic purposes, but also associated with improved overall survival (Level 3). However, the main reasons why clear recommendations on the extent of pelvic lymphadenectromy cannot yet be given are:
- Interindividual differences in the number of lymph nodes found with a uniform lymphadenectomy template12
- Lack of standardisation with regard to the pathologic processing of the lymphatic tissue.
There is some evidence which suggests that extending the template of lymphadenectomy at least up to the crossing of the ureters with the common iliac arteries improves overall survival.13 In this respect, the results of prospective randomised trial, entitled the German AUO 25/02 study, evaluating outcomes after limited versus extended pelvic lymphadenectomy are keenly awaited.
In the last year, several studies have demonstrated the feasibility of performing laparoscopic or robotic-assisted laparoscopic RC according to principles of open surgery in a relatively small series, both in male and female patients.14 In many of these studies, urinary diversion was performed extracorporeally. Nevertheless, in the absence of oncological and functional long-term data, and because of possible biases associated with patient selection and unproven advantages in terms of reduced perioperative complications, these techniques have still to be considered as experimental (Grade C).
For urinary diversion, orthotopic neobladder substitution using the terminal ileum is the diversion of choice and should be offered to both male and female patients, if urethral margins are negative at intra-operative frozen section analysis.15 Furthermore, patients should lack any of the following contra-indications:
- Glomerular filtration rate <60ml/min
- High-dose preoperative local radiation therapy
- Complex urethral strictures
- Severe sphincter-related incontinence
- Severely reduced life expectancy
- Physical and mental impairments which would preclude the patient’s ability to catheterise the pouch in case of urinary retention (Grade B).
Alternative diversions include different forms of non-continent and continent urinary diversion such as the ileum-conduit, ureterocutaneostomy, continent cutaneous reservoirs and ureterosigmoidostomy with interposition of an ileal segment to avoid direct contact of faeces and urine, without which there is an increased risk of developing colon cancer in the long term.
Bladder-sparing multimodality treatment in MIBC
In the current 2010 guideline, the combination of transurethral bladder resection, chemotherapy and external beam radiation therapy in MIBC has been advocated as an alternative organ-preserving option in selected, well-informed and highly compliant patients who are either not eligible for RC due to their comorbidities or refuse radical cystectomy for personal reasons (Grade B). With a trimodality treatment, long-term survival rates similar to those of cystectomy series have been described (Level 3).
Nevertheless, both therapeutic options have not been compared in prospective trials so far and patients included in multimodality approaches are highly selected.
As a categorical prerequisite, multimodal strategies in MIBC require close interdisciplinary co-operation, long-life surveillance and a high patient compliance. A pT0 status at transurethral resection of the bladder (TURB) at the time of initiation of multimodal therapy has been shown to be of utmost prognostic importance.
Notwithstanding, it has to be kept in mind that the bladder still remains a potential source of recurrence.
Moreover, in patients with chemo- and radio-insensitive tumours, a delay of RC increases the risk of lymph node tumour involvement at RC performed to a later time-point and, thus, might compromise survival outcomes. In this respect, it has to be pointed out that any of the three modalities is not recommended as a single therapy in localised MIBC, since its oncological efficacy has been shown to be inferior to that of RC alone (Grade B).
Adjuvant chemotherapy
The use of adjuvant cisplatin-based chemotherapy was intended to reduce the burden of micrometastatic disease in patients with locally advanced bladder cancer.
Possible benefits of the adjuvant approach are that chemotherapy is administered after exact pathological staging, thereby avoiding the risk of overtreatment and delay of radical surgery especially in those patients with chemoresistant bladder cancers.
The administration of adjuvant chemotherapy in patients with locally advanced disease (pT3/4 and/or lymph node positive disease) without evidence of clinically detectable metastastes has been addressed in five randomised trials and one meta-analysis. Owing to serious statistical deficiencies and methodological flaws, there is currently no compelling evidence in favour of adjuvant treatment in locally advanced disease (Level 1a).
Therefore, given the scarce data available, patients with locally advanced disease who are eligible for cisplatin-based chemotherapy (ECOG performance status ≤1 and glomerular filtration rate ≥60ml/min) should be included in prospective randomised trials (Grade A). Patients ‘unfit’ for cisplatin-containing chemotherapy should not be offered adjuvant chemotherapy, since there is a lack of evidence for the efficacy of carboplatin-based chemotherapy.
Treatment options in metastatic bladder cancer
Approximately 15% of patients present with metastatic disease at primary diagnosis. Moreover, 40-50% of the patients with localised MIBC undergoing radical surgery will relapse after a median time of 12 to 18 months.2 Since urothelial cancer is chemosensitive, various regimens have been evaluated in prospective trials. Important independent prognostic factors (so-called ‘Bajorin criteria’) for the response to chemotherapy include a Karnofsky performance status ≥80% and the abscence of visceral metastases (Level 3). These criteria can be used for treatment selection (Grade B). By contrast, age as an independent prognostic parameter has not been associated with response to chemotherapy or chemotherapy-related toxicity.
Cisplatin-based chemotherapy is the first-line treatment option in patients with good performance status and renal function (ECOG≤1 and GFR≥60ml/min; Level 1a, Grade A) demonstrating improved survival (median 14 months) compared to best supportive care (median: 3–6 months) with up to 20% of the patients achieving long-term survival.
Two different cisplatin-based regimens have been evaluated in a prospective, randomised trial using the methotrexat/vinblastine/adramycine/cisplatin (MVAC) and gemcitabine/cisplatin (GC) scheme. Response rates were similar for both regimes with 46% in the GC and 49% in the MVAC arm, respectively. However, toxicity was significantly less common in the GC arm.
Carboplatin-based chemotherapy or single agent chemotherapy (i.e. gemcitabine) is less effective in terms of complete response and overall survival and it should only be considered as a first-line treatment in those patients unfit for cisplatin-containing chemotherapy. Nevertheless, it has to be pointed out that a standard chemotherapeutic regimen in patients ‘unfit’ for cisplatin-based chemotherapy has not been established so far (Grade C).
Different regimens have been evaluated for second-line treatment using single- or multi-agent protocols containing gemcitabine, docetaxel, oxaliplatin, ifosfamide, topotecan, lapatinib, gefitinib and bortezomib. Unfortunately, there is only one phase III, prospective, randomised, controlled trial with vinflunine, a novel third-generation vinca alkaloid (Level 1b).
After failure of platinum-based chemotherapy, vinflunine has shown an overall response rate of 8.6% with a marginal but significant improvement in overall survival of approximately three months compared to best supportive care in the eligible patient population but not in the intention-to-treat population. This fact weakens the general recommendation for an unequivocal use of vinflunine in the second-line setting. In patients with osseous metastatic disease the use of bisphosphonates has been demonstrated to reduce the rate of skeletal-related events (Level 1b, Grade A).
There is some evidence that post-chemotherapeutic surgery after partial response may contribute to long-term survival in selected patients. Yet, the data available derive from retrospective analyses with relatively small patient collectives.
Summary
The updated guidelines of the European Association of Urology on muscle-invasive and metastatic bladder cancer provide detailed insights into treatment recommendations based on the type of evidence available in current literature.16 Radical cystectomy still remains the mainstay of treatment in localised MIBC and neoadjuvant chemotherapy has shown promising results to further improve survival outcomes.
Large retrospective studies suggest a curative benefit of an extended pelvic lymphadenectomy approach in MIBC but its significance has still to be confirmed in a prospective setting.
Female patients undergoing cystectomy for bladder cancer have a worse prognosis regarding outcome compared to male patients.
A multimodal, bladder-sparing approach is only recommendable in patients unfit for radical surgery or in well-informed, highly-compliant patients who refuse cystectomy for personal reasons. Since, in these patients, the bladder remains a potential source of recurrence and progression, a close follow-up is mandatory to timely detect those patients who might still profit from early radical surgery.
Adjuvant chemotherapy has not been able so far to demonstrate a beneficial outcome in patients with locally advanced non-metastasised bladder cancer and therefore should only be offered in prospective clinical trials.
In metastatic disease, cisplatin-based chemotherapy is the standard of care in the first-line treatment for patients with Karnofsky performance status ≥80% and a GFR of ≥60ml/min. In the second-line treatment, vinflunine has reached the highest level of evidence ever reported. Moreover, the administration of bisphosphonates reduces the risk of skeletal-related events in patients with osseous metastatic disease.
Emerging evidence from ongoing prospective randomised clinical trials will address current equivocal issues in the management of patients with muscle-invasive and metastatic bladder cancer and further improve the recommendations given within the next years.
References
- Stenzl A et al. Eur Urol 2009;55:815-25.
- Stein JP et al. J Clin Oncol 2001;19:666-75.
- Grossman HB et al. N Engl J Med 2003;349:859-66.
- Advanced Bladder Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: Eur Urol 2005;48:202-5.
- Chang SS et al. J Urol 2003;170:1085-7.
- Stenzl A. Eur Urol 2010;57:729.
- Hautmann RE et al. J Urol 2010;184:990-4.
- Ong CH et al. J Urol 2010;183:1337-41.
- Pettus JA et al. Eur Urol 2008;53:370-5.
- Revelo MP et al. J Urol 2004;171:646-51.
- Gakis G et al. BJU Int 2010;105:468-71.
- Dhar NB et al. J Urol 2008;179:873-8.
- Dangle PP et al. J Urol 2010;183:499-503.
- Ng CK et al. Eur Urol 2010;57:274-81.
- Stenzl A et al. Cancer 2001;92:1864-71.
- http://www.uroweb.org/guidelines/online-guidelines/
