5.1. The role of chemotherapy in treatment of organ confined muscle-invasive bladder cancer

If the bladder cancer has invaded the muscle of the bladder wall, then there is a very high risk that the patient will die of bladder cancer unless radical treatment with either radical cystectomy or radical radiotherapy is done. Although radical cystectomy or radical radiotherapy offers the best chance of cure, unfortunately up to half of these people still go on to die of bladder cancer. This is usually due to the cancer returning in the region of the bladder, existing unsuspected spread to lymph nodes or, more typically, recurrence in other parts of the body such as the lymph nodes, lungs, liver or bones. For many cancers this risk of relapse can be reduced or delayed by giving chemotherapy before and/or after surgery or radical radiotherapy. However, these treatments are associated with significant side effects. These side effects may be more problematic in people with other illnesses or people who are generally less fit.

5.1.1. Neoadjuvant chemotherapy

Neoadjuvant chemotherapy is given before surgery or radical radiotherapy. It is believed that neoadjuvant chemotherapy may act by eradicating unrecognised micro-metastatic disease. There are two commonly used regimens but there is uncertainty over which is the most clinically effective. There is no consensus on which patients would benefit most from neoadjuvant chemotherapy.

Clinical question: Which patients with bladder cancer should be offered neoadjuvant chemotherapy?

Clinical evidence (see also full evidence review)

Evidence is summarised in table 81.

Table 81

GRADE evidence profile: Which patients with bladder cancer should be offered neoadjuvant chemotherapy?

Evidence statements

One systematic review and meta-analysis of individual patient data (3,005 patients from 11 randomised trials) was identified (Advanced Bladder Cancer Meta-Analysis Collaboration (ABC), 2004). No other randomised trials were identified. High quality evidence about overall survival came from 10 trials with a total of 2,809 patients. There was no clear evidence of statistical heterogeneity (p=0.47) or inconsistency between trials (I²=0%). All trials were reported to have adequate allocation concealment at randomisation. The pooled hazard ratio (HR) of 0.89 (95% CI 0.81 to 0.98) for these trials represents an 11% relative reduction in the risk of death associated with neoadjuvant chemotherapy. This is equivalent to an absolute improvement of 4% at five years (95% CI 0% to 7%), increasing overall survival from 45% to 49%.

When trials were grouped by chemotherapy type there was uncertainty about the effect of single-agent cisplatin on overall survival, as the 95% confidence interval of the effect estimate included the null value (HR 1.15, 95% CI 0.90 to 1.47). The pooled HR for trials using combination chemotherapy was 0.86 (95% CI 0.77 to 0.95), equivalent to a 14% relative reduction in the risk of death with neoadjuvant chemotherapy; an absolute benefit of 5% at five years (95% CI 2% to 9%), improving survival from 45% to 50%.

The trials of combination chemotherapy were grouped by planned local treatment: cystectomy alone, radical radiotherapy alone, or combined radiotherapy and cystectomy. There was no evidence of a difference in the effect of chemotherapy in the three local treatment groups (interaction p=0.656).

10 trials including 2,486 patients and 1,847 events (1,606 (87%) recurrences and 241 (13%) deaths) provided high quality evidence on disease-free survival, with a HR of 0.81 (95% CI 0.74 to 0.89) in favour of neoadjuvant chemotherapy. When grouped by chemotherapy type, moderate quality evidence from two trials showed no statistically significant effect of single-agent cisplatin on disease-free survival, as the 95% confidence intervals of the effect estimate included the null value (HR 1.14, 95% CI 0.83 to 1.55). The pooled HR for trials using combination chemotherapy was 0.78 (95% CI 0.71 to 0.86), equivalent to a 22% relative reduction in the risk of locoregional recurrence, metastases or death with neoadjuvant chemotherapy; an absolute disease-free survival benefit of 9% at five years (95% CI 5% to 12%).

For metastases-free survival, data from seven trials including 2,180 patients and 1,345 events were available. The numbers of events in each group were not provided in the systematic review. The pooled results for metastases-free survival shows a similar pattern to survival, both in terms of chemotherapy type and local treatment, with a significant benefit of platinum-based combination chemotherapy (HR 0.82, 95% CI 0.73 to 0.92); an absolute metastases-free survival benefit of 7% (95% CI 3% to 11%).

The systematic review states that there was insufficient data to formally investigate toxicity or health-related quality of life in these trials. However, where it was reported in the publications, the most common chemotherapy-related toxicities included nausea and vomiting, haematological toxicities, and impaired renal function.

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.

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Recommendations	Offer neoadjuvant chemotherapy using a cisplatin combination regimen before radical cystectomy or radical radiotherapy to people with newly diagnosed muscle-invasive urothelial bladder cancer for whom cisplatin-based chemotherapy is suitable. Ensure that they have an opportunity to discuss the risks and benefits with an oncologist who treats bladder cancer.
Relative value placed on the outcomes considered	All outcomes from the PICO were considered important by the GDG. Overall survival and disease-free survival are the most reliable and important indicators of clinical benefit. Quality of life is important for the patient. Quality of life and treatment-related mortality were specified as outcomes in the PICO but were not reported in the evidence. No additional outcomes were used by the GDG to make recommendations.
Quality of the evidence	The quality of the evidence was moderate to high as assessed with GRADE. The evidence was limited by the outdated regimens that were used in the trials and there have since been improvements in radical therapy. The GDG considered that modern regimens are at least as effective as those in the trials. The benefits reported in the evidence should be seen as the minimum gain that modern day patients should expect. As the effects of neoadjuvant chemotherapy are on distant disease control it is unlikely that improvements in radical treatment would impact on this effect. A research recommendation was made because current subgroup definitions do not predict clinical benefits. The evidence presented suggests that the patient group as a whole benefits from neoadjuvant chemotherapy but the GDG recognised that it is likely that not all patients benefit equally. For instance, some data suggests that patients who attain a complete response to chemotherapy are most likely to have a survival benefit and non responders are unlikely to benefit. If the subgroups that did not benefit could be identified between treatment, intensive treatment with significant side effects could be avoided and definitive local treatment be administered immediately. Research to better target treatment could therefore improve treatment delivery and the patient experience.
Trade-off between clinical benefits and harms	The GDG weighed up the clinical benefits of improved clinical outcomes in patients with MIBC who are suitable for cisplatin-based chemotherapy against the harm of the toxicity of additional chemotherapy and prioritised the survival benefit. The GDG considered that increased survival outweighs short-term toxicity.
Trade-off between net health benefits and resource use	No health economic evidence was identified and no economic model was developed for this topic. The GDG considered the potential costs of the recommendation arise from the chemotherapy delivery and management of toxicity. The potential savings include cessation of best supportive care. Neoadjuvant chemotherapy will improve survival and is therefore likely to be cost-effective. The GDG considered that the QALY gain is likely to be sufficient to make the recommendation cost-effective
Other considerations	The GDG considered that there are no equalities issues as the recommendations would still consider those with hearing impairments for neoadjuvant chemotherapy. The GDG was unsure of the extent of change in practice required to implement the recommendation. Specialist and patient choice were considered in the recommendation. The GDG considered a ‘do not use’ recommendation regarding non-cisplatin based combination regimens, but there was insufficient evidence to make a specific recommendation.

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Research recommendation

In which people with muscle-invasive bladder cancer does neo-adjuvant chemotherapy improve outcomes?

Why is this important

Level 1 evidence shows that neoadjuvant chemotherapy produces a significant survival benefit for people with muscle invasive bladder cancer. The majority of this benefit is thought to accrue in those who have a major (particularly complete response) to chemotherapy. A small proportion of people may progress during chemotherapy have a poorer prognosis and may suffer a survival detriment by delay of definitive treatment. If the outcome of chemotherapy could be predicted by a pre-treatment ‘biomarker’ (in this context a biomarker could be, for example, a specific biological profile or change or by a certain imaging characteristic) then neoadjuvant chemotherapy could be directed at those with most to gain from it and alternative strategies defined for those likely to respond poorly, avoiding unnecessary toxicity and treatment delays. This could result in an overall improvement of outcomes.

5.1.2. Adjuvant chemotherapy

Chemotherapy after radical treatment (adjuvant chemotherapy) is not commonly used but is usually confined to people who have had radical cystectomy but who have not had neoadjuvant chemotherapy. In these people it is considered when the pathology findings from the radical cystectomy show invasion into the deep layers of muscle or beyond, involvement of lymph nodes, lymphovascular invasion or variant pathology.

A practical problem is that these people with a poor prognosis may not be suitable for chemotherapy because their recovery from radical cystectomy may be prolonged or may have been complicated.

There is uncertainty about which patients should be offered adjuvant chemotherapy and which regimens are most effective.

Clinical question: Which patients with bladder cancer should be offered adjuvant chemotherapy?

Clinical evidence (see also full evidence review)

The evidence is summarised in table 82.

Table 82

GRADE evidence profile: Which patients with bladder cancer should be offered adjuvant chemotherapy? ComparisonL Adjuvant chemotherapy + radical treatment verses radical treatment alone (or deferred chemotherapy)

Evidence statements

Overall survival

One systematic review and meta-analysis of nine randomised trials including 945 patients, reported a pooled hazard ratio (HR) for overall survival of 0.77 (95% CI 0.59 to 1.00) (Leow et al., 2014). The addition of data from 284 patients from the EORTC trial (Sternberg et al., 2014) provided a pooled HR of 0.77 (95% CI 0.62 to 0.96) in favour of adjuvant chemotherapy, equivalent to a 23% relative decrease in the risk of death with local treatment and adjuvant chemotherapy compared to local treatment alone (moderate quality evidence).

In an analysis of trials based on the type of chemotherapy used, the HR for one trial with only 45 events that used single-agent cisplatin was 1.02 (95% CI 0.57 to 1.84), suggesting uncertainty about the effect of adjuvant chemotherapy on overall survival. For the seven trials that used cisplatin-based combination chemotherapy, the pooled HR was 0.75 (95% CI 0.62 to 0.91), representing a 26% relative decrease in the risk of death on chemotherapy compared to that on control (moderate quality evidence). For two trials using gemcitabine-cisplatin combination chemotherapy the pooled HR was 0.71 (95% CI 0.21 to 2.35), with wide confidence intervals suggesting uncertainty about the effect of adjuvant chemotherapy on overall survival (low quality evidence).

Disease-free survival

A meta-analysis of nine trials including 1,106 patients provided an overall HR of 0.64 (95% CI 0.49 to 0.85), representing a 36% relative decrease in the risk of recurrence or death on chemotherapy compared to that on control. However, a moderate amount of between-trial heterogeneity or inconsistency was identified between the trials (p=0.007; I²=62%) (low quality evidence). For the six trials (690 patients) that used cisplatin-based combination chemotherapy the HR was 0.60 (95% CI 0.47 to 0.75), representing a 40% relative decrease in the risk of recurrence or death on chemotherapy compared to that on control (moderate quality evidence).

Metastases-free survival

Low quality evidence from the Advanced Bladder Cancer (ABC, 2006) meta-analysis reported that only two trials of 192 patients with 115 events provided data for metastases-free survival. This analysis was therefore extremely limited due to the low number of patients and was not presented.

Treatment-related morbidity

Treatment-related morbidity was not reported in the existing meta-analyses. Cognetti et al. (2012) provided low quality evidence on toxicities resulting from adjuvant gemcitabine and cisplatin therapy. Out of the 89 patients who received adjuvant chemotherapy 28.1% experienced grade three or four neutropenia, 14.6% experienced grade three or four thrombocytopenia, and 12.4% experienced grade three or four leukopenia. These were the most common toxicities reported. In the trial by Lehmann et al. (2006), three patients in the MVAC/MVEC chemotherapy arm had severe and recurrent vomiting. None of the patients had loss of renal function.

Treatment-related mortality

Treatment-related mortality was not reported in the existing meta-analyses. Cognetti et al. (2012) reported that there were no drug toxicity-related deaths. There was one death due to treatment toxicity in the immediate adjuvant chemotherapy arm in one trial (Sternberg et al., 2014).

Health-related quality of life

Quality of life was not reported in the existing meta-analyses. Cognetti et al. (2012) provided low quality evidence that global quality of life was similar for patients in both arms of the trial. In the adjuvant chemotherapy arm there was a slight worsening of general quality of life during the last two months of chemotherapy, which improved during follow-up and was then comparable to the control group (number of patients and mean values not reported).

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.

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Recommendations	Consider adjuvant cisplatin combination chemotherapy after radical cystectomy for people with a diagnosis of muscle-invasive or lymph-node-positive urothelial bladder cancer for whom neoadjuvant chemotherapy was not suitable (because muscle invasion was not shown on biopsies before cystectomy). Ensure that the person has an opportunity to discuss the risks and benefits with an oncologist who treats bladder cancer.
Relative value placed on the outcomes considered	All outcomes from the PICO were considered important by the GDG. Overall survival and disease-free survival are the most reliable and important indicators of clinical benefit. Quality of life is important for the patient. No additional outcomes were used by the GDG to make recommendations.
Quality of the evidence	The quality of the evidence was low to moderate as assessed with GRADE. The evidence was limited by the outdated regimens that were used in the trials and there have since been improvements in radical therapy. However, because there have been improvements in radical therapy since most of the trials were published, modern regimens are at least as effective as those used in the trials. The benefits reported in the evidence should be seen as the minimum gain that modern day patients should expect. There was heterogeneity in the meta-analysis and most trials had small patient numbers. Potential biases were highlighted in several studies as the trials closed prematurely. These issues and the quality of the evidence affected the strength of the recommendation that could be made. The GDG also considered the evidence on neoadjuvant chemotherapy . There was moderate quality evidence of improved survival with adjuvant cisplatin-based chemotherapy, so the GDG felt that there was enough evidence to make a ‘consider’ recommendation. The strong recommendation for neoadjuvant chemotherapy made in section 5.1.1 should ensure that all suitable patients receive neoadjuvant chemotherapy. However, the above recommendation was made because the GDG wanted to ensure that if neoadjuvant chemotherapy was not given, because muscle invasion was not shown on biopsies before cystectomy, that patients would receive adjuvant chemotherapy. No research recommendation was made. The GDG considered making a research recommendation but were aware of an adjuvant chemotherapy trial that closed early due to poor recruitment. It is possible that patients in this category could be included in the research recommendation made in section 5.1.1.
Trade-off between clinical benefits and harms	The GDG weighed up the clinical benefits of improved clinical outcomes in patients with MIBC who are suitable for cisplatin-based chemotherapy against the harm of the toxicity of additional chemotherapy. The GDG considered that increased survival outweighs short-term toxicity.
Trade-off between net health benefits and resource use	No health economic evidence was identified and no economic model was developed for this topic. The GDG considered the potential costs of the recommendation arise from the chemotherapy delivery and management of toxicity. There may also be an increase in post-cystectomy oncology review. The potential savings include cessation of best supportive care. The GDG agreed that improved survival is likely to be cost-effective. The GDG considered that the QALY gain is likely to be sufficient to make the recommendation cost-effective
Other considerations	The GDG considered that there are no equalities issues as the recommendations would still consider those with hearing impairments for adjuvant chemotherapy. The GDG was unsure of the extent of change in practice required to implement the recommendation but acknowledged that there is likely to be an increase in the use of adjuvant chemotherapy. Consideration was given to patient choice. The GDG felt strongly that the focus should be on neoadjuvant chemotherapy and that adjuvant chemotherapy is not a suitable alternative. They recognised that there may be patients who are not eligible for neoadjuvant chemotherapy who may still benefit from adjuvant treatment.

5.2. Treatment of organ confined muscle-invasive bladder cancer

5.2.1. Radical cystectomy versus radical radiotherapy

In people with muscle invasive bladder cancer, either radical radiotherapy or radical cystectomy are almost always advised.

Radical cystectomy is major abdominal surgery with a long hospital stay, a high risk of post operative complication and long post operative recovery. Life changing consequences include a urostomy for many patients, a profound impact on sexual function and associated psychological consequences. Radical radiotherapy involves daily treatment over 4-6 weeks, and is associated with side effects including effects on bladder and bowel function, general debilitation and adverse impact on sexual function. In many countries at present, including the UK, there is a view that the chance of cure may be higher with radical cystectomy than radical radiotherapy, and this is the justification for the common recommendation of radical cystectomy rather than radical radiotherapy, despite the greater adverse impact of radical cystectomy on quality of life.

There are patient related factors that may affect the suitability of radical cystectomy or radical radiotherapy for them. Radical cystectomy may not be suitable for those who are frail or elderly, those who have other serious medical conditions, or those who do not have sufficient mental capacity to be able to participate actively in recovery from radical cystectomy. Radical radiotherapy may not be suitable for people who have had previous pelvic radiotherapy, who have certain bowel disorders (inflammatory bowel disease), who have had significant previous pelvic surgery (that might result in adhesions with bowel stuck to the bladder), or who have obstruction to one or both kidneys, or who have carcinoma in situ.

Given that the treatments differ so much in terms of their impact, it is crucial to identify those patients who would have better outcomes with surgery than with radical radiotherapy, and vice versa.

Clinical question: In which patient groups with muscle invasive bladder cancer would radical cystectomy produce better outcomes than radical radiotherapy and in which groups would radical radiotherapy produce better outcomes?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 83 to 86.

Table 83

GRADE evidence profile: In which patient groups with muscle invasive bladder cancer would radical cystectomy versus radical radiotherapy produce better outcomes (randomised trials).

Table 84

GRADE evidence profile: In which patient groups with muscle invasive bladder cancer would radical cystectomy versus radical radiotherapy produce better outcomes (comparative observational studies).

Table 85

GRADE evidence profile: In which patients with bladder cancer would trimodality therapy produce better outcomes (non-comparative series).

Table 86

GRADE evidence profile: In which patients with bladder cancer would radical cystectomy produce better outcomes (non-comparative series).

Evidence statements

Low quality evidence from one systematic review of three randomised trials (439 patients) suggests that pre-operative radiotherapy followed by radical cystectomy (surgery) more effective than radical radiotherapy with salvage cystectomy (radiotherapy) in terms of overall survival at three years (OR 1.91, 95% CI 1.30 to 2.87) and at five years (OR 1.87, 95% CI 1.22 to 2.87). Overall survival at three years was 45% for surgery and 28% for radiotherapy, giving an absolute improvement of 16%. One trial reported low quality evidence of disease-specific survival with an odds ratio in favour of surgery but this was not statistically significant at three years (OR 1.66, 95% CI 0.92 to 2.99) or five years (OR 1.39, 95% CI 0.75 to 2.57) (Shelley et al., 2001).

Six comparative observational studies (4,328 patients) provided very low quality evidence about overall survival at five years, which ranged from 37% to 53% across studies for cystectomy and from 21% to 68% for radiotherapy (Munro et al., 2010; Gore et al., 2010; Bekelman et al., 2012; Kotwal et al., 2008; van der Steen-Banasik et al., 2009; Koga et al., 2009). Five out of the six studies reported no significant difference between treatments in terms of overall survival. One study of 10,807 patients provided low quality evidence suggesting an overall survival advantage for those who had radical cystectomy compared to bladder preserving therapy (including radiotherapy) in all age groups (Chamie et al., 2008). The survival benefit was smaller for patients over 79 years old (18 months versus 15 months) although the 95% confidence intervals still suggest a significant difference in favour of surgery (HR 1.32, 95% 1.19 to 1.46). In four series of bladder trimodality therapy (TURBT + chemoradiotherapy) five-year overall survival ranged from 51% to 68%, which compares to 58% in one large cystectomy series of 1100 patients (Mak et al., 2012; Shipley et al., 2002; Rodel et al., 2002; Perdona et al., 2008).

Five comparative observational studies reported very low quality evidence of five-year disease-specific survival, with none of the studies reporting a significant difference between radical cystectomy (53% to 67%) and radiotherapy (48% to 75%) (Gore et al., 2010; Bekelman et al., 2012; Kotwal et al., 2008; van der Steen-Banasik et al., 2009; Koga et al., 2009). In three large cystectomy series, five-year disease-specific survival ranged from 65% to 76% (Rink et al., 2012; Hautmann et al., 2012; Otto et al., 2012). One study of 10,807 patients provided low quality evidence suggesting an advantage in disease-specific survival for those who had radical cystectomy compared to bladder preserving therapy (including radiotherapy) in all age groups (Chamie et al., 2008).

One study of 141 patients with T2N0M0 bladder cancer provided very low quality evidence about adverse events after cystectomy or brachytherapy (van der Steen-Banasik et al., 2009). Acute toxicity (<3 months) after cystectomy was seen in 34 patients (52%), including sepsis, UTI, and wound problems. Late toxicity was seen in 30 patients (46%) after cystectomy, including stoma problems and ureter/ureter anastomosis problems. In the brachytherapy group, acute toxicity was observed in 13 patients (17%), with six patients developing wound infections. Eight cases of late toxicity were observed, including five cases of fistula requiring a temporary suprapubic catheter.

In one observational study 19% (57/302) of patients received subsequent salvage cystectomy after primary radical radiotherapy (Munro et al., 2010). Similarly, in three trimodality therapy series bladder preservation rates in long-term survivors ranged from 80% to 83% (Shipley et al., 2002; Rodel et al., 2002; Perdona et al., 2008).

Quality of life was reported by one observational study of 58 patients after radical radiotherapy and 251 patients after radical cystectomy (Henningsohn et al., 2002). Distress from bowel function was reported in 24% of cystectomy patients and 32% of radiotherapy patients (RR 0.74, 95% CI 0.45 to 1.21). Factors related to sexual dysfunction were lower after radiotherapy than after cystectomy.

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.

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Recommendations	Ensure that a specialist urology multidisciplinary team reviews all cases of muscle-invasive bladder cancer, including adenocarcinoma, squamous cell carcinoma and neuroendocrine carcinoma, and that the review includes histopathology, imaging and discussion of treatment options. Offer a choice of radical cystectomy or radiotherapy with a radiosensitiser to people with muscle-invasive urothelial bladder cancer for whom radical therapy is suitable. Ensure that the choice is based on a full discussion between the person and a urologist who performs radical cystectomy, a clinical oncologist and a clinical nurse specialist. Include in the discussion: the prognosis with or without treatment the limited evidence about whether surgery or radiotherapy with a radiosensitiser is the most effective cancer treatment the benefits and risks of surgery and radiotherapy with a radiosensitiser, including the impact on sexual and bowel function and the risk of death as a result of the treatment.
Relative value placed on the outcomes considered	The GDG considered all outcomes to be important except for subsequent treatment. Survival was considered an important outcome for patients and quality of life as important for survivorship. Subsequent treatment was not considered an important outcome because the GDG felt that in this situation survival and quality of life outweighed issues regarding subsequent treatment. All outcomes from the PICO were reported in the evidence and no additional outcomes were used by the GDG to make recommendations.
Quality of the evidence	The quality of the evidence was very low to low as assessed with GRADE. The main limitation of the evidence was that no relevant contemporary randomised studies were identified. The non-comparative studies were considered to be of limited use due to potential for bias which included patient selection for treatments, retrospective design, stage migration, and non comparable groups. These limitations meant that the GDG could not recommend one treatment over the other, so the GDG made the recommendation to discuss the risks and benefits of both treatments with the patient within a SMDT. The recommendation that patients should have some treatment rather than no treatment at all was based on clinical consensus, because survival for these patients without any treatment is very poor. Discussion with cystectomist and oncologist was based on the existing urological cancer IOG and consensus within the GDG. No research recommendation was made to compare surgery and radiotherapy because a randomised trial has been attempted in the UK but it was unfeasible due to clinician and patient bias. The GDG did make a research recommendation to assess if selecting treatment using biomarkers is an effective strategy because it is unclear which groups of patients will benefit from surgery or radiotherapy. Research into quality of life was recommended as little is known about quality of life in these patients.
Trade-off between clinical benefits and harms	The potential benefits of the recommendations include more informed patient decision-making and patient support, improved equality of access to both treatment options, improved MDT working and improved cancer outcomes for patients. The GDG considered that a potential harm of the recommendations is that some patients may find decision-making stressful. The GDG agreed that offering treatment choice to every patient was very important. The GDG agreed that giving this opportunity to all patients was of greater benefit than of giving too much information to some patients.
Trade-off between net health benefits and resource use	No health economic evidence was identified and no economic model was developed for this topic. The GDG considered the potential costs of the recommendation to be from increased specialist consultations/ SMDT discussion, and increased treatment costs. The extent of these costs is unknown. The potential savings included reduced costs of best supportive care/palliative treatment.
Other considerations	The GDG considered that these recommendations will be beneficial because older patients and/or those with significant co-morbidities, or those with disabilities who still need a discussion will be considered. The GDG considered it important that all clinicians should give patients a choice of treatment for MIBC. Increased centralisation of specialist services and improved access to CNS support will be required. The GDG acknowledged that it is difficult to know how much of a change in practice this will require and may vary across the country.

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Research recommendation

In patients with muscle-invasive bladder cancer suitable for radical treatment, does the use of biomarkers enable patients to select more effective treatment, and improve their outcomes compared with treatment selected without biomarkers?

Why is this important

Response to surgery or radiotherapy is difficult to predict for individuals. There is variation not only in the cure rates for patients with muscle-invasive bladder cancer treated with either surgery or radiotherapy, but also in the side effects experienced during and after treatment. The usefulness of current biomarkers in predicting treatment outcomes for individual patients has not been clearly established. Currently treatment decisions are based on patient-related factors, and patient and clinician preference. Research into biomarkers that can predict the response of the patient's muscle-invasive bladder cancer to either radiotherapy or surgery could help individual patients and clinicians decide which treatment is more suitable and is considered an important step toward individualised treatment.

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Research recommendation

What is the quality of life (and other patient-reported outcomes) of patients with muscle-invasive bladder cancer before, during and after radical treatment?

Why is this important

Very little is known about quality of life and other patient reported outcomes for bladder cancer patients with muscle-invasive bladder cancer during the course of their diagnosis and treatment and after treatment. From the National Patient Experience Survey we know that urological cancer patients other than prostate cancer have a worse experience then prostate cancer patients. Many of these patients will have been treated for bladder cancer. The potential physical and psycho-social side effects following radical treatment for bladder cancer are known but their prevalence and impact on patients' lives are not. Moreover, it is important to know whether radical treatment has different impacts on patient sub-groups for example females and males, younger and older patients.

5.2.2. Optimal radical radiotherapy regimen

5 year survival rates of around 50% can be achieved for people with muscle-invasive bladder cancer using external beam radiotherapy or surgery. Within the UK, there are two commonly used radiotherapy schedules to treat bladder cancer. These are 52.5-55 Gy in 20 fractions over 4 weeks and 64Gy in 32 fractions over 6.5 weeks. The two schedules have never been directly compared and to date, radiotherapy trials in the UK have included both regimes. Treatment side-effects and disease-outcome are considered to be comparable between the two protocols.

Although many UK centres now treat potentially curative patients with radical radiotherapy and a radiosensitiser, there are a group of patients who are not fit or able to tolerate radiosensitisation. These patients are treated with radical radiotherapy alone as their definitive treatment.

There are differences of opinion about the volume of tissue to be treated, the radical radiotherapy regimens to be used and the use of radiosensitisers.

Clinical question: What is the optimal radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 87 to 95.

Table 87

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Radiotherapy with carbogen and nicotinamide (RT+CON) versus radiotherapy alone

Table 88

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Chemoradiotherapy (CRT) with 5-fluorouacil and mitomycin C versus radiotherapy alone (more...)

Table 89

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Reduced high-dose volume versus standard volume radiotherapy

Table 90

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Accelerated fractionation versus conventional fractionation radiotherapy

Table 91

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Neoadjuvant MVC and RT versus Concurrent cisplatin CRT

Table 92

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Neoadjuvant MVC + RT versus Neoadjuvant MVC + Concurrent platinum-based CRT

Table 93

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: RT only versus Concurrent CRT

Table 94

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Conventional single-phase RT to whole bladder versus two-phase reduced volume treatment (more...)

Table 95

GRADE evidence profile: What is the optiam radiotherapy regimen (including chemoradiotherapy) for patients offered radical radiotherapy for bladder cancer? Comparison: Concomitant CRT with Gemcitabine versus RT alone

Evidence statements

Radiotherapy with carbogen and nicotinamide (RT+CON) versus radiotherapy alone

Moderate quality evidence from one randomised trial (Hoskin, et al., 2009; 2010) of 333 participants suggests that there is a 13% improvement in three-year overall survival from 46% to 59% in favour of RT+CON compared to radiotherapy alone (HR 0.85, 95% CI 0.73 to 0.99). There was an 11% increase in relapse-free survival at three years in favour of RT+CON (43% vs 54%), although the confidence interval of the hazard ratio includes the null value, suggesting uncertainty about the difference between groups (HR 0.86, 95% CI 0.74 to 1.00). Rates of urinary (39% and 32%) and GI (7% and 5%) complications were similar between groups. Larger doses per fraction did not increase bladder or bowel morbidity. Two deaths (1.2%) were considered due to RT+CON and one death (0.6%) to radiotherapy alone.

Chemoradiotherapy (CRT) with 5-fluorouacil and mitomycin C versus radiotherapy alone

Moderate quality evidence from one randomised trial (James et al., 2012) of 360 participants suggests that loco-regional disease free survival is better with chemoradiotherapy (mitomycin C and 5-fluorouacil) compared to radiotherapy alone, with two-year recurrence free rates of 67% versus 54% (HR 0.68, 95% CI 0.48 to 0.96). The chemoradiotherapy effect did not vary significantly between radiotherapy type or dose fractionation or with neoadjuvant chemotherapy. Overall there were 98 deaths in the chemoradiotherapy group and 110 in the radiotherapy group, with an absolute difference in five-year survival of 7% (95% CI, -3% to 17%) in favour of chemoradiotherapy, although the confidence interval of the hazard ratio includes the null value, suggesting uncertainty of a difference between groups (HR 0.82, 95% CI 0.63 to 1.09). There was also uncertainty about the relative effectiveness in terms of disease-specific survival (HR 0.77, 95% CI 0.57 to 1.05) and disease-free survival (0.78, 95% CI 0.6 to 1.03). Metastases-free survival was better in the chemoradiotherapy group, with an improvement of 11.3% (0.4% to 21.1%) at five years (HR 0.72, 95% CI 0.53 to 0.99). Acute grade three or four toxic effects were increased in the chemoradiotherapy groups compared to radiotherapy alone (36% vs 27.5%), although the risk ratio includes the null value suggesting uncertainty of a difference between groups (RR 1.31, 95% CI 0.96 to 1.78). Grade three or four RTOG late events occurred at some point during follow-up in 8.3% (10/120) of the chemoradiotherapy group and 15.7% (17/108) of the radiotherapy group (RR 0.53, 95% CI 0.25 to 1.11). Very low quality evidence from one observational study of 50 patients treated with chemoradiotherapy (cisplatin and 5-fluorouracil) reports that mean scores for global quality of life and subscales were slightly improved six months after treatment and were maintained at over 70% (best quality of life score is 100%) for all patients alive without relapse.

Moderate quality evidence from the BC2001 trial reported in Huddart et al. (2013) suggest that rates of late side-effects were not significantly different between patients receiving reduced high-dose volume radiotherapy and standard whole-bladder radiotherapy (OR 1.34, 95% CI 1.42 to 4.28). The effect estimates for time to locoregional recurrence (HR 0.80, 95% CI 0.51 to 1.26) and overall survival (HR 0.82, 95% 0.58 to 1.16) also suggest uncertainty of a difference between treatment groups.

Accelerated fractionation (AF) versus conventional fractionation (CF) radiotherapy

Moderate quality evidence from one randomised trial of 229 participants suggests that there was no difference in relapse-free survival, overall survival, and local failure between accelerated fractionation (60.8Gy in 32 fractions over 26 days) and conventional fractionation (64Gy in 32 fractions over 45 days) (Horwich et al., 2005). At five years overall survival was 37% for AF and 40% for CF. There were two treatment related deaths, both on the AF arm. Acute grade two or three RTOG bowel toxicity was reported in 44% of AF patients compared to 26% of CF patients (RR 1.68, 95% CI 1.14 to 2.49). Late radiation toxicity was reported in 44% of the AF group and 35% of the CF group (RR 1.26, 95% CI 0.91 to 1.76).

Neoadjuvant MVC and RT versus concurrent cisplatin CRT

Very low quality evidence from one observational study reported that five-year overall survival was 73% for patients treated with either neoadjuvant chemotherapy and radiotherapy (n=41) or concurrent radiotherapy (n=39), with no difference between treatment protocols (Zapatero et al., 2012). There were also no differences between protocols for cancer-specific survival and distant metastases. Disease-free survival was improved with concurrent chemoradiotherapy compared to neoadjuvant chemotherapy (82% versus 67%). There were no differences in GI complications, although urinary toxicity was higher in the concurrent chemoradiotherapy group (33% versus 12%, RR 0.37, 95% CI 0.14 to 0.93).

Neoadjuvant MVC + RT versus Neoadjuvant MVC + Concurrent platinum-based CRT

Very low quality evidence from one observational study suggests that five year overall survival (60% versus 72%, p=.008) and disease-specific survival (63% versus 79%, p=.003) are improved with neoadjuvant chemotherapy and concurrent chemoradiotherapy compared to neoadjuvant chemotherapy and radiotherapy alone (Perdona et al., 2008). There were no significant differences between treatment protocols in terms of acute grade three or four bone marrow (16% overall), bladder (12% overall), or intestinal (12% overall) toxicity.

RT only versus Concurrent CRT

Very low quality evidence from one observational study reported on 473 patients with a median overall survival of 28.5 months in patients treated with RT compared to 70 months in those treated with concurrent chemoradiotherapy (Krause et al., 2011). One quality of life study including 48 long-term survivors after trimodality therapy reported that the mean physical functioning score was 89 (possible range 0-100) and the general health perceptions score was 74 (possible range 0-100) (Zietman et al., 2003). This suggests that global health-related quality of life is good in this population (very low quality evidence).

Conventional single-phase RT to whole bladder versus two-phase reduced volume treatment

One observational study (very low quality evidence) comparing conventional single phase radiotherapy with a two-phase technique limiting the high-dose area reported that median overall survival was 2.8 years with both techniques (HR 0.91, 95% CI 0.64 to 1.3) (Mangar et al., 2006). The two-phase treatment was associated with a lower rate of overall grade 3 to 4 late toxicity (44% versus 25%, RR 0.56, 95% CI 0.33 to 0.95), and fewer acute bladder and bowel toxicities.

Concomitant CRT with Gemcitabine versus RT alone

One very low quality study of 69 patients reported three year overall survival of 38% with concurrent chemoradiotherapy with gemcitabine and 27% with radiotherapy alone (Asadauskiene et al., 2010). One quality of life study of 23 patients treated with concurrent gemcitabine and radiotherapy reported that there were no statistically significant changes in general quality of life scores before, during or after treatment (Herman et al., 2004).

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.

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Recommendations	Use a radiosensitiser (such as mitomycin in combination with fluorouracil [5-FU] f or carbogen in combination with nicotinamideg) when giving radical radiotherapy (for example, 64 Gy in 32 fractions over 6.5 weeks or 55 Gy in 20 fractions over 4 weeks) for muscle-invasive urothelial bladder cancer.
Relative value placed on the outcomes considered	The GDG considered all of the outcomes specified in the PICO as important for people receiving treatment for muscle-invasive bladder cancer. These included Overall survival Disease-free survival Treatment-related morbidity Treatment-related mortality Health-related quality of life, inc patient reported outcomes Metastases free survival Loco-regional recurrence free survival was not specified in the PICO but was used to make recommendations because this was a primary outcome in the BC2001 randomised trial and was considered the most relevant end-point. This outcome was supported by improvements in metastases-free survival in the trial.
Quality of the evidence	The evidence was assessed with GRADE as being of very low to moderate quality. The GDG considered the limitations of the evidence. Notably, the wide confidence intervals in the accelerated radiotherapy study meant the GDG could not infer non-inferiority of the regimen and therefore the GDG did not recommend accelerated fractionation radiotherapy The age of the included studies limits the applicability of the evidence to current UK practice. Both randomised trials were devised in the late 1990s and newer systemic agents are currently in use. Aside from the randomised trials, much of the data regarding other chemosensitisers came from retrospective observational studies and small phase 2 studies, which diluted the strength of the recommendation about precisely which agents the GDG could recommend. The GDG felt that the evidence of benefit for a radiosensitisation (either chemotherapy or Carbogen/Nicotinamide) was clearly demonstrated by the evidence and the limitations were not pertinent to these views. There was evidence to support both treatment approaches, but it was unclear as to which was superior and therefore both have been recommended as treatment options. The GDG considered that although there is evidence which suggests that radiotherapy with a chemosensitiser is more beneficial than radiotherapy alone, there is uncertainty as to which patients will benefit from the use of chemotherapy and which will benefit most from the use of Carbogen plus Nicotinamide and/or whether they will benefit more from using both drugs. The research recommendation will help to clarify which patients are most likely to benefit from the use of a chemosensitiser.
Trade-off between clinical benefits and harms	The GDG considered that the main benefit from these recommendations is improved treatment outcomes for patients and this was weighed against the possible increased toxicity to patients. The GDG considered that there was more evidence for better outcomes without excessive increased toxicity. The benefit of improved survival and local control was considered to outweigh harms.
Trade-off between net health benefits and resource use	No health economic evidence was identified and no economic model was developed for this topic. The GDG considered that there are potential savings due to improved outcomes for patients e.g. fewer cystectomies, reduced treatment for metastases and reduced palliative care costs. The potential costs from the recommendations include the costs of increased use of radiosensitisers and more preserved bladders with the associated increase in cystoscopic follow-up. The GDG feels the recommendations are likely to be cost-effective in cost per QALY terms.
Other considerations	No equality issues were identified. The GDG considered the potential change in practice required to implement the recommendation. They noted that a significant number of UK centres are currently using radiosensitisation but there are likely to be a number of centres which have not, to date, adopted this treatment. There is also a potential need for more surveillance resulting from the recommendations.

f

At the time of publication (February 2015), mitomycin in combination with fluorouracil did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicinesfor further information.

g

Although this use is common in UK clinical practice, at the time of publication (February 2015), carbogen in combination with nicotinamide did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information.

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Research recommendation

Can biomarkers accurately predict the effectiveness of radiosensitisers (for example mitomycin C and 5-FU or carbogen and nicotinamide) in muscle-invasive bladder cancer treated with radical radiotherapy?

Why is this important

There is some evidence that response to the use of radiosensitisers with radical radiotherapy varies with biomarker expression. Reliable prediction of which radiosensitiser (carbogen or Mitomycin/5-FU) to use when treating a person with muscle invasive bladder cancer with radiotherapy, would improve cancer treatment outcomes and reduce the need for consideration of salvage cystectomy. It would be a step towards personalised medicine. The question is of high importance and applicable to thousands of people with bladder cancer across England and Wales. It would probably result in no overall increase in the use of radiotherapy, and would have cost consequences in laboratory staff capacity and consumables. There would probably be savings through more appropriate use of both radiotherapy and less need for salvage cystectomy. There would be no equality consequence, and the logistics of the research would be deliverable.

5.2.3. Urinary stoma versus bladder reconstruction

After radical cystectomy, drainage of urine has to be re-established. This can be done by using bowel either to create a urinary stoma or some form or urinary reconstruction. A urinary stoma necessitates continuous drainage into an external bag. Urinary reconstruction involves either a bladder substitute, or a catheterisable reservoir

Rehabilitation after radical cystectomy is much quicker with a stoma than with urinary reconstruction. The majority of people with a stoma learn very quickly how to empty and change their bag but will have a piece of bowel at the skin surface and will need an external bag for the rest of their life. Bladder reconstruction leaves only a scar, and no external bag. A bladder substitute allows urine to be held and passed in a more or less normal way, and a catheterisable reservoir is emptied by passage of a catheter around three to four times each day. Learning how to use and care for a bladder substitute or a catheterisable reservoir requires much more time and diligence in the short and longer term than learning how to use a stoma.

There is variation in both provision of bladder reconstruction and which options are presented to patients resulting in large variations in accessibility which are neither related to outcomes or choice.

Clinical question: Is bladder reconstruction or urinary stoma the more effective method of urinary diversion?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 96 and 97.

Table 96

GRADE evidence profile: Is bladder reconstruction or urinary stoma the more effective method of urinary diversion? Urinary diversions and adverse events Note: The Continent diversions category was computed by summing any data reported for each adverse (more...)

Table 97

GRADE evidence profile: Is bladder reconstruction or urinary stoma the more effective method of urinary diversion? Urinary diversions and Health Related Quality of Life (HRQoL) and Patient Satisfaction

Evidence statements

Low quality evidence from one systematic review of 557 studies (46,921 patients) (Somani et al., 2009) assessing adverse events associated with type of urinary diversion indicates uncertainty over the most effective surgical option. Whilst the percentage of patients reporting some adverse events varied depending on type of urinary diversion (in some instances varied considerably according to study design) none of the differences presented reached statistical significance (unclear how this was assessed as no statistical analyses are presented in the article). Somani et al. (2009) proposed that the lack of statistical significance does not provide evidence of lack of equivalence or evidence of lack of superiority of one intervention over the other but could be attributable to better patient selection for type of urinary diversion (e.g. younger and fitter patients undergoing bladder replacement).

Prospective studies favoured ileal conduit for fewer operative complications compared to the continent diversions (6.1% versus 25.7%, respectively). However, postoperative morbidity favoured the continent diversions compared to ileal conduit (11.4% versus 27%, respectively).

More upper tract UTIs were reported in the ileal conduit patients compared to the continent diversions patients (26.5% versus 8.1%, respectively). Further, Ileal conduit patients reported more metabolic alkalosis (23.8% versus 2.7%), higher rates of bone disease (70.4% of ileal conduit patients versus 19.8% of continent patients), and increased problems with odour (67.6% versus 28.6%) compared to continent diversion patients.

A higher incidence of urinary stones were reported in the continent diversion patients (14.1% [prospective studies] and 15.9% [retrospective studies]) compared to the ileal conduit patients versus (5.2% [retrospective studies]). In addition, continent diversion patients reported higher rates of faecal incontinence (10.8% of continent patients versus 0% of ileal conduit patients) and flatus leakage (28.6% of continent patients versus 5% of ileal conduit patients) compared to the ileal conduit patients.

There was no comparative data for lower tract UTIs or clean intermittent self-catheterisation but in both adverse events over 20% of continent patients reported these issues (prospective data: 23.8% lower tract UTIs; 28.3% clean intermittent self-catheterisation). No comparative for prospective studies was found comparing types of diversion for metabolic acidosis, with 39.4% of continent diversion patients reporting this event. However, comparative data for retrospective studies reported a higher frequency of the adverse event in the continent patients compared to ileal conduit patients (25.0% versus 3.1%, respectively).

Health related quality of life and patient satisfaction was reported by one low quality systematic review of 46 studies (4,186 patients) (Somani et al., 2010) and ten very low quality observational studies (725 patients) (Erber et al., 2012; Gacci et al., 2013; Harano et al., 2007; Metcalfe et al., 2013; Sherwani et al., 2009; Vakalopoulos et al., 2011; Shim et al., 2014; Asgari et al., 2013a; Asgari et al., 2013b; Singh et al., 2014) . The majority of the 56 studies reviewed reported that patients had good HRQoL/global satisfaction (13/56 studies: 23%) or that there were no statistically significant differences between the groups compared on HRQoL/satisfaction (19/56 studies: 34%). Of the remaining studies 20/56 (36%) reported that there were differences between the groups compared. The systematic review provided minimal information on these statistically differences, and implied that the pooled results reveal inconsistent findings across the different types of urinary diversions. For example, three studies reported poorer outcomes for patients receiving an orthotopic bladder replacement compared to patients receiving ileal conduit diversions or control participants (e.g. more urinary leakage; reduced physical health, reduced emotional problems and higher bodily pain; low body image), whereas three other studies reported better outcomes for these orthotopic bladder patients (e.g. HRQoL better in all domains; higher physical functioning). Inconsistent results across the different types of urinary diversions were also found in the ten very low quality observational studies. In addition, the majority of these significant differences were in one or two sub-scale analyses and did not reflect global HRQoL differences between the compared groups.

Four studies (two retrospective, two prospective) out of the 46 studies included in the low quality systematic review (Somani et al., 2010) assessed the impact of psychological interventions (e.g. pre-operative counselling [no additional information provided on what the “interventions” were, how they were measured]) on HRQoL and patient satisfaction outcomes. The two retrospective studies reported an increase in satisfaction scores post-surgery following pre-operative counselling.

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.

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Recommendations	Offer people who have chosen radical cystectomy a urinary stoma, or a continent urinary diversion (bladder substitution or a catheterisable reservoir) if there are no strong contraindications to continent urinary diversion such as cognitive impairment, impaired renal function or significant bowel disease. Members of the specialist urology multidisciplinary team (including the bladder cancer specialist urological surgeon, stoma care nurse and clinical nurse specialist) should discuss with the person whether to have a urinary stoma or continent urinary diversion, and provide opportunities for the person to talk with people who have had these procedures.
Relative value placed on the outcomes considered	The GDG considered treatment-related morbidity, adverse events, patient satisfaction, and health-related quality of life as important outcomes because they influence the treatment decisions made by patients. The GDG also considered it important to know that treatment-related mortality was similar between the two options for urinary diversion. All outcomes from the PICO were reported in the evidence and no additional outcomes (i.e. not specified in the PICO) were used to make recommendations.
Quality of the evidence	The evidence was of very low quality as assessed with GRADE. The main limitations of the evidence were that the included studies were mostly retrospective studies, and there were no controlled studies comparing the interventions.It was difficult to compare studies because they used different metrics for assessing quality of life. Because of these limitations the GDG could not conclude that one urinary diversion method was better than the other. The recommendation for discussion between the patient and the multidisciplinary team and other patients was based on clinical consensus because there was minimal and conflicting evidence about the efficacy of pre-operative counselling. The GDG considered their knowledge that large numbers of patients are currently not being offered a choice of urinary diversion. The GDG considered it highly important for people to have the opportunity to discuss options for urinary diversion with trained multi-disciplinary team members and with patients who have undergone these procedures. No research recommendation was made. The GDG were aware of an ongoing quality of life study (OTIS study) in this area.
Trade-off between clinical benefits and harms	The GDG considered the benefits of the recommendations made to be improved informed decision making and increased choice for patients and improved quality of life. The GDG noted that there is a risk that during implementation the recommendation may lead to procedures being carried out by surgeons with inadequate training in bladder reconstruction. However, current commissioning and governance arrangements should mitigate against the risk of harm. The benefits to patients are thought to outweigh the risks.
Trade-off between net health benefits and resource use	No health economic evidence was identified and no economic model was developed for this topic. The GDG considered potential costs and savings of the recommendations. There may be travel costs to patients when their preferred diversion method is not available locally. There may be an increase in reconstructive surgery which is more expensive, increased specialist nurse involvement, extra time for consultation with patients, training costs, expenses for patient and carer discussion with other patients, more catheters and washout equipment for neobladders. The potential savings include reduced stoma care and use of disposables. The GDG considered that the recommendations will incur a net cost increase.
Other considerations	The GDG are aware of contemporary NHS evidence indicating inequality of access to a choice of urinary diversion by cancer network, and suggesting that there may be inequality by gender, age, socioeconomic status and ethnicity. In the recommendations, the GDG suggested that cognitive impairement may be a contraindication to bladder reconstruction. The GDG considered that there will be a need for substantial change in practice due to an increase in the numbers of discussions between patients and health care professionals and a potential increase in reconstructive surgery.

5.3. Managing side effects of treatment for muscle-invasive bladder cancer

The management of side effects of treatment for muscle invasive bladder cancer was investigated alongside the management of side effects of treatment for non-muscle-invasive bladder cancer. Recommendations on this can be found in section 4.4.

5.4. Follow-up after radical treatment of organ confined muscle-invasive bladder cancer

People previously treated for muscle invasive bladder cancer are at high risk of recurrence. These may occur locally and/or as distant metastases. The majority of recurrences are ultimately fatal. The goal of any follow-up protocol is appropriate detection of recurrences such that treatment outcomes may be optimised. Furthermore, people who have had radical cystectomy need additional follow-up related to the anatomical and functional consequences of their surgery.

Follow-up protocols should therefore define the type and frequency of tests necessary to diagnose recurrences. Follow up protocols currently include imaging and urine tests, as well as cystoscopy (for people who have had radical radiotherapy) and urethroscopy (for people who have had radical cystectomy). There is variation in current follow-up protocols many of which are not evidence based. People who have had radical surgery, radical radiotherapy or non-curative treatment may require different follow-up protocols. In addition patients may develop symptomatic recurrences between follow-up visits.

Nomograms have been developed to predict the risk of recurrence for an individual patient but these have not been widely validated. However, they may be useful in allowing a stratified approach to follow-up based on risk and site of recurrence and thus inform the type and frequency of follow-up tests.

People with bladder cancer are at increased risk of developing upper tract urothelial cancer and there is considerable variation in practice regarding detection of these cancers.

Clinical evidence (see also full evidence review)

The evidence is summarised in table 98. There was no direct evidence about the optimum follow-up protocol for muscle invasive bladder cancer.

Table 98

GRADE evidence profile: What is the optimal follow-up protocl for muscle-invasive bladder cancer? Follow-up after radical cystectomy

Evidence statements

Follow-up after radical cystectomy

Low quality evidence from eight observational studies including 6,398 patients report overall recurrence rates of between 20% and 46% after radical cystectomy. Most studies report that the risk of both recurrence and metastasis increases with the stage of the primary tumour.

The proportion of asymptomatic recurrences detected by routine follow-up reported in four studies is 12% (Volkmer et al., 2009), 10% (Slaton et al., 1999), 22% (Boorjian et al., 2011) and 34% (Nieuwenhuijzen et al., 2014) indicating that the majority of recurrences are diagnosed through symptom-driven examinations.

One observational study of 574 patients (Perlis et al., 2013) reported a Finnish cohort which received regular urethral washings for cytology compared to a Canadian cohort where routine cytology was often not performed. Urethral recurrences occurred more often in the Finnish than in the Canadian cohort, but this difference was not statistically significant (6% vs 2.6%, p=0.06) and no difference in overall survival was reported between patients with urethral recurrence at both sites (very low quality evidence).

One study of 479 patients (Giannarini et al. 2010) using a risk-based follow-up protocol (with bone scan and CT scan only if ≥pT3 or T1-4 N+) reports five-year overall survival of 61.9% (95% CI 57.4-66.7%) and five-year disease-specific survival of 69.8% (95% CI 65.5-74.3%). One study of 1599 patients reports that five- and ten-year overall survival is lower in patients with symptomatic recurrence (22% and 10%) than the five- and ten-year overall survival in patients with asymptomatic recurrence (46% and 26%). Patients who were symptomatic at recurrence were at almost 60% increased risk of death than those who were asymptomatic (HR 1.59 (95% CI 1.26 to 2.02) (Boorjian et al., 2011). Similarly, one study of 343 patients reported that patients who were symptomatic at recurrence had shorter survival than those who were asymptomatic (HR 1.58 (p=0.013) (Nieuwenhuijzen et al., 2014).

Very low quality evidence from one observational study of CT urograms reported that findings related to surgery (eg.hydronephrosis, parastomal hernia, urinary tract calculi) were found in 60/105 (57%) of patients during surveillance after radical cystectomy (Shinagare et al., 2013).

5.5. References

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