6.1. Managing people with distant metastases

Most patients who die of bladder cancer will do so with metastatic disease. The main treatment used to prolong life and palliate/alleviate the symptoms is chemotherapy. Most studies on chemotherapy report benefits in terms of response, symptom control and survival but this comes at the cost of significant treatment related toxicity. Not all patients are able to receive chemotherapy, eg, because of debility, impaired kidney function or over the age for safe use of chemotherapy, and others choose not to have it. There are anecdotal reports of long term survivors, but these are rare. The role of chemotherapy in people who progress or relapse on first line treatment is less clear because their prognosis is usually measured in months, so benefits and drawbacks of chemotherapy are very finely balanced.

Pelvic radiotherapy can also be used to treat patients with symptoms of incurable bladder cancer, especially bleeding from the bladder or pain from the bladder or sites of metastatic spread.

Other forms of specialist intervention may be considered for serious complications of advanced bladder (such as pain, bleeding or upper urinary tract obstruction) including:

• embolisation
• nephrostomy or stent drainage
• nerve blocks

6.1.1. First-line chemotherapy

Chemotherapy is widely used as the first treatment for many people with advanced bladder cancer. Cisplatin based multiagent chemotherapy is most commonly used in people with normal renal function and good performance status.

Many of these people are elderly and/or have impaired performance status and/or impaired renal function. All chemotherapy regimens are associated with a toxicity profile for example sickness, fatigue, neuropathy or myelosuppression.

There is uncertainty about a number of issues related to first line chemotherapy, including:

• Does chemotherapy improve outcomes compared to best supportive care ?
• What is the best regimen?
• Are there subgroups of people who benefit most or least from chemotherapy ?
• What is the best treatment for people who cannot tolerate Cisplatin regimens?

Clinical question: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 99 to 112.

Table 99

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Cisplatin & Methotrexate (CM) versus Cisplatin (C)

Table 100

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: MVAC (Methotrexate, Vinblastine, Doxorubicin & Cisplatin) versus Methotrexate & (more...)

Table 101

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: CMV (Cisplatin, Methotrexate & Vinblastine) versus MV

Table 102

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: MVAC (Methotrexate, Vinblastine, Doxorubicin & Cisplatin) versus Cisplatin

Table 103

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: High-dose MVAC versus MVAC

Table 104

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Docetaxcel & Cisplatin (DC) with GCSF versus MVAC with GCSF

Table 105

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine & Cisplatin (GC) versus MVAC

Table 106

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Dose dense MVAC (DD-MVAC) versus Dose dense Gemcitabine & Cisplatin (DD-GC)

Table 107

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine & Cisplatin & Paclitaxel (PCG) versus Gemcitabine & (more...)

Table 108

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: MVAC versus Carboplatin & Paclitaxcel (CaP)

Table 109

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine & Cisplatin (GC) versus Gemcitabine & Carboplatin (GCarbo)

Table 110

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: MVAC versus M-CAVI (Methotrexate, Carboplatin, Vinblastine)

Table 111

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Cisplatin-based chemotherapy versus Carboplatin-based chemotherapy

Table 112

GRADE evidence profile: What is the optimal first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine & Carboplatin (GCarbo) versus Methotrexate, Carboplatin & Vinblastine (more...)

Evidence Statements

Cisplatin-based chemotherapy

One phase II trial (Hillcoat et al., 1989) of 108 participants provided low quality evidence that there was no difference in overall survival between those treated with single agent Cisplatin (C) therapy or a combination of Cisplatin and Methotrexate (CM). Time to progression was longer with CM, but this difference was only significant during the first 12 months of therapy. Toxicity was greater in the CM arm, including haematological toxicity (26% vs. 7%) and mucositis (19% vs. 0%). Single agent Cisplatin was also compared to MVAC in one trial of 246 participants (Loehrer et al., 1992). Overall survival and progression-free survival were greater for MVAC than Cisplatin alone (low quality evidence). At 6-year follow-up, MVAC still showed a survival advantage over Cisplatin (Saxman et al., 1997). However, combined MVAC was more toxic than Cisplatin, with increased rates of grade 3-4 leukopenia, granulocytopenic fever, and mucositis. There were no differences in treatment-related mortality (4% vs. 0%). There was no evidence about health-related quality of life.

One trial (220 participants) of moderate quality reported increased duration of overall survival (14.2 months vs. 9.3 months) and time-to-progression (9.4 months vs. 6.1 months) with MVAC and granulocyte colony-stimulating factor (GCSF) compared to Docetaxel and Cisplatin with GCSF (Bamias et al., 2004). There were no differences in rates of grade 3-4 thrombocytopenia or anaemia. Neutropenia (36% vs. 19%) and neutropenic sepsis were more common in the MVAC arm. There were no differences in treatment-related mortality. One moderate quality trial (263 participants) compared high-dose intensity MVAC and GCSF (HD-MVAC) with classic MVAC (Sternberg et al., 2001a/2006). After a median of 7.3 years follow-up, HD-MVAC produced a small improvement in risk of death and risk of progression. There were lower rates of whole blood cell toxicity and neutropenic fever with HD-MVAC, with no differences between arms for thrombocytopenia, mucositis and treatment-related mortality. Health-related quality of life was not reported.

One phase III trial (405 participants) of MVAC versus Gemcitabine and Cisplatin (GC) providing high quality evidence reported no differences in overall survival and progression-free survival between trial arms (von der Maase et al., 2000/2005). Rates of grade 3-4 anaemia and thrombocytopenia were greater in the GC arm, whereas neutropenia and neutropenic sepsis were more common in the MVAC arm. Mean quality of life scores were not reported but the authors state that quality of life (as measured by the EORTC QLQ C30) was maintained on both arms throughout the study with improvements in emotional functioning and pain. One observational study, where oncology professionals were interviewed as patient representatives, provided very low quality evidence that respondents were more likely to choose GC over MVAC for a reduced incidence of neutropenic sepsis, mucositis, or serious weight loss. Respondents were more willing to accept GC over MVAC even when a hypothetical life expectancy was reduced from 60 weeks to 45 weeks.

One randomised phase III trial (130 patients) of dose dense MVAC versus dose dense GC provided low quality evidence of no difference in overall survival or progression-free survival between groups. Grade 3-5 toxicities were reported in 50% of the DD-MVAC group and 44% of the DD-GC group. Two toxicity-related deaths were both in the DD-MVAC arm due to non-neutropenic sepsis (Bamias et al., 2013).

GC was compared with Pacitaxel, Gemcitabine and Cisplatin (PCG) in one randomised phase II trial of 85 patients (Lorusso et al., 2005) and one randomised phase III trial of 626 participants (Bellmunt et al., 2012). The phase III trial provided high quality evidence of no difference in overall survival and progression-free survival between trial arms. However, there was a small effect in the subgroup of patients with primary bladder tumours, with longer overall survival in patients treated with PCG (15.9 vs. 11.9 months, HR 0.80, 95% CI 0.66 to 0.97). Grade 3-4 thrombocytopenia was more common in the GC arm, and grade 3-4 neutropenia was more common in the PCG arm (64% vs. 51%). Health-related quality of life was not reported.

Cisplatin-based versus carboplatin-based chemotherapy

Bellmunt et al. (1997) provided low quality evidence, comparing MVAC with methotrexate, carboplatin and vinblastine (M-CAVI) in 47 patients. Median disease-related survival was greater in the MVAC arm (hazard ratios were not reported). There were no differences in toxicity between arms. The study was terminated early and failed to reach accrual target. One underpowered trial (84 participants), which was closed early for slow accrual provided very low quality evidence comparing MVAC with carboplatin and paclitaxcel (CaP) (Dreicer et al., 2004). There were no differences between arms for overall survival and progression-free survival. Rates of neutropenia and anaemia were higher in the MVAC arm, but there were no differences in rates of thrombocytopenia and treatment-related mortality. It was reported that there were no differences in quality of life over time by treatment arm, but low numbers of participants were assessed for quality of life, which limits the precision of this outcome. One underpowered trial (110 participants) provided very low quality evidence of no difference in overall survival, time-to-progression, and toxicity between patients treated with Gemcitabine and Cisplatin versus Gemcitabine and Carboplatin (Dogliotti et al., 2007).

Four trials comparing cisplatin-based chemotherapy with carboplatin-based chemotherapy were included in the meta-analysis by Galsky et al. (2012). Very low quality evidence from two studies showed no difference in survival rate at 12 months (RR 0.76, 95% CI 0.56 to 1.07). Progression-free survival was not reported consistently across studies and could not be pooled in a meta-analysis. Therefore, overall tumour response rates and complete tumour response rates were pooled and risk ratios (95% CIs) were calculated. A partial tumour response was defined as a 50% reduction in bidimensional tumour measurements and a complete response as a resolution of radiographic abnormalities. A majority of patients had a performance status of 0 to 1 with adequate renal function. The meta-analysis demonstrated a higher likelihood of achieving an overall response (RR 1.34, 95% CI 1.04 to 1.71) and a complete response (RR 3.54, 95% CI 1.48 to 8.49) with cisplatin-based chemotherapy. However, this analysis is based on three small phase II studies and one phase III trial which was closed early due to poor accrual. The chemotherapy agents used and the doses of carboplatin used differed across studies.

Chemotherapy in ‘unfit’ patients

Moderate quality evidence for overall survival and progression-free survival was provided by one phase III RCT (238 participants) comparing Gemcitabine & Carboplatin (GCarbo) with Methotrexate & Carboplatin & Vinblastine (M-CAVI) (De Santis et al., 2012) in patients unfit for cisplatin-based therapy. After a median of 4.5 years follow-up there were no differences in overall survival (HR 0.94, 95% CI 0.72 to 1.02) and progression-free survival (HR 1.04, 0.8 to 1.35) between the two treatments. GCarbo produced a lower rate of severe acute toxicity than M-CAVI (9% vs. 21%). There were no differences between treatments for changes in health-related quality of life from baseline to end of cycle 2, although mean scores were not reported and there was less than 50% response rate after the baseline assessment.

Cost-effectiveness evidence

The primary results of the analysis by Robinson et al. 2004 are summarised in table 113.

Table 113

Modified GRADE table showing the included evidence on the optimal first-line chemotherapy regimens for treating metastatic bladder cancer.

The base case results of the cost-effectiveness analysis showed that, in comparison to the MVAC regimen, the combination of gemcitabine and cisplatin provided one additional quality adjusted life year (QALY) at a cost of £22,925. This ICER value is slightly higher than the threshold typically adopted by NICE (£20,000 per QALY) and so gemcitabine and cisplatin would not strictly be considered cost-effective.

Exceptions are made in instances where there may be some aspects that are not captured in the model. In this case, the cost of gemcitabine used in the model is unlikely to reflect the cost in current practice as the drug has come off patent in the intervening years. With the lower cost of gemcitabine in current practice, it is possible that the cost-effectiveness result would be improved significantly and could fall below the threshold of £20,000 per QALY.

However, there were concerns about the utility values that were used in the model as they were derived from healthcare professionals rather than patients and thus the QALY estimates may be unreliable. Furthermore, the applicability of this study to current practice is debatable as the MVAC regimen used in the study has largely been replaced with a more efficacious accelerated MVAC regimen. Thus, overall, the available evidence base was not considered to provide a reliable estimate of cost-effectiveness that is relevant to current clinical practice.

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Recommendations	Discuss the role of first-line chemotherapy with people who have locally advanced or metastatic bladder cancer. Include in your discussion: prognosis of their cancer and advantages and disadvantages of the treatment options, including best supportive care Offer a cisplatin-based chemotherapy regimen (such as cisplatin in combination with gemcitabine, or accelerated [high-dose] methotrexate, vinblastine, doxorubicin and cisplatin [M-VAC] in combination with granulocyte-colony stimulating factor [G-CSF]) to people with locally advanced or metastatic urothelial bladder cancer who are otherwise physically fit (have an Eastern Cooperative Oncology Group [ECOG] performance status of 0 or 1) and have adequate renal function (typically defined as a glomerular filtration rate [GFR] of 60 ml/min/1.73 m2 or more). Offer carboplatin in combination with gemcitabineh to people with locally advanced or metastatic urothelial bladder cancer with an ECOG performance status of 0 - 2, if a cisplatin-based chemotherapy regimen is unsuitable, for example, because of ECOG performance status, inadequate renal function (typically defined as a GFR of less than 60 ml/min/1.73 m2) or comorbidity. Assess and discuss the risks and benefits with the person. For people having first-line chemotherapy for locally advanced or metastatic bladder cancer: carry out regular clinical and radiological monitoring and actively manage symptoms of disease and treatment- related toxicity and stop first-line chemotherapy if there is excessive toxicity or disease progression.
Relative value placed on the outcomes considered	All the outcomes specified in the PICO were reported in the evidence. The GDG considered progression-free survival, overall survival, and toxicity as the most important outcomes. Improvements in these outcomes were considered the most meaningful endpoints for patients/patient care. Survival is threatened by metastatic or locally advanced disease and overall prognosis is poor. Therefore, significant improvement in survival associated with chemotherapy treatment is considered to be an important outcome. Chemotherapy treatments have toxic adverse events so the GDG considered regimens delivering lower levels of toxicity. Tumour response was not specified in the PICO but was reported in the systematic review of cisplatin versus non-cisplatin based chemotherapy (Galsky, 2012) as no other outcomes could be pooled. Tumour response was considered by the GDG as a surrogate outcome for treatment effectiveness.
Quality of the evidence	The evidence ranged from low to high quality across comparisons as assessed with GRADE. The GDG considered the limitation of the post-hoc analysis of overall survival for the subgroup of bladder tumours in the PCG trial (Bellmunt, 2012). Post-hoc selections can introduce bias. Less weight was placed on the positive outcome reported in the PCG trial due to these limitations. In light of this concern, PCG was recommended as an option to consider because the GDG did not believe the evidence warranted recommending offering this treatment as the best option. The recommendation that patients should be carefully monitored for toxicity was based on clinical experience. No specific evidence on how to monitor patients was examined, although all included trials stopped treatment if patients progressed or if there was excessive toxicity. The GDG reached consensus that treatment options, including the use of chemotherapy and best supportive care should be discussed with the patient. The GDG considered making a research recommendation for a trial of GC versus HDMVAC but considered this unlikely to be funded or to have sufficient support to take forward. Low quality health economic evidence was identified. The economist highlighted a potential bias in that it was a manufacturer sponsored study. Other limitations of the study include the cost of drug was not included in sensitivity analysis, utility data was not reported directly from patients, drug costs have changed since analysis conducted (come off patent),the comparator of MVAC is outdated (HDMVAC is now more widely used). The GDG therefore considered the economic analysis to be of limited value to current practice.
Trade-off between clinical benefits and harms	The main benefits of the recommendations made are that they provide clear guidance for patients to be offered chemotherapy and for which patient groups cisplatin-based chemotherapy is appropriate. This should improve outcomes for patients in terms of overall and progression-free survival. The recommendations made may increase the use of cisplatin-based chemotherapy and therefore increased toxicity and adverse effects may be expected. The GDG considered survival to be more important than toxicity and that patients are likely to consider the survival advantage and toxicity when deciding on treatment. The GDG considered that the potential for increased toxicity is mitigated by recommending the careful monitoring of patients for adverse events and discontinuing treatment if there is excessive toxicity. There was weak evidence to suggest a benefit of doublet chemotherapy as second line chemotherapy, when indirectly compared with best supportive care or single agent chemotherapy. The GDG therefore recommended doublet chemotherapy be considered. The GDG considered making a ‘do not offer’ recommendation for single agent chemotherapy, but decided after extensive discussion and following stakeholder feedback that there was insufficient evidence to make a recommendation either way.
Trade-off between net health benefits and resource use	The GDG considered that the economic evidence identified was not applicable to current practice and no economic model was built. The potential costs of the recommendations made include the increased use of chemotherapy and GCSF. The potential savings include the avoidance of ineffective chemotherapy and possibly the avoidance or delay of the costs of palliative care. Improved survival means that chemotherapy is potentially cost-effective in cost/QALY terms.
Other considerations	The GDG considered that the recommendations equalise access to treatment for patients who currently don't have access. Patients who are both suitable and unsuitable for cisplatin-based chemotherapy are accounted for in recommendations. The GDG considered that the implementation of these recommendations would not cause a significant change in current practice.

h

Although this use is common in UK clinical practice, at the time of publication (February 2015), carboplatin in combination with gemcitabine 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.

6.1.2. Second-line chemotherapy

Management options for people who progress on or relapse after first line treatment are controversial. Their prognosis is poor with median survivals measured in a few months. There is a wide variety of practice in whether to offer second line therapy to such people. It is likely that response rates are less; and toxicity may be higher thus questioning the clinical benefits of treatment. A key question is first therefore whether there is a role for further chemotherapy in some or all of these people? If so, can the people that are most likely to benefit be identified, therefore allowing treatment to be avoided in those for whom chemotherapy is ineffective?

Clinical question: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 114 to 142.

Table 114

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Topotecan for second-line chemotherapy

Table 115

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Iritonecan for second-line chemotherapy

Table 116

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Lapatanib for second-line chemotherapy

Table 117

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Bortezomib for second-line chemotherapy

Table 118

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Sorafenib for second-line chemotherapy

Table 119

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Oxaliplatin for second-line chemotherapy

Table 120

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Pemetrexed for second-line chemotherapy

Table 121

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Docetaxel for second-line chemotherapy

Table 122

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Ifosfamide for second-line chemotherapy

Table 123

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Sunitinib for second-line chemotherapy

Table 124

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Paclitaxel for second-line chemotherapy

Table 125

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine for second-line chemotherapy

Table 126

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine & Paclitaxel for second-line chemotherapy

Table 127

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Short-term versus prolonged gemcitabine and paclitaxel

Table 128

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Paclitaxel & Carboplatin for second-line chemotherapy

Table 129

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) for second-line chemotherapy (more...)

Table 130

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine, cisplatin for second-line chemotherapy

Table 131

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Paclitaxel, cisplatin, methotrexate for second-line chemotherapy

Table 132

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Paclitaxel, cisplatin for second-line chemotherapy

Table 133

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Methotrexate, paclitaxel for second-line chemotherapy

Table 134

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Paclitaxel, ifosfamide for second-line chemotherapy

Table 135

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Docetaxel, ifosfamide for second-line chemotherapy

Table 136

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Docetaxel, oxaliplatin for second-line chemotherapy

Table 137

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Cisplatin, Gemcitabine & Ifosfamide for second-line chemotherapy

Table 138

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine, Ifosfamide for second-line chemotherapy

Table 139

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine, Docetaxel for second-line chemotherapy

Table 140

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Gemcitabine, carboplatin, docetaxel for second-line chemotherapy

Table 141

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Methotrexate, Paclitaxel, Epirubicin, Carboplatin for second-line chemotherapy

Table 142

GRADE evidence profile: What is the optimal post first-line chemotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Best supportive care after progression from first-line chemotherapy

Evidence Statements

Single-agent chemotherapy

Very low quality evidence about the effectiveness of Topotecan, Iritonecan, Lapatanib, Sorefanib, Oxaliplatin and Sunitinib was provided by one non-comparative phase II study for each regimen. Overall survival ranged from 4.2 months (Lapatanib) to 7.1 months (Sunitinib). Progression-free survival ranged from 1.5 months (Topotecan) to 2.4 months (Sunitinib). Overall tumour response rate was highest for Topotecan at 9%. Toxicity rates were highest for Topotecan with 43%, 61%, and 77% of participants developing grade 3-4 thrombocytopenia, anaemia, and leucopenia, respectively. Two studies (46 participants) provided very low quality evidence on Bortezomib, with median overall survival durations of 3.5 months (Gomez-Aubin et al., 2007) and 5.7 months (Rosenberg et al., 2008). Both studies were closed early due to a lack of tumour response to the treatment, with no responses reported in either study. One study (47 participants) provided very low quality evidence of Pemetrexed, with a median overall survival of 9.2 months and a response rate of 28% for those previously treated in the metastatic setting (Sweeny et al., 2006). A second smaller study (13 participants) of Pemetrexed reported a lower response rate of 8% (Galsky et al., 2007). Across both studies, 12% of participants reported grade 3-4 neutropenia and thrombocytopenia. Very low quality evidence about the effectiveness of Gemcitabine was provided by four studies (133 participants), with overall survival ranging from 5 months to 13 months across studies and an overall tumour response of 22%. Grade 3-4 neutropenia was the most common adverse event (37% of participants) (2 studies, 79 participants). In one study (Albers et al., 2002), 25 participants reported health-related quality of life, where responders to Gemcitabine showed an improvement in pain score from 4.3 to 5.8 on a 7-point scale. In contrast, non-responders reported an increase in pain during treatment.

Multi-agent chemotherapy

The combination of Gemcitabine and Paclitaxel (GP) was reported by 6 non-comparative observational studies (109 participants, very low quality evidence). The overall response rate was 30%, with median overall survival ranging from 8 months to 12.4 months. One study reported a median progression-free survival of 6.1 months (Ikeda et al., 2011). Four studies reported grade 3-4 neutropenia, with an overall rate of 42%. One randomised phase III trial (Albers et al., 2011) and one randomised phase II trial (Fechner et al., 2006) provided low quality evidence of short-term (three-week schedule) versus prolonged (maintenance until progression) GP regimes (123 participants). No differences in overall survival and progression-free survival were reported between trial arms. In the phase III trial median overall survival was 7.8 months in the subgroup of patients who had first-line chemotherapy for metastatic cancer (Albers et al., 2011). The pooled overall tumour response rate was 41% in both trial arms. Grade 3-4 leucopenia was the most common toxicity with no difference in rate between short-term and maintenance GP treatment (36% versus 23%). Two treatment-related deaths were reported on the prolonged GP arm in the phase III study. Several small non-randomised studies providing very low quality evidence, generally show that other non-platinum based regimens (e.g. Methotrexate & Paclitaxel; Paclitaxel & Ifosfamide; Docetaxel & Ifosfamide; Docetaxel & Oxaliplatin; Gemcitabine & Ifosfamide; Gemcitabine & Docetaxel) have lower response rates and overall survival durations than Gemcitabine and Paclitaxel.

Three studies (93 participants) reported very low quality evidence about Carboplatin and Paclitaxel, with median overall survival ranging from six to 11 months, and an overall response rate of 25%. Progression-free survival was around four months in all three studies. Grade 3-4 neutropenia was reported in 50 out of 93 (54%) participants. Health-related quality of life was reported by one study, where there were no differences between pre-treatment and post-treatment scores on the EORTC-QLQ C30. Cisplatin based multi-agent chemotherapy regimens (MVAC; Gemcitabine & Cisplatin (GC); Paclitaxel, Methotrexate & Cisplatin (PMC); Paclitaxel & Cisplatin; Cisplatin, Gemcitabine & Ifosfamide) produced response rates of 30% to 40% and overall survival durations of 9.5 to 11 months (very low quality evidence). Rates of grade 3-4 neutropenia were 30%-67% and rates of grade 3-4 thrombocytopenia were 30%-32% for MVAC, GC and PMC. Lower toxicity rates were reported for the regimen of Paclitaxel & Cisplatin, with 5% grade 3-4 neutropenia and 1% grade 3-4 thrombocytopenia and anaemia (Uhm et al., 2007). One study (26 participants, very low quality evidence) reported a median overall survival and progression-free survival of 12.6 months and 5 months with Gemcitabine, Carboplatin & Docetaxel (Tsuruta et al., 2011). Excluding those who had received combination radiation therapy, the overall tumour response rate was 56%. Toxicity data were not reported separately for patients receiving second-line chemotherapy. Grade 3-4 neutropenia was reported in 80% of participants, thrombocytopenia in 51%, and anaemia in 43%. There were no treatment-related deaths.

Best supportive care

Moderate quality evidence came from the control arm of a phase III randomised trial which reported a median overall survival of 4.6 months and a median progression-free survival of 1.5 months for 117 participants receiving best supportive care for progression after first-line chemotherapy (Bellmunt et al., 2009). There were no tumour responses. One patient reported grade 3-4 neutropenia and one patient reported grade 3-4 thrombocytopenia. Nine participants reported grade 3-4 anaemia. Health-related quality of life as measured by the EORTC QLQ-C30, decreased continuously from baseline through to week 18 (mean scores were not reported).

6.2. Managing symptoms of locally advanced or metastic bladder cancer

6.2.1. Bladder symptoms

Radiotherapy can be used to help people with symptoms of incurable bladder cancer. It is sometimes given at the time of diagnosis but may be deferred and used when people are symptomatic. It is most commonly used to treat bleeding from the bladder or pain from the bladder cancer itself or sites of spread. Radiotherapy is also used to improve local control rates in people with advanced pelvic disease. Side-effects are related to the area treated but are usually well-tolerated and include short term urinary frequency and discomfort or diarrhoea and nausea.

The total dose and fractionation of radiotherapy varies across the UK.

Clinical question: What is the optimal pelvic radiotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 143 to 145.

Table 143

GRADE evidence profile: What is the optimal pelvic radiotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Palliative radiotherapy – 35Gy in 10 fractions versus 21Gy in 3 fractions

Table 144

GRADE evidence profile: What is the optimal pelvic radiotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Hypofractionated radiotherapy versus conventional palliative radiotherapy

Table 145

GRADE evidence profile: What is the optimal pelvic radiotherapy regimen for patients with incurable locally advanced or metastatic bladder cancer? Comparison: Palliative radiotherapy for bladder cancer (observational studies)

Evidence statements

Moderate quality evidence about the relative effectiveness of two hypofractionated radiotherapy schedules (35 Gy in 10 fractions over two weeks versus 21 Gy in 3 fractions over one week) for local symptom control of muscle invasive bladder cancer came from one randomised trial (Duchesne et al., 2000). 500 patients were randomised with three month follow-up data available in 272 patients. Overall symptom improvement, defined as improvement of at least one symptom by one grade without worsening another symptom, was 71% in those receiving 35-Gy compared with 64% in the 21-Gy arm, though there is uncertainty about thedifference between treatments (absolute improvement 3%, 95% CI -6% to 12%). Comparing the 35 Gy group with the 21 Gy group for patients with specific pre-treatment symptoms, urinary frequency resolved in 43% and 42%, respectively, nocturia in 51% and 35%, haematuria in 58% and 61%, and dysuria in 47% and 49%. Median survival was 7.5 months in both groups. Two-thirds of participants reported that quality of life symptom scores were either unchanged or improved by the end of treatment and at three months after treatment.

One observational study (Srinivasan et al., 1994) provided low quality evidence about the relative effectiveness of hypofractionated (two-fraction) radiotherapy and conventional palliative radiotherapy in 41 patients selected by performance status. 59% of those receiving two-fraction radiotherapy had clearance of haematuria compared to 16% of those receiving conventional palliation (RR 3.74, 95% CI 1.25 to 11.19). Pain improved in 73% of those treated with two-fraction radiotherapy compared to 37% of those treated with conventional palliation (RR 1.97, 95% CI 1.04 to 3.75). All patients died during follow-up. Mean survival was 9.77 and 14.47 months in the hypofractionated and conventional radiotherapy groups respectively.

Very low quality evidence was reported from seven observational studies using various palliative radiotherapy regimens. Median survival ranged from six to nine months across studies. Complete palliation of symptoms was achieved in 51% of 65 elderly patients treated with 30 Gy in five fractions on a weekly basis, although 28 patients experienced transient worsening of their urinary symptoms with eight requiring hospital admission due to toxicities (McLaren et al., 1997). Jose et al. (1999) reported on a similar radiotherapy schedule with control of haematuria in 50%, frequency in 63%, dysuria 38%, and nocturia 5%. This study also reported toxicity rates of 36% for acute bowel and 63% for acute bladder toxicity. One study of short-term radiotherapy (7Gy 3 times or 5Gy 4 times) reported that none of the 17 patients with severe local symptoms improved after radiotherapy, although improvement was difficult to assess as 10 of these patients died within four months (Holmang et al., 1995). Haematuria was present in 14 patients but it continued in only two after radiotherapy. Another study of short-term radiotherapy (Wijkstrom et al., 1991) reported an improvement in tumour associated symptoms in 75/162 (46%) patients, although 42% had various minor acute side effects and over half the population were treated for tumours considered to be curable. Five-year survival in patients considered to be curable was 21%, compared to 6% in patients treated for bleeding and 0% for patients with other local symptoms.

6.2.2. Loin pain and symptoms of renal failure

In people with locally advanced bladder cancer, with or without metastases, the cancer can sometimes obstruct one or both ureters. If only one kidney is obstructed, the opposite kidney can often maintain normal kidney function. Here the decision to intervene is often based on whether the person has symptoms, such as loin pain, or whether optimal kidney function is essential e.g to enable safe administration of systemic chemotherapy.

However if both kidneys are obstructed, then kidney failure will occur and may be fatal if untreated. Fortunately, this is not common. One option is to manage kidney failure conservatively with no intervention. However, the obstruction can be relieved though, either by a urologist inserting a retrograde stent, or by a radiologist inserting a nephrostomy tube or an antegrade stent.

Treatment is often based on opinion or local resources, leading to widespread variation in practice across the UK.

Clinical question: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 146 to 151

Table 146

GRADE evidence profile: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer? Open nephrostomy, percutaneous nephrostomy, retrograde stents

Table 147

GRADE evidence profile: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer? Retrograde stents for malignant obstructions

Table 148

GRADE evidence profile: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer? Percutaneous nephrostomy for malignant obstructions secondary to bladder cancer

Table 149

GRADE evidence profile: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer? Percutaneous nephrostomy for malignant obstructions

Table 150

GRADE evidence profile: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer? Retrograde stent versus percutaneous nephrostomy for malignant obstructions

Table 151

GRADE evidence profile: What is the best way to manage cancer related ureteric obstruction in patients with bladder cancer? Subcutaneous nephro-vesical/ nephro-cutaneous bypass for malignant obstructions

Evidence statements

Very low quality evidence was identified from 30 retrospective observational studies. All studies report an improvement of renal function and symptom relief in a majority of patients after percutaneous nephrostomy (PCN) or stent placement. Seven studies reported the comparative outcomes of patients who received PCN and those who received retrograde stents for malignant obstructions. Ku et al. (2004) reported that both ureteral stenting and PCN resulted in a decrease of serum creatinine, with no significant difference between groups. One study reported that serum creatinine increased in all patients (n=110), with a smaller elevation of creatinine levels in the PCN group than in the stent group (Chang et al. 2012). This study also reported that residual hydronephrosis after diversion was more common in the stent group than the PCN group (65% versus 27%).

Four studies reported complications of PCN (n=218) and ureteral stents (n=156). Similar rates of complications were reported with ureteral stents (28.8%) and PCN (30.3%). A further study (Chang et al. 2012) reported that the stent group had more frequent UTI, including urosepsis and pyelonphritis, than the PCN group, although this difference was non-significant.

Two studies reported overall survival in patients who underwent stenting and in those who underwent PCN (Kanou et al., 2007; Wong et al., 2007). Average overall survival was 5.6 and 9.2 months for ureteral stents and 5.9 and 6.5 months for PCN.

One study reported that 21% (11/52) of patients were treated with chemotherapy after successful drainage of the kidneys. It is not reported which intervention these patients received (Hubner et al. 1993). In one study, 1/30 patients with bladder cancer had a total cystectomy with urinary diversion for muscle-invasive disease after relief of obstruction (Chitale et al., 2002).

One study reported that responses to quality of life surveys were not significantly different for patients receiving nephrostomy tubes (n=16), double-J stents (n=15) or nephroureteral stents (NUS, n=15). Patients who had double-J stents reported more pain, dysuria, and urinary frequency, compared with nephrostomy tubes and NUS at 30 and 90 days after placement (Monsky et al., 2013).

6.2.3. Intractable haematuria

Intractable bleeding from the bladder is one of the most serious terminal complications for patients with bladder cancer because it is usually painful because clots form and block bladder drainage, it is frightening for the affected person and their carers, it is difficult to manage, and almost certainly means that the person will have to be admitted to hospital for care. Intractable bladder bleeding may occur before the person is in a terminal phase but it may be the terminal event for people with bladder cancer. This means that they may die in hospital and certainly may lose precious hours and days that they would have rather spent at home with their family.

Severe bleeding can arise from the bladder cancer itself, or from the effects of radiation or cyclophosphamide, and infection can complicate and worsen bleeding from all of these. Patients with severe haematuria are often elderly and already extremely frail.

Treatments for intractable bleeding include:

• Palliative TURBT
• Tranexamic acid
• Palliative radiotherapy
• Embolisation
• Palliative chemotherapy
• Urinary diversion

Clinical question: What specific interventions are most effective for patients with incurable bladder cancer and intractable bleeding?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 152 to 154. No evidence was identified for palliative TURBT, urinary diversion, or tranexamic acid.

Table 152

GRADE evidence profile: The effectiveness of hypofractionated radiotherapy versus conventional palliative radiotherapy for intractable bleeding.

Table 153

GRADE evidence profile: The effectiveness of embolisation for intractable bleeding.

Table 154

GRADE evidence profile: The effectiveness of regional intra-arterial chemotherapy (RIAC) for intractable bleeding.

Evidence statements

Palliative radiotherapy

One observational study (Srinivasan et al., 1994) provided very low quality evidence about the relative effectiveness of hypofractionated (two-fraction) radiotherapy and conventional palliative radiotherapy in 41 patients selected by performance status. 59% of those receiving two-fraction radiotherapy had clearance of haematuria compared to 16% of those receiving conventional palliation (RR 3.74, 95% CI 1.25 to 11.19). One observational study of 32 patients also selected for hypofractionated radiotherapy if they had a poor performance status (Lacarriere et al., 2013). After 2 weeks of radiotherapy, 79% of patients receiving hypofractionated radiotherapy (20Gy/5 fractions/1 week) and 54% of the conventional radiotherapy (30Gy/10 fractions/2 weeks) group had complete clearance of hematuria (RR 1.47, 95% CI 0.84 to 2.55). At six months 37% and 23% in the hypofractionated and conventional radiotherapy group had no haematuria (RR 1.60, 95% CI 0.5 to 5.06).

Embolisation

Four observational studies including a total of 67 patients provided very low quality evidence for embolisation of the internal iliac arteries. Immediate control of bleeding was seen in 57/67 (85%) patients, with control rates ranging from 82% to 100% across studies. Permanent control of bleeding with mean follow-up ranging from 10 to 22 months across studies was achieved in 34/66 (51.5%) patients. The range of permanent bleeding control rates ranged from 43% to 100% across studies. After embolisation, 27% of patients required transfusion for haematuria. None of the studies reported any major treatment-related complications, except for Jenkins & McIvor (1996), where one patient who did not receive prophylactic antibiotics died from septic shock 12 hours after embolisation. Ligouri et al. (2010) reported that minor complications were post-embolisation syndrome (27%), fever (11%), gluteal pain (14%), and nausea (2%).

Chemotherapy

One observational study (Mantadakis et al., 2003) provided very low quality evidence of regional intra-arterial chemotherapy (RIAC) for the symptomatic relief of patients with advanced bladder cancer who were unsuitable for surgery. Gross haematuria was present in all 32 patients prior to RIAC, which had resolved in 24/32 (75%) after treatment. There were no hemorrhagic, thrombotic or embolic complications, and no episodes of nausea or emesis. One patient developed grade three mucositis.

6.2.4. Intractable pelvic pain

Intractable pelvic pain is one of the most serious end of life complications for people with bladder cancer. The pain is very distressing for them and their family/carers and is difficult to manage. It is important to take into account prognosis in shared decision making about intractable pelvic pain. It is not only the treatment but also where this takes place (for example home, hospital, hospice) that is important to the person and their family/carers. The effects of poor management of intractable pelvic pain can also markedly worsen the bereavement process for family and carers.

Important issues regarding pelvic pain in people with incurable bladder cancer include:

• Communication with the person and their family and explanation that this could be a terminal event
• The treatment options for the pain
• Other supportive care options
• Options for place of care: hospital, hospice, home, nursing home

Clinical question: What specific interventions are most effective for patients with incurable bladder cancer and pelvic pain?

Clinical evidence (see also full evidence review)

The evidence is summarised in tables 155 to 157.

Table 155

GRADE evidence profile: The effectiveness of radiotherapy for cancer-related pelvic pain in patients with advanced cancer.

Table 156

GRADE evidence profile: The effectiveness of chemotherapy for cancer-related pelvic pain in patients with advanced cancer.

Table 157

GRADE evidence profile: The effectiveness of hypogastric plexus block for cancer-related pelvic pain in patients with advanced cancer.

Evidence statements

Radiotherapy

One observational study (Srinivasan et al., 1994) provided very low quality evidence about the relative effectiveness of hypofractionated (two-fraction) radiotherapy and conventional palliative radiotherapy in 41 patients selected by performance status. Pain improved in 73% of those treated with two-fraction radiotherapy compared to 37% of those treated with conventional palliation (RR 1.97, 95% CI 1.04 to 3.75). One study (58 patients) of hypofractionated radiotherapy and one study (12 patients) of short course accelerated 3D-CRT both reported a decrease in patient-reported pain after treatment, as measured on a visual analogue scale (VAS). These two studies reported an acute Grade 1-2 GI toxicity rate of 21% and an acute Grade 1-2 GU toxicity rate of 35% (Kouloulias et al., 2013; Caravatta et al., 2012). One study provided very low quality evidence for quality of life in 13 patients, reporting no statistically significant difference between baseline and post-treatment scores, although an improvement was noted in all indexes (Caravatta et al., 2012).

Chemotherapy

Very low quality evidence from one prospective nonrandomised phase II study (30 patients) of second-line gemcitabine chemotherapy in cisplatin-refractory patients, reported that VAS pain values significantly improved in the group of patients who responded to chemotherapy (Albers et al., 2002). One retrospective study of 35 patients receiving second-line gemcitabine and paclitaxel chemotherapy, reported very low quality evidence that 80% (28/35) of patients reported a decrease in VAS scores without increasing the dose of analgesics or had a decrease in analgesic consumption (Miyata et al., 2012). The most common toxicity reported in both studies was Grade 3-4 leucopenia (36% with gemcitabine monotherapy, 14% with gemcitabine/paclitaxel). Very low quality evidence for quality of life as measured by the 10-point Spitzer scale was reported in one study (Albers et al., 2002). Mean quality of life scores for patients who did not respond to chemotherapy decreased before and after treatment (7.8 ±2.4 to 6.7 ±2.2), representing a worsening of quality of life. Quality of life scores for responders were similar before and after treatment (8.0 ±1.6 to 8.1 ±2.5).

Nerve block

Evidence of very low quality was provided by five studies reporting on the treatment of pelvic pain with a hypogastric plexus block. Two studies reported that satisfactory pain relief was achieved in 72% (133/185) of patients after one or two procedures, who all reported a VAS pain score of 8 or more out of 10 (worst possible pain) before the procedure (De Leon-Casasola et al., 1993; Plancarte et al., 1997). One study of 28 patients reported a mean pain reduction of 70% as assessed with verbal and visual analogue scales before and after treatment, although mean patient scores at baseline and follow-up were not reported (Plancarte et al., 1990). One study reported that VAS pain scores decreased from baseline at 24h, 1 week, 1 month and 2 months after treatment (p<0.05), but at three months mean scores increased and were no different from baseline (Gamal et al., 2006). Four studies (including 225 patients) provided very low quality evidence for treatment-related morbidity, with three studies reporting no intraoperative complications and one study (Gamal et al., 2006) reporting intravascular puncture (n=2, 13%) and urinary injury (n=4, 27%).

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