UK Guidelines Offer Coherent Approach to Rare Bladder Cancer

Liam Davenport

October 07, 2019

BARCELONA — A standardised approach to the diagnosis of a rare and aggressive form of bladder cancer has been developed by UK experts after conducting, for the first time, a national audit that gave a picture of the typical patient presentation and outcomes with current treatment approaches.

Small cell bladder cancer (SCBC) accounts for less than 1% of all carcinomas of the bladder and is associated with poor outcomes due to early metastatic spread.

However, there is currently no standardised management pathway in the UK for the disease, and treatment varies between institutions.

Bladder Cancer Audit

A team led by Dr Caroline Chau, consultant oncologist, Queen Alexandra Hospital, Portsmouth, therefore conducted an audit of more than 400 patients treated over a 10-year period at 26 centres.

Presenting their results at the European Society for Medical Oncology Congress 2019, they said that, to their knowledge, this is "the largest reported European retrospective study in small cell bladder cancer to date".

Dr Simon Crabb, associate professor in medical oncology at University of Southampton, who also took part in the study, said that one of the most important findings was that the prognosis of SCBC is "not good".

He told Medscape News UK that, even when the disease is localised to the bladder, "over half of patients will die of the disease", which he emphasised underlines the "significant unmet need in terms of how we treat people".

Dr Crabb added that, as is "inevitable if you don’t have any prospective clinical trials in a rare disease", the audit showed that "there is a degree of diversity in what people have been doing".

Consequently, they developed a UK management pathway in conjunction with the National Cancer Research Institute (NCRI) to standardise the staging and treatment of SCBC.

Dr Crabb, who is also a member of the NCRI Bladder and Renal Group, said that, while the underlying evidence was "not strong", the aim was to ensure that there is "at least consistency" in the management of SCBC across the UK.

Treatment Variations

The current study came about after Dr Chau and colleagues conducted a regional audit 2 years ago in Southampton, Portsmouth and Bournemouth, involving 52 patients.

Dr Chau told Medscape News UK that: "This showed a very varied treatment approach between the three centres, and so this was the reason for expanding it to a national level, as I know this has not been done before."

The researchers therefore conducted a retrospective analysis of patients presenting with SCBC at 26 institutions across the UK, including two in Scotland and one in Northern Ireland, between 2006 and 2016.

They included 409 eligible patients, who had a median age of 71 years, and 75% of whom were male. More patients (65.3%) presented between 2011 and 2015 than between 2006 and 2010.

Pure histology was seen in 46.2% of cases, while in 52.1% of patients it was mixed. There was also a fairly even split by disease stage at diagnosis, with 48.9% having N0M0 disease and the remaining 42.1% having N+ or M+ SCBC.

Unlike previous studies, just six (1.5%) of patients had brain metastases, which the researchers say suggests that "there is unlikely to be a role for prophylactic brain radiotherapy".

Primary chemotherapy was given to 60.4%, while 22.2% of patients were deemed unfit for treatment. Primary chemotherapy was more commonly given to N+/M+ patients, at 69.2%.

The most frequently used chemotherapy regimen was carboplatin + etoposide in 54.7%, followed by cisplatin + etoposide in 17.0% and cisplatin + gemcitabine in 14.2%, with the majority (55.9%) of patients receiving 4–6 cycles.

The mean time from diagnosis to first chemotherapy was 47 days.

Definitive treatment in N0M0 disease was radiotherapy in 52.0% and cystectomy in 30.5%.

By the data cut-off of 1st February 2018, the median overall survival was 15.9 months, with 28.3 months for N0M0 disease and 12.7 months for N+/M+ SCBC.

The median overall survival for N0M0 patients who underwent cystectomy was 26.7 months versus 30.0 months for those given radiotherapy.

Median overall survival was 21.6 months for patients given chemotherapy versus 11.3 for those who did not receive it.

Controversial Treatment Choices

Dr Chau told Medscape News UK that it was "interesting to see that there was an equal split between pure and mixed SCBC, and that their outcomes are similar", whereas a worse outcome with pure cell disease could be expected.

She also highlighted that there was an even split in the use of radical radiotherapy and cystectomy, and no significant difference in outcomes.

Dr Crabb said the choice between the two treatments is "controversial for the more common version of bladder cancer and so it’s even more so for this because there’s even less data to base that on".

An attempt was made to conduct a randomised controlled trial to compare radical radiotherapy and cystectomy, but it "wasn’t possible to randomise patients, primarily because patients wanted to have a choice - not unreasonably".

Dr Crabb continued: "The indications for either are largely overlapping. There is a minority of patients where it’s clear one is a more appropriate choice but that’s actually a relatively small group of people, and so the majority should be offered a choice [and] the stance of the UK community overall is that choice is what matters."

Consensus Pathway

Based on their findings, the researchers, supported by the UK NCRI Advanced Bladder Cancer subgroup, developed a UK Consensus Pathway  for the management of SCBC, which they presented at the 2019 British Uro-oncology Group Annual Meeting in September.

This sets out the criteria for histologically confirmed SCBC and how to manage the disease by stage, underlying the need for a "prompt start" to chemotherapy and how to approach cases of progressive disease.

For early stage disease, chemotherapy is to be used in the neoadjuvant setting prior to radical cystectomy or radiotherapy, while six cycles of platinum-based chemotherapy is the first line treatment in more advanced disease.

Dr Crabb said that the consensus is that "everyone, if they’re fit enough, should have chemotherapy first, and that was a clear recommendation of the group of authors that were involved in this".

"Then, again, that there should be choice, with a clear explanation that we don’t have strong data on making these recommendations, because we don’t have prospective or high-quality evidence."

Dr Crabb said that, following chemotherapy "most of us would feel you should then go on to have either radiotherapy or cystectomy, and also that this should be done relatively rapidly," and in specialised centres.

This is in line with the National Institute for Health and Care Excellence (NICE) bladder cancer guidelines, which Dr Crabb noted "talks about common bladder cancer but it specifically excludes this disease and some other rare histologies".

Consequently, the Consensus Pathway "was a way of providing a national approach where there was a gap".

Continuing Research

The researchers plan to continue with the audit to gather prospective data that should help not only drive up standards of care but also allow the continuous development of the care pathway.

"There’s always the challenge when you look into a retrospective review of risk that it contains bias," Dr Crabb noted.

He added that, if the Consensus Pathway means that patients will be treated in "a coherent manner and that people across the country will get the same advice and recommendations, then you can collect prospective data, which by its nature will be better quality".

Dr Crabb said: "We hope then that we could refine in the future what the guidelines actually say so that this becomes an iterative process."

Whether that could lead to an interventional prospective trial "in a disease that is as rare as this, is not clear," he continued.

"We are trying to develop a prospective trial in another rare bladder cancer subtype, squamous cell carcinoma, at the moment and so if that’s a success, then it may be possible to expand out into small cell carcinoma or other rare subtypes."

He concluded that studies such as this "are important because they’re not going to be done by the pharmaceutical industry".

"We will have to go about it from the academic community."

Dr Crabb said that the NCRI is trying to "fill in gaps of this sort, and so we’re very pleased with the fact that we’ve managed to do this ... and we hope that it will be successful going forwards".

No conflicts of interest or funding declared.

ESMO Congress 2019: Abstract 928P. Presented 30th September.

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