Synergo for non-muscle-invasive bladder cancer

The patient and clinical experts said that there are few alternatives to radical cystectomy for people with high-risk non-muscle-invasive bladder cancer (NMIBC) that has not responded to or has recurred after Bacillus Calmette-Guerin (BCG) treatment, or when people cannot have BCG treatment. The clinical experts explained that if people do not want or cannot have a cystectomy, the only options are to have experimental treatment through clinical trials, or cystoscopy every 3 months to monitor disease progression and resection to remove visible tumours. The committee agreed that there is an unmet clinical need for additional treatment options in high-risk NMIBC after BCG failure or when people cannot have or do not want BCG treatment. Mitomycin C (MMC) using Synergo may offer an additional option for these people.

The clinical experts noted that, compared with MMC alone or BCG therapy, treatment with Synergo requires additional nurse time. This is because a specialist nurse has to accompany the patient throughout the treatment session. Because there are a lot of people with intermediate-risk cancer, or high-risk cancer needing first-line treatment (indicated for BCG), routine use of Synergo in these groups would be resource intensive and it would be difficult to cope with the demand in clinical practice. They agreed that the area with the greatest clinical need, and therefore the most appropriate place for Synergo in the pathway, was as an alternative to further intravesical therapy with BCG or radical cystectomy for high-risk NMIBC that has not responded to, or recurred after, BCG treatment. The clinical experts said it could also be considered for people who cannot tolerate BCG or who have a contraindication, or if access to BCG is limited. Clinical experts noted that there had been a national BCG shortage in the past and MMC using Synergo was used during this time as an alternative first-line treatment in high-risk NMIBC. The committee concluded that it would base its decision making on using Synergo for high-risk NMIBC that has not responded to or has recurred after BCG treatment, or when people cannot or do not want to have BCG treatment.

The 3 randomised controlled trials (RCTs) positioned Synergo differently in the clinical pathway and all stopped early. The clinical experts agreed that, of the 3 RCTs, the HYMN trial (a phase 3, multicentre, open-label RCT) best reflected the most appropriate position in the NHS clinical pathway. This is because it included people with recurrence of NMIBC after BCG therapy. However, they explained that a second course of BCG therapy (which was the comparator in the HYMN trial) is not usually offered for high-risk NMIBC that does not respond to BCG. Overall, the committee considered the RCT evidence was not particularly generalisable to these groups because of the comparators in the trials (MMC alone [Colombo et al. 2003, 2011], further BCG therapy [HYMN trial] or MMC-EMDA [Arends et al. 2016]). The trials also had a heterogenous patient population that included people with intermediate-risk and high-risk cancer, different categories of BCG failure, and people with both papillary and carcinoma in-situ (CIS) tumours. And none of the trials involved an appropriate ablative dose for people with CIS tumours, which introduced further uncertainty in this subgroup. Experts advised the committee that CIS tumours differ from papillary tumours and appear to be more difficult to treat. The committee concluded that the clinical benefit at the appropriate position in the NHS treatment pathway was unclear from the available RCT evidence. But, based on expert advice, it agreed that Synergo showed promise.

A clinical expert said that data published from their NHS centre shows that outcomes (time to recurrence and mortality) are the same after radical cystectomy for people who had treatment with Synergo and people who did not (Sri et al. 2020; see section 3.7). The committee was reassured that offering treatment with Synergo after BCG failure does not seem to affect patients' long-term outcomes.

The clinical experts said patient selection was important when considering treatment with Synergo. They said that before starting treatment with Synergo, the person should have an up-to-date cystoscopy and repeat transurethral resection of bladder tumour (TURBT) to confirm the absence of residual papillary tumours and ensure the prostatic urethra is free of disease. The clinical experts said that Synergo would not be recommended for cancer that is suspected to have spread outside the bladder or in people with bladder wall diverticulum (a pouch, pocket or sac that protrudes out of the bladder wall). One of the clinical experts said that Synergo may be more effective than suggested by the HYMN trial because of suboptimal case selection in the trial.

The clinical experts said that Synergo should not be delivered in every hospital but in specialised centres only, and offered on a regional cancer network basis. This is because patient selection and treatment require consultants specialised in treating bladder cancer and a dedicated team of bladder cancer nurse specialists trained in using the technology. The clinical experts and company confirmed that currently treatment with MMC using Synergo is delivered at 5 NHS centres. The patient expert noted that, because access to Synergo is limited to a small number of NHS centres, some people may have to travel long distances for treatment. However, they said that people were willing to travel because there were few other acceptable treatment options available. The patient expert also said that many clinicians do not seem to be aware of Synergo as a treatment option, or are reluctant to offer it if travel is needed. They noted this may disadvantage some people who may be willing to have treatment with Synergo. The clinical experts also explained that the company provides theory-based and practical training with the system. One clinical expert said that their centre has also developed specific in-house training for nurse competency.

The patient expert said that pain during treatment with Synergo built up over the course of treatment sessions, but that it was possible to learn how to manage the side effects. They said it did not stop them from continuing with treatment. The clinical experts explained that treatment with Synergo is intensive and that side effects vary between people. But they noted they are mostly tolerated and can normally be managed by a dedicated nurse team. The patient and clinical experts also said that the posterior wall of the bladder can be burnt during treatment with Synergo. The clinical experts explained that this is an anticipated side effect of Synergo, is often symptomless and is normally seen during routine follow-up cystoscopies. They said that this reaction appears to resolve without medical treatment. The committee also acknowledged that adverse events and treatment side effects may differ for men and women and that treatment with Synergo is contraindicated in pregnancy.

The clinical experts explained that caution is needed when Synergo is used for people with pacemakers or implantable cardiac devices. They said these people should have a cardiologist involved in their treatment. The company confirmed that there is information on cardiac monitoring for these people in the user manual for the technology. A clinical expert also explained that 1 person with metal in their pelvis had increased pain with Synergo treatment. Metallic implants are also listed as a precaution in the user manual.

The committee accepted the external assessment centre's (EAC) changes to the company model, which showed treatment with MMC using Synergo was cost saving when compared with MMC alone. However, the committee agreed that the modelled clinical scenario comparing MMC using Synergo with MMC alone does not reflect use of the technology in the NHS so has limited relevance. The committee agreed that the additional analysis by the EAC using data from the HYMN trial better reflected current NHS use and that, in this clinical scenario, use of Synergo is likely to be cost incurring. But the committee also noted that the clinical evidence used to populate the model had substantial limitations, which affected the robustness of the model and the certainty of the results. The committee accepted the EAC's additional economic modelling but considered that, because of the uncertainties and the lack of robust clinical data to inform the model, it was difficult to draw firm conclusions about any cost benefits in high-risk NMIBC after BCG failure or when people cannot have BCG.

The EAC's additional economic model compared MMC using Synergo with second-line BCG. It assumed that everyone who subsequently has a recurrence is offered and accepts cystectomy. The clinical experts said that not all people are fit enough or willing to have surgery, and that these people would normally have repeat cystoscopy and TURBT every 3 months to monitor disease progression and remove recurrent tumours. The clinical experts also noted that some people with a high risk of progression would not be offered further BCG and would be considered for cystectomy instead. The committee understood the difficulties in modelling because of the lack of relevant data, but did not believe an appropriate comparison was made. The EAC explored the cost impact of reducing how many people had a cystectomy for recurrence after intravesical treatment in all models through additional sensitivity analysis. It also did exploratory modelling evaluating the cost of MMC using Synergo compared with cystectomy. It emphasised that these analyses were exploratory only and had several limitations, including uncertainty about the mortality rate for people unable or unwilling to have a cystectomy. The committee concluded that the modelling and assumptions do not fully capture the clinical management of all people eligible for Synergo. Based on the analyses presented at its preferred position in the treatment pathway Synergo was not likely to be cost saving.

The committee noted that in all the models using Synergo resulted in a reduction in radical cystectomies, an increase in total life years and an increase in quality-adjusted life years (QALYs). But the committee concluded that these results were highly uncertain because the models, and the data used to populate them, had limited relevance to the NHS.

Two of the RCTs for Synergo did not recruit enough people. The clinical experts highlighted the challenges of doing RCTs in a patient population with high-risk cancer after BCG failure or in people who cannot have BCG. The relatively small number of patients per NHS centre for whom BCG had not worked, and who would be eligible for Synergo treatment, makes trial recruitment difficult. Because there are few NHS centres currently offering treatment with Synergo, some people will need to travel for treatment, which would further affect participation in trials. One clinical expert noted that single-arm trials are now being accepted because of the ethical implications of doing RCTs in patients with high-risk NMIBC that has not responded to BCG. The committee accepted the challenges in doing RCTs in this patient population and agreed that further evidence from RCTs may not be feasible.

The clinical experts confirmed that all NHS centres using Synergo are required to prospectively collect outcome data in accordance with recommendations set out by NICE interventional procedures guidance on intravesical microwave hyperthermia and chemotherapy for NMIBC. The committee concluded that analysing the data collected from UK centres using Synergo may help address the uncertainty in the evidence base. In addition, collecting resource use data will inform a revised cost analysis comparing Synergo to cystectomy or repeat cystoscopies in people who cannot have cystectomy. Outcomes should include bladder preservation rates and bladder cancer-specific mortality.

The committee felt that without more robust evidence of clinical effectiveness, further information is needed to better understand how Synergo works and if the microwave energy has an additional biological effect beyond heating. The committee understood that the frequency of radiofrequency used by the Synergo system (915 MHz) is an unlicensed and safe frequency used in radiocommunication. The company explained that preclinical data showed a direct and selective effect of radiofrequency on cancer cells. It also said that studies showed increased concentrations of MMC in the bladder wall of people having treatment with Synergo. The committee noted there are other device-assisted chemotherapy options currently used in the NHS. In particular, conductive hyperthermic intravesical chemotherapy, which heats the circulating chemotherapy drug outside the bladder. The committee was aware that published evidence on the efficacy of other device-assisted chemotherapy options is limited at present. However, it agreed that information on the benefits and costs of Synergo, compared with other device-assisted chemotherapy technologies available in the NHS, could improve clinical decision making.