Clinical and technical evidence

A literature search was carried out for this briefing in accordance with the interim process and methods statement. This briefing includes the most relevant or best available published evidence relating to the clinical effectiveness of the technology. Further information about how the evidence for this briefing was selected is available on request by contacting mibs@nice.org.uk.

Published evidence

Six studies are summarised in this briefing, selected based on the most relevant technology and outcomes. They include 3 trials and 3 observational studies. There were 829 people with non-muscle-invasive bladder cancer in the selected studies.

The clinical evidence, and its strengths and limitations, is summarised in the overall assessment of the evidence.

Overall assessment of the evidence

Evidence was collected from an open label trial (Tan et al. 2018). This showed that there was no significant difference in disease-free survival. Also, there was no significant difference in complete response rate of carcinoma in situ between people having radiofrequency-induced thermo-chemotherapeutic effect (RITE) and a control group who had Bacille Calmette‑Guérin (BCG) instillation. People included in the study were from 14 sites throughout the UK, but the trial terminated early and did not reach its target number of people. A proportion of people in the control group (up to 23%) also had electromotive drug administration, and no subgroup analysis of this group was included in the study. There was also no difference in recurrent-free survival between the chemohyperthermia and BCG group (Arends et al. 2016). But the results of an early trial (Colombo et al. 2011) reported a significantly better survival rate for thermo-chemotherapy than chemotherapy alone.

One comparative observational study compared disease-free survival in people who had treatment with Synergo with those who had electromotive drug administration (Ragonese et al. 2019). The study is reported as an abstract with no details of methods. Two non-comparative studies reported outcomes including recurrence-free survival (van Valenberg et al. 2018, Arends et al. 2014). The limitations of the studies are retrospective study design and selection bias.

Two studies (Arends 2016, Colombo 2011) used Synergo in people who had not had BCG before. There were 4 other studies that used Synergo in people whose disease had not responded to BCG treatment. More evidence is needed from randomised controlled trials for this technology in the NHS, and on benefits and costs. A multicentre prospective randomised trial could address the overall risks and benefits of the Synergo system.

Ragonese et al. (2019) (an abstract)

Study size, design and location

A retrospective single-centre interventional study. The study evaluated 142 people who had non-muscle-invasive bladder cancer and whose disease did not respond to BCG treatment (a form of immunotherapy). They either had chemohyperthermia (n=72, group A) or radical cystectomy (n=70, group B).

Intervention and comparator

Synergo for chemohyperthermia (device-assisted therapy). Electromotive drug administration of mitomycin C (EMDA-MMC system) was the comparator.

Key outcomes

The median follow up was 59 months (standard deviation 5.3). Overall high-grade disease-free survival (HGDFS) was 51.4% in group A and 84.3% in group B (p<0.05). Within group A, 42 patients had chemohyperthermia using Synergo and 30 patients had electromotive drug administration (EMDA-MMC system). HGDFS was 50% in EMDA and 52.4% in Synergo group (p<0.05).

Strengths and limitations

This is a retrospective comparative study. In group A only 42 patients had chemohyperthermia using Synergo.

Tan et al. (2018)

Study size, design and location

An open-label, two-arm, phase 3 randomised controlled trial done in the UK. The study included 104 patients with recurring intermediate or high-risk non-muscle-invasive bladder cancer who either had RITE (n=48) or BCG instillation and then maintenance therapy.

Intervention and comparator

Synergo was used for RITE, comprised of 2 30-minute cycles, each with 20 mg mitomycin C at 42°C (range 40°C to 44°C, 40 mg mitomycin C in total).

People in the control arm had either 6 consecutive weekly BCG instillations followed by maintenance therapy, or institutional standard of care defined at randomisation.

Key outcomes

All people were followed up for a minimum of 24 months. No significant overall benefit was seen in disease-free survival when comparing RITE with the control group (HR=1.33, 95% confidence interval [CI] 0.84 to 2.10, p=0.23). There was no significant difference in the complete response rate of carcinoma in situ at 3 months between RITE and the control group (odds ratio 0.43, 95% CI 0.18 to 1.28, p=0.15). There were 5 people in RITE group who did not complete 6 or more instillations because of adverse events. These included skin rash, urinary urgency and nocturia. There were 42 patients in the RITE group who experienced one or more adverse events, and there was no difference seen in adverse events between each treatment group.

Strengths and limitations

The trial stopped early at interim analysis stage and did not reach its target number of people. People having treatment in the control group also had electromotive drug administration (23%).

van Valenberg et al. (2018)

Study size, design and location

A retrospective study including 150 people with histologically proven carcinoma in situ of non-muscle invasive bladder cancer. People were treated with radiofrequency-induced chemohyperthermia using mitomycin C (MMC). People included in the study were from 6 international centres including 2 units in the UK.

Intervention and comparator

Synergo was used for radiofrequency-induced chemohyperthermia. Typically, MMC was used in a dose of 40 mg/50 ml with a total of 80 mg MMC in an hour. People were treated weekly for 4 weeks to 8 weeks depending on the planned induction schedule. This was followed by maintenance instillations (one instillation every 4 weeks to 8 weeks). The study had no comparator.

Key outcomes

The complete response rate after 6 months was 66.2%. For people whose disease did not respond to BCG, the complete response was 46.0%. This significantly differed from other people who had BCG treatment and people who had not had treatment before (71.7% and 83.0% respectively, p<0.001). In patients with a complete response, the subsequent recurrence rate and recurrent-free survival after 2 years of follow up were 18.8% and 74.5%. The rates did not differ significantly regardless of treatment history. In 13.3% of people, progression to muscle-invasive bladder cancer with or without lymph node or distant metastasis at final follow up was seen. This consisted of 16.0% in people whose disease did not respond to BCG treatment, 13.0% in others who had BCG treatment, and 10.6% in people who had not had treatment before (p=0.74). There were 13.4% of people who stopped induction because of adverse events, and 17.8% of people who stopped maintenance RF‑CHT instillations because of adverse events.

Strengths and limitations

The study is a retrospective review of people who had treatment with RF‑CHT. The authors noted that the collected data were very heterogeneous because of randomly missing values and different standards of treatment and follow up between the participating centres. Study population was selected based on pathology or combined cystoscopy and cytology availability. This may result in potential bias towards higher tumour rates or non-response in the study.

Arends et al. (2016)

Intervention and comparator

Synergo was used for intravesical chemohyperthermia with MMC (n=92). The comparator was BCG immunotherapy (n=98).

Key outcomes

All people were followed up at least 24 months after randomisation. There was no significant difference in recurrent-free survival when comparing chemohyperthermia with the BCG group in people with no carcinoma in situ (intention-to-treat analysis, 78.1% compared with 64.8%, p=0.08). The complete response rate of people with carcinoma in situ at 3 months was 88.9% in the chemohyperthermia group compared with 85.7% in the BCG group. No statistically significant difference was seen (p=1).

In the chemohyperthermia group, 0 patients (0.0%) showed progression to muscle-invasive disease, compared with 1 (1.4%) in the BCG group. The most common adverse events during chemohyperthermia treatment sessions were bladder spasms (n=206, 14.4%) and bladder pain (n=202, 14.1%).The most prevalent adverse events after treatment were dysuria (n=167, 11.7%), nocturia (n=147, 10.3%) and urinary frequency (n=141, 9.9%).

Strengths and limitations

The authors noted that the trial closed prematurely and so is underpowered. This is a randomised trial but blinding of treatment for patients and physicians was impossible, which may have resulted in bias. Survival outcomes were not reported in people with carcinoma in situ.

Arends et al. (2014)

Intervention and comparator

The Synergo system simultaneously gave local microwave-induced hyperthermia and intravesical chemotherapy. There was no comparator.

Key outcomes

Of those included in the study, 20 people (13%) had treatment with Epirubicin and 129 (81%) had previous BCG treatment. Median follow up was 75.6 months. The 1‑ and 2‑year recurrence-free survival was 60% and 47%, respectively. Muscle-invasive progression was seen in 7 patients (4.3%). Adverse events were mild, transient and mostly limited to the genitourinary tract.

Strengths and limitations

The retrospective study design is subject to selection bias and information bias. There was no comparator.

Colombo et al. (2011 and 2003)

Intervention and comparator

The Synergo system gave intravesical thermo-chemotherapy. The comparator was intravesical chemotherapy alone.

Key outcomes

All 75 people who completed the study (35 of 42 in the treatment arm, 40 of 41 in the control arm) were followed up for a minimum of 2 years. The median follow up for people who were tumour free was 91 months. The 10-year disease-free survival rate for thermo-chemotherapy and chemotherapy alone was 53% and 15%, respectively (p<0.001). An intention-to-treat analysis also showed a significant higher survival using thermo-chemotherapy compared with the control treatment. Bladder preservation rates for thermo-chemotherapy and chemotherapy alone were 86% and 79%, respectively (p value was not reported).

Strengths and limitations

An analysis of long-term follow up was done of people who had intravesical thermo-chemotherapy. The risk of bias cannot be assessed based on the information in the abstract (Colombo et al. 2011).

Sustainability

The company claims that the technology could support sustainability by reducing the need for cystectomy in some patients and reducing the need for in-hospital theatre resources. This is because Synergo is used in an outpatient setting. There is no published evidence to support these claims.

Recent and ongoing studies

Severity of overactive bladder symptoms in patients after Synergo treatment (OACSYNERGO). ClinicalTrials.gov Identifier: NCT01955408. Status: recruitment completed. No interim results published. Indication: overactive bladder, bladder cancer. Devices: Synergo. Last update on 6 October 2017.