Scientific information

The evidence for Hexvix®

Hexvix® blue-light cystoscopy significantly improves the detection of bladder tumors compared to white light cystoscopy

A number of studies have demonstrated the improved detection with Hexvix® blue-light cystoscopy compared to white light cystoscopy alone. 12, 13, 14, 15, 19, 20, 21, 22, 23

A recent published meta-analysis based on raw data shows that one single Hexvix® blue-light cystoscopy detects a significant number of additional patients with bladder cancer compared to white light cystoscopy alone. The meta-analysis confirms the findings of previous studies, which show that the benefit is particularly high in patients with carcinoma in situ (CIS) and persists in both primary and recurrent patients. 16

 

Detection at a patient level

*Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

*Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

  • More than 25% of patients with CIS might not have had their CIS detected and received the correct treatment, such as Bacillus Calmette-Guérin (BCG), if only examined with white light cystoscopy.

  • Even patients with primary Ta/T1 tumors benefit significantly from Hexvix® blue-light cystoscopy compared to white light cystoscopy alone.
  • There is a significant improvement in detection of lesions with Hexvix® blue-light cystoscopy in all risk groups.

    *Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

    *Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

Click here for more data on detection.

 

*NMIBC=non-muscle invasive bladder cancer

*NMIBC=non-muscle invasive bladder cancer

In a phase III study of 58 patients with CIS: 17

  • More lesions were found by Hexvix® blue-light cystoscopy than by white light cystoscopy, in 42% of patients (n=22).
  • Of a total 113 CIS lesions in these 58 patients, Hexvix® blue-light cystoscopy detected 92% (n=104), while 68% (n=77) were detected by white light cystoscopy alone.

In another phase III study: 12

  • 32% of the patients with CIS were detected with Hexvix® blue-light cystoscopy only.
  • Ta/T1 tumors that had not been seen under conventional white light cystoscopy were detected in 16% (n=47) of the patients by using Hexvix® blue-light cystoscopy.

 

Hexvix® blue-light cystoscopy leads to more appropriate treatment decisions

Hexvix® blue-light cystoscopy reduces tumor recurrence by up to 12 months

The recent meta-analysis by Burger et al confirms that the improved detection with Hexvix® blue-light cystoscopy is associated with a significant overall reduction in recurrence at 12 months of approximately 11% and 16.6% in patients with CIS or T1 tumors, respectively, which might translate into less frequent need for resection. 16

Graph 5

Reduction in the risk of recurrence was confirmed at a patient level

  • By 10.9% overall (p=0.006, RR=0.761) and in all risk groups
  • The highest reduction was observed in the low-risk group 16.8% (p=0.029, RR=0.561)
  • Prior intravesical therapy did not affect the ability of Hexvix® blue-light cystoscopy to identify additional patients with Ta/T1 or CIS (Note: only one recurrence study provided information on prior therapy)

In a phase III study: 12

  • In patients with Ta/T1 lesions, Hexvix® blue-light cystoscopy demonstrated a 16% relative reduction of tumor recurrence, compared to white light cystoscopy alone.
  • During the 9-month follow-up (intent to treat) there was tumor recurrence in 47% of patients (n=128/271) in the Hexvix® blue-light group and 56% (n=157/280) in the white light group.
  • The absolute decrease in tumor recurrence for patients in the Hexvix® group was 9%. This means that only 11 patients need to be treated to avoid one recurrence.

In another study: 15

  • Recurrence rate at 12 months for patients with Ta/T1 lesions was 47% (n=35/74) following white light TURB and 31% (n=18/59) following Hexvix® blue-light TURB.
  • Kaplan-Meier analyses showed that the recurrence-free period was significantly longer in the Hexvix® blue-light TURB group than in the white light TURB group.

They also found that Hexvix® blue-light cystoscopy after complete white light TURB identified residual tumor tissue in 44 of 90 patients (49%): 15

  • In 37 of 83 (45%) patients, residual Ta tumor was found.
  • In 3 of 7 (43%) patients, residual T1 was found.
  • In four cases, CIS was found.

In a phase III study, use of Hexvix® blue-light cystoscopy led to more complete management than was planned with white light cystoscopy alone: 14

  • Additional post-operative procedures were recommended in 10% of patients (n=15) when they were re-examined using Hexvix® blue-light cystoscopy.

    Jocham-data-cakes

  • More extensive treatment was done intraoperatively in a further 7% (n=10) following re-examination with Hexvix® blue-light cystoscopy.
  • The reason for more complete management was improved tumor detection compared to white light cystoscopy.
  • Of all tumors, 96% were detected with Hexvix® blue-light cystoscopy compared with 77% using standard white light cystoscopy.
  • The difference was particularly noticeable for dysplasia (93% vs. 48%), CIS (95% vs. 68%) and superficial papillary tumors (96% vs. 85%).
  • Overall, one in five patients (22%) with tumors received more appropriate treatment at the time of the study, because of the more exact assessment of risk categories following Hexvix® blue-light cystoscopy compared to white light cystoscopy.

Benefits of Hexvix blue-light cystoscopy in real-world clinical practice

Two studies have confirmed that the benefits of Hexvix blue-light cystoscopy seen in clinical trials can also be achieved in real-world settings, with relatively unselected patient populations.86, 87

Hexvix® blue-light cystoscopy TURB reduces the risk of early recurrence in a real‑world setting

Mariappan et al compared data from two prospective cohorts of patients who had either good-quality white light cystoscopy (GQ-WLC) TURB in 2007–2008 or blue-light cystoscopy TURB in 2009–2011. Patients had early re-TURB within 6 weeks if they had high-risk disease; all other patients had follow-up cystoscopy at 3 months. 86

Hexvix® blue-light cystoscopy significantly reduced the recurrence rate at first follow-up cystoscopy

The recurrence rate at first follow-up cystoscopy (including early re-TURB) was: 86

  • 30.9% (48 of 155 patients) in the GQ-WLC group
  • 13.6% (26 of 191 patients) in the Hexvix® blue-light cystoscopy group

The difference between the two groups was statistically significant in favor of Hexvix® blue-light cystoscopy (odds ratio 2.9, p<0.001). The significant benefit of Hexvix blue-light cystoscopy was seen regardless of tumor size (<3 cm or ≥3 cm), number of lesions (single or multiple), and risk category (low or intermediate).

 

Hexvix® blue-light cystoscopy TURB reduces the risk of early recurrence 86

Adapted from Mariappan P et al., Real-Life Experience: Early Recurrence with Hexvix Photodynamic Diagnosis–Assisted Transurethral Resection of Bladder Tumour (TURBT) vs Good-Quality White Light TURBT in New Non–Muscle-Invasive Bladder Cancer. Urology 2015;86(2):327-31.

Hexvix® blue-light cystoscopy allowed the most appropriate treatment to be given from the start

In the GQ-WLC group, 22% of patients initially classified as having low-risk disease required a change in treatment after the first follow-up cystoscopy, compared with only one patient in the Hexvix® blue-light cystoscopy group. 86

In patients classified as having intermediate-risk disease at initial TURB, 9% of the GQ-WLC group and 3% of the Hexvix® blue-light cystoscopy group required a change in treatment at first follow-up cystoscopy. 86

Hexvix® blue-light cystoscopy and immediate post-TURB chemoprophylaxis effectively reduce the risk of recurrence and the number of follow-up procedures in routine clinical practice

A recent single-center retrospective study investigated the effect of Hexvix® blue-light cystoscopy and post-TURB chemoprophylaxis with MMC, introduced simultaneously under routine clinical conditions.

The results of this study showed that in comparison to white light cystoscopy TURB, blue-light cystoscopy TURB + MMC: 87

Lykke et al slide 2

Blue-light cystoscopy TURB + MMC significantly reduced the risk of NMIBC recurrence by 41% 87

Lykke et al slide 9

  • The median NMIBC recurrence-free survival (RFS) increased from 13.6 months in the white light cystoscopy TURB group to 36.8 months in the blue-light cystoscopy TURB + MMC group (blue dashed line in graph)
  • The 2-year recurrence rate was 60% in the white light cystoscopy TURB group and 38% in the blue-light cystoscopy TURB + MMC group (pink dashed line in graph), giving an absolute risk reduction of 22% and a relative risk reduction of 33%

One third of follow-up TURBs avoided with blue-light cystoscopy TURB + MMC 87

Lykke et al slide 12

  • Blue-light cystoscopy TURB + MMC treatment resulted in a statistically significant 32% relative reduction in TURBs per patient year of follow up versus white light cystoscopy TURB
  • Treatment was well tolerated, with most adverse events seeming to be related to the tumor and TURB rather than to Hexvix® or MMC

Blue-light cystoscopy TURB + MMC achieved cost savings in the first year of follow up87

Hexvix® blue-light cystoscopy improves long-term outcomes compared to white light cystoscopy

Analysis of long-term follow-up data (4.5 years): 13

Grossman-kaplan-plot

7_months_difference

  • After initial resection, 32% (n=83) of patients in the white light group and 38% (n=97) of patients who underwent Hexvix® blue-light cystoscopy remained tumor free.
  • T2–4 bladder cancer occurred twice as often in the white light group (16 patients, 6%) compared to the blue-light group (8 patients, 3%). However, these differences were not significant.
  • The cystectomy rate was 8% (n=22/280) for patients who were initially resected using white light alone and 5% (n=13/271) for patients who received Hexvix® blue-light cystoscopy. However, these differences were not significant.
  • There were also small increases in overall and disease-specific survival but the study was not sufficiently powered to detect possible statistical improvements in these outcomes.
  • The median time to recurrence was significantly better in the group randomized to Hexvix® blue-light cystoscopy than those in the white light cystoscopy group (16.4 vs. 9.4 months).

This long-term data showed that: 13

  • Patients in the blue-light cystoscopy group had a lower recurrence rate and a longer disease-free interval compared to those in the white light cystoscopy group.
  • There was a trend toward a lower rate of cystectomy in the blue-light cystoscopy group compared to the white light cystoscopy group, which was possibly an indirect indicator of lower disease progression.

Hexvix® blue-light cystoscopy is an independent predictor for improved survival after radical cystectomy

Radical cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). RFS in these patients is known to depend on pathologic tumor and nodal stage and on soft-tissue surgical margins. 70

A retrospective, observational study investigated the prognostic value of blue-light cystoscopy TURB in patients undergoing subsequent radical cystectomy for bladder cancer. In this single-center study, patients undergoing TURB between 2002 and 2010 had received blue-light cystoscopy TURB if bladder cancer was suspected and recurrent/persistent disease was seen >8 weeks after last resection. 5-Aminolevulinic acid (ALA) blue-light cystoscopy TURB was performed in eligible patients up until 2006 and Hexvix® blue-light cystoscopy TURB thereafter. 88

  • 3-year RFS, cancer-specific survival, and overall survival were significantly higher following Hexvix® blue-light cystoscopy TURB versus ALA blue-light cystoscopy TURB or white light cystoscopy TURB, indicating that the prognostic benefit of blue-light cystoscopy TURB appear to be specifically due to Hexvix®
  • The observed superiority of Hexvix® over ALA blue-light cystoscopy TURB in MIBC reflects clinical trials in NMIBC, which reported improved outcomes with recurrence rates in Hexvix® but not ALA treated recipients
    12, 69

Gakis et al slide 8

For further reading: Read clinical summaries

The need to improve…

…the diagnosis and treatment of bladder cancer has been documented in numerous acknowledged publications

 

“Bladder cancer has the highest lifetime treatment costs per patient of all cancers.” “TURBs represent, by far, the largest bladder cancer expenditure, accounting for 71% of treatment costs in the UK.”10Gåseøyne

“…up to 70% of patients with non-muscle invasive bladder cancer recur after transurethral resection. Therefore, it is critical to identify small tumors and carcinoma in situ (CIS) that may not be readily visualized by standard white light cystoscopy, as one strategy to help reduce recurrences.” 36

“That we need something of therapeutic value for the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC) and CIS is obvious.” 7

“Numerous studies have clearly shown that hexaminolevulinate fluorescence cystoscopy (HAL-FC) significantly improves the detection of bladder tumors in general and CIS in particular, resulting in better staging and therapy, which explains the reason for longer (long term) recurrence-free rates.” 7

“The conclusion is simple. HAL-FC [Hexvix®] improves identification of papillary bladder tumors and especially CIS, resulting in better therapy, longer recurrence-free intervals, improved patient care and reduced costs.” 7

Health Economic Benefits

“HAL [Hexvix]-guided BLC is a clinically effective and cost-effective tool for improving NMIBC detection and management, thereby reducing the burden of disease for patients and the healthcare system.” [European Expert Panel, 2014] 67

“Photodynamic diagnosis appears to be a cost-effective alternative to WLC as an initial diagnostic test.” [NICE, 2015] 66

Given the pressures on healthcare systems in all countries, it is important to look at the impact that an intervention has on resources and service delivery as well as its clinical benefits for patients. The health economic benefits of Hexvix® blue-light cystoscopy have been addressed in budget impact models, as well as numerous publications looking at cost effectiveness at patient, hospital and national levels.

At the patient and hospital level

Patient_hospital

“Given the clinical benefits for patients and the need for lifelong management of these patients because of the risk of recurrence, we believe that short-term economic arguments about the initial costs of treatment should not prevail, and patients should not be denied access to HAL on the basis of the fact that the cost benefit would not be achieved immediately. Over the long term, there is a clear benefit with HAL-guided BLC versus WLC, both for the healthcare system and, critically, for the patient.” [European Expert Panel, 2014] 67

The long-term savings over the lifetime management of the patient arise from a number of factors that contribute to reduced overall use of healthcare resources, including: 67

  • Improved lesion detection and resection, leading to more appropriate patient management
  • Fewer repeat procedures and hospital visits because of:
    • Reduced risk of recurrence
    • Longer RFS

In addition, when used at initial resection, Hexvix® blue-light cystoscopy improves quality-adjusted life years (QALYs) over the lifetime of a patient compared with resection under white light cystoscopy. 67

Long-term savings with Hexvix®

Several groups in Europe (Germany, Sweden, UK, and Denmark) and the USA have independently reported patient-level cost analyses of Hexvix® use in NMIBC. These results are summarized in the table below.
10, 353941, 6387 

The studies calculated the total costs of white light cystoscopy + TURB and blue-light cystoscopy + TURB, based on local unit costs and time/resources allocated.

The findings from these studies indicate that Hexvix® is cost effective in the long-term management of patients across a range of healthcare systems, even taking into account the need for upfront investment in equipment and training.

Table adapted from the following studies:
– Garfield SS et al., The Canadian Journal of Urology 2013;20(2):6682-668941
– Witjes JA et al., Eur Urol 2014; 2014; 66:863-8767
– Lykke MR et al., Scandinavian Journal of Urology 2015;49:230-23687

 

At the national level

A health care model has been developed to estimate the cost effectiveness and health utility of Hexvix® blue-light cystoscopy at initial TURB versus white light cystoscopy alone over the lifetime of the patient.

  • In the healthcare systems of both England/Wales79 (table) and Italy80 (figure), various modeled scenarios of the use of Hexvix® blue-light cystoscopy consistently demonstrated small but significantly increased patient QALYs and lower costs over the lifetime management of the patient versus white light cystoscopy.

Slide 60(JS) v2

Base case result (per patient) Reference 79

Probablistic sensitivity analyses redraw

Probabilistic sensitivity analyses Reference 80

In the Swedish healthcare system, a decision-tree model based on European Association of Urology guidelines for NMIBC has also demonstrated significant clinical benefits with Hexvix blue-light cystoscopy TURB and the potential for this approach to be cost neutral or cost saving over 5 years, compared with white light cystoscopy.85

HEXP1509 Chart 2

Figure adapted from Rose et al 2015 85

HEXP1509 Chart 3

The benefits outweigh the cost

The long-term benefits of Hexvix® outweigh the cost 4, 28

BENEFITS OF HEXVIX® COMPARED TO WHITE LIGHT CYSTOSCOPY COSTS
  • Improved detection and staging = more appropriate management decisions 12, 14, 15, 17, 20, 37, 38,
  • More complete resection = reduced tumor recurrence and longer recurrence-free survival1215, 38
  • Fewer repeat resections and less intravesical therapy for recurrence = reduced overall disease management costs 28
  • Equipment (purchase/ upgrading)
  • Purchase of Hexvix®
  • Staff training

 

The evidence for Hexvix® has been reviewed in the context of cost analyses for its use in the diagnosis and management of non-muscle invasive bladder cancer (NMIBC). In one such review, the authors concluded that the use of blue-light cystoscopy is “at least cost neutral”. 4 In terms of budget impact, it has been shown that compared to white light cystoscopy alone, blue-light cystoscopy used as an adjunct to white light in guiding TURBT in patients with non-muscle invasive bladder cancer may result in a reduction in invasive, time-intensive and high-cost procedures and considerable cost savings. 39 Furthermore, blue-light cystoscopy-related costs are reimbursed in all risk groups as a result of reduced follow up costs, 40 and Hexvix® may be cost-effective when used at first TURBT for patients with suspected new or recurrent non-muscle invasive bladder cancer. 41

Quantifiable cost savings

Hexvix® demonstrates quantifiable costs savings compared to white light cystoscopy

The cost savings associated with using Hexvix® blue-light cystoscopy compared to white light cystoscopy for TURBT have been quantified by various cost analysis models in different settings. These consistently show long-term savings as a result of implementing Hexvix®:

    • 140,28€ ($168,57) saving in the context of a diagnosis-related group in a German Hospital. 10
    • $4,650 over 5 years per patient in the US. 41
    • £4.95m to the UK National Health Service over a five year period.

Studies in detail – Sievert et al.

Sievert et al showed that blue-light cystoscopy using Hexvix® “enhances tumor visibility and improves TURBT results, potentially reducing recurrence rates and lowering treatment costs.” 10

TURBT cost calculation:long-t-bene-outw-cost-Recovered

A comparison of conventional white light TURBT versus TURBT using Hexvix® blue-light cystoscopy based on a diagnosis-related group in a German Hospital. 10

The costs shown in the graph include pre-op catheter, Hexvix®, equipment/10 yearsa, TURBTb, histology tumor, histo 4 corner Bxc, 20% chance of second TURBT after 3/6 months (DRG)d.

Footnotes
ahardware equipment cost calculated for an individual TURBT and PDD based on an estimated 300 TURBs/year over 10 years; bTURBT cost (includes average time of surgeon, anesthesiologist, nurse/technician, equipment cost); cpathologist cost for four random biopsies; dthe chance of a re-TURBT. The exchange rate was calculated on the basis 1 €=1.33 US$; DRG=diagnosis-related group;

Studies in detail – Garfield et al.Helseoekonomi-tabell-over-fem-aarv2

Garfield et al. demonstrated a cost saving of $4,650 over 5 years compared to patients who initially received white light cystoscopy. 41

The costs shown in the graph included: cystoscopy, transurethral resection of the bladder tumor (TURBT), Bacillus Calmette-Guérin (BCG) therapy, radical cystectomy, partial cystectomy, Hexvix®, biopsy and pathology, urine cytology, chemotherapy, neoadjuvant chemotherapy, imaging studies, and ongoing surveillance of muscle invasive disease.

 

 

 

Studies in detail – NHS Technology Adoption Centre

The NHS Technology Adoption Centre (NTAC) has reviewed over 200 healthcare technologies and selected 10 for ‘Technology Implementation Projects’ in real-time clinical settings in the NHS. 42

The cost analysis for blue-light cystoscopy for the diagnosis of NMIBC (referred to in NTAC publications as photodynamic diagnosis or PDD) as an adjunct to white light cystoscopy specifically considered Hexvix®. The results of this cost analysis demonstrated that that using Hexvix® improves the diagnosis of patients with NMIBC, reduces the number of progressed tumors and associated surgeries and reduces hospital stay in the long-term. The main findings based on the UK national patient population from the model were as follows: 43

    • Overall cost impact of £4.95m to the NHS over a five year period.
    • Detection of NMIBC in an additional 1,308 patients each year.
    • Potential reduction of patients progressing to muscle invasive bladder cancer (MIBC)
    • Reduction of over 2,100 bed days by implementing Hexvix®.
    • The use of Hexvix® results in an enhanced care pathway for the treatment of high risk patients.

NHS encourages Hexvix® uptake

The National Health Service (NHS) is actively encouraging uptake of blue-light cystoscopy in the UK

As a result of NTAC’s review of Hexvix®, including clinical evidence and the cost analysis, it has produced a ‘How to Why to Guide’ on the implementation of Hexvix® blue-light cystoscopy to provide comprehensive, relevant information for clinicians, managers, key decision makers and other stakeholders, on how to implement the technology and unlock the benefits. This guide summarizes the benefits of blue-light cystoscopy as follows: 42

  • A reduction in hospital admissions for certain patients. Improved diagnosis and subsequent treatment plans for primary bladder cancer patients.
  • Reduction in overall length of stay. By providing an enhanced diagnostic service and eliminating the need for a second operation for certain patients, subsequent length of stay is lowered by approximately 2,116 bed days over a 5-year period.
  • Delivery of 31- and 62-day cancer treatment targets. This technology has the potential to reduce recurrence rates and the need for subsequent procedures. This may increase service capacity and enable trusts to deliver cancer treatment targets.
  • Improved efficiency for the NHS. Being able to move to adjuvant therapies straight after initial surgery ensures that a more enhanced service is introduced.
  • Improved quality of life. Removing the number of hospital visits and subsequent procedures provides an improved quality of life for patients and their families over the follow-up period.
  • Higher quality services and support for patients. A systematic approach to implementation will deliver an enhanced clinical service and will allow appropriate therapies to start straight away.
  • Long-term savings to the NHS. This is achieved through a reduction in subsequent demands on health service expenditure as a result of fewer surgical procedures.

The NTAC guide also acknowledges that there may be some barriers to overcome in order to “unlock the full benefits of the technology” and succinctly outlines these along with the benefits to different stakeholders involved in bladder cancer management.

Read more about the NTAC guidance on overcoming barriers to Hexvix® implementation.