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Keywords:

  • vascular;
  • photodynamic;
  • VTP;
  • focal therapy;
  • TOOKAD® Soluble;
  • prostate

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Objectives

  • To evaluate the optimal treatment conditions and effects of TOOKAD® Soluble vascular-targeted photodynamic (VTP) therapy in patients with localised prostate cancer.
  • To evaluate the safety and quality of life after TOOKAD® Soluble VTP treatment in patients with localised prostate cancer.

Patients and Methods

  • Men (aged >18 years) diagnosed with localised prostate cancer, who were suitable for active surveillance, were invited to take part in the study. Patients who had received prior or current treatment for their cancer were excluded.
  • There were two parts to the study: in part one, patients were assigned to one of two treatment groups based on the size of their prostates (patients with prostate size <60 mL would receive 4 mg/kg TOOKAD® Soluble and patients with prostate size ≥60 mL would receive 6 mg/kg TOOKAD® Soluble both activated with 200 J/cm light). In part two, patients were assigned to one of two treatment groups based on predefined criteria and received either 4 or 6 mg/kg TOOKAD® Soluble and 200 or 300 J/cm light.
  • VTP was conducted under general anaesthesia using TOOKAD® Soluble administered intravenously and activated by light-diffusing fibres within the prostate via the perineum.
  • Follow-up was conducted for 6 months. Magnetic resonance imaging (MRI) carried out at 1 week after VTP and transrectal prostate biopsy at 6 months were the key endpoints. Adverse event (AE) recording and patient-reported outcome measures were collected.

Results

  • In all, 86 patients were enrolled in the study and 85 patients received treatment. Of the 85 treated patients, one patient discontinued (due to withdrawal of consent).
  • At 6 months, 61/83 (74%) patients who underwent prostate biopsy had histopathology that was negative for prostate cancer (95% confidence interval (CI) 62.7–82.6%). Considering patients who received 4 mg/kg TOOKAD® Soluble and 200 J/cm light (unilateral), which are considered optimal treatment parameters, 38/46 (83%) patients had histopathology from the biopsies that was negative for prostate cancer at 6 months (95% CI 68.6–92.2%; P < 0.001).
  • The mean percentage of necrosis of the targeted prostate tissue at 7 days after VTP was 78% overall (83 patients) with extraprostatic necrosis reported in 76% (63/83) of patients. Considering patients who received 4 mg/kg TOOKAD® Soluble and 200 J/cm light (unilateral), the mean 7-day necrosis percentage was 88% (46 patients) with extraprostatic necrosis reported in 72% (33/46) of patients. All occurrences of extraprostatic necrosis were considered clinically acceptable and none were associated with any clinical sequelae.
  • The mean percentage prostate necrosis at 7 days was statistically significantly higher (P < 0.001) in patients treated with a therapeutic light density index (LDI) of ≥1 than those treated with a LDI of <1. The percentage of patients with negative biopsies at 6 months was also higher in patients treated with a therapeutic LDI of ≥1 than those treated with a LDI of <1 (78.6% and 63.0%, respectively).
  • In all, 87% (75/86) of patients reported at least one treatment-emergent AE during the study. Most AEs were mild or moderate in intensity and considered related to the technical procedures of the study. No treated patients had hypotension or discontinued due to AEs. Eight patients (9.3%) had serious AEs; none resulted in discontinuation from the study.

Conclusions

  • Biopsy data, post-treatment dynamic contrast-enhancement MRI at 1 week after VTP and analysis of the safety data have shown that 4 mg/kg TOOKAD® Soluble and 200 J/cm light are the optimal treatment conditions for the VTP procedure resulting in >80% of patients treated with this regimen having a negative biopsy at 6 months.
  • Overall, the treatment was well tolerated and exhibited early signs of efficacy for minimally invasive focal treatment of localised prostate cancer.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Currently, men diagnosed with early prostate cancer face the dilemma of whether to undergo active surveillance or to have treatment directed to the whole prostate, by means of either surgery or radiotherapy [1-4]. There is considerable interest in directing the treatment to the cancer rather than the prostate to balance the benefits and harms of treatment. This has spawned the discipline of focal therapy [5-7].

Vascular-targeted photodynamic (VTP) therapy has a mode of action that is reliant on three essential elements: a photosensitising agent to enhance the sensitivity of tumour vasculature to light energy; light of a specific wavelength; and sufficient oxygen to drive the reaction. VTP uses an i.v. administered photosensitiser. Optical fibres within hollow plastic needles allow accurate positioning in the prostate. The light activates the photosensitiser in the prostate, generating reactive oxygen species that activate thrombosis within the vessels. This results in obliteration of the microvessel anatomy with resultant deprivation of oxygen and nutrients to the tumour cells and surrounding prostate tissue in the treated area.

Light-activated vascular occluding agents under development include a novel generation of photosensitisers, the bacteriochlorophyll derivatives: WST09 (padoporfin; palladium bacteriopheophorbide) and its water-soluble derivative TOOKAD® Soluble (WST11) (padeliporfin; palladium bacteriopheophorbide monolysotaurine). Both WST09 and TOOKAD® Soluble remain confined to the vascular bed [8]. Pre-clinical studies have shown their efficacy for the ablation of prostatic tissue [9]. Phase II studies have shown that WST09 produced ablation in targeted volumes of prostate tissue. However, intraoperative hypotension occurred with cardiovascular effects [10, 11] that were thought to be linked to the solubilising excipient Cremophor® as observed when used with other pharmaceuticals [12]. To avoid these side-effects, the hydrophilic derivative TOOKAD® Soluble was developed. Preclinical studies in several animal models have shown that TOOKAD® Soluble leads to occlusion of the entire tumour vasculature within a few minutes of treatment, leading to tumour ablation [13-15].

Photosensitisation of TOOKAD® Soluble generates cytotoxic reactive oxygen species that target the tumour's vasculature [16] rather than just the cellular components, inducing an inflammatory response and hypoxia and initiating lipid peroxidation, which can spread through the treated tissue within hours [13]. The resulting cell death and enhanced necrosis leads to tumour destruction [14, 15]. The focal nature of delivery keeps damage to surrounding tissue to a minimum.

A recently published retrospective analysis of 28 patients who had been treated with TOOKAD® Soluble in multicentre trials [17], proposed a semi-empirical model based on three parameters of photodynamic therapy: dose of drug, energy fluence, and delivery time. This analysis was able to establish a correlation between the illuminated volume of prostate tissue and the necrosis as measured by MRI 7 days after VTP.

The present paper reports the findings from a Phase II, prospective, multicentre, open-label, multiple-arm, single i.v. dose study designed to confirm the optimal drug concentration and light dose parameters necessary to achieve prostate cancer tumour ablation in men with localised prostate cancer. It included a 6-month follow-up with an end of study transrectal biopsy. The safety and quality of life associated with the optimal conditions were assessed. Patients found to have persistent or recurrent localised prostate cancer at the 6-month follow-up visit were offered a second treatment with TOOKAD® Soluble VTP.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

The study included men diagnosed with prostate cancer (up to clinical stage T2b-N0/Nx-M0/Mx and including radiological or pathological T2c). Exclusion criteria were prior/current prostate cancer treatment, including hormonal manipulation (excluding 5α-reductase inhibitors) or androgen supplements in the last 6 months, radiation therapy, chemotherapy, or TURP. In men diagnosed by TRUS-guided biopsy, the histological entry criterion was limited to Gleason pattern 3+3. For men diagnosed by transperineal template-guided biopsy, secondary Gleason pattern 4 was permitted provided that it was low burden (<3 cores positive per lobe and ≤3 mm maximum cancer core length). The upper limit of the PSA level before consent was 10 ng/mL (although patients with larger prostates and a PSA level of >10 ng/mL could be included at the discretion of the medical monitor).

Ethics Statement

The study was conducted within seven university hospital centres in Europe (France, The Netherlands and UK). Approval of the protocol, all protocol amendments and the proposed Patient Informed Consent Document were obtained from the relevant national and local authorities in each country. All patients gave their signed informed consent to participate before any study-related activities were performed.

Study Design

This was a multicentre, Phase II, open-label, multiple-arm, single i.v. dose escalation, 6-month, non-randomised clinical trial, designed to determine the optimal treatment conditions to achieve prostate cancer ablation and to assess the efficacy of TOOKAD® Soluble VTP in patients with localised prostate cancer. In part one, patients were assigned to 4 or 6 mg/kg TOOKAD® Soluble depending on whether the prostate was <60 mL (4 mg/kg) or ≥60 mL (6 mg/kg). The light dose was set at 200 J/cm. In part two, patients were assigned to treatment groups (4 or 6 mg/kg TOOKAD® Soluble activated with 200 or 300 J/cm) based on criteria assessed by the Central Treatment Planning Group (prostate shape, volume and axial dimensions, tumour location, suprapubic arch dimensions, and likely outcome of treatment plan based on prior experience of treatment effect on MRI 7 days after VIP observed at each dosage level).

Patients were followed for 6 months after VTP. Prostate MRI was performed before, and at 1 week and 6 months after VTP. A prostate biopsy was taken at 6 months after VTP. PSA levels were measured at 1, 3 and 6 months after VTP.

The trial was registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT00975429; Title: Study of WST11 in patients with localised prostate cancer).

VTP Procedure

VTP treatment consisted of a single i.v. administration of TOOKAD® Soluble (WST11 – STEBA Biotech S.A. – 7 place du théatre – L 2613 Luxembourg) at 4 or 6 mg/kg, activated using 753 nm laser light at a power of 150 mW/cm and light energy of 200 J/cm, or a power of 200 to 250 mW/cm and light energy of 300 J/cm.

The procedure was performed under general anaesthesia. The procedure has been described in detail previously [10, 11] and is described only briefly here. Hollow, transparent, plastic brachytherapy catheters were positioned into the prostate, using TRUS-image guidance in accordance with a previously devised MRI-based treatment plan. Cylindrically diffusing optical fibres were inserted into the catheters. Examples of different treatment plans are shown in Fig. 1. Laser light was delivered to the prostate, using a multichannel diode laser (V-Gen Electro Optics Ltd, Israel, model 8CH-753 Mk II).

figure

Figure 1. Schematic diagram of treatment plans and corresponding MRI at 7 days after VTP. Examples of two treatment plans that were considered by the Treatment Planning Guidance Committee, are displayed. The possible different fibre configurations used are illustrated. The red circles indicate the possible location of the fibres; the blue circle indicates the position of the urethra in the prostate gland.

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The single TOOKAD® Soluble i.v. dose was a 10-min infusion. This was followed by continuous illumination of the prostate gland through optical fibres for between 20 and 25 min. Light delivery was initiated at the end of the infusion to coincide with the peak serum concentration of TOOKAD® Soluble. The study medication administration and the light delivery were planned to last not >32 min. The total duration of the whole procedure was ≈2 h (including anaesthesia, fibre placement and illumination). At the end of the illumination, the laser was turned off and the fibres withdrawn from the prostate.

Efficacy and Safety Criteria

The primary efficacy criterion was the result of a 12-core prostate biopsy, taken 6 months after VTP. Success was defined as a negative biopsy in the treated lobe(s).

Secondary efficacy criteria were: (i) change from baseline in PSA levels at 1, 3 and 6 months after VTP, (ii) MRI quantitation of treatment effect (volume of hypoperfusion within and outside the prostate at 7 days and 6 months after VTP).

The overall time to perform the procedure was also assessed.

Adverse events (AEs) were recorded and laboratory evaluations were performed periodically during the 6-month follow-up period. Patients also underwent 12-lead electrocardiograms at baseline, during the VTP procedure and perioperatively. Toxicities were graded according to the National Cancer Institute's Common Terminology Criteria for AEs (CTCAE), version 4.0. The relationship of the AEs was assessed with respect both to the study treatment and to the technical procedure of the VTP. Urinary and erectile function, before VTP and at 1, 3 and 6 months after VTP were assessed using the IPSS and five-item version of the International Index of Erectile Function (IIEF-5) quality-of-life questionnaires, respectively.

Statistical Methods

Analyses were performed by actual treatment groups (4 mg/kg TOOKAD® Soluble with 200 J/cm light [unilateral or bilateral], 6 mg/kg TOOKAD® Soluble with 200 J/cm light [unilateral] and 4 mg/kg TOOKAD® Soluble with 200 J/cm and 300 J/cm light [bilateral]) and overall patients' population.

Descriptive statistics (n, mean, sd, median, minimum and maximum) were calculated for quantitative variables; frequency count by category was given for qualitative variables. The only statistical inference performed was the one-sided binomial exact test for the proportion of patients with negative biopsy assessment at 6 months after VTP.

An upper ceiling of 90 patients was set for this Phase II study. An increase in the percentage of patients with a negative biopsy 6 months after VTP from the population norm of 40% to 65% under treatment was determined, a priori, as constituting a clinically relevant benefit. The population norm of 40% of men having no cancer found on repeat biopsy after an initial biopsy showing low-risk prostate cancer was determined from the literature [18]. A sample size of 30 patients was determined for part one of the study using at least 80% power to detect a difference in negative biopsy result of 25% using a one-sided exact binomial test. The target significance level was 0.10 allowing for potential losses over the duration of the study and for the uncertainty regarding response assumptions for some treatment groups. Recruitment of an additional 60 patients for part two was planned to add to the precision of the data on safety.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

In all, 86 patients (mean age, 62.7 years) were enrolled. One patient was excluded as he received no dose of TOOKAD® Soluble due to the occurrence of hypotension after general anaesthesia but prior to dosing with TOOKAD® Soluble. Another patient discontinued before the 6-month follow-up, due to withdrawal of consent. In all, 84 patients completed the study. The biopsy was not done at 6 months in one patient for safety reasons (large fluid collection on MRI) resulting in 83 evaluable patients based on biopsy criteria, and 84 evaluable patients for other criteria.

The screening biopsy was done as per local standard of care. All patients at baseline had at least one positive core. The mean (range) number of positive cores was 2.1 (1–10) overall and the mean (median) total cancer core length was 4.7 (3) mm. The most common Gleason score overall was 3+3 (95.3% of patients). These characteristics were generally balanced across the actual treatment groups.

Demographic and baseline characteristics are presented in Table 1. Of the 85 patients treated, 61 patients received 4 mg/kg TOOKAD® Soluble and 200 J/cm light (47 unilateral and 14 bilateral), 21 patients received 6 mg/kg TOOKAD® Soluble and 200 J/cm light (unilateral) and three patients received 4 mg/kg TOOKAD® Soluble and 200 and 300 J/cm light in different lobes (bilateral treatments).

Table 1. Patient demographics and other baseline characteristics (safety population)
 Treatment group
TOOKAD® Soluble dose, light energy 
4 mg/kg, 200 J/cm6 mg/kg, 200 J/cm4 mg/kg, 200 J/cm and 300 J/cmAll doses
VariableUnilateralBilateralUnilateralBilateralUnilateral/bilateral
  1. *One patient did not receive study treatment as he discontinued due to an AE prior to dosing.

Number of patients471421386*
Mean (sd):     
Age at enrolment, years62.1 (5.6)62.5 (6.1)63.5 (5.2)65.0 (2.6)62.7 (5.5)
Time since biopsy, months5.0 (2.4)5.2 (2.4)6.6 (4.5)4.6 (2.7)5.4 (3.1)
N (%) or n/N:     
Gleason score     
3+2001 (4.8)01 (1.2)
3+347 (100)14/1418 (85.7)2/382 (95.3)
3+4002 (9.5)1/33 (3.5)
Mean (sd):     
Gleason grade (sum of the 2 Gleason scores)6.0 (0.0)6.0 (0.0)6.0 (0.4)6.3 (0.6)6.0 (0.2)
Number of positive cores1.8 (1.1)3.1 (2.3)1.9 (1.7)3.3 (1.2)2.1 (1.6)
Total length of VTP fibres, mm301.8 (117.8)418.2 (121.7)311.2 (156.1)376.7 (156.9)325.9 (134.8)
LDI1.456 (0.357)0.968 (0.284)0.857 (0.296)0.827 (0.193)1.206 (0.429)
N (%) or n/N:     
LDI Category     
LDI <14 (8.5)7/1414 (66.7)3/328 (32.9)
LDI ≥143 (91.5)7/147 (33.3)057 (67.1)

Efficacy

At the 6-month follow-up, 61/83 (74%) patients had negative biopsies (95% CI 62.7–82.6%). The difference between this proportion and the proportion of men described in the literature with low-risk disease who test negative on re-biopsy (40%) was statistically significant (P < 0.001).

In patients treated with 4 mg/kg TOOKAD® Soluble and 200 J/cm light (unilateral), 38/46 (83%) patients had negative biopsies at the 6-month follow-up (95% CI 68.6–92.2%; P < 0.001). The results obtained from the 6-month follow-up biopsy are presented in Table 2.

Table 2. Biopsy results at Month 6 according to treatment group
 Treatment group
TOOKAD® Soluble dose, light energy 
4 mg/kg, 200 J/cm6 mg/kg, 200 J/cm4 mg/kg, 200 J/cm and 300 J/cmAll doses, all energies
VariableUnilateralBilateralUnilateralBilateralUnilateral/bilateral
  1. *One-sided binomial exact test for the proportion of patients with negative biopsy assessment at Month 6; actual value vs 40% (considered the population norm).

Number of patients4714213N = 86
Prostate biopsy available at Month 6, n461321383
N (%) or n/N:     
Positive8 (17.4)4/14 (30.8)8 (38.1)2/322 (26.5)
Negative38 (82.6)9/14 (69.2)13 (61.9)1/361 (73.5)
Exact 95% CI, %(68.6–92.2)(38.6–90.9)(38.4–81.9)(0.8–90.6)(62.7–82.6)
P*<0.0010.0320.0350.784<0.001

The mean percentage of necrosis of the targeted prostate tissue was defined by the volume of necrosis at 7 days after VTP in the treated lobes or lobe divided by the mean of the before and after treatment of the whole prostate volume or half the prostate volume, respectively. This derived volume was used as the prostate tends to swell after the treatment, resulting in a larger prostate volume at 7 days after VTP than at baseline. At 7 days after VTP, the mean necrosis percentage was 78% overall (83 patients) with some evidence of extraprostatic necrosis reported in 76% (63/83) of patients. In all patients, the extraprostatic necrosis did not have noxious consequences or sequelae. In patients treated with 4 mg/kg TOOKAD® Soluble and 200 J/cm light (unilateral), the mean necrosis percentage at 7 days after VTP was 88% (46 patients) with some evidence of extraprostatic necrosis reported in 72% (33/46) of patients.

The mean percentage of necrosis reduced at later time-points (overall values were 8.5% [25 patients] and 7.3% [21] at 3 and 6 months, respectively). The results of analysis of the prostate MRI at 7 days after VTP are presented in Table 3.

Table 3. Prostate MRI results (mean percentage necrosis and extraprostatic necrosis) at 7 days after VTP
 Treatment group
TOOKAD® Soluble, light energy 
4 mg/kg, 200 J/cm6 mg/kg, 200 J/cm4 mg/kg, 200 J/cm and 300 J/cmAll doses, all energies
UnilateralBilateralUnilateralBilateralUnilateral/bilateral
N461420383
Prostate percentage necrosis :     
Mean (sd)87.6 (20.5)71.5 (17.8)63.9 (24.7)47.7 (17.0)77.7 (23.8)
Range47.0–125.720.9–94.623.1–115.434.3–66.820.9–125.7
Extraprostatic necrosis, n (%) or n/N     
Yes33 (71.7)13/1414 (70.0)3/363 (75.9)
Possible001 (5.0)01 (1.2)
No13 (28.3)1/145 (25.0)019 (22.9)

To see if it was possible to determine the number and length of fibres required for a given treatment effect, the use of a threshold of 1 for the light density index (LDI) was explored. The LDI is defined as the ratio between total light-emitting length of inserted VTP fibres (cm) and the baseline volume by planimetry (cm3) of targeted prostate (half the prostatevolume for unilateral treatment and the whole prostate volume for bilateral treatment).

Overall, 67% (57/85) of patients were treated at a LDI of ≥1 with a mean percentage necrosis at 7 days after VTP (88%) higher than that of patients treated with a LDI of <1 (58%). In patients treated with 4 mg/kg TOOKAD® Soluble and 200 J/cm light (unilateral), the mean percentage necrosis at 7 days after VTP was 91% in patients treated with a LDI of ≥1 (42 patients).

Overall, a higher percentage of patients treated with a LDI of ≥1 than those treated with a LDI of <1 had negative biopsies at the 6-month follow-up (79% vs 63%, respectively).

PSA values were measured at baseline and at 1, 3, and 6 months after VTP. The mean changes from baseline were -1.01 ng/mL, -2.10 ng/mL, and -2.20 ng/mL at 1, 3, and 6 months after VTP overall, respectively. The PSA results should be carefully considered as the treatment given in this study is not a whole gland treatment. Results of the PSA assessments are presented in Table 4.

Table 4. PSA levels (ng/mL) at baseline and changes from baseline at 1, 3, and 6 months after VTP
 Treatment group
TOOKAD® Soluble, light energy 
4 mg/kg, 200 J/cm6 mg/kg, 200 J/cm4 mg/kg, 200 J/cm and 300 J/cmAll doses, all energies
VariableUnilateralBilateralUnilateralBilateralUnilateral/bilateral
N at baseline451421282
PSA level at baseline, ng/mL :     
Mean (sd)5.87 (2.47)7.11 (2.15)7.07 (1.80)5.40 (1.27)6.38 (2.29)
Range0.8–12.91.9–9.82.3–9.74.5– 6.30.8–12.9
PSA level changes from baseline, ng/mL     
1 month after VTP(n = 45)(n = 14)(n = 20)(n = 2)(n = 81)
Mean (sd)−1.07 (3.09)−1.49 (6.70)−0.49 (3.23)−1.70 (1.41)−1.01 (3.90)
Range−7.2 to 11.0−7.3 to 18.9−4.5 to 7.6−2.7 to –0.7−7.3 to 18.9
3 months after VTP(n = 44)(n = 14)(n = 20)(n = 2)(n = 80)
Mean (sd)−2.10 (2.15)−3.65 (2.95)−0.95 (5.94)−2.65 (1.63)−2.10 (3.64)
Range−8.4 to 2.9−8.2 to 0.9−5.4 to 22.9−3.8 to –1.5−8.4 to 22.9
6 months after VTP 6(n = 43)(n = 14)(n = 21)(n = 2)(n = 80)
Mean (sd)−1.79 (2.20)−4.12 (2.21)−1.67 (2.69)−3.05 (1.06)−2.20 (2.46)
Range−8.4 to 4.6−7.9 to -1.0−4.8 to 7.0−3.8 to –2.3−8.4 to 7.0

Treatment-emergent AEs (TEAEs)

In all, 87% (75/86) of patients reported 228 treatment-emergent AEs (TEAEs). Most TEAEs were mild or moderate. All 75 patients who had a TEAE reported at least one TEAE that was considered related to the technical procedures of the study (194 TEAEs in total). Overall, 61% (52/86) of patients reported a TEAE that was considered related to study drug and 64% (55/86) of patients reported at least one TEAE that was considered related to the study device. The most frequently reported TEAEs overall were dysuria (29/86; 34%), UTI (12/86; 14%), urinary retention (11/86; 13%), constipation (11/86; 13%), and perineal pain (10/86; 12%); most of these were considered related to the technical procedures of the study.

One patient had hypotension after general anaesthesia and was discontinued from the study before receiving TOOKAD® Soluble. No patients who received the VTP procedure discontinued due to AEs.

Overall, 9% (8/86) of patients had nine serious TEAEs of which five events in four patients were considered related to the study procedure (all received 4 mg/kg and 200 J/cm): One man had prostatitis 9 days after VTP. One man had haematuria on the same day as VTP. One man had worsening epididymo-orchitis 32 days after VTP. One man had cystoprostatitis 8 days after VTP. The same man was hospitalised 199 days after VTP for prostatic stricture that was treated with a TURP. Those four patients made a complete recovery after hospitalisation and treatment.

Two patients had serious TEAEs considered related to study drug. One man (4 mg/kg and 200 J/cm light in one lobe and 300 J/cm light in the other lobe) had ischaemic optic neuropathy that resolved with a small defect in the visual field and was considered possibly related to study drug by the investigator but not by the sponsor. One man had an inflammatory prostatic cyst 193 days after the VTP (4 mg/kg and 200 J/cm), which was considered related to study drug and device by both the investigator and the sponsor.

Two patients had serious TEAEs that were not considered related to study procedure, study drug, or device; one man reported gastritis and one man reported bulbar ulcer, oesophageal ulcer, and haematemesis.

There were some minor changes in the biochemical parameters including elevation of hepatic enzymes, which was mild to moderate in severity. The elevation in hepatic enzymes may have been related to anaesthesia, as it is not unusual to observe such increases after a general anaesthetic. There was no evidence of renal toxicity.

Quality of Life Questionnaires

The questionnaires were evaluable for at least 79 patients at each time point e.g. baseline, and at 1, 3, and 6 months after VTP. The mean sums of the answers to the IIEF-5 and IPSS (questions 1 to 7) patient questionnaires, at the different time-points, is given for all patients in Fig. 2.

figure

Figure 2. The mean scores of the IIEF-5 and IPSS (questions 1–7) for all patients.

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IPSS questionnaire

The mean IPSS score for questions 1–7 decreased from 6.0 at baseline, to 4.8 at 3 months and 4.7 at 6 months after VTP, indicating an overall reduction in urinary symptoms. There was an increase to 8.5 at 1 month after the VTP. For the quality-of-life domain of the IPSS score (question ‘How would you feel if your urinary symptoms stayed the same for the rest of your life?’), where a higher score indicates greater unhappiness with symptoms, there was a decrease from 1.6 at baseline to 1.1 at 6 months after VTP.

IIEF-5 questionnaire

With the IIEF-5, a higher score indicates a greater degree of erectile function. The mean baseline score was 19.7, falling to 13.7 at 1 month, then rising to 15.7 at 3 months, and 15.3 at 6 months after VTP. Over the 6-month period of the study, nine patients reported TEAEs of erectile dysfunction.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

A benefit of the TOOKAD® Soluble targeted approach is a reduction in the significant morbidity (i.e. urinary incontinence and erectile dysfunction) associated with radical therapies.

TOOKAD® Soluble is administered by i.v. injection and the light is provided from a laser through optical fibres inserted transperineally in the prostate under ultrasound control in the targeted area. TOOKAD® Soluble VTP may offer the potential to treat patients with early prostate cancer in a minimally invasive manner and does not exclude patients from having androgen suppression or radical treatments in the future. Because it is a single-session treatment, and can be performed within a couple of hours, it lends itself to administration in an ambulatory care setting and may be repeatable. TOOKAD® Soluble (WST11) and the earlier, non-water soluble WST09, have shown promise in preclinical trials [9] and in early phase clinical trials as a treatment of solid tumours, such as recurrent prostate cancers [10, 11].

We report the results of a prospective study (CLIN902 PCM203) that was designed to investigate the optimal treatment conditions to achieve prostate cancer tumour ablation and to assess the effects of TOOKAD® Soluble VTP treatment in patients with localised prostate cancer.

In the 47 patients who received the optimal treatment combination of 4 mg/kg and 200 J/cm light dose, 83% had negative biopsy results at 6 months after VTP. For these patients, the mean necrosis percentage at 7 days after VTP was 88%. Results of an exploratory analysis indicated that efficacy was improved when the LDI was ≥1.

Overall, the tolerability and safety of TOOKAD® Soluble were considered satisfactory. Most TEAEs were mild or moderate and no patients who received the complete VTP procedure discontinued due to AEs. Eight patients reported serious TEAEs of which two were considered possibly related to study drug by the investigator (ischaemic optic neuropathy and inflammatory prostatic cyst). In all, five serious TEAEs were considered related to the study procedure (prostatitis, haematuria, worsening epididymo-orchitis, cystoprostatitis and prostatic stricture). None of the serious TEAEs resulted in discontinuation from the study.

There was a reduction in the IPSS questionnaire scores suggesting improvement of the urinary symptoms at 6 months after VTP. A reduction in the score of question 8 was also seen, suggesting an improvement in the quality of life. The results of the IIEF-5 showed that the mean response to all questions was decreased and that at 6 months after VTP, the mean value for all doses combined was 15.3 vs 19.7 at baseline, suggesting a mild deterioration of the sexual quality of life of the patients.

The present study was carried out in men who had low-risk prostate cancer, which might be considered suitable for active surveillance. After the publication of a randomised control of surgery vs observation (the Prostate Cancer Intervention vs Observation Trial, PIVOT) there has been debate about whether these men need any treatment at all [5]. However, as around two thirds of men in the UK and a higher proportion in Europe do receive treatment for low-risk prostate cancer it seems a reasonable patient population in which to explore the potential of a new treatment method. To further clarify its' place, investigation in men with intermediate-risk disease will be required.

The biopsy strategy used within the present study could have been changed from the standard of care (10–12 core TRUS biopsy) to a transperineal template-guided biopsy at the start and end of the study to increase the ability to detect cancer, and its' subsequent treatment. However, as this would have required an additional two general anaesthetic procedures it was decided not to pursue this.

Biopsy status remains a surrogate outcome for predicting clinical progression, requirement for additional therapies and ultimately for predicting prostate cancer-related death. In a Phase II study such as this, these downstream end-points cannot be assessed. Only time will tell whether rendering someone ‘free-of-disease’ by virtue of a negative biopsy results in an improved overall life-time risk.

The time-scale of the study does allow us to assess the short to medium term toxicity profile of this intervention, as toxicities such as urinary incontinence and erectile dysfunction tend to improve with time.

Since the present study was initiated, there have been other reports of Phase II focal therapy studies conducted prospectively within a registered and regulated framework [19]. The present results compare favourably with these studies for biopsy status and also for risk profile.

On face value, TOOKAD® Soluble VTP, appears complex when compared with other physical interventions, i.e. high-intensity focused ultrasound (HIFU) and cryotherapy. In a sense it is as it combines a drug and light. This apparent ‘complexity’ may prove to be its greatest attribute. Our early experience shows that the intervention is both ‘teachable’ and repeatable. The challenges of TOOKAD® Soluble are limited to the accurate placement of needles within the prostate using a grid and working to a plan. This is a skill that many urologists have and is one that can be acquired relatively easily.

The other benefit that a drug–light intervention has over and above the physical therapies is that opportunities exist for targeting at the cellular and molecular level. There is nothing to prevent the TOOKAD® Soluble compound becoming the ‘toxic payload’ coupled to an antibody or marker that is targeted to the prostate cancer. Extremes of heat or cold cannot, on their own, be exploited in this manner.

The results reported in the present paper were used to inform the design and conduct of a Phase III multi-centre study in which men fulfilling criteria for low-risk prostate cancer are randomised to either active surveillance or TOOKAD® Soluble VTP in the form of a prostate hemi-ablation. At the time of writing, this study is more than half way recruited (305/400, 76%).

In conclusion, the results of the present study indicate that TOOKAD® Soluble VTP therapy is well tolerated and is effective at rendering men free of cancer by virtue of a negative prostate biopsy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

We would like to thank the patients that gave their consent to take part in this study.

The authors acknowledge the help of Mrs J. Mitchell of TMC Pharma Services (provided by STEBA Biotech) in preparation and revision of the manuscript.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

A. Scherz is the incumbent of the Robert and Yaddele Sklare Professorial Chair in Biochemistry.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
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Abbreviations
(TE)AE

(treatment-emergent) adverse event

IIEF-5

five-item version of the International Index of Erectile Function

LDI

light density index

VTP

vascular-targeted photodynamic (therapy)