Effectiveness of focal therapy in men with prostate cancer (ENFORCE)

In the Netherlands, most men with PCa are treated with radical whole-gland
treatment, i.e. prostatectomy or radiotherapy. The burden of complications such
as incontinence and erectile dysfunction associated with radical treatment is
considerable [1].
A recent systematic review by our group has shown that focal therapy of PCa
seems to reduce the burden of treatment side-effects in men with
intermediate-risk disease, maintaining their quality of life without
compromising oncological effectiveness [2]. The costs of side-effects that can
be prevented are estimated at ¤5456 per patient, resulting in total expected
cost savings of about ¤22 million per year in The Netherlands. Furthermore,
exploration of the benefit-risk balance under patients showed that they are
willing to sacrifice some survival for an improvement in quality of life (QoL)
[3, 4].
Focal therapy comprises a modern alternative to selectively treat a specific
part of the prostate while preserving the rest of the gland. There is, however,
a lack of high-quality evidence, and numerous papers therefore recommend to
perform a multicenter randomized controlled trial (RCT). The RCT should have
long-term follow-up, predefined assessment of cancer-specific and
health-related QoL outcome measures, and economic evaluations to inform
policymakers regarding cost-effectiveness. This RCT on focal therapy versus
usual care is urgently needed to enable focal therapy to overgrow the
experimental status, provide the evidence needed for guidelines, and make this
available for selected patients who benefit from this strategy. Because of its
promising results in other countries, focal therapy is increasingly requested
by patients, but due to the lack of high-quality evidence, it is not reimbursed
yet. This has been designated by both the PCa patient support group and
physicians as a failure of both the market and the funding agencies.
At present, all devices that are used in the proposed study are CE approved and
no safety issues were reported in IDEAL stage 1 and 2a studies [4-7]. For
high-risk PCa, local radical therapy has been found to significantly improve
oncological endpoints [8]. However, for low- and intermediate-risk localized
PCa, the different recommended options by guidelines (radical prostatectomy
(RP), radiotherapy (RT), or active surveillance (AS)) have similar short- to
medium-term oncological outcomes in randomized studies [9]. A PROZIB database
[10] search and a KWF report showed that about 65% of the intermediate-risk
patients that are eligible for focal therapy currently undergo either RP or RT.
Furthermore, brachytherapy is only used to a limited extent (7%) in
intermediate-risk patients in the Netherlands, and since it is not offered as a
treatment option in the participating hospitals in this proposal, we do not
include this option in our study.
Active surveillance is mainly used for low-risk patients rather than for the
intermediate-risk patients we are aiming for in this study. Our systematic
review concluded that more high-quality evidence is required before focal
therapy can become available as a standard treatment [2]. The majority of focal
therapy studies were prospective development IDEAL stage 2a studies
(feasibility studies), showing the limited adverse impact on functional
outcomes and favorable oncological outcomes. Overall, focal therapy studies
reported a median of 95% pad-free at 1-year and 85% of the patients had no
clinically significant cancer in the treated area, respectively. High-quality
multi-center comparative clinical trials, however, appear to be lacking. The
appropriate management of patients with recurrent PCa following focal therapy
has been an ongoing point of discussion. Marra et al. [11] showed that evidence
from assessments of salvage treatments after focal therapy failure is low and
is derived from four retrospective salvage series. Available salvage options
after focal therapy include RP and RT. Overall oncological outcomes are
acceptable, although biochemical recurrence is slightly higher compared to
primary PCa treatment, probably because of the higher aggressiveness of
recurrent/persistent PCa. Functional outcomes and complications are not
markedly worse compared to primary treatment [12]. Salvage RP and salvage RT,
therefore, seem feasible treatment options with acceptable oncological control
and functional outcomes. Thus, re-treatment with salvage radiotherapy or
salvage surgery remains a clinical option after focal therapy failure.
Experience from other countries and our qualitative research on this topic
taught us that many patients will consciously opt for an initial focal therapy
to maintain their quality of life and because they can be treated later when
deemed necessary with the other options [13].
All patients included in our trial will undergo intensive follow-up. Patients
undergoing focal therapy will undergo quarterly PSA measurement and yearly
prostate MRI, followed by a prostate biopsy after 12 months and thereafter if
indicated based on the MRI. Since focal therapy is a one-time intervention,
there will be no patients left in treatment or that require alternative
fallback treatments. Ablation devices can be returned after the completion of
the trial. The disposables are single-use and are depreciated. There are no
specific costs associated with the discontinuation of focal treatment after the
trial.
We, therefore, aim to perform a high-quality multi-center RCT to provide the
evidence needed to decide on reimbursement and implementation of focal therapy
in patients with intermediate-risk, unilateral clinically localized PCa in the
Netherlands. This study is funded by a national grant (Veelbelovende Zorg) from
the Dutch Health Institute (Zorginstituut Nederland).

We hypothesize that a significant proportion of the patients will benefit more
from focal therapy as compared to usual care in terms of morbidity and quality
of life, without compromising oncological effectiveness.

Primary objective: To study the oncological effectiveness and quality of life
of focal therapy versus usual care (i.e. radical prostatectomy or radiotherapy)
in patients with intermediate-risk, unilateral clinically localized PCa.

Secondary objectives: To study the cost-effectiveness of focal therapy versus
usual care (i.e. radical prostatectomy or radiotherapy) in patients with
intermediate-risk, unilateral clinically localized PCa.

Primary endpoints:
- Oncological effectiveness (non-inferiority), defined as treatment failure,
i.e. the need for retreatment with salvage treatment (RP or RT) in the focal
therapy group and as biochemical recurrence followed by salvage treatment in
the usual care group. Follow-up will be for at least 48 months so that more
data on (metastasis-free) survival can be collected for oncological
effectiveness
- Quality of life (superiority), measured with the EPIC-26 questionnaire at 12
months follow-up

Secondary endpoints:
- Metastasis-free survival as a validated surrogate endpoint of overall [11].
- Health-related quality of life at baseline, 3, 6, 12, 24, 36, 48 and 60
months using validated questionnaires (EPIC-26, EORTC QLQ-PR25 scale for sexual
symptoms, ICIQ, IPSS, SHIM IIEF-5, and EuroQol 5D). The patients in which focal
treatment fails will also be followed and their outcomes will be measured.
- Oncologic safety
- Disease progression
- Disease-specific mortality and all-cause mortality
- Operating time
- Hospital care stay
- Pathology results
- Adverse events
- Cost-effectiveness

We will perform a prospective, multi-center randomized controlled trial in 356
men with localized intermediate PCa. Patients will be randomized to either:
a) Focal treatment with ultrasound ablation (HIFU/TULSA) or irreversible
electroporation (IRE) (n=178)
b) Usual care comprising of either radical prostatectomy (RP) or radiotherapy
(RT) (n=178).

This multi-center study will be coordinated by the Radboudumc.
Patients will be recruited by the treating physician of the urology department
from patients presenting in the participating center i.e. Prosper network
(Radboudumc, Canisius Wilhelmina Ziekenhuis (CWZ) Nijmegen, Catharina
Ziekenhuis Eindhoven (CZE)), Isala klinieken Zwolle, St Antonius ziekenhuis
Nieuwegein, Amsterdam UMC (within the prostate cancer network, including AVL),
and Embraze network (Amphia Breda, Admiraal de Ruiter ziekenhuis (ADRZ) Goes,
Bravis ziekenhuis Roosendaal, Erasmus Medisch Centrum (EMC) Rotterdam,
Elizabeth-TweeSteden Ziekenhuis (ETZ) Tilburg).
Focal therapy will be performed in the 5 centers in which the focal equipment
(i.e. Radboudumc, Isala, St Antonius, Amsterdam UMC, HIFU kliniek) is
available and patients will be referred from the other participating centers in
the region; usual care and follow-up measurements will be performed in all
participating centers in this trial.

1. After the patient has signed for informed consent, a baseline visit (V1)
will be scheduled with the urologist and a clinical PhD student. At this visit,
questions about the trial will be answered and baseline measurements will be
performed; the patient will be asked to complete some questionnaires (EPIC-26,
EORTC QLQ-PR25 scale for sexual symptoms, ICIQ, IPSS, SHIM IIEF-5, and EuroQol
5D).
2. Randomization. The patient*s urologist (and interventional radiologist) will
be notified about the result of randomization. Patients will be scheduled for
surgery/focal therapy/radiotherapy within 6 weeks. Patients who randomize for
focal therapy will be referred to the closest participating focal therapy
center.
3. Patients will be scheduled for focal therapy (HIFU/TULSA/IRE) or radical
prostatectomy/radiotherapy within 6 weeks. Patients who randomize for focal
therapy will be referred to the closest participating focal therapy centre. A
detailed and standardized operation report is kept. If during follow-up the
medical condition of the patient warrants medical attention, the study
physician will refer the patient to his/her local physician for further
management. If the local physician decides to perform an alternative
intervention (e.g. salvage RP or salvage RT for patients first treated with
focal therapy) during the follow-up period, the patient will be classified as
cross-over and followed up as planned.
4. Patients will be followed for minimum 36 months, up to a maximum of 60
months over the entire study period. The clinical follow-up takes place at 6
weeks, and 3, 6, 12, 24, 36, 48 and 60 months after randomization. Clinical
follow-up in both arms consist of pre- and posttreatment PSA measurements and
adverse events monitoring. Conferring to international consensus guidelines
follow-up will include laboratory tests including tumor marker (PSA) and
clinical examination every 3 months for the first year and every 12 months
hereafter. The extra follow-up due to the RCT comprises the assessment of
quality of life questionnaires at baseline at 3, 6, 12, 24, 36, 48 and 60
months. Because PSA is not reliable in focal therapy, the patients in the focal
therapy arm will have an additional annual MRI-scan performed at 12, 24, 36, 48
and 60 months after the initial treatment as well as a biopsy at 12 months
(targeted both at the ablation zone and random). In case recurrence or residual
disease is suspected based on the follow-up MRI at 24, 36, 48 or 60 months,
both targeted and random biopsy will be performed. The MRI follow-up scheme is
according to the international consensus meeting on focal therapy in prostate
cancer [13]. Patients who have a significant in-field tumor recurrence (ISUP
grade 2 (Gleason 3+4) with >=4 mm tumour length, or any focus of ISUP grade >=3
in the treated area after focal treatment during the follow-up, detected with
MRI and subsequent random/targeted biopsy [13], will return to the clinical
standard pathway comprising of salvage radical prostatectomy or salvage
radiotherapy. Treatment failure in radical prostatectomy or radiotherapy is
based on biochemical recurrence and subsequently patients will be treated
according to the available guidelines. The Phoenix criteria are used to define
biochemical recurrence in postradiation therapy, which requires an increase in
PSA of at least 2 ng/mL above the postradiation PSA nadir, whereas biochemical
recurrence post-RP is defined as at least two PSA values that are 0.2 ng/mL or
higher. Patients who fail RP will undergo salvage radiotherapy. Patients who
fail RT will undergo a form of treatment, for example, salvage prostatectomy.
The effects of these re-treatments will also be followed and measured.

Possible complications associated with focal therapy are hemorrhage,
inflammation, minute risk of perforation of urethra or bladder, and fistula
formation. The use of MRI-guidance may have a burden of local heating and
noise, risks of contrast reactions against gadolinium, or serious unexpected
events and patient burden in form of time investment.
These drawbacks are outweighed by potential benefits for patients, since focal
therapy has a lower chance on developing impotence and incontinence when
comparing it to the standard treatment of radical prostatectomy of
radiotherapy.
At present, all devices that are used in the proposed study are CE approved and
no safety issues were reported in IDEAL stage 1 and 2a studies [5-8].
Marra et al. [9] showed that evidence from assessments of salvage treatments
after focal therapy failure is low and is derived from four retrospective
salvage series. Available salvage options after focal therapy include RP and
RT. Overall oncological outcomes are acceptable, although biochemical
recurrence is slightly higher compared to primary PCa treatment, probably
because of the higher aggressiveness of recurrent/persistent PCa. Functional
outcomes and complications are not markedly worse compared to primary treatment
[10]. Salvage RP and salvage RT, therefore, seem feasible treatment options
with acceptable oncological control and functional outcomes. Thus, re-treatment
with salvage radiotherapy or salvage surgery remains a clinical option after
focal therapy failure.
All patients included in our trial will undergo intensive follow-up. Patients
undergoing focal therapy will undergo quarterly PSA measurement and yearly
prostate MRI, followed by a prostate biopsy after 12 months and thereafter if
indicated based on the MRI. Since focal therapy is a one-time intervention,
there will be no patients left in treatment or that require alternative
fallback treatments.