Download Ablative Techniques for the Treatment of Localised Prostate Cancer

Health Policy Advisory Committee on
Technology
Technology Brief
Ablative Techniques for the Treatment of Localised Prostate
Cancer
November 2014
© State of Queensland (Queensland Department of Health) 2014
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Technology, Company and Licensing
Register ID
WP198
Technology name
Ablative techniques for localised prostate cancer
Patient indication
Focal treatment of localised prostate cancer
Description of the technology
Prostate cancer is common and is increasingly detected in its early stages through prostatespecific antigen (PSA) screening. The traditional approach to localised prostate cancer
involves removal of the whole prostate gland. While this is designed to maximise the
likelihood of a cure, it is also associated with a range of adverse effects in the adjacent
genitourinary and gastrointestinal systems.
Presented in this report are four emerging technologies that aim to treat localised prostate
cancer by focal tissue ablation using various forms of energy1, rather than by removal of the
whole prostate gland. The four technologies and the forms of energy they use are:
1. Cryosurgery / cryotherapy / cryoablation (via extreme cold);
2. Radiofrequency ablation (RFA) (via heat);
3. Irreversible electroporation (IRE) (via electric current);
4. Magnetic resonance (MR)-guided focal laser ablation (via heat).
All techniques employ similar overall approaches. With the patient in the operating room
under general (or in some cases, spinal) anaesthesia, several needle electrodes are passed
through the perineal skin into the targeted prostate tissue using imaging guidance. The type
of imaging guidance varies by technique, and may include transrectal ultrasound [TRUS],
magnetic resonance [MR] imaging, or MR-TRUS fusion.1
Cryosurgery: gas at temperatures colder than -40◦ C is passed through needle electrodes,
creating ice balls that destroy the targeted tissue in several freeze-thaw cycles.2, 3
Cryoablation of the prostate was first introduced in the 1960s; however, it was abandoned
due to an unacceptably high complication rate. It was reintroduced in the 1990s as a result
of improvements in percutaneous and cryogenic instrumentation, and the development of
TRUS, which allowed monitoring of the freezing process. 2, 4
RFA: thermal energy, at a temperature of about 100°C, is generated from high frequency
alternating current by a radiofrequency generator. The thermal energy is delivered to the
prostate tumour(s) through monopolar or bipolar needle electrodes and the targeted tissue
is irreversibly destroyed by coagulative necrosis.5
IRE: low voltage direct electric current delivered via multiple electrodes. This creates a
strong electrical field that permanently damages cell membranes, leading to cell death,
without a thermal effect.1
Ablative techniques for localised prostate cancer: November 2014
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MR-guided focal laser ablation: thermal energy is used for tissue destruction, leading to
homogeneous tissue necrosis. MR imaging can be used during the treatment to provide
real-time temperature monitoring and visualisation of the treatment zone. 6
Company or developer
There are a number of cryotherapy and RFA devices available for use in Australia. A nonexhaustive list of devices that appear on the ARTG is provided in Table 1. These devices are
for use in ablative surgical procedures, and it is unclear whether they are specifically
applicable to treatment of localised prostate cancer.
One of the included studies in this technology brief used the NanoKnife® System
(AngioDynamics, USA) in the provision of IRE.1, 7 This device does not appear on the ARTG.
One of the studies focussing on MR-guided focal laser ablation used a US Food and Drug
Administration approved MR-guided laser system promoted for use in minimally invasive
neurosurgery.6 Originally marketed by Visualase, Inc. (Houston, Texas, USA) the company
was acquired by Medtronic, Inc. (Minneapolis, Minnesota, USA) in late July 2014.8
Reason for assessment
Prostate cancer is common and is increasingly being detected in its early stages. There is
growing interest in focal treatment for localised cancers because it preserves some of the
prostate gland. This may help prevent complications associated with treating the entire
prostate, including urinary incontinence or retention, erectile dysfunction and diarrhoea.
Focal treatment of localised prostate cancer could have major health and cost benefits.
Stage of development in Australia
Yet to emerge (RFA, IRE, and MR
Guided focal laser ablation)
Experimental (cryosurgery)
Investigational
Established
Established but changed indication
or modification of technique
Should be taken out of use
Nearly established
Licensing, reimbursement and other approval
There are a number of devices available to perform cryotherapy and RFA. Table 1 provides a
non-exhaustive list of the devices which have received Therapeutic Goods Administration
(TGA) approval. The public summary documents do not provide the specific use for which
each device is indicated.
Ablative techniques for localised prostate cancer: November 2014
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Table 1 Non-exhaustive list of TGA approved local ablative devices
Technology
Sponsor
ARTG number (s)
Cryotherapy
Atricure Inc., United States, cryosurgical unit, general
purpose
162597
Brymill Cryogenic Systems, United States, cryosurgical
unit, general purpose
136300
Galil Medical Inc. Israel, cryotherapy system for
minimally-invasive systems
224583; 223036; 221468
MedGyn Products Inc., United States, cryosurgical unit,
general purpose
219261
Medtronic CryoCath LP, Canada, cryosurgical unit,
general purpose
164650; 205503
MyoScience Inc., United States, percutaneous
cryotherapy applications
212518
New Medical Technologies GmbH, Switzerland,
cryosurgical unit, general purpose
181716
Wallach Surgical Devices Inc., United States,
cryosurgical unit, general purpose
174582; 134600
Walmay Holdings P/L, Australia, cryosurgical unit,
general purpose
170073
AD Elektronik GmbH, Germany, radiofrequency
ablation unit, general purpose
158953; 35156
Atricure Inc., United States, radiofrequency ablation
unit, general purpose
157231
Biosense Webster Inc., United States, radiofrequency
ablation unit, general purpose
216163
Irvine Biomedical Inc., United States, radiofrequency
ablation unit, general purpose
128900
Kimberley Clarke, United States, radiofrequency
ablation unit, general purpose
211836
IRE
NA
NA
MR-guided focal laser
NA
NA
RFA
Australian Therapeutic Goods Administration approval
Yes
ARTG number (s) See Table 1
No
Not applicable
Technology type
Procedure / Device
Technology use
Therapeutic
Ablative techniques for localised prostate cancer: November 2014
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Patient Indication and Setting
Disease description and associated mortality and morbidity
The prostate is part of the male reproductive system, located immediately below the
bladder and just in front of the bowel. Doughnut-shaped, it surrounds the beginning of the
urethra and the nerves that control penile erections are nearby. The prostate’s main
function is to produce fluid that protects and enriches sperm. Prostate cancer occurs when
some of the cells of the prostate reproduce more rapidly than in a normal prostate, causing
a tumour to develop. When the tumour is confined to the prostate gland it is considered to
be localised. However, the cancer can metastasise to other parts of the body, particularly
the bones and lymph nodes.9 One of the symptoms of localised prostate cancer is difficulty
passing urine, although the condition is often diagnosed at an asymptomatic stage,
particularly when serum PSA levels are monitored.10
Number of patients
According to the Australian Institute of Health and Welfare (AIHW), prostate cancer is the
most commonly diagnosed non-cutaneous cancer in the country, with 21,808 new cases
being diagnosed in 2009.11 The age-standardised incidence is increasing, from 79 new cases
per 100,000 males in 1982, to 194 new cases per 100,000 males in 2009. The increase is
expected to continue owing to more testing, changes in diagnostic practices and population
ageing. Prostate cancer was the fourth leading cause of death among Australian males in
2011 (3294 deaths), although the age-standardised mortality rate has been decreasing and
this trend is expected to continue. Recent 5-year survival rates are relatively high, for
example the rate was 90 per cent in 2007.
Aboriginal or Torres Strait Islander men are less likely to be diagnosed with, but equally
likely to die, from prostate cancer. This may be due to variations in the number of men
undergoing screening, population risk profiles and population age profiles. International
data from 2008 show that the incidence of prostate cancer was higher in Australia than in
other country groups studied. The mortality rate in Australia was similar to those in
Northern Europe and New Zealand, and higher than those in North America and Asia. AIHW
data do not report on prostate cancer by grade or stage, so the proportion of localised to all
prostate cancers was not available.
New Zealand Ministry of Health data from 2010 reveal similar rates and trends.12 Prostate
cancer was the most common cancer in men, accounting for 27 per cent of all male cancer
registrations. It accounted for 13 per cent of all male deaths from cancer, making it the third
most common cause of cancer death in New Zealand men. The incidence of prostate cancer
among Māori men is lower than in non-Māori men; in 2010 the incidence was 86 per
100,000 versus 100 per 100,000 respectively. However, the mortality rate is 72 per cent
Ablative techniques for localised prostate cancer: November 2014
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higher among Māori men. From 2000 to 2010, the mortality rate declined by 32 per cent for
non-Māori men but only by six per cent for Māori men.
Speciality
Men’s health and sexual health
Technology setting
Specialist hospital / general hospital / outpatient service
Impact
Alternative and/or complementary technology
The four ablative technologies described are considered direct substitutes for the current
approach to treating focal prostate cancer. The current technique involves removing or
obliterating the whole prostate gland through procedures such as radical prostatectomy,
external-beam radiotherapy (EBRT) and brachytherapy. The complications associated with
current treatments are an important factor. An estimated 27 to 56 per cent of men who
receive treatment for prostate cancer do so for cancers that would not have become
clinically evident during their lifetime.6 New evidence suggests that the natural history of
prostate cancer is driven by the largest lesion with the highest grade, known as the index
lesion. Focal therapy, which involves targeting the index lesion while sparing the rest of the
gland, is of increasing interest for men with low- and intermediate-volume prostate cancer.
Such tissue-preserving strategies offer a compromise between the benefits of cancer
treatment and the adverse effects associated with such treatment. 13
Current technology
The approach to treating prostate cancer depends on a number of factors including cancer
stage (localised or metastasised); Gleason score (reflects the degree of cellular
differentiation); PSA level and trend; patient age and general health; potential treatment
side-effects and patient preference.14 The most common approaches to treatment of
localised prostate cancer are radical prostatectomy, EBRT and brachytherapy.15 Radical
prostate surgery is generally reserved for men with localised prostate cancer, at least a 10year life expectancy and who are good surgical candidates. EBRT and brachytherapy also
require men to have localised cancer and at least a 10-year life expectancy.11 Watchful
waiting and active surveillance with regular PSA testing and digital rectal exams are also
possible strategies, particularly for men older than 75 years and for those with significant
comorbidities.14 Hormone therapy may be used as a neoadjuvant therapy (a treatment
given prior to the primary therapy) for up to six months before radiotherapy. This aims to
shrink the tumour before treatment, particularly for men with medium- or high-risk, or
locally advanced prostate cancer. It may also be given for a period of time after
radiotherapy as an adjuvant therapy.14
Ablative techniques for localised prostate cancer: November 2014
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Diffusion of technology in Australia
According to web-based advertising there is one urologist in Australia offering cryosurgery
for focal prostate cancer.16 Additional focal therapies for prostate cancer currently available
in Australia include: IRE, High intensity focused ultrasound, Photo Dynamic Therapy, and
focal interstitial low dose rate brachytherapy. The availability of these techniques; however,
is limited to one urologist in each instance (personal correspondence, University of South
Australia). No evidence was located to suggest that RFA, or MR-guided focal laser ablation
therapies are being used to treat localised prostate cancer in Australia or New Zealand.
International utilisation
Country
Level of Use
Trials underway or completed
Australia
 (IRE)
Belgium
 (RFA)
Canada
 (cryosurgery, MR-guided focal laser ablation)
England
 (IRE)
Netherlands
 (focal laser ablation)
United States
 (cryosurgery, IRE, MR-guided focal laser ablation)
Limited use
Widely diffused
Unclear –
unlikely, with the
possible
exception of
cryosurgery
Table notes: IRE = irreversible electroporation; MR = magnetic resonance; RFA = radiofrequency ablation
Cost infrastructure and economic consequences
Australian health care expenditure on prostate cancer was estimated to be $349 million in
2008-09. This was an increase of 23 per cent over 2004-05 and is attributed to an increase in
new diagnoses. Just over half of the total cost (56%) was due to inpatient services, followed
by prescription drugs (36%) and out-of-hospital medical expenses (9%).11 Men aged 75 to
84 years are the peak age group affected. Data on the proportion of prostate cancer cases
that are considered localised was not available. However, changes in practice patterns to
reduce the aggressiveness of treatment (assuming outcomes are at least as favourable)
would provide cost savings.
Ethical, cultural or religious considerations
No ethical, cultural or religious implications were identified in the included literature.
Evidence and Policy
Safety and effectiveness
Four technologies are reviewed. Table 2 shows the number of studies and types of evidence
included for each technology.
Ablative techniques for localised prostate cancer: November 2014
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Table 2 Included evidence for four ablation technologies to treat prostate cancer
Technology
Systematic reviews
Cryosurgery
NICE 2012 (all included studies were level IV
intervention evidence)
Xiong et al 2014 (both included studies were
level I intervention evidence)
RFA
--
IRE
--
MR-guided focal
laser ablation
--
Primary studies
Chin et al 2008 (level I intervention evidence)
Donnelly et al 2010 (level I intervention evidence)
Williams et al 2012 (level III-2 intervention
evidence)
Shariat et al 2005 (level IV intervention evidence)
-Lindner et al 2012 (conference abstract) (level IV
intervention evidence)
Oto et al 2013 (level IV intervention evidence)
Table notes: IRE = irreversible electroporation; MR = magnetic resonance; NICE = National Institute for Health and Care Excellence; RFA = radiofrequency
ablation.
Cryosurgery
Two relevant systematic reviews (SRs) were located and are outlined in Table 2.10, 17 A SR
published by the National Institute for Health and Clinical Excellence (NICE) in the United
Kingdom (UK) focused on cryosurgery for localised prostate cancer but did not identify any
comparative studies (level IV intervention evidence).10 A more recent SR,17 also from the
UK, included two randomised trials of cryosurgery versus EBRT (level I intervention
evidence). As the SR by Xiong et al provided limited detail, the two randomised trials
covered by the SR are presented in this technology brief. 2, 4 A recent non-randomised
comparative study (level III-2 intervention evidence) that utilised data from a large USA
Medicare-linked database has also been included. 15
Table 3 Systematic reviews of prostate cancer treatment that included cryosurgery
Study/
location, level
of evidence
Main focus
Literature search
details
NICE 2012/
UK
Level IV
evidence
Interventional
procedure
overview of
cryoablation for
localised prostate
cancer
Extensive w/o
language
restrictions;
November 2011
Xiong et al
2014/
UK
Level I
evidence (for
cryosurgery)
Efficacy & safety
of various
therapies for
localised prostate
cancer
MEDLINE w/o
language
restrictions;
September
2012
Number of
technologies
covered
1
4
Number of
studies reporting on
cryosurgery
Findings related to
cryosurgery as compared with
other treatments
Included one registry
study & four case
series; total n=1330
men; follow-up range
15-70 months.
No direct comparative
evidence. From registry
(n=1160), 164 had biopsy
due to increased PSA & 26%
of these were positive; in
case series 0-40% were
positive at follow-up.
Two randomised
trials reporting on
cryosurgery versus
EBRT (out of 21
randomised trials
covering different
technologies)
No evidence of superiority for
any of the compared
treatments in 5-year allcause mortality. Cryotherapy
had less GI & GU toxicity than
RT.
Table notes: EBRT = external beam radiotherapy; GI = gastrointestinal; GU = genitourinary; NICE = National Institute for Health & Care Excellence; PSA =
prostate specific antigen; RT = radiotherapy; UK = United Kingdom; w/o = without.
As a greater amount of higher lever evidence is available for cryotherapy, as opposed to the
other techniques included in this technology brief, essential details of the identified
comparative literature are reported in Table 4 below.
Ablative techniques for localised prostate cancer: November 2014
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Table 4 Comparative studies of cryosurgery for prostate cancer treatment
Study/
location, level
of evidence
Comparison;
follow up
Patients
Safety
Efficacy
Chin 2008/
Canada
Randomised
trial (level I
interventional
evidence)
CRYO vs EBRT;
all patients
received 6 mos.
AA therapy;
mean follow-up
37 months
Clinically locally
advanced prostate CA
(T2C-T3B) (salvage for
patients who failed
RT); n=64 (CRYO=33,
EBRT=31); mean age
70 years; median
PSA=9.9 ng/mL
SAEs: CRYO= One each of acute
urinary retention, CVA & severe
constipation; EBRT= One each of
bloody diarrhoea & perforated
cecum.
4-yr DSS & OS NSD between
groups.
Significantly different AEs between
study arms: GI: CRYO=45% vs EBRT
100% (primarily diarrhoea, melena &
proctalgia); GU: CRYO 32% vs EBRT
3% perineal/genital pain.
4-year bDFS = CRYO 13% vs
EBRT 47%.
Donnelly
2010/ Canada
Randomised
trial (level I
interventional
evidence)
CRYO vs EBRT;
all patients
received six
mos. AA
therapy;
median followup 100 months
Clinically localised
prostate CA; n=244
(122 in each arm);
mean age 69 years;
median PSA=8.6
ng/mL
Deaths: Five in each study arm.
5-yr DSS & OS NSD between
groups.
Williams
2012/ USA
Data from a
USA Medicarelinked
database
CRYO vs
brachytherapy;
follow-up>2
years
n=10,928 with
localised prostate CA:
primary CRYO= 943;
brachytherapy=9985
Grade 3 of 4 toxicity (no grade 4): GI:
CRYO= 3 vs EBRT=8 pts (mainly
proctitis in EBRT arm); GU: CRYO=10
vs EBRT=7 pts (mainly urinary
retention).
Sexual intercourse at 36 mos. for
those active preRx: 14 in each grp:
CRYO= Four unassisted (not defined);
EBRT=12 unassisted.
CRYO was associated with more
urinary AEs (41% vs 22%, p<0.001) &
ED (35% vs 21%, p<0.001) but
brachytherapy was associated with
more bowel complications (19% vs
12%, p<0.001).
Mean bDFS = CRYO 28 mos.
vs EBRT 41 mos.
Failure at 36 mos. (defined
as biochemical failure,
radiologic disease, or further
prostate CA Rx):
CRYO=23.9% vs
EBRT=23.7%; NSD.
CA-positive Bx at 36 mos.:
CRYO=8% vs EBRT=29%.
CRYO was associated with
greater use of salvage AA
therapy (1.4 vs 0.5 per 100
person-years, p< 0.001),
suggesting poorer CA control.
Table notes: AA = antiandrogen; AE = adverse event; bDFS = biochemical disease-free survival; Bx = biopsy; CA = cancer; CRYO = cryosurgery; DSS =
disease-specific survival; EBRT = external beam radiotherapy; ED = erectile dysfunction; GI = gastrointestinal; GU = genitourinary; NSD = not significantly
different; OS = overall survival; PSA = prostate specific antigen; RT = radiation therapy; Rx = treatment; SAE = serious adverse event; USA = United States of
America.
Radiofrequency ablation
One publication describing the use of RFA to treat prostate cancer was located.5 The study
primarily focussed on safety and feasibility, with some 12-month efficacy data available. A
German-language SR of RFA to treat several diseases, including prostate cancer, was also
located. However, the English executive summary stated that no studies on prostate cancer
were identified that met the (unspecified) inclusion criteria.18
Shariat et al 20055
In a small, prospective, phase I/II case series study (level IV interventional evidence) in
Texas, researchers assessed the feasibility, safety, morbidity and preliminary efficacy of RFA
for men with recurrent localised prostate cancer who were hormone-naïve. Diagnosis of
recurrence was based on rising serum PSA levels on at least three separate occasions at
least two weeks apart. Of the 11 participants in the study, eight had failed prior radiation
therapy with curative intent and three had been followed via watchful waiting, as they were
Ablative techniques for localised prostate cancer: November 2014
8
not candidates for curative primary therapy. It was not reported whether the patients were
enrolled consecutively.
The median patient age was 77 years (range, 60 to 82 years), median baseline PSA level was
5.7 ng/mL (range, 0.66 to 10.8 ng/mL) and median pre-radiofrequency interstitial tumour
ablation (pre-RITA) Gleason score was 7 (range, 6 to 8). Treatment was delivered in an
outpatient setting in a cystoscopy suite under intravenous sedation. RFA energy was applied
via needles placed transperineally under TRUS guidance and only areas of biopsy-proven
cancer were ablated. Median follow-up was 20 months (range, 3 to 38 months).
Safety
Early complications (immediately after treatment) were transient macrohaematuria (blood
in the urine) in two patients (19%), bladder spasm in one patient (9%) and dysuria (painful
urination) in one patient (9%). The only late complication (not defined) was moderate
constipation in one patient (9%).
Efficacy
PSA levels decreased after RFA by more than 50 per cent in 10 patients, eight of these
patients decreased more than 70 per, and seven of these eight decreased more than 80 per
cent. The mean PSA doubling time (PSADT) after RFA was slower (37 months, standard
deviation [SD] 22) than it was before RFA (14 months, SD 13; p=0.008). In the group of eight
patients for whom radiation therapy had failed, PSADT after RFA was 127 per cent longer
than it had been before RFA. In the watchful-waiting group, PSADT after RFA was 285 per
cent longer.
At 12 months, three of the six patients (50%) in the radiation-failure group of eight patients
with sufficient follow-up had no residual cancer on repeat systematic 12-core biopsy cores.
In the watchful waiting group of three patients, two (66%) were free of cancer in biopsy
cores sampled from the areas treated. Two of the four patients who had persistent cancer
cells in the treated areas had received incomplete treatment due to high rising temperature
in the rectal probe during the procedure. The researchers concluded that RFA is feasible and
safe in patients with prostate cancer who have failed local radiation therapy, or who are not
candidates for primary curative therapy.
Irreversible electroporation
No studies were located that included results. One study was described in a publication but
results were not provided. 1
MR-guided focal laser ablation
Two studies were located.6 , 19 One was reported only in a conference abstract but was
included here due to the lack of available evidence.19
Ablative techniques for localised prostate cancer: November 2014
9
Lindner et al 201219
Authors from Canada reported their experience using MR-guided focal laser ablation as an
outpatient treatment for 23 men with low-intermediate-risk prostate cancer (level IV
intervention evidence).19 It was not reported whether the study was prospective and
whether patients were enrolled consecutively. Under MR guidance, a 1.5 Tesla device, laser
fibres were inserted into the prostate using locally developed surgical planning and
guidance software. Thermal ablation was monitored using MR thermal mapping. Real-time
ablation size was calculated using a Visulase Inc. workstation.
Safety
There were no perioperative complications. All patients who were sexually potent before
the procedure maintained potency, and urinary continence was not compromised.
Efficacy
The treatment created an identifiable hypovascular defect on MR immediately after
treatment that coincided with the targeted prostatic lesion. Mean targeted volume was 0.77
cc and mean ablated volume was 5.5 cc. Oncological results were not reported. This group
is running trial NCT01094665, which is outlined in the section on ongoing research.
Oto et al 20136
A phase I study in the USA (level IV intervention evidence) focusing on feasibility and safety
prospectively enrolled nine men with low-risk prostate cancer. It was not indicated whether
enrolment was consecutive. Median patient age was 61 years (range, 52 to 77 years) and
mean PSA level was 5.5 ng/mL (SD 2.6). Eight patients (89%) had Gleason grade 6 cancer and
one patient (11%) had grade 7 cancer. Transperineal MR-guided focal laser ablation was
undertaken with patients under conscious sedation. Patients were released home the day of
treatment. The mean duration of the overall MR procedure was 2.5 to 4 hours and the
duration of laser treatment to the prostate was 4.3 minutes (range, 1.5 to 7.5 minutes).
Most of the procedure time was spent on localising and targeting the lesion. Follow-up
examinations occurred at one, three and six months post-treatment (plus or minus two
weeks), with follow-up biopsies at six months. All patients completed the six month followup.
Safety
All nine patients tolerated the procedure well. There were no major complications or
serious adverse events. Of particular interest was the lack of adverse effects in the urinary
system (incontinence or urinary retention requiring surgical intervention) or new-onset
erectile dysfunction not responsive to medication. No patients experienced these adverse
effects. One patient developed an abrasion on the perineum that resolved with conservative
measures, while another patient developed transient paresthesia (numbness, tingling or
Ablative techniques for localised prostate cancer: November 2014
10
burning sensation) involving one quarter of the glans penis, which resolved within three
weeks.
Efficacy
The primary outcomes measured were changes in urinary function (incontinence or
retention), as assessed by the International Prostate Symptom Score (IPSS), and new onset
erectile dysfunction, assessed by the Sexual Health Inventory for Men (SHIM) score. Results
showed no significant changes in these two areas. With respect to PSA levels, results
showed no significant changes. Prior to surgery the PSA levels were 5.5 ng/mL (SD 2.6); at
one month: 5.7 ng/mL (SD 4.4); three months: 4.7 ng/mL (SD 3.6); and at six months: 5.5
ng/mL (SD 4.0) (p=0.8). MR imaging-guided biopsy of the ablation zone at six months
revealed benign prostatic tissue in seven of nine patients (78%) and Gleason grade 6 cancer
in the remaining two (22%). In the latter two, review by the researchers suggested that the
initial malignant tissue was not completely covered by the ablation zone.
Economic evaluation
The only economic information located was in the USA Medicare clinical study of Williams et
al15 that used registry data to compare cryosurgery and brachytherapy for the treatment of
localised prostate cancer. This study reported expenditures in 2008 USD and they are
presented here alongside a conversion to the 2008 Australian dollar1. While median
baseline health care expenditures in the six months before prostate cancer diagnosis were
significantly higher for men who received cryotherapy versus those who underwent
brachytherapy (US$1,941 vs US$1,799, p<0.001) ($2,913 vs $2,700), median health care
costs six months after diagnosis were higher for the patients who underwent brachytherapy
(US$15,146 vs US$19,398, p<0.001) ($22,734 vs $29,116). The authors determined that the
costs attributable to cryotherapy compared with brachytherapy were US$12,629 vs
US$16,887 respectively (p<0.001) ($18,956 vs $25,347). Williams et al found no other cost
analyses aside from a 2003 assessment performed by Hummel et al20 from the UK, who
included quality of life considerations. They found that cryotherapy was inferior to the other
treatments available at the time with respect to cost-effectiveness owing to the greater
likelihood of erectile dysfunction following the procedure.
1
Based on the calculator at https://eppi.ioe.ac.uk/costconversion/default.aspx.
Ablative techniques for localised prostate cancer: November 2014
11
Ongoing research
A search of ClinicalTrials.gov and the Australian and New Zealand Clinical Trials Register
identified a large number of studies exploring the treatments outlined in this technology
brief. Five studies were found for cryosurgery, one for RFA, four for IRE and five for MRguided focal laser therapy. The studies are described briefly in Tables 4, 5 and 6.
Cryosurgery
At least five studies are underway, either ongoing or recruiting. Four are in different centres
in the USA and one is in Taiwan (Table 4). The total enrolled patient group across the five
studies is more than 1,200 men, with study end dates ranging from estimates of October
2014 to January 2019.
Table 4
Ongoing trials of cryosurgery for localised prostate cancer
Trial number* /
location / note
Study design
Status
n=
Patients / indication
Outcomes /
length of follow-up
Estimated
completion
date
NCT01398657/
Taiwan
Randomised
open-label:
CRYO alone,
or CRYO with
adjuvant ADT
Recruiting
182
High-risk localised
prostate CA (PSA>20
ng/mL, Gleason score
≥8, or clinical staging
≥T2c
Safety & efficacy.
Treatment failure at 3
years (determined by PSA,
Bx or initiation of hormone
therapy)
Follow-up: 36 months
Jun. 2016
NCT00774436/
USA
Cohort
Ongoing
50
Low-risk localised
prostate cancer
Efficacy & QOL
Follow-up: 6 months
Oct. 2014
NCT00824928/
USA
Manufacturer
listed as
collaborator
Cohort
Recruiting
800
Salvage CRYO for
recurrent prostate CA
Development of a registry.
Treatment failure (via PSA)
at 2+ years
Dec. 2014
NCT00877682/
USA
Manufacturers
listed as
collaborators
Cohort
Ongoing
100
Localised prostate CA –
focal CRYO to be used
to treat tumour only
Safety, efficacy & QOL
Follow-up: 6, 12 and 36
months
Apr. 2016
NCT01727284/
USA
(MR-guided CRYO)
Cohort
Recruiting
100
Prostate bed
recurrences <5cm; not
good candidates for
surgery or RT, or RT can
be postponed
Safety & efficacy
Follow-up: 36 months
Jan. 2019
* Information is from clinicaltrials.gov
Table notes: ADT = androgen deprivation therapy; Bx = biopsy; CA = cancer; CRYO = cryosurgery; MR = magnetic resonance; PSA = prostate specific
antigen; QOL = quality of life; RT = radiotherapy; USA = United States of America.
Ablative techniques for localised prostate cancer: November 2014
12
Radiofrequency ablation
Study NCT01423006, a small pilot study in the USA, treated five patients with very low-risk
prostate cancer with RFA using ENCAGE™ technology (Trod Medical, Leuven, Belgium).
Patient selection criteria were not reported. The primary outcome measure was negative
prostate biopsy rate at six months. The study also aimed to measure adverse events and
quality of life at six months. The study started in August 2011 and final data collection
occurred in March 2013, although the results of the study are not yet available. The device
manufacturer recently raised EUR 4.75m ($8.15m) to perform clinical studies in both Europe
and the USA on the use of the technology for the focal treatment of prostate cancer.21
Irreversible electroporation
Although there is little published information about this technology there are five studies
ongoing or recruiting. There is one study each in Australia, England and the USA, and two in
the Netherlands (Table 5). The status of the small Australian study is unclear as the
information has not been updated for two years. Including the 200 men in the Dutch
randomised controlled trial, the total enrolled population will be about 250 men.
Table 5
Ongoing trials of IRE for localised prostate cancer
Trial number* /
location / note
Study design
Status
n=
Patients / indication
Outcomes /
length of follow-up
Estimated
completion
date
NCT01835977/
Netherlands
Randomised
single blind
(patients): IRE
to whole
prostate or
affected half
Not yet
recruiting
200
High volume, low- or
intermediate-risk
prostate CA
Safety & efficacy
Follow-up: 36
months
Jan. 2018
NCT01790451/
Netherlands
Manufacturer
(Angiodynamics Ltd.) is
listed as a collaborator
Cohort
Enrolling
by
invitation
16
Low- or intermediaterisk prostate CA,
scheduled for radical
prostatectomy 30 days
later
Safety, efficacy &
QOL
Follow-up: 12
months
Sept. 2014
NCT01726894/
England
Cohort
Ongoing
20
Locally contained, MRvisible cancer of the
anterior prostate
Safety & efficacy
Follow-up: 12
months
Aug. 2015
NCT01972867/
USA
Manufacturer
(Angiodynamics Ltd.) is
listed as sponsor
Cohort
Recruiting
6
Low-risk prostate
cancer
Feasibility, safety &
effectiveness
Follow-up: 24
months
Aug. 2016
ACTRN
12612000523808/
Australia
Cohort
Recruiting
6
Low- or intermediaterisk prostate CA,
scheduled for radical
prostatectomy 2 to 4
weeks later
Safety, efficacy,
patient satisfaction
& cost-effectiveness
Follow-up: 1 week
post prostatectomy
Registered
in 2012.
Current
status
unclear
* Information is from clinicaltrials.gov and the Australian New Zealand Clinical Trials Registry.
Table notes: CA=cancer; MR=magnetic resonance; QOL=quality of life; USA=United States of America.
Ablative techniques for localised prostate cancer: November 2014
13
MR-guided focal laser ablation
Five case series studies have enrolled or will enrol a total of about 130 men (Table 6). The
trials are being conducted in the USA (three trials), Canada (one trial) and the Netherlands
(one trial). Four of the five studies should be complete by mid-2015. The fifth study aims to
track 3-year disease-free survival and will not be complete until mid-2019.
Table 6
Ongoing trials of MR-guided focal laser ablation for localised prostate cancer
Trial number* /
location / note
Study
design
Status
n=
Patients /
indication
Outcomes /
length of follow-up
Estimated
completion
date
NCT 01192438/
USA
Collaborator is MR-guided
laser company (Visualase)
Cohort
Completed Sept.
2011
(no publications
yet)
9
Low grade
prostate CA
Safety
Follow-up: 6 months
Sept. 2011
NCT 01094665/
Canada
Presumably the Lindner et
al (2012) abstract, which
forms part of this
technology brief, reports
on 23 men from this
cohort
Cohort
Recruiting
(start date Nov
2009)
60
Early stage
prostate CA, as
yet untreated
Safety & feasibility
Follow-up: 4 months
Dec. 2013
NCT 01792024/
USA
Cohort
Ongoing
(start date Jan
2013)
27
Early stage
prostate CA, as
yet untreated
Safety, efficacy & QOL
Follow-up: 12 months
Feb. 2015
NCT 01377753/
USA
Cohort
Ongoing
(start date May
2011)
15
Localized
prostate CA
visible on MR
Safety & feasibility
Follow-up: 3 years
Apr. 2015
NCT 02200809/
Netherlands
Cohort
Recruiting
(start date July
2014)
20
Intermediaterisk prostate
CA, as yet
untreated
Efficacy (3-year
disease-free survival)
Follow-up: 3 years
Jul. 2019
* Information from clinicaltrials.gov
Table notes: CA = cancer; MR = magnetic resonance; NCI = National Cancer Institute; NR = not reported; QOL = quality of life; USA = United States of
America.
Other issues
The Williams et al15 Medicare database study from the USA noted several interesting sociodemographic differences between men who received cryosurgery and those who were
treated with EBRT. Men who underwent cryotherapy were significantly:
more likely to have a higher grade (36% versus 13%) and clinical stage of disease
(T3/unknown 5% versus 2%); be older than 75 years (41% versus 31%); be African
American (12% versus 6%); and live in urban areas (11% versus 9%);
less likely to live in areas where at least 90 per cent of the population had graduated
high school (32% versus 40%); and have median household income of more than
USD 60,000 (13% versus 21%)
Ablative techniques for localised prostate cancer: November 2014
14
It is unclear whether these differences between the treatment populations would be seen in
other countries.
There are also questions regarding appropriateness of focal therapy for prostate cancer as a
viable technique because of safety and efficacy issues. The Urology Society of Australia and
New Zealand (USANZ) position below summarises these concerns:
Due to the lack of long-term data on focal therapy regarding the ability to accurately target
a lesion, on the long-term cancer control, on the side effects of treatment, and on the ability
to provide safe salvage options should treatment failure occur – USANZ believe that focal
therapy for prostate cancer remains an experimental technique.22
It is important to note, that focal therapy may require more frequent surveillance then
whole gland therapy, which in turn may have an impact on cost considerations.
Summary of findings
Australian data shows a rising incidence in the diagnosis of prostate cancer, which is largely
attributable to increased testing, changes in diagnostic practices and ageing of the
population. In many cases the cancer is localised within the prostate gland, yet current
treatments often target the entire gland and can result in significant complications in
adjacent organ systems. In particular, current treatments can result in urinary incontinence
or retention, bowel disturbances and erectile dysfunction. Focal treatment of only the
cancerous tissue may lead to fewer adverse effects, and a number of avenues are being
explored, including the ablation of tissue via extreme cold (cryosurgery), thermal energy
(RFA and MR-guided focal laser) and electric current (IRE). The treatment can often be
delivered in an outpatient setting and this may provide cost savings.
At present the evidence is sparse, particularly in terms of comparative studies although a
number of studies are underway. Cryosurgery has been the most extensively explored, with
the published literature including two randomised controlled trials and one comparative
database study. These three studies had follow-up ranging from 24 to 100 months, although
the two randomised studies were both small. The database study examined outcomes for
943 men undergoing cryosurgery compared with 9985 men undergoing brachytherapy. The
evidence from the two randomised trials, looking at cryosurgery compared with EBRT, did
not show a consistent benefit. Similarly, the database study of patients receiving
cryosurgery, compared with brachytherapy, reported greater use of antiandrogen therapy
in the cryotherapy group, suggesting poorer cancer control. However, cryosurgery
techniques may be improving with attendant improvements in patient outcomes.
The remaining three focal ablation techniques are early in their development cycles;
however, they do show promise. Although no studies for IRE were located, five are
underway or planned with one being a randomised trial that aims to enrol 200 men.
Similarly, only two small cohort studies for MR-guided focal laser therapy were located but
Ablative techniques for localised prostate cancer: November 2014
15
five cohort studies are underway. The evidence for RFA is scarce, with one very small cohort
study located. Another small cohort study is underway, and there is a media report of
recent funding for additional research in this area.
HealthPACT assessment
Despite a paucity of rigorous evidence describing the use of ablative therapies for localised
prostate cancer, non-TGA approved technologies such as the Nanoknife© system are being
marketed in Australia and New Zealand through ‘free trials’. Studies included in this
assessment are flawed as they did not use radical prostatectomy, which is a good treatment
option especially for younger or high-risk patients, as the comparator. At this point in time
focal therapy for prostate cancer should be considered experimental and should only be
conducted under the auspices of a clinical trial. HealthPACT recommends that the evidence
around this technology be updated and monitored for more information in 24-months and
that other local ablation techniques should be included in any future technology update.
Number of studies included
All evidence included for assessment in this technology brief has been assessed according to
the revised NHMRC levels of evidence. A document summarising these levels may be
accessed via the HealthPACT web site.
Total number of studies
7 (including a level IV SR for cryosurgery)
Total number of Level I studies
2 (randomised trials for cryosurgery)
Total number of Level III-2 studies
1 (registry study for cryosurgery)
Total number of Level IV studies
4 (an SR of level IV studies for cryosurgery, two
studies for MR-guided focal laser ablation, one
study for RFA and no studies for IRE)
Search criteria to be used (MeSH terms)
cryotherapy OR cryosurgery OR cryoablation OR cryo-ablation OR radioablation OR radioablation OR radiofrequency ablation OR radio-frequency ablation OR focal laser ablation OR
irreversible electroporation AND prostate AND cancer OR tumour OR tumor
Limits: English, Humans, Abstract available. (EMBASE limit 2005 to present)
References
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2.
Valerio, M., Dickinson, L. et al (2014). 'A prospective development study investigating
focal irreversible electroporation in men with localised prostate cancer: Nanoknife
Electroporation Ablation Trial (NEAT)'. Contemp Clin Trials, 39 (1), 57-65.
Chin, J. L., Ng, C. K. et al (2008). 'Randomized trial comparing cryoablation and
external beam radiotherapy for T2C-T3B prostate cancer'. Prostate Cancer Prostatic
Dis, 11 (1), 40-5.
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