Download Intravesical microwave hyperthermia with intravesical

IP 395
NATIONAL INSTITUTE FOR HEALTH AND
CLINICAL EXCELLENCE
INTERVENTIONAL PROCEDURES PROGRAMME
Interventional procedure overview of intravesical
microwave hyperthermia with intravesical
chemotherapy for superficial bladder cancer
This procedure is used for early-stage bladder cancer, and may be used
before or after surgery. Solutions of chemotherapeutic drugs are delivered
into the bladder using a thin tube inserted through the urethra. At the
same time, an antenna placed inside the bladder emits microwaves that
heat up the bladder lining. The heating is intended to damage the cancer
cells and enhance the effect of the chemotherapeutic drugs.
Introduction
This overview has been prepared to assist members of the Interventional
Procedures Advisory Committee (IPAC) in making recommendations about
the safety and efficacy of an interventional procedure. It is based on a rapid
review of the medical literature and specialist opinion. It should not be
regarded as a definitive assessment of the procedure.
Date prepared
This overview was prepared in March 2007.
Procedure name
•
Intravesical microwave hyperthermia with intravesical chemotherapy for
superficial bladder cancer
Specialty societies
•
British Association of Urological Surgeons
Description
Indications
Superficial transitional cell carcinoma of the urinary bladder
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Transitional cell carcinoma is the most common form of bladder cancer. It
begins in the bladder lining (urothelium). Superficial disease is defined as
cancer that is confined to the bladder lining and has not invaded the muscle
layer below.
The indication encompasses bladder cancers classified as stage Ta (in the
innermost layer of the bladder lining), T1 (having grown into the connective
tissue below the lining) or Carcinoma In Situ (a tumour confined to the
transitional cell layer). Superficial transitional cell carcinomas can be graded
from G1 (low grade, least aggressive) to G3 (high grade, most aggressive).
Current treatment and alternatives
Surgical interventions for superficial transitional cell carcinoma include
transurethral resection (TUR), in which malignant tissue is removed with an
electrocautery device during cytoscopy. Bacillus Calmette-Guérin (BCG)
vaccine or chemotherapeutic drugs may be instilled directly into the bladder,
either as a treatment in itself, or as adjuvant therapy after TUR. Cystectomy
may also be necessary in some patients.
What the procedure involves
Two treatment modes are possible. Intravesical microwave hyperthermia with
intravesical chemotherapy can be used prior to TUR, as neoadjuvant therapy
(sometimes referred to as ablative treatment), with the aim of eradicating
tumours. Alternatively the procedure can be used after TUR, as adjuvant
therapy (sometimes referred to as prophylactic treatment), with the aim of
preventing recurrence.
The procedure is conducted on an outpatient basis, using an anaesthetic
urethral gel. A special balloon catheter, containing an antenna and several
insulated thermocouples, is inserted through the urethra into the bladder
under ultrasound guidance. The antenna emits microwaves, generally at 915
MHz, heating the superficial layers of the bladder wall. The thermocouples,
which are spread out from the catheter and pushed against the bladder lining,
monitor temperature; the target temperature is typically 42°C. A solution of
cytostatic agent (usually mitomycin C [MMC] dissolved in water) is repeatedly
circulated through the catheter into the space between the bladder wall and
the balloon surface, pumped out, cooled and re-instilled, to prevent
overheating. Treatment sessions typically last 40–60 minutes, and the drug
solution is replaced halfway through the procedure. The treatment is typically
repeated weekly for 4–8 weeks. When used for adjuvant treatment, patients
may then undergo a series of ‘maintenance’ sessions at longer intervals.
All studies identified used the Synergo device (Medical Enterprises Europe).
Efficacy
Neoadjuvant treatment before TUR
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One randomised controlled trial (RCT)1 and one non-randomised trial2
reported that a complete response to treatment was more frequent with
combined hyperthermia and MMC than with MMC alone (RCT: 66% [19/29] vs
22% [5/23]; p < 0.001; non-randomised trial: 66% [19/29] vs 28% [10/36], p
value not reported). Complete response was defined in the RCT as no viable
tumour cells remaining at biopsy, and in the non-randomised RCT as no
macroscopic, cytological or histological evidence of disease.
A case series of 44 patients who received combined treatment reported a
complete response (evaluated by histology) in 70% (31/44) of patients.3 A
second case series of patients with grade G3 tumours at baseline reported a
complete response in 75% (21/28) of patients.4
In the RCT, tumours recurred more frequently among the patients who
received MMC alone (39% [9/23], mean follow-up 36 months) than in the
group who received combined treatment (28% [8/29], mean follow-up 38
months), but the difference was not significant.1 In a case series of 44 patients
who received combined treatment, 18% (7/38) of patients with recurrent
disease had tumour recurrences. It was not stated whether tumours recurred
in any patients with primary tumours.3
A case series of patients who had grade G3 tumours at baseline and received
combined hyperthermia and MMC reported that 21% (6/28) of patients were
referred for cystectomy during follow-up (median 15 months).4
Adjuvant treatment following TUR
An RCT reported that recurrence during the 24 months after treatment was
significantly more frequent in patients who received MMC alone (56% [23/41])
than in those who received combined treatment (14% [6/42], p = 0.0002).5
Regression analysis showed that the rate of recurrence was 4.8 times higher
in the MMC-alone group (95% confidence interval 2.0 to 11.9).
Two case series of patients who received adjuvant combined treatment
reported on tumour recurrence.4,6 The risk of recurrence was 14.3% (standard
error [SE] 4.5%) after 1 year and 24.6% (SE 5.9%) after 2 years in one case
series of 90 patients. No progression in stage or grade was observed during
follow-up (mean 18 months).6 (Fourteen patients who did not adhere to the
protocol of this study were excluded and were not reported on.) In the other
cases series, of 24 patients with grade G3 disease (treated with MMC, except
for one patient who received epirubicin), 38% (9/24) of patients experienced a
recurrence, on average 10 months after the first treatment session. (Mean
follow-up of patients who did not experience a recurrence was 35 months.)4
Safety
Bladder-related adverse effects
Urethral stricture occurred in one patient in each of two case series of
combined neoadjuvant treatment (72 patients in total)3,4 and in four patients in
a case series of 90 patients (4%) receiving adjuvant combined treatment.6 In
one RCT, 7% (3/42) of patients receiving combined adjuvant treatment
developed urethral stricture compared with 2% (1/41) of those receiving MMC
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alone (difference not significant).5 In a study of 28 patients receiving
neoadjuvant treatment, one developed a hypotonic bladder and one
developed macrohaematuria.4 Reduced bladder capacity was reported in 1/42
of patients (2%) receiving combined adjuvant treatment 5 and in 3/28 of
patients (11%) receiving combined neoadjuvant treatment.4
Skin rash
Incidence of skin rash varied from 2% (1/44)3 to 7% (2/28)4 in patients who
received neoadjuvant combined treatment. (Another study including 29
patients who received combined neoadjuvant treatment reported no systemic
adverse effects but did not mention skin rash specifically.)1 The incidence
ranged from 8% (2/24)4 to 12% (5/42)5 in patients who received adjuvant
treatment. In the latter study, 5% (2/41) of patients who received MMC alone
experienced skin rash (no significant difference between treatment groups).
Cystitis syndrome
All studies, of both neoadjuvant and adjuvant treatment, stated that most or all
patients reported transient symptoms of cystitis (primarily urgency and
nocturia) after each treatment session. Symptoms almost always resolved a
few days later. One RCT of adjuvant treatment (combined treatment: n = 29;
MMC alone: n = 23)1 and one non-randomised controlled trial of neoadjuvant
treatment (combined treatment: n = 29; MMC alone: n = 36)2 used a
symptoms questionnaire and presented mean scores for all cystitis symptoms
combined. The best possible mean score was 7 and the worst was 24. In the
RCT, mean scores in the combined-treatment group rose from 10.5 (standard
deviation [SD] 1.6) at baseline to 18.3 (SD 2.3) after four sessions, decreasing
to 12.6 (SD 2.1) after the last session.1 Mean scores in the MMC-alone group
were 9.8 (SD 1.4), 13.1 (SD 2.1) and 10.7 (SD 1.8) at each time point,
respectively (p values not provided). Scores in the non-randomised trial were
largely similar to those in the RCT.2 In the non-randomised trial, scores were
not significantly different between the treatment groups.
In the RCT of adjuvant treatment, mild to moderate pain was reported by 33%
of patients (14/42) in the combined treatment group and severe pain by 7%
(3/42).5 None of the MMC-alone group reported pain (difference between
treatment groups: p < 0.001). Other differences in the incidence of adverse
effects were not significant. In a case series of 90 patients who received
adjuvant combined treatment, pain was reported by 33 (37%) of patients,
dysuria in 22 (24%), tissue reaction (redness or oedema on the bladder wall)
in 22 (24%) and haematuria in 8 (9%).6 A case series of 28 patients who
received neoadjuvant combined treatment reported pain during treatment in 6
(21%) of patients, dysuria for more than 48 hours in 16 (57%), bladder
spasms in 4 (14%) and urinary tract infection in 2 (7%).4
Thermal reaction of the bladder wall
Some studies reported a reaction of the posterior wall of the bladder, visible
on cytoscopy as a black patch usually less than 3cm in diameter. In most
patients this disappeared spontaneously within 2-3 days. The authors state
that the likely cause was more intense heating near the tip of the microwave
antenna. In an RCT of adjuvant treatment, the frequency of posterior-wall
thermal reaction was significantly higher in the combined-treatment group
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(24% [10/42] compared with the MMC-alone group (2% [1/41]; p < 0.001).5 In
a case series of 90 patients who received adjuvant combined treatment,
posterior-wall thermal reaction was reported in 23 patients (26%).6 A case
series of 28 patients who received neoadjuvant combined treatment reported
posterior-wall thermal reaction in 18 (64%).4
Literature review
Rapid review of literature
The medical literature was searched to identify studies and reviews relevant
to intravesical hyperthermia with intravesical chemotherapy for superficial
bladder cancer. Searches were conducted via the following databases,
covering the period from their commencement to 26/2/2007: Medline,
PreMedline, EMBASE, Cochrane Library and other databases. Trial registries
and the Internet were also searched. No language restriction was applied to
the searches. (See appendix C for details of search strategy.)
The following selection criteria (table 1) were applied to the abstracts
identified by the literature search. Where these criteria could not be
determined from the abstracts the full paper was retrieved.
Table 1 Inclusion criteria for identification of relevant studies
Characteristic
Publication type
Patient
Intervention/test
Outcome
Language
Criteria
Clinical studies were included. Emphasis was placed on identifying
good quality studies.
Abstracts were excluded where no clinical outcomes were reported, or
where the paper was a review, editorial, or laboratory or animal study.
Conference abstracts were also excluded because of the difficulty of
appraising methodology.
Patients with superficial transitional cell carcinoma of the bladder
Intravesical hyperthermia with intravesical chemotherapy of the
bladder
Articles were retrieved if the abstract contained information relevant to
the safety and/or efficacy.
Non-English-language articles were excluded unless they were
thought to add substantively to the English-language evidence base.
List of studies included in the overview
This overview is based on reports of two RCTs, one non-randomised
controlled trial, one report that included two parallel case series, and two other
case series.
Other studies that were considered to be relevant to the procedure but were
not included in the main extraction table (table 2) have been listed in
appendix A.
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Existing reviews on this procedure
There were no published systematic reviews with meta-analysis or evidence
based guidelines identified at the time of the literature search.
Related NICE guidance
Below is a list of NICE guidance related to this procedure. Appendix B details
the recommendations made in each piece of guidance listed below.
Interventional procedures
Laparoscopic cystectomy (of the urinary bladder) (December 2003) available
from www.nice.org.uk/guidance/IPG26).
Technology appraisals
None
Clinical guidelines
Cancer service guidance: Improving outcomes in Urological Cancers
(September 2002), available from www.nice.org.uk/guidance/csguc.
Public health
None
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Table 2 Summary of key efficacy and safety findings on intravesical microwave hyperthermia with intravesical chemotherapy
for superficial bladder cancer
Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
Colombo R (1996)1
Randomised controlled trial
Italy
Study period: 1989–1993
HT + MMC: n = 29
MMC alone: n = 23
(5% men, mean age 64 years
(range 44–81)
Patients included:
84% had a recurrent tumour and
had received chemotherapy or BCG
previously.
Technique:
Neoadjuvant treatment: 6–8
sessions over a maximum of
6 weeks; session duration
60 minutes; MMC dose: 40 mg in
50 ml water, replaced halfway
through session; Synergo device
used; ‘medium temperature range’:
42.5–46°C.
Follow-up:
mean 38 months for HT + MMC,
36 months for MMC alone
Response
Tumour response was evaluated 7–10 days after the
last session using cytoscopy and hot and cold
biopsies. Complete response was defined as no
residual viable tumour cells after treatment in any
specimen obtained by biopsy. Partial response was
defined as overall decrease of initial tumours by more
than 50%, determined endoscopically, and overall
necrosis noted in more than 50% of the neoplastic
tissue on hot biopsy.
Complete response
HT + MMC: 19/29 (66%)
MMC alone: 5/23 (22%)
p < 0.001
Partial response
HT + MMC: 10/29 (34%)
MMC alone: 6/23 (26%)
(Test for significance not reported).
Recurrence during follow-up
HT + MMC: 8/29 (28%)
MMC alone 9/23 (39%)
(no significant difference between groups)
Patient-reported symptoms
HT + MMC group
All patients reported a cystitis syndrome
immediately after each session, which
lasted for 1–2 days. 21/29 (72.4%) had mild
or moderate urgency and nocturia. During
the procedure, patients reported urge but
not urethral burning.
Maximum flow rate improved by 3.4 ml/s at
1 month post-treatment and 4.5 ml/s at
3 months post-treatment, compared with
before treatment.
For 2 patients (6.9%) treatment was
terminated after 5 and 6 sessions
respectively (reason not stated).
MMC alone group
Most patients reported mild urgency and
urethral burning.There were ‘only minimal
changes’ in flow rate 1 and 3 months after
treatment.
Symptoms questionnaire
The questionnaire used a score of 1–4 (best
to worst) for daytime frequency, nocturia
and dysuria and 1–3 (best to worst) for
urgency, haematuria, urethrorrhagia and
urethral pain. Scores for each symptom
were added, and a mean calculated for all
patients. The best possible score is 7 and
the worst is 24.
Conflict of interest: none stated
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The methods of patient selection
and randomisation were not
described.
17 patients in this study also
participated in the Gofrit (2004)
study included in this overview.
Randomisation method was not
stated.
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Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
Mean score (SD)
HT +
MMC
MMC
alone
Before treatment
10.5
9.8
(1.4)
(1.6)
After 4 sessions
18.3
13.1
(2.3)
(2.1)
7–10 days after
12.6
10.7
last session
(2.1)
(1.8)
There was no significant difference between
treatment groups in mean questionnaire
scores.
Systemic or major side effects
None were reported (including no cases of
urethral stricture or contracted bladder).
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Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
Colombo R et al (2001)2
Complete tumour response
Symptoms questionnaire
Non-randomised controlled trial
Complete response was defined as no macroscopic
evidence of disease, negative cytology and negative
histology in TUR specimens.
[Same method as for Colombo 1996.
Mininum possible score is 7 and maximum
is 24.]
Italy
Study period: 1996–1998
HT + MMC: n = 29
MMC alone: n = 36
(age and sex not stated)
Patients included:
Superficial (Ta–T1), low grade (G1–
G2), recurrent, single, small
(< 2 cm) bladder tumours, not
previously treated with MMC
Technique:
Neoadjuvant treatment:
MMC dose: 40 mg in 50 ml saline;
Synergo device used; mean
temperature 42.5°C; session
duration at least 60 minutes;
treatment regimen: 4 sessions, 1
per week
1
HT + MMC: 19/29 (66.0%)
MMC alone: 10/36 (27.8%)
(No p values reported)
Before treatment
Immediately after
last session
7–10 days after
last session*
Mean score (SD)
HT +
MMC
MMC
alone
11.6
10.3
(1.8)
(1.2)
17.4
13.2
(2.6)
(1.6)
12.7
11.0
(1.5)
(0.8)
There were no significant differences
between the treatment groups (p value not
stated).
“Most patients complained about a cystitis
syndrome… Local side effects related to
thermochemotherapy were mainly described
as urgency and nocturia… inflammatory
symptoms disappeared almost completely
within a few days after the last session in all
patient groups”.
Follow-up: 7–10 days after last
treatment (when TUR is
performed)
Conflict of interest: none stated
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The method of patient selection
was not described.
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Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
Colombo R et al (1995) 3
Case series
Italy
Study period: 1988–1992
n = 44
Mean age 57 years (range 34–78),
sex not stated
Patients included:
Ta or T1, G1–G3 (27% G3),
recurrent (86%) or primary (14%)
tumours. 27% of patients had
tumours in > 5 locations.14% also
had a tumour of the bladder neck. A
proportion had previously had
chemotherapy (45%) or BCG
treatment (18%).
Technique:
Neoadjuvant treatment with HT +
MMC before TUR; MMC dose:
30 mg in 60 ml water; Synergo
device used; mean temperature
42.5–44.5°C; session duration:
60 minutes; treatment regimen: 8
sessions, roughly 2 per week over a
maximum of 6 weeks
Tumour response
Complete response was defined as no residual
tumour seen in any histological specimen after
treatment. Partial response was defined as an overall
reduction in tumour mass of more than 50% and
overall necrosis of more than 50% of the neoplastic
tissue at hot biopsies (subjective assessment, always
by the same clinician).
If no response was seen after four sessions, the
patient was referred for TUR.
All patients
Complete response: 31/44 (70.5%)
Partial response: 9/44 (20.5%)
No response: 4/44 (9.1%)
Systemic or serious adverse effects
One patient developed a skin rash (selfhealing) and one developed a stricture of
the external meatus of the urethra 6 months
after treatment “but it cannot be concluded
that this was due to TUR”.
Uroflowmetry
Flow rate improved (not significant) at 3–
6 months’ follow-up compared with 7–10
days after treatment.
Symptoms questionnaire
1
Same method as for Colombo 1996.
Minimum score for each symptom is 1;
maximum is 3 for the first 3 symptoms in the
table and 4 for the next 4 symptoms.
Patients with fewer than 3 previous recurrences:
Complete response: 16/22 (72.7%)
Partial response: 2/22 (9.1%)
No response: 2/22 (9.1%)
Patients with 3 or more previous recurrences:
Complete response: 13/16 (81.3%)
Partial response: 3/16 (18.8%)
No response: 0/16
Patients with primary tumours:
Complete response: 6/6 (100%)
Mean score (SD)
Daytime
frequency
Nocturia
Dysuria
Urgency
Recurrence
“7 tumour relapses were noted in the recurrent cases”
(mean follow-up 24 months). It is not stated whether
recurrence occurred in any of the patients with
primary tumours.
Follow-up: mean 24 months,
range 3–57 months
Haematuria
Urethrorrhagia
Urethral
pain
Before
treatment
After 4
sessions
2.6
(0.8)
2.8
(1.0)
1.9
(1.2)
2.2
(0.8)
0.9
(0.6)
0.2
(0.2)
1.8
(0.8)
3.5
(0.6)
3.7
(0.8)
2.3
(1.1)
2.9
(0.8)
1.4
(0.4)
0.6
(0.6)
2.9
(0.5)
Conflict of interest: none stated
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7–10
days
after
last
session
2.8
(0.6)
3.3
(0.4)
2.1
(0.8)
2.2
(0.4)
0.8
(0.6)
0.3
(0.6)
2.1
(0.8)
The method of patient selection
was not described.
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Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
Gofrit ON et al (2004) 4
Two parallel case series, one
with neoadjuvant treatment and
one with adjuvant treatment
Israel, the Netherlands, Italy
Study period: not stated
Neoadjuvant: n = 28
20 (71%) men, mean age 69 years
(SD 15 years)
Adjuvant: n = 24
21 (88%) men, mean age 68 years
(SD 9 years)
Patients included:
G3 only, stage Ta or T1, primary (1
patient) or recurrent disease.
The adjuvant protocol was given to
patients with G3 Ta or T1 tumours
determined from their last TUR
specimen with neither visible
tumour on the baseline cytoscopy
nor CIS in the preceding random
bladder biopsies. All other patients
were allocated to the neoadjuvant
protocol.
Technique:
MMC dose: 40 mg in 50 ml water in
neoadjuvant protocol, 20 mg in
50 ml water in adjuvant protocol;
epirubicin (50 mg, dilution not
stated) was given to 4 patients who
were allergic to MMC; the solution
In the neoadjuvant group, patients who did not have
at least 50% reduction in tumour size after four
sessions were regarded as non-responders and were
referred to treatment outside the trial. Complete
response was defined as being tumour-free,
assessed by cytoscopy.
Posteriorwall
thermal
reaction
Dysuria for
> 48 hours
Pain during
treatment
Bladder
spasms
Urinary
tract
infection
Reduced
bladder
capacity
Palmar or
plantar
rash
There were no cases of tumour progression to stage
T2 and no bladder-cancer related deaths during
follow-up.
Tumour response and recurrence
Neoadjuvant group:
Complete response to treatment was seen in 21/28
(75%) of patients.
4 of the 21 responders (19%) subsequently had a
recurrence (mean time to recurrence: 14 months from
tumour eradication date). For the remaining 17, mean
follow-up was 20 months.
Adjuvant group:
9 patients (37.5%) had a recurrence (mean time to
recurrence 10 months).
For the remaining 15, mean follow-up was 35 months
from the first treatment session.
Avoidance of cystectomy during follow-up
Neoadjuvant group: 22/28 (78.6%)
Adjuvant group: 23/24 (95.8%) (but no tumour was
found in the specimen of the one patient who had a
cystectomy).
There were no statistically significant differences
between patients with Ta and T1 tumours, or
between patients who had not received previous
BCG treatment, in either treatment group (statistics
not provided).
Number of patients (%)
Neoadjuvant
Adjuvant
group
group
n = 28
n = 24
18 (64.3)
15 (62.5)
16 (57.1)
14 (58.3)
6 (21.4)
6 (25.0)
4 (14.3)
4 (16.7)
2 (7.1)
3 (12.5)
3 (10.7)
2 (8.3)
2 (7.1)
2 (8.3)
Urethral stricture, hypotonic bladder and
macrohaematuria each occurred in one
patient in the neoadjuvant group.
Treatment was stopped in two patients after
four and five sessions after they
experienced palmar rash.
Three patients reported general weakness
and malaise.
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
“This report summarizes the
results of virtually all the patients
with Stage Ta or T1 G3 tumours
treated with combined
chemotherapy.” The authors do
not state why some patients
were not included.
4 patients (1 in the adjuvant
group and 3 in the neoadjuvant
group) were allergic to MMC and
received epirubicin instead.
Results for these patients are
combined with those for patients
who received MMC.
It is not clear what the MMC
dosage was. The main text of the
paper states that the dose used
was 20 mg in the adjuvant group
and 40 mg in the neoadjuvant
group (in 50 ml water), replaced
halfway through the session. In
Table 1 of the paper and the
abstract, the authors state that
the doses were double this.
In addition, 3 patients in each
group received the MMC dose
initially described for the other
group (i.e. twice the initially
stated dose in the adjuvant
group, and half the dose in the
neoadjuvant group). These
patients are not separated in the
analysis.
17 patients in the neoadjuvant
group had participated in another
1
trial (Colombo et al 1996,
included in this overview). It is
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Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
not stated which treatment these
patients had received in the
previous trial.
was replaced after 20 minutes;
Synergo device used; “goal
temperature”: 42 ± 2°C; session
duration: 40 minutes; treatment
regimen: 8 sessions weekly
followed by 4 sessions monthly.
The percentages of adverse
events presented in the paper
could not be calculated using the
numbers presented in the paper,
Percentages have been recalculated using the
denominators that were
presented in the paper (n = 24
and n = 28 in the adjuvant and
neoadjuvant groups,
respectively).
Follow-up: median 15 months,
mean 23 months, range 6-90
months.
Conflict of interest: Two authors
were paid consultants to Medical
Enterprises Europe (manufacturer
of the Synergo device) and another
author had a relative in
management at the company at the
time of publication.
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Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
Colombo R et al (2003)5
Randomised controlled trial
Italy and Israel
Study period: 1994–1999
HT + MMC: n = 42
83% men, 41% over 65 years of
age
MMC alone: n = 41
83% men, 61% over 65 years of
age
Patients included:
Intermediate and high-risk disease
(Ta–T1, G1–G2, multifocal, primary
or recurrent) or high-risk disease
(T1, G3 and CIS in association with
papillary tumours). Patients had
already had complete TUR,
confirmed by cytoscopy, biopsy and
cytology.
Patients excluded:
Patients with low-risk disease (Ta,
G1, single, primary cancer),
residual tumours after TUR, pretreatment with systemic
chemotherapy or radiotherapy
within past 3 months, TCC of
prostatic urethra, allergy to MMC,
large benign prostatic hyperplasia,
residual urine > 100 ml after
voiding, bladder capacity < 150 ml
or neurogenic hypotonic bladder
Recurrence within 24 months
HT + MMC: 6/42 (14.3%)
MMC alone: 23/41 (56.1%)
No side
effects
Tissue
reaction
Pain*
Recurrence was significantly more frequent and
earlier among patients who received MMC alone
(p = 0.0002).
Hazard ratio for recurrence among patients receiving
MMC alone vs patients receiving HT + MMC:
4.8 (95% confidence interval 2.0 to 11.9), i.e. risk of
recurrence was 4.8 times higher in the MMC alone
group compared with the HT + MMC group.
Dysuria
Haematuria
Urethral
stenosis
Posteriorwall
thermal
reaction*
Skin allergy
HT +
MMC
(n = 42)
5
(11.9%)
21
(50.0%)
17
(40.5%)
10
(23.8%)
3
(7.1%)
3
(7.1%)
10
(23.8%)
MMC
alone
(n = 41)
15
(36.6%)
20
(48.8%)
0
(0.0%)
4
(9.8%)
2
(4.9%)
1
(2.4%)
1 (2.4%)
5
(11.9%)
2
(4.9%)
* p < 0.001between treatment groups
Pain occurred only during heating, and
resolved after each treatment. In the HT +
MMC group; 3 patients (7.1%) said the pain
was severe.
Thermal reaction resolved in a few days in
most patients but lasted for 3 months in one
case (healed spontaneously).
Other clinical complications
There was one case of reduced bladder
capacity with urge incontinence in the HT +
MMC group.
Voiding patterns
No change was found in residual urine or
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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Some or all of the patients who
received HT + MMC may have
also been included in the case
series by van der Heijden et al
6
(2004).
The percentages given in the
paper for frequency of
recurrence do not correspond
with the absolute numbers given.
Therefore the figures presented
here are the analyst’s own
calculations based on the
numbers given in the paper.
The authors note that some
studies assessing MMC alone
use double the dose of MMC that
is used here, and so the dose in
this study may have been
suboptimal.
No significant difference in
demographic or baseline tumour
characteristics was found
between treatment groups.
Of 83 patients, 8 did not
complete the study (4 withdrew
and 4 did not comply with
protocol), but outcomes are
presented for all patients.
The study statistician assessed
sample size adequately.
The method of randomisation
was well described and
adequate.
IP 395
Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
uroflowmetry after treatment.
Technique:
Adjuvant treatment, 20–40 days
after complete TUR
MMC dose: 20 mg in 50 ml water,
replaced after 30 minutes; Synergo
device used; placement of device
assessed by ultrasound; session
duration: 40–60 minutes; treatment
regimen: induction cycle of 8
treatments, 1 per week, followed by
maintenance cycle of 4 treatments,
1 per month.
Symptom questionnaire
Same method as for Colombo 1996.1
Minimum possible score is 7 and maximum
is 24.
Before
treatment
After induction
cycle
After
maintenance
cycle
Follow-up: minimum 24 months
Conflict of interest: none stated
van der Heijden AG et al (2004) 6
Case series of adjuvant treatment
Mean score (SD)
HT +
MMC
MMC
alone
9.1
9.4
(1.8)
(1.7)
18.4
14.6
(2.6)
(1.5)
12.7
12.2
(1.5)
(1.5)
Statistical significance was not stated.
Recurrence
Tumour recurrence (proved by pathology or clear on
cytoscopy) occurred in 14/90 patients (15.6%, mean
follow up 18 months, range 4–24 months). 5 of these
65/90 (72%) of patients experienced one or
more adverse effects. All adverse effects
were localised and resolved after treatment
without residual effects, except for one
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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Some of the patients in this case
series may have been included
in the RCT by Colombo et al
5
(2003).
IP 395
Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
the Netherlands, Israel, Italy,
Germany
Study period: 1994–2003
n = 90
87% men, mean age 65 years
(range 35–92)
Patients included:
Intermediate and high-risk TCC,
histologically confirmed Ta or T1,
multiple (43%) or recurrent (84%)
disease. Patients had already had
complete resection of all visible
papillary tumours (Ta/T1), but no
chemo- or immunotherapy since the
last TUR. 62% of patients had
received chemo- or immunotherapy
in the past.
Patients excluded:
Patients with bladder capacity
< 150 ml, concomitant malignancy,
extravesical TCC or presence of a
diverticle of the bladder
patients had multiple tumours with previous
recurrences (5/90, 5.6%). (Mean follow up was 18
months, range 4–24 months.)
patient who had a severe and prolonged
posterior-wall thermal reaction that took
3 months to heal.
Risk of recurrence (n = 90)
After 1 year: 14.3% (standard error 4.5%)
After 2 years: 24.6% (standard error 5.9%)
Patients generally had mild urgency during
the procedure but rarely reported urethral
burning.
No progression in stage or grade was observed.
Adverse effect
Risk of recurrence was significantly higher for
patients with intermediate-risk TCC at baseline
compared with patients with high-risk TCC.
Dysuria
Haematuria
Pain
Posterior-wall
thermal reaction
Skin allergy
Urethral stenosis
Tissue reaction*
None
Recurrence was more frequent in the subset of
patients (n = 22) who had received BCG treatment
before the trial.
After 1 year: 23.1% (standard error 7.7%)
After 2 years: 41.2% (standard error 9.9%)
Number of patients
(%)
22 (24.4)
8 (8.9)
33 (36.7)
23 (25.6)
8 (8.9)
4 (4.4)
22 (24.4)
25 (27.8)
*Tissue reaction was characterised by
redness and/or oedema or any other effect
seen on the bladder wall except for
posterior-wall thermal reaction.
Technique:
Adjuvant treatment with HT +
MMC, on average 55 days after last
TUR
MMC dose: 20 mg in 50 ml water,
replaced after 30 minutes; Synergo
device used; temperature range:
41–44°C; session duration:
60 minutes; treatment regimen: 6–8
sessions weekly followed by 4–6
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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14 patients who did not have six
treatments or follow-up
cytoscopy (i.e. who did not
comply with the protocol) were
excluded. No data were
presented for these patients.
IP 395
Abbreviations used: BCG, Bacillus Calmette-Guérin vaccine; CIS: carcinoma in situ; HT: hyperthermia; MMC: mitomycin C; SD: standard deviation; TCC: transitional cell
carcinoma; TUR: transurethral resection of the bladder
Study details
Key efficacy findings
Key safety findings
Comments
sessions monthly; mean number of
sessions: 10.
Follow-up: mean 18 months,
range 4–24 months
Conflict of interest: none stated
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IP 395
Validity and generalisability of the studies
•
•
•
•
•
•
Only two RCTs and one non-randomised controlled trial were identified.
However, these were consistent in showing greater efficacy for combined
hyperthermia and chemotherapy than for chemotherapy alone.
The largest study included was a case series of 90 patients.
The patient sample of the largest case series may partly overlap with that
of one of the RCTs, although it is not possible to determine this definitively.
All studies used MMC and the Synergo device. Protocols for each session
were similar across studies, except for variation in the dose of MMC.
Treatment regimens varied between studies.
Some studies did not adequately report on patients who did not comply
with the protocol, potentially giving biased results.
The proportion of patients with each grade and stage of superficial bladder
cancer varied between studies.
Specialist advisers’ opinions
Specialist advice was sought from consultants who have been nominated or
ratified by their Specialist Society or Royal College.
Mr Noel Clarke, Mr William Turner
•
•
•
•
•
•
The Specialist Advisers both believed this procedure was of uncertain
safety and efficacy but one thought it was novel and another thought it was
no longer new.
A Specialist Adviser commented that this procedure is indicated for
patients with intermediate and high risk superficial transitional cell
carcinoma of the bladder.
One Specialist Adviser thought that risk of recurrence was the key efficacy
outcome.
The Specialist Advisers stated that theoretical adverse events and adverse
events reported in the literature included symptoms of severe cystitis such
as dysuria, haematuria and bladder pain, which were usually short–term,
urethral stenosis, bladder contracture, extravastation and chemical
peritonitis. Both Specialist Advisers referred to thermal injury to the pelvis;
one said this was usually relatively minor and transient thermal injury to
the bladder. One Specialist Adviser thought that there may be unforeseen
synergistic effects of heat and intravesical chemotherapy.
One Specialist Adviser commented that the long-term effects of the
procedure and its suitability for all patient types have not been evaluated.
One Specialist Adviser commented that training in the procedure would be
necessary but another considered that training for standard intravesical
chemotherapy and management of superficial bladder cancer was
sufficient.
.
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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Issues for consideration by IPAC
•
•
The way in which efficacy was assessed differed for neoadjuvant and
adjuvant treatment modalities; frequency of adverse events may also
differ.
The studies identified did not compare different chemostatic agents or
attempt to determine the optimal dosage or treatment regimen.
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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References
1. Colombo R, Da Pozzo LF, Lev A, Freschi M, Gallus G, Rigatti P. (1996)
Neoadjuvant combined microwave induced local hyperthermia and topical
chemotherapy versus chemotherapy alone for superficial bladder cancer.
Journal of Urology 155: 1227–32.
2. Colombo R, Brausi M, Da Pozzo L, Salonia A, Montorsi F, Scattoni V et al.
(2001) Thermo-chemotherapy and electromotive drug administration of
mitomycin C in superficial bladder cancer eradication. a pilot study on
marker lesion. European Urology 39: 95–100.
3. Colombo R, Lev A, Da Pozzo LF, Freschi M, Gallus G, Rigatti P. (1995) A
new approach using local combined microwave hyperthermia and
chemotherapy in superficial transitional bladder carcinoma treatment.
Journal of Urology 53: 959–63.
4. Gofrit ON, Shapiro A, Pode D, Sidi A, Nativ O, Leib Z et al. (2004)
Combined local bladder hyperthermia and intravesical chemotherapy for
the treatment of high-grade superficial bladder cancer. Urology 63: 466–
71.
5. Colombo R, Da Pozzo LF, Salonia A, Rigatti P, Leib Z, Baniel J et al.
(2003) Multicentric study comparing intravesical chemotherapy alone and
with local microwave hyperthermia for prophylaxis of recurrence of
superficial transitional cell carcinoma. Journal of Clinical Oncology 21:
4270–6.
6. van der Heijden AG, Kiemeney LA, Gofrit ON, Nativ O, Sidi A, Leib Z et al.
(2004) Preliminary European results of local microwave hyperthermia and
chemotherapy treatment in intermediate or high risk superficial transitional
cell carcinoma of the bladder. European Urology 46: 65–71.
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Appendix A: Additional papers on intravesical
microwave hyperthermia with intravesical
chemotherapy for superficial bladder cancer not
included in summary table 2
The following table outlines studies that are considered potentially relevant to
the overview but were not included in the main data extraction table (table 2).
It is by no means an exhaustive list of potentially relevant studies.
Article title
Colombo R, Lev A, Freschi M, Da
Pozzo L, Rigatti P. (1998) Intracavitary
approach combined with hyperthermia
and chemotherapy in the treatment of
superficial neoplasia of the bladder.
Preliminary clinical results. Acta
Urologica Italica 7: 87–8.
Colombo R, Da Pozzo LF, Lev A,
Grasso M, Francesca F, Montorsi F et
al. (1995) Local microwavehyperthermia and intravesical
chemotherapy with mitomycin C as
neoadjuvant treatment for selected
multifocal and unresectable superficial
bladder tumors. Acta Urologica Italica 9:
167–71.
Number of
patients/
follow-up
n = 44
Case series
n = 14
Case series
Neoadjuvant
treatment
Median
follow-up:
11 months
(possible
overlap of
patients with
those
described in
Colombo
19987)
Direction of
conclusions
“Clinical and
histological
evaluation
confirmed the
feasibility and
safety of this
combined
preoperative
approach. A very
high tumour
response rate was
observed.”
Complete tumour
disappearance in
50% (7/14) and
partial response in
others. TUR was
subsequently
performed in 79%
(11/14). 55%
(6/11) of these
had small
recurrent tumours
(removed by TUR)
during follow-up.
Cystectomy was
performed in three
patients following
the initial
procedure.
Reasons for noninclusion in
Table 2
Paper in Italian;
abstract in English
Larger case series
are included in table
2.
Patients reported
cystitis symptoms
for 2–4 days.
3/112 sessions
were stopped
because of
detrusoral
contractions. No
other major
complications.
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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Colombo R, Da Pozzo LF, Lev A,
Salonia A, Rigatti P, Leib Z et al. (1998)
Local microwave hyperthermia and
intravesical chemotherapy as bladder
sparing treatment for select multifocal
and unresectable superficial bladder
tumors. Journal of Urology 159 :783–7
n = 19
Case series
of
neoadjuvant
treatment
Median
follow-up:
33 months
Moskovitz B, Meyer G, Kravtzov A,
Gross M, Kastin A, Biton K et al. (2005)
Thermo-chemotherapy for intermediate
or high-risk recurrent superficial bladder
cancer patients. Annals of Oncology 16:
585–9.
2 parallel
case series
Neoadjuvant:
n = 10
mean followup 170 days
Adjuvant:
n = 22
mean followup for
recurrencefree patients:
289 days;
mean time to
recurrence:
431 days
Rigatti P, Lev A, Colombo R. (1991)
Combined intravesical chemotherapy
with mitomycin C and local bladder
microwave-induced hyperthermia as a
preoperative therapy for superficial
bladder tumors. A preliminary clinical
study. European Urology 20: 204–10.
n = 12
Case series
Neoadjuvant
treatment
Mean followup: 16
months
Complete
disappearance of
tumours in 42%
(8/19). 84%
(16/19) were
subsequently
deemed suitable
for TUR.
Cystitis symptoms
usually reported,
16% (3/19)
described
symptoms as
severe. One
patient had
vesicoureteral
reflux and one had
a contracted
bladder, 6 and 9
months after
treatment,
respectively.
Larger case series
are included in table
2.
Neo-adjuvant
group:
Complete
response in 8/10
(80%)
Larger case series
are included in table
2.
Adjuvant group:
91% (20/22) were
recurrence free
after a mean of
289 days. 9%
(2/22) had
recurrence, after
417 and 445 days.
42% (5/12) had a
complete
response, 33%
(4/12) had > 75%
reduction in
tumour mass. The
remainder had
> 50% reduction
in tumour mass.
40% of patients
had bladder
spasms and
urethral irritability.
7.1% (6/84) were
cancelled in
advance as a
result. One patient
had mild skin
rash. Cystitis
symptoms were
common. No
major
complications
were reported.
Larger case series
are included in table
2.
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Appendix B: Related published NICE guidance for
intravesical microwave hyperthermia with intravesical
chemotherapy for superficial bladder cancer
Guidance programme
Interventional procedures
Recommendation
IPG26 Laparoscopic cystectomy (of the urinary
bladder) (December 2003)
Technology appraisals
Clinical guidelines
1.1 Current evidence on the safety and efficacy of
laparoscopic cystectomy does not appear
adequate to support the use of this procedure
without special arrangements for consent and
for audit or research. Clinicians wishing to
undertake laparoscopic cystectomy should
inform the clinical governance leads in their
Trusts. They should ensure that patients
offered it understand the uncertainty about the
procedure’s safety and efficacy and should
provide them with clear written information. Use
of the Institute’s Information for the Public is
recommended. Clinicians should ensure that
appropriate arrangements are in place for audit
or research. Publication of safety and efficacy
outcomes will be useful in reducing the current
uncertainty. NICE is not undertaking further
investigation at present.
1.2 Special training is required to perform the
procedure. The British Association of Urological
Surgeons has agreed to produce standards for
training.
None applicable
Cancer service guidance: Improving outcomes
in Urological Cancers (September 2002)
Superficial tumours
Patients with newly diagnosed, apparently
superficial, tumours should be treated by complete
transurethral resection (TUR), which should be
carried out by designated urologists in local district
general hospitals (DGHs). After recovery from
resection, these patients should normally have a
single instillation of chemotherapy (mitomycin or
epirubicin) or glycine into the bladder (intravesical
therapy). They should be allocated to one of the
groups described below when the results of
pathological review are available.
Lower-risk superficial cancer (pTa G1 or G2 or T1,
G1 or G2). About 50% of newly diagnosed patients
have superficial tumours which carry a relatively
IP Overview: Intravesical microwave hyperthermia with intravesical chemotherapy for superficial bladder cancer
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IP 395
low risk of progression after treatment but the
majority of tumours will recur locally in the bladder.
Guidelines for the frequency and timing of followup cystoscopy should be agreed and adopted
throughout each network.
High-risk superficial cancer (pTa G3, or T1 G3
tumours, extensive, recurrent or multifocal G2
tumours, and carcinoma in situ)
These tumours are associated with higher risk of
progression and death, and many patients are not
receiving adequate treatment at present. Protocols
for treatment and follow-up of patients with high
risk superficial tumours should be jointly agreed by
the urological cancer multidisciplinary teams
(MDTs) of each network and adopted throughout
the network.
Although these patients may be treated – at least
initially – by urologists who are members of local
urological cancer teams, the options should be
discussed with each patient in a joint meeting
which includes a urologist, an oncologist and a
nurse specialist who are also members of the
MDT. The range of appropriate options may
include intravesical treatment with bacillus
Calmette-Guèrin (BCG) or referral to the specialist
urological cancer team for possible radical
treatment. If the tumour fails to respond to BCG or
recurs within a short time, radical treatment
(normally cystectomy) should be offered. Patients
with high-risk tumours should be encouraged,
when appropriate, to participate in randomised
trials such as the MRC BS06 trial comparing
radical radiotherapy with intravesical therapy.
Adjuvant and neo-adjuvant chemotherapy
Public health
It is not yet clear whether adjuvant or neo-adjuvant
chemotherapy is beneficial for patients with bladder
cancer. Patients at high risk of progression, such
as those with tumour in lymph nodes, should be
encouraged to participate in trials of these forms of
treatment. Chemotherapy should be initiated only
by an oncologist member of the specialist MDT
treating the patient.
None applicable
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Appendix C: Literature search for intravesical
hyperthermia with intravesical chemotherapy for
superficial bladder cancer
IP:
Database
Cochrane Library
Date searched
26/02/2007
Version searched
2007, Issue 1
CRD databases (DARE
& HTA)
26/02/2007
2007, Issue 1
Embase
26/02/2007
1980 to 2007 Week 08
Medline
26/02/2007
Premedline
26/02/2007
1950 to February
Week 2 2007
Feb. 23, 2007
CINAHL
26/02/2007
British Library Inside
Conferences
NRR
27/02/2007
1982 to February
Week 3 2007
-
28/02/2007
2007, Issue 1
Controlled Trials
Registry
28/02/207
-
The following search strategy was used to identify papers in Medline. A similar
strategy was used to identify papers in other databases.
# Search History
1
(microwave$ adj3 (hyperthermia or
heat$)).tw.
2
(microwave-induced adj3 (hyperthermia or
heat$)).tw.
3
(microwave$ adj3 induced adj3
(hyperthermia or heat$)).tw.
4
((intravesical or endovesical or bladder) adj3
microwave$).tw.
5
thermochemotherapy.tw.
6
((endovesical or intravesical or bladder) adj3
thermochemotherapy).tw.
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IP 395
7
chemo-thermotherapy.tw.
8
thermo-chemotherapy.tw.
9
thermocouple$.tw.
10 thermotherapy.tw.
11 hyperthermia.tw.
12 Hyperthermia, Induced/
13 heat$.tw.
14 synergo.tw.
15 or/1-14
(bladder adj3 (neoplasm$ or cancer$ or
16 carcinoma$ or adenocarcinom$ or tumour$
or tumor$ or malignan$)).tw.
17 Urinary Bladder Neoplasms/th
18 (sarcoma adj3 bladder).tw.
19
(transitional adj3 cell adj3 carcinoma$ adj3
bladder).tw.
20 or/16-19
21 15 and 20
22 animals/
23 humans/
24 22 not (22 and 23)
25 21 not 24
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