2010 THE AUTHORS; JOURNAL COMPILATION
Urological Oncology
2010 BJU INTERNATIONAL
RCT COMPARING THERMOCHEMOTHERAPY WITH MITOMYCIN-C ALONE AS ADJUVANT TREATMENT FOR NMIBC
COLOMBO
ET AL.
BJUI
Long-term outcomes of a randomized controlled
trial comparing thermochemotherapy with
mitomycin-C alone as adjuvant treatment for
non-muscle-invasive bladder cancer (NMIBC)
BJU INTERNATIONAL
Renzo Colombo, Andrea Salonia, Zvi Leib*, Michele Pavone-Macaluso† and
Dov Engelstein*
Departments of Urology, University Vita-Salute San-Raffaele, Milan, and †University of Palermo, Palermo, Italy, and
*Department of Urology, Rabin Medical Center Beilinson Campus, Petach Tikva, Israel
Accepted for publication 22 April 2010
Study Type – Therapy (RCT)
Level of Evidence 1b
OBJECTIVE
• To present long-term efficacy data of
intravesical thermochemotherapy vs
chemotherapy alone with mitomycin-C
(MMC) randomly administered to patients
with non-muscle-invasive bladder cancer
(NMIBC) as an adjuvant treatment after
complete transurethral resection.
PATIENTS AND METHODS
• In all, 83 patients with intermediate-/
high-risk NMIBC, following complete
transurethral resection, were randomly
assigned to receive either intravesical
thermochemotherapy by means of
Synergo® (Medical Enterprises, Amsterdam,
The Netherlands) or intravesical
chemotherapy alone, for prophylaxis of
tumour recurrence.
• Two doses of MMC (20 mg dissolved in
50 mL distilled water administered
throughout two consecutive sessions) was
used as the chemotherapeutic agent in both
arms.
• In all, 75 patients completed the original
study (35 of 42 in the treatment arm, 40 of
41 in the control arm), whose results at
minimum 2-year follow-up have already
been published.
912
What’s known on the subject? and What does the study add?
Microwave-induced hyperthermia and mitomycin C is a device-assisted approach used to
treat non-muscle invasive bladder cancer (NMIBC) either in the adjuvant (prophylactic)
set-up or in an ablative regimen. Until recently, around 20 different studies have been
published with data on the short term results of treatment. Previous prospective
randomized studies showed the superiority of the chemo-hyperthermia regimen when
compared to intravesical chemotherapy alone in terms of recurrence-free survival in
intermediate and high-risk NMIBC patients at minimum 24-month follow-up. The current
study confirmed the result also in long-term (minimum 10 years) follow-up. It also
represents one of a few to show such extended follow-up periods for any intravesical
therapy for NMIBC.
• Recently, the files of these patients have
been updated for long-term outcome
definition. Data on general health, follow-up
examinations, tumour relapse or
progression, and cause of death were
collected and analysed.
RESULTS
• Updated complete data collection was
available for 65/75 (87%) of the original
patients.
• The median follow-up for tumour-free
patients was 91 months. The 10-year
disease-free survival rate for
thermochemotherapy and chemotherapy
alone were 53% and 15%, respectively
(P < 0.001).
• An intent-to-treat analysis performed to
overcome the potential bias introduced by
the asymmetrical discontinuation rate still
showed a significant advantage of the active
treatment over the control treatment.
Bladder preservation rates for
thermochemotherapy and chemotherapy
alone were 86% and 79%, respectively.
CONCLUSION
• This is the first analysis of long-term
follow-up of patients treated with
intravesical thermochemotherapy. The high
rate (53%) of patients who were tumourfree 10 years after treatment completion, as
well as the high rate (86%) of bladder
preservation, confirms the efficacy of this
adjuvant approach for NMIBC at long-term
follow-up, even in patients with multiple
tumours.
KEYWORDS
bladder cancer, non-muscle-invasive
bladder cancer (NMIBC), treatment, local
hyperthermia, chemotherapy, mitomycin-C
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2010 THE AUTHORS
2 0 1 0 B J U I N T E R N A T I O N A L | 1 0 7 , 9 1 2 – 9 1 8 | doi:10.1111/j.1464-410X.2010.09654.x
RCT COMPARING THERMOCHEMOTHERAPY WITH MITOMYCIN-C ALONE AS ADJUVANT TREATMENT FOR NMIBC
TABLE 1 Tumour characteristics for both groups
Characteristic
Primary or recurrent
Primary
Recurrent*
Highly recurrent†
Size, cm:
<2
≥2
Stage:
Ta
T1
CIS
Grade:
G1
G2
G3
Multifocality:
1–4 tumours
≥5 tumours
N (%)
HT +
MMC
MMC
alone
15 (35.7)
12 (28.6)
15 (35.7)
16 (39.0)
11 (26.8)
14 (34.1)
22 (52.4)
20 (47.6)
18 (43.9)
23 (56.1)
15 (35.7)
26 (61.9)
1 (2.4)
17 (41.5)
24 (58.5)
0
4 (9.5)
27 (64.3)
11 (26.2)
1 (2.4)
33 (80.5)
7 (17.1)
30 (71.4)
12 (28.6)
29 (70.7)
12 (29.3)
*Maximum of two episodes in last year; †more
than two episodes in last year.
designed system (Synergo®; Medical
Enterprises, Amsterdam, The Netherlands)
which delivers local HT at a temperature of
42 ± 2 °C, by means of a microwave
applicator working at 915 MHz. Intravesical
instillation of a cooled cytotoxic solution is
simultaneously administered through a
closed circulatory circuit. Technical
characteristics of this system have already
been described [7].
The short-term results of a randomized
controlled trial comparing MMC alone vs
combined HT and MMC (HT + MMC) using this
technology for the adjuvant treatment of
NMIBC were already published in 2003 [11].
According to this preliminary report at a
2-year minimum follow-up, the recurrence
rate was significantly lower in the
thermochemotherapy group (17.1%), as
compared with MMC-alone group (57.5%,
P < 0.001). The long-term follow-up data of
this original cohort of patients were recently
collected and clinical outcomes are presented
in the present article.
PATIENTS AND METHODS
INTRODUCTION
Transurethral resection of bladder tumours
(TURBT) remains the first-line standard
treatment in patients with non-muscleinvasive bladder cancer (NMIBC), but
the high rate of both recurrence and
progression after TURBT mandates the
use of additional adjuvant treatments
[1–3].
A wide variety of drugs has been administered
intravesically over the years with prophylactic
intent. However, limited efficacy on the one
hand [4,5] and toxicity that is not negligible
on the other [6], resulted in the search of
novel therapeutic strategies such as deviceassisted drug administration. A combined
regimen with intravesical cytotoxic solution
of mitomycin-C (MMC) and microwaveinduced bladder wall hyperthermia (HT),
namely, thermochemotherapy, specifically
administered for bladder tumours stage Ta–T1
treatment, was first published in 1995 [7].
Since then, many clinical trials have been
conducted and, to date, this approach has
gained clear clinical evidence of efficacy
[8–10]. In those studies, thermochemotherapy
was administered by means of a specifically
©
From January 1994 to June 1999, 83 patients
with primary or recurrent stage Ta and T1,
grade G1 to G3 TCC of the bladder were
enrolled into the original randomized
controlled study. One patient presenting with
carcinoma in situ (CIS) associated with a T1G2 tumour was included in the T1-G2
subgroup. Patients with low-risk disease (as
defined by the European Association of
Urology (EAU) guidelines [2]), TCC of the
prostate urethra and solitary CIS were
excluded from the study. Before entering the
study, patients underwent complete TURBT of
all tumours. Only tumour-free patients after
TURBT, as confirmed by a cystoscopy after
TURBT, with negative cold-cup biopsies of any
suspicious areas and negative urinary
cytology, were recruited. Patients were
then randomly assigned to either
thermochemotherapy (HT + MMC, 42
patients) or chemotherapy alone (MMC, 41
patients), using two doses of 20 mg MMC
dissolved in 50 mL distilled water for each
treatment session (namely, a whole amount of
40 mg of MMC). The HT + MMC group
consisted of 35 (83.3%) men and seven
(16.7%) women, whereas, there were 34
(82.9%) men and seven (17.1%) women in the
MMC-alone group. In the HT + MMC group, 25
(59.5) patients were aged ≤65 years, while the
remaining 17 (40.5%) were older. Similarly, in
the MMC-alone group, 16 (39%) patients were
aged ≤65 years and 25 (61%) were older.
Figure 1 shows patients’ accountability, with
patients grouped as randomized for baseline
and safety evaluations.
Previous tumour characteristics are presented
in Table 1. Both groups included patients who
had previously failed intravesical treatments
(57.1% in HT + MMC and 58.5% in MMCalone groups, respectively); in this context,
seven (16.6%) and 11 (26.8%) patients
previously received MMC treatment, in the
HT + MMC and in the MMC-alone group,
respectively (P = 0.261). Several patients with
more than five tumours were also included in
both groups (28% in HT + MMC and 29% in
MMC-alone groups, respectively). There was
no statistically significant difference in the
patients’ characteristics in both groups.
The design of the study, as well as the
technical procedure adopted for both groups
of patients, have already been described in
detail in our early report [11]. Briefly, all
patients in both groups received 8 weekly,
60 min treatment sessions, followed by
4-monthly sessions performed in an
outpatient setting. The follow-up included
cystoscopy and cytology starting from the
end of the induction phase, and every 3
months then after, for 2 years. After the
original study ended, the patients were
followed-up at their physicians’ discretion.
From mid-2007 to date, all available data on
disease and patient status were extracted and
updated from the clinical records of the
patients who completed the treatment
protocol. For patients who died during the
follow-up period, an effort was made to verify
the cause of death and the status of the
urinary bladder over the intervening years
and before they died. If a file was not located,
or no additional information was available, the
data from the original study were used for
analysis.
The primary goal of the present study was to
present long-term efficacy of intravesical
HT + MMC vs MMC alone administered
to patients with NMIBC as an adjuvant
treatment after complete TURBT. The primary
endpoint was disease-free survival (DFS). The
secondary endpoints were the assessment of
disease progression and rates of radical
cystectomy (RC), the bladder preservation
rate, and the rate of cancer-related deaths.
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C O L O M B O ET AL.
FIG. 1. Patients’ accountability and flow through the study.
Enrollment
(n = 83)
All included in
"Worst case scenario"
ITT analysis
Randomization
Allocation
Allocated to HT+MMC
(n = 42)
Received HT+MMC
(n = 38)
Two protocol violations
One had deteriorating general
health before treatment
One withdrew consent
Not evaluated for
recurrence
(n = 1)
One was withdrawn due to
allergy before first outcome
evaluation cystoscopy
Follow-Up
Not evaluated for
recurrence
(n = 3)
Two resided far from hospital
and refused further treatment
One was withdrawn due to
allergy before first outcome
evaluation cystoscopy
Analyzed (n = 40)
Analysis
Analyzed (n = 35)
Allocated to CT
(n = 41)
Received CT
(n = 41)
The present results include all original
‘randomized’ patients. All tests had a
significance level set at 0.05.
Protocol, informed consent, case report
forms as well as data collection were
approved by Ethics Committees of
all institutes taking part in the study
and all patients signed an informed
914
consent agreeing to participate in the
study.
RESULTS
included in the present analysis, either with
new data (65 patients, 86.7%) or with the
original data (10 patients, 13.3%) for whom
the updated data could not be obtained.
Of the 83 randomly assigned patients, 75
(90.4%) completed the original study and
underwent follow-up cystoscopy according to
the protocol design. All 75 patients were
Efficacy results according to the primary
endpoints are presented in Table 2. The
median (range) follow-up of tumour-free
patients was 90 (6–154) months. A recurrent
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RCT COMPARING THERMOCHEMOTHERAPY WITH MITOMYCIN-C ALONE AS ADJUVANT TREATMENT FOR NMIBC
HT + MMC
MMC
91
29
87
10
60.0
61.7
52.8
20.0
21.3
14.6
2
1
3
3
86.1
78.9
6
NR
9
NR
TABLE 2
Primary efficacy outcomes
for both groups
FIG. 4. Incidence of RCs over time.
Legend
MMC
HT+MMC
MMC-censored
HT+MMC-censored
1.0
Cystectomies over time
Outcome
Median follow-up, months
Of tumour-free patients
To recurrence
DFS rates, %
Crude rate
5-year KM estimated
10-year KM estimated
Progression and RC, n
Tumour progression (T > T1)
RC for superficial disease
Bladder preservation rate, %
10-year KM estimated
Death, n
Total
Specific
KM, Kaplan–Meier; NR,
none reported.
0.8
P = 0.129 (NS)
0.6
0.4
MMC
0.2
HT+MMC
0.0
0
FIG. 2. Kaplan–Meier curve of the DFS of evaluable
patients.
FIG. 3. Kaplan–Meier curve of the DFS in the ITT
worst-case scenario.
0.8
0.8
P < 0.0001
0.2
MMC
HT+MMC
P = 0.004
MMC
0.4
0.2
Survival Proability
0.8
Disease Free Survival
Disease Free Survival
1.0
0.6
8
10
12
Legend
MMC
HT+MMC
MMC-censored
HT+MMC-censored
1.0
0.4
6
Years
FIG. 5. Kaplan–Meier curve of overall survival.
1.0
HT+MMC
4
Legend
MMC
HT+MMC
MMC-censored
HT+MMC-censored
Legend
MMC
HT+MMC
MMC-censored
HT+MMC-censored
0.6
2
HT+MMC
0.6
0.4
MMC
0.2
P = 0.558(NS)
0.0
0.0
0
2
4
6
Years
8
10
To overcome any possible bias introduced by
patients who discontinued the study, we
performed an intent-to-treat (ITT) analysis,
taking all 83 randomized patients. Outcome
data was not available for six of eight
‘unevaluable’ patients, as they left the
study before the first outcome evaluation
cystoscopy (three patients), or even before
receiving any treatment at all (three). To
©
0
12
tumour was diagnosed in 14 (40%) of the 35
patients in the HT + MMC group, as compared
with 32 (80%) of the 40 patients in the MMCalone group. As shown in the Kaplan–Meier
curve (Fig. 2), the difference in DFS was highly
significant (P < 0.001) and favoured the HT +
MMC approach.
0.0
2
4
6
Years
8
10
12
overcome this problem we created a ‘worstcase scenario’ by making the following false
assumptions:
a) All study group (HT + MMC) patients for
whom outcome data was not available were
analysed as if they had tumour recurrence on
day 0; and
b) All control group (MMC-alone) patients for
whom data was not available were analysed
as if they were tumour-free for 10 years.
Using this unrealistic scenario, a Kaplan–
Meier survival analysis was performed (Fig. 3),
which showed that the advantage of HT +
MMC over MMC alone was still considerable
and statistically significant (P = 0.004) in this
ITT population.
0
2
4
6
8
Years
10
12
There was tumour progression at the time of
recurrence, requiring RC, in five patients: two
in the HT + MMC group, and three in the
MMC-alone group. Four additional patients
underwent RC for recurrent high-risk NMIBC.
The bladder preservation rate after 10 years
was 86.1% and 78.9% for HT + MMC and
MMC-alone groups, respectively. Figure 4
shows that there was a trend for a higher
probability of undergoing RC in the MMCalone group as compared with the HT + MMC
group, but the difference did not reach
statistical significance (P = 0.129).
As shown in Fig. 5, there was no significant
difference in the overall survival between the
treatment groups, although of the 15 deaths,
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C O L O M B O ET AL.
The influence of demographic factors and
tumour characteristics on DFS were analysed
using the stratified log-rank test. Gender, age,
previous tumour size, prior treatment with
MMC or BCG as well as current tumour stage
and grade, did not influence tumour
recurrence rate (P > 0.05).
A previous history of multiple tumour sites
(i.e. <5 or ≥5) had no effect (P = 0.77) on the
results for HT + MMC-treated patients. In
contrast, this parameter significantly
(P = 0.001) affected the outcome of patients
treated with MMC alone. In this context, all
MMC-alone treated patients with a history
of ≥5 tumour locations, had a tumour
recurrence within the first 24 months after
the beginning of their treatment. Figure 6
shows the Kaplan–Meier curve of DFS for
tumour focality (i.e., <5 or ≥5 locations).
DISCUSSION
Intravesical chemotherapy has been
investigated in both single-arm and
randomized clinical trials for >30 years.
However, the best schedule and duration of
intravesical chemotherapy still remain
unknown [2]. In this context, long-term
outcome studies are extremely rare [12,13].
Today, there is a general agreement that,
considering clinical outcome and costeffectiveness, the indications and the
schedules of adjuvant intravesical
chemotherapy should be adapted to the
expected prognosis after TURBT. The 5-year
probability of disease recurrence and
progression after TURBT for NMIBC can
be calculated using the risk tables based
on six clinical and pathological prognostic
parameters, provided by the European
Organization for Research and Treatment of
Cancer (EORTC) [14] and adopted by the EAU.
According to these tables, NMIBC can be
distinguished into low-, intermediate- and
high-risk subcategories. The risk of recurrence
at 5 years is 45–67% for intermediate-risk
and 54–82% for high-risk, respectively. On
916
the other hand, the risk of progression varies
from 1.8 to 17.4% and from 15 to 47.6% for
intermediate- and high-risk, respectively.
Although controversies still exist, a single
immediate instillation after TURBT is
recommended for patients with low-risk
NMIBC [15–18], whereas there is no general
consensus for adjuvant treatment for both
intermediate- and high-risk NMIBC
populations [18]. Intravesical
chemoprophylaxis mostly remains the firstline adjuvant approach for patients with
intermediate-risk NMIBC; chemotherapeutic
instillations, usually with either MMC or
epirubicin, are safe and effective in reducing
the risk of recurrence in the short term, but
efficacy is only marginal in the long term [18].
In contrast, in high-risk NMIBC, or patients in
whom chemotherapy fails, BCG is the best
choice with lower rates of recurrence and
progression [18]. In this context, a systematic
review by Nillson et al. [19] on 234 reports
including two meta-analyses, 75 randomized
studies and 143 prospective trials including a
31 974 patients, reported that adjuvant
intravesical chemotherapy reduced shortterm (up to 3 years) recurrence rate by ≈20%.
However, after a median follow-up of 8 years,
there were only 8% fewer recurrences after
intravesical adjuvant chemotherapy when
compared with TURBT alone, without any
benefit in cancer-specific survival [19]. This
appears in agreement with a previous metaanalytic revision by Lamm [20] that showed a
14% net benefit only for intravesical adjuvant
chemotherapy when evaluated at the 5-year
mean follow-up.
FIG. 6. DFS rates in relation to treatment and
number of tumours.
Legend
HT+MMC, <5 tumors
HT+MMC, ≥5 tumors
MMC, <5 tumors
MMC, ≥5 tumors
HT+MMC, <5 tumors-censored
HT+MMC, ≥5 tumors-censored
MMC, <5 tumors-censored
MMC, ≥5 tumors-censored
1.0
0.8
Disease Free Survival
there were more deaths in the MMC-alone
group (nine) than in the HT + MMC group
(six). Six deaths were from other unrelated
tumours, there was one cerebral accident, one
heart attack, two were due to the ageing
process; and five were from unknown causes.
No disease-specific mortality could be
established, as the cause of death was missing
in five patients.
HT+MMC, <5 tumors
0.4
MMC, <5 tumors
0.2
MMC, ≥5 tumors
0.0
0
Pawinski et al. [1] compared the long-term
efficacy of adjuvant chemotherapy and TURBT
alone in 2535 patients diagnosed with
NMIBC. That study reported only a 6%
reduction in recurrence rate (47%) after
adjuvant chemotherapy at a median followup of 4.6 years when compared with TURBT
alone (52.6%). In agreement with previous
reports, no difference in terms of time to
muscle invasion or progression-free survival
could be shown by this study in favour of
intravesical chemotherapy. In addition, there
is evidence [14] that the risk of recurrence is
significantly higher for multifocal than
single-site high-risk NMIBC.
During the last decade, much effort has
been made to identify novel methods for
intravesical chemotherapy administration to
improve its efficacy. The combination of
chemotherapy using select cytotoxic agents
HT+MMC, ≥5 tumors
0.6
2
4
6
8
Years
P < 0.0001
10
12
and local HT (41–45 °C), showed a synergistic
or supra-additive cell killing effect against
various solid tumours in several studies [21–
24]. Particularly, combined bladder wall HT
and intravesical chemotherapy with MMC,
delivered by means of a dedicate system
(Synergo), proved to be safe and effective for
the treatment of NMIBC in several clinical
trials for both neoadjuvant and adjuvant
approaches. As far as prophylaxis is
concerned, Gofrit et al. [8] used this
combination in a selected cohort of patients
with high-grade (G3) NMIBC submitted to
complete TURBT. After a mean follow-up of 35
month, 63% of the patients were tumour free,
bladder preservation rate was 96% and there
was no case of progression to muscleinvasive disease. In a multicentre European
study aimed at investigating the efficacy of
HT + MMC as a prophylactic treatment,
mainly in patients with intermediate- and
high-risk NMIBC, van der Heijden et al. [9]
described a Kaplan–Meier estimate of DFS at 2
years of 75%.
The present study describes for the first time
the long-term efficacy of adjuvant HT + MMC
when compared with MMC alone. The original
study started in 1994 and was completed in
1999 and included 83 patients with primary
or recurrent, Ta–T1, G1–G3 NMIBC who were
randomly assigned to receive either HT +
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RCT COMPARING THERMOCHEMOTHERAPY WITH MITOMYCIN-C ALONE AS ADJUVANT TREATMENT FOR NMIBC
MMC or MMC alone. The results of the study
at 24 month showed a statistically significant
superiority (P < 0.001) of the combined
treatment (Kaplan–Meier estimate of 17%
recurrence probability) over MMC alone
(57.5%). The present study reports the clinical
outcomes at a median of 90 months followup. More than half of the patients submitted
to the HT + MMC regimen were documented
to be tumour-free after 10 years, despite 49%
of them having already failed previous
intravesical treatments. At the median 90month follow-up, the efficacy of the HT +
MMC approach appeared to be significantly
better than MMC alone. There were similar
results for both the intermediate- and highrisk NMIBC subgroups. Even tumour
multiplicity (i.e., ≥5 concurrent tumours),
which was a severe negative prognostic factor
in the MMC-alone group, did not significantly
influence the efficacy of the HT + MMC
treatment.
discontinuation rate at the beginning of the
study, but an ITT worst-case scenario analysis
proved that the significant advantage of HT +
MMC over chemotherapy was not influenced
by this potential bias. Finally, long-term
surveillance for NMIBC (with the advanced
age of patients at onset) is extremely difficult
as evidenced by the paucity of the articles
presenting such results for intravesical
treatments.
7
In conclusion, the present paper reports for
the first time the long-term efficacy of an
innovative device-assisted intravesical drug
administration combined with local HT,
showing its significant superiority as an
adjuvant approach for DFS over MMC alone in
patients with intermediate- and high-risk
NMIBC.
9
None declared.
The safety of HT + MMC was acceptable and
similar to that of MMC alone in the shortterm follow-up report [11]. No additional
treatment-related toxicity was evident at the
long-term follow-up. At >10 years, bladder
preservation rates were better in the patients
that had received HT + MMC than in those
that had intravesical chemotherapy alone, but
the difference was not statistically significant.
2
11
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©
10
CONFLICT OF INTEREST
As a major strength of the present study, it is
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Correspondence: Renzo Colombo,
Department of Urology, University Vita-Salute
San Raffaele, Via Olgettina, 60, 20132 Milan,
Italy.
e-mail: [email protected]
Abbreviations: CIS, carcinoma in situ; DFS,
disease-free survival; EAU, European
Association of Urology; HT, hyperthermia;
MMC, mitomycin-C; NMIBC, nonmuscleinvasive bladder cancer; RC, radical
cystectomy; TURBT, Transurethral resection of
bladder tumour; ITT, intent-to-treat.
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2010 THE AUTHORS
2010 BJU INTERNATIONAL