Regional
Original
Hyperthermia
for
Bladder
Cancer •E
T.
Ohguri
et
al.
Contribution
Initial Experience of Bladder Therapy Using Chemoradiotherapy Hyperthermia for Muscle-invasive TAKAYUKI FUMIO
OHGURI*,
KATO,
KATSUYA
KEITA Department
HAJIME
YAHARA,
NAKANO,
of Radiology,
IMADA,
organ-preserving
SATOSHI
TOMOAKI
YUKUNORI
University
regimens
using
NOMOTO, MORIOKA,
KOROGI
of Occupational
Health. Kitakyushu-shi,
Abstract : Recently,
Preservation with Regional Bladder Cancer
and Environmental
Japan
predominantly
multiple-modality
therapy , consisting of endoscopic transurethral resection followed by irradiation with concurrent chemotherapy, are emerging as viable alternatives for muscle-invasive bladder cancer, although radical cystectomy has been the standard treatment. Three cases with muscle-invasive bladder cancer (5-7 cm in size) , two of T2N1M0 and one of T2NOMO, underwent bladder preservation therapy with regional hyperthermia for improvement of the local effect. A total dose of 66-7OGy in the conventional methods , chemotherapy composed
of methotrexate,
doxorubicin,
cisplatin
and/or
vinblastine,
and 3 to
12 sessions of
hyperthermia during radiotherapy were delivered. All three cases showed complete response without any local recurrence or distant metastasis in follow-ups. Toxicity during the treatment was acceptable, and late toxicity was not recognized.
Bladder preservation therapy adding regional hyperthermia is
potentially useful for improving the treatment results for muscle-invasive bladder cancer of large tumor size. Key word : bladder cancer, chemotherapy, hyperthermia, radiotherapy Introduction Muscle-invasive tumors comprise 20 % to 25 % of all newly diagnosed bladder cancerso.
The most
appropriate treatment algorithm for muscle-invasive bladder cancer remains controversial. Although radical cystectomy has been the standard treatment for two decades, organ-preserving regimens using predominantly multiple-modality therapy, consisting of endoscopic transurethral resection (TUR) followed by irradiation with concurrent chemotherapy, are emerging as viable alternatives in a subset of patients. A major limitation of pelvic external beam radiation therapy is that the dose required to achieve an adequate level of local control in such tumors exceeds the tolerance of the surrounding normal tissues . Received 9 Febrary 2005, Accepted 8 March 2005. *Corresponding E-mail :
[email protected]
author, Tel : +81-93-691-7264 ; Fax : 4-81-93-692-0249 ;
151
( 23 )
Jpn. J. Hyperthermic Oncol. 21 (3) : 2005
日本 ハ イ パ ー サ ー ミ ア 誌21〔3〕:(平
成17年)
Hyperthermia has been used in combination with radiation therapy and/or chemotherapy, and considered to be effective for certain type of tumors2-6). Treatment results of radiotherapy and/or chemotherapy plus hyperthermia for bladder cancer were also reported7-12). Improvement of the local effect by hyperthermia is especially expected in large tumors.
In the present three cases, bladder
preservation therapy, consisting of TUR followed by irradiation with concurrent chemotherapy and regional hyperthermia, was used to treat with muscle-invasive bladder cancer of large tumor size. Materials and methods Patients Between January 2000 and December 2002, three patients with invasive bladder cancer were treated with chemoradiotherapy
plus regional hyperthermia at our hospital.
Characteristics and treatments of
patients are given in Table I. TUR was used for both diagnosis and treatment as reducing the tumor volume in all the three patients. Acute toxicity was scored according to criteria of radiation therapy oncology group13). Late toxicity was mainly investigated by a telephone to the patients or their family. Table
I
Characteristis
SCC : squamous (doxorubicin),
of patients
cell carcinoma, CDDP
and treatment
TCC : transitional
for bladder
cancer
cell carcinoma,
MTX : methotrexate,
VBL : vinblastine,
ADM : adriamycin
: cisplatin
Hyperthermia Hyperthermia was applied with radiofrequency (RF)-capacitive heating device (Thermotron RF-8) within 30 min after radiotherapy once or twice a week.
Heating duration was 40-50 min.
and lower electrodes were 30 cm in diameter, placed on opposite sides of urinary bladder.
Both upper The out-put
power was about 400-600W. A treatment posture of all cases was prone position. For cooling of the skin surface, the overlay boluses were applied in addition to regular boluses attached in front of the metal electrodes. The intravesical temperature was measured using a 4-point microthermocouple-sensor. The maximum intravesical temperature (Tmax)was defined as the maximum intravesical temperature obtained during the steady state and at the end of treatment. The steady state was defined at 20 min after the start of heating. The minimum intravesical temperature (Tmin) was defined as the minimum temperature obtained by the same method. The averages of these parameters (Tave) were calculated over the steady state. In all cases, Tmax,Tmin and Tave were measured at the third session. Table I summarizes the thermometry.
( 24 )
152
Regional
Hyperthermia
for
Bladder
Cancer •E
T.
Ohguri
et
al.
Radiation All
patients
radiation case
dose 1
and
3,
technique,
in
11 •~10 3,
cm2
18Gy
treated
was
66-7OGy.
the
initial
case and
2,
In
case
in
case
case
fractions
whole case
cm2
pelvic
covered
1,
1 and
in
1, 7•~7.5
external
The
covered
technique, in
with
fields
48Gy
respectively.
conformal
3,
were
2, 3, with
and
were
18•~15 fields 4-field
14Gy
2Gy
whole pelvis
the
radiotherapy
plus
using
daily,
bladder with
cm2
and
were box
regional
in to
technique,
and
linear
lymph the
case
tumor the
cm2
10MV
5 days/week
technique,
46Gy
shrunk
5.2•~5.5
given and
same
a
field
2,
field
the
size
lOGy
in
and
nodes
with and
2,
dose
8•~
X-ray
total .
In
4-field
total
and
with
total
case
1OMV
cm2
boost
A
using
size
12•~10
for
accelerator.
box
dose
4OGy
in
are case
three-dimensional are
7 cm2
7.6
and
X 8 cm2
26Gy
in
and case
respectively.
Chemotherapy Two 1,
15,
and on of
22,
of
the
29,
43
three and
doxorubicin days 70
1, mg/m2
Evaluation
patients 50,
of 15,
22, on
30 29,
day
received
vinblastine mg/m2
43
on
and
3 and
50, 43.
the of
day
following
3 mg/m2 3 and
chemotherapy on
43.
vinblastine Radiotherapy
of
days
The
15,
22,
remaining
3 mg/m2 was
3,
: methotrexate
started
on
one days
on
32,
day
43
and
50,
received
3, 3,
15, 7
22, and
of
30
mg/m2
cisplatin
of
methotrexate 32,
43
and
15,
respectively.
of 50,
and
on 70
days
mg/m2,
30
mg/m2
cisplatin
of tumor response
The clinical tumor response was evaluated by measuring the tumor size with MR imaging before and after the radiation therapy. Grading of tumor response was as follows : complete response (CR), 50 % regression in volume as partial response (PR), < 50 % response or < 25 % increase as no change (NC). Results Table II summarizes the treatment result.
CR was achieved in all the three patients.
They did not
have both local recurrence and distant metastasis. Fig. 1. shows MRI images of case 1 with bulky bladder cancer which responded completely to combined treatments. Toxicity consisted of cystitis and diarrhea noted during the treatment was acceptable and did not get serious. Acute toxicity of chemotherapy was also within the tolerance level. Severe late toxicity was not recognized in our retrospective research. Table
II
Treatment
results
NED : no evidence of disease Toxicity : criteria of radiation therapy oncology group (RTOGY")
153
( 25 )
Jpn. J. Hyperthermic Oncol. 21 (3) : 2005
日本 ハ イ パ ー サ ー ミア 誌21〔3〕:(平
Fig. la. Case 1. MR imaging (T2 weighted image) showed bulky bladder cancer (arrows).
Fig. lb. There
was no tumor
2 weeks
成17年)
after completion
of
treatment.
Discussion Radical radiation therapy as the sole treatment modality for muscle-invasive bladder cancer has produced a clinical complete response in 40 % to 50 % of patients14-16). Several authors have reported promising results of concurrent chemoradiotherapy for muscle-invasive bladder cancer17-22). Pelvic failure is less common with chemoradiotherapy than with radiation monotherapy22). For the modern bladder preservation series, TUR followed by irradiation with concurrent chemotherapy, the overall survival at 5 years ranged from 45 to 52 % ; 54 to 67 % of surviving patients have a tumor-free, normally functioning bladder1). Hyperthermia is biologically known as an effective modality for treatment of cancer.
Clinical
studies including randomized trials on hyperthermia have promising results for various sites of tumor2-12). A Dutch phase III trial showed improvement of local efficacy in a mixed cohort of patients with locally advanced cervical, bladder or rectal carcinoma, and a major survival benefit was obtained in patients with cancer of the uterine cervix by adding regional hyperthermia to standard radiation therapy12). For patients with bladder cancer, the addition of hyperthermia significantly increased the complete-response rate from 51 % to 73 % ; however, long-term local control and overall survival were not significantly improved. The value of hyperthermia in these patients might have been underestimated for various reasons as lack of thermal data analysis and the problem of patients who received insufficient hyperthermia treatment. Clinical and laboratory studies have also shown that hyperthermia enhance the cytotoxic effects of several chemotherapeutic
drug7)23)24).Kakehi et al.
showed the treatment results of RF-capacitive
regional hyperthermia with chemotherapy in patients with bladder cancer ; total response rate was obtained in 6 out of 8 cases7). Although there were a few reports of combined treatment of hyperthermia, irradiation and chemotherapy for invasive bladder carcinoma, their results were satisfactory8-10). In the combination therapy consisted of radiation and hyperthermia administered by way of warmed saline and
( 26 )
154
Regional
bleomycin
irrigation,
noted
among
T2-3
hyperthermia of
For
the
no
bladder
(>
showed
(44-47•Ž)
in
our
Although
of at
to
treat
of
the
series
patients
T.
and
Ohguri
PR
4
of
et
in
results
in
the
overlay with
a
of
al.
21,
and
an
including
the
5
84
% response
rate
RF-capacitive
patients
the
better
fat
consisted
, including
was
3
regional cases
of
T2
and
intra-vesical
RF-8. for
the
cystitis
temperature. for
three
that
tumors
with
of
tumor
the
number
of is
heating
patients
and
of
diarrhea
the
we
to
in
maximum
complete
could
obtain
bladder
temperature
tumors
average
of
excellent of
intravesical
meet
TUR
degeneration
than
higher
needs 5 cm
visibly
average
studies
session
of
with
low
intravesical
such 40-50
the
rise water06).
did
not
get
average
temperature
of
serious
and detailed
the
1 and are
fatty
could
than
in
the
potentially providing treatment
three
.
are
patients useful
for
reduced
by
, it is possible strong
cooling
despite
of
improving
therapeutic protocols
three
problems
be
by
not
Excessive
major
thick
tumor
are
probably
often
3 cm
deep-seated
2,
sufficient
layer
edge less
treatments
case
minutes
fat
seems
cancer with
as
electrode
subcutaneous
of
hyperthermia
subcutaneous
hyperthermia bladder
Further
and 5 cm,
high
of
near with
point
Regional
than
histological
obtained,
duration
a temperature
freezing
in
that
less
bladder
degeneration
believe
overheating
obtain
preservation
size
exceeded
reported
We
the
patients
Thermoesthesia
muscle-invasive protocols.
tumor
temperature
slender and
unifocal, of
bladder
response. and
and
with of
local
method
electrodes
outputs
bladder-preservation
al.
for
capacity
our
41.5•Ž25).
with
RF
results
good of
candidate
are
influence
treatment
As
intravesical
are
good
bolus.
subcutaneous
treatment
to
using
more
ideal
that
et
than
heating if
edge
the
size
higher less
led
hyperthermia
Toxicity
cases
Cancer •E
treatment
tumors
Nishimura
of
hyperthermia
higher
56
obtained
cancer,
tumor
significantly
strictly,
an
Bladder
thermoradiotherapy,
optimal
established
using
of
obstruction,
survival.
temperature
deep
25
was
T2-3a
ureteral
preoperative
intravesical
for
combined CR
Although
and
41.5•Ž)
heating
The
bladder
of
tumor1).
after
sessions
in
: primary
presence
control
cancer
observed
reported
muscle-invasive criteria
diameter,
local
also
for
T48).
following
the
was
cases10).
were
2 cases
the
CR
Hyperthermia
the the
flexibility in
large
in
number
of
recommended.
References 1) Gunderson L. L., Tepper J. E. : Bladder cancer : clinical radiation oncology, Churchill Livingstone, pp819-843, 2000. 2) Abe M., Hiranka M. Takahashi M., Egawa S., Matsuda C., Onoyama Y., Morita K., Kakehi M., Sugahara T. : Multi-institutional studies on hyperthermia using an 8-MHz radiofrequency capacitive heating device (Thermotron RF-8) in combination with radiation for cancer therapy. Cancer, 58 : 1589-1595, 1986. 3) Terashima H., Nakata H., Yamashita S., Imada H., Tsuchiya T., Kunugita N. : Pancoast tumour treated with combined radiotherapy and hyperthermia-a preliminary study. Int J Hyperthermia, 7 : 417-424, 1991. 4) Lee C. K., Song C. W., Rhee J. G., Foy J. A., Levitt S. H. : Clinical experience using 8 MHz radiofrequency capacitive hyperthermia in combination with radiotherapy : results of a phase I/II study . Int J Radiat Oncol Biol Phys, 32 : 733-745, 1995. 5) Imada H., Nomoto S., Tomimatsu A., Kosaka K., Kusano S., Ostapenko V. V., Terashima H. : Local control of nonsmall cell lung cancer by radiotherapy combined with high power hyperthermia using an 8 MHz RF capacitive heating device. Jpn J Hyperthermic Oncol, 15 : 15-19, 1999. 6) Ohguri T., Imada H., Yahara K., Kakeda S., Tomimatsu A., Kato F., Nomoto S., Terashima H., Korogi Y . : Effect of
155
( 27 )
Jpn. J. Hyperthermic Oncol. 21 (3) : 2005
8-MHz radiofrequency-capacitive colorectal
regional hyperthermia
cancer. Int J Hyperthermia,
7) Kakehi M., Ueda K., Mukojima studies on hyperthermia J Hyperthermia, 8) Ueda
radiofrequency
with strong superficial cooling for unresectable
成17年)
or recurrent
20 : 465-475, 2004.
T., Hiraoka
M., Seto 0., Akanuma
combined with radiotherapy
A., Nakatsugawa
or chemotherapy
S. : Multi-institutional
clinical
in advanced cancer of deep-seated organs. Int
6 : 719-740, 1990.
K., Sakagami
H., Kato
hyperthermia,
invasive bladder 9) Noguchi
日本 ハ イ パ ー サ ー ミア 誌21〔3〕:(平
F., Mogami
T., Ohtaguro
HPC-adriamycin,
carcinoma. Nippon
K., Masui Y. : A combined
immunotherapy,
Hinyokika
radiation,
local hyperthermia
for bladder cancer. Nippon
systemic chemotherapy
Hinyokika
therapy of intra-arterial
and irradiation
for
chemotherapy
and
Gakkai Zasshi. 81 : 1817-1824, 1990. (Japanese).
S., Watai K., Kakehi M., Kubota Y., Yao M., Shuin T. : Combination
bladder carcinoma with chemohyperthermia.
with 8 MHz
Gakkai Zasshi. 81 : 1330-1336, 1990. (Japanese).
R., Sasaki A., Miyanaga N., Kanoh S., Koiso K. : Combination
10) Matsui K., Takebayashi
treatment
Int J Hyperthermia.
radiotherapy
of urinary
7 : 19-26, 1991.
11) Colombo R., Da Pozzo L. F., Lev A., Salonia A., Rigatti P., Leib Z., Servadio C., Caldarera E., Pavone-Macaluso Local microwave hyperthermia
and intravesical
unresectable
tumors. J Urol, 159 : 783-787, 1998.
superficial bladder
chemotherapy
as bladder
M. :
sparing treatment for select multifocal
and
12) van der Zee J., Gonzalez Gonzalez D., van Rhoon G. C., van Dijk J. D., van Putten W. L., Hart A. A. : Comparison of radiotherapy randomised,
alone with radiotherapy
multicentre
plus hyperthermia
trial. Dutch Deep Hyperthermia
in locally
advanced
pelvic tumours : a prospective,
Group. Lancet, 355 : 1119-1125, 2000.
13) Cox J. D., Stetz J., Pajak T. F. : Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization 14) Jahnson
for Research and Treatment
of Cancer (EORTC).
S., Pedersen J., Westman G. : Bladder carcinoma--a
Int J Radiat Oncol Biol Phys, 31 : 1341-1346, 1995.
20-year review of radical irradiation
therapy. Radiother
Oncol, 22 : 111-117, 1991. 15) Bloom
H. J., Hendry
pre-operative 16) Mameghan transitional
W. F., Wallace
radiotherapy
of
Br J Urol, 54 : 136-151, 1982. for invasive
radiation
and cisplatin in the treatment of advanced
report. J Urol, 128 : 1031-1033, 1982.
T4_,Zur Nedden D. : Combined radiation
of the urinary bladder.
and chemotherapy
for locally advanced transitional
Cancer, 55 : 1659-1664, 1983.
19) Shipley W. U., Prout G. R. Jr., Einstein A. B., Coombs L. J., Wajsman Z., Soloway M. S., et al. bladder cancer by cisplatin and radiation 20) Tester W., Poter A., Asbell S., Coughlin organ preservation
trial
of the bladder. Int J Radiat Oncol Biol Phys, 31 : 247-254, 1995.
bladder cancer : a preliminary
cell carcinoma
cancer : controlled
J., Brook S. : Analysis of failure following definitive radiotherapy
17) Soloway M. S., Ikard M., Sceinberg M., Evans J. : Concurrent
18) Jakse G., Frommhnld
of T3 bladder
and radical cystectomy versus radical radiotherapy.
H., Fisher R., Mameghan cell carcinoma
D. M., Skeet R. G. : Treatment
Treatment of invasive
in patients unsuited for surgery. J Am Med Assoc, 258 : 931, 1987. C., Heaney J., Krall J., et al. : Combined
modality
program with possible
for invasive bladder carcinoma : results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys, 25 :
783-790, 1993. 21) Dunst J., Sauer R., Schrott K. M., Kuhn
R., Wittekind
C., Altendorf-Hoffman
A. : Organ-sparing
treatment
of
advanced bladder cancer : 10-year experience. Int J Radiat Oncol Biol Phys, 30 : 261-266, 1994. 22) Coppin C. M. L., Gospodarowicz
M. K., James K., Tannock
I. F., Zee B., Carson J., et al. : Improved local control of
invasive bladder cancer by concurrent cisplatin and preoperative
or definitive radiation.
J Clin Oncol, 14 : 2901-2907,
1996. 23) Kawai H., Minamiya doxorubicin
Y., Kitamura
concentration
M., Matsuzaki
I., Hashimoto
M., Suzuki H., Abo S. : Direct measurement
in the intact, living single cancer cell during hyperthermia.
24) Schopman E. M., Van Bree C., Kipp J. B. Barendsen G. W. : Enhancement treatment of solid tumours by application
( 28 )
of local hyperthermia.
156
Cancer, 15 : 214-219, 1997.
of the effectiveness of methotrexate
Int J Hyperthermia,
of
11 : 561-573, 1995.
for the
Regional
25) Nishimura
Y., Hiraoka
J Hyperthermic
Hyperthermia
M. : Relationship
for
Bladder
Cancer •E
T.
Ohguri
et
al.
between thermometry results and tumor response in thermoradiotherapy.
Jpn
Oncol, 14 : 162-169, 1998.
157
( 29 )
Jpn. J. Hyperthermic Oncol. 21 (3) : 2005
日本 ハ イ パ ー サ ー ミア 誌21〔3〕:(平
成17年)
浸潤性膀胱癌 に対 す る温熱化学放射 線治療 による 膀胱温存療法 の初期経験 大 栗 隆 行 ・今 田 肇 ・野 元 諭 ・加 藤 文 雄 矢 原 勝 哉 ・森 岡 丈 明 ・中 野 敬 太 ・興 梠 征 典 産業医科大学放射線科学教室
要
旨: 近 年,浸 潤 性 膀 胱 癌 に対 して経 尿 道 的 腫瘍 切 除,放 射線 治療 と化 学 療 法 の併 用 に よ る膀 胱 温
存 を 目的 と した 治 療 が施 行 され,膀 胱全 摘 除 術 に 匹敵 す る成 績 が報 告 され て い る.我 々 は,3例 の腫 瘍 径 の大 きな浸 潤 性 膀 胱 癌 に対 し,局所 効 果 の増感 を 目的 に,化 学 放 射線 治療 に温 熱 療 法 を加 えた膀 胱 温 存 療 法 を施 行 した.病 期 はT2N 分割 で66-70Gy,温
lMO(2例),
熱 療 法 を3-12回,ま
T2NOMO(1例),平 たM-VACを
均 腫瘍 径 は5.7cmで
あ った.放 射 線 治 療 は通 常
主体 とした化 学 療 法 を施 行 した.治 療 後,全3例
と
も腫瘍 は完 全 消 失 し,局 所 再 発 や 遠 隔 転移 を生 じなか った.治 療 期 間 中 に膀 胱炎 や下 痢 を生 じた が,治 療 終 了後 改善 し,重篤 な晩 期 障害 も認 め られ なか った.腫 瘍 径 の大 きな浸潤 性 膀 胱 癌 に対 す る化 学 放 射 線 治 療 に温 熱療 法 を加 えた 膀 胱 温存 療 法 は有 用 で 治療 成績 の改 善 が 期 待 で き る.
( 30 )
158