Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalJanuary 2004
931
Original Article
RADIOTHERAPY AND HYPERTHERMIA IN FOR LOCALLY ADVANCED PROSTATE CANCER
M. VAN VULPEN
et al.
Radiotherapy and hyperthermia in the treatment of
patients with locally advanced prostate cancer:
preliminary results
M. VAN VULPEN, A.A.C. DE LEEUW, B.W. RAAYMAKERS, R.J.A. VAN MOORSELAAR*, P. HOFMAN, J.J.W. LAGENDIJK and
J.J. BATTERMANN
Departments of Radiation Oncology and *Urology, University Medical Centre Utrecht, Utrecht, the Netherlands
Accepted for publication 15 August 2003
OBJECTIVE
was delivered using a conformal three-field
interstitial group. The actuarial probability of
technique, administering 70 Gy in 2-Gy
freedom from biochemical relapse was 70% at
To report an interim clinical evaluation of
fractions in 7 weeks.
36 months for all patients together, 79% for
combined external beam irradiation (EBRT)
regional and 57% for interstitial. No factors
and interstitial or regional hyperthermia in
RESULTS
were found that could be used to predict
the treatment of locally advanced prostate
relapse.
cancer.
The mean initial prostate-specific antigen
level was 26 ng/mL. Three patients had a T4
CONCLUSIONS
PATIENTS AND METHODS
and 23 a T3 tumour; the tumours were
classified as well (four), moderately (16) and
The clinical outcome in these patients with
From 1997 to 2001, 26 patients with T3-4/NX/
poorly (six) differentiated. The mean follow-
advanced localized prostate cancer seems to
0M0 prostate carcinoma were treated with
up was 36 months. In the combined
compare favourably with most series using
a combination of conformal EBRT and
treatments there was no toxicity of more than
irradiation alone, and the treatment caused
hyperthermia. Fourteen patients received five
grade 2. In regional hyperthermia the mean
no severe complications.
weekly regional hyperthermia treatments
index temperature (T90 and T50, i.e. exceeded by
within an optimization (phase II) study, using
90% and 50% of the measurements) was
the coaxial transverse electrical magnetic
40.2 C and 40.8 C, and for interstitial
KEYWORDS
system. Twelve patients received one
hyperthermia 39.4 C and 41.8 C,
interstitial hyperthermia treatment within a
respectively. All patients survived; seven
prostate carcinoma, hyperthermia, regional
feasibility study (phase I), using the multi-
patients had a biochemical relapse (27%),
interstitial, radiotherapy, follow-up,
electrode current source system. Irradiation
three in the regional and four in the
hyperthermia dose
INTRODUCTION
a benefit for relapsed hormone-refractory
promising, the possibilities were evaluated for
patients. Furthermore, additional
future randomized trials (20th European
The outcome of treatment for locally
hyperthermia does not seem to decrease the
Society for Hyperthermic Oncology
advanced prostate carcinoma (T3,4 NX/0 M0)
quality of life of patients with prostate
conference, Bergen, Norway, 23­25 May,
using conventional radiotherapy alone is
carcinoma [8].
2002). Only a few studies have described the
insufficient. Zagars et al. [1] described a 10-
clinical results after prostate hyperthermia
year biochemical relapse rate of 76% after
Different hyperthermia techniques can be
[6,12]. Although we realise that data on the
conventional external beam irradiation
used to treat prostate carcinoma; promising
clinical outcome of phase I/II studies are
(EBRT). An improvement in local control may
methods include both interstitial [9] and
inconclusive and that the results remain
result in a better disease-specific survival [2].
regional hyperthermia [6,10]. Transurethral
preliminary, they might serve to support
Local control can be enhanced by androgen
and/or transrectal hyperthermia produces a
future discussions.
suppression with local irradiation [3] or by
highly variable heat distribution, because of
increasing the radiation dose [4], e.g. by using
the limited heat penetration depth [11]. Algan
intensity-modulated radiotherapy.
et al. [12] used transrectal hyperthermia and
PATIENTS AND METHODS
reported no improvement in treatment
Adding hyperthermia to conventional
outcome. The feasibility of interstitial and
From December 1997 to October 2001, 26
radiotherapy may also improve local control
regional hyperthermia for locally advanced
men with locally advanced prostate cancer
in prostate carcinoma. Hyperthermia is known
prostate carcinoma was reported earlier by us
(T3,4 NX/0 M0) received EBRT combined with
to enhance the radiation effect in prostate
[13,14].
regional or interstitial hyperthermia. The
cancer cells in vitro [5]. One study suggested a
toxicity in all patients was measured using the
gain from hyperthermia in newly diagnosed
Because added hyperthermia for treating
Common Toxicity Criteria (CTC, version 2.0).
patients [6], and Kalapurakal et al. [7] reported
locally advanced prostate cancer seems
All patients were irradiated using CT-planned
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R A D I O T H E R A P Y A N D H Y P E R T H E R M I A I N F O R L O C A L L Y A D V A N C E D P R O S T A T E C A N C E R
three-dimensional (3D) conformal EBRT in a
remains compulsory to estimate the thermal
hyperthermia (mean eight), which makes the
linear accelerator. Then the clinical target
dose for each patient.
calculation of T90 each minute less reliable. For
volume (CTV) was defined as the prostate and
interstitial hyperthermia there were more
seminal vesicles; 66­70 Gy in 2-Gy fractions
Twelve patients were treated to assess the
sensors (mean 100) [14]. Thus the thermal
(five fractions/week) were delivered to the
technical feasibility (phase I) of one interstitial
variables are only shown for the eight
CTV. The seminal vesicles were excluded from
hyperthermia treatment in the last week of
treatments with a calculated 3D temperature
the irradiation field after 50 Gy when they
the EBRT, as outpatients [14]. Hyperthermia
distribution. The calculated 3D T90
were not invaded by tumour. A conformal
was delivered with the 27 MHz multi-
temperature was converted into the CEM T90
three-field isocentric technique was applied,
electrode current source interstitial
and CM T90, as used by others [19].
using 6 and 18 MV photons and a multileaf
hyperthermia technique (MECS-IHT) lasting
collimator. The dose was prescribed according
60 min. Guided by TRUS, a mean of 12 (7­16)
Before treatment all patients provided a
to ICRU-50 [15]. The dose was 100% at the
catheters were placed in the prostate through
history and were physically examined. The
reference point, the allowed dose gradient
a template. A probe containing two electrodes
primary tumour was assigned a T-category
within the planning target volume was ± 5%;
was inserted and thermometry used within
based on a DRE and TRUS; four patients had
the 95% isodose line was at 8 mm from the
the probes for online temperature control; a
no TRUS. All patients had abdominopelvic
CTV.
mean of 84 (49­112) sensors were available
CT to exclude the presence of nodal
per treatment. The temperature was also
metastases. Eight patients also had a pelvic
HYPERTHERMIA
measured in the prostate, rectum, urethra and
lymphadenectomy. The metastatic evaluation
bladder. A reconstruction of the implant was
included a bone scan for all patients.
There were two studies of hyperthermia, one
created using ultrasonography. Only when a
The latest American Joint Committee
using regional and one interstitial treatment.
sufficient temperature decline was measured
classification system was used for staging
The selection criteria, evaluation of the
could the full 3D temperature distribution be
[20].
feasibility and quality of life of the patients
calculated using the treatment planning
are described elsewhere [8,13,14]. The local
system. This was possible in eight patients,
Patients attended for a follow-up 4 weeks
ethical committee has approved both studies.
and considerable experience was required
after completing the combined hyperthermia-
Briefly the studies were as follows.
for successful implantation, verifying the
radiotherapy treatment. Subsequently, they
position, reconstruction and temperature
were assessed every 3 months for 2 years, and
Fourteen patients were treated in an
simulation. It was concluded that MECS-IHT is
at 6-month intervals thereafter. At each
optimization study (phase II) with regional
technically feasible and significant normal
follow-up a history was taken and they were
hyperthermia during the radiotherapy course
tissue protection was possible. Because of a
physically examined. PSA was measured at
[13]. Hyperthermia was delivered with the
high perfusion (47 ± 5 mL/100 g per min) and
least twice per year; other investigations were
coaxial transverse electrical magnetic system,
limitations to implantation near the rectum
used only when indicated by symptoms.
one treatment/week, for five treatments.
and bladder, there as a very heterogeneous
Thermometry was used in the bladder, urethra
temperature distribution. This resulted in
The major criteria for disease outcome were
and rectum, and in the oesophagus to
under-dosed regions and therefore interstitial
relapse or an increasing PSA level [21].
measure body temperature. Invasive
hyperthermia is unlikely to be sufficient when
Patients were classified as free of disease if
temperatures in the prostate were measured
the target volume is the entire prostate.
there was no clinical or radiographic evidence
in one or two treatments for each patient by
However, a high minimum temperature was
of local or distant disease, and if the PSA was
placing a central and a peripheral catheter
possible in the macroscopic tumour regions.
not rising. An increase in the PSA on two
transperineally. A mean (range) of 8 (2­11)
Further technical optimization of MECS-IHT
consecutive measurements was considered
invasive sensors were available per treatment.
seems possible.
a relapse [21]. Curves of freedom from
All patients completed the five hyperthermia
(biochemical) relapse were calculated
treatments for 75 min, except two who had
Thermal variables were calculated from the
using the Kaplan-Meier method [22], and
five treatments of 60 min because of back
invasively measured temperature in each
proportional hazards regression analysis used
pain when upright for treatment. Absorbers
treatment. The temperature Tx, exceeded by
to determine which factors were associated
(agar-bound saline blocks) placed on the skin
x% (where x = 90, 50) of the measurements,
with time to relapse [23].
were used to reduce local pain caused by `hot
was determined and termed the index
spots'. The invasive and tumour-related
temperature [17]. Index temperatures give an
intraluminal temperatures were compared;
indication of the quality of the hyperthermia
RESULTS
there was a heterogeneous distribution of
treatment, like the mean and minimum
temperatures in the prostate because the
temperature reached and the temperature
The patients' characteristics for both groups
mean perfusion was 14 (±2) mL/100 g/min
heterogeneity. To estimate a thermal dose the
are shown in Table 1. The prostate volume was
[16]. Intraluminal thermometry could not
cumulative time at T90 of >40.5 C (CM T90)
measured using CT data, which were available
reliably predict the invasive temperatures. It
was calculated [17], as was the cumulative
for both groups. Only one patient in each
was concluded that regional hyperthermia
equivalent minutes (CEM) at a T90 of 43 C for
group received adjuvant hormonal therapy.
for locally advanced prostate carcinoma
each treatment [18].
Irradiation doses were according to the
is clinically feasible. For guidance and
department protocol at the time. Although
optimizing treatment urethral temperatures
Only a few thermometry sensors were
the patient groups differed in prognostic
are sufficient, but invasive thermometry
available in the prostate for regional
factors, both had stage III tumours. Therefore
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M . V A N V U L P E N E T A L .
both patient groups were also evaluated
Regional
Interstitial
All
TABLE 1
together (Table 1), with a mean follow-up of
No. of patients
14
12
26
The patients' characteristics
36 months.
Mean (range):
age, years
65 (56­75)
65 (45­74)
65 (45­75)
TOXICITY
prostate vol., mL
64 (35­128)
46 (32­66)
56 (35­128)
EBRT dose, Gy
69.4 (66­70)
70
69.9 (66­70)
Because there were no significant differences
Follow-up, months
38 (16­60)
33 (25­42)
36 (16­60)
in the distribution of side-effects between
Initial PSA, ng/mL
32 (4­86)
20 (9­60)
26 (4­86)
hyperthermia techniques (data not shown)
No. with PSA, ng/mL, of
and no complications above grade 2, the CTC
0­20
7
7
14
scores of the combined radiotherapy-
21­80
5
5
10
hyperthermia treatments are shown for
> 81
2
­
2
all patients together in Table 2. No late
Clinical stage (23)
complications worse than grade 2 occurred,
T3
11
12
23
although the follow-up is still limited.
T4
3
­
3
Differentiation
After regional hyperthermia, acute
Well
1
3
4
complications consisted of local pain (46 of
Moderate
8
8
16
70 treatments), mostly in the pubic region, but
Poor
5
1
6
sometimes also at the hips, sacrum and in the
Hormonal therapy
1
1
2
testicles. Absorbers were used successfully to
reduce pain to an acceptable level, although
in 10 cases an additional power reduction was
required. In two of 70 treatments systemic
stress, caused by general discomfort, limited
CTC item
0
1
2
TABLE 2
the treatment [13]. No infections or bleeding
Constitutional: fatigue
19
69
12
CTC score of the combined
occurred from the invasive procedures. To
Renal/genitourinary:
treatments
investigate the effect of absorbers, invasive
urinary frequency urgency
12
69
19
thermometry in the pubic region was applied
urinary retention
96
4
0
during regional hyperthermia. This resulted,
bladder spasms
92
8
0
on three of five occasions, in a palpable mass
incontinence
96
4
0
(1­3 cm) developing over several days and
haematuria
88
12
0
lasting up to a year, probably resulting from
dysuria
46
50
4
a combination of trauma from the needle
Gastrointestinal:
*Score for 19 patients, as
insertion and fibrosis. During interstitial
proctitis
8
69
23
seven already had erectile
treatments there were no side-effects [14],
(peri-)rectal pain
73
23
4
dysfunction before
and afterwards all patients noticed self-
sexual function: erectile dysfunction*
32
47
21
treatment.
limiting transperineal pain.
TEMPERATURES
The thermal variables are shown in Table 3;
Mean (SD) or (range)
Regional (70)
Interstitial (8)
TABLE 3
for regional hyperthermia the mean (SD)
T90, C
40.2 (0.6)
39.4 (0.9)
Thermal variables per
temperature range (over each minute, all
T50, C
40.8 (0.6)
41.8 (1.6)
treatment
treatments) was 1.1 (0.2) C, indicating a
CM T90, min
22 (0­50)
0
heterogeneous temperature distribution. For
CEM T90, min
1.9 (0.2­6.1)
0.47 (0.0­1.4)
interstitial hyperthermia there was a very
heterogeneous temperature distribution, with
high temperature peaks on the heating
catheters (up to 60 C) and low temperatures
patients in the regional group had a
relapse rate was 70%, for the regional 79%
between the catheters and at the prostate
biochemical relapse; two of them had T4
and for the interstitial 57%.
border (some areas as low as 37 C). The
grade 3 tumours with PSA values of 86 and
differences in temperature heterogeneity
30 ng/mL, and were treated with an
Distant metastases were detected in one
between the techniques can be explained by
irradiation dose of 66 Gy. In the interstitial
patient from the regional group and in two in
differences in calculated perfusion values and
group four patients had a biochemical
the interstitial group (Fig. 1b). For all patients
the differences in technique.
relapse. Fig. 1a shows the actuarial probability
together the actuarial probability of freedom
of freedom from biochemical relapse for both
from distant metastasis after 36 months was
All patients survived during a mean (range)
groups and together. For the combined group
86%. There were two local recurrences, both
follow-up of 36 (16­60) months. Three
the 36-month freedom from biochemical
in the interstitial group; for all patients
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R A D I O T H E R A P Y A N D H Y P E R T H E R M I A I N F O R L O C A L L Y A D V A N C E D P R O S T A T E C A N C E R
FIG. 1. Freedom from (a) biochemical relapse, (b)
were too few patients and events, and the
hyperthermia treatments, treatment duration,
distant metastasis, and (c) local relapse for all
short follow-up.
thermal variables and temperature
patients (green line), and the interstitial (red dotted
distribution [13,14], perfusion [16] and
line) and regional (light green dashed line)
applied selection criteria [8]. Furthermore,
hyperthermia groups.
both groups comprised few patients. The
DISCUSSION
regional hyperthermia study was phase II,
a
focusing on optimization. Most feasibility
1.0
There is a strong rationale for adding
aspects were already investigated and the
0.9
hyperthermia to EBRT in men with locally
treatments administered according to the
0.8
advanced prostate carcinoma. Treatment
current standards and quality-assurance
0.7
results after conventional irradiation alone
protocols. Interstitial hyperthermia was a
0.6
are unsatisfactory [1,3,24,25]. A thermal
phase I study mainly of technical feasibility,
0.5
enhancement ratio has been established
which resulted in an insufficient temperature
0.4
for prostate cancer [5]. Early studies on
distribution, using the criteria of Emami et al.
0.3
hyperthermia for prostate carcinoma showed
[26] for prostate cancer treatment. Further
0.2
evidence for an improved clinical outcome
optimization of the interstitial hyperthermia
0.1
[6,7] and prostate hyperthermia does not
technique is necessary before it can be used in
Freedom from biochemical relapse 0.0
seem to decrease the quality of life [8].
clinical trials.
0
12
24
36
48
60
72
Although the present data on clinical
outcome are preliminary, they might serve
The thermal dose concept was developed to
b
to support present discussions on future
evaluate the quality of the hyperthermia
1.0
randomized trials.
[17,18]. A more homogeneous temperature
0.9
distribution seems to produce better clinical
0.8
The toxicity of the combined hyperthermia-
results. There was a strong correlation
0.7
radiotherapy treatment is acceptable; no
between the minimum thermal dose, tumour
0.6
toxicity above grade 2 was reported. The
coverage, local control and duration of
0.5
side-effects of the hyperthermia treatments
control [17,26]. It is likely that the minimum
0.4
were mild, as was also reported by others
temperature in the entire prostate volume will
[6,9,10].
also be clinically relevant. In 83% of men
0.3
prostate cancer has more than one cancer
0.2
Freedom from distant relapse
The 36-month freedom from biochemical
focus and 95% of these are situated in both
0.1
relapse rate was 70% for all 26 patients
the peripheral and the central or transitional
0.0
(Fig. 1a), with actuarial probabilities of
zone [27].
0
12
24
36
48
60
72
freedom from local relapse rate of 91%
c
(Fig. 1c) and from distant metastasis of 86%
There are limitations to the thermal dose
1.0
(Fig. 1b). Anscher et al. [6] delivered regional
variables T90, T50, CM T90 and CEM T90 [17,18].
0.9
hyperthermia to 18 patients with newly
Most of these concepts are based on the
0.8
diagnosed prostate cancer; the actuarial local
availability of very sparse thermometry data
0.7
control and freedom from distant failure at
[28]. Because of this it is likely that the
36 months were 93% and 68%, respectively.
minimum temperatures in the tumour will be
0.6
The results of Anscher et al. [6] and the
missed, and that the thermal dose will be
0.5
present results on clinical outcome compare
overestimated. In the regional treatments
0.4
favourably with series of patients treated with
only a mean of eight invasive sensors was
0.3
radiotherapy alone [1,3,24,25]. Zagars et al. [1]
present, whereas there were many for
0.2
Freedom from local relapse
reported a 50% freedom from PSA relapse
interstitial hyperthermia and a 3D
0.1
rate after 36 months in 260 patients with T3
temperature distribution could be calculated.
0.0
NXM0 disease. Pilepich et al. [24] found in 230
In Table 3 the mean CEM T90 was 0.47 min for
0
12
24
36
48
60
72
patients with T2­T4 tumours that ª40% were
interstitial hyperthermia using only the mean
Time, months
free from local relapse and 70% free from
T90. However, especially in the catheter tracts,
distant metastases after 3 years.
high temperatures were reached, up to 60 C,
which must have caused severe thermal
together the actuarial probability of freedom
To date the optimal treatment temperature,
damage [14]. When averaging the thermal
from local relapse was 91% after 36 months
the required number of hyperthermia
dose in the entire prostate volume, the CEM
(Fig. 1c).
treatments and treatment duration remain
T90 could be 13­45 000 min. Thus temperature
unclear. Thus we report the clinical results of
heterogeneity is not properly incorporated
The proportional hazards regression analysis
both groups separately and together; it is
in the CEM T90 and CM T90 formulae. A
of the items in Table 1 showed that no factor
inappropriate to compare the clinical results
comparison between these hyperthermia
was significantly associated with time to
of both groups. There were differences
methods is therefore not valid using the
biochemical relapse, mainly because there
between the groups in the number of
present thermal dose concepts.
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M . V A N V U L P E N E T A L .
There is a marked improvement in treatment
6
Anscher MS, Samulski TV, Dodge RD
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outcome in locally advanced prostate
et al. Combined external beam irradiation
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carcinoma when using androgen suppression
and external regional hyperthermia for
16 Van Vulpen M, Raaymakers BW, De
as an adjuvant to conventional irradiation
locally advanced adenocarcinoma of the
Leeuw AAC et al. Prostate perfusion in
[1,3,24,25]. In the present study only two of
prostate. Int J Radiat Oncol Biol Phys
patients with locally advanced prostate
the 26 patients received adjuvant androgen
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carcinoma treated with different
suppression. This has the advantage of
7
Kalapurakal JA, Mittal BB, Sathiaseelan
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hyperthermia in locally advanced
17 Oleson JR, Samulski TV, Leopold KA
with adjuvant androgen suppression. The
radiation recurrent, hormone refractory
et al. Sensitivity of hyperthermia trial
combination of hyperthermia, androgen
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8
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