Strahlentherapie
und Onkologie
Original Article
Regional Hyperthermia in Conjunction with Definitive
Radiotherapy against Recurrent or Locally Advanced
Prostate Cancer T3 pN0 M0
Wolfgang Tilly1, Johanna Gellermann1, Reinhold Graf1, Bert Hildebrandt2, Lothar Weißbach3,
Volker Budach4, Roland Felix1, Peter Wust1
Background and Purpose: Since long-term results of the standard treatment of locally advanced or recurrent prostatic carci-
noma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study.
Patients and Methods: From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in
combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant)
hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local
recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (pros-
tate-specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters.
Results: Mean maximum temperatures along the urethra of 41.4 °C (41.0 °C for the recurrences), and mean T values of 40.7 °C
90
could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one,
and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and
at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival
curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recur-
rences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation
between higher temperatures or thermal doses with long-term PSA control.
Conclusion: Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules.
Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.
Key Words: Regional hyperthermia · Prostate carcinoma · PSA control
Strahlenther Onkol 2005;181:3541
DOI 10.1007/s00066-005-1296-8
Definitive externe Radiotherapie mit regionaler Hyperthermie beim lokal fortgeschrittenen oder rezidivierten
Prostatakarzinom Stadium T3pN0M0
Hintergrund und Ziel: Die Langzeitergebnisse der Standardtherapie beim lokal fortgeschrittenen oder rezidivierten Prostatakar-
zinom sind unbefriedigend. Daher wurde eine zusätzliche regionale Hyperthermie in einer Phase-I/II-Studie evaluiert.
Patienten und Methodik: Von 08/1996 bis 03/2000 wurden 22 Patienten mit einer Standardradiotherapie von 68,4 Gy in Kom-
bination mit regionaler Hyperthermie (wöchentlich, fünf bis sechs Sitzungen) behandelt. Bei fünf von 22 Patienten wurde eine
neoadjuvante Hormonbehandlung durchgeführt. Bei 15 Patienten lag ein primäres Prostatakarzinom T3 pN0 M0 vor; sieben Pa-
tienten hatten ein histologisch bestätigtes Lokalrezidiv nach radikaler Prostatektomie. Geprüft wurden die Durchführbarkeit der
Hyperthermie, die akute und späte Toxizität sowie die Langzeitkontrolle (PSA-Kontrolle [prostataspezifisches Antigen], Gesamt-
überleben). Die klinischen Endpunkte wurden mit thermischen Parametern korreliert.
Ergebnisse: Es konnten mittlere Maximaltemperaturen entlang der Urethra von 41,4 °C (41,0 °C für die Rezidive) sowie mittlere
T von 40,7 °C erreicht werden. Schwere akute Nebenwirkungen vom Grad 3 traten am Rektum bei drei, an der Urethra bei vier,
90
am Dünndarm bei einem sowie durch Hyperthermie bedingt (Verbrennung) bei einem von 22 Patienten auf. Spätfolgen wurden
nur bei einem Patienten am Rektum (Grad 3) und bei zwei Patienten an der Urethra (Grad 2) festgestellt. Es bestand keine Korre-
lation zwischen thermischen Parametern und irgendeiner Toxizität. Die Überlebenskurven zeigten eine PSA-Kontrolle von > 50%
beim primären Prostatakarzinom nach 6 Jahren, jedoch keine Langzeit-PSA-Kontrolle bei den Rezidiven. Das Gesamtüberleben
betrug nach 6 Jahren 95% für die primären Prostatakarzinome und 60% für die Rezidive. Es fand sich eine deutliche Korrelation
zwischen hohen Temperaturen bzw. thermischen Dosen und der langfristigen PSA-Kontrolle.
1 Department of Radiation Medicine, Charité Medical School, Berlin, Germany,
2 Department of Internal Medicine Hematology and Oncology, Charité Medical School, Berlin, Germany,
3 Department of Urology, Urban Hospital, Berlin, Germany,
4 Department of Radiation Oncology, Charité Medical School, Berlin, Germany.
Received: March 11, 2004; accepted: July 2, 2004
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Tilly W, et al. Hyperthermia and Definitive Radiotherapy in Prostate Cancer
Schlussfolgerung: Die regionale Hyperthermie könnte eine gut verträgliche Zusatztherapie sein, um die PSA-Kontrolle von übli-
chen Therapieschemata zu verbessern. Hier ist eine weitere Evaluation sinnvoll, insbesondere auch unter Anwendung verbesserter
Hyperthermietechnologien.
Schlüsselwörter: Regionale Hyperthermie · Prostatakarzinom · PSA-Kontrolle
Introduction
bidity, in particular vascular diseases, and interferences with
For locally advanced prostate cancer cT3/4 with cN0 or pN0,
radio-frequency hyperthermia, cardiac pacemakers and other
external-beam radiotherapy (EBRT) is accepted as standard
electronic or metallic implants, e.g. endoprostheses.
treatment.
External radiotherapy was performed with a linear ac-
The role of radical prostatectomy in case of periprostatic
celerator (Siemens Mevatron KD, 18 MV) using fractions of
tumor extension (T3) is controversially discussed. Reports
5 × 1.8 Gy up to 68.4 Gy at the reference point (ICRU). Plan-
with large numbers of T3 carcinomas describe a 5-year pros-
ning was carried out based on a three-dimensional CT data set
tate-specific antigen (PSA) relapse-free survival of only
using the planning system Helax®. Prostate and seminal vesi-
3040% paralleled by considerable rates of local recurrences
cles with a safety margin of 1 cm (78 mm dorsally to spare the
in the range of 20% [12, 24]. These results are similar to those
rectum) were specified as planning target volume. A confor-
of other nonsurgical series. Therefore, taking the peri-/post-
mal four-field box technique was used.
operative morbidity into account, EBRT is widely favored.
Regional hyperthermia was carried out about 30 min be-
However, in T3/T4 tumors definitive radiotherapy alone
fore or after a single fraction once a week five to six times
with standard doses of about 72 Gy is also inadequate. On av-
during the radiotherapy course as described elsewhere [29].
erage, in 60% PSA progression occurs after 5 years and in
We used the SIGMA-60 applicator of the BSD 2000 system.
80% after 10 years [32]. Innovative strategies include dose es-
The midplane (feed points of the antennas, central plane of
calation by intensity modulation, additive interstitial radio-
the applicator) was positioned a few centimeters cranial to the
therapy, and/or cytoreduction by hormonal manipulation,
symphysis defining the longitudinal position [21]. The patient
either neoadjuvant and/or adjuvant, for several years. None-
was also transversally centered in the applicator (defining the
theless, these approaches could not improve the outcome, but
vertical and lateral position). We inserted minimally invasive
imply some late normal tissue reactions.
hyperthermia catheters (closed-end catheters for housing the
Dose escalation with three-dimensional conformal irra-
Bowman thermistors) into the rectum and urethra. In addi-
diation led to an increased late rectal toxicity grade 2, and in
tion, a bladder catheter was positioned parallel to the thin hy-
fact, investigators found a higher rate of proctitis grade 2 [19,
perthermia catheter (diameter about 1.6 mm). We could reg-
22]. Long-term hormonal treatment causes specific side ef-
ister temperature position curves along the catheters in the
fects of the medication, impotency, and increased late reac-
rectum and the urethra in 10- to 15-min intervals. For the tem-
tions [8].
perature-time curves in between, we left the point probe at the
There is currently no standard of care for locally advanced
maximum.
prostatic carcinoma. Regional hyperthermia might be a useful
We assume that these reference points for the tempera-
option, because it is known to enhance the locoregional effi-
ture-time curves characterize the central part and the periph-
cacy of radiotherapy [16, 25, 27]. An advantage of regional hy-
ery of the prostate. Using the temperature-time curves at the
perthermia might be its low toxicity profile, observed in many
beginning (power-on) and at the end (power-off) of heat treat-
studies in terms of acute and late reactions [17]. We conducted
ment, we could derive specific absorption rates (SARs) in W/kg
a phase II study to further investigate the role of regional hy-
at the reference points. We could also derive index tempera-
perthermia for locally advanced prostatic carcinoma.
tures T and T
(T is the temperature exceeded by 90% of
90
max
90
the tumor/prostate-related measurement points) as well as
Patients and Methods
thermal dose parameter cumulative minutes (cummin) T
90
We established a protocol for concurrent thermoradiation for
> 40.5 °C, i.e., the time in minutes for the whole series with a
locally advanced primary prostatic carcinoma at stage
T > 40.5 °C at the prostate [29]. The thermal parameters were
90
T3 pN0 M0 or recurrent rTx cN0 M0 tumors. This protocol
correlated with clinical endpoints (toxicity, PSA control).
has been approved by the ethics committee of the Charité in
We started the heat treatment with a total power of
November 1996. We enrolled 22 patients with histologically
400500 W (depending on habitus and general status) and syn-
proven primary or recurrent prostatic carcinoma. Capsular
chronous adjustment (0.0; i.e., a phase delay 0 at every channel
penetration was verified either by ultrasound or by clinical
or antenna pair) or a slight shift to the bottom with a phase
examination. Only pN0 categories (verified by lymphadenec-
delay of 3050° at the dorsal channel. According to patient
tomy) were included. Exclusion criteria were severe comor-
tolerance (heat stress, hot spots) and achieved temperatures
36
Strahlenther Onkol 2005 · No. 1 © Urban & Vogel
Tilly W, et al. Hyperthermia and Definitive Radiotherapy in Prostate Cancer
in the measurement points (attempting to achieve > 41.5 °C),
rectal carcinomas [23]. On the other hand, the specific absorp-
we increased or reduced the total power and, in particular, the
tion rate and total power were lower than achieved for rectal
weights at the dorsal or ventral channel or modified the phase
cancers. We conclude that perfusion and thermal conduction
delay.
must be higher in rectal carcinomas preventing temperature
Toxicity was documented according to WHO criteria
increase even for higher SARs. The toxicity per treatment and
(acute toxicity) or according to the LENT score (late effects of
normal tissues) [18]. For the heat treatments we defined a tox-
icity score as follows: 0 no complaints or some discomfort by
Table 1. Characteristics of 22 patients entering the study from 1996 to
2000. PSA: prostate-specific antigen.
bolus pressure, thermal stress or positioning; 1 power-de-
pendent discomfort, which resolves completely at the end of
Tabelle 1. Patientencharakteristik (22 Patienten; Studienzeitraum
1996 2000). PSA: prostataspezifisches Antigen.
heat treatment; 2 hot spot sensation, which persists or occurs
after the end of heat exposure and resolves in days or (rarely)
Age
69 years (5675 years)
weeks; 3 burn or thermal lesion.
The follow-up was based on a PSA monitoring every 4
Stage
Primary
Recurrent
months. PSA control was defined as a nadir of < 1 ng/ml. PSA
cT3a pNO 9
rTX
cNO
7
cT3b
pN0
6
progression according to ASTRO was defined for cases ex-
ceeding 2 ng/ml. PSA levels between 12 ng/ml were also
Hormonal Manipulation
judged to be a progression, if PSA increased at two successive
Primary
Recurrent
controls. Local progression was defined according to WHO as
None
9 None 7
Neoadjuvant
6
macroscopic tumor growth of > 25%.
All statistical analyses were conducted with SPSS soft-
Grading
Primary
Recurrent
ware version 10 (SPSS Inc, Chicago, IL, USA). Tests for sub-
G1
3 G1 0
groups were performed using the distribution-free Mann
G2
9 G2 1
G3
3 G3 6
Whitney test. Overall survival and biochemical disease-
free survival were analyzed using the actuarial method by
PSA
Primary
Recurrent
Kaplan-Meier.
< 10 ng/ml
5
< 10 ng/ml
3
10 20 ng/ml 4
10 20 ng/ml
4
>
20
ng/ml
6
Results
Mean = 16.7 ng/ml
Mean = 10.8 ng/ml
Feasibility
From 1996 until 2000 we included 15 patients with de novo
locally advanced prostatic carcinoma and seven recurrences.
Table 2. Thermal parameters (mean ± standard deviation) measured in
the urethra (map along the prostatic urethra) and power-related pa-
The patient characteristics are given in Table 1. Some pa-
rameters in n = 122 heat treatments. The parameters are differentiated
tients with primary carcinoma (n = 6/15) were on LHRH
for primaries and recurrences, and compared with corresponding pa-
(luteinizing hormone-releasing hormone) agonists before
rameters in rectal cancer achieved along endoluminal catheters under
radiotherapy started. In these patients the medication was
similar conditions [17]. P: total power; SAR: specific absorption rate.
continued for 2 months and finished at the end of external
Tabelle 2. Thermische Parameter (Mittelwert ± Standardabweichung)
radiotherapy.
in der Urethra (Scan entlang dem Prostataabschnitt der Urethra) und
Thermoradiation was well tolerated. The prescribed ra-
leistungsabhängige Parameter bei n = 122 Wärmebehandlungen. Auf-
teilung der Parameter bei primären und rezidivierten Karzinomen und
diation dose could be delivered to all 22 patients. Concomitant
Vergleich mit den Ergebnissen beim Rektumkarzinom (Scan mittels en-
regional hyperthermia was given in four to six sessions to 21
doluminaler Katheter) unter ähnlichen Bedingungen [17]. P: Leistung;
patients. Only in one patient hyperthermia had to be inter-
SAR: ,,spezifische Absorptionsrate".
rupted after the first heat treatment due to patient refusal. The
total number of heat treatments was 122. The prescribed en-
Prostate Cancer
Rectal Cancer
Primary
Recurrent
Primary
Recurrent
doluminal thermometry in bladder, urethra and rectum could
be performed in the majority of heat treatments. In a few pa-
T (°C)
40.7 ± 0.3 40.6 ± 0.8
40.2 ± 1.2 40.7 ± 0.4
90
tients the routine insertion of a bladder catheter during each
T
(°C)
41.4 ± 0.4 41.0 ± 0.7
41.4 ± 0.6 41.7 ± 0.5
max
heat session had to be waived. Insertion of the small flexible
Cummin T
179 ± 92
148 ± 138
110 ± 93
184 ± 85
90
40,5 °C (min)
hyperthermia catheters in the urethra, however, was tolerated
SAR (W/kg)
31.9
21.9
36.3
30.8
by most patients at each treatment session.
P (W)
525
425
615
580
The statistical evaluation of the temperature position
Rel. SAR (W/kg/100 W) 6.9
5.3
5.9
5.3
curves along the urethra is shown in Table 2 (see Patients and
Mean toxicity
0.5
0.5
0.6
0.8
Methods for definitions). The temperature distribution ap-
(per treatment)
Maximal toxicity
1.2
1.6
1.2
1.6
pears quite homogeneous with a relatively high minimum
(per patient)
temperature (T ~ 40.640.7 °C) compared with a series of
90
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Tilly W, et al. Hyperthermia and Definitive Radiotherapy in Prostate Cancer
Table 3. Acute toxicity according to WHO and CTC (above). For the tox-
served. Grade 2 reactions at the urethra or caused by heat (per-
icity score of hyperthermia see text. Late toxicity (below) is scored ac-
sistent hot spot sensations) are frequent (55%), but moderate
cording to LENT (late effects of normal tissues) [18].
urinary toxicity is common during radiotherapy. Persistent hot
Tabelle 3. Akute Toxizität gemäß WHO and CTC (oben). Toxizitätsgrade
spots (muscle-skeletal pain syndrome) heal within a few days
der Hyperthermie s. Text. Die Spättoxizität (unten) wurde nach dem
or, at most, several weeks without any late morbidity.
LENT-Score klassifiziert (Spätwirkungen auf das Normalgewebe) [18].
No correlation was observed between thermal parame-
Acute
Grade 0 Grade 1
Grade 2
Grade 3 Grade 4
ters (T
, T ) and acute toxicity. Conversely, we even found
max
90
a trend linking higher temperatures with less acute radio-in-
Rectum
2
10
7
3
duced toxicity. However, this might be explained by an in-
Bladder/urethra
3
3
12
4
creased tolerance for more aggressive heating in cases of less
Intestine
12
5
4
1
Skin
5
15
2
radio-induced toxicity.
Heat
1
8
12
1
Late reactions (see Table 3 below) were moderate. Fol-
low-up was at least 24 months in 20 patients. Of these, only 5%
Late
Grade 1
Grade 2
Grade 3/4
had rectal toxicity grade 3 (with permanent loss of mucus and
Gastroinestinal
2/20 (10%)
0
1/20 (5%)
urgency) and 10% (n = 2/20) suffered from long-term urinary
Urogenital
1/20 (5%)
2/20 (10%)
0
reactions grade 2 (intermittent urgency and dysuria). Our
analysis showed no correlation between thermal parameters
and chronic toxicity.
patient was comparable for both tumor entities. However, tol-
erance was generally reduced in recurrent tumors. This cor-
Follow-Up
responds to a higher total power and gained SAR in primary
A subdivision of the clinical events according to death, PSA
tumors compared with recurrences. Nevertheless, the tem-
failure, local progression, and distant metastases is shown in
peratures achieved for recurrences are similar or even higher,
Table 4. During a median observation time of 6 years (4280
which is probably based on a reduced perfusion and perfusion
months) only one patient deceased in the primary group and
regulation capacity.
three patients in the recurrence group. Relapse-free survival
Table 2 illustrates that primary prostatic carcinomas are
(i.e., PSA control) is shown in Figure 1, and overall survival in
easier to heat than primary rectal carcinomas with higher rela-
Figure 2. We found a PSA control of about 50% after 6 years.
tive SAR and T (for lower total power) [21, 23]. However,
Much less favorable was the PSA control for (macroscopic)
90
this is not the case for recurrent prostatic carcinoma as com-
recurrences, where PSA progression occurred in all patients
pared to recurrent rectal cancer (see Discussion).
after 18 months. However, local progression of a recurrence
verified by ultrasound was only seen in one patient. In four of
Toxicity
seven patients (57%) a salvage androgen ablation kept the
Acute and late reactions are summarized in Table 3. Acute
progressive disease under control. One patient developed
reactions were acceptable. Only 14% grade 3 reactions at the
rectum, 18% at the urethra (dysuria), < 5% at the small intes-
100
tine and hyperthermia-related (burn), respectively, were ob-
90
Primary
100
80
80
70
al (%) 60
60
viv 50
Recurrent
Primary
A control (%) 40
40
PS
verall surO 30
20
Recurrent
20
0
10
0 20 40 60 80 100
Time (months)
010 20 30 40 50 60 70 80 90
Figure 1. Survival under PSA control (ASTRO consensus, < 1 ng/ml) for
Time (months)
primary carcinomas (15 patients) and recurrences (seven patients).
Abbildung 1. Überleben unter PSA-Kontrolle (ASTRO-Konsensus,
Figure 2. Overall survival for primary carcinomas and recurrences.
< 1 ng/ml) bei primären Karzinomen (15 Patienten) und Rezidiven (sie-
Abbildung 2. Gesamtüberlebenszeit bei primären und fortgeschritte-
ben Patienten).
nen Karzinomen.
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Strahlenther Onkol 2005 · No. 1 © Urban & Vogel
Tilly W, et al. Hyperthermia and Definitive Radiotherapy in Prostate Cancer
early distant metastases of unproven origin and was excluded
Table 4. Subdivision of the clinical endpoints in the follow-up of 22
from the analysis of local control.
patients with a mean observation time of 6 years (4280 months).
Overall survival after 6 years reached 95% in the primary
Tabelle 4. Aufschlüsselung der klinischen Endpunkte bei 22 Patienten
group and about 60% in the recurrence group (Figure 2).
im Beobachtungszeitraum bei einer mittleren Beobachtungszeit von
6 Jahren (4280 Monate).
A clear correlation was found between the quality of heat
treatments (T
, T , cummin) and the PSA control according
max
90
Alive
PSA
Local
Distant
to Table 5. In the group with PSA control (n = 8) significantly
progression
progression
metastases
higher temperatures and thermal doses were achieved (p-val-
ues of 0.010.02) in spite of the small number of patients. The
Primary n = 15
14
6
0
1
Recurrent n = 7
4
4
1
2
best distinction was achieved for mean T
(measured in the
max
urethra). In fact, T
was the only relevant predictive factor
max
for PSA control with five local PSA failures for patients with
T
< 41.2 °C and only one PSA failure for T
41.2 °C
monal treatment in patients with either lymphatic involve-
max
max
(p = 0.037, Mann-Whitney test).
ment (pN+) or clinical stage T3 (palpable tumor infiltration
Even though the (pretherapeutic) PSA value is well es-
beyond the capsula). A large improvement of biochemical
tablished as prognostic factor (see, e.g., [14]), the correlation
control was seen after 5 years (55% vs. 20%). RTOG trial
between the initial PSA and the PSA control was not as high
92-02, dealing with a patient group similar to ours (T2cT4
in this small group according to Table 5. Surprisingly, the
tumors), found a biochemical control of 21% after 5 years in
thermal parameters are better correlated with the outcome
the reference arm with radiotherapy and neoadjuvant andro-
than the pretreatment PSA values. For example, in the group
gen suppression (2 months), while additional long-term an-
with an initial PSA > 20 ng/ml, a PSA control of 33% is found
drogen deprivation improved PSA control to 46% [8].
as compared to 67% for a PSA 20 ng/ml (p = 0.22, Mann-
An EORTC trial [4] investigated a patient group of 415
Whitney test).
men with locally advanced prostate cancer treated with either
EBRT or radiotherapy and long-term androgen deprivation.
Discussion
This study exclusively showed a survival benefit for the com-
We evaluated a regimen of a standard radiotherapy using
bined treatment group of 79% versus 62%. Unfortunately, the
moderate doses of 68.4 Gy in combination with regional hy-
biochemical control was not documented in this trial making a
perthermia, which causes low acute or late morbidity. Such a
comparison with other studies difficult.
regimen appears feasible in order to improve outcome with a
Another strategy to enhance the local effectiveness of
good therapeutic ratio.
standard radiotherapy is a dose escalation. These techniques
Generally, long-term PSA control is unsatisfactory, if
mainly used intensity-modulated radiotherapy or high-dose-
macroscopic infiltration of the periprostatic tissue is diagnosed
rate brachytherapy. Various studies have consistently con-
by clinical criteria or imaging. The widespread therapeutic op-
firmed a dose-response relationship for the PSA control.
tion was radiotherapy alone with radiation doses of 6670 Gy
Most dose escalation studies of prostatic carcinomas treat
resulting in a long-term PSA control of only 30% for observa-
patients with T13 tumors, i.e., locally advanced carcinomas
tion times > 5 years [31]. PSA control in a similar range is
are only a small part of the whole patient group. Therefore, a
achieved for high-risk tumors (e.g., T3/4)
by other groups applying standard ra-
Table 5. Univariate analysis of thermal parameters correlates the effectiveness of the heat
diotherapy, e.g., a 5-year PSA control of
treatments with the major clinical endpoint PSA control (for primary prostatic carcinoma, 14
35% [28] or a 3-year PSA control of 60%
patients alive). The one patient with metastatic disease was excluded from the thermal analy-
[6]. Therefore, various approaches have
sis (n = 6), which can only characterize local PSA control, whereas the whole patient group is
described by the initial PSA value (n = 7).
been considered to enhance the effec-
tiveness of the standard treatment.
Tabelle 5. Univariate Analyse der thermischen Parameter zur Korrelation der Effektivität der
Wärmebehandlungen mit der PSA-Kontrolle (beim primären Prostatakarzinom, 14 lebende Pa-
In a large study, Zietman et al. [32]
tienten). Der Patient mit metastasierender Erkrankung wurde aus der thermischen Analyse
prescribed a tumor dose of 68.4 Gy, and
genommen (n = 6), da diese nur die lokale PSA-Kontrolle betrifft, während die gesamte Patien-
found a biochemical control of < 40%
tengruppe (n = 7) durch den initialen PSA-Wert beschrieben wurde.
after 5 years declining to < 20% after 10
years. Additional hormonal treatment
T
T
Cummin
T
PSA
90
max
90
40.5 °C
(initial)
was suggested for these cases (see [10]
for a survey). Two RTOG trials address-
PSA control ( 1 ng/ml)
40.8 °C
41.7 °C
202 ± 92 min
13.3 ng/ml
ing locally advanced prostate cancer are
(n = 8)
available. RTOG trial 85-31 [11] com-
PSA progression
40.4 °C
40.9 °C
93 ± 35 min
26.6 ng/ml
(n = 6)
(n = 7)
pared radiotherapy alone with radio-
p 0.013
0.010
0.020
0.18
therapy plus long-term adjuvant hor-
39
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Tilly W, et al. Hyperthermia and Definitive Radiotherapy in Prostate Cancer
proper selection of patients for such a comparison is difficult.
25%, which looks worse as compared to our results. However,
Pollack et al. [15] performed a randomized dose escalation
the distribution of prognostic factors was more unfavorable in
study (70 vs. 78 Gy) in 305 T1T3 patients including 20%
this patient group. In particular, the average pretreatment
(60 patients) with T3. The 5-year PSA control for T3 carci-
PSA value was much higher (38 ng/ml in the work of Anscher
noma is comparable to our data (40%).
et al. [2] versus 17 ng/ml in our study).
Radical prostatectomy, eventually combined with post-
operative radiotherapy, might be the treatment option with
Conclusion
maximum effectiveness. However, a summary of studies
Regional hyperthermia is a very feasible and well-tolerated
showed that the long-term biochemical control of the surgical
procedure, which might increase the local effectiveness of ra-
approach is not superior to conservative treatments, achieving
diotherapy or any combination therapy against locally ad-
a PSA control of < 40% [19] and even with postoperative ra-
vanced prostate cancer. Regional hyperthermia might further
diotherapy of only 57%. Complications and burden are not
enhance the effectiveness of more aggressive treatments such
negligible for this radical treatment with long-term inconti-
as radiotherapy plus long-term androgen suppression or
nence in 2030% of patients, a postoperative morbidity around
dose-escalated EBRT. Then, a long-term PSA control better
30%, late urinary complications of 2030%, and a surgery-re-
than 5060% is expected. Regional hyperthermia might as
lated mortality of 0.5% [3].
well replace dose-intensifying modules of higher toxicity. For
From these data we may conclude, that a combined and/
example, standard radiotherapy plus regional hyperthermia
or more aggressive treatment strategy can improve the 5-year
might be as effective as standard radiotherapy plus long-term
biochemical control of radiotherapy alone from 2040% up to
androgen suppression or a dose-escalated schedule, but less
slightly > 50%. On the other hand, overall survival at 10 years
burdensome (or less expensive). Further investigations in a
is not depending on the treatment. It can be 80% (at 5 years)
randomized study are highly desirable.
under favorable conditions, or 62% for radiotherapy alone
[4]. In particular, surgery plus radiotherapy is not increasing
Acknowledgment
survival as compared to other less aggressive procedures.
This work has been supported by the "Lieselotte-Beutel-Stiftung",
Therefore, a careful evaluation of all treatment combinations
Berlin.
with respect to toxicity is required.
In our small series we gained a long-term PSA control
References
(> 5 years) of 50%, and an excellent overall survival of > 90%
1. Aebersold DM, Isaak B, Thalmann G, et al. Applicability and dosimetric
for primary locally advanced prostatic carcinoma T3 pN0.
impact of ultrasound-based preplanning in high-dose-rate brachytherapy
This is near the biochemical control achieved with the most
of prostate cancer. Strahlenther Onkol 2004;180:3517.
aggressive regimens such as radiotherapy plus long-term an-
2. Anscher MS, Samulski TV, Dodge R, et al. Combined external beam irradia-
tion and external regional hyperthermia for locally advanced adenocarci-
drogen suppression or radical prostatectomy plus adjuvant
noma of the prostate. Int J Radiat Oncol Biol Phys 1997;37:105965.
radiotherapy. Therefore, regional hyperthermia appears to
3. Begg CB, Riedel ER, Bach PB, et al. Variations in morbidity after radical
enhance the effectiveness of standard radiotherapy [9] as sug-
prostatectomy. N Engl J Med 2002;346:113844.
4. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with lo-
gested in various trials of other tumor entities [30].
cally advanced prostate cancer treated with radiotherapy and goserelin.
Remarkably, regional hyperthermia is very untoxic and is
N Engl J Med 1997;337:295300.
not increasing radiation-induced toxicity. This has already
5. De Meerleer G, Vakaet L, De Gersem W, et al. Direct segment aperture and
been shown in other prospective trials reported by Rau et al.
weight optimization for intensity-modulated radiotherapy of prostate can-
cer. Strahlenther Onkol 2004;180:13643.
or van der Zee et al. [17, 25]. In our study, the frequency of
6. Geinitz H, Zimmermann F, Wedel E von, et al. Biochemische Kontrolle nach
chronic side effects is only 10% for grade 3 urinary toxicity
konformaler, dreidimensionaler Strahlentherapie des Prostatakarzinoms.
and 5% for grade 3 rectal toxicity. This is in the range (or even
Strahlenther Onkol 2002;178:36977.
7. Gellermann J, Wlodarczyk W, Ganter H, et al. A practial approach to perform
lower) what we would expect from radiotherapy at a standard
the thermography in a hyperthermia/MR hybrid system validation in an
dose of 70 Gy. The acute hyperthermia-specific toxicity is ac-
anthropomorphous phantom. Int J Radiat Oncol Biol Phys 2005;61:
ceptable to the patients and, in every case, reversible. No
in press.
long-term toxicity can be addressed to hyperthermia. There-
8. Hanks GE, Lu JD, Machtay M, et al. RTOG protocol 92-02: a phase III trial of
the use of long term total androgen suppression following neoadjuvant
fore, hyperthermia might increase efficacy, but is not increas-
hormonal cytoreduction and radiotherapy in locally advanced carcinoma of
ing toxicity.
the prostate. Int J Radiat Oncol Biol Phys 2000;48:Suppl:112.
In a study including 26 patients, van Vulpen et al. [26]
9. Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of
hyperthermia. Crit Rev Oncol Hematol 2002;43:3356.
added either interstitial or regional hyperthermia. They found
10. Lawton CA. Hormones and radiation therapy in locally advanced adenocar-
after a shorter observation time a 3-year biochemical con-
cinoma of the prostate. Semin Radiat Oncol 2003;13:14151.
trol of 70%, which is fairly in agreement with our data (see
11. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Ra-
Figure 1). Anscher et al. [2] performed an earlier study in 18
diation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential
benefit of androgen suppression following standard radiation therapy for
patients adding regional hyperthermia to a standard radio-
unfavourable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol
therapy regimen. The 3-year biochemical control was only
Phys 2001;49:93746.
40
Strahlenther Onkol 2005 · No. 1 © Urban & Vogel
Tilly W, et al. Hyperthermia and Definitive Radiotherapy in Prostate Cancer
12. Lerner SE, Blute ML, Zincke H. Extended experience with radical prostatec-
25. Van der Zee J, Gonzalez Gonzales D, van Rhoon GC, et al. Comparison of
tomy for clinical stage T3 prostate cancer: outcome and contemporary mor-
radiotherapy alone with radiotherapy plus hyperthermia in locally advanced
bidity. J Urol 1995;154:144752.
pelvic tumors: a prospective, randomised, multicentre trial. Lancet 2000;
13. Martin T, Baltas D, Kurek R, et al. 3-D conformal HDR brachytherapy as
355:111925.
monotherapy for localized prostate cancer. A pilot study. Strahlenther
26. Van Vulpen M, De Leeuw AAC, Raaymakers BW, et al. Radiotherapy and hy-
Onkol 2004;180:22532.
perthermia in the treatment of patients with locally advanced prostate
14. Mayer R, Pummer K, Quehenberger F, et al. Analysis of competing risk pa-
cancer: preliminary results. BJU International 2004:93;3641.
rameters in irradiated prostate cancer patients. Strahlenther Onkol 2003;
27. Vernon C, Hand JW, Field SB, et al. Radiotherapy with or without hyperther-
179:4526.
mia in the treatment of superficial localized breast cancer: results from five
15. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose
randomized controlled trials. Int J Radiat Oncol Biol Phys 1996;35:73144.
response: Results of the M.D. Anderson phase III randomized trial. Int J
28. Wachter-Gerstner N, Wachter S, Goldner G, et al. Biochemical response after
Radiat Oncol Biol Phys 2002;53:1097105.
3-D conformal radiotherapy of localized prostate cancer to a total dose of
16. Overgaard J, Gonzalez-Gonzalez D, Hulshof MC, et al. Randomised trial of
66 Gy. Strahlenther Onkol 2002;178:5427.
hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malig-
29. Wust P, Gellermann J, Harder C, et al. Rationale for using invasive thermom-
nant melanoma. Lancet 1995;345:5403.
etry for regional hyperthermia of pelvic tumors. Int J Radiat Oncol Biol Phys
17. Rau B, Wust P, Tilly W, et al. Preoperative radio-chemotherapy in locally
1998;41:112937.
advanced recurrent rectal cancer: regional radiofrequency hyperthermia
30. Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in a combined
correlates with clinical parameters. Int J Radiat Oncol Biol Phys 2000;
treatment of cancer. Lancet Oncol 2002;3:48797.
48:38191.
31. Zagars GK, Pollack A, Smith LG. Conventional external-beam radiation ther-
18. Rubin P, Constine L, Fajardo L. Overview: late effects of normal tissues
apy alone or with androgen ablation for clinical stage III (T3, Nx/N0, M0)
(LENT) scoring system. Int J Radiat Oncol Biol Phys 1995;31:10412.
adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1999;44:
19. Skinner EC, Glode LM. High-risk localized prostate cancer: primary surgery
80919.
and adjuvant therapy. Urol Oncol 2003;21:21927.
32. Zietman AL, Coen JJ, Dallow KC, et al. The treatment of prostate cancer by
20. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after
conventional therapy: an analysis of long-term outcome. Int J Radiat Oncol
conformal radiotherapy of prostate cancer (I): mutivariate analysis and
Biol Phys 1995;32:28792.
dose-response. Int J Radiat Oncol Biol Phys 2000;47:10313.
21. Sreenivasa G, Gellermann J, Rau B, et al. Clinical application of the hyper-
thermia treatment planning system HyperPlan comparison of algorithms
Address for Correspondence
and clinical observables. Int J Radiat Oncol Biol Phys 2003;55:40719.
Professor Peter Wust, MD
22. Storey MR, Pollack A, Zagars G, et al. Complications from radiotherapy dose
Department of Radiation Medicine
escalation in prostate cancer: preliminary results of a randomized trial. Int
J Radiat Oncol Biol Phys 2000;48:63542.
Charité Medical School Campus Virchow-Klinikum
23. Tilly W, Wust P, Rau B, et al. Temperature data and specific absorption rates
Augustenburger Platz 1
in pelvic tumours: predictive factors and correlations. Int J Hyperthermia
13353 Berlin
2001;17:17288.
Germany
24. Van den Ouden D, Hop WC, Schroder FH. Progression and survival of patients
Phone (+49/30) 450-557202, Fax -557979
with locally advanced prostate cancer (T3) treated with radical prostatec-
e-mail: peter.wust@charite.de
tomy as monotherapy. J Urol 1998;160:13927.
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