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Prostate Cancer BJUI Mini Reviews - How Quality Influences the Clinical Outcome of External Beam Radiotherapy for Localized Prostate Cancer
Prostate Cancer BJUI Mini Reviews - How Quality Influences the Clinical Outcome of External Beam Radiotherapy for Localized Prostate Cancer | BJUI Mini Reviews - How Quality Influences the Clinical Outcome of External Beam Radiotherapy for Localized Prostate Cancer |
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BJUI Mini Reviews - This overview describes what the urologist should expect from radiation oncologists to obtain the optimum results for the patients.
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![©
2007 THE AUTHORS
944
JOURNAL COMPILATION
©
2007 BJU INTERNATIONAL | 101, 944–947 | doi:10.1111/j.1464-410X.2007.07346.x
How quality influences the clinical outcome of external
beam radiotherapy for localized prostate cancer
Marco van Vulpen, Uulke A. van der Heide and Jeroen R.J.A. van Moorselaar*
Department of Radiation-Oncology, University Medical Center Utrecht, Utrecht, and *Department of Urology, VU
University Medical Centre, Amsterdam, the Netherlands
Accepted for publication 14 September 2007
position of the prostate, and the use of
magnetic resonance imaging (MRI) in
delineation. Currently these are demands
on quality that should be incorporated in
each radiotherapy department. The use of
MRI in staging is also expected to improve
patient selection for EBRT. Furthermore,
an adequate radiation dose should be
delivered. In this overview we describe
what the urologist should expect from
radiation oncologists to obtain the optimum
results for the patients.
For the delivery of good-quality external
beam radiotherapy (EBRT) in localized
prostate cancer, under-dosage to the
peripheral zone (tumour) is one likely
cause of poor results. The quality is
improved by daily verification of the
INTRODUCTION
The clinical results of external beam
radiotherapy (EBRT) alone for localised
prostate cancer have been reported
extensively. For T1 and T2 tumours the
results of EBRT are estimated to be equal
to those from radical prostatectomy and
brachytherapy. The 10-year survival rates
are considered excellent, at 90–94% for
well-differentiated tumours and 45–67%
for poorly differentiated tumours [1].
However, the outcome of randomized trials is
considered more reliable to predict the ‘true’
treatment results. To our knowledge there is
only one randomized trial specifically on
localized tumours, where 70 Gy radiation
alone resulted in a 5-year survival of only
≈
78% [2]. Randomized trials have mainly
been conducted for locally advanced tumours,
questioning hormone therapy [3,4] or dose-
escalation [5,6]. These trials reported a 5-year
78% [2]. Randomized trials have mainly
been conducted for locally advanced tumours,
questioning hormone therapy [3,4] or dose-
escalation [5,6]. These trials reported a 5-year
survival of only
≈
60% in the RT-alone arm [3].
When assessing more closely the data from
the randomized trials, it seems that in most
studies the relapse or survival curves start
with an overlap of both curves; the curves
only begin to separate after a few years [2–5].
In these trials, 20–30% of patients have
already had failure in the first few years
of follow-up. There was no gain for the
experimental arm because of a more
substantial failure in the RT-alone arm.
Reasons for these failures can be divided into
staging errors, where patients in whom the
treatment failed already had metastases, or
into RT delivery errors, where the prostate was
not adequately dosed by the radiation (an
‘anatomical miss’). If both staging errors and
anatomical misses are reduced, a significant
improvement of clinical outcome can be
expected.
In prostate cancer, randomized trials take a
long time before producing results. Because
of many technical improvements, both
staging accuracy and the accuracy of
radiation delivery have developed rapidly in
recent years. Therefore it is likely that the
outcome of current treatments already differs
from the outcome reported in these
randomized trials. The question arises as to
how quality in EBRT for localised prostate
cancer influences the clinical outcome, or
stated differently; what can urologists
currently expect from radiation oncologists to
ensure optimum treatment results for their
patients. In this review we present an
overview of previous reports to try to answer
this question. There was no report that
specifically addressed this question. As quality
is a broad concept, here we chose only to
discuss the most relevant topics, i.e. staging
errors, anatomical misses and the required
radiation dose.
STAGING ERRORS
Locally advanced tumours are known to have
a poorer outcome than localized tumours. The
main cause for this is probably that these
patients usually have a higher tumour
volume, a higher PSA level and extracapsular
tumour extension, which probably causes
early dissemination. In patients with
metastases the quality of local EBRT will, of
course, not directly influence the outcome.
Underlying all studies reporting clinical
outcome is the specificity of TRUS and a DRE
to differentiate between localized (T1 and T2)
and locally advanced (T3) tumours. The
specificity of a DRE, together with plain TRUS,
is only 41% [7], and this explains why radical
prostatectomies are often incomplete [8].
Consequently, the clinical stages in the cited
studies, which mainly used TRUS for staging,
are less reliable. Some tumours were staged as
being localized while they were actually
locally advanced, and vice versa. Compared to
radical prostatectomy there is no final
pathology report after EBRT, and thus the
reason for poor results from EBRT cannot be
easily addressed.
The staging error in differentiating between
localized and locally advanced tumours is
especially important for the benefits of
adjuvant and neoadjuvant hormonal
treatment in T3 tumours [2–4]. Hormonal
therapy increases the 5-year overall survival
from 62% to 78% [3], and the 10-year
survival from 39% to 49% [4].
Another possible reason to explain the
outcome of EBRT is extracapsular tumour
extension. In (limited) T3 tumours after radical
prostatectomy, extracapsular extension is
>
2 mm in
≈
85% and
>
5 mm in
≈
15% of
patients [8]. Thus, given the relatively small
margins of EBRT around the prostate,
anatomical misses are to be expected in larger
T3 tumours.
QUALITY AND OUTCOME OF EBRT FOR PROSTATE CANCER
©
2007 THE AUTHORS
JOURNAL COMPILATION
©
2007 BJU INTERNATIONAL
945
ANATOMICAL MISSES
The uncertainties in radiation delivery have
been extensively described; the two
uncertainties that produce the largest
treatment errors are movement of the
prostate and delineation errors [9,10]. Both
might cause an anatomical miss.
The prostate moves from day to day; at the
time the cited randomized studies were
conducted there was only limited knowledge
about prostate translations and rotations. If
there was any verification of target position it
was by reference to the bony anatomy, and
only in the first treatment fractions. Currently
there is strong evidence showing that the
position of the prostate does not correlate
with the bony anatomy in the anterior-
posterior direction [11]. The mean uncorrected
systematic radiation error of the prostate
position is large, especially a 2.8-mm shift of
the prostate dorsally (towards the rectum)
occurs with a
SD
of 4.8 mm. Random errors in
this direction are on average 3.5 mm, again
towards the rectum [12]. There is also a time
trend, where the prostate is situated more
ventrally (towards the symphysis) at the start
of treatment, and gradually shifts
≈
1.5 mm
towards the rectum during treatment (Fig. 1)
[12]. This means that with no verification of
prostate position, the peripheral zone (where
most of the tumours are located [13]) shifts
out of the radiation field in most treatments,
even if large radiation margins are used. The
same is true for the apex, which moves
caudally during treatment with a
SD
of
2.9 mm and a random error of 2.3 mm [12].
These are strong reasons for poor results from
EBRT. There is published confirmation, where
patients with an initially distended rectum are
shown to have a greater risk of failure [14].
The main reason for movement of the
prostate in the anterior-posterior direction is
an altered rectum, filling during therapy by
feces or gas [14]. Hence, an empty rectum is
very important at the time of treatment
planning, and should be ensured during daily
treatment delivery, to improve local control in
EBRT for prostate cancer [14]. Efforts are
made to modify rectal filling, e.g. by diet or
medication, although to date the evidence for
this approach remains limited. Therefore, the
proper verification of position will always be
necessary. This stresses the need for image-
guided RT, e.g. by fiducial markers or cone-
beam CT. The current consensus is that the
position of the prostate should be verified in
EBRT during the entire treatment period.
There are many different ways of verification,
e.g. gold fiducial markers, TRUS or cone-beam
CT. Using gold-fiducial markers in 452
patients, with daily verification, our
systematic positioning error was reduced to
0.2 mm in all directions, with a
SD
of 0.8 mm
[12]. Although there are no long-term clinical
results yet, toxicity was limited, with
<
1%
acute and late grade 3 or 4 bladder or rectal
toxicity (Lips, submitted).
The delineation of the prostate is the basis of
the EBRT plan; if the prostate is not correctly
delineated, e.g. if a tumour-bearing part
of the prostate is missed, the delivery of
radiation is less likely to be successful. The
commonly used imaging method to delineate
the prostate is CT. Unfortunately, the prostate,
and particularly the apex, is hardly visible on
CT, due to poor soft-tissue contrast. The
tumour within the prostate is invisible. Also,
the borders between prostate and rectum are
not clearly visible, mostly in the caudal parts
of the prostate. MRI has excellent soft-tissue
contrast and therefore seems preferable for
delineation. CT-derived prostate volumes are
larger than MRI-derived volumes, especially
toward the seminal vesicles and the apex of
the prostate [10]. However, it is likely that
there are many individual cases where the
sole use of CT resulted in an anatomical miss
of the tumour itself, or of the apex, where
most of the tumour is situated [13]. In the
study of Milosevic
et al.
[15], if only CT had
been used, the apex would have been under-
dosed in 17% of the patients [15]. Using MRI
for delineation reduces the amount of rectal
wall irradiated, and probably would decrease
rectal and urological complications. MRI
can also be used to visualize the tumour
within the prostate, and visualize the apex.
Furthermore, the specificity for differentiating
between T2 and T3 is higher than with TRUS,
with a specificity of up to 97% when using
dynamic contrast-enhanced MRI [16].
Currently several consensus articles have
been published on delineating the prostate
and its implications for treatment planning
[17]. CT delineation was the starting point in
all the clinical trials cited above, and this
might partly explain the disappointing results
of EBRT.
REQUIRED RADIATION DOSE
As recurrence after treatment with
conventional RT used to be common, the
hypothesis was proposed that prostate cancer
needs a higher radiation dose. In several
randomized trials, conventional radiation
doses of up to 70 Gy were compared to higher
doses of
≈
80 Gy [5,6,18]. Freedom from
biochemical relapse was significantly better in
the high-dose arm than in the conventional
dose-arm, with increase in the 5-year value
from 15–30% to 60–80% [5,6,18]. This gain is
very impressive considering that the
peripheral zone will have been under-dosed in
these trials, which lacked the required daily
verification of position, as described above.
THE FUTURE
Currently the clinical outcome of EBRT is
difficult to interpret; if there is a biochemical
recurrence it is not clear whether there is a
local relapse (a result of sub-optimal
irradiation) or disseminated disease (not
related to EBRT). At present there is no easy
way to reliably find or exclude a local
recurrence; this will be necessary to gain
knowledge about the effect of radiation on
the tumour, the probability of tumour control.
Currently new MRI techniques are being
developed which are expected to identify local
recurrences in the future; these new
techniques are already used for biological (or
functional) imaging. Biological characteristics
are considered more important for RT choices
than merely anatomical imaging [19], and
especially the imaging of hypoxia is expected
to be of clinical value [20]. Another important
FIG. 1.
The trend in prostate position in the vertical
direction (towards the rectum) during the 35
radiation fractions (452 patients). The left upper
corner of the picture shows two MRI scans of the
same patient. The left MRI is before the first
treatment and the right during treatment. If the
planning target volume is the black line, it is
apparent that the peripheral zone would shift
outside the treatment volume.
3
2
V
e
rt
ic
a
l
d
e
v
ia
t
io
n
(t
ow
a
rd
s
r
e
c
tu
m
)
, m
m
1
0
0 5 10 15
Fraction number
20 25 30 35
VAN VULPEN
ET AL.
©
2007 THE AUTHORS
946
JOURNAL COMPILATION
©
2007 BJU INTERNATIONAL
biological characteristic is PSA kinetics. A
higher PSA doubling time will probably mean
faster cell doubling, a higher risk of metastasis
and possibly more radio-resistance.
The technical aspects of delivery have also
changed, from conventional and conformal
RT to intensity-modulated (IM) RT. With IMRT
the radiation beam can be shaped to avoid the
organs at risk, e.g. bladder or rectum. This will
probably not directly result in a better
outcome, only in reducing toxicity. In the
future IMRT will be required for a the safety of
further dose increases. Another way to enable
further dose increases is to combine EBRT
with brachytherapy, as with brachytherapy it
is possible to deliver a very high local dose.
The future of prostate RT will be an
individualized dose distribution with a
heterogeneous dose based on biological local
tumour characteristics, termed image-guided
RT, and used to improve the daily anatomical
localization of the prostate.
DISCUSSION
What can urologists currently expect from
radiation oncologists to optimise the outcome
for their patients? For the quality of delivery
of EBRT in men with local prostate cancer,
severe under-dosage to the peripheral zone
(tumour) has partly caused the poor results of
EBRT. Quality is improved by daily verification
of the position of the prostate and the use of
MRI in delineation; these quality demands
should be incorporated in each RT
department.
For localized prostate cancer (T1,2) recent
reports suggest that EBRT might have poorer
long-term results than prostatectomy [21],
possibly explained by staging errors and
anatomical misses. In a large study the
outcome of EBRT was shown to be
significantly worse when there were
inadequate radiation doses (
<
72 Gy) than for
prostatectomy, brachytherapy or high-dose
EBRT (
>
72 Gy) [22].
For optimal results from EBRT of locally
advanced tumours, higher doses (
≥
78 Gy) are
needed, and in selected cases the addition of
hormonal therapy. However, randomized
studies of dose escalation and hormonal
therapy were conducted without the required
quality of delivery described above. It is not
clear whether the clinical improvements from
adding hormonal therapy or increasing the
dose compensates for the poor delivery of RT.
Quality of life and toxicity are valid factors if
these trials were repeated using current and
optimum RT standards. However, in prostate
cancer randomized trials take a long time
before producing results, and by that time the
results might be outdated.
CONFLICT OF INTEREST
None declared.
REFERENCES
1
Lu-Yao GL, Yao SL.
Population-based
study of long-term survival in patients
with clinically localised prostate cancer.
Lancet
1997;
349
: 906–10
2
D’Amico AV, Manola J, Loffredo M,
Renshaw AA, DellaCroce A, Kantoff
PW.
6-month androgen suppression plus
radiation therapy vs Radiation Therapy
alone for patients with clinically localized
prostate cancer: a randomized controlled
trial.
JAMA
2004;
292
: 821–7
3
Bolla M, Collette L, Blank L
et al.
Long-
term results with immediate androgen
suppression and external irradiation in
patients with locally advanced prostate
cancer (an EORTC study): a phase III
randomised trial.
Lancet
2002;
360
: 103–
6
4
Pilepich MV, Winter K, Lawton CA
et al.
Androgen suppression adjuvant to
definitive radiotherapy in prostate
carcinoma – long-term results of phase III
RTOG 85–31.
Int J Radiat Oncol Biol Phys
2005;
61
: 1285–90
5
Peeters ST, Heemsbergen WD, Koper PC
et al.
Dose–response in radiotherapy for
localized prostate cancer. results of the
Dutch multicenter randomized phase III
trial comparing 68 Gy of radiotherapy
with 78 Gy.
J Clin Oncol
2006;
24
: 1990–6
6
Pollack A, Zagars GK, Antolak JA,
Kuban DA, Rosen II.
Prostate biopsy
status and PSA nadir level as early
surrogates for treatment failure: analysis
of a prostate cancer randomized radiation
dose escalation trial.
Int J Radiat Oncol
Biol Phys
2002;
54
: 677–85
7
Hsu CY, Joniau S, Oyen R, Roskams T,
Van Poppel H.
Detection of clinical
unilateral T3a prostate cancer – by digital
rectal examination or transrectal
ultrasonography?
BJU Int
2006;
98
: 982–
5
8
Teh BS, Bastasch MD, Mai WY, Butler
EB, Wheeler TM.
Predictors of
extracapsular extension and its radial
distance in prostate cancer: implications
for prostate IMRT, brachytherapy, and
surgery.
Cancer J
2003;
9
: 454–60
9
Dehnad H, Nederveen AJ, van Der Heide
UA, Van Moorselaar RJ, Hofman P,
Lagendijk JJ.
Clinical feasibility study for
the use of implanted gold seeds in the
prostate as reliable positioning markers
during megavoltage irradiation.
Radiother Oncol
2003;
67
: 295–302
10
Rasch C, Barillot I, Remeijer P, Touw A,
van Herk M, Lebesque JV.
Definition of
the prostate in CT and MRI. a multi-
observer study.
Int J Radiat Oncol Biol
Phys
1999;
43
: 57–66
11
Nederveen AJ, Dehnad H, van Der Heide
UA, Van Moorselaar RJ, Hofman P,
Lagendijk JJ.
Comparison of
megavoltage position verification for
prostate irradiation based on bony
anatomy and implanted fiducials.
Radiother Oncol
2003;
68
: 81–8
12
Van der Heide UA, Dehnad H, Hofman
P, Kotte ANTJ, Lagendijk JJW, Van
Vulpen M.
Analysis of fiducial marker
based position verification in the
intensity-modulated radiotherapy of
patients with prostate cancer.
Radioth
Onc
2007;
82
: 38–45
13
Chen ME, Johnston DA, Tang K,
Babaian RJ, Troncoso P.
Detailed
mapping of prostate carcinoma foci:
biopsy strategy implications.
Cancer
2000;
89
: 1800–9
14
De Crevoisier R, Tucker SL, Dong L
et al.
Increased risk of biochemical and local
failure in patients with distended rectum
on the planning CT for prostate cancer
radiotherapy.
Int J Radiat Oncol Biol Phys
2005;
62
: 965–73
15
Milosevic M, Voruganti S, Blend R
et al.
Magnetic resonance imaging (MRI) for
localization of the prostatic apex:
comparison to computed tomography
(CT) and urethrography.
Radiother Oncol
1998;
47
: 277–84
16
Futterer JJ, Engelbrecht MR, Huisman
HJ
et al.
Staging prostate cancer with
dynamic contrast-enhanced endorectal
MR imaging prior to radical
prostatectomy: experienced versus less
experienced readers.
Radiology
2005;
237
: 541–9
17
Villeirs GML, Verstraete K, De Neve WJ,
De Meerleer GO.
Magnetic resonance
imaging anatomy of the prostate
and periprostatic area: a guide for
QUALITY AND OUTCOME OF EBRT FOR PROSTATE CANCER
radiotherapists.
Radiother Oncol
2005;
76
: 99–106
18
Zietman AL, DeSilvio ML, Slater JD
et al.
Comparison of conventional-dose vs
high-dose conformal radiation therapy in
clinically localized adenocarcinoma of the
prostate: a randomized controlled trial.
JAMA
2005;
294
: 1233–9
19
Ling CC, Humm J, Larson S
et al.
Towards
multidimensional radiotherapy (MD-CRT).
biological imaging and biological
conformality.
Int J Radiat Oncol Biol Phys
2000;
47
: 551–60
20
Nahum AE, Movsas B, Horwitz EM,
Stobbe CC, Chapman JD.
Incorporating
clinical measurements of hypoxia into
tumor local control modeling of prostate
cancer: implications for the alpha/beta
ratio.
Int J Radiat Oncol Biol Phys
2003;
57
: 391–401
21
Albertsen PC, Hanley JA, Penson DF,
Barrows G, Fine J.
13-year outcomes
FollowIng treatment for ClInically
localized prostate cancer In a population
based cohort.
J Urol
2007;
177
: 932–6
22
Kupelian PA, Potters L, Khuntia D
et al.
Radical prostatectomy, external beam
radiotherapy
<
72 Gy, external beam
radiotherapy
>
or
=
72 Gy, permanent
seed implantation, or combined seeds/
external beam radiotherapy for stage T1–
T2 prostate cancer.
Int J Radiat Oncol Biol
Phys
2004;
58
: 25–33
Correspondence: Marco Van Vulpen, UMC
Utrecht – Radiotherapy, Heidelberglaan 100
HP Q00.118 Utrecht, Utrecht 3584CX, the
Netherlands.
e-mail:
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Abbreviations:
(EB)RT
, (external beam)
radiotherapy;
IM
, intensity-modulated.](http://urotoday.com/images/stories/bjui_april2008cover.jpg)
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