Intensity modulated radiotherapy for localized prostate cancer: rigid compliance to dose-volume constraints as a warranty of acceptable toxicity?

Abstract

To report the toxicity after intensity modulated radiotherapy (IMRT) for patients with localized prostate cancer, as a sole treatment or after radical prostatectomy.
Between August 2001 and December 2003, 132 patients with prostate cancer were treated with IMRT and 125 were evaluable to acute and late toxicity analysis, after a minimum follow-up time of one year. Clinical and treatment data, including normal tissue dose-volume histogram (DVH) constraints, were reviewed. Gastro-intestinal (GI) and genito-urinary (GU) signs and symptoms were evaluated according to the Radiation Therapy Oncology Group (RTOG) toxicity scales. Median prescribed dose was 76 Gy. Median follow-up time was of 26.1 months.
From the 125 patients, 73 (58.4%) presented acute Grade 1 or Grade 2 GI and 97 (77.2%) presented acute Grade 1 or Grade 2 GU toxicity. Grade 3 GI acute toxicity occurred in only 2 patients (1.6%) and Grade 3 GU acute toxicity in only 3 patients (2.4%). Regarding Grade 1 and 2 late toxicity, 26 patients (20.8%) and 21 patients (16.8%) presented GI and GU toxicity, respectively. Grade 2 GI late toxicity occurred in 6 patients (4.8%) and Grade 2 GU late toxicity in 4 patients (3.2%). None patient presented any Grade 3 or higher late toxicity. Non-conformity to DVH constraints occurred in only 11.2% of treatment plans. On univariate analysis, no significant risk factor was identified for Grade 2 GI late toxicity, but mean dose delivered to the PTV was associated to higher Grade 2 GU late toxicity (p = 0.042).
IMRT is a well tolerable technique for routine treatment of localized prostate cancer, with short and medium-term acceptable toxicity profiles. According to the data presented here, rigid compliance to DHV constraints might prevent higher incidences of normal tissue complication.

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BioMed Central
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Radiation Oncology
Open Access
Short report
Intensity modulated radiotherapy for localized prostate cancer:
rigid compliance to dose-volume constraints as a warranty of
acceptable toxicity?
Michael J Chen*1, Eduardo Weltman1,2, Rodrigo M Hanriot1, Fábio P Luz1,
Paulo J Cecílio1, José C da Cruz1, Frederico R Moreira3, Adriana S Santos1,
Lidiane C Martins1 and Wladmir Nadalin1,2
Address: 1Department of Radiation Oncology, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/701 – Sao Paulo, Brazil, 2Department of
Radiation Oncology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255 – Sao
Paulo, Brazil and 3Instituto Israelita de Ensino e Pesquisa, Av. Albert Einstein, 627/701 – Sao Paulo, Brazil
Email: Michael J Chen* - michael.chen@ig.com.br; Eduardo Weltman - eweltman@einstein.br; Rodrigo M Hanriot - hanriot@einstein.br;
Fábio P Luz - michaelchen@einstein.br; Paulo J Cecílio - josecarlosc@einstein.br; José C da Cruz - josecarlosc@einstein.br;
Frederico R Moreira - fredericorm@einstein.br; Adriana S Santos - michaelchen@einstein.br; Lidiane C Martins - michaelchen@einstein.br;
Wladmir Nadalin - wladimirn@einstein.br
* Corresponding author
Abstract
Background: To report the toxicity after intensity modulated radiotherapy (IMRT) for patients
with localized prostate cancer, as a sole treatment or after radical prostatectomy.
Methods: Between August 2001 and December 2003, 132 patients with prostate cancer were
treated with IMRT and 125 were evaluable to acute and late toxicity analysis, after a minimum
follow-up time of one year. Clinical and treatment data, including normal tissue dose-volume
histogram (DVH) constraints, were reviewed. Gastro-intestinal (GI) and genito-urinary (GU) signs
and symptoms were evaluated according to the Radiation Therapy Oncology Group (RTOG)
toxicity scales. Median prescribed dose was 76 Gy. Median follow-up time was of 26.1 months.
Results: From the 125 patients, 73 (58.4%) presented acute Grade 1 or Grade 2 GI and 97 (77.2%)
presented acute Grade 1 or Grade 2 GU toxicity. Grade 3 GI acute toxicity occurred in only 2
patients (1.6%) and Grade 3 GU acute toxicity in only 3 patients (2.4%). Regarding Grade 1 and 2
late toxicity, 26 patients (20.8%) and 21 patients (16.8%) presented GI and GU toxicity,
respectively. Grade 2 GI late toxicity occurred in 6 patients (4.8%) and Grade 2 GU late toxicity in
4 patients (3.2%). None patient presented any Grade 3 or higher late toxicity. Non-conformity to
DVH constraints occurred in only 11.2% of treatment plans. On univariate analysis, no significant
risk factor was identified for Grade 2 GI late toxicity, but mean dose delivered to the PTV was
associated to higher Grade 2 GU late toxicity (p = 0.042).
Conclusion: IMRT is a well tolerable technique for routine treatment of localized prostate cancer,
with short and medium-term acceptable toxicity profiles. According to the data presented here,
rigid compliance to DHV constraints might prevent higher incidences of normal tissue
complication.
Published: 15 January 2007
Radiation Oncology 2007, 2:6doi:10.1186/1748-717X-2-6
Received: 14 October 2006
Accepted: 15 January 2007
This article is available from: http://www.ro-journal.com/content/2/1/6
© 2007 Chen et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Background
External-beam radiotherapy is the most utilized radio-
therapy modality for treatment of localized prostate can-
cer and local control is related to delivered dose [1-4].
Three-dimensional conformal radiotherapy [3D-CRT) is a
technique used to achieve this "dose escalation", but is
limited by the consequent risk of excessive rectal and
bladder complications [5,6].
Recently, the development of the intensity modulated
radiotherapy (IMRT) has been shown to be a reasonable
option to deliver higher radiation doses to prostate cancer
patients, with acceptable low rates of complications [7-9].
This study presents a retrospective evaluation of the initial
toxicity following the technical implementation of IMRT,
for treatment of localized prostate cancer patients. Clini-
cal and treatment related factors, including normal tissue
dose-volume histogram (DVH) constraints, were ana-
lyzed as possible risk factors for gastro-intestinal (GI) or
genito-urinary (GU) toxicity.
Methods
Selection of patients
Between August 2001 and December 2003, 132 consecu-
tive patients with prostate cancer were treated with IMRT.
From this patient group, 125 patients with a minimum
follow-up time of one year were considered evaluable to
acute and late toxicity analysis, as they were staged as with
localized disease and treated with IMRT as a sole treat-
ment, or in adjuvant manner, after surgical resection, to
the prostatic bed. Data regarding patient clinical and stag-
ing characteristics are shown on Table 1.
At admission, all patients had a positive histologic diag-
nosis of prostate cancer, graded according to Gleason
Score specification [10]. The 1997 American Joint Com-
mission on Cancer (AJCC) staging system [11] was uti-
lized and, specifically for operated patients, surgical
staging was done based on anatomic-pathological infor-
mation. Also, patients were stratified into prognostic
groups, according to criteria adapted from the data pub-
lished by Bolla et al. [12]. This stratification was also used
as an "in house" treatment guideline to IMRT dose levels
prescription (Table 2).
There was no restriction concerning hormone therapy and
the usage was determined by physician's discretion, as an
adjunct treatment to reduce prostatic volume or to "high
risk" patients.
Radiotherapy planning
At the moment of the IMRT technique implantation, a
class solution was established to be applied to all treat-
ment plans. Before effective IMRT delivery, all patients
were submitted to a pelvic CT simulation (CT-Sim) proce-
dure. Using the CT-Sim data, and for planning calcula-
tion, the following structures were contoured: femoral
heads, prostate and seminal vesicles, bladder and rectum
(entirely contoured from the anal canal to rectum-sig-
moid transition). The clinical target volume (CTV) corre-
sponded to prostate and the entire seminal vesicles. For
operated patients, (i.e.: after radical prostatectomy), the
CTV corresponded to the prostatic and seminal vesicles
bed, according to pre-operative CT or MRI scans. Margins
of 0.6 cm (posterior) and 1.0 cm (cranial, caudal, anterior
and laterals) were applied to the CTV when defining the
planning target volume (PTV).
All patients were treated at a Clinac 23-EX® linear acceler-
ator (Varian Medical Systems, Palo Alto, CA, USA), utiliz-
ing a dynamic IMRT technique ("sliding window"), with
a 5 isocentric coplanar beam arrangement and photons
with beam energy of 15 MVs. Inverse planning was calcu-
lated using the Helios® software (Varian Medical Systems,
Palo Alto, CA, USA), according to pre-established DHV
constraints and treatment dose specifications (Table 3,
based on previously published data [5-7,13]). Daily pre-
scribed dose was of 200 cGy.
Immobilization and target localization's verification were
regularly done utilizing a customized anatomical pelvic
mold and weekly isocenter's anterior-posterior and later-
als radiographs. Furthermore, all patients were ordered to
evacuate before and keep the bladder full during the CT-
Sim and all the daily applications, according to a proper
routine. Treatment started effectively only after plan
Table 1: Patients characteristics
Patients number
Age:
≤ 65
> 65 e ≤ 75
> 75
Highest serum PSA level (ng/ml):
≤ 10
> 10 e < 20
≥20
Stage (AJCC 1997):
T2aN0M0 or lower
T2bN0M0 or higher
Gleason Score:
≤ 6
7
8 – 10
Exclusive radiotherapy treatment
Post-operative radiotherapy:
adjuvant treatment
PSA-relapse rescue
Neo-adjuvant hormonal therapy
43 (34.4%)
57 (45.6%)
25 (20.0%)
77 (61.6%)
31 (24.8%)
17 (13.6%)
88 (70.4%)
37 (29.6%)
63 (50.4%)
49 (39.2%)
13 (10.4%)
90 (72.0%)
16 (12.8)
19 (15.2%)
57 (45.6%)

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approval by both the radiation oncologist and the medi-
cal physicist and after "quality assurance" testing, also
according to a proper routine.
All IMRT treatments were delivered successfully and
median follow-up time was 26.1 months (range: 12.1 to
42.2 months). The median prescribed dose was 76 Gy,
(range: 68 to 78 Gy), and the mean administered dose was
76.5 Gy, with median maximum and minimum doses of
81.8 Gy and 72 Gy, respectively.
Toxicity evaluation and follow-up
Data collection was done by retrospective review of med-
ical files. Also, for each patient, a GI and GU toxicity
assessment profile was created by the time of the IMRT
treatment. Data obtained included relevant previous med-
ical history (i.e.: diabetes, hypertension, previous surgery
and ano-rectal or urinary diseases), medications and GI
and GU symptoms. During treatment, all patients were
evaluated on a weekly basis, regarding any new or worsen-
ing symptoms. Afterwards, patients were suggested to
return to consultation with the radiation oncologist regu-
larly, for clinical and digital rectal evaluation, which also
included appraisal of GI and GU symptoms and serum
PSA levels.
Acute toxicity was defined as the appearance or worsening
of any GI or GU symptoms during treatment time or until
after 6 months of it. Late toxicity was defined the same
way, but after the 6th month of follow-up time. Either
acute or late toxicity grading was scored based on the
respective toxicity scales proposed by the Radiation Ther-
apy Oncology Group (RTOG) [14-16].
Statistical analysis
Univariate exact logistic regression [17] was applied to test
the association between any potential predictor and
RTOG Grade 2 toxicity or higher. All significance proba-
bilities (p values) presented are two-sided and values
lower than 0,05 were considered statistically significant.
"Odds ratios" and their respective 95% confidence inter-
vals were estimated. The Logxact 6.3® software (Cytel Soft-
ware Corporation, Cambridge, MA, USA) was utilized in
all the statistical analysis.
Table 3: Dose-volume histogram and treatment volumes constraints:
StructureMaximum Volume/Maximum Total Dose
Bladder
Rectum
≤ 55%/≥ 47 Gy
≤ 55%/≥ 47 Gy
≤ 10%/≥ 75 Gy
Maximum dose: 50 Gy
Maximum dose ≤ 20% of prescription dose to PTV
Minimum dose of 70 Gy if prescription dose of 72 Gy to PTV
Minimum dose of 72 Gy if prescription dose of 74 Gy to PTV
Minimum dose of 74 Gy if prescription dose of 76 Gy to PTV
Minimum dose of 76 Gy if prescription dose of 78 Gy to PTV
PTV's coverage to a minimum of 95% of the entire volume
≤ 30%/≥ 70 Gy
≤ 40%/≥ 65 Gy
Maximum dose: 82 Gy
Maximum dose: 82 Gy
≤ 25%/≥ 70 Gy
Femoral head
PTV
PTV: planning target volume
Table 2: Prognostic groups stratification and radiation doses prescriptions:
Prognostic groups§
Low RiskIntermediate RiskHigh Risk
Highest serum PSA level (ng/ml)
≤ 10
AND
≤ T2aN0M0
AND
≤ 6 (3 + 3)
> 10 e < 20
OR
T2bN0M0
OR
7
≥ 20
OR
≥ T3N0M0
OR
≥ 7
OR 2 Intermediate Risk factors associated
57 (45.6%)
31/57
25/57
Stage (AJCC 1997)
Gleason Score
Patients number*
Neo-adjuvant hormonal therapy
Post-operative therapy
38 (30.4%)
12/38
6/38
28 (22.4%)
14/28
4/28
§ Suggested radiation dose prescription: 72 Gy to post-operative radiotherapy, 74 Gy to low risk, 76 Gy to intermediate risk and 78 Gy to high risk
patients, respectively PTV: planning target volume
* 2 patients could not have their risks assessed

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Results
Of all the patients, 60.0% (75 patients) and 80.0% (100
patients) presented some grade of acute GI or GU toxicity,
respectively. Acute Grade 3 GI toxicity occurred in 2
patients (1.6%, a case of diarrhea requiring parenteral
support and a case of severe blood discharge necessitating
sanitary pads), and acute Grade 3 GU toxicity occurred in
3 patients (2.4%, all of them with frequency of urination
or nocturia of more than every hour, with urgency, dysuria
and irritative symptoms). For late toxicity, of all the
patients, 20.8% (26 patients) presented some grade of late
GI toxicity and 16.8% (21 patients) presented some grade
of GU toxicity (Table 4). Late Grade 2 GI toxicity occurred
in 6 patients (4.8%, a case of episodes of moderate
diarrhea but frequently requiring parenteral support, two
cases of frequent episodes of moderate diarrhea and colic
and three cases of frequent episodes of intermittent bleed-
ing, but requiring minor non-surgical procedures). Late
Grade 2 GU toxicity occurred in 4 patients (3.2%, all of
them with moderate frequency with urgency, dysuria and
irritative symptoms).
Treatment plans were able to be performed with a high
level of compliance to DVH constraints and for only 14 of
the 125 patients (11.2% of the cases) there was some
degree of non-conformity, with doses 3% higher than the
acceptable value for each constraint. Regarding this, viola-
tions were more frequent when patients were prescribed
to lower dose levels, with 7 cases (16.1%) out of the 44
patients receiving prescription doses of 74 Gy, and at
"inferior" DVH constraints' levels (lower dose levels and
bigger volumes). On the contrary, violations were rare for
the "superior" DVH constraints' levels (higher dose levels
and smaller volumes) and, for each organ (i.e.: bladder
and rectum) and constraint, level of compliance was
above 90% (Table 5).
By performing an evaluation of possible factors related to
acute toxicity, it was observed that a patient's personal his-
tory of systemic arterial hypertension was a significant risk
factor for Grade 2 or higher GI acute toxicity (p = 0.042).
However, for Grade 2 or higher GU acute toxicity, signifi-
cant risk factors were both minimum and mean PTV doses
Table 5: Compliance to DVH constraints as to different prescription dose:
Prescription doses levels
D74 (n = 44 patients)D76 (n = 40 patients)D78 (n = 41 patients)
Rectum Bladder Rectum Bladder RectumBladder
D55 (Gy)
D30 (Gy)
D25 (Gy)
D10 (Gy)
Dmax (Gy)
93.2% (41/44)
Not evaluated
97.7% (43/44)
100%
100%
93.2% (41/44)
100%
Not evaluated
Not evaluated
100%
90% (36/40)
Not evaluated
100%
100%
97.5% (39/40)
100%
100%
Not evaluated
Not evaluated
100%
95.1% (39/41)
Not evaluated
100%
100%
100%
100%
100%
Not evaluated
Not evaluated
100%
D74: doses up to 74 Gy; D76: doses from 74 to 76 Gy; D78: doses of 78 Gy; D55: dose at 55% of the volume (rectum or bladder); D30: dose at
30% of the volume (rectum or bladder); D25: dose at 25% of the volume (rectum or bladder); D10: dose at 10% of the volume (rectum or bladder);
Dmax: maximum dose (rectum or bladder)
Table 4: Acute and late gastro-intestinal (GI) and genito-urinary (GU) toxicities profiles:
Pre-treatmentAcute Late
GIGUGI GU GI GU
RTOG
G1
RTOG
G2
RTOG
G3
RTOG
G4/G5
3 (2.4 %)19 (15.2%) 54 (43.2%) 47 (37.6%) 20 (16.0%)17 (13.6%)
None2 (1.6%)19 (15.2%) 50 (40.0%)6 (4.8%)4 (3.2%)
None None2 (1.6%) 3 (2.4%)None None
NoneNone None NoneNone None
RTOG: Radiation Therapy Oncology Group

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(p = 0.049 and 0.042, respectively), and also the patient's
surgical "status" when treated with RT, (if previously oper-
ated or not, p = 0.009) (Table 6).
No significant risk factor for GI Grade 2 or higher late tox-
icity was observed. Mean PTV doses correlated to GU
Grade 2 or higher late toxicity as a significant risk factor (p
= 0.042).
Results of local control, disease-free survival, PSA relapse-
free survival or even global survival were not assessed, at
the present study.
Discussion
IMRT raised to radiation oncologists a possibility of
tumour dose escalation without compromising doses to
normal tissues. Since an initial publication by Zelefsky et
al. [9], clinical utilization of this technique has been dem-
onstrated to be safe, with acute and late rectal and bladder
complications incidences at "acceptable" levels [8,18-21].
This report adds some information about routine usage of
dynamic IMRT technique, describing treatment complica-
tion frequencies, in a small, but consecutive sample of
localized prostate cancer patients. Results of late GI and
GU toxicities of about 15% (Grade 1) and lower than 5%
(Grade 2) published here are very comparable to what has
already been shown elsewhere [19,21], as well as the ele-
vated frequency of acute GI and GU toxicities, beyond
50%, but with rare cases of more severe complications
[18-20].
Although results might seem to be very similar, proposed
criteria to toxicity evaluation are very heterogeneous
among the different already published reports. This anal-
ysis, however, was conceived taking advantage of widely
used and very simple tools, which are the RTOG toxicities
scales, in order to make data here easily understandable.
An example is the report from Zelefsky et al. in which a
higher importance was given to rectal bleeding as a sign of
increased toxicity. Some of the bleeding complications
were scored as Grade 3, (0.5% versus 1.5% for Grade 2
symptoms frequency), due to necessity of transfusion or
laser cauterization procedures [19]. In the data demon-
strated here, however, of the total number of six patients
(4.8%) who presented GI Grade 2 late toxicity, only three
of them (2.4%) presented rectal bleeding which necessi-
tated laser cauterization procedures and all of them remit-
ted after treatment, neither evolving to obstruction nor to
bleeding requiring surgery (data not shown).
On univariate analysis it was not observed any significant
association between clinical factors or DVH constraints
and risk of GI late toxicity, which could predict a Grade 2
or higher index, as is usually described [5-7,22-24]. Fre-
quency of complications was certainly low enough and
there is no point to draw any precipitated conclusions
about predisposing factors to rectal and bladder toxicity.
A criticism to the data presented here could obviously be
the negative influence of a heterogeneous group and of
different treatment doses. These facts has certainly under-
powered the analysis, leading to the absence of more insti-
gating results.
Table 6: Univariate analysis of prognostic factors to grade 2 or higher acute and late gastro-intestinal (GI) and genito-urinary (GU)
toxicities:
P values
Variable acute GIacute GU late GI late GU
Surgical status: operated
Neo-adjuvant hormonal
therapy
Diabetes mellitus
Systemic Arterial
Hypertension
Dmean (Gy)
Dmax (Gy)
Dmin (Gy)
D55 (Gy)
D30 (Gy)
D25 (Gy)
D10 (Gy)
V47 (%)
V70 (%)
0.667
0.939
0.009
0.115
1.000
0.137
0.527
0.492
0.428
0.042
0.889
0.905
0.317
1.000
0.825
1.000
0.176
0.118
0.178
0.164
--
0.889
0.352
0.088
0.731
0.042
0.215
0.049
0.885
0.593
--
--
0.614
0.394
0.600
0.702
0.205
0.568
--
0.426
0.321
0.583
0.852
0.042
0.202
0.582
0.552
0.860
--
--
0.626
0.696
D55: dose at 55% of the volume (rectum or bladder); D30: dose at 30% of the volume (rectum or bladder); D25: dose at 25% of the volume
(rectum or bladder); D10: dose at 10% of the volume (rectum or bladder); Dmean: mean dose to PTV; Dmax: maximum dose to PTV; Dmin:
minimum dose to PTV; V47: volume receiving 47 Gy (rectum or bladder); V70: volume receiving 70 Gy (rectum or bladder)