Journal of Cancer Therapy, 2013, 4, 1452-1458
Published Online December 2013 (
Open Access JCT
Predictability and Management of OARs Toxicity in
Patients with Prostate Cancer Treated with High-Dose
Vincenzo Ravo1, Domenico Borrelli2, Sara Falivene3, Rossella Di Franco3, Matteo Muto2,
Angela Argenone1, Valentina Borzillo1, Fabrizio Cammarota1, Paolo Muto1
1Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”—IRCCS, Naples, Italy;
2Radiotherapy Emicenter, Naples, Italy; 3Radiotherapy of Second University of Naples, Naples, Italy.
Received November 7th, 2013; revised November 27th, 2013; accepted December 4th, 2013
Copyright © 2013 Vincenzo Ravo et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intellectual
property Vincenzo Ravo et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
Aim: To evaluate the predictability of toxicity analyzing the dose-volume histograms (DVHs) and to verify the effec-
tiveness of preventive measures limiting side toxicity considering the evolution of the radiation techniques for prostate
cancer treatment. Materials and Methods: 208 patients with localized prostate cancer were treated with exclusive ra-
diotherapy until 73.8 Gy (group A) or 79.2 Gy (group B) with the dose escalation technique. Preventive measures to
minimize the side effects were recommended in group B. Results: The assessment of genitourinary toxicity was similar
while gastrointestinal toxicity was better in group B. Valuating the treatment plans, we found that most of the patients
developing toxicity had “borderline” DVHs. Conclusion: Our analysis led to the establishment of a protocol for the
management of patients with “border-line” DVH.
Keywords: Toxicity; Radiotherapy; Prostate Cancer; Prevention
1. Introduction
Prostate cancer is the most common male cancer in in-
dustrialized countries and the diagnosis is made more
frequently in the initial stage. It plays an important role
in public health and in oncological clinical practice. The
therapeutic process for prostate cancer underwent a deep
change both in surgical management and in medical ap-
proach and above all in radiation therapy (RT) treatment,
reaching high levels of efficiency and improvement of
quality of life (QoL) of patients (pts). The evolution of
the radiation techniques has made it possible to conform
radiation beams looking at the target and saving adjacent
organs at risk (OARs) so this has allowed treatments in
the so-called “dose escalation”. The increased dose has
enabled more and more curative treatments, resulting, at
the same time, in an increase in side effects to OARs as
rectum and bladder [1,2]. The primary aim of our study
was to evaluate if it is possible to predict the toxicity to
OARs analyzing the dose-volume histograms (DVHs) in
pts treated with RT alone for localized prostate cancer
[3-8]. Secondary objective of our study was to evaluate
the effectiveness of preventive measures to limit as much
as possible gastrointestinal and urinary side effects.
2. Materials and Methods
From January to December 2010, 208 pts with localized
prostate cancer were treated with exclusive RT. The pa-
tients mean age was 66 years (range 49 - 83) and the
Gleason Score average was 7 (range 5 - 9). All pts were
treated with concomitant hormone therapy with bicalu-
tamide alone or maximal androgen blockade (MAB). Pts
that refused or could not receive these therapies are ex-
cluded from the study. All patients were subjected to TC
scan using a personalized immobilization system
(Vac-Lock). In order to obtain a better reproducibility of
the daily treatment all pts had to drink 500 cc of water
Predictability and Management of OARs Toxicity in Patients with
Prostate Cancer Treated with High-Dose Radiotherapy
(filled bladder) and to empty the rectum before the TC
scan and then before each treatment session. On CT im-
ages processed with a system of treatment planning the
contouring of the Target and OARs (bladder, rectum and
femoral heads) were made; then the treatment plans were
elaborated. The treatment plan was elaborated with the
technique of “dose escalation” and it was divided into
two phases:
the first phase up to 66.6 Gy (1.8 Gy per fraction for
37 fractions);
the second phase from 66.6 Gy to 73.8 Gy or 79, 2Gy
(1.8 Gy per fraction for 4 or 7 fractions).
In the first phase prostate and seminal vesicles were
considered as Clinical Target Volume (CTV, i.e. GTV-
Gross Tumor Volume—plus the area of supposed micro-
scopical local diffusion) while in the second time CTV
was only comprehensive of the prostate gland volume.
The Planning Target Volume (PTV) was obtained by
adding a margin of 1 cm in all directions and only 0.5 cm
posteriorly. The treatment plan was developed with
3D-Conformal technique (3DCRT) and the treatment
was performed with a Linear Accelerator with multi-
lamellar collimator. The dose was distributed through six
or seven fields of 18 MV photon. During the planning it
was assessed the dose distribution to the PTV and to the
organs at risk according the dose costraints reported in
Table 1 and using the analysis of DVHs (Dose Volume
Histograms). Patients (Ptz) were divided into two groups:
the group A of 100 pts treated with a total dose of 73.8
Gy (1.8 Gy in 41 fractions) and the group B of 108 pts
treated with a total dose of 79.2 Gy (1.8 Gy in 44 frac-
tions). An important difference between the two groups
was the adoption of preventive measures to minimize the
side effects from RT in group B. In particular it was ra-
commended a low-fiber diet and the use of lactic fer-
ments symbiotic (probiotic-prebiotic) to prevent acute
gastrointestinal toxicity, the intake of supplement based
on D-mannose and Proctocyanide to prevent urinary tox-
icity. Before starting, the radiation oncologist may sug-
gest a proper diet, with drastic reduction of fat correlat-
ing with a reduced release of bile salts and fewer epi-
sodes of diarrhea. Than the pharmacological aids such as
antiinflammatory, anti-diarrheal, anticholinergics, and
Table 1. Constraints of dose for rectum, bladder, femoral
Rectum 30% V < 70 Gy - 60% V < 40 Gy
Bladder 50% V < 70 Gy
Femoral heads 50% V < 50 Gy
probiotics strengthing the antioxidant defense systems of
the mucosal cells can be recommended. In the treatment
of actinic cystitis anti-inflammatory drugs and/or antibi-
otics or supplements based on blueberry, hibiscus, D-
mannose. Among the products used in a preventive way
there are the proantocyanide and the D-mannose. For all
pts was scheduled weekly medical examination in order
to evaluate acute lower gastrointestinal toxicity and/or
urinary toxicity using Acute Radiation Morbidity Scoring
Criteria of Radiation Therapy Oncology Group (RTOG).
International Prostate symptom score (IPSS) question-
naire was administered every week allowing to obtain an
early detection of the onset or increasing of any urinary
disorders. The follow up visits were made at 45 days, 3
months, and then every 6 months for two years after the
end of RT. During follow up it was focused on IPSS to
observe the eventual variation of urinary disorders and
was evaluated chronic toxicity using Late Radiation
Morbidity Scoring Criteria of RTOG.
3. Results
In Group A it was observed:
Acute toxicity: 2.2% of urinary incontinence, 4.4% of
dysuria/strangury; 13.3% of proctitis, rectal bleeding
2.2% and 2.2% of diarrhea/rectal tenesmus;
Chronic Toxicity: 2.2% of hematuria, 6.6% of pro-
ctitis, rectal bleeding of 4.4% and 4.4% of diarrhea/
In Group B it was observed:
Acute toxicity: 2.5% urinary retention, urinary incon-
tinence of 0.6%, 4.3% of dysuria/strangury, 4.9% of
proctitis, rectal bleeding 1.2% and 3.1% of diar-
rhea/rectal tenesmus;
Chronic Toxicity: 1.8% of hematuria, 1.2% urinary
retention, urinary incontinence 1.8%, 0.6% actinic
cystitis, 6.7% of proctitis, rectal bleeding 1.8% and
1.8% of diarrhea/rectal tenesmus (Table 2).
In the group A, no one developed urinary toxicity G2,
G3 or G4, while in the group B the acute toxicity was G2
in 4 pts without G3 or G4 cases. The late toxicity was G2
in 2 pts, G3 in 1 pt and G4 in none pts. In the group A
the acute rectal toxicity was G2 in 2 pts but none had G3
or G4 toxicity in the same way the late rectal toxicity was
G2 in 2 pts and none had G3 or G4 toxicity. In the group
B 6 pts developed acute rectal toxicity G2 and none
G3-G4 then the late rectal toxicity was G2 in 5 pts and
G3 in 1 pts (Table 3).
Later, re-evaluating the treatment plans, we found that
most of patients developing toxicity had DVHs that
could be defined as “borderline”, considering the respect
of the dose constraints, into the limits of tolerance dose
to OARs. In these cases theent was performed treatm
Open Access JCT
Predictability and Management of OARs Toxicity in Patients with
Prostate Cancer Treated with High-Dose Radiotherapy
Open Access JCT
Table 2. The urinary and rectal toxicity observed in acute and chronic phases both in Group A and in Group B.
Group A (% of patients) Group B (% of patients)
Hematuria 0 2.2
Urinary Retention 0 0
Urinary Incontinence 2.2 0
Dysuria/Strangury 4.4 0
Urinary Toxicity Acute
Actinic Cystitis 0
Proctitis 13.3 6.6
Rectal Bleeding 2.2 4.4
Gastrointestinal Toxicity Acute
Diarrhea/Rectal Tenesmus 2.2
% %
Hematuria 0 1.8
Urinary Retention 2.5 1.2
Urinary Incontinence 0.6 1.8
Dysuria/Strangury 4.3 0
Urinary Toxicity Acute
Actinic Cystitis 0
Proctitis 4.9 6.7
Rectal Bleeding 1.2 1.8
Gastrointestinal Toxicity Acute
Diarrhea/Rectal Tenesmus 3.1
Table 3. Urinary and Gastrointestinal Toxicity observed in
the two groups of patients.
Urinary and Gastrointestinal Toxicity
G2 G3G4
Group A 0 0 0
RTOG Urinary Acute
Group B 4 0 0
G2 G3G4
Group A 0 0 0
RTOG Urinary Chronic
Group B 2 1 0
G2 G3G4
Group A 2 0 0
RTOG Gastrointestinal Acute
Group B 6 0 0
G2 G3G4
Group A 2 0 0
RTOG Gastrointestinal
Group B 5 1 0
without any change in the dose prescription and the
“risk” of side effects were justified in the majority of
cases by the particular anatomy of the patient (Figures
1(a), (b) and Figure 2(a) ). But if it is true that there were
a high probabilities that a “border-line” DVHs could
produce genitourinary or rectal toxicities, the opposite
could not be true: but we founded that not all cases of
toxicity are associated with “borderline” DVH parame-
ters (Figure 2(b)). This means that the toxicity appear-
ance is not only linked to the dose of radiations absorbed
by the rectum and the bladder, but that there are other
factors that could influence acute toxicity. From the
comparison between borderline DVH and toxicity ac-
cording to the RTOG scale, we noticed the presence of
borderline DVH in 70% of patients with G1 toxicity, in
85% of those with G2 toxicity, in 100% of those with G3
toxicity. This suggest that when we obtained a “border-
line” DVH during planning it means that we can have the
85% chance that the patient will develop acute toxicity.
In cases of toxicity non related to a borderline DVH, we
have to consider other factors that could be: diet, con-
comitant use of medical therapy, difficulty of the patient
to empty the bladder for a concomitant benign prostatic
hypertrophy or for another impediment, individual sensi-
tivity, variability of positioning for poor compliance of
patient to the treatment, organ interfraction and intrafrac-
tion motion.
4. Discussion
In the clinical management of pts undergoing RT for
prostate cancer, the use of supportive therapies is useful
for a better management of local toxicity and to improve
the QoL. The gastrointestinal tract can develop acute
actinic enteritis and proctitis around the second week of
treatment, or chronic forms over a period of between 18
months and 6 years after treatment [1,2]. Acute cystitis is
a frequent complication of RT for prostate cancer in fact
over 20% of pts develop a chronic cystitis even many
years after RT, while 9% have a macroscopic hematuria
that is often recurrent.
Predictability and Management of OARs Toxicity in Patients with
Prostate Cancer Treated with High-Dose Radiotherapy
Figures 1. a-b: Bladder’s and Rectal’s DVHs in pts with higher risk of toxicity.
Figures 2. a-b: “Border-line” DVHs in pts with radiation cystitis and proctitis.
The onset of toxicity of high grades can become a
dose-limiting condition invalidating the results of the RT
so the evaluation of rectal DVH and bladder DVH is a
crucial time in the planning phase [3-8].
Obviously the modern radiotherapy techniques have
led to a significant reduction of the toxicity. The dose
volume constraints are key starting points for the RT
planning. For the treatment planning in 3D, the values of
V50 < 50%, V60 < 35%, V65 < 25%, V70 < 20%, and
V75 < 15% of rectum should limit the Grade 2 rectal
toxicity to <15% and the probability of a Grade 3 rectal
toxicity to <10% for prescriptions up to 79.2 Gy in frac-
tions of 1.8 - 2Gy. Higher doses have a greater impact on
the probability of complications so we should try to
minimize the V70 and V75 without compromising the
coverage of the target [9]. It is known that the treatment
in dose-escalation improves local and biochemical con-
trol in localized prostate cancer but it leads to an increase
in late toxicity of normal tissues so it becomes essential
the implementation of all the principals in order to mini-
mize the effects side, especially in pts at higher risk of
toxicity [10-13]. Obviously it is important to identify the
patients who have a higher risk of toxicity. We know that
in the treatment planning the anatomy of the patient is an
important variable (Figures 1 and 2) in fact, in some
cases it is unattainable reaching an acceptable DVH be-
cause of the anatomical variations. Various methods of
evaluation of toxicity are available. Different scales for
assessment the QoL have been developed and validated
by measuring the impact of therapy after treatment of
prostate cancer [14-17]. The scales of RTOG toxicity
have been changed [18], and different gastrointestinal
indicators have been used to characterize origin and
clinical course of toxicity, for example, Peeters et al. [19]
have characterized the gastrointestinal toxicity consider-
ing these indicators related to specific anatomical pa-
rameters and dose-volume. Post-void residual bladder
volume was variable because bladder volume changed
with the filling; the bladder may also move with the posi-
tioning, breathing, or filling of the intestine, so had to be
considered bladder DVH obtained from the planning on
centering CT. In the last decade the escalation of dose
dispensed with conformant techniques, such as Intensity
Modulated RT (IMRT), allowed to deliver high doses
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Predictability and Management of OARs Toxicity in Patients with
Prostate Cancer Treated with High-Dose Radiotherapy
(>70 Gy) to prostate, so also to the lower portion of the
With these techniques, the upper part of the bladder is
outside the field of treatment, but the region of the tri-
gone may receive the same dose of target. Some studies
have shown an association between the dose to the pros-
tate and acute or chronic genitourinary toxicity. Zelefsky
reported a cumulative incidence of genitourinary toxicity
at 10 years from the end of RT to prostate that was 20%
after 81 Gy in pts treated with IMRT compared with 12%
in non-IMRT pts treated at lower doses. However, only
3% of the entire cohort had developed a genitourinary
toxicity G3, while it was not observed toxicities G4 [20].
In our experience, the use of preventive measures in
pts at high risk of toxicities predictable by DVHs exami-
nation allowed us to greatly reduce the side effects in pts
treated with higher doses. The first procedure adopted
was to prescribe a therapy with Bicalutamide or maximal
androgen blockade (MAB) prior to the start of RT. This
treatment was conducted for a minimum of two months
according the AiroPros 01 - 02 study that showed a pro-
tective effect of hormonal therapy on G > 2 acute gastro-
intestinal toxicity [21,22].
To prevent gastrointestinal toxicities we have sug-
gested a diet low in fiber, to fill bladder before each RT
session in order to keep away the bowel from the treat-
ment field, the use of rectal gel made of hyaluronic acid
to increase the trophism of the rectal mucosa, the ad-
ministration of probiotics (lactic ferments such as Bac.
Coagulans, St. thermophilus, Lb. Rhamnosus, Lb. Sub-
tilis, Saccharomyces Boulardii) and prebiotics (inulin) of
up to 30 days RT. Probiotics have a regulating effect on
the epithelial barrier in different ways: a direct action on
the epithelium bowel increasing the synthesis and secre-
tion of mucin by goblet cells; competition with the patho-
gens and commensal; improvement the stability of the
tight-junctions reducing epithelial permeability to patho-
gens and their products; down-regulation of nuclear
genes that encode for pro-inflammatory cytokines; down-
regulation of apoptosis maintaining a balance between
proliferation and cell degeneration; positive effects on
immunity increasing the local proliferation of IgA-se-
creting cells in the lamina propria and promoting the se-
cretion of IgA in the intraluminally mucous layer. The
inulin is a non-digestible food component that induces
selective stimulation of the growth and of activity of one
or more genera/bacterial species of intestinal microbiota
with beneficial properties for the host [23]. To prevent
genitourinary toxicities we had administered proantocya-
nide and D-mannose based preparations. Proantocyanide
based substance contrast the adhesion of Bacterium Coli
to the mucosa of the urinary tract facilitating their expul-
sion in the urine. The D-mannose based drug arrives in
the urinary canal and binds to the walls and to the bacte-
ria that may have started the colonization determining the
gap thanks to the sticky structure so it promotes their
expulsion with urination.
We have recommended the adoption of preventive
measures illustrated throughout the period of time be-
tween the TC centering and a month after the end of the
RT. Comparing the two groups of pts, we noticed that
acute urinary toxicity was comparable except for the ap-
pearance of a case of urinary retention in the group B;
instead chronic urinary toxicity was registered only in
group B with the appearance of 1 case of actinic cystitis,
2 cases of urinary retention and 3 of urinary incontinence.
Both acute than chronic rectal toxicity, paradoxically,
was higher in pts of Group A, with appearance of procti-
tis and rectal bleeding. We have attributed this paradox
to the absence of prescription of preventive measures in
Group A. Therefore we retain that is useful to adopt
those aids limiting the toxicity of RT in all pts candidates
for pelvic RT.
5. Conclusions
Our study has shown that it is possible to predict the tox-
icity to OARs analyzing the dose-volume histograms
(DVHs) in patients treated with RT for localized prostate
cancer. Preventive measures can help limit gastrointesti-
nal and urinary side effects. Our analysis led to the estab-
lishment of a protocol for the management of patients
with prostate so-called “border-line” DVH with the plan
more aggressive preventive treatments, such as pre-
scription of lactic ferments and probiotics since the
simulation session and up to 30 days after the end of
RT, the prescription of a diet lacking in fiber and
products containing D-mannose and proantocyanide
that would restrict the risk of cystitis;
weekly clinical visit during RT period;
prescription uroflowmetry and bladder ultrasound
with evaluation of post-void residual before RT;
visits and follow-up examinations more frequently.
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