Predictability and Management of OARs Toxicity in Patients with Prostate Cancer Treated with High-Dose Radiotherapy

doi:10.4236/jct.2013.410174

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Journal of Cancer Therapy, 2013, 4, 1452-1458

Published Online December 2013 (http://www.scirp.org/journal/jct)

http://dx.doi.org/10.4236/jct.2013.410174

Open Access JCT

Predictability and Management of OARs Toxicity in

Patients with Prostate Cancer Treated with High-Dose

Radiotherapy

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.

Email: [email protected]

Received November 7th, 2013; revised November 27th, 2013; accepted December 4th, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-

ABSTRACT

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

1453

(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

heads.

CONSTRAINTS of DOSE

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/

tenesmus.

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

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Predictability and Management of OARs Toxicity in Patients with

Prostate Cancer Treated with High-Dose Radiotherapy

Open Access JCT

1454

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

Chronic

Proctitis 13.3 6.6

Rectal Bleeding 2.2 4.4

Gastrointestinal Toxicity Acute

Diarrhea/Rectal Tenesmus 2.2

Chronic

4.4

% %

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

Chronic

0.6

Proctitis 4.9 6.7

Rectal Bleeding 1.2 1.8

Gastrointestinal Toxicity Acute

Diarrhea/Rectal Tenesmus 3.1

Chronic

1.8

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

Chronic

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

1455

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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Prostate Cancer Treated with High-Dose Radiotherapy

1456

(>70 Gy) to prostate, so also to the lower portion of the

bladder.

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

of:

● 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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