Introduction
Prostate cancer is a quite common type of cancer in
men and 1.6 million new cases are reported each year.
[] Prostate cancer is one of the tumors that can be cured, especially when diagnosed at an early stage.
Different treatments may be preferred depending on
the cancer growth rate, spreading status, overall health
status of the patient and the efficacy of the treatment
to be performed, as well as possible side effects in the treatment of prostate cancer. While active monitoring
is also an option of treatment in patients with lowrisk
prostate cancer, in moderate or high-risk groups,
surgery or radiotherapy (RT) with or without hormonotherapy
constitutes radical treatment. The superiority
of surgery or radiotherapy for survival has not
been shown in local treatment.[-]
There are many studies showing that increased radiation
doses significantly improved the rates of progression-
free survival.[-] However, higher radiation
doses increase acute and late adverse effects. Recently,
the use of Intensity Modulated Radiotherapy (IMRT)
somewhat reduced adverse effects compared to conventional
radiotherapy.[,] However, organs at risk,
such as bladder, rectum which are in the irradiation
area, cannot be entirely protected from radiation. Thus,
the quality of life of patients may alter due to the occurrence
of radiation-related adverse effects.[,]
After the diagnosis, patients should deal with many
problems, including the disease itself and the adverse
effects related to the treatments. For diseases with alternative
treatment options, the effects of therapies
on quality of life (QoL) are important in choosing the
treatment type. For this aim, the European Organization
for Research and Treatment of Cancer (EORTC)
has developed general and disease-specific QoL questionnaires
to be used for cancer patients. EORTC
QLQ-C30 is a questionnaire developed by EORTC
that generally assesses the health-related QoL for cancer
patients.[] However, this questionnaire does not
include issues specific to prostate cancer. Therefore, to
specifically evaluate QoL of prostate cancer patients,
EORTC has evolved a complementary module, QLQPR25.[] Both questionnaires are reliable and commonly
used in research all over the world.[]
The present study aims to investigate the impacts
of RT-related toxicity and its effects on the quality of
life, using EORTC QLQ-C30 and QLQ-PR25 questionnaires
in patients who received definitive or adjuvant
RT for prostate cancer.
Methods
The Departmental Ethics Committee of Cumhuriyet
University"s Faculty of Medicine on non-invasive clinical
research approved this trial in accordance with
the Declaration of Helsinki with the decision no 2017-
11/21, on 8 November 2017. Eighty-seven localized
prostate cancer patients who underwent RT in our
department between January 2011 and June 2016 were
enrolled. A consent form was obtained from all patients who participated in this study. Prostate cancer
patients who received curative or adjuvant RT were
considered eligible.
Radiotherapy-induced side effects were assessed according
to the Radiotherapy Oncology Group (RTOG)
criteria.[]
Quality of Life Scale
Each patient filled the EORTC QLQ-C30 and QLQPR25
at four different times: the start of RT (T1); the
end of RT (T2); one month after completion of RT
(T3); six months after completion of RT (T4).
Quality of life was judged using the EORTC
QLQ-C30 version 3.0, a 30-item questionnaire.
EORTC QLQ-C30 questionnaire consists of global
health status, five functional (physical, role, cognitive,
emotional, social) and nine symptom scales (fatigue
nausea/vomiting, pain, dyspnea, insomnia, appetite
loss, constipation, diarrhea and financial difficulties).
[] Cancer-specific QoL was evaluated utilising the
EORTC QLQ-PR25 version 3.0, a 25-item questionnaire.
EORTC QLQ-PR25 consists of two functional
(sexual activity and sexual functioning) and four
symptom scales (urinary, bowel, hormonal treatmentrelated,
incontinence aid).[] Patients" responses were
assessed using the EORTC QLQ-C30 and QLQ-PR25
scoring manual. Scores as the symptom constituents
were linearly turned into a scale of 0 to 100. A high
score as a functional scale indicated a comparatively
high level of functioning, while a high score as a symptom
scale demonstrated severe symptoms or financial
influences.[]
Radiotherapy was conducted utilising a linear accelerator
device (Varian Clinac DHX, Varian Medical
Systems, Inc., Palo Alto, CA, USA) and TomoTherapy
(Accuray). Three-dimensional conformal RT planning
was carried out using ECLIPS (Varian Medical
Systems, Inc., Palo Alto, CA, USA). IMRT planning
was done using Tomotherapy Planning Workstation
(TomoTherapy Inc., Madison, WI). Of the 87 patients,
sixty-two patients (71%) were treated on the linear accelerator
device, and twenty-five patients (29%) were
treated on the TomoTherapy. Doses of RT ranged from
66 to 80 Gy.
Statistical Analysis
SPSS version 23 was employed in the calculation of statistical
data. Medians and frequencies were computed
for patient demographics. Questionnaire scores were
matched across the four times using the repeated-measures
analysis of variance (ANOVA) and Freidman test (when distribution was not normal). A p?0.05 was regarded
as statistically significant.
Results
Eighty-seven patients who underwent definitive and adjuvant
RT were included in this study. Their median age
was 67 years (range 49-78 years). There were comorbid
diseases in 55 of the patients (63%), 31 of these patients
(56%) had hypertension, 26 (47%) had heart disease,
and 18 (33%) had diabetes mellitus. Secondary primary
malignancy was also present in four (5%) patients.
When the risk of disease was examined, 12 patients
(14%) had low-risk disease, 18 patients (21%) had a
moderate-risk disease and 57 patients (65%) had highrisk
disease.
Sixty-three patients (72%) were treated with definitive
RT and 24 patients (28%) received adjuvant RT.
Sixty of the patients (69%) also received hormonotherapy
treatment (GnRH analogue as leuprolide acetate
11.25 mg, and goserelin acetate 10.8 mg was used for
three months in moderate-risk patients, and two years in high-risk patients). There was a surgical margin
positivity in 18 patients (75%) who received adjuvant
radiotherapy. In addition, 17 patients (71%) with adjuvant
RT had extracapsular invasion and 11 patients
(46%) had seminal vesicle invasion. Median radiation
dose was 66 Gy (range 66-72 Gy) in patients treated
with adjuvant RT, whereas the median radiation dose
was 76 Gy (range 66-80 Gy) in patients who underwent
definitive RT. Radiotherapy fields were prostate in 12
patients (14%), prostate+seminal vesicle in 57 patients
(65%), and prostate+seminal vesicle+pelvic lymph
nodes in 18 patients (21%). Patient characteristics and
treatment details were given in Table 1.
Table 1: Patient characteristics and treatment
When radiation-induced acute and late toxicities
were examined, grade 3-4 lower gastrointestinal acute
toxicity was observed in only one patient (1%), grade
3-4 genitourinary acute toxicity was observed in two
patients (2%). Grade 3-4 late adverse effects were not
observed. Radiotherapy-induced acute and late toxicities
of scored according to RTOG were shown in Table
2. In addition, 56 of the patients (64%) had erectile dysfunction, 54 of patients (62%) had a loss of libido, and
21 of patients (24%) had urinary incontinence.
Table 2: Radiotherapy-induced early and late toxicities of
scored according to RTOG
Table 3 shows the results of the mean and standard
deviation of EORTC QLQ-C30 measurements at the
four-time points. EORTC QLQ-C30 questionnaire response
ratios were 100 % (n=87) at T1, 100% (n=87) at
T2, 72% (n=63) at T3, and 68% (n=59) at T4. According
to the EORTC QLQ-C30 questionnaire, the results
of global health status score, emotional score in functional
scale, fatigue and diarrhea score in symptoms
scale were statistically significant.
Table 3: The EORTC QLQ-C30 QOL results at the four-time points
Table 4 summarizes the EORTC QLQ-PR25 QOL
results at the four-time points. EORTC QLQ_PR25 questionnaire response rates were 44% (n=38) at T1,
38% (n=33) at T2, 28% (n=24) at T3, and 16% (n=14)
at T4. According to the EORTC QLQ-PR25 questionnaire,
the result of the only urinary score in symptoms
scale was statistically significant.
Table 4: The EORTC QLQ-PR25 QOL results at the four-time points
Figure 1 shows the graphics of the statistical significance
results in the EORTC QLQ-C30 and QLQ-PR25
questionnaires.
Fig 1: The graphics of the statistical significance results in both questionnaire.
When patients" QLQ were compared concerning
treatment type (definitive RT vs. adjuvant RT),
RT technique (3D conformal radiotherapy vs. IMRT)
and RT field (prostate/prostate+seminal vesicle vs.
prostate+seminal vesicle+pelvic lymph node); EORTC QLQ C-30 and EORTC QLQ PR-25 functional and
symptom scales were not different between groups
(p>0.05).
Discussion
Prostate cancer constitutes a patient group with longer
life expectancy compared to other cancer types. The effects
of treatments on the quality of life are very essential, especially for patients with early-stage, slow-growing
tumors that are expected to live longer. In patients
without metastatic disease, radical prostatectomy and
RT constitute local treatments. In the present study, we
investigated the effects of RT-related toxicity and its
effects on the quality of life in patients with prostate
cancer received definitive or adjuvant RT. Acute, grade
3-4 lower gastrointestinal toxicity was observed in only
one patient (1%), acute grade 3-4 genitourinary toxicity
was observed in two patients (2%). Fifty-six of the patients (64%) had erectile dysfunction, 54 of patients
(62%) had a loss of libido and 21 of patients (24%) had
urinary incontinence. In the EORTC QLQ-C30 questionnaire,
global health status, emotional score in functioning
scale, fatigue and diarrhea scores in symptoms
scale were negatively affected during RT. However, all
these scores showed improvement from the first month
after RT. In the EORTC QLQ-PR25 questionnaire, only
the urinary score was negatively affected by RT, which
also improved as the others.
Marchand et al.[] examined radiotherapy-induced
toxicity and its effect on QoL of 55 patients receiving
RT for localized prostate cancer. External RT
was applied with IMRT technique in doses of 76 Gy.
EORTC QLQ C30 and QLQ PR25 questionnaires,
which were used to assess QoL, were administered on
patients before RT (baseline) and 2, 6 and 18 months
after RT. The results of the study showed acute grade
1 and grade 2 urinary toxicity was 56.4% and 38.2%,
respectively, while acute grade 1 and grade 2 bowel
toxicity were 36.4% and 12.7%, respectively. Significant
improvements were reported in the bowel and urinary
toxicity six months after RT. Urethral stenosis was observed
in a patient as an acute grade 3 genitourinary
adverse effect. In addition, grade 1 and grade 2 sexual
impotence were reported in 33% and 12% of patients,
respectively, in the 18th month after RT.[] In another
similar study, Goineau et al.[] studied the effects of
high dose (76 Gy) RT on acute and late toxicity and
on QoL in 38 patients with localized prostate cancer.
They utilised the Common Terminology Criteria for
Adverse Events questionnaire (version 3.0) to assess
toxicity and EORTC QLQ-C30 and QLQ-PR25 questionnaires
to assess QoL. Questionnaires were applied
before and 2, 6, 18 and 54 months after RT. Acute urinary
and gastrointestinal grade 1 toxicities were 36.8%
and 23.7%, grade 2 toxicities were 5.3% and 5.3%, and
grade 3 toxicities were 2.6% and 0%, respectively.[]
In the same study, grade 1 urinary and gastrointestinal
toxicities in 18th month were 23.7% and 10.3%,
grade 2 were 26.3% and 13.2% and grade 3 were 0%
and 2.6%, respectively, while in the 54th-month grade
1 toxicities were 34.2% and 23.7%, grade 2 were 5.3%
and 5.8% and grade 3 were 5.3% and 0%, respectively.
In the present study, relatively higher side effects due
to radiotherapy were observed compared to those two
studies.[,] However, the patients undergoing both
conformal RT and IMRT were included in our study.
Acute grade 1-2 gastrointestinal toxicity was observed
in 46% of patients and grade 3-4 toxicity in 1% of patients, while acute grade 1-2 urinary toxicity was observed
in 81% and grade 3-4 toxicity in 2% of patients
in the present study. As late toxicity, urinary and gastrointestinal
grade 1-2 toxicities were seen in 8% and
35% of patients, respectively, whereas none of the patients
had grade 3-4 toxicities.
In the present study, other adverse effects, observed
in late periods, were erectile dysfunction (64%), loss of
libido (62%) and urinary incontinence (24%). In our
patients, the rate of sexual impotence was also high
with the addition of hormone therapy (69%) and adjuvant
RT (28%), which cause loss of libido. In addition,
urinary continence was the most commonly encountered
adverse effect in patients receiving adjuvant RT.
In their studies examining the side effects of RT after
2-3 years, Little et al.[] determined that 83% of patients
had an erectile function before RT, they showed
that this rate decreased to 49% two years after RT and
to 41% after three years. A urinary incontinence rate of
36% was also reported in the same study.
Marchand et al.[] reported significant impairments
in some scores of QoL questionnaires after RT applied to
patients with localized prostate cancer at 76 Gy doses. In
the second month after RT, deteriorations in QoL were
seen in fatigue and dyspnea scores of symptoms scale,
in emotional, social, cognitive, physical scores of the
functional scale of EORTC QLQ C-30 questionnaire,
and in urinary symptom scores of EORTC QLQ PR-25
questionnaire. In the sixth month after RT, there were
improvements in emotional, social, cognitive, physical,
fatigue scores, and in 18th month, only treatment-related
symptoms score was higher compared to baseline.
[] In the present study, global health status, emotional
scores of functional scale, fatigue and diarrhea scores of
symptom scale in the EORTC QLQ C-30 questionnaire
were negatively affected at the end of RT. These scores,
which had been impaired as a result of early adverse
effects of RT, returned completely to baseline levels in
the first and sixth months after RT. In the EORTC QLQ
PR-25 questionnaire, only urinary score was negatively
affected, which returned to normal in the first and sixth
months after RT, similar to other scores. Since enough
number of patients did not answer the questions related
to sexual function in the questionnaire, the sexual functioning
score was not assessed. Although some studies
reported permanent impairments in QoL associated
with sexual activity after RT,[-] there was no change
in sexual activity score compared to before RT in the
present study.
Lips et al.[] compared 88 patients with localized
prostate cancer who received 70 Gy doses via 3D Conformal radiotherapy technique and 92 patients
who received 76 Gy doses using the IMRT technique
concerning their quality of life. RAND-36, EORTC
QLQ C-30 and QLQ PR25 questionnaires were used
to evaluate QoL of patients before RT (baseline), one
and six months after RT. No grade 3-4 bowel and urinary
toxicities were reported in both treatment groups.
Only one patient had grade 3 urinary infection in
the high dose treatment group. Based on the EORTC
questionnaire, the patients who had 70 Gy RT had a
temporary deterioration in pain and urinary symptom
scores of symptoms scale. In higher doses, i.e. in the
group of IMRT, QoL did not alter significantly compared
to conformal RT. Despite higher dose application
to patients receiving IMRT, impairment of QoL
due to bowel functioning was reported to be lower
compared to patients receiving conformal RT.[] In
another similar study from Japan, 110 patients with
prostate cancer who underwent conformal RT (median
70 Gy) and 30 patients who underwent IMRT (median
76 Gy) were compared in terms of their quality of life.
[] As a difference, the authors assessed QoL using
the Medical Outcomes Study 36-Item Short Form
(SF-36) and prostate-specific QoL using the University
of California, Los Angeles, Prostate Cancer Index
(UCLA PCI). There was no difference between the two
groups for urinary symptoms, but the Japanese study
demonstrated that bowel functions and sexual activity
of the patients were significant impaired in the third
and sixth months after RT in the conformal radiation
group.[] In the present study, RT was applied to 71%
of patients with 3D-conformal RT technique. Similar
to the above-mentioned studies,[,] there were no
differences in the scores of the QoL questionnaires between
the groups of patients receiving conformal radiotherapy
and IMRT. Also, no significant difference
was found between patients who had undergone definitive
and adjuvant RT concerning QoL.
Some researchers have shown that pelvic lymph
node irradiation in high-risk patient groups negatively
affects symptom-related QoL, especially diarrhea because
more intestine enters the RT field.[,] Majewski
et al.[] studied the effects of RT on QoL of 180
prostate cancer patients using EORTC questionnaires.
A total of 76 Gy was implemented to 85% of the patients
using the IMRT technique and the remaining 15%
to the patients using the conformal technique. Pelvic
lymph node irradiation (44 Gy) was performed for a
high-risk patient group (41%). Especially, in patient
group receiving pelvic lymph node irradiation, significant
deteriorations in symptom-related QoL (urinary symptoms and diarrhea) were observed.[] Unlike
the above-mentioned studies, no significant difference
was found in any of the QoL questionnaire scores of
patients who were irradiated to the pelvic lymph nodes
compared to patients without pelvic lymph node irradiation
in our study.
Conclusion
The RT approach in prostate cancer caused temporary
impairment in some scores of QLQ, but all these scores
showed improvement from the first month after RT.
Peer-review: Externally peer-reviewed.
Conflict of Interest: No conflict of interest.
Ethics Committee Approval: The Departmental Ethics
Committee of Cumhuriyet University's Faculty of Medicine
on non-invasive clinical research approved this trial in accordance
with the Declaration of Helsinki with the decision no
2017-11/21, on 8 November 2017.
Financial Support: None declared.
Authorship contributions: Concept - B.Y.; Design - B.Y.;
Supervision - None; Funding - None; Materials - E.E.; Data
collection and/or processing - E.E.; Data analysis and/or
interpretation - B.Y.; Literature search - G.G.A.; Writing -
G.G.A.; Critical review - G.G.A., B.Y.
References
Crawford ED. Epidemiology of prostate cancer. Urology
2003;62(6 Suppl 1):3-12.
Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor
BC, Kane RL. Systematic review: comparative effectiveness
and harms of treatments for clinically localized
prostate cancer [published correction appears in
Ann Intern Med. 2008 Jun 3;148(11):888]. Ann Intern
Med 2008;148(6):435-48.
Bolla M, Collette L, Blank L, Warde P, Dubois JB,
Mirimanoff RO, 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(9327):103-6.
Heidenreich A, Aus G, Bolla M, Joniau S, Matveev
VB, Schmid HP, Zattoni F; European Association of
Urology. EAU guidelines on prostate cancer. Eur Urol
2008;53(1):68-80.
Peeters ST, Heemsbergen WD, Koper PC, van Putten
WL, Slot A, Dielwart MF, 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(13):1990-6.
Zietman AL, DeSilvio ML, Slater JD, Rossi CJ Jr, Miller
DW, Adams JA, et al. Comparison of conventionaldose
vs high-dose conformal radiation therapy in clinically
localized adenocarcinoma of the prostate: a randomized
controlled trial. JAMA 2005;294(10):1233-9.
Pollack A, Zagars GK, Starkschall G, Antolak JA,
Lee JJ, Huang E, et al. Prostate cancer radiation
dose response: results of the M. D. Anderson phase
III randomized trial. Int J Radiat Oncol Biol Phys
2002;53(5):1097-105.
Ling CC, Burman C, Chui CS, Kutcher GJ, Leibel
SA, LoSasso T, et al. Conformal radiation treatment
of prostate cancer using inversely-planned intensitymodulated
photon beams produced with dynamic
multileaf collimation. Int J Radiat Oncol Biol Phys
1996;35(4):721-30.
Chauvet I, Gaboriaud G, Pontvert D, Zefkili S, Giraud
P, Rosenwald JC, et al. Constraints and dosage
for prostate cancer patients treated with conformal radiotherapy
and intensity modulated radiation therapy.
Cancer Radiother 2004;8(6):337-51.
Zelefsky MJ, Fuks Z, Hunt M, Yamada Y, Marion C,
Ling CC, et al. High-dose intensity modulated radiation
therapy for prostate cancer: early toxicity and biochemical
outcome in 772 patients. Int J Radiat Oncol
Biol Phys 2002;53(5):1111-6.
Fayers P, Aaronson NK, Bjordal K, Groenvold M,
Curran D, Bottomley A. EORTC QLO-C30 scoring
manual. 3rd ed. Brussels: European Organisation for
Research and Tretament Cancer Data Center; 2001.
Borghede G, Sullivan M. Measurement of quality of
life in localized prostatic cancer patients treated with
radiotherapy. Development of a prostate cancer-specific
module supplementing the EORTC QLQ-C30.
Qual Life Res 1996;5(2):212-22.
van Andel G, Bottomley A, Fosså SD, Efficace F, Coens
C, Guerif S, et al. An international field study of the
EORTC QLQ-PR25: a questionnaire for assessing the
health-related quality of life of patients with prostate
cancer. Eur J Cancer 2008;44(16):2418-24.
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation
Therapy Oncology Group (RTOG) and the
European Organization for Research and Treatment
of Cancer (EORTC). Int J Radiat Oncol Biol Phys
1995;31(5):1341-6.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M,
Cull A, Duez NJ, et al. The European Organization for
Research and Treatment of Cancer QLQ-C30: a quality-
of-life instrument for use in international clinical
trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
Marchand V, Bourdin S, Charbonnel C, Rio E, Munos
C, Campion L, et al. No impairment of quality of life
18 months after high-dose intensity-modulated radiotherapy
for localized prostate cancer: a prospective
study. Int J Radiat Oncol Biol Phys 2010;77(4):1053-9.
Goineau A, Marchand V, Rigaud J, Bourdin S, Rio E,
Campion L, et al. Prospective evaluation of quality of
life 54 months after high-dose intensity-modulated radiotherapy
for localized prostate cancer. Radiat Oncol
2013;8:53.
Little DJ, Kuban DA, Levy LB, Zagars GK, Pollack A.
Quality-of-life questionnaire results 2 and 3 years after
radiotherapy for prostate cancer in a randomized
dose-escalation study. Urology 2003;62(4):707-13.
Namiki S, Ishidoya S, Tochigi T, Kawamura S, Kuwahara
M, Terai A, et al. Health-related quality of life
after intensity modulated radiation therapy for localized
prostate cancer: comparison with conventional
and conformal radiotherapy. Jpn J Clin Oncol
2006;36(4):224-30.
Wahlgren T, Brandberg Y, Häggarth L, Hellström M,
Nilsson S. Health-related quality of life in men after
treatment of localized prostate cancer with external
beam radiotherapy combined with (192)ir brachytherapy:
a prospective study of 93 cases using the EORTC
questionnaires QLQ-C30 and QLQ-PR25. Int J Radiat
Oncol Biol Phys 2004;60(1):51-9.
Korfage IJ, Essink-Bot ML, Borsboom GJ, Madalinska
JB, Kirkels WJ, Habbema JD, et al. Five-year follow-
up of health-related quality of life after primary
treatment of localized prostate cancer. Int J Cancer
2005;116(2):291-6.
Yoshimura K, Arai Y, Ichioka K, Matsui Y, Ogura K,
Terai A. A 3-y prospective study of health-related
and disease-specific quality of life in patients with
nonmetastatic prostate cancer treated with radical
prostatectomy or external beam radiotherapy. Prostate
Cancer Prostatic Dis 2004;7(2):144-51.
Lips I, Dehnad H, Kruger AB, van Moorselaar J, van
der Heide U, Battermann J, et al. Health-related quality
of life in patients with locally advanced prostate
cancer after 76 Gy intensity-modulated radiotherapy
vs. 70 Gy conformal radiotherapy in a prospective
and longitudinal study. Int J Radiat Oncol Biol Phys
2007;69(3):656-61.
Majewski W, Tabor K, Prokop E, Kulik R. Quality
of life in patients with prostate cancer treated with
radical image-guided radiotherapy. Contemp Oncol
(Pozn) 2014;18(4):285-9.
Pinkawa M, Piroth MD, Holy R, Fischedick K, Klotz
J, Székely-Orbán D, et al. Quality of life after whole
pelvic versus prostate-only external beam radiotherapy
for prostate cancer: a matched-pair comparison.
Int J Radiat Oncol Biol Phys 2011;81(1):23-8.
