VALUE IN HEALTH REGIONAL ISSUES 10C (2016) Available online at journal homepage:

VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/vhri Conventionally Fractionationed Volumetric Arc Therapy versus Hypofractionated Stereotactic Body Radiotherapy: Quality of Life, Side Effects, and rostate-specific Antigen Kinetics in Localized rostate Cancer Makbule Tambas, MD 1, Fulya Agaoglu, MD 1, *, Ayca Iribas, MD 1, Murat Guveli, MD 1, Yavuz Dizdar, MD 1, Murat Okutan, hd 2, Dilek Sahin, MD 3, Nuri Tenekeci, MD 3, Emin Darendeliler, MD 1 1 Department of Radiation Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey; 2 Department of Medical hysics, Institute of Oncology, University of Istanbul, Istanbul, Turkey; 3 Department of Radiology, Institute of Oncology, University of Istanbul, Istanbul, Turkey ABSTRACT Objectives: To compare conventionally fractionationed volumetric arc therapy (VMAT) and hypofractionated stereotactic body radiotherapy (SBRT) modalities in terms of prostate-specific antigen (SA) kinetics, toxicity, and quality of life (QOL) in patients with localized prostate cancer. Methods: atients received radical radiotherapy as either 33.5 Gy/5 fr for SBRT or 75.6 Gy/35 fr for VMAT. International rostate Symptom Score (ISS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire rostate Cancer Module (QLQ-R25) forms were used to assess QOL. Results: Of the 48 patients(28 in SBRT and 20 in VMAT)includedinthestudy,40(20inSBRTand20inVMAT)were evaluated for QOL status. SA control rate was 100% and SA nadir value was 0.5 ng/dl in both arms during the median follow-up period of 23 months. The magnitude of SA bounce was higher in the SBRT arm than in the VMAT arm ( ¼ 0.01). The SA decline rate in the VMAT arm was higher than in the SBRT arm ( ¼ 0.028). Three (10.7%) patients treated with SBRT who had a history of transurethral resection of the prostate (TUR) experienced grade 3 urinary toxicity. No significant difference was observed concerning sexual activity and sexual functioning scores, whereas scores at 10.5 and 13.5 months were decreased in both arms. The SBRT and VMAT arms had similar urinary incontinence, bowel symptoms, and ISS obstruction scores. The magnitude of increase in ISS scores at treatment completion was higher in the VMAT arm than in the SBRT arm ( ¼ 0.046). The decrease in hormonal symptom scores at 4.5, 10.5, and 13.5 months was higher in the VMAT arm than in the SBRT arm ( ¼ 0.007, 0.027, and 0.021, respectively). Conclusions: Both treatment modalities had similar effectiveness and provided acceptable outcomes in terms of toxicity and QOL. Grade 3 urinary toxicities might be eliminated with careful patient selection for SBRT. Keywords: prostate cancer, quality of life, SBRT, toxicity, VMAT. Copyright & 2016, International Society for harmacoeconomics and Outcomes Research (ISOR). ublished by Elsevier Inc. Introduction rostate cancer is the most common type of cancer in men. In 2014, some 233,000 patients were newly diagnosed as having prostate cancer, which constitutes 27% of new cancer cases in men [1]. Nevertheless, deaths due to prostate cancer were reduced by 4.1% per year between 1994 and 2001; 29,480 deaths occurred because of prostate cancer in 2014 [1]. This low mortality rate can be explained by the awareness of early detection in the community and increased disease control through effective treatment modalities. Nevertheless, early diagnosis and treatment of prostate cancer that does not threaten life expectancy may result in unnecessary adverse effects, deterioration in quality of life (QOL), and an increase in health care costs. Thus, the determination of treatment indication and treatment modalities to be applied is one of the most important issues in prostate cancer management. There are many different options for the treatment of localized prostate cancer, including active surveillance, surgery, brachytherapy, cryotherapy, and high-intensity focused ultrasound, but each has its unique adverse effects. External beam radiotherapy (RT) is another treatment modality that increased biochemical control rates in patients with prostate cancer [2,3]. The results of dose escalation studies in the 1990s revealed that increased RT doses led to higher prostate-specific antigen (SA) control rates, as well as increased toxicity, mainly in the form of rectal bleeding [2 4]. The therapeutic index has increased considerably through the ability of highly conformal dose constraints for normal tissue provided by modern technology. Intensity-modulated radiation Conflict of interest: The authors have indicated that they have no conflicts of interest with regard to the content of this article. *Address correspondence to: Fulya Agaoglu, Department of Radiation Oncology, Institute of Oncology, Istanbul University, Capa 34390, Istanbul, Turkey. E-mail: agaoglufulya@gmail.com 2212-1099$36.00 see front matter Copyright & 2016, International Society for harmacoeconomics and Outcomes Research (ISOR). ublished by Elsevier Inc. http://dx.doi.org/10.1016/j.vhri.2016.08.001

92 VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 therapy (IMRT) led to decreased toxicity rates while increasing local control rates [5,6]. In addition, volumetric arc therapy (VMAT) was shown to provide better outcomes than other IMRT techniques in terms of target organ coverage, conformity index, homogeneity index, the dose received by organs at risk, monitor unit (MU) delivered, and acute toxicities in many dosimetric studies [7 9]. Therefore, the use of VMAT has become widespread instead of other IMRT techniques in centers with available infrastructure for the arc therapy. The therapeutic index is theoretically expected to be increased with hypofractionated regimens because the α/β ratio of prostate cancer cells is approximately 1.5. On the basis of this hypothesis, many studies were conducted that investigated the efficacy of the linear accelerator based or robotic-based stereotactic body radiotherapy (SBRT). The results of these studies involving 1100 patients with localized prostate cancer who received a median dose of 36.25 Gy (range, 35 40 Gy)/4 to 5 fr for noncoplanar robotic SBRT were reported in the SBRT consortium. Five-year biochemical relapse-free survivals for low-, medium-, and high-risk patients were detected as 95%, 84%, and 81%, respectively [10]. Both SBRT and VMAT treatments have unique theoretical advantages. Nevertheless, a much shorter total treatment time in SBRT treatment compared with VMAT treatment is one of the greatest advantages of SBRT for treatment centers and patients. Although the efficacy of both treatments was illustrated in several studies, the follow-up period of SBRT treatment is not as long as that of fractionationed regimens, which makes longterm follow-up periods important regarding adverse effects [10]. Nowadays, the satisfaction and QOL of patients have become as important as the success of treatment. Treatment toxicity and QOL of patients are decisive factors in choosing the treatment modality to be administered among different treatment options for prostate cancer, which has a high control ratio and long survival expectancy. Therefore, for the first time in the literature, we intended to compare conventionally fractionationed VMAT with hypofractionated SBRT in terms of SA kinetics, treatmentrelated adverse effects, and QOL inpatients with localized prostate cancer. Methods atients diagnosed with localized prostate cancer who were admitted to our institution between March 2010 and December 2013 and met the study criteria were included in this prospective study. The terms of the study were approved by the institutional ethics committee. rocedures were conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2000. The informed consent from patients was taken before treatment. Forty-eight patients were included in the study (28 in SBRT and 20 in VMAT). In addition, of these 48 patients, 40 (20 in SBRT and 20 in VMAT) were evaluated for their QOL status with appropriate forms and questionnaires. The remaining 8 patients in the SBRT arm were excluded from the QOL assessment because of incompliance while responding to the questions in the QOL forms. Androgen deprivation therapy (ADT) was administered as a monotherapy including bicalutamide 50 mg (1 1) for 10 days followed by leuprolide acetate at 3-month intervals. RT treatment planning was scheduled after 3 months following ADT initiation. Two weeks before RT simulation, three to four gold fiducial markers were inserted transrectally by an experienced radiologist. The fiducials were placed in the apex, lateral zone, and base of the prostate. Contrast-enhanced planning computed tomography with 1-mm slice thickness was done using the hilips Brilliance (hilips Switzerland, Amsterdam, the Netherlands) device. RT Treatment lanning The prostate gland, seminal vesicles, rectum, bladder, penile bulb, femoral heads, and fiducials were contoured. A clinical target volume (CTV) was created with no margin to the prostate and in very low risk and low-risk patients, whereas the CTV included the prostate and the 1-cm proximal part of the vesicula seminalis in other patients without margin. A 3-mm margin posteriorly and a 5- mm margin from other directions were given to the CTV to create a planning target volume. Conturing was performed using a Varian Eclipse TS version 8.9 (Varian Medical Systems, alo Alto, CA) planning system for VMAT planning. Double full arcs with 179.9 to 180.1 gantry angles counterclockwise and 180.1 to 179.9 gantry angles clockwise were planned using 6-MV photon energy. RT was performed using a Varian DHX RapidArc (Varian Medical Systems, alo Alto, CA) device. Delineation was performed using the Multilan MD Suite planning system (Accuray, Sunnyvale, CA, USA) for SBRT planning. RT was administered with a (Accuray, Sunnyvale, CA, USA) device to patients in the SBRT arm. atients received radical RT with doseschedulesofeither33.5gy/5frforsbrtor75.6gy/35frfor VMAT, the biological 2-Gy equivalent dose for both of which was 78 Gy/39 fr. RT Toxicity Assessments Acute and late toxicity of RT were evaluated on the basis of Common Terminology Criteria for Adverse Events version 4. QOL Assessments The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire rostate Cancer Module (QLQ-R25) module questionnaire and the International rostate Symptom Score (ISS) form were used to assess the QOL of patients before and at the end of treatment, 1.5 months posttreatment, and during subsequent control periods at 3-month intervals. The EORTC QLQ-R25 module consists of parameters to evaluate the functionality and symptoms of patients. All scales were scored from 0 to 100. Higher scale scores indicate a greater level of response. Higher scores for functioning scales show higher/healthier levels of functionality, but higher symptom scale scores indicate greater symptoms/problems [11]. The ISS comprises eight questions (seven symptom questions and one QOL question) to screen symptoms of the lower genitourinary track. The seven symptom questions are related to the following: 1) feeling of incomplete bladder emptying, 2) frequency, 3) intermittency, 4) urgency, 5) weak stream, 6) straining, and 7) nocturia. Each could be scored from 1 to 5 for a maximum of 35 points. The eighth question on QOL is assigned a score of 1 to 6. The ISS obstruction (ISS-O) score is the sum of ISS questions 1, 3, 5, and 6, which show the degree of symptoms related to the obstruction of the urinary tract. The QOL measures were recorded face to face before seeing the physician, and the same order was followed each time. Figure 1 shows the medical interventions and the timing of the administration of QOL assessments. Statistical Analysis For descriptive statistics of the data, mean, SD, median, minimum, maximum, frequency, and ratio values were used. The distribution of variables was measured using the Kolmogorov- Smirnov test. The independent samples t test and the Mann- Whitney U test were used for the analysis of quantitative data. The paired Wilcoxon test was used to analyze repeated

VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 93 measures. The chi-square test was used to analyze qualitative data. The SSS version 22.0 software (SSS Inc., Chicago, IL., USA) was used for statistical analysis. Results The median follow-up period was 23 months. There was no difference between the SBRT and VMAT arms in terms of median age (38.5 years [range 57 82 years] vs. 65.1 years [range 52 79 years]; ¼ 0.11), rates of patients undergoing ADT (32% vs. 55%; ¼ 0.11), and disease risk group according to the National Comprehensive Cancer Network guidelines classification ( ¼ 0.84). The numbers of very low, low-, medium-, and highrisk patients were 2 (7.1%), 10 (35.7%), 15 (53.6%), and 1 (3.6%) in the SBRT group and 4 (20%), 4 (20%), 10 (50%), and 2 (10%) in the VMAT group, respectively. The demographic characteristics of patients at baseline are presented in Table 1. Fig. 1 The medical interventions and the timing of administration of QOL assessments. QOL, quality of life; RT, radiotherapy; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy. SA Kinetics No significant differences were detected between the SBRT and VMAT arms in terms of SA values pre-rt (6.9 2.8 vs. 7.7 4.2 ng/ml; ¼ 0.61) and 4.5 months (1.8 2.0 vs. 1.0 1.5 ng/ml; ¼ 0.10) and 13.5 months (0.8 0.5 vs. 0.5 1.1 ng/ml; ¼ 0.81) after RT. Nevertheless, SA values in the SBRT arm 1.5 months (2.8 3.0 vs. 1.5 2.0 ng/ml; ¼ 0.04), 7.5 months (1.2 0.9 vs. 0.8 1.3 ng/ml; Table 1 The demographic characteristics of patients at baseline. Characteristic SBRT VMAT Mean SD/n (%) Median (min. max.) Mean SD/n (%) Median (min. max.) Age (y) 68 6.5 68.5 (57 82) 65 7.4 63 (52 79) 0.116 Alcohol consumption No 21 (75) 14 (70) 0.701 Yes 7 (25) 6 (30) Smoking No 13 (46.4) 5 (25) 0.131 Yes 15 (53.6) 15 (75) Hypertension No 12 (43) 8 (40) 0.843 Yes 16 (57) 12 (60) Coronary artery disease No 18 (64.3) 16 (80) 0.238 Yes 10 (35.7) 4 (20) Diabetes mellitus No 25 (89.3) 14 (70) 0.091 Yes 3 (10.7) 6 (30) Gastrointestinal system disease No 28 (100) 20 (100) Yes 0 (0.0) 0 (0) ADT No 19 (68) 9 (45) 0.113 Yes 9 (32) 11 (55) Risk classification Very low 2 (7.1) 4 (20) 0.843 Low 10 (35.7) 4 (20) Intermediate 15 (53.6) 10 (50) High 1 (3.6) 2 (10) Note. Independent samples t test, Mann-Whitney U test, and χ 2 test were used. ADT, androgen deprivation therapy; max., maximum; min., minimum; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy.

94 VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 ¼ 0.02) compared with pre-rt scores in the SBRT arm. Nevertheless, a significant increase in the total ISS score at the end of RT ( ¼ 0.02) and significant reductions in both ISS and ISS-O scores at 13.5 months ( ¼ 0.04 and ¼ 0.02) were observed in the VMAT arm (Table 3). Fig. 2 Changes in SA values over time in the SBRT and VMAT groups. SA, prostate-specific antigen; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy. ¼ 0.02), and 10.5 months (0.8 0.7 vs. 0.6 1.0 ng/ml; ¼ 0.04) after RT were found to be significantly higher than those in the VMAT arm (Fig. 2). SA control, SA nadir, and SA bounce According to the hoenix criteria, which accept SA relapse as 2 ng/ml or more increase than SA nadir (SAn), no SA recurrence was observed during follow-up and the SA control rate was 100%. The SAn value (0.5 0.6 vs. 0.5 0.8 ng/ml; ¼ 0.2), SAn time value (12.7 8.3 vs. 8.3 5.8 months; ¼ 0.08), the first SA bounce (SAb) frequency (57% vs. 50%; ¼ 0.6), the time when the first SAb was observed (8.7 5.4 vs. 7.2 2.6 months; ¼ 0.4), the second incidence of SAb (35.7% vs. 25%; ¼ 0.4), the time when the second SAb was seen (13.2 4.8 vs. 9.9 2.5 months; ¼ 0.2), the magnitude of the second SAb (0.2 0.3 vs. 0.1 0.1 ng/ml; ¼ 0.6), and the total number of SAb detected (2.5 1.2 vs. 2.3 1.8; ¼ 0.5) did not differ significantly between the SBRT and VMAT arms. The first SAb value, however, was found to be significantly higher in the SBRT arm than in the VMAT arm (0.8 1.9 vs. 0.1 0.1 ng/ml; ¼ 0.01). Evaluation of QOL and ISS Score Results Comparison of the mean scores of the SBRT and VMAT arms No significant difference was detected between the SBRT and VMAT arms in sexual activity and sexual functioning; urinary, incontinence, bowel, and hormonal symptoms; and ISS and ISS-O scores before RT, at RT completion, and 1.5, 4.5, 7.5, 10.5, and 13.5 months after RT (Table 2). Changes over time relative to baseline scores in SBRT and VMAT arms In both the SBRT and VMAT arms, sexual activity scores at 10.5 months ( ¼ 0.015 and ¼ 0.028) and 13.5 months ( ¼ 0.01 and ¼ 0.008) showed a significant decrease compared with baseline scores. A significant decrease in sexual functioning score was detected at 13.5 months ( ¼ 0.02) in the SBRT arm and at 10.5 months ( ¼ 0.046) and 13.5 months ( ¼ 0.016) in the VMAT arm compared with baseline scores. No significant difference was found in urinary, incontinence, bowel, and hormonal symptom scores at the end of RT and during follow-ups compared with pre-rt scores in either the SBRT arm or the VMAT arm. Nevertheless, bowel ( ¼ 0.04) and hormonal ( ¼ 0.03) symptom scores at 13.5 months were significantly lower than baseline scores in the VMAT arm (Table 3). The ISS and ISS-O scores were significantly lower at 4.5 months ( ¼ 0.016 and ¼ 0.02) and 7.5 months ( ¼ 0.02 and Comparison of SBRT and VMAT arms in terms of amount of changes over time relative to baseline scores The amount of change in sexual activity and sexual functioning; urinary, incontinence, and bowel symptoms; ISS and ISS-O scores during follow-ups after RT from baseline scores did not differ significantly between the SBRT and VMAT arms. The magnitude of increase in ISS scores, however, compared with baseline scores was significantly higher in the VMAT arm than in the SBRT arm ( ¼ 0.046) at the completion of RT. In addition, the decrease in hormonal symptom scores at 4.5 months ( ¼ 0.007), 10.5 months ( ¼ 0.027), and 13.5 months ( ¼ 0.021) from baseline scores was significantly higher in the VMAT arm than in the SBRT arm (Table 4). Toxicity Evaluation The SBRT and VMAT arms showed no significant difference regarding pretreatment transurethral resection of the prostate (TUR) incidence (17.9% vs. 20%; ¼ 0.8), the complication rate due to fiducial insertion (3.6% vs. 5%; ¼ 0.999), incidence of TUR or catheter requirement after RT (17.9% vs. 5%; ¼ 0.1), and rate of incontinence development after RT (7.1% vs. 5%; ¼ 0.999). Genitourinary system toxicities The incidence of genitourinary system (GUS) adverse effects according to grades in the SBRT and VMAT arms is presented in detail in Table 5. The presence of GUS toxicity during RT and during follow-ups was observed to be similar in the SBRT and VMAT arms, but the incidence of GUS toxicity at 4.5 months was found to be significantly higher in the SBRT arm than in the VMAT arm (50% vs. 30%; ¼ 0.03). No significant difference was detected between the SBRT and VMAT arms concerning the incidence of grade 2 or higher GUS toxicity during RT or during follow-ups. Gastrointestinal system toxicities Grade 3 gastrointestinal system (GIS) toxicity was not observed in either arm. Neither did the incidence of GIS toxicity presence nor grade 2 GIS toxicity rates during RT and during follow-ups differ significantly between the SBRT and VMAT arms. Discussion Several studies have established various questionnaires for patient self-assessment to investigate morbidity in detail. Repetitive assessments may provide more useful information in understanding long-term adverse effects and their changes over time instead of peak scores [12 14]. To succeed in these goals, 28 patients treated with SBRT and 20 patients who received VMAT (N ¼ 48) were included in our study and monitored regularly. In addition, of these 48 patients, 20 in the SBRT arm and 20 in the VMAT arm were evaluated in terms of QOL and detailed toxicity analysis using the EORTC QLQ-R25 module and ISS forms at baseline, RT completion, and during follow-ups. First, SA kinetics in our study were consistent with those in the literature[15]. The SA decline rate was significantly slower in the SBRT arm than in the VMAT arm, whereas SAn values were similar between the two groups. In addition, the magnitude of the first SAb was significantly higher in the SBRT group than in

VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 95 Table 2 Comparison of SBRT and VMAT groups in terms of mean EORTC QLQ-R25 functioning (sexual activity and sexual functioning) and symptom (urinary, incontinence aid, bowel, and hormonal) scores and ISS and ISS-O scores. Time (mo) Sexual activity functioning scores Sexual functioning scores Baseline 74.2 37 (100) 73.3 31 (83) 0.53 51.7 34 (46) 54.2 33 (50) 0.79 RT completion 71.7 37 (92) 74.2 37 (100) 0.75 52.5 34 (42) 54.2 38 (67) 0.85 1.5 64.2 38 (67) 68.3 36 (75) 0.78 50.0 32 (50) 55.0 30 (28) 0.65 4.5 65.8 36 (67) 53.3 45 (67) 0.48 46.7 29 (42) 38.3 37 (25) 0.37 7.5 60.8 35 (67) 54.2 46 (67) 0.78 47.1 29 (46) 37.9 34 (25) 0.30 10.5 45.0 37 (50) 45.8 44 (33) 0.98 31.7 30 (29) 31.7 36 (21) 0.79 13.5 49.2 41 (50) 38.3 44 (17) 0.35 32.1 31 (25) 28.3 38 (0) 0.50 Urinary symptoms scores Incontinence aid scores Baseline 24.2 26 (15) 37.1 35 (27) 0.17 3.3 15 (0) 3.3 15 (0) 0.99 RT completion 24.0 27 (19) 33.3 20 (35) 0.10 6.7 23 (0) 3.3 10 (0) 0.96 1.5 23.3 25 (19) 24.4 22 (19) 0.68 6.7 23 (0) 1.7 8 (0) 0.53 4.5 17.5 21 (15) 26.5 26 (19) 0.34 1.7 8 (0) 8.3 21 (0) 0.28 7.5 18.5 24 (13) 26.7 26 (17) 0.39 5.0 16 (0) 8.3 21 (0) 0.62 10.5 19.6 22 (17) 30.2 28 (25) 0.21 8.3 21 (0) 8.3 21 (0) 0.99 13.5 18.5 23 (15) 28.7 30 (21) 0.33 3.3 15 (0) 10.0 22 (0) 0.17 Bowel symptom scores Hormonal symptom scores Baseline 15.4 20 (8) 22.9 21 (21) 0.15 13.9 15 (11) 21.4 15 (22) 0.09 RT completion 18.3 21 (13) 22.5 23 (13) 0.63 16.9 12 (14) 18.6 15 (17) 0.71 1.5 24.6 26 (17) 20.0 20 (17) 0.74 20.0 15 (17) 20.3 18 (17) 0.99 4.5 15.4 21 (8) 17.1 20 (13) 0.88 20.8 14 (19) 16.1 20 (6) 0.22 7.5 15.0 19 (8) 19.6 25 (8) 0.88 20.0 17 (19) 19.4 23 (14) 0.64 10.5 12.5 16 (8) 18.8 26 (4) 0.77 20.0 16 (17) 16.4 20 (8) 0.20 13.5 12.9 17 (8) 12.5 21 (0) 0.41 19.4 17 (17) 13.9 18 (6) 0.13 ISS scores ISS obstruction scores Baseline 11.0 10 (8) 10.3 5 (10) 0.81 6.4 7 (4) 5.5 4 (6) 0.95 RT completion 11.1 10 (10) 13.5 8 (13) 0.27 6.7 7 (6) 6.7 4 (6) 0.60 1.5 10.0 10 (10) 10.5 8 (8) 0.47 5.5 6 (4) 4.8 4 (4) 0.84 4.5 7.2 8 (5) 8.3 7 (8) 0.27 3.6 5 (2) 4.0 4 (3) 0.49 7.5 7.0 9 (4) 8.9 7 (8) 0.13 3.4 6 (1) 4.0 4 (3) 0.39 10.5 8.2 9 (7) 9.7 8 (8) 0.36 4.5 6 (2) 4.6 6 (3) 0.96 13.5 7.9 8 (5) 7.9 7 (8) 0.82 4.2 5 (2) 3.5 4 (2) 0.77 Note. Mann-Whitney U test/wilcoxon test. EORTC QLQ-R25, Quality of Life Questionnaire rostate Cancer Module; ISS, International rostate Symptom Score; ISS-O, ISS obstruction; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy. the VMAT group. Furthermore, repetitive SAb was observed in our study and other previous studies [16]. In a recently published study that included patients treated with brachytherapy (n ¼ 230), conventional RT (76 Gy/38 fr, n ¼ 58), or hypofractionated RT (45 Gy/9 fr, n ¼ 74), no significant difference was observed between the different modalities in terms of SAb. The authors concluded that SAb might be caused by the late RT damage to the healthy prostate tissue because the SAb was more common among patients with lower risk and fewer positive biopsies [17]. The median SAn values reported in the studies ranged between 0.1 and 1.6 ng/ml, which is consistent with our results [18]. After a rapid decline in SA following RT, SA values continue to decline slowly accompanied by SAb fluctuations, whereas lower SA nadir values are observed with longer follow-ups. Therefore, the decision for biopsy should not be taken immediately after RT in patients with an increase in SA; a benign SA bounce should be excluded by monitoring SA kinetics. When evaluating treatment complications, an infection that was treated with antibiotics developed in one patient in each group after fiducial insertion, and these patients completed RT without any problems. The infection incidence due to fiducial insertion was reported at about 7.7%, where one-third was in the form of urosepsis [19]. Concerning GIS toxicities, no grade 3 adverse effects or differences between the SBRT and VMAT arms were observed in the present study. The frequency of late grade 3 GIS or GUS toxicities was reported as 1% to 3% in SBRT studies [10]. Likewise, the two arms were similar in terms of grades 1 to 2 GUS toxicities in which adverse effects were prominent during the acute period after RT, and improved during follow-up. The most frequent GUS complication was urinary obstruction, which required TUR [20]. A grade 3 urinary retention due to an obstruction developed at 7.5 months and continued at 13.5 months in the SBRT arm. The group of patients with a history of TUR mostly constituted those with grade 3 toxicity. Catheter placement or TUR was needed in all of the five patients with a history of TUR in the SBRT arm and one of the four patients in the VMAT arm. TUR history has been reported as an obvious risk factor for late GUS toxicity in patients treated with SBRT [21]. In addition, Yu et al. [22] reported that GUS toxicities were significantly higher in the SBRT arm than in the IMRT arm at 24 months post-treatment, and toxicities were mainly in the form of urethritis, stricture, urinary incontinence, and/or obstruction (43.9%

96 Table 3 Changes over time relative to baseline EORTC QLQ-R25 functioning (sexual activity and sexual functioning) and symptom (urinary, incontinence aid, bowel, and hormonal) scores and ISS and ISS-O scores in SBRT and VMAT arms. Time (mo) Sexual activity functioning scores Sexual functioning scores RT completion 3 29 (0) 0.34 0.8 39 (0) 0.69 0.8 24 (0) 0.81 0.0 29 (0) 0.94 1.5 10 37 (0) 0.14 5 41 (0) 0.69 1.7 22 (0) 0.68 0.8 36 (0) 0.81 4.5 8 33 (0) 0.11 20 53 (0) 0.13 5.0 29 (0) 0.47 15.8 45 ( 4) 0.13 7.5 13 40 (0) 0.10 19 53 (0) 0.10 4.6 29 (0) 0.39 16.3 45 ( 17) 0.19 10.5 29 48 ( 33) 0.01 28 50 (0) 0.02 20 43 ( 25) 0.06 22.5 47 ( 17) 0.046 13.5 25 39 ( 25) 0.01 35 50 ( 17) 0.008 20 36 ( 17) 0.02 25.8 44 ( 21) 0.016 Urinary symptoms scores Incontinence aid scores RT completion 0.2 21 ( 2) 1.00 3.7 39 (0) 1.00 3.3 10 (0) 0.16 0.0 19 (0) 1.00 1.5 0.8 16 (0) 0.70 12.7 37 ( 4) 0.15 3.3 10 (0) 0.16 1.7 17 (0) 0.66 4.5 6.7 16 ( 4) 0.09 10.6 34 ( 6) 0.18 1.7 8 (0) 0.32 5.0 27 (0) 0.45 7.5 5.6 19 ( 4) 0.16 10.4 35 ( 2) 0.22 1.7 17 (0) 0.66 5.0 27 (0) 0.45 10.5 4.6 26 ( 2) 0.66 6.9 36.7 (0) 0.50 5.0 27 (0) 0.45 5.0 27 (0) 0.45 13.5 5.6 27 ( 4) 0.49 8.3 36.1 (0) 0.47 0.0 22 (0) 1.00 6.7 28 (0) 0.33 Bowel symptom scores Hormonal symptom scores RT completion 2.9 13 (0) 0.35 0.4 19 (0) 0.68 3.1 16 (6) 0.29 2.8 11 (0) 0.28 1.5 9.2 22 (0) 0.07 2.9 16 (0) 0.86 6.1 13 (6) 0.09 1.1 15 (0) 0.65 4.5 0.0 20 (0) 0.92 5.8 14 (0) 0.18 6.9 17 (8) 0.07 5.3 15 (0) 0.13 7.5 0.4 20 (0) 0.89 3.3 20 (0) 0.38 6.1 21 (8) 0.13 1.9 16 (0) 0.64 10.5 2.9 23 (0) 0.64 4.2 24 (0) 0.43 6.1 21 (8) 0.10 5.0 15 ( 3) 0.15 13.5 2.5 24 (0) 0.73 10.4 19 (0) 0.04 5.6 23 (3) 0.18 7.5 14 ( 6) 0.03 ISS scores ISS obstruction scores RT completion 0.1 7( 1) 0.83 3.2 6 (2.5) 0.02 0.3 5 (0) 0.97 1.2 3 (0) 0.17 1.5 1.0 7( 1) 0.47 0.3 5 (0) 0.83 0.9 5( 1) 0.29 0.7 3 (0) 0.41 4.5 3.8 7( 2) 0.01 2.0 4( 2) 0.06 2.9 5( 2) 0.02 1.5 3( 1) 0.07 7.5 4.0 7( 2) 0.02 1.4 5( 1) 0.22 3.0 5( 1) 0.02 1.5 4( 1) 0.09 10.5 2.8 6( 2) 0.11 0.6 8( 2) 0.32 2.0 4( 1) 0.10 0.9 6( 1) 0.12 13.5 3.1 7( 1) 0.12 2.4 5( 3) 0.04 2.3 6( 1) 0.12 2.0 3( 2) 0.024 VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 EORTC QLQ-R25, Quality of Life Questionnaire rostate Cancer Module; ISS, International rostate Symptom Score; ISS-O, ISS obstruction; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy.

VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 97 Table 4 Comparison of SBRT and VMAT arms in terms of amount of changes over time relative to baseline EORTC QLQ-R25 functioning (sexual activity and sexual functioning) and symptom (urinary, incontinence aid, bowel, and hormonal) scores and ISS and ISS-O scores. Time (mo) Sexual activity functioning scores Sexual functioning scores RT completion 3 29 (0) 0.8 39 (0) 0.12 0.8 24 (0) 0.0 29 (0) 0.89 1.5 10 37 (0) 5 41 (0) 0.39 1.7 22 (0) 0.8 36 (0) 0.56 4.5 8 33 (0) 20 53 (0) 0.87 5.0 29 (0) 15.8 45 ( 4) 0.54 7.5 13 40 (0) 19 53 (0) 0.81 4.6 29 (0) 16.3 45 ( 17) 0.40 10.5 29 48 ( 33) 28 50 (0) 0.63 20.0 43 ( 25) 22.5 47 ( 17) 0.97 13.5 25 39 ( 25) 35 50 ( 17) 0.61 19.6 36 ( 17) 25.8 44 ( 21) 0.66 Urinary symptoms scores Incontinence aid scores RT completion 0.2 21 ( 2) 3.7 39 (0) 0.97 3.3 10 (0) 0.0 19 (0) 0.67 1.5 0.8 16 (0) 12.7 37 ( 4) 0.18 3.3 10 (0) 1.7 17 (0) 0.32 4.5 6.7 16 ( 4) 10.6 34 ( 6) 0.88 1.7 8 (0) 5.0 27 (0) 0.19 7.5 5.6 19 ( 4) 10.4 35 ( 2) 0.81 1.7 17 (0) 5.0 27 (0) 0.43 10.5 4.6 26 ( 2) 6.9 36.7 (0) 0.85 5.0 27 (0) 5.0 27 (0) 1.00 13.5 5.6 27 ( 4) 8.3 36.1 (0) 0.90 0.0 22 (0) 6.7 28 (0) 0.26 Bowel symptom scores Hormonal symptom scores RT completion 2.9 13 (0) 0.4 19 (0) 0.98 3.1 16 (6) 2.8 11 (0) 0.08 1.5 9.2 22 (0) 2.9 16 (0) 0.31 6.1 13 (6) 1.1 15 (0) 0.09 4.5 0.0 20 (0) 5.8 14 (0) 0.42 6.9 17 (8) 5.3 15 (0) 0.007 7.5 0.4 20 (0) 3.3 20 (0) 0.47 6.1 21 (8) 1.9 16 (0) 0.10 10.5 2.9 23 (0) 4.2 24 (0) 0.76 6.1 21 (8) 5.0 15 ( 3) 0.027 13.5 2.5 24 (0) 10.4 19 (0) 0.21 5.6 23 (3) 7.5 14 ( 6) 0.021 ISS scores ISS obstruction scores RT completion 0.1 7( 1) 3.2 6 (2.5) 0.046 0.3 5 (0) 1.2 3 (0) 0.30 1.5 1.0 7( 1) 0.3 5 (0) 0.63 0.9 5( 1) 0.7 3 (0) 0.61 4.5 3.8 7( 2) 2.0 4( 2) 0.50 2.9 5( 2) 1.5 3( 1) 0.40 7.5 4.0 7( 2) 1.4 5( 1) 0.30 3.0 5( 1) 1.5 4( 1) 0.46 10.5 2.8 6( 2) 0.6 8( 2) 0.57 2.0 4( 1) 0.9 6( 1) 0.99 13.5 3.1 7( 1) 2.4 5( 3) 0.92 2.3 6( 1) 2.0 3( 2) 0.79 EORTC QLQ-R25, Quality of Life Questionnaire rostate Cancer Module; ISS, International rostate Symptom Score; ISS-O, ISS obstruction; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy. vs. 36.3%; ¼ 0.001). Furthermore, King et al. [23] detected that the incidence of late urethral stricture that required dilatation was 3.5% for SBRT, which was higher than that reported for IMRT (0.5%). In our study, repetitive TURs were required in 3 of 28 (10.7%) patients in the SBRT arm. To avoid such toxicities, attention should be paid to patient selection; SBRT should not be administered to patients with a history of TUR. A significant reduction in sexual activity scores from baseline was observed at 10.5 and 13.5 months in both groups, which is in agreement with previous studies that reported that sexual dysfunction was a late-emerging adverse effect [24]. In a multicenter cohort study with 864 patients who underwent SBRT, urinary and bowel scores were found to decline in the first 3 months and returned to the initial values up to 6 months later, whereas sexual QOL was detected to have deteriorated, independent of ADT or age during the first 9 months [23]. In our study, no significant difference was observed in terms of urinary, incontinence, bowel, and hormonal symptom scores between the two groups. This is consistent with the study by Evans et al. [25], which compared IMRT, brachytherapy, or SBRT regarding QOL. The authors established that the three modalities were substantially similar to each other regarding QOL. In our study, ISS scores were found to increase during the early period following RT and significantly declined after 1 year, which is also congruous with other studies[26]. The ISS scores, however, decreased significantly at 1.5 and 4.5 months and then increased at 10.5 and 13.5 months from baseline in the SBRT arm. Similarly, ISS-O scores increased during the late period. These findings are consistent with previous reports that detected an increase in late urinary toxicities in patients treated with SBRT [27]. Conclusions It was found that both SBRT and VMAT treatments were effective options for localized prostate cancer. Grade 3 GUS toxicities were mainly observed in patients with a history of TUR in the SBRT arm. Deterioration was detected in sexual activity and sexual functioning QOL as a late toxicity in both arms. Acute hormonal and bowel symptoms were resolved in patients who received VMAT during follow-up. Although acute urinary symptoms were found to increase in the VMAT arm, late urinary toxicities were more common in patients who underwent SBRT. It may be concluded that both treatment modalities had similar effectiveness and provided acceptable outcomes in terms of toxicity and QOL. Acknowledgment We thank Mr David Chapman, who is a native-english speaker with scientific expertise, for language editing of the article.

98 Table 5 Genitourinary and gastrointestinal system toxicities according to CTCAE version 4 (grades in SBRT and VMAT groups). VMAT (%) SBRT (%) Toxicity Grade RT 1.5 mo 4.5 mo 7.5 mo 10.5 mo 13.5 mo RT 1.5 mo 4.5 mo 7.5 mo 10.5 mo 13.5 mo Genitourinary system toxicities ollakuria 0 63 68 83 82 80 90 67 82 71 78 81 86 1 0 21 6 12 13 1 4 0 8 4 5 0 2 37 11 11 0 6.7 0 30 18 21 17 14 14 Nocturia Mean 1 1 2 1 1 1 2 2 2 2 1 1 Min. 0 0 0 0 0 0 0 0 0 0 0 0 Max. 5 5 8 5 4 4 9 10 6 5 5 5 Incontinence 0 95 95 94 94 93 100 89 100 100 100 100 100 1 0 0 0 0 0 0 4 0 0 0 0 0 2 5 5 6 6 7 0 7 0 0 0 0 0 Retention 0 90 100 100 100 87 100 78 82 96 91 86 91 1 5 0 0 0 0 0 0 5 0 0 5 5 2 5 0 0 0 13 0 15 5 0 0 0 0 3 0 0 0 0 0 0 7 9 4 9 10 5 Obstruction 0 100 95 100 100 93 100 85 82 96 91 91 91 1 0 5 0 0 0 0 0 4.5 0 0 0 5 2 0 0 0 0 67 0 15 14 4 4 0 0 3 0 0 0 0 0 0 0 0 0 4 10 5 Dysuria 0 42 84 83 77 73 100 67 59 58 65 76 67 1 2 16 11 24 27 0 7 23 17 17 10 24 2 37 0 6 0 0 0 19 18 25 13 10 5 3 0 0 0 0 0 0 7 0 0 4 5 5 Urgency 0 95 100 100 94 93 100 96 96 96 96 95 95 1 0 0 0 0 0 0 0 0 0 0 0 0 2 5 0 0 6 7 0 7 5 4 4 5 5 Gastrointestinal system toxicities roctitis 0 79 100 100 100 93 100 82 86 88 96 95 95 1 21 0 0 0 7 0 4 5 4 4 5 5 2 0 0 0 0 0 0 15 9 8 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 Bleeding 0 95 100 100 100 93 100 93 96 96 100 95 90 1 5 0 0 0 7 0 4 0 0 0 0 5 2 0 0 0 0 0 0 3 4 4 0 5 5 3 0 0 0 0 0 0 0 0 0 0 0 0 VALUE IN HEALTH REGIONAL ISSUES 10C (2016) 91 99 CTCAE, Common Terminology Criteria for Adverse Events; Max., maximum; Min., minimum; RT, radiotherapy; SBRT, stereotactic body radiotherapy; VMAT, volumetric arc therapy.

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