Clinical Investigations Original paper Five-year quality of life in patients with high-risk localized prostate cancer treated with external beam radiotherapy alone versus external beam radiotherapy with high-dose-rate brachytherapy boost: a prospective multicenter study Evelyn Martínez, MD1*, Olatz Garin, PhD2,3,4, Yolanda Pardo, PhD2,3,5, Pablo Fernández, MD6, Benjamin Guix MD, PhD7, Cristina Gutiérrez, MD, PhD1, Ana Boladeras, MD, PhD1, Ferran Ferrer, MD, PhD1, Tania Hernández, MD1*, Adriana Ayala, MD6, Mikel Egiguren, MD6, Gema Fernández, MD8, Víctor Muñoz, MD9, Víctor Macías, MD, PhD10, Joan Pera, MD, PhD1, Àngels Pont, B.Stat2,3, Montserrat Ferrer, MD, PhD2,3,5, Ferran Guedea, MD, PhD1, and the Multicentric Spanish Group of Clinically Localized Prostate Cancer The Multicentric Spanish Group of Clincally Localized Prostate Cancer: Montse Ferrer, Àngels Pont, Olatz Garin, Yolanda Pardo, Jordi Alonso, Mónica Ávila, Víctor Zamora, Ferran Guedea, Montse Ventura, Cristina Gutiérrez, Ferran Ferrer, Ana Boladeras, José Francisco Suárez, Manel Castells, Xavier Bonet, Pastor S, Carmen Bonet, Gemma Sancho, Javier Ponce de León, Joan Palou, Belén de Paula, Alai Goñi, Pablo Fernández, Ismael Herruzo, Asunción Hervás, Alfredo Ramos, Víctor Macías, Josep Solé, Marta Bonet, Alfonso Mariño, Patricia Cabrera, Maria José Ortiz 1Servicio de Oncología Radioterápica, Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain, 2Unidad de Investigación en Servicios Sanitarios, IMIM-Hospital del Mar, Barcelona, Spain, 3CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain, 4Pompeu Fabra University (UPF), Barcelona, Spain, 5Universitat Autónoma de Barcelona, Bellaterra, Spain, 6Servicio de Oncología Radioterápica, Instituto Oncológico de Guipuzkoa, San Sebastián, Spain, 7Fundación IMOR, Institut Mèdic Onco-Radioterapia, Barcelona, Spain, 8Servicio de Oncología Radioterápica, Hospital Universitario Central de Asturias, Oviedo, Spain, 9Servicio de Oncología Radioterápica, Hospital do Meixoeiro, Vigo, Spain, 10Servicio de Oncología Radioterápica, Hospital Universitari i Politècnic La Fe, Valencia, Spain, and Hospital Universitari General de Catalunya Quiron Salut, Sant Cugat del Vallés, Barcelona, Spain *Present address: Departamento de Radio Oncología, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional de Occidente (CMNO) del Instituto Mexicano del Seguro Social (IMSS), Mexico DF Abstract Purpose: Brachytherapy (BT) and external beam radiation therapy (EBRT) are effective treatments for high-risk prostate cancer (PCa). However, the impact of these treatments on health-related quality of life (HRQL) remains unclear. In this study, we compared EBRT alone with EBRT plus a boost with high-dose rate (HDR)-BT to determine the impact on HRQL in patients with high-risk PCa. Material and methods: Prospective, multicenter study comparing patients with high-risk PCa treated with EBRT alone or EBRT + HDR-BT from 2004 to 2006. HRQL was assessed at baseline (pre-treatment) and periodically over the 5-year follow-up, using the SF-36 (v.2), EPIC, and FACT-G and FACT-P questionnaires. Results: A total of 129 patients were included in the study, of these, 41 received EBRT alone and 88 EBRT + HDR-BT. All patients received hormonotherapy. Baseline clinical characteristics were similar, except for a slightly higher mean number of comorbidities in the EBRT group. During follow-up, the only significant between-group difference was a greater worsening on EPIC hormonal domain in the EBRT alone group (p = 0.028). There were no significant differences in time and interaction of treatment in SF-36, and FACT-G and FACT-P questionnaires or EPIC urinary incontinence, urinary irritative-obstructive, and bowel and sexual domains over the 5-year follow-up. Oncological outcomes were similar in both groups. Conclusions: After five years of follow-up, EBRT alone or combined with HDR-BT boost had a similar impact on HRQL in patients with high-risk localized PCa. However, patients in the EBRT alone group experienced greater wors- ening of hormonal domain according to EPIC questionnaire. J Contemp Brachytherapy 2021; 13, 1: 1–11 DOI: https://doi.org/10.5114/jcb.2021.103580 Key words: quality of life, prostate cancer, external beam radiotherapy, high-dose-rate brachytherapy. Address for correspondence: Evelyn Martínez, MD, Servicio de Oncología Radioterápica, Institut Català Received: 27.09.2020 d’Oncologia (ICO), Gran Via de l’Hospitalet 199-203, E-08908 L’Hospitalet de Llobregat, Barcelona, Spain, Accepted: 24.12.2020 phone: +34 932607722, fax: +34 932607725,  e-mail: emperez@iconcologia.net Published: 18.02.2021 Creative Commons licenses: This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY -NC -SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/). 2 Evelyn Martínez, Olatz Garin, Yolanda Pardo, et al. Purpose Treatment Radical radiotherapy is a well-established treatment Treatment decisions were made jointly by patients option for clinically localized and locally advanced and physicians. All patients received neoadjuvant an- prostate cancer (PCa) [1]. Technological advances in ra- drogen deprivation therapy (ADT). Adjuvant ADT was diotherapy have been rapidly incorporated into clinical prescribed for 2-3 years, in accordance with clinical practice to reduce treatment-related morbidity and im- guidelines [13]. In most cases, patients received an anti­ prove oncological outcomes [2,3]. Several randomized androgen combined with LHRH analogues. trials have demonstrated that dose-escalated radiother- In all cases, EBRT was performed with the patient apy-external beam radiotherapy (EBRT) or EBRT plus in supine position, with legs and feet immobilized. All high-dose-rate (HDR) brachytherapy (BT) boost, im- patients underwent a computed tomography (CT) scan prove both local and biochemical control in intermedi- in the treatment position. The results of this scan were ate- and high-risk PCa [3,4,5,6], despite an increased risk entered into three-dimensional (3D) treatment planning of late genitourinary and gastrointestinal toxicities. The system and used to contour the prostate, vesicles, blad- addition of HDR-BT boost allows for highly conformal der, and rectum. External beam clinical target volume dose escalation and greater sparing of the surrounding (CTV) was defined on CT imaging to cover the prostate healthy organs [5]. gland and seminal vesicles with a 1 cm margin, except All of the main treatments for PCa have side effects, posteriorly, where the margin was reduced to 5 mm to and radical prostatectomy (RP) seems to produce greater create planning target volume (PTV). Custom blocking urinary incontinence. BT is associated with an increase with multileaf collimators was designed using a beam’s- in urinary irritative/obstructive symptoms, while EBRT eye-view, and additional margins were adjusted to pro- has a greater impact on bowel-related indications [7,8,9]. vide minimum dose of 95% to the prostate PTV. Risk or- In selected patients, BT is an alternative to RP, limiting gan constraints included the femoral heads (mean dose the risk of urinary incontinence as well as the potential ≤ 45 Gy) and bladder/rectum (V70 < 25%; V60 preferably impact of sexual dysfunction on health-related quality of < 40%, maximum 60%; V40< 60%, maximum 80%) [14]. life (HRQL) [7]. Off-line setup control was assessed weekly by comparing In this context, the main objective of this study was to orthogonal portal images with the corresponding digital- determine whether EBRT alone or EBRT + HDR-BT was ly-reconstructed radiographs. associated with better HRQL outcomes in patients with External beam radiation therapy was performed us- high-risk PCa, five years after the treatment. Secondary ing 3D conformal technique by photons from 15 to 18 MV outcome measures included biochemical relapse-free sur- isocentric conformal fields. In most patients, a six-field vival (BRFS), overall survival (OS), and cancer-specific technique without pelvic irradiation was used. The EBRT survival (CSS) at 5 years. alone group received daily fractions of 1.8/2 Gy, 5 days per week, for a mean total dose of 73 Gy to the PTV. For the HDR-BT boost, the patients were placed in Material and methods lithotomy position under spinal anesthesia. A needle guid- Design and study population ance template was attached to an ultrasound probe close to the perineum, and the needles were inserted under This was a prospective, multicenter study of pa- transrectal ultrasound guidance. Needle depth was deter- tients with high-risk PCa, treated at participating centers mined by direct visualization on ultrasound and fluoros- from 2004 to 2006, and followed for ≥ 5 years after the copy. A CT scan was performed for volume delineation of treatment. The study protocol was approved by clinical the prostate and risk organs. The dose constraints for the research ethics committees of the six participating hos- HDR-BT boost after EBRT were as follows: PTV with V100 pitals. Written informed consent was obtained from all ≥ 98%, V150 ≤ 50%, and 105% < D90 < 115%. The constraints patients. for the rectum were: D2cc ≤ 75% and Dmax < 100%; and for Staging and risk group classification were performed the urethra: D2% < 120%. The details of radiotherapy tech- using a TNM staging system of the American Joint Com- nique performed at our center have been published else- mittee on Cancer [10] and a risk group classification sys- where [15]. The HDR-BT boost was administered using tem developed by D’Amico et al. [11]. a temporary iridium-192 implant in one or two fractions Inclusion criteria were biopsy-proven high-risk PCa separated by 6 hours: 21 patients (23.5%) received one frac- (≥ stage T2c, prostate specific antigen [PSA] > 20 ng/ml, tion (20/2: 9 Gy and 1/21: 9.5 Gy) and 68 patients (76.4%) or Gleason > 7) without previous transurethral resection. received two fractions (dose range, 6-11.5 Gy). For the pa- tients treated with EBRT + HDR-BT, the mean EBRT dose Clinical evaluation was 51.08 Gy and the mean BT dose was 17 Gy. Serum PSA levels were measured at all follow-up Assessment of HRQL visits, performed every six months for the first two years and annually thereafter. Biochemical failure was defined Health-related quality of life questionnaires were ad- as an increase in PSA levels ≥ 2 ng/ml above the nadir af- ministered telephonically by trained interviewers with ter radiotherapy, in accordance with updated recommen- wide expertise on this population, before treatment and dations from the Radiation Therapy Oncology Group- during follow-up at 1, 3, 6, 12, 24, 36, 48, and 60 months ASTRO Phoenix consensus panel [12]. after the treatment. Journal of Contemporary Brachytherapy (2021/volume 13/number 1) Five-year quality of life in patients with high-risk localized prostate cancer treated with external beam radiotherapy alone versus external beam radiotherapy with high-dose-rate brachytherapy boost: a prospective multicenter study 3 HRQL was evaluated using validated Spanish-lan- All patients received neoadjuvant ADT. Adjuvant ADT guage versions of the following instruments: Short was prescribed for 2-3 years in accordance with clinical form-36 (SF-36), version 2 [16], Functional Assessment guidelines [13], although the final date of ADT adminis- of Cancer Therapy – general and prostate (FACT-G and tration was not registered. FACT-P) [17], Expanded Prostate Cancer Index compos- Table 1 shows patients’ clinical characteristics at base- ite (EPIC) [18], and International Prostate Symptom Score line, mean pre-treatment HRQL scores, and response (IPSS) [19]. The SF-36 contains 36 items with two summa- rate during follow-up. The only statistically significant ry scores: the physical and mental component summary differences between treatment groups at baseline were (PCS and MCS), with scores ranging from 0 to 100 on each a slightly higher mean number of comorbidities in the dimension. The FACT-G (version 4.0) contains 27 items in EBRT group (3.1 with EBRT vs. 2.5 with EBRT + HDR-BT, four dimensions, measuring physical, social, emotional, p = 0.043) and a higher SF-36 PCS score in the EBRT + and functional well-being. The prostate module (FACT-P) HDR-BT group (50.8 vs. 53, p = 0.04). Overall, the re- is specific for PCa patients and includes 12 questions sponse rate to the HRQL questionnaires during the study about urinary symptoms, bowel and sexual function, and period was high in both study groups: at 5-years of fol- pain. Scores range from 0 to 108 on the FACT-G and from low-up, the response rate was 100% (EBRT) and 97.1% 0-48 on the FACT-P. The 50-item EPIC instrument evalu- (EBRT-BT), without significant between-group differenc- ates four domains (urinary, bowel, sexual, and hormon- es (p = 0.354). al), with two urinary scales that distinguish between irri- Mean changes in QoL scores from baseline to 5-year tative/obstructive symptoms and incontinence. The final follow-up are shown in Table 2. Compared with patients score ranges from 0 to 100. Higher scores indicate better treated with EBRT + HDR-BT, the EBRT alone group had quality of life (QoL) in all these questionnaires. significantly lower (worse) hormonal scores (–10.6 vs. The IPSS assesses urinary symptoms, with one ques- –2.4, respectively, p = 0.028). tion about HRQL. The total score range from 0 to 35, with Tables 3 and 4 present the results from GEE models higher score indicating worse symptoms. constructed for the specific and generic HRQL scores, re- spectively. For the EBRT alone group, statistically signif- Sample size icant differences from baseline were only found 5 years after the treatment for FACT-P (β = –2.4), EPIC bowel and Sample size calculations were based on expected be- hormonal (β = –3.1 and β = –10.4, respectively), among tween-group differences on change of HRQL scores as the specific HRQL scores evaluated. No statistically sig- being the principal objective of the present study. It was nificant differences were found between the two treat- calculated that a total of 129 patients would be required to ment groups, with the exception of a lower impact on the detect a difference in change between treatments’ groups hormonal domain at the EBRT + HDR-BT group. of 0.5 standard deviation in any HRQL score, given a sta- At 5-years post-treatment, the EBRT alone group tistical power of at least 80% at a significance level of 5%. showed greater deterioration in SF-36 PCS (β = –9.8 at years) and in SF-36 MCS (β = –7.1) compared to the com- Statistical analysis bined group. The same pattern was demonstrated by al- Categorical variables were expressed as frequencies and most all FACT-G domains (Table 3). percentages, and continuous variables as mean and stan- Figures 1 and 2 show the differences between groups dard deviation (SD). Differences in the distribution of vari- in the mean HRQL scores during 5-year follow-up. We ables between the study groups were compared using chi- did not observe any substantial short- or long-term dif- square (χ2) test or one-way analysis of variance (ANOVA) ferences between the groups. Moreover, no statistically with post-hoc Tukey’s procedure, whenever appropriate. significant differences in BRFS, OS, and CSS between the To assess HRQL changes over time, while accounting study groups were observed (Figures 3-5). for correlation among repeated measures, separate gener- alized estimating equation (GEE) models were construct- Discussion ed for each specific HRQL score (FACT-P and EPIC) and for the generic ones (SF-36 and FACT-G), all included as Health-related quality of life is an important outcome dependent variables. Time was included in the model measure in patients with prostate cancer. However, long- as a categorical variable, and interactions between treat- term differences in HRQL outcomes in these patients ment and time were considered to test differences in have rarely been reported. Most of the available data on trends among treatment groups, after adjusting for age, HRQL comes from studies, which have assessed the im- risk group, and pre-treatment prostate volume. pact of treatment (BT, RP, and EBRT) on low- and inter- Differences in BRFS, OS, and CSS at 5 years were an- mediate-risk patients [20,21,22]. Few studies have com- alyzed with Kaplan-Meier method and log-rank test. Sta- pared EBRT alone to EBRT + HDR-BT in high-risk PCa tistical significance was set at p < 0.05. SPSS, v.22.0 and patients in terms of HRQL [23,24]. SAS/STAT®, v.9.4. were used to perform data analyses. In our study, we did not observe any significant be- tween-group differences in mean changes in the HRQL questionnaire scores from baseline to 5-year follow-up. Results However, we did notice a significant difference in the The study population was comprised of 129 patients, EPIC hormonal domains. Although both groups experi- 41 treated with EBTR alone and 88 with EBRT + HDR-BT. enced substantial deterioration in this domain, the EBRT Journal of Contemporary Brachytherapy (2021/volume 13/number 1) 4 Evelyn Martínez, Olatz Garin, Yolanda Pardo, et al. Table 1. Patients’ characteristics and quality of life scores at pre-treatment evaluation and response rate at each follow-up assessment Variables EBRT EBRT + HDR brachytherapy P-value (n = 41) (n = 88) Age (years), mean (SD) 71.1 (5.6) 70.5 (38.5) 0.921 PSA (ng/ml), mean (SD) 28.7 (46.8) 19.8 (13.8) 0.103 ≤ 10 12 (29.3) 30 (34.1) 0.771 10-20 12 (29.3) 21 (23.9) > 20 17 (41.5) 37 (42.0) Gleason score, mean (SD) 7.3 (0.8) 7.0 (1.1) 0.142 <7 6 (15.0) 27 (30.7) 0.060 ≥7 34 (85.0) 61 (69.3) Clinical T stage, n (%) T1 5 (12.2) 6 (6.8) 0.581 T2 15 (36.6) 36 (40.9) T3 21 (51.2) 46 (52.3) Prostate volume, mean (SD) 44.6 (29.8) 40.5 (19.0) 0.520 Comorbidities, n (%) 3.1 (1.7) 2.5 (1.5) 0.043 0 1 (2.4) 8 (9.1) 0.465 1 7 (17.1) 19 (21.6) 2 8 (19.5) 14 (15.9) 3 25 (61.0) 47 (53.4) Quality of life scores, mean (SD) SF-36 PCS 50.8 (7.2) 53.0 (4.4) 0.040 SF-36 MCS 56.2 (5.3) 55.3 (5.3) 0.362 FACT-G 79.2 (10.0) 79.6 (7.4) 0.777 FACT-P 38.0 (5.2) 39.0 (4.0) 0.237 FACT physical well-being 26.4 (2.4) 26.7 (1.8) 0.453 FACT social well-being 17.5 (3.9) 17.8 (2.9) 0.613 FACT emotional well-being 19.2 (3.7) 18.9 (3.3) 0.677 FACT functional well-being 16.2 (3.8) 16.3 (3.3) 0.954 EPIC urinary Incontinence 90.8 (17.2) 94.8 (14.6) 0.181 Irritative/obstructive 94.1 (9.1) 93.2 (10.3) 0.662 EPIC bowel 97.8 (7.6) 98.5 (3.6) 0.477 EPIC sexual 38.6 (23.2) 37.2 (23.4) 0.742 EPIC hormonal 93.7 (8.6) 90.8 (10.6) 0.135 IPSS 9.0 (7.9) 6.6 (6.5) 0.078 Response rate HRQL questionnaires, n (%) Pre-treatment 41/41 (100.0) 88/88 (100.0) Follow-up, month 1 34/41 (82.9) 50/88 (56.8) 0.004 Follow-up, month 3 40/41 (97.6) 78/88 (88.6) 0.091 Follow-up, month 6 39/40 (97.5) 81/87 (93.1) 0.313 Follow-up, month 12 39/40 (97.5) 79/86 (91.9) 0.227 Follow-up, month 24 39/39 (100.0) 79/83 (95.2) 0.163 Follow-up, month 36 34/37 (91.9) 65/82 (79.3) 0.088 Follow-up, month 48 24/33 (72.7) 73/77 (94.8) 0.001 Follow-up, month 60 29/29 (100.0) 67/69 (97.1) 0.354 EBRT – external beam radiotherapy, HDR – high-dose-rate, SF-36 – medical outcomes study 36-item short form, PCS – physical component summary, MCS – mental component summary, FACT-G and FACT-P – Functional Assessment of Cancer Therapy (general and prostate module), EPIC – Expanded Prostate Cancer Index com- posite, IPSS – International Prostate Symptom Score. Data as frequencies and percentages in parenthesis unless otherwise stated Journal of Contemporary Brachytherapy (2021/volume 13/number 1) Five-year quality of life in patients with high-risk localized prostate cancer treated with external beam radiotherapy alone versus external beam radiotherapy with high-dose-rate brachytherapy boost: a prospective multicenter study 5 Table 2. Mean differences in scores in HRQL questionnaires at 5 years of follow-up as compared with baseline Variables EBRT EBRT + HDR brachytherapy P-value (n = 41) (n = 88) SF-36 PCS –10.2 (8.5) –7.2 (8.7) 0.121 SF-36 MCS –6.3 (11.1) –2.7 (10.5) 0.131 FACT physical well-being –3.0 (4.9) –1.9 (3.7) 0.212 FACT social well-being –2.1 (3.6) –1.6 (2.8) 0.433 FACT emotional well-being –2.5 (4.0) –1.6 (3.6) 0.290 FACT functional well-being –1.0 (5.2) 1.0 (4.6) 0.062 FACT-G –8.7 (12.5) –4.2 (10.2) 0.064 FACT-P –2.6 (6.3) –2.6 (5.7) 0.989 EPIC domains Urinary incontinence –6.1 (24.7) –12.8 (24.8) 0.238 Urinary irritative/obstructive –4.8 (22.7) –8.6 (19.1) 0.416 Bowel –2.5 (7.2) –3.6 (11.1) 0.614 Sexual 0.8 (30.1) –0.8 (26.4) 0.798 Hormonal –10.6 (17.2) –2.4 (16.2) 0.028 IPSS –0.8 (11.1) –3.2 (9.1) 0.263 EBRT – external beam radiotherapy, HDR – high-dose-rate, SF-36 – medical outcomes study 36-item short form, PCS – physical component summary, MCS – mental component summary, FACT-G and FACT-P – Functional Assessment of Cancer Therapy (general and prostate module), EPIC – Expanded Prostate Cancer Index com- posite, IPSS – International Prostate Symptom Score. Data expressed as mean difference (standard deviation, SD) alone group had significantly lower (worse) hormonal probably because of the small number of patients. Certain- scores at 5-year follow-up. Moreover, the GEE model re- ly, the lack of significant differences in survival outcomes in vealed greater worsening mainly in the FACT-P, FACT-G, our study may be due to the limited sample size, which was SF-36, and bowel domain in the EBRT group in the fifth- powered to detect differences in the main study variable year post-treatment. The greater deterioration of hormon- (HRQL), but not for survival outcomes. al and sexual scores was most marked until the second Other authors, such as Ferrer et al. [18], have reported year after the treatment. After this time point, there was that the addition of ADT causes temporary deterioration a trend towards an improvement in these scores, proba- in some HRQL domains, a finding that is consistent with bly due to the finalization of ADT and the consequent im- the worsening observed in our patients in the EPIC hor- provement in ADT-related side effects. This finding could monal domain. Those authors observed that ADT was be due to the slightly better (p = 0.135) baseline EPIC hor- associated with worse results related to vitality, hormon- monal summary scores in the EBRT group. al function, and sexuality. Only a few studies with long Overall, findings of this study suggest that EBRT follow-up have been performed to assess HRQL in pa- alone or combined with HDR-BT appear to have similar tients with high-risk PCa [22,27]. In this group of patients, effects on HRQL. However, in our sample, patients in it is necessary to achieve the most appropriate treatment the BT boost group had fewer comorbidities at baseline, to improve local control with the lowest toxicity and the which could partially explain why we observed no major best possible HRQL. between-group differences. Indeed, this probably also ex- The main limitations of our study are the relatively plains why they were eligible for HDR-BT boost. Further small study population, the differences in group size, and studies with longer series and longer follow-up would the lack of randomization. Another limitation is the use of provide more information about the impact of these ra- conformal 3D-RT rather than more advanced techniques, diotherapy modalities on HRQL. such as intensity modulated radiation therapy (IMRT) or Dose escalation with EBRT followed by brachythera- volumetric modulated arc therapy (VMAT). However, py boost have been shown to improve BRFS [5,15,25]. In during the study period (2004-2006), neither of those tech- the ASCENDE-RT trial [26], patients were randomized niques was available in the participating hospitals. Never- to dose-escalated EBRT (78 Gy) or EBRT plus low-dose- theless, given the similar clinical characteristics at baseline rate BT boost. The patients in the boost group were twice in the two groups, the comparison can be considered val- as likely to be free of biochemical failure at a median of id. Study strengths include the prospective design and the 6.5 years of follow-up, without significant differences in OS. fact that the same two trained interviewers administered Theoretically, dose escalation with HDR allows for an in- all HRQL questionnaires during the entire period of study. crease in biologically-effective dose, improving tumor con- trol and sparing organs at risk [22]. However, in our series, Conclusions we found no statistical significance between-group differ- ences in BRFS, OS, or CSS. Moreover, our BRFS results dif- In the present study, EBRT administered alone or in fer from those reported in randomized trials [22,23,25,26], combination with HDR-BT boost had a similar impact on Journal of Contemporary Brachytherapy (2021/volume 13/number 1) Table 3. Generalized estimating equation models of the association between treatment groups and clinical variables with specific HRQL scores at each year of 6 follow-up. β coefficients (standard error) FACT-P EPIC urinary EPIC urinary EPIC EPIC EPIC incontinence irritative/obstructive bowel summary sexual summary hormonal summary β (SE) P-value β (SE) P-value β (SE) P-value β (SE) P-value β (SE) P-value β (SE) P-value Intercept 41.9 (2.1) < 0.0001 104.1 (9.5) < 0.001 100.6 (8.6) < 0.001 103.8 (5.4) < 0.001 60.2 (6.8) < 0.001 98.0 (7.4) < 0.001 Age 0.0 (0.0) 0.004 0.0 (0.0) 0.019 –0.1 (0.0) < 0.001 0.0 (0.0) 0.475 0.0 (0.0) 0.043 0.0 (0.0) 0.096 Gleason –0.1 (0.3) 0.663 –1.2 (1.1) 0.268 –0.1 (1.2) 0.930 –0.6 (0.7) 0.352 –1.2 (0.8) 0.124 0.9 (0.9) 0.314 PSA 0.0 (0.0) 0.334 0.1 (0.0) 0.045 0.0 (0.0) 0.158 0.0 (0.0) 0.648 0.0 (0.0) 0.053 –0.1 (0.0) 0.001 Chronic conditions –1.2 (0.3) < 0.0001 –1.0 (1.1) 0.344 –1.7 (1.2) 0.149 –0.9 (0.7) 0.199 –4.3 (1.1) < 0.001 –3.0 (0.8) 0.000 Treatment group (differences at baseline) Radiotherapy (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) Radiotherapy + brachytherapy 0.7 (1.0) 0.437 2.1 (3.1) 0.485 0.0 (2.1) 0.991 0.4 (1.3) 0.745 –2.6 (4.4) 0.549 –4.0 (2.0) 0.047 Time (radiotherapy change from baseline) Baseline (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) 1 month –4.2 (0.9) < 0.0001 –4.2 (2.7) 0.129 –16.3 (3.4) < 0.001 –8.5 (1.9) < 0.001 –12.9 (3.8) 0.001 –7.6 (2.1) 0.000 3 months –2.4 (0.7) 0.001 0.8 (3.3) 0.810 –6.3 (2.5) 0.013 –2.9 (1.4) 0.042 –11.8 (3.6) 0.001 –9.9 (1.9) < 0.001 6 months –1.8 (0.9) 0.037 –0.2 (2.3) 0.927 –1.9 (2.4) 0.424 –0.4 (1.6) 0.827 –12.3 (3.9) 0.002 –11.6 (2.5) < 0.001 12 months (1 year) –1.7 (0.8) 0.040 –5.2 (2.9) 0.073 –3.9 (2.3) 0.090 –0.7 (1.0) 0.465 –12.5 (3.9) 0.001 –17.1 (3.6) < 0.001 24 months (2 years) –4.1 (1.1) < 0.0001 –7.5 (3.6) 0.036 –5.9 (2.8) 0.036 –3.3 (1.7) 0.052 –10.9 (4.4) 0.014 –18.0 (3.4) < 0.001 36 months (3 years) –2.7 (1.1) 0.017 –4.4 (3.6) 0.224 –11.4 (3.5) 0.001 –3.9 (2.4) 0.101 –4.2 (4.5) 0.354 –11.0 (3.2) 0.001 48 months (4 years) –3.0 (1.2) 0.014 –6.8 (4.6) 0.140 –6.3 (3.1) 0.041 –4.3 (2.1) 0.035 1.0 (5.2) 0.840 –12.7 (3.4) 0.000 60 months (5 years) –2.4 (1.2) 0.039 –6.9 (4.2) 0.100 –5.3 (4.1) 0.193 –3.1 (1.5) 0.045 4.6 (5.2) 0.372 –10.4 (3.1) 0.001 Interaction radiotherapy + brachytherapy * Time (difference from radiotherapy) Baseline (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) 1 month 0.1 (1.1) 0.960 2.2 (3.5) 0.542 –1.2 (4.6) 0.789 –8.5 (3.2) 0.007 1.9 (4.6) 0.682 2.0 (2.7) 0.470 3 months –0.3 (0.9) 0.751 –3.6 (3.7) 0.333 –2.5 (3.1) 0.427 –4.6 (2.0) 0.025 0.9 (4.3) 0.836 2.5 (2.4) 0.296 6 months –0.2 (1.0) 0.868 –0.1 (2.9) 0.959 –3.7 (2.9) 0.195 –5.7 (2.2) 0.010 3.0 (4.7) 0.527 3.3 (3.0) 0.270 12 months (1 year) –1.3 (1.0) 0.200 –2.1 (3.5) 0.558 –4.6 (3.1) 0.147 –5.2 (1.8) 0.003 5.5 (4.8) 0.253 5.9 (4.2) 0.156 24 months (2 years) 1.7 (1.2) 0.157 –4.4 (4.5) 0.335 –3.8 (3.6) 0.288 –3.5 (2.4) 0.138 7.7 (5.5) 0.162 9.1 (4.0) 0.023 36 months (3 years) –0.4 (1.3) 0.785 –9.6 (4.8) 0.048 –0.4 (4.4) 0.935 –6.2 (3.3) 0.057 5.5 (5.5) 0.318 5.5 (3.8) 0.148 48 months (4 years) –0.1 (1.4) 0.969 –3.5 (5.5) 0.521 –4.8 (4.0) 0.228 –2.6 (2.7) 0.328 –1.0 (6.1) 0.873 7.8 (4.0) 0.049 60 months (5 years) –0.3 (1.3) 0.815 –5.7 (5.1) 0.267 –2.7 (4.6) 0.565 –0.6 (2.1) 0.757 –4.6 (5.9) 0.434 8.1 (3.6) 0.025 HRQL – health-related quality of life, FACT-G and FACT-P – Functional Assessment of Cancer Therapy (general and prostate module), EPIC – Expanded Prostate Cancer Index composite; SE – standard error. Time was included in the model as a categorical variable with six categories, so as not to assume a linear association: baseline (reference), month 12, month 24, month 36, month 48, and month 60. Interaction variables between each treatment group and time Evelyn Martínez, Olatz Garin, Yolanda Pardo, et al. Journal of Contemporary Brachytherapy (2021/volume 13/number 1) were included: for interaction with external beam radiotherapy, coefficients refer to changes from baseline, and for the external beam radiotherapy with HDR brachytherapy boost group, coefficients refer to difference from the external beam radiotherapy group (reference group) in the changes from baseline Table 4. Generalized estimating equation models of the association between treatment groups and clinical variables with generic HRQL scores at each year of follow-up. β coefficients (standard error) SF-36 physical compo- SF-36 mental compo- FACT FACT FACT FACT nent summary nent summary physical well-being social well-being emotional well-being functional well-being β (SE) P-value β (SE) P-value β (SE) P-value β (SE) P-value β (SE) P-value β (SE) P-value Intercept 56.1 (3.6) < 0.001 53.8 (3.8) < 0.0001 27.9 (1.5) < 0.0001 18.4 (1.3) < 0.0001 22.3 (2.0) < 0.0001 15.8 (2.0) < 0.0001 Age 0.0 (0.0) 0.007 0.0 (0.0) 0.002 0.0 (0.0) 0.531 0.0 (0.0) 0.373 0.0 (0.0) 0.747 0.0 (0.0) 0.191 Gleason 0.1 (0.5) 0.844 0.4 (0.5) 0.350 0.1 (0.2) 0.760 –0.1 (0.2) 0.416 –0.2 (0.2) 0.371 0.3 (0.2) 0.214 PSA 0.0 (0.0) 0.373 0.0 (0.0) 0.235 0.0 (0.0) 0.318 0.0 (0.0) 0.001 0.0 (0.0) 0.056 0.0 (0.0) 0.597 Chronic conditions –2.2 (0.4) < 0.001 –0.5 (0.4) 0.223 –0.7 (0.2) < 0.0001 –0.1 (0.2) 0.538 –0.6 (0.2) 0.007 –0.8 (0.2) 0.001 Treatment group (differences at baseline) Radiotherapy (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) Radiotherapy + brachytherapy 1.7 (1.1) 0.130 –1.1 (1.0) 0.252 0.1 (0.4) 0.803 0.3 (0.7) 0.620 –0.5 (0.7) 0.478 –0.2 (0.7) 0.811 Time (radiotherapy change from baseline) Baseline (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) 1 month –2.0 (1.1) 0.073 –0.4 (1.1) 0.702 –1.9 (0.5) 0.000 –1.5 (0.5) 0.003 1.0 (0.5) 0.042 –2.0 (0.5) 0.000 3 months –2.6 (0.9) 0.005 0.0 (0.8) 0.968 –1.3 (0.4) 0.002 –1.3 (0.6) 0.037 1.5 (0.5) 0.003 –0.9 (0.5) 0.061 6 months –3.2 (1.5) 0.033 –0.2 (1.3) 0.867 –1.4 (0.6) 0.030 –1.3 (0.6) 0.023 1.1 (0.8) 0.146 –1.3 (0.7) 0.056 12 months (1 year) –4.7 (1.0) < 0.001 –2.6 (1.6) 0.103 –2.0 (0.6) 0.001 –1.8 (0.6) 0.003 –0.7 (0.6) 0.270 –0.8 (0.7) 0.256 24 months (2 years) –6.6 (1.3) < 0.001 –3.6 (2.1) 0.082 –2.3 (0.6) 0.000 –1.4 (0.5) 0.007 –2.0 (0.8) 0.011 –1.4 (0.8) 0.076 36 months (3 years) –6.6 (1.1) < 0.001 –5.7 (2.1) 0.006 –2.8 (0.9) 0.002 –0.8 (0.7) 0.234 –2.8 (0.7) < 0.0001 –0.4 (0.8) 0.600 Journal of Contemporary Brachytherapy (2021/volume 13/number 1) 48 months (4 years) –8.1 (1.6) < 0.001 –5.7 (2.3) 0.013 –3.2 (1.1) 0.004 –1.7 (0.7) 0.020 –2.6 (0.8) 0.002 –0.8 (1.0) 0.445 60 months (5 years) –9.8 (1.6) < 0.001 –7.1 (2.0) 0.001 –2.6 (0.8) 0.001 –1.5 (0.7) 0.032 –2.5 (0.7) 0.000 –1.2 (0.9) 0.155 beam radiotherapy with high-dose-rate brachytherapy boost: a prospective multicenter study Interaction radiotherapy + brachytherapy * Time (difference from radiotherapy) Baseline (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) (ref.) 1 month –0.7 (1.4) 0.602 0.0 (1.3) 0.977 –0.1 (0.7) 0.854 1.2 (0.7) 0.092 –0.4 (0.6) 0.544 0.1 (0.8) 0.923 3 months –0.5 (1.2) 0.669 0.6 (1.1) 0.565 –0.3 (0.5) 0.617 0.8 (0.7) 0.279 –0.6 (0.6) 0.321 1.0 (0.7) 0.118 6 months 0.0 (1.7) 0.994 0.9 (1.4) 0.542 0.2 (0.7) 0.810 0.4 (0.7) 0.613 0.1 (0.8) 0.939 1.0 (0.8) 0.201 12 months (1 year) –0.2 (1.2) 0.859 3.1 (1.8) 0.089 –0.1 (0.7) 0.939 0.7 (0.7) 0.287 0.5 (0.7) 0.436 0.6 (0.8) 0.471 24 months (2 years) 1.8 (1.5) 0.235 0.3 (2.5) 0.887 0.2 (0.8) 0.806 0.4 (0.6) 0.574 0.9 (0.9) 0.319 1.1 (1.0) 0.265 36 months (3 years) –1.1 (1.6) 0.500 3.9 (2.4) 0.111 0.2 (1.0) 0.859 0.5 (0.8) 0.495 0.4 (0.9) 0.649 0.9 (1.0) 0.360 48 months (4 years) 0.6 (1.9) 0.740 2.2 (2.7) 0.415 0.5 (1.2) 0.666 0.3 (0.8) 0.719 0.3 (1.0) 0.790 1.0 (1.2) 0.412 60 months (5 years) 2.3 (1.9) 0.220 3.9 (2.4) 0.101 0.6 (0.9) 0.527 0.1 (0.8) 0.918 0.8 (0.8) 0.341 2.0 (1.0) 0.052 Five-year quality of life in patients with high-risk localized prostate cancer treated with external beam radiotherapy alone versus external HRQL – health-related quality of life, SF-36 – medical outcomes study 36-item short form, FACT-G and FACT-P – Functional Assessment of Cancer Therapy (general and prostate module), SE – standard error. Time was included in the model as a categorical variable with six categories, so as not to assume a linear association: baseline (reference), month 12, month 24, month 36, month 48, and month 60. Interaction variables between each treatment group and time 7 were included: for interaction with external beam radiotherapy, coefficients refer to changes from baseline, and for the external beam radiotherapy with HDR brachytherapy boost group, coefficients refer to difference from the external beam radiotherapy group (reference group) in the changes from baseline 8 Evelyn Martínez, Olatz Garin, Yolanda Pardo, et al. A B 60 60 55 55 SF-36 MCS SF-36 PCS 50 50 45 45 40 40 0* 1 3 6 12 24* 36 48 60 01 3 6 12 24 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR C D 100 100 EPIC urinary incontinence EPIC urinary obstructive, 80 80 60 irritative 60 40 40 01 3 6 12 24 36 48 60 01 3 6 12 24 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR E F 100 100 EPIC sexual summary EPIC bowel summary 80 80 60 60 40 40 0 1 3 6* 12 24 36 48 60 01 3 6 12 24 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR G H 100 35 EPIC hormonal summary 30 80 25 20 IPSS 60 15 40 10 5 0 01 3 6 12 24 36 48 60 01 3 6 12 24 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR Fig. 1. Differences between EBRT alone and EBRT combined with HDR brachytherapy regarding the impact on mean scores of HRQL questionnaires during the 5 years of follow-up for short form-36 (SF-36) physical component score (PCS; A); SF-36 mental component score (MCS; B); expanded prostate cancer index composite (EPIC) urinary incontinence (C), urinary obstructive/irrita- tive (D), bowel (E), sexual (F), hormonal domains (G), and international prostate symptom score (IPSS; H); one-way analysis of vari- ance of QoL scores among the two treatment groups for each follow-up assessment; Tukey’s studentized range pos-hoc comparisons: *p < 0.05 for external-beam radiotherapy (grey) vs. external-beam radiotherapy combined with HDR brachytherapy boost (black) Journal of Contemporary Brachytherapy (2021/volume 13/number 1) Five-year quality of life in patients with high-risk localized prostate cancer treated with external beam radiotherapy alone versus external beam radiotherapy with high-dose-rate brachytherapy boost: a prospective multicenter study 9 A B 100 100 80 80 FACT prostate FACT general 60 60 40 40 01 3 6 12 24 36 48 60 01 3 6 12 24* 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR C D 35 35 FACT physical well-being 30 30 FACT social well-being 25 25 20 20 15 15 10 10 5 5 0 0 01 3 6 12 24 36 48 60 01 3 6 12 24 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR E F 30 35 FACT functional well-being FACT emotional well-being 25 30 25 20 20 15 15 10 10 5 5 0 0 01 3 6 12 24 36 48 60 01 3 6 12 24 36 48 60 Month Month EBRT EBRT-HDR EBRT EBRT-HDR Fig. 2. Differences between EBRT alone and EBRT combined with HDR brachytherapy regarding the impact on mean scores in HRQL questionnaires during 5 years of follow-up for functional assessment cancer therapy-general (FACT-general; A) and prostate-specific (FACT-prostate; B); FACT physical well-being (C); FACT social well-being (D); FACT emotional well-being (E) and FACT functional well-being (F). One-way analysis of variance of QoL scores among the two treatment groups for each follow-up assessment. Tukey’s studentized range post-hoc comparisons: *p < 0.05 for external-beam radiotherapy (grey) vs. external-beam radiotherapy combined with HDR brachytherapy boost (black) HRQL in patients with high-risk localized PCa over 5-year haps due to the higher EPIC hormonal summary scores at follow-up. However, patients in the EBRT alone group baseline in this group. Longer follow-up would be need- experienced significantly greater worsening in hormonal ed to minimize the effects of ADT on HRQL and to deter- symptoms (EPIC questionnaire) at 5-year follow-up, per- mine the best treatment in terms of HRQL. Journal of Contemporary Brachytherapy (2021/volume 13/number 1) 10 Evelyn Martínez, Olatz Garin, Yolanda Pardo, et al. 1.0 1.0 Biochemical relapse-free survival 0.8 0.8 Overall survival 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Time (in years) Time (in years) Treatment Treatment EBRT EBRT + HDR EBRT EBRT + HDR Fig. 3. Biochemical relapse-free survival curves in pa- Fig. 4. Overall survival curves in patients treated with tients treated with EBRT alone and EBRT + HDR-BT. EBRT alone and EBRT + HDR-BT. Kaplan-Meier method Kaplan-Meier method and log-rank test: *p < 0.05 for ex- and log-rank test: *p < 0.05 for external-beam radiothera- ternal-beam radiotherapy (black) vs. external-beam radio- py (black) vs. external-beam radiotherapy combined with therapy combined with HDR brachytherapy boost (grey) HDR brachytherapy boost (grey) Acknowledgments 1.0 The authors would like to thank Marta Pulido, MD, and Bradley Londres for professional English language 0.8 editing. Cancer specific survival Disclosure 0.6 The authors report no conflict of interest. References 0.4 1. Chen RC, Basak R, Meyer AM et al. Association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and patient-reported quality of life among men with localized prostate cancer. 0.2 JAMA 2017; 317: 1141-1150. 2. Sheets NC, Goldin GH, Meyer AM et al. Intensity-modulat- ed radiation therapy, proton therapy, or conformal radiation 0 therapy and morbidity and disease control in localized pros- tate cancer. JAMA 2012; 307: 1611-1620. 0 1 2 3 4 5 3. Hamdy FC, Donovan JL, Lane JA et al. 10-year outcomes af- Time (in years) ter monitoring, surgery, or radiotherapy for localized pros- Treatment tate cancer. N Engl J Med 2016; 375: 1415-1424. EBRT EBRT + HDR 4. Kee DLC, Gal J, Falk AT et al. Brachytherapy versus exter- Fig. 5. Cancer-specific survival curves in patients treated nal beam radiotherapy boost for prostate cancer: Systematic review with meta-analysis of randomized trials. Cancer Treat with EBRT alone and EBRT + HDR-BT. Kaplan-Meier Rev 2018; 70: 265-271. method and log-rank test: *p < 0.05 for external-beam ra- 5. Hoskin PJ, Rojas AM, Bownes PJ et al. 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