Advertisement

Health-related Quality of Life of Patients Treated with Different Fractionation Schedules for Early Prostate Cancer Compared to the Age-standardized General Male Population

Open AccessPublished:August 02, 2022DOI:https://doi.org/10.1016/j.clgc.2022.07.013

      Bullet points

      • The overall health-related quality of life (HRQoL) of the patients with an early prostate cancer treated with modern image guided RT techniques and without hormonal treatment is equal at three years after treatment to the age-standardized general male population measured with the 15D instrument.
      • More support to the patients with an early prostate cancer should be given in mental health issues at the beginning of treatment and in the sexual issues after the treatment.
      • The HRQoL of the patients with an early prostate cancer treated with three different radiotherapy fractionation was measured with the 15D instrument and The Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and compared. Continuation to treat with stereotactic body radiotherapy seems rational regarding to the HRQoL results.

      Abstract

      Background

      The effects of radiotherapy (RT) patients’ health-related quality of life (HRQoL) are usually compared to those of other treatment modalities instead of HRQoL of the general population in oncological studies. We examined HRQoL of patients with an early prostate cancer (PC) not receiving hormonal treatment up to three years after RT using the 15D instrument and the FACT-P questionnaire.

      Methods

      The 15D results were compared to those in the age-standardized general male population (N = 952) using an independent-sample t test. The study population (N = 73) received RT either with 78/2 Gy, 60/3 Gy or 36.25/7.25 Gy fractionation.

      Results

      No significant differences in the mean total HRQoL scores were found between the RT groups and the general male population at any time point. Patients with PC had more depression (P = .015) and distress (P = .029) than the general male population before the treatment and depression up to three months after treatment (P = .019), which did not persist at three years. The sexual activity dimension had declined by the end of treatment, and this decline persisted three years later (P = .033). Excretion functions were worse compared to those in peers at the end of treatment (P < .001) but no longer at three months and later after RT. Regarding the FACT-P, HRQoL remained good at three years after RT in all the treatment groups and there were no significant differences between the different RT groups at this time point.

      Discussion

      This study demonstrated that patients treated with RT for early PC had similar HRQoL compared to the age-standardized general male population at three years after treatment.

      Keywords

      Introduction

      External beam therapy (EBRT) along with radical prostatectomy (RP), is the gold standard for the treatment of local prostate cancer (PC).
      • Schaeffer EM
      • Srinivas S
      • Antonarakis ES
      • Armstrong AJ
      • Cheng H.
      NCCN Clinical, Practice Guidelines in Oncology (NCCN Guidelines ®): Prostate Cancer. Version 2.2021.
      Over the past decades, the reporting of health-related quality of life (HRQoL) results and other patient-related outcome measures have become a norm in modern oncological research, including in EBRT for PC.
      • Bottomley A
      • Reijneveld JC
      • Koller M
      • et al.
      Current state of quality of life and patient-reported outcomes research.
      ,
      • Bottomley A
      • Pe M
      • Sloan J
      • et al.
      Moving forward toward standardizing analysis of quality of life data in randomized cancer clinical trials.
      Although PC had global the fourth highest incidence of all cancers in 2020, and the highest incidence of all cancers in Finland in 2019, the independent effects of external beam therapy on HRQoL have been relatively poorly studied in the absence of other treatments.
      • Sung H
      • Ferlay J
      • Siegel RL
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
      • Pitkäniemi J
      • Malila N
      • Tanskanen T
      • Degerlund H
      • Heikkinen S
      • Seppä K.
      Cancer In Finland 2019.
      • Taylor JM
      • Chen VE
      • Miller RC
      • Greenberger BA.
      The impact of prostate cancer treatment on quality of life: A narrative review with a focus on randomized data.
      Androgen-deprivation therapy (ADT) seems to have a detrimental effect on HRQoL, which implies that the results of studies consisting of men receiving hormonal treatment cannot be generalized to men not receiving ADT.
      • Sanda MG
      • Dunn RL
      • Michalski J
      • et al.
      Quality of Life and Satisfaction with Outcome among Prostate-Cancer Survivors.
      The primary objective of this trial was to investigate, how radiation therapy for the prostate affects HRQoL in the absence of treatment-related confounding factors. We could not find any previous studies that would have been comparing differences in HRQoL between men treated with EBRT for PC and the age-standardized general population and excluded men receiving ADT. In the New South Wales Prostate Cancer Care and Outcomes Study (PCOS) men receiving either EBRT or brachytherapy had a predetermined clinically significant difference in quality of life (QoL) in terms of bowel function up to ten years and in terms of sexual function during the whole 15 year follow-up.
      • Mazariego CG
      • Egger S
      • King MT
      • et al.
      Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
      ,
      • Smith DP
      • King MT
      • Egger S
      • et al.
      Quality of life three years after diagnosis of localised prostate cancer: population based cohort study.
      In another population-based study by Schaake et al., men treated with EBRT had worse QoL measured in role functioning, emotional functioning, social functioning, dyspnoea and insomnia compared to the general population at 3 years after EBRT.
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      This study included both men with and without hormonal treatment (proportions of 69% and 31%, respectively).
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      After the development of intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), both an increase in the fraction dose and a decrease in the target volume without additional toxicity have become possible, thus reducing side-effects and hospital visits, costs and patient inconvenience.
      • Dearnaley D
      • Syndikus I
      • Mossop H
      • et al.
      Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.
      • Line Krhili S
      • Créhange G
      • Albert-Dufrois H
      • Guimas V
      • Minsat M
      • Supiot S
      Hypofractionnement modéré ou extrême et cancers prostatiques localisés : les temps sont en train de changer.
      • Jackson WC
      • Silva J
      • Hartman HE
      • et al.
      Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies.
      Hypofractionated radiotherapy is currently the preferred form of radiotherapy for local PC recommended by National Cancer Comprehensive Network (NCCN) guidelines.
      • Schaeffer EM
      • Srinivas S
      • Antonarakis ES
      • Armstrong AJ
      • Cheng H.
      NCCN Clinical, Practice Guidelines in Oncology (NCCN Guidelines ®): Prostate Cancer. Version 2.2021.
      ,
      • Mottet N.
      • Cornford P.
      • van den Bergh R.C.N.
      EAU - EANM - ESTRO - ESUR - ISUP - SIOG Guidelines on Prostate Cancer.
      Current research, as well as our trial, focuses on ultrahypofractionated radiotherapy, which employs stereotactic body radiation therapy (SBRT), aiming to further increase the fraction dose, reduce toxicity and limit the treatment schedule even to 5 7 visits.
      • Jackson WC
      • Silva J
      • Hartman HE
      • et al.
      Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies.
      The secondary objectives were to compare HRQoL between groups undergoing either conventional, hypofractionated or ultrahypofractionated, (Stereotactic Body RT, SBRT) treatment schedules. HRQoL in men treated with ultrahypofractionated schedules has been previously studied only in two randomized controlled trials (RCTs), neither of which permitted androgen-deprivation.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ,
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      Both trials had both low- and intermediate-risk patients, the HYPO-RT-PC trial used the ASTRO classification and the PACE-B trial used the NCCN classification.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ,
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      In the HYPO-RT-PC trial, HRQoL was weaker compared in global health, role functioning, emotional functioning, pain, and diarrhoea at the end of radiation of therapy than after conventional therapy, but no difference was observed at follow-ups.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      The PACE-B trial did not find differences in HRQoL between the ultrahypofractionation and control group during the three-month follow-up at any point (the control group consisted of men receiving either conventional or hypofractionated therapy).
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      Moderate hypofractionation has been studied in at least three RCTs, which reported acceptable toxicity profile and no differences in HRQoL between hypofractionated therapy and conventional therapy.
      • Staffurth JN
      • Haviland JS
      • Wilkins A
      • et al.
      Impact of Hypofractionated Radiotherapy on Patient-reported Outcomes in Prostate Cancer: Results up to 5 yr in the CHHiP trial (CRUK/06/016).
      • Wortel RC
      • Oomen-de Hoop E
      • Heemsbergen WD
      • Pos FJ
      • Incrocci L.
      Moderate Hypofractionation in Intermediate- and High-Risk, Localized Prostate Cancer: Health-Related Quality of Life From the Randomized, Phase 3 HYPRO Trial.
      • Bruner DW
      • Pugh SL
      • Lee WR
      • et al.
      Quality of Life in Patients With Low-Risk Prostate Cancer Treated With Hypofractionated vs Conventional Radiotherapy: A Phase 3 Randomized Clinical Trial.
      At present, the treatment results of modern RT for early prostate cancer are excellent in Finland.
      • Lehtonen M
      • Heiskanen L
      • Reinikainen P
      • Kellokumpu-Lehtinen PL.
      Both comorbidity and worse performance status are associated with poorer overall survival after external beam radiotherapy for prostate cancer.
      Therefore, studying the patients’ mental and overall health after PC diagnosis is important, as the vast majority of patients are expected to recover (the metastasis-free 5-year survival almost 95 %) and compare HRQoL between the patients with PC treated using three RT fractionating schemes and the age-standardized general male population to explore the need for individual psychosocial support for patients with radically treated PC.

      Materials and Methods

      Patients and radiation therapy planning

      Men up to 85 years of age with a biopsy-confirmed localized T1c-T2cN0M0 prostate cancer with one or two intermediate risk factors (IFRs) according to NCCN criteria were eligible for this study.
      • Mohler JL
      • Kantoff PW
      • Armstrong AJ
      • et al.
      Prostate cancer, version 1.2014: Featured updates to the NCCN Guidelines.
      IFRs were T2b-T2c disease, Gleason score of 7 or a prostate-specific antigen (PSA) level of 10-20 ng/mL. Androgen deprivation therapy (ADT) or need of transurethral resection of the prostate (TURP) were exclusion criteria. Between May 2014 and December 2017, a total of 73 patients (approximately 90-95% of eligible patients) were recruited from Tampere University Hospital. The first 42 patients were treated with a fraction dose of 2 Grays (Gy), five fractions per week to a total dose of 78 Grays (78/2 Gy) or 60/3 Gy according to the clinician's decision, and the next 31 patients were then treated with a higher fraction dose: 7.25 Gy and only five times = 36.25/7.25 Gy. The Tampere University Hospital Ethics Committee approved the study (R14009), and patients provided written informed consent. The clinical trial identifier was NCT02319239 at www.ClinicalTrials.gov.
      Prior to RT, all patients had three gold fiducial markers implanted into the prostate gland under transrectal ultrasound guidance. After implantation, planning computed tomography (CT) and magnetic resonance imaging (MRI) were performed (with empty bladder and rectum). The prostate and the base of the seminal vesicles were delineated as the prostate clinical target volume (CTV). A symmetric 5-mm margin was used to achieve prostate planning target volume (PTV). If the seminal invasion (SV) risk was greater than 15%, SV sites were contoured and given 7-mm expansion as SV-PTV in the RT 78/2 Gy and 60/3 Gy groups, and the RT doses to the SV-PTV were 56/2 Gy and 46/2.3 Gy, respectively.

      Prediction Tools/Prostate Cancer Nomograms: Pre- Radical Prostatectomy. Memorial Sloan Kettering Cancer Center. www.mskcc.org.

      In the 36.25/7.25 Gy group SV sites were not included. The bladder, rectum, and femoral heads were defined as organs at risk. Treatment localization was performed by orthogonal kilo voltage (kv) imaging. In the 36.25/7.25 Gy group cone beam CT (CBCT) was used to evaluate the bladder and rectum before every treatment session. In the 78/2 Gy and 60/3 Gy groups radiotherapy was administered daily from Monday to Friday, and the 36.25/7.25 Gy group received treatment every other day for ten days. Volumetric modulated arch therapy (VMAT) with two full arcs and 6-MV flattened beams was used for treatment in all groups.

      Health-related quality of life instruments

      In this study, we used two internationally validated patient-reported outcome questionnaires in Finnish to evaluate the HRQoL of patients with PC treated with RT: the 15D instrument and the Functional Assessment of Cancer Therapy-Prostate (FACT-P). These questionnaires were completed before RT (baseline), at the end of treatment, and three months, one year, two years and three years after the RT. Altogether, 787 questionnaires were collected during the study, yielding a response rate of 92%.
      The 15D is a generic instrument with 15 dimensions (mobility, vision, hearing, breathing, sleeping, eating, speech, excretion, usual activities, mental function, discomfort and symptoms, depression, distress, vitality and sexual activity) and developed in Finland and used in different type of diseases, interventions, and compare costs using Quality Adjusted Life Years (QALYs) and is comparable to EQ-5D.
      • Vuorinen RL
      • Paunu N
      • Turpeenniemi-Hujanen T
      • et al.
      Sunitinib first-line treatment in metastatic renal cell carcinoma: Costs and effects.
      • Bergius S
      • Torvinen S
      • Muhonen T
      • Roine RP
      • Sintonen H
      • Taari K.
      Health-related quality of life among prostate cancer patients: real-life situation at the beginning of treatment.
      • Roine E
      • Sintonen H
      • Kellokumpu-Lehtinen PL
      • et al.
      Health-related quality of life of breast cancer survivors attending an exercise intervention study: A five-year follow-up.
      • Roine E
      • Sintonen H
      • Kellokumpu-Lehtinen PL
      • et al.
      • Vartiainen P
      • Mäntyselkä P
      • Heiskanen T
      • et al.
      Validation of EQ-5D and 15D in the assessment of health-related quality of life in chronic pain.
      Each dimension has five different answers ranging from no problems to extreme problems.
      • Sintonen H.
      The 15D instrument of health-related quality of life: properties and applications.
      The 15D score ranges from 0 to 1, where 1 indicates full health. The minimum clinically important change in the 15D score is interpreted as follows: |0.015-0.035| for slightly better/worse and over |0.035| for much better/worse. A 15D score change of ≥ 0.015 is considered clinically meaningful, with the patient feeling the difference in his or her wellbeing.
      • Alanne S
      • Roine RP
      • Räsänen P
      • Vainiola T
      • Sintonen H.
      Estimating the minimum important change in the 15D scores.
      An age-standardized sample of the Finnish male population (N = 952) was used as a comparison group for patients treated with RT, which was obtained from the National Health 2011 Survey.
      • Koskinen S
      • Lundqvist A
      • Ristiluoma N.
      Health, functional capacity and welfare in Finland in 2011.
      The National Health 2011 Survey was a combination of health interview and health examination aimed to obtain information on public health problems in working-aged and the aged population. It captured 7964 persons aged 30 and over living in the mainland Finland.
      The FACT-P is a validated 39-item questionnaire that was developed to measure HRQoL in men with prostate cancer and consists of five subscales: seven items for physical wellbeing (PWB), seven items for social and family wellbeing (SWB), six items for emotional wellbeing (EWB), seven items for functional wellbeing (FWB) and 12 items for the prostate cancer subscale (PCS).
      • Esper P
      • Mo F
      • Chodak G
      • Sinner M
      • Cella D
      • Pienta KJ.
      Measuring quality of life in men with prostate cancer using the Functional Assessment of Cancer Therapy-prostate instrument.
      Items are scored from zero to four and it can be worded in a positive or negative direction. The FACT-P total score ranges from 0 to 156. Higher values of total or any subscales indicate better HRQoL. The FACT-G (general) measures general HRQoL in patients with cancer and consist of 27 items (PWB, SWB, EWB and FWB). The FACT-P Trial Outcome Index (TOI) is based on physical, functional and prostate cancer -specific subscales of the FACT-P (PWB, FWB and PCS).
      One method to evaluate meaningful changes in the FACT-P total score or in its subscales at different timepoints, is to compare scores to the published minimal important difference (MID) scores. Most of the publications in this area correspond to men with metastatic prostate cancer. Meaningful changes vary from six to ten points for the total FACT-P score, from five to seven points for the FACT-P TOI score, from two to three points for the FACT-P PCS score and five to eight points for the FACT-G score, respectively.
      • Cella D
      • Nichol MB
      • Eton D
      • Nelson JB
      • Mulani P.
      Estimating Clinically Meaningful Changes for the Functional Assessment of Cancer Therapy—Prostate: Results from a Clinical Trial of Patients with Metastatic Hormone-Refractory Prostate Cancer.
      ,
      • Beaumont JL
      • Butt Z
      • Li R
      • Cella D.
      Meaningful differences and validity for the NCCN/FACT-P Symptom Index: An analysis of the ALSYMPCA data.

      Statistical analysis

      Statistical analyses were performed with IBM SPSS Statistics version 25.0 for Windows (SPSS Inc. Chicago, Illinois). The statistical significance of the difference between mean 15D scores between the general male population and patients treated with RT was tested using independent-sample t tests. The same test was used for differences between 15D scores and FACT-P scores in the RT treatment groups. Treatment changes within the RT groups before the RT and at the appointed follow-up timepoint were analysed using paired-sample t tests. If the 15D or FACT-P variables were not normally distributed, a corresponding nonparametric test was performed. The Mann-Whitney two independent samples test was used to compare two RT groups, and changes within the RT group between different time points were analysed using the Wilcoxon signed-rank test. All tests used a 2-sided P < .05 for statistical significance.

      Results

      The mean and median age of the patients treated with RT was 69 years (range 59-78 years). Most of the patients had a Gleason 3+4 disease, and the mean PSA was 9.5 ng/mL. After three years of follow-up, 66 patients were included in the study. Of the seven discontinuations, three were in 78/2 Gy group, and two in 60/3 Gy and 36.25/7.25 Gy groups. Four men developed another aggressive malignant disease that was not related to RT, and one man in 78/2 Gy group and two men in 60/3 Gy group had a biochemical relapse according to the Phoenix definition.
      • Abramowitz MC
      • Li T
      • Buyyounouski MK
      • et al.
      The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer.
      All three relapses had a Gleason 3+4 disease at baseline. The clinical demographics of the patients treated with RT are presented in Table 1.
      Table 1Patients clinical demographs
      Radiation therapy group
      AllN = 7339 × 2 GyN = 2120 × 3 GyN = 215 × 7.25 GyN = 31
      Age, years
      Mean (range)69 (59–78)68 (59–78)70 (60–78)70 (63–78)
      BMI
      Mean (range)28.1 (21.4–40.6)28.4 (21.4–40.4)27.8 (22.4–34.8)28.1 (21.8–40.6)
      BMI ≥ 30, N (%)19 (26)6 (29)5 (24)8 (26)
      Comorbidities, N (%)
      Diabetes type II17 (23)4 (19)6 (29)7 (23)
      Hypertension44 (60)11 (52)10 (48)23 (74)
      ASO11 (15)4 (19)3 (14)4 (13)
      AF8 (11)3 (14)3 (14)2 (7)
      Gleason score, N (%)
      3+321 (29)7 (33)8 (38)6 (19)
      3+449 (67)13 (62)13 (62)23 (74)
      4+33 (4)1 (5)0 (0)2 (7)
      T stage, N (%)
      T1c11 (15)2 (10)3 (14)6 (19)
      T2a18 (25)5 (24)4 (19)9 (29)
      T2b9 (12)3 (14)3 (14)3 (10)
      T2c35 (48)11 (52)11 (52)13 (42)
      PSA baseline, ng/mL
      Mean (range)9.5 (3.2–19.1)10.5 (4.0–15.2)8.7 (3.4–18.4)9.5 (3.2–19.1)
      Questionnaires returned, N (%)
      Baseline70 (96)21 (100)21 (100)28 (90)
      End of RT67 (92)21 (100)21 (100)25 (81)
      3 months70 (96)21 (100)21 (100)28 (90)
      12 months68 (93)19 (90)21 (100)28 (90)
      24 months64 (88)17 (81)20 (95)27 (87)
      36 months63 (86)18 (86)18 (86)27 (87)
      Abbreviations: Gy = Gray; BMI = Body mass index; ASO = Atherosclerosis; AF = atrial fibrillation; PSA = Prostate specific antigen; N = number of patients

      Results from the 15D instrument

      Changes in the 15D score and scores for different dimensions in patients treated with RT are demonstrated in Figure 1. No statistically significant differences in the mean 15D score were found between patients treated with RT and the general male population at the beginning of treatment or at the three-year follow-up (Table 2). The acute toxicity of RT treatments did not correspond to the 15D score at the end of RT, or at any timepoint compared to observations in the general male population. The 15D scores of the patients treated with RT ranged from 0.735 to 1.000 (mean 0.913) at the baseline. Six patients were in full health (15D score 1.000). At the end of the treatment two patients were in full health and 15D scores ranged from 0.675 to 1.000 (mean 0.898). Three years after RT, four patients had a 15D score of 1 and, 15D scores ranged from 0.504 to 1.000 (mean 0.890). The 15D score difference decrease between baseline and the three-year follow-up was statistically significant (P = .001).
      Figure 1
      Figure 1The mean 15D dimension scores of RT patients and the age-standardized general male population at different timepoints. Population 1 is the control population for the treatment group at baseline until three months and population 2 is the control population for the treatment group at 36 months. Statistically significant changes in RT patients’ dimension scores between the baseline and follow-up timepoints are marked with asterisks (*).
      Table 2The mean 15D scores and dimension values of RT patients at different timepoints compared to the age-standardized general male population.
      BaselineEnd of RT3 months after RT3 years after RT
      MeanΔMeanΔMeanΔMeanΔ
      15D score0.9130.0130.898-0.0120.899-0.0110.8900.006
      Mobility0.9340.0230.9610.048**0.9240.0110.915-0.019
      Vision0.9750.029*0.9640.0180.927-0.0190.927-0.011
      Hearing0.9270.0240.9430.040*0.9380.0350.8980.016
      Breathing0.9320.0070.9260.0010.886-0.0390.886-0.018
      Sleeping0.853-0.0060.833-0.0260.8630.0040.8630.009
      Eating1.0000.0041.0000.0041.0000.0040.983-0.010
      Speech0.9920.0170.9870.0120.9870.0120.9720.003
      Excretion0.8920.0320.721-0.139**0.8790.0190.8620.020
      Usual activities0.9160.0240.9160.0240.8990.0070.8830.018
      Mental function0.8940.047*0.9070.053*0.8850.0380.8630.041
      Discomfort and symptoms0.8300.0320.8250.0270.8300.0320.8350.046*
      Depression0.912-0.040*0.907-0.045*0.912-0.040*0.918-0.028
      Distress0.911-0.040*0.905-0.046*0.922-0.0290.934-0.010
      Vitality0.881-0.0080.8930.0040.868-0.0210.8720.002
      Sexual activity0.757-0.0360.650-0.143**0.661-0.132**0.651-0.089*
      Δ, difference compared to the age-standardized male population (positive values for better score to RT patients in comparison to general population).
      Differences between RT population and age-standardized male population were analyzed using independent-sample t test: * P < .05; ** P < .001.
      At the baseline, patients treated with RT had lower mean scores for depression and distress (P = .015 and P = .029, respectively) than the general male population. At the end of RT, these mental problems continued, and three months after the treatment, the mean dimension score for depression was still significantly lower (P = .019). However, in the end of the follow-up at three years, the mental health of the patients treated with RT was similar to the general population (P > .05 for both distress and depression). The sexual activity of patients treated with RT was also nonsignificantly lower at the baseline. Immediately and three years after the treatment sexual activity was significantly lower than that in the general male population. When bowel and bladder symptoms (Excretion) were compared, patients treated with RT had better mean scores at baseline and significantly worse scores at the end of RT (P < .001), but subsequently, no differences compared to the general male population were identified. Patients seemed to score better than the general male population for physical discomfort and symptoms at three years after RT (P = .027). Patients also had better cognitive function scores at all timepoints.
      When observing the changes within the RT groups (supplementary Table S1), the HRQoL measured by the 15D score worsened significantly in the 78/2 Gy and 60/3 Gy groups, but not in the SBRT 36.25/7.25 Gy group between baseline and three years after treatment (P = .034, P = .044 and P = .153, respectively). Bowel and bladder problems (Excretion) were present in all RT groups at the end of treatment. According to the mean dimension scores at three years after the RT, the scores in the 78/2 Gy and 60/3 Gy groups were worse than the baseline scores. Sexual activity worsened in all RT groups from baseline to the three-year of follow-up. The men in the 60/3 Gy group felt less energetic (Vitality) and more depressed (Depression) three years after RT, but they had less physical discomfort and fewer symptoms. The men in the 36.25/7.25 Gy group had more discomfort and symptoms during the follow-up. Three years after RT the men in the 78/2 Gy group had more symptoms related to ageing than the men in the other groups. The dimensions related to vision, hearing, breathing and sleeping became worse between the baseline and the three-year follow-up.
      At the end of RT, the 36.25/7.25 Gy group had a better HRQoL than the 78/2 Gy group when comparing 15D total scores (P = .023) (Figure S1). The men in the 36.25/7.25 Gy group had fewer problems with excretory functions (P = .014) and were more satisfied with their sexual activity (P = .013) at the end of RT than men in the 78/2 Gy group. The difference in the dimension of sexual activity was at three months after RT in favour of the 36.25/7.25 Gy group (P = .034). One year after treatment, the men in the 36.25/7.25 Gy group reported better HRQoL with respect to the 15D total score than the men in the 78/2 Gy group (P = .015). The men in the 36.25/7.25 Gy group were more content with usual activities (UACT) than the men in the 78/2 Gy group (P = .006). Between the 60/3 Gy and 36.25/7.25 Gy groups, the men treated with SBRT had less distress at three years after RT (P = .045), and between the 78/2 Gy and 60/3 Gy groups, men treated with hypofractionated RT had less discomfort and symptoms (P = .028) at one year after RT.

      Results from the FACT-P questionnaires

      The baseline FACT-P total score of the whole study population was 128.5 (SD 16.9). The treatments had a transient negative effect on HRQoL (Table 3.). At the end of the RT, the FACT-P total score declined significantly (124.7, SD 18.1, P = .013). However, after three years of follow-up the FACT-P total score returned to baseline level (128,5, SD 18.8, P = .364). At the end of RT, significant negative changes in physical activity (PWB, P = .002), the prostate-cancer-specific subscale (PCS, P = .002), and the trial outcome index (TOI) (P = .002) were observed. Negative changes in physical activity in the whole study population were still observed after three years of follow-up (P = .019).
      Table 3The mean FACT-P scores and standard deviations (SD) of RT patients (N = 73).
      Baseline(N = 70)End of RT(N = 67)3 months(N = 70)12 months(N = 68)24 months(N = 64)36 months(N = 63)
      FACT-P total128.5 (16.9)124.7 (18.1)*126.9 (18.9)126.6 (16.9)127.6 (17.0)128.5 (18.8)
      FACT-G total90.8 (12.3)89.3 (13.5)89.9 (14.5)89.0 (12.3)89.8 (12.0)90.7 (13.7)
      Physical (PWB)25.7 (2.7)24.4 (3.4)*25.1 (3.2)25.2 (3.2)25.1 (3.1)24.9 (3.4)*
      Social (SWB)22.0 (4.9)21.9 (5.1)21.8 (5.9)21.2 (5.6)21.7 (4.5)22.0 (5.0)
      Emotional (EWB)20.4 (3.0)20.7 (3.0)20.8 (2.7)20.8 (3.0)20.4 (2.9)20.9 (3.0)
      Functional (FWB)22.4 (4.9)22.1 (5.3)22.2 (5.8)21.9 (5.3)22.3 (4.3)22.7 (4.6)
      Prostate cancer specific (PCS)37.7 (6.0)35.2 (6.4)*37.2 (5.7)37.4 (5.8)37.7 (5.9)37.9 (6.1)
      Trial Outcome Index (TOI)85.9 (11.2)81.7 (12.9)*84.4 (12.5)84.5 (12.0)85.2 (12.1)85.5 (12.9)
      Changes between baseline and timepoints were analyzed using paired-sample t test: * P < .05; ** P < .001.
      The FACT-P, FACT-G and subscales score (range): FACT-P (0-156); FACT-G (0-108); PWB, SWB, FWB (0-28); EWB (0-24); PCS (0-46); TOI (0-104).
      No significant changes in the FACT-P total scores were identified in any of the RT groups between baseline and the three-year of follow-up (Table S2). The highest scores were in the 36.25/7.25 Gy group. The 60/3 Gy group was the only group in which the FACT-P total score decreased between baseline and three years after RT. At the end of RT, the mean TOI worsened in the 60/3 Gy group by six points (P = .011). Between baseline and the end of RT, the mean score in PCS of the 60/3 Gy group decreased by 3.9 points (P = .006), and at three months after RT, these patients still had more symptoms than at baseline (P = .014). None of the RT groups had significant changes in the PCS scores between baseline and the three-year of follow-up.

      Discussion

      This study had several strengths. According to our review, this is the first prospective trial comparing short-term (<5 year) results in patients of exclusively after EBRT for early prostate cancer treated with modern RT techniques to results in an age-standardized general male population. The PCOS study reported results for a combined group of EBRT and brachytherapy group, which does not accurately depict the effects of EBRT since the QoL effects differ, particularly considering urinary functions.
      • Mazariego CG
      • Egger S
      • King MT
      • et al.
      Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
      ,
      • Freiberger C
      • Berneking V
      • Vögeli TA
      • Kirschner-Hermanns R
      • Eble MJ
      • Pinkawa M.
      Quality of life up to 10 years after external beam radiotherapy and/or brachytherapy for prostate cancer.
      To our knowledge, this study is also the first to compare short-term results in men exclusively without ADT, therefore accurately depicting the HRQoL effects of EBRT without confounding factors. However, this factor can also be considered a limitation, because most men treated with EBRT will receive adjuvant or neoadjuvant ADT (approximately 80% in Finland).
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      ,
      • Lehtonen M
      • Heiskanen L
      • Reinikainen P
      • Kellokumpu-Lehtinen PL.
      Both comorbidity and worse performance status are associated with poorer overall survival after external beam radiotherapy for prostate cancer.
      HRQoL effects of EBRT for prostate cancer seem tolerable, and acceptable, and minor compared with those of adjuvant EBRT treatment of breast cancer, for instance.
      • Roine E
      • Blomqvist C
      • Kellokumpu-Lehtinen PL
      • Sintonen H
      • Saarto T.
      Health-related Quality of Life in Breast Cancer Patients after Adjuvant Treatments.
      Overall, our results are in line with those in the PCOS study and Schaake et al. considering general HRQoL and sexual functions.
      • Mazariego CG
      • Egger S
      • King MT
      • et al.
      Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
      ,
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      Compared to the PCOS study results, no decrease in excretory functions was observed at 3 months or later after EBRT.
      • Mazariego CG
      • Egger S
      • King MT
      • et al.
      Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
      However, the 15D instrument does not separate urinary and faecal excretory functions, which could also be viewed as a limitation. Compared to our study, in the PCOS study, the mental well-being scores were lower in the patient population than in the reference population at 1, 2 and 3 years after EBRT, but the result did not exceed the clinically significant difference.
      • Mazariego CG
      • Egger S
      • King MT
      • et al.
      Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
      Our study did not use an identical time frame, and the results are therefore not directly comparable, but our results support the results of the PCOS study considering 3-year HRQoL.
      • Mazariego CG
      • Egger S
      • King MT
      • et al.
      Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
      In our study, depression was more common in the patient population than in the general population for at least three months, and distress was more common until the end of treatment. Our results suggest that mental health interventions may be beneficial. However, according to the previous research, nontargeted approaches are unlikely to improve mental health-related QoL.
      • Parahoo K
      • McDonough S
      • McCaughan E
      • et al.
      Psychosocial interventions for men with prostate cancer: a Cochrane systematic review.
      A recent review by Mundle et al. suggested screening of mental problems in men treated for PC and targeted treatment, although more study is needed on what exact form or method should be used for screening.
      • Mundle R
      • Afenya E
      • Agarwal N.
      The effectiveness of psychological intervention for depression, anxiety, and distress in prostate cancer: a systematic review of literature.
      Sexual rehabilitation programs seem to reduce sexual bother and improve adherence to the standard pharmaceutical treatments for erectile dysfunction, but whether they actually improve HRQoL or its sexual domain, requires more study and one of the key issues is to include an uro-oncological nurse to PC team and she/he should have enough time to discuss with the patient and his spouse about the multidimensional issues related to PC and its treatments.
      • Latini DM
      • Hart SL
      • Coon DW
      • Knight SJ.
      Sexual rehabilitation after localized prostate cancer. Current interventions and future directions.
      Electronic patient reported outcomes (PROs) is a modern way to follow-up patients HRQoL life and increase it as we have first done with patients with breast cancer.
      • Takala L
      • Kuusinen TE
      • Skyttä T
      • Kellokumpu-Lehtinen PL
      • Bärlund M.
      Electronic Patient-reported Outcomes During Breast Cancer Adjuvant Radiotherapy.
      The same system was initiated in 2019 for patients with prostate cancer treated with RT.
      Compared to those in Schaake et al., our patients did not have weaker sleep- or breathing-related HRQoL at 3 years.
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      As Schaake et al. showed that increased reported dyspnoea was related to the prevalence of chronic obstructive pulmonary disease (COPD) and asthma in this cohort, indicating that the difference was likely caused by differences in the characteristics of the study populations.
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      However, the difference in sleep-related quality of life cannot be explained and remains a topic for further study.
      • Schaake W
      • de Groot M
      • Krijnen WP
      • Langendijk JA
      • van den Bergh ACM.
      Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
      Considering the FACT-P results, Monga et al. reported a similar decline in PWB and PCS subdomains at the end of radiotherapy.
      • Monga U
      • Kerrigan AJ
      • Thornby J
      • Monga TN
      • Zimmermann KP.
      Longitudinal study of quality of life in patients with localized prostate cancer undergoing radiotherapy.
      In their study, the differences in FACT-P were not present any longer at two months, similar to our three-month result.
      • Monga U
      • Kerrigan AJ
      • Thornby J
      • Monga TN
      • Zimmermann KP.
      Longitudinal study of quality of life in patients with localized prostate cancer undergoing radiotherapy.
      This suggests that HRQoL declines are transient. Compared to the HYPO-RT-PC and PACE-B trials, our study included only intermediate-risk patients.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ,
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      Compared to the PACE-B study, which also used the NCCN classification, we report HRQoL results up to three years versus the three months in the PACE-B study.
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      No results from RCTs that combine ADT and SBRT have yet been published, although studies are ongoing.
      • Wortel RC
      • Oomen-de Hoop E
      • Heemsbergen WD
      • Pos FJ
      • Incrocci L.
      Moderate Hypofractionation in Intermediate- and High-Risk, Localized Prostate Cancer: Health-Related Quality of Life From the Randomized, Phase 3 HYPRO Trial.
      ,
      • Martin J
      • Keall P
      • Siva S
      • et al.
      TROG 18.01 phase III randomised clinical trial of the Novel Integration of New prostate radiation schedules with adJuvant Androgen deprivation: NINJA study protocol.

      Limitations

      This study has also several limitations. First, the number of patients with PC in our study was quite small compared to those in the HYPO-RT-PC and PACE-B trials for evaluating the secondary objective.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ,
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      The sample size was large enough to evaluate patients as one group (N = 73) in relation to the general population but unfortunately is too small to account for statistically powerful comparisons between different fractionation groups. Small sample size bears a risk for false negative results. However, as the results of HYPO-RT-PC and PACE-B are in conflict with each other considering the HRQoL at the end of treatment, our trial provides further information on the long-term HRQoL and thus we decided to report also the results for different fractionation groups briefly.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ,
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      Our study reports also HRQoL results for three years after RT, which neither of the aforementioned trials do not, since PACE-B HRQoL results were reported up to a year and HYPO-RT-PC long-term results 1, 2, 4 and 6 years after RT.
      • Fransson P
      • Nilsson P
      • Gunnlaugsson A
      • et al.
      Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
      ,
      • Brand DH
      • Tree AC
      • Ostler P
      • et al.
      Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
      The study was not randomized, which predisposes to both unknown and known types of confounders, such as selection bias.
      • Lim CY
      • In J.
      Randomization in clinical studies.
      Our study was also single-centre design, which may limit its generalizability. The study population was superior compared to the age-matched general population in some features (vision and mental/cognitive functions at baseline), likely because we did not account for possible differences in educational levels between populations. There is also some possible bias in relation with time, since the population sample (N = 952) used in comparison was collected in 2011, and the study took place between 2014-2017. Also, the first patients were assigned either 78/2 Gy or 60/3 Gy fractionation, but the later participants were systematically assigned to 36.25/7.25 Gy fractionation, which is another source of possible bias. It is known that certain phenomena that occur periodically, such as economic crises or pandemics, may affect physical and mental health and thus also HRQoL.
      • Hone T
      • Mirelman AJ
      • Rasella D
      • et al.
      Effect of economic recession and impact of health and social protection expenditures on adult mortality: a longitudinal analysis of 5565 Brazilian municipalities.
      • Ng KH
      • Agius M
      • Zaman R.
      The global economic crisis: effects on mental health and what can be done.
      • Poudel AN
      • Zhu S
      • Cooper N
      • et al.
      Impact of Covid-19 on health-related quality of life of patients: A structured review.
      Finally, our results only apply to those men belonging to NCCN intermediate-risk group and treated with EBRT. There are currently many good care options for men belonging to those group, including active surveillance, brachytherapy and RP.
      • Schaeffer EM
      • Srinivas S
      • Antonarakis ES
      • Armstrong AJ
      • Cheng H.
      NCCN Clinical, Practice Guidelines in Oncology (NCCN Guidelines ®): Prostate Cancer. Version 2.2021.
      According to the current NCCN guideline, observation is preferable to the EBRT, if life expectancy is under 10 years and the disease belongs to the favourable intermediate risk group.
      • Schaeffer EM
      • Srinivas S
      • Antonarakis ES
      • Armstrong AJ
      • Cheng H.
      NCCN Clinical, Practice Guidelines in Oncology (NCCN Guidelines ®): Prostate Cancer. Version 2.2021.
      Our study did not distinguish between favourable and unfavourable intermediate risk groups.

      Conclusion

      The HRQoL of our patients treated with RT for PC seems to be at a high level except for sexuality-related issues, and more attention should be devoted to this important aspect of HRQoL and to the development of possible therapeutic interventions/approaches according to patients’ personal needs. SBRT was also tolerated as conventional and moderately hypofractionated treatment, and the overall HRQoL of EBRT-treated PC patients in this study compared with the age-standardized general population was good. SBRT seems to be a convenient treatment in daily clinical practice.

      Clinical Practice Points

      There are limited studies comparing the effects of curative-intent RT on early PC patients’ to HRQoL in the general population. In this study we demonstrated that the overall HRQoL of early PC patients treated with modern image guided RT techniques and without hormonal treatment is equal at three years after treatment to the age-standardized general male population measured with the 15D instrument. The patients with prostate cancer had more depression and distress in the time of active treatment to their cancer when compared to the age-standardized male population. Patients’ sexual activity declined during RT and remained at the lower level during three-year follow-up. In the future, more support should be given to the PC patients at the beginning of the treatment to mental issues and also later to address sexual issues.
      The HRQoL of three different RT groups; conventional fractionation (78/2 Gy), moderate hypofractionation (60/3 Gy) or stereotactic body radiotherapy (36.25/7.25 Gy), were compared with the 15D instrument and the FACT-P questionnaire. The changes within the RT groups measured by the 15D score worsened significantly in the 78/2 Gy and 60/3 Gy groups, but not in the SBRT 36.25/7.25 Gy group, but there were no significant changes in the FACT-P total scores in any of the RT groups, between baseline and three years after treatment. This study confirms the rationale of treating early PC with stereotactic body radiotherapy.

      Credit Author Statement

      Conceptualization: Petri Reinikainen, Miikka Lehtonen, Ilari Lehtinen, Tiina Luukkaala, Harri Sintonen, Pirkko-Liisa Kellokumpu-Lehtinen
      Data curation: Petri Reinikainen, Ilari Lehtinen, Tiina Luukkaala
      Formal analysis: Petri Reinikainen, Tiina Luukkaala
      Funding acquisition: Pirkko-Liisa Kellokumpu-Lehtinen
      Investigation: Pirkko-Liisa Kellokumpu-Lehtinen
      Methodology: Petri Reinikainen, Miikka Lehtonen, Ilari Lehtinen, Tiina Luukkaala, Harri Sintonen, Pirkko-Liisa Kellokumpu-Lehtinen
      Project administration: Pirkko-Liisa Kellokumpu-Lehtinen
      Supervision: Pirkko-Liisa Kellokumpu-Lehtinen
      Validation: Petri Reinikainen, Miikka Lehtonen, Ilari Lehtinen, Tiina Luukkaala, Pirkko-Liisa Kellokumpu-Lehtinen
      Visualization: Petri Reinikainen, Miikka Lehtonen
      Writing – original draft: Abstract, Material and Methods, Results, Conclusions: Petri Reinikainen, Abstract, Introduction and Discussion: Miikka Lehtonen.
      Writing – review and editing: Tiina Luukkaala, Pirkko-Liisa Kellokumpu-Lehtinen

      Microabstract

      This prospective study investigated the health-related quality of life (HRQoL) of the patients with an early prostate cancer (PC) treated with radiotherapy (RT) without hormonal treatment compared to that in the age-standardized general male population. Patients have equal overall HRQoL measured with the 15D instrument compared to the general male population. Patients had more depression at the beginning of RT, and their sexual activity remained at a lower level after RT.

      Funding

      This research was funded by Seppo Nieminen foundation and by the Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital.

      Institutional Review Board Statement

      The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Expert Responsibility area of Tampere University Hospital (protocol code R14009, 2014-02-24).

      Informed Consent Statement

      Informed consent was obtained from all subjects involved in the study.

      CRediT authorship contribution statement

      Petri Reinikainen: Conceptualization, Data curation, Formal analysis, Methodology, Validation, Visualization, Writing – original draft. Miikka Lehtonen: Conceptualization, Methodology, Validation, Visualization. Ilari Lehtinen: Conceptualization, Data curation, Methodology, Validation. Tiina Luukkaala: Conceptualization, Data curation, Formal analysis, Methodology, Validation, Writing – review & editing. Harri Sintonen: Conceptualization, Methodology. Pirkko-Liisa Kellokumpu-Lehtinen: Conceptualization, Funding acquisition, Methodology, Project administration, Validation, Writing – review & editing.

      Declaration of interest

      Harri Sintonen is the developer of the 15D and obtains royalties from its electronic versions. The other authors declare no conflict of interest.

      Acknowledgments

      To Irja Kolehmainen, research coordinator and research nurses Tuula Nuuttila and Jasmin Salmi.

      Appendix. Supplementary materials

      References

        • Schaeffer EM
        • Srinivas S
        • Antonarakis ES
        • Armstrong AJ
        • Cheng H.
        NCCN Clinical, Practice Guidelines in Oncology (NCCN Guidelines ®): Prostate Cancer. Version 2.2021.
        National Comprehensive Cancer Network (NCCN), 2021 (Available from) (Published online August 24)
        • Bottomley A
        • Reijneveld JC
        • Koller M
        • et al.
        Current state of quality of life and patient-reported outcomes research.
        European journal of cancer. 2019; 121 (1990): 55-63https://doi.org/10.1016/j.ejca.2019.08.016
        • Bottomley A
        • Pe M
        • Sloan J
        • et al.
        Moving forward toward standardizing analysis of quality of life data in randomized cancer clinical trials.
        Clin Trials. 2018; 15: 624-630https://doi.org/10.1177/1740774518795637
        • Sung H
        • Ferlay J
        • Siegel RL
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
        CA Cancer J Clin. 2021; 71: 209-249https://doi.org/10.3322/caac.21660
        • Pitkäniemi J
        • Malila N
        • Tanskanen T
        • Degerlund H
        • Heikkinen S
        • Seppä K.
        Cancer In Finland 2019.
        Cancer Soc Finl Publ, 2021 ([Internet] Available from) (Published online)
        • Taylor JM
        • Chen VE
        • Miller RC
        • Greenberger BA.
        The impact of prostate cancer treatment on quality of life: A narrative review with a focus on randomized data.
        Res Rep Urol. 2020; 12: 533-546https://doi.org/10.2147/RRU.S243088
        • Sanda MG
        • Dunn RL
        • Michalski J
        • et al.
        Quality of Life and Satisfaction with Outcome among Prostate-Cancer Survivors.
        N Engl J Med. 2008; 358: 1250-1261https://doi.org/10.1056/NEJMoa074311
        • Mazariego CG
        • Egger S
        • King MT
        • et al.
        Fifteen year quality of life outcomes in men with localised prostate cancer: population based Australian prospective study.
        BMJ. 2020; 371 (-m3503): m3503https://doi.org/10.1136/bmj.m3503
        • Smith DP
        • King MT
        • Egger S
        • et al.
        Quality of life three years after diagnosis of localised prostate cancer: population based cohort study.
        BMJ. 2009; 339: 2011-2195https://doi.org/10.1136/bmj.b4817
        • Schaake W
        • de Groot M
        • Krijnen WP
        • Langendijk JA
        • van den Bergh ACM.
        Quality of life among prostate cancer patients: A prospective longitudinal population-based study.
        Radiotherapy and oncology. 2013; 108: 299-305https://doi.org/10.1016/j.radonc.2013.06.039
        • Dearnaley D
        • Syndikus I
        • Mossop H
        • et al.
        Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.
        The lancet oncology. 2016; 17: 1047-1060https://doi.org/10.1016/S1470-2045(16)30102-4
        • Line Krhili S
        • Créhange G
        • Albert-Dufrois H
        • Guimas V
        • Minsat M
        • Supiot S
        Hypofractionnement modéré ou extrême et cancers prostatiques localisés : les temps sont en train de changer.
        Cancer radiothérapie. 2019; 23: 503-509https://doi.org/10.1016/j.canrad.2019.07.139
        • Jackson WC
        • Silva J
        • Hartman HE
        • et al.
        Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies.
        Int J Radiat Oncol Biol Phys. 2019; 104: 778-789https://doi.org/10.1016/j.ijrobp.2019.03.051
        • Mottet N.
        • Cornford P.
        • van den Bergh R.C.N.
        EAU - EANM - ESTRO - ESUR - ISUP - SIOG Guidelines on Prostate Cancer.
        2022 (Available from)
        • Fransson P
        • Nilsson P
        • Gunnlaugsson A
        • et al.
        Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.
        The lancet oncology. 2021; 22: 235-245https://doi.org/10.1016/S1470-2045(20)30581-7
        • Brand DH
        • Tree AC
        • Ostler P
        • et al.
        Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.
        The lancet oncology. 2019; 20: 1531-1543https://doi.org/10.1016/S1470-2045(19)30569-8
        • Staffurth JN
        • Haviland JS
        • Wilkins A
        • et al.
        Impact of Hypofractionated Radiotherapy on Patient-reported Outcomes in Prostate Cancer: Results up to 5 yr in the CHHiP trial (CRUK/06/016).
        Eur Urol Oncol. 2021; 4: 980-992https://doi.org/10.1016/j.euo.2021.07.005
        • Wortel RC
        • Oomen-de Hoop E
        • Heemsbergen WD
        • Pos FJ
        • Incrocci L.
        Moderate Hypofractionation in Intermediate- and High-Risk, Localized Prostate Cancer: Health-Related Quality of Life From the Randomized, Phase 3 HYPRO Trial.
        Int J Radiat Oncol Biol Phys. 2019; 103: 823-833https://doi.org/10.1016/j.ijrobp.2018.11.020
        • Bruner DW
        • Pugh SL
        • Lee WR
        • et al.
        Quality of Life in Patients With Low-Risk Prostate Cancer Treated With Hypofractionated vs Conventional Radiotherapy: A Phase 3 Randomized Clinical Trial.
        JAMA Oncol. 2019; 5: 664-670https://doi.org/10.1001/jamaoncol.2018.6752
        • Lehtonen M
        • Heiskanen L
        • Reinikainen P
        • Kellokumpu-Lehtinen PL.
        Both comorbidity and worse performance status are associated with poorer overall survival after external beam radiotherapy for prostate cancer.
        BMC Cancer. 2020; 20 (-324): 324https://doi.org/10.1186/s12885-020-06812-6
        • Mohler JL
        • Kantoff PW
        • Armstrong AJ
        • et al.
        Prostate cancer, version 1.2014: Featured updates to the NCCN Guidelines.
        Journal of the National Comprehensive Cancer Network. 2013; 11: 1471-1479https://doi.org/10.6004/jnccn.2013.0174
      1. Prediction Tools/Prostate Cancer Nomograms: Pre- Radical Prostatectomy. Memorial Sloan Kettering Cancer Center. www.mskcc.org.

        • Vuorinen RL
        • Paunu N
        • Turpeenniemi-Hujanen T
        • et al.
        Sunitinib first-line treatment in metastatic renal cell carcinoma: Costs and effects.
        Anticancer Res. 2019; 39: 5559-5564https://doi.org/10.21873/anticanres.13749
        • Bergius S
        • Torvinen S
        • Muhonen T
        • Roine RP
        • Sintonen H
        • Taari K.
        Health-related quality of life among prostate cancer patients: real-life situation at the beginning of treatment.
        Scand J Urol. 2017; 51: 13-19https://doi.org/10.1080/21681805.2016.1247293
        • Roine E
        • Sintonen H
        • Kellokumpu-Lehtinen PL
        • et al.
        Health-related quality of life of breast cancer survivors attending an exercise intervention study: A five-year follow-up.
        In vivo (Athens). 2020; 34: 667-674https://doi.org/10.21873/invivo.11821
        • Roine E
        • Sintonen H
        • Kellokumpu-Lehtinen PL
        • et al.
        Long-term health-related quality of life of breast cancer survivors remains impaired compared to the age-matched general population especially in young women. Results from the prospective controlled BREX exercise study. 2021; (Published online)
        • Vartiainen P
        • Mäntyselkä P
        • Heiskanen T
        • et al.
        Validation of EQ-5D and 15D in the assessment of health-related quality of life in chronic pain.
        Pain (Amsterdam). 2017; 158: 1577-1585https://doi.org/10.1097/j.pain.0000000000000954
        • Sintonen H.
        The 15D instrument of health-related quality of life: properties and applications.
        Annals of medicine (Helsinki). 2001; 33: 328-336https://doi.org/10.3109/07853890109002086
        • Alanne S
        • Roine RP
        • Räsänen P
        • Vainiola T
        • Sintonen H.
        Estimating the minimum important change in the 15D scores.
        Quality of life research. 2015; 24: 599-606https://doi.org/10.1007/s11136-014-0787-4
        • Koskinen S
        • Lundqvist A
        • Ristiluoma N.
        Health, functional capacity and welfare in Finland in 2011.
        National Institute for Health and Welfare (THL), Helsinki2012 (Report 68/2012)
        • Esper P
        • Mo F
        • Chodak G
        • Sinner M
        • Cella D
        • Pienta KJ.
        Measuring quality of life in men with prostate cancer using the Functional Assessment of Cancer Therapy-prostate instrument.
        Urology. 1997; 50https://doi.org/10.1016/S0090-4295(97)00459-7
        • Cella D
        • Nichol MB
        • Eton D
        • Nelson JB
        • Mulani P.
        Estimating Clinically Meaningful Changes for the Functional Assessment of Cancer Therapy—Prostate: Results from a Clinical Trial of Patients with Metastatic Hormone-Refractory Prostate Cancer.
        Value in health. 2009; 12: 124-129https://doi.org/10.1111/j.1524-4733.2008.00409.x
        • Beaumont JL
        • Butt Z
        • Li R
        • Cella D.
        Meaningful differences and validity for the NCCN/FACT-P Symptom Index: An analysis of the ALSYMPCA data.
        Cancer. 2019; 125: 1877-1885https://doi.org/10.1002/cncr.31973
        • Abramowitz MC
        • Li T
        • Buyyounouski MK
        • et al.
        The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer.
        Cancer. 2008; 112: 55-60https://doi.org/10.1002/cncr.23139
        • Freiberger C
        • Berneking V
        • Vögeli TA
        • Kirschner-Hermanns R
        • Eble MJ
        • Pinkawa M.
        Quality of life up to 10 years after external beam radiotherapy and/or brachytherapy for prostate cancer.
        Brachytherapy. 2018; 17: 517-523https://doi.org/10.1016/j.brachy.2018.01.008
        • Roine E
        • Blomqvist C
        • Kellokumpu-Lehtinen PL
        • Sintonen H
        • Saarto T.
        Health-related Quality of Life in Breast Cancer Patients after Adjuvant Treatments.
        Breast J. 2016; 22: 473-475https://doi.org/10.1111/tbj.12613
        • Parahoo K
        • McDonough S
        • McCaughan E
        • et al.
        Psychosocial interventions for men with prostate cancer: a Cochrane systematic review.
        BJU Int. 2015; 116: 174-183https://doi.org/10.1111/bju.12989
        • Mundle R
        • Afenya E
        • Agarwal N.
        The effectiveness of psychological intervention for depression, anxiety, and distress in prostate cancer: a systematic review of literature.
        Prostate Cancer Prostatic Dis. 2021; 24: 674-687https://doi.org/10.1038/s41391-021-00342-3
        • Latini DM
        • Hart SL
        • Coon DW
        • Knight SJ.
        Sexual rehabilitation after localized prostate cancer. Current interventions and future directions.
        The cancer journal (Sudbury, Mass). 2009; 15: 34-40https://doi.org/10.1097/PPO.0b013e31819765ef
        • Takala L
        • Kuusinen TE
        • Skyttä T
        • Kellokumpu-Lehtinen PL
        • Bärlund M.
        Electronic Patient-reported Outcomes During Breast Cancer Adjuvant Radiotherapy.
        Clin Breast Cancer. 2021; 21: e252-e270https://doi.org/10.1016/j.clbc.2020.10.004
        • Monga U
        • Kerrigan AJ
        • Thornby J
        • Monga TN
        • Zimmermann KP.
        Longitudinal study of quality of life in patients with localized prostate cancer undergoing radiotherapy.
        J Rehabil Res Dev. 2005; 42: 391-399https://doi.org/10.1682/JRRD.2004.06.0071
        • Martin J
        • Keall P
        • Siva S
        • et al.
        TROG 18.01 phase III randomised clinical trial of the Novel Integration of New prostate radiation schedules with adJuvant Androgen deprivation: NINJA study protocol.
        BMJ Open. 2019; 9 (-e030731)e030731https://doi.org/10.1136/bmjopen-2019-030731
        • Lim CY
        • In J.
        Randomization in clinical studies.
        Korean J Anesthesiol. 2019; 72: 221-232https://doi.org/10.4097/kja.19049
        • Hone T
        • Mirelman AJ
        • Rasella D
        • et al.
        Effect of economic recession and impact of health and social protection expenditures on adult mortality: a longitudinal analysis of 5565 Brazilian municipalities.
        The Lancet global health. 2019; 7: e1575-e1583https://doi.org/10.1016/S2214-109X(19)30409-7
        • Ng KH
        • Agius M
        • Zaman R.
        The global economic crisis: effects on mental health and what can be done.
        J R Soc Med. 2013; 106: 211-214https://doi.org/10.1177/0141076813481770
        • Poudel AN
        • Zhu S
        • Cooper N
        • et al.
        Impact of Covid-19 on health-related quality of life of patients: A structured review.
        PLoS One. 2021; 16 (-e0259164)e0259164https://doi.org/10.1371/journal.pone.0259164