(17) - Imperial College London



MRI-guided focal HDR-brachytherapy for localised prostate cancer: median 4 year results of a phase I studyM. Peters1*, M.J. van Son1*, M.A. Moerland1, L.G.W. Kerkmeijer1, W.S.C. Eppinga1, R.P. Meijer2, J.J.W. Lagendijk1, T.T. Shah3-5, H.U. Ahmed3-4, J.R.N. van der Voort van Zijp1Author affiliations: University Medical Center Utrecht, Department of Radiotherapy.University Medical Center Utrecht, Department of UrologyDivision of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK; Department of Urology.Division of Surgery and Interventional Sciences, University College London, London, UK.*Authors share first authorship due to equal contribution[ Guidelines scientific articles Red Journal ]Manuscript ≤ 3500 words, tables and figures ≤ 6, references ≤ 50Summary ( ≤75 words)Abstract ( ≤ 300 words)AbstractIntroduction: For the treatment of localised prostate cancer, focal therapy has the potential to cure with less side-effects than traditional whole-gland treatments. We report an update of toxicity, quality of life (QoL) and tumour control of our MRI-guided focal high-dose-rate (HDR) brachytherapy cohort.Materials and methods: Disease status was evaluated by systematic biopsies and 3T MRI. The brachytherapy implant procedure under fused transrectal ultrasound/MRI guidance was followed by 1.5T MRI for contour adjustments and catheter position verification. In a single dose, 19 Gy was delivered to the tumour with a margin of 5 mm. Genitourinary (GU) toxicity, gastro-intestinal (GI) toxicity and erectile dysfunction (ED) were graded according to the CTCAE 4.0. QoL was measured with RAND-36, EORTC QLQ-C30 and EORTC QLQ-PR25. In addition, IPSS and IIEF-5 scores were obtained. PSA was monitored, with biochemical recurrence defined as nadir+2 (Phoenix definition).Results: Thirty patients with localised prostate cancer were treated between May 2013 and April 2016. Median follow-up was 4 years. Median age was 71 years (interquartile range [IQR] 68-73), median iPSA 7.3 ng/ml (IQR 5.2-8.1), highest Gleason grade was 4+3=7 (n=2) and all tumours were stage T2. No grade >2 GU or >1 GI toxicity occurred. No significant changes in IPSS were seen. IIEF scores showed a downward trend. There were no significant differences in any QoL domains. Clinically relevant deteriorations of ≥10 points were seen in sexual activity and tiredness, while emotional and cognitive functioning improved compared to baseline. At 4 years, biochemical disease-free survival (BDFS) was 70% (95% CI 52-93%) and metastases-free survival 93% (85-100%). If local salvage treatment was not considered failure, BDFS increased to 91% (79-100%).Conclusion: Focal HDR-brachytherapy for localised prostate cancer conveys minimal toxicity and has a marginal effect on QoL. Although initial biochemical failure was 30% at 4 years, there is still potential for successful local salvage treatment. Introduction: Due to opportunistic PSA-testing and diagnostic advancements including improved imaging and biopsy methods, prostate cancer has undergone a stage migration to more localised disease ADDIN RW.CITE{{843 Shao,Y.H. 2009}}(1). Whole-gland radical prostatectomy and radiotherapy are seen as standard of care primary treatments. However, both have not shown an overall survival advantage compared to active monitoring in the recent randomised controlled ProtecT trial, while side-effects were frequently observedADDIN RW.CITE{{845 Hamdy,F.C. 2016; 846 Donovan,J.L. 2016}}(2,3). Even though most patients in this trial had a low-risk profile potentially eligible for active surveillance, 10% of patients represented an intermediate-risk subgroup of whom it is believed will benefit from curative treatment ADDIN RW.CITE{{847 Donaldson,I.A. 2015}}(4). To counter this trade-off between toxicity and prevention of disease progression, the use of primary focal therapy (FT) for localised prostate cancer is increasing. Such a strategy could offer a suitable alternative to whole-gland treatment in terms of cancer control, while decreasing genitourinary (GU) and gastro-intestinal (GI) toxicity, and erectile dysfunction (ED)ADDIN RW.CITE{{848 Valerio,M. 2017}}(5). Evidence for this is increasing as cohorts get larger and follow-up is extended. The largest cohorts of FT with median 5-years follow-up report biochemical disease-free survival (BDFS) rates of 88-92%ADDIN RW.CITE{{851 Nguyen,P.L. 2012; 849 Guillaumier,S. 2018}}(6,7), with favourable toxicity profilesADDIN RW.CITE{{849 Guillaumier,S. 2018; 848 Valerio,M. 2017}}(5,7).Nowadays, advancements in magnetic resonance imaging (MRI) such as the use of multiparametric MRI (mp-MRI) and MRI-guidance during treatment have made a so-called ultrafocal approach possible. This approach is applied in MRI-guided focal high-dose-rate (HDR)-brachytherapy, which is performed at our institute. HDR-brachytherapy carries technical and radiobiological advantages over I-125 brachytherapy, which make this a particularly suitable technique for FT. We have previously described preliminary results of our prospective phase I study regarding MRI-guided focal HDR-brachytherapy at median 2 years follow-up ADDIN RW.CITE{{852 Maenhout,M. 2018}}(8). In the current paper, we report updated results regarding toxicity, quality of life (QoL) and tumour control at a median of 4 years follow-up.Materials and methods:Between May 2013 and April 2016, 30 consecutive patients underwent primary MRI-guided focal HDR-brachytherapy at our centre. This treatment was performed within a phase I feasibility study, with toxicity as a primary outcome. The study was approved by the Institutional Review Board (IRB) of the University Medical Centre Utrecht and written informed consent was obtained from all patients. Patient selection criteria, treatment procedures and follow-up assessment have been described previouslyADDIN RW.CITE{{852 Maenhout,M. 2018; 859 Maenhout,M. 2018}}(8,9). They are briefly discussed below.Patient selection criteriaPatients were eligible for MRI-guided focal HDR-brachytherapy if they had the following clinical characteristics: 1. Karnofsky score ≥70, 2. T-stage ≤T2c, 3. Gleason sumscore ≤7, 4. PSA <10 ng/mL, and 5. IPSS <15.Diagnostic procedures and treatment Imaging of the intraprostatic lesion was performed using 3T mp-MRI, consisting of T2-weighted, diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) sequences. If deemed necessary, exclusion of metastases was performed in the referring centre. At least 2 patients received Technetium-99m bone scan and/or abdominopelvic CT. In all other cases, this was either not performed or information was missing. PET-scans were not part of the diagnostic work-up. Tumour lesions were verified using systematic biopsies with a varying amount of cores taken, dependent on the referring centre. Radiological concordance with positive biopsy location was required for patients to undergo treatment.The diagnostic MR-images were used for delineations of the prostate, gross tumour volume (GTV) and organs at risk in the vicinity (urethra, bladder, rectum). An intraprostatic margin of 5mm was applied around the GTV to indicate the clinical target volume (CTV), allowing coverage of microscopic spreadADDIN RW.CITE{{857 Groenendaal,G. 2010}}(10). Using a treatment planning system (Oncentra Prostate; Elekta/Nucletron,Veenendaal, the Netherlands), a pre-treatment plan was constructed, abiding by the following dose goals and constraints: 1. CTV D95% (minimal dose to 95% of the CTV) ≥19 Gy, or at least a CTV D90% ≥17 Gy if D95% ≥19 Gy proved to be unfeasible, 2. D1cc (minimal dose in most irradiated 1cc volume) of the bladder and rectum < 12 Gy and 3. urethra D10% (dose to 10% of the urethra ) <21 GyADDIN RW.CITE{{860 Holly,R. 2011}}(11). Intra-operatively, live transrectal ultrasound (TRUS)-images were rigidly fused with the pre-treatment MR- delineations. Using this visual guidance, MR-compatible self-anchoring catheters were inserted in and around the CTV via the perineum. After insertion, an intra-operative MRI was made for catheter reconstruction and adaptation of delineations to account for anatomical changes such as swelling due to catheter insertion. Based on these reconstructions, the treatment plan was updated. A final MRI was performed for position verification and to check for major anatomical deviations. Afterwards, the HDR afterloader was connected to the catheters to deliver the radiation dose according to the final treatment plan.Outcome assessmentThe Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used for GU, GI and ED toxicity assessment. QoL was measured using the RAND-36, EORTC-QLQ-C30 and PR-25 questionnairesADDIN RW.CITE{{863 Aaronson,N.K. 1998; 861 Aaronson,N.K. 1993; 862 van Andel,G. 2008}}(12-14). In addition, International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF) were assessed. For tumour control assessment, serial PSA measurements were performed at 1, 3, 6, 9 and 12 months after treatment, subsequently every 6 months until 24 months and yearly afterwards for up to 10 years. The nadir+2 ng/ml (Phoenix) definition was used to assess biochemical failure, which was considered an indication for a PET/CT-scan to investigate the cause of failure. If localised intraprostatic recurrence was found in the absence of metastatic disease, an mp-MRI was performed for further local disease assessment. In each case, the tumour control probability and toxicity risk were carefully weighed to decide whether a patient was eligible for (re-focal or whole-gland) salvage radiotherapy. Statistical analysesContinuous variables are described as medians with interquartile ranges (IQR) and categorical variables as absolute numbers with percentages. Differences in continuous variables were tested with the Wilcoxon signed rank test. To correct for multiple testing at different follow-up time points, statistical significance was pragmatically set at <0.001. Furthermore, in the QoL analysis, an absolute median difference of ≥10 points was deemed clinically relevant, apart from statistical considerationsADDIN RW.CITE{{864 Osoba,D. 1998}}(15). BDFS and metastases-free survival (MFS) were assessed using Kaplan-Meier survival analyses. No subgroups were investigated. BDFS was further analysed using two different definitions of failure. First, by considering biochemical failure patients who underwent local salvage treatment (either focal or whole-gland) as no failure (with salvage(1); BDFS-WS1). Second, as recommended by an FT consensus meetingADDIN RW.CITE{{847 Donaldson,I.A. 2015}}(4), a subdivision was made by considering only whole-gland salvage treatments as failure (with salvage(2); BDFS-WS2) . An exploratory univariable Cox-regression analysis was performed to assess potential characteristics associated with the first biochemical failure event. IBM SPSS version 23.0 was used for descriptive statistics. R version 3.5.1 was used for QoL and survival analyses (). Results:Baseline characteristicsAt the time of treatment, median age of patients was 71 years (IQR 68-73). Prostatic volume on MRI was median 40 cc (32.3-41.7). Median PSA was 7.3 ng/ml (5.2-8.1) and median PSA doubling time (PSADT) was 4.7 years (2.4-10.6). The radiological T-stage was T2a in 13 (43.3%), T2b in 4 (13.3%) and T2c in 13 (43.3%) patients. The Gleason score distribution was 3+3=6 in 16 (53.3%), 3+4=7 in 12 (40%) and 4+3=7 in 2 (6.7%) patients. Most tumours were located at the midgland or apex, or a combination of the two. More baseline characteristics are shown in table 1. Treatment characteristics and dosimetryA median of 14 brachytherapy catheters were implanted to allow adequate coverage of the CTV. The GTV had a median volume of 3.3 cc (2.1-4.9), with margin expansion resulting in a median CTV volume of 20.8 cc (12.6-25). The CTV D95% was median 19.1 Gy (17.9-20.5); in 14 patients, the D95% was below 19 Gy. CTV D90% was median 20.8 Gy (19.4-22.6); 2 patients had a D90% below 17 Gy. The constraint for D10% of the urethra was met in all patients. The constraint for the rectum D1cc was slightly exceeded in 10 patients (up to a maximum of 12.8 Gy) and the bladder D1cc in 2 patients (up to a maximum of 12.4 Gy). ToxicityGU, GI toxicity and ED scores according to the CTCAE 4.0 are depicted in figure 1. In our previous report, we described one grade 3 GU toxicity: one patient experienced acute prostate haemorrhage resulting in gross haematuria due to improper post-operative removal of an unfolded brachytherapy catheter. He was admitted to the hospital for three days with a urinary catheter in situ. However, since this was not a direct side-effect of the radiation treatment itself, we consider this a perioperative complication in the current report.New grade 2 GU toxicity developed at different times during follow-up in 4 patients, consisting of urinary frequency (n=3) or cystitis (n=1), all successfully treated with temporary medication. No grade 2 or higher GI toxicity was observed.New grade 3 ED after treatment was observed in 8 patients during follow-up, of which 2 were persistent and 6 were transient.IPSS showed the largest increase in the first month, from a median score 5 (IQR 4-7) to median score 8 (6-13). This difference was not significant at the 0.001 level (p=0.03). Median IIEF score decreased from 19 (5-22) at baseline to 6 at 6 months (significant at the 0.001 level) and 8 at 48 months follow-up. This corresponds to a general clinical decrease from mild to moderate/severe ED over time. IPSS and IIEF trends are depicted in figure 2. QoLSupplementary figures 1 through 3 give an overview of the course of patient-reported QoL as measured with the RAND-36, EORTC QLQ-C30 and PR25 questionnaires. No significant differences at the 0.001 level were seen within the RAND-36. A clinically relevant decrease in median score was seen in the domains social functioning (>10 points after 1 and 24 months), vitality (10 points after 9 months) and pain (>10 points decrease after 1 month). These deteriorations were not significant at the 0.001 level and all scores returned to baseline value. Mental health and general health remained relatively constant during follow-up and showed no median increase >10 points contrary to our previous reportADDIN RW.CITE{{852 Maenhout,M. 2018}}(8). Regarding the QLQ-C30 questionnaire, there were no significant median differences at the 0.001 level in any of the subdomains. Clinically relevant deterioration was seen in tiredness (>10 points after 48 months) and sleeping disturbances (only at 24 months). On the contrary, improvement was seen in the domains emotional functioning (>10 points after 48 months) and cognitive functioning (>10 points after 36 months) Within the PR25 domains, there were also no significant differences at the 0.001 level. Urinary symptoms increased from median score 10 at baseline to a median score of 17 in the first month, after which this recovered to baseline in the subsequent follow-up. Bowel symptoms remained stable at a median of 0. Treatment-related symptoms went from median score 0 at baseline to a score of 6 at all follow-up time points after treatment. A clinically relevant decrease of >10 points was seen in sexual activity at all follow-up time points after treatment. Sexual functioning, on the contrary, remained relatively stable. Tumour controlA total of 10 patients experienced biochemical failure during follow-up, of which 9 had a local prostatic recurrence on PET/CT imaging (18F-Choline [n=1] and later 68Ga-prostate specific membrane antigen [PSMA] [n=9]). MRI-guided biopsies for recurrence verification were performed in 2 patients. Of all intraprostatic recurrences, 7/9 were out-of-field lesions with respect to the primary tumour area. Of these 9 patients with local recurrence, 3 had synchronous metastatic disease. Two of these patients were referred to their urologist for deferred ADT. One patient underwent stereotactic body radiotherapy (SBRT, 1x18 Gy) twice to different solitary bone metastases, before receiving whole-gland salvage Iodine-125 brachytherapy. One year later, PSA-levels started to rise again and he started ADT. Out of 6 patients with local recurrence only, 4 received salvage local therapy: either focal salvage HDR-brachytherapy (n=2) or whole-gland salvage Iodine-125 brachytherapy (n=2). Until now, PSA-levels remain low in these patients, with follow-up ranging between 1 and 3 years. The other 2 patients requested an active surveillance strategy with PSA follow-up. One patient had a solitary metastasis in the L4 vertebra without local prostatic recurrence, for which he received SBRT(1x18 Gy). Unfortunately, this did not result in a PSA-response and he subsequently received ADT. Initial BDFS was 70% (95% CI 52-93%) at 4 years. Taking into account local salvage treatments, BDFS increased: at 4 years, BDFS-WS1 was 91% (79-100%) and BDFS-WS2 was 73% (54-97%). MFS was 93% (85-100%) and overall survival 100% at 4 years. Kaplan-Meier curves are depicted in figure 3. An explorative univariable Cox regression analysis of potential risk factors for a first biochemical failure event included the variables age, American Joint Committee on Cancer (AJCC) grade group, T-stage, PSA, PSADT, AJCC prognostic stage group and PSA nadir post-treatment. Only age showed a significant hazard ratio (HR) at the 0.05 level: HR 1.27 (95% CI 1.01-1.59; p=0.04), meaning higher age at treatment conveyed higher risk of biochemical failure in these patients. DiscussionThe main goal of focal ablation for localised prostate cancer is to reduce treatment-related side-effects and thereby maintain QoL while not compromising tumour control. The medium-term results of our phase I focal HDR-brachytherapy study show that this is possible for toxicity and QoL. Both are mostly in line with our previous report, in which we saw no treatment-related severe GU or GI toxicity and a minor impact on patient-reported QoL. Regarding patient-reported toxicity, we saw a transient increase in IPSS in the first month after treatment and a clear downward trend in IIEF scores over time. The latter is also reflected in the CTCAE-graded ED scores, with more patients experiencing grade 2-3 ED during follow-up compared to the previous analysis. QoL did not deteriorate significantly, although on some levels there were clinically relevant changes. A general evaluation of health status (as measured by RAND-36) showed only transient deterioration of subdomains, with all scores returning back to baseline level. Regarding cancer-specific QoL (as measured by QLQ-C30), patients reported more tiredness, but at the same time improvement of emotional and cognitive functioning. Prostate cancer-related QoL (as measured by PR-25) showed a transient increase in urinary symptoms, no bowel symptoms and a decrease in sexual activity (although relatively stable sexual functioning). To our knowledge, no other FT studies have reported such an extended QoL analysis. Our QoL data therefore provides new and detailed insight into the domains that are affected by focal HDR-brachytherapy.Since no other literature on primary focal HDR-brachytherapy is available, we can only compare our results to small focal Iodine-125 brachytherapy series. Interestingly, one study showed stable IIEF during follow-up (mean score around 20 until 12 months follow-up, in 21 patients)ADDIN RW.CITE{{865 Cosset,J.M. 2013}}(16). Better maintenance of erectile function in this cohort could potentially be explained by smaller target volumes or the substantially lower patient age (mean 62 versus median 71 in our cohort). However, depending on tumour location, it is also possible that HDR-brachytherapy has a larger influence on erectile function than I-125 brachytherapy. The same study showed a temporary increase in IPSS, comparable to our report. Another small study on ultrafocal I-125 brachytherapy (n=17) reported no grade >1 toxicity, no significant deterioration in IIEF and again, a transient slight increase in IPSS after the first month(17).A general comparison with other FT modalities learns that there is a common trend: IPSS and IIEF scores remain stable over time and approximately ≥70% leak-free continence and potency preservation is reportedADDIN RW.CITE{{848 Valerio,M. 2017}}(5). A study evaluating prospective data on different FT modalities within the same centre, included 50 cryotherapy (hemi-ablation), 21 HIFU (hemi-ablation), 23 photodynamic therapy (focal) and 12 brachytherapy (focal) patients. Between baseline and 12 months follow-up, IPSS remained relatively stable (<5 points median difference). IIEF however, deteriorated in all groups (5-10 points median decrease). The decrease of erectile function might in part be attributable to the absence of a clear identifiable neurovascular bundle structure and a knowledge gap with regard to radiation sensitivity of this structure. In addition, 43% of patients had radiological bilateral (T2c) disease, which might have led to a higher dose burden on both neurovascular bundles. Lastly, part could be explained by the natural course of developing ED with increasing age.We can also compare our results with whole-gland HDR-brachytherapy series, most commonly studies using schedules with multiple fractionsADDIN RW.CITE{{855 Tselis,N. 2017}}(18). In these series, late grade 3 GU and GI toxicity were observed in 0-16% and 0-2%, respectively. Late grade 2 GU and GI toxicity were 0-40% and 0-13%. Our focal HDR-brachytherapy results have shown favourable toxicity numbers with no grade 3 and only 13% grade 2 GU toxicity (4/30), and no grade >1 GI events. There is also literature available on single-dose HDR-brachytherapy studies. Morton et al. directly compared single-dose 19 Gy (n=87) with 2 fractions of 13.5 Gy (n=83) in a randomised controlled trial in low/intermediate-risk patientsADDIN RW.CITE{{867 Morton,G. 2017}}(20). Median follow-up was 20 months. Grade 2 GU toxicity was frequent in both treatment arms (51% acute and 31% late toxicity) and grade 3 GU toxicity occurred in 2 patients. IPSS temporarily increased in a fashion comparable to our cohort. Grade 2 GI toxicity was limited to 2% in the acute phase and 3% in the late phase. Grade 2 ED occurred in 12% and in 29% (single-dose versus 2-fraction). Significant patient-reported ED (as measured by Expanded Prostate Cancer Index Composite [EPIC]) occurred in 34% and in 58%, respectively. Although CTCAE-graded ED scores are favourable compared to our results (27% newly developed grade 3 ED), patient-reported erectile function shows more comparable numbers. Furthermore, in our cohort grade 3 ED eventually regressed to grade 1-2 ED in 6/8 patients. New grade 2 ED occurred in 20% of our patients, of which 2 regressed to grade 0-1. A possible explanation for the favourable ED results of Morton et al. could be that the median age in their study is 6 years below the median age of our cohort (65 versus 71 years).Better GU/GI toxicity results have been reported by Prada et al. Their study of 60 low/intermediate-risk patients receiving 1x19 Gy reports no new grade 2 GU or GI toxicity at a median follow-up of 72 months. Rectal spacers were used to limit the rectal dose. Potency was not reportedADDIN RW.CITE{{866 Prada,P.J. 2016}}(19). Similar results are seen in their subsequent study of 60 low/intermediate-risk patients, using an increased dose of 1x20.5 Gy, with a median follow-up of 51 months: no grade 2 GU or GI toxicity was observedADDIN RW.CITE{{868 Prada,P.J. 2018}}(22). In both studies, data on patient-reported QoL is lacking. Another recent report by Gomez-Iturriaga et al. (1x19 Gy, 43 low/intermediate-risk patients, median follow-up 20 months) shows 9% acute and 9% late grade 2 GU toxicity. EPIC urinary urgency and obstructive complaints did show a significant increase after 3 monthsADDIN RW.CITE{{869 Gomez-Iturriaga,A. 2018}}(21).The tumour control rate in our focal HDR-brachytherapy cohort (BDFS 70% at 4 years) does not match the 79-100% BDFS rates at 3-10 years in fractionated whole-gland HDR-brachytherapy series ADDIN RW.CITE{{855 Tselis,N. 2017}}(18). Lower BDFS was also reported in the single-dose 19 Gy whole-gland series by Prada et al., with 66% low-risk and 63% intermediate-risk patients being free of biochemical disease at 6 years follow-upADDIN RW.CITE{{866 Prada,P.J. 2016}}(19). In their report on single-dose 20.5 Gy HDR-brachytherapy, biochemical control was increased (82% at 6 years), even though relatively more intermediate-risk patients were treated (57% vs. 27%)ADDIN RW.CITE{{868 Prada,P.J. 2018}}(22). So, although the α/β ratio of prostate cancer is thought to be low (approximately 1.5)ADDIN RW.CITE{{871 Miralbell,R. 2012}}(23), which is an argument for hypofractionation, 19 Gy in a single dose might be a suboptimal therapeutic dose. We sub-analysed disease-free survival taking into account the possibility of salvage treatment. In patients with a prostatic recurrence, focal or whole-gland salvage radiotherapy was well tolerated without exacerbated toxicity (1 grade 2 urinary frequency at 48 months and 2 patients with transient grade 3 ED). This increased BDFS significantly to 91% at 4 years. The use salvage FT was classified as no treatment failure by an international consensus meeting on FTADDIN RW.CITE{{847 Donaldson,I.A. 2015}}(4). With the absence of increased toxicity and stable patient-reported QoL after primary FT, such a strategy could favour FT over a primary whole-gland approach, especially with increased adoption of ultrafocal targeting.Within the exploratory univariable analysis increasing age seemed to convey a higher risk of first biochemical failure. We do not have a definitive explanation for this correlation. Higher age did not correlate with other known prognostic variables such as PSA, PSADT and AJCC prognostic stage group. With only 10 biochemical failure events, there is a possibility that this reflects a type I error. The patient selection procedure at the time of inclusion for this study could be a potential reason behind our lower tumour control rates. First , the use of systematic biopsies could have led to sampling error of clinically significant tumours. According to the recent PRECISION trial results, the diagnostic yield of MRI-targeted biopsies is higher compared to TRUS-guided systematic biopsiesADDIN RW.CITE{{870 Kasivisvanathan,V. 2018}}(24), and this might have led to undertreatment of potentially missed higher-risk disease in this group. Second, for low/intermediate-risk patients (predominant Gleason pattern <4), the current EAU guidelines do not advise additional imaging for staging purposes(25). However, this means there is a considerable risk of missing metastatic disease. Although well-designed controlled trials regarding PET/CT imaging for nodal and metastatic staging are lacking in the primary setting, evidence is building that a more sensitive detection than the classical bone scan and abdominopelvic CT can be achieved (26). A disadvantage of focal MRI-guided HDR-brachytherapy is the labour-intensiveness of the procedure. The total procedure time is quite long, ranging from 5-8 hours in this cohort to currently 3-4 hours (indicating a learning curve). This procedure will inherently remain time-consuming, considering all the steps that are necessary for dose delivery: MRI/TRUS-guided insertion of catheters, subsequent transport to the MRI for scanning, catheter reconstruction and dose planning, another MRI scan for verification just before dose delivery and if necessary adjustment of the plan. In the future, MRI-guided external radiotherapy systems such as the MR-Linac could provide ultra-hypofractionated focal stereotactic radiation treatmentADDIN RW.CITE{{872 Pathmanathan,A.U. 2018}}(27), potentially matching the current focal HDR-brachytherapy procedure in terms of tumour control and morbidity.ConclusionMRI-guided focal HDR-brachytherapy for localized prostate cancer conveys minimal grade 2 GU toxicity and no grade >1 GI toxicity. Erectile function shows a downward trend during follow-up. Accordingly, patient-reported QoL is marginally affected, although clinically relevant deteriorations are seen in the domains fatigue and sexual activity. Overall biochemical failure is 30% after 4 years. However, an important note of consideration is the possibility of successful (focal or whole-gland) local salvage treatment, thereby increasing the disease-free survival rate at 4 years to 91% in this cohort.ReferencesADDIN RW.BIB(1) Shao YH, Demissie K, Shih W, Mehta AR, Stein MN, Roberts CB, et al. Contemporary risk profile of prostate cancer in the United States. J Natl Cancer Inst 2009 Sep 16;101(18):1280-1283. (2) Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med 2016 Oct 13;375(15):1415-1424. (3) Donovan JL, Hamdy FC, Lane JA, Mason M, Metcalfe C, Walsh E, et al. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. 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