Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10
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1 Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 Original article Development and internal validation of prediction models for biochemical failure and composite failure after focal salvage high intensity focused ultrasound for local radiorecurrent prostate cancer: Presentation of risk scores for individual patient prognoses Max Peters, M.D., Ph.D., M.Sc. a,,1, Abi Kanthabalan, M.D. b,c,1, Taimur T. Shah, M.D., B.Sc. b,c,d,1, Neil McCartan, M.Sc. b,c, Caroline M. Moore, M.D., M.B.B.S., F.R.C.S. b,c, Manit Arya, M.D., M.B.B.S., F.R.C.S. c,e, Jochem R. van der Voort van Zyp, M.D., Ph.D. a, Marinus A. Moerland, Ir. Ph.D. a, Richard G. Hindley, M.D., M.Sc., M.B.B.S., F.R.C.S. g, Mark Emberton, B.Sc., M.B.B.S., M.D., F.R.C.S. b,d,f, Hashim U. Ahmed, M.D., Ph.D., F.R.C.S. b,h,i a Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands b Division of Surgery and Interventional Science, University College London, London, UK c Department of Urology, UCLH NHS Foundation Trust, London, UK d Department of Urology, Whittington Hospital NHS Trust, London, UK e Department of Urology, Princess Alexandra Hospital NHS Trust, Harlow, UK f NIHR UCLH/UCL Comprehensive Biomedical Research Center, London, UK g Department of Urology, Basingstoke Hospital, Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK h Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK i Imperial Urology, Imperial Healthcare NHS Trust, London, UK Received 29 April 2017; received in revised form 29 July 2017; accepted 22 August 2017 Abstract Purpose: Patient selection for focal salvage remains difficult. Therefore, we developed and internally validated prediction models for biochemical failure (BF) and a composite endpoint (CE) following focal salvage high intensity focused ultrasound (HIFU) for radiorecurrent prostate cancer. Materials and methods: A prospective HIFU registry identified 150 cases (November 2006 August 2015). Recurrence was assessed with multiparametric magnetic resonance imaging (MRI) combined with template prostate mapping biopsies, targeted biopsies, or systematic transrectal ultrasound-guided biopsies. Metastatic disease was ruled out with a positron emission tomography-computed tomography and a bone scan. Focal salvage HIFU consisted of quadrant-ablation, hemi-ablation, or index-lesion ablation. Cox-regression was used for BF (Phoenix-definition) and CE (BF/MRIþ/biopsiesþ/local or systemic treatment/metastasesþ/prostate cancer specific mortalityþ). Internal validation was performed using bootstrap resampling (500 datasets) after which C-statistic and hazard ratios were adjusted. Models were calibrated and risk scores created. Results: Median follow-up was 35 months (interquartile range: 22 52). Median biochemical disease-free survival (DFS) was 33 months (95% CI: 23 45). Median CE-free survival was 24 months (95% CI: 21 35). After multivariable analysis, DFS interval after primary radiotherapy, presalvage prostate-specific antigen (PSA), PSA-doubling time, prostatic volume, and T-stage (both MRI based) predicted BF. For the CE, PSA-doubling time was not predictive but additionally, primary Gleason score was. The adjusted C-statistics were 0.68 and 0.64 for BF and CE, respectively. Calibration was accurate until 48 months. The risk scores showed 3 groups, with biochemical DFS of 60%, 35%, and 7% and CE-free survival of 40%, 24%, and 0% at 4 years. 1 Authors contributed equally to this research. Corresponding author. Tel.: þ address: M.Peters-10@umcutrecht.nl (M. Peters) /Crown Copyright r 2018 Published by Elsevier Inc. All rights reserved.
2 13.e2 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 Conclusion: Our model, once externally validated, could allow for better selection of patients for focal salvage HIFU. Crown Copyright r 2018 Published by Elsevier Inc. All rights reserved. Keywords: Focal salvage high intensity focused ultrasound (HIFU); Prostate cancer; Prediction models; Biochemical failure; Composite endpoint 1. Introduction Radiotherapy is an effective treatment for prostate cancer, especially with increasing dose escalation [1]. However, based on pretreatment risk factors, 10% to 50% of patients experience recurrent disease after 10 years [1]. Recurrence is often prostateconfined and related to the index lesion [2,3]. Although most men with radiorecurrent disease receive androgen deprivation therapy (ADT), many might be suitable for local salvage treatment. Whole-gland salvage therapies, such as radical prostatectomy, can confer significant side-effects [4]. Focal salvage therapy where individual areas of recurrent disease are targeted, preserving normal prostatic tissue, might confer fewer side-effects and offer oncological control. Several (pilot) studies using cryosurgery, high intensity focused ultrasound (HIFU) and brachytherapy (BT) have indicated seemingly comparable biochemical control rates, while showing favorable toxicity [5,6]. However, optimal patient selection is unknown. We often use factors associated with biochemical failure (BF) in the primary setting or with whole-gland salvage techniques, since these studies are of adequate size to allow multivariable modeling [4,7 11]. However, the identified risk factors differ in their predictive ability across studies with current prediction models being available only for cryotherapy and I-125 BT [10 12]. Furthermore, established risk factors such as PSA, T-stage, and Gleason score might have different predictive profiles in patients undergoing focal salvage (FS). To date, FS series have been too small and with too short a follow-up to allow adequate modeling of factors to use in patient selection. Our FS-HIFU dataset has recently reported on overall toxicity and disease control rates in 150 men [6]. We believe this series enables us to create multivariable prediction models to assess the predictive value of a range of risk factors in patients contemplating FS treatment. 2. Materials and methods 2.1. FS-HIFU patients Exemption from institutional review board was obtained from the UCLH Joint Research Office. Independent prospective academic HIFU registry analysis at 2 centers (University College London Hospitals and NHS Basingstoke Trust) identified 150 men who underwent FS-HIFU between November 2006 and August 2015 for histologically confirmed localized radiorecurrent disease. Selection, diagnostic assessment and treatment details have been described in detail earlier [6,13]. To summarize, all patients were primarily treated with external beam radiotherapy (EBRT) or a combination of EBRT with a high-dose rate (HDR-BT) boost. Patients experiencing BF according to the Phoenix-definition (PSA-nadir þ 2 ng/ml) after primary therapy were assessed with multiparametric (mp-)1.5 T-MRI consisting of a T2- weighted, dynamic contrast enhanced and diffusion weighted imaging sequences compliant with international guidelines and the previously published PROMIS study [14]. No endorectal coil was used. Metastatic disease was ruled out using 18 F-FDG or choline positron emission tomography-computed tomograph (PET-CT) as well as radio-isotope bone-scan. Patients with radiological stage T3bN0M0 were eligible for FS-HIFU provided T3b patients had minimal ( 1 cm) seminal vesicle invasion. Histological confirmation was obtained using either transperineal 5 mm template prostate mapping biopsies (TPM), multiparametric magnetic resonance imaging (mpmri) cognitively targeted biopsies or transrectal ultrasound (TRUS)-guided biopsies with treatment offered if histology was concordant with the mpmri. Other factors such as age, total PSA, PSA-kinetics, and biopsy outcomes were not standardised for selection. Our tertiary center had a policy of offering salvage therapy to men technically suitable for FS-HIFU provided their imaging was negative for metastatic disease. For the purposes of our current modeling, this improves the external validity of our findings Treatment details and follow-up In case of TRUS-guided biopsies, hemi-ablation was applied if the biopsies and MRI were concordant. Patients with TPM and mpmri agreement were treated with a focal approach or quadrant-ablation. Index lesion ablation was applied only if the patient had a MRI visible lesion with a concordant transperineal biopsy. It was permissible to leave behind biopsy positive clinically insignificant cancer ( 1 core with 3mmGleason3þ 3 or lower) in the contralateral lobe. T3b patients had (part of) the involved seminal vesicle additionally targeted. Follow-up consisted of PSA and toxicity assessment every 3 months. Additional mpmri and biopsies were performed in cases of rising PSA, clinical suspicion of recurrence or, for biopsies, a suspicious lesion on mpmri. For residual/recurrent disease, if suitable, a second FS-HIFU procedure was allowed and not deemed failure Variables assessed before primary therapy Before primary therapy initial PSA value, T-stage, Gleason grade, D'Amico stage, and ADT use were assessed.
3 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 13.e Variables assessed presalvage Variables presalvage included age, PSA-nadir after primary treatment, the disease-free survival interval (DFSI), measured as the time between the end of primary treatment and MRI date performed during assessment of recurrence. This MRI date was taken rather than the BF date after primary radiotherapy, since the latter was not systematically registered. Other variables included PSA, PSA-doubling time (PSADT), PSA-density (PSA value divided by the prostatic MRI volume), PSA velocity (PSAV), radiological (MRI based) T-stage (T3 vs. T2þT1), Gleason score, maximum cancer core length (in mm and %), and preoperative ADT use. PSA-kinetics (PSADT and PSAV) were obtained using the Memorial Sloan Kettering Cancer Center tool ( The type of ablation (hemi vs. focal) was also assessed. PSA-nadir after salvage was separately evaluated, but excluded from the multivariable analyses due to the redundancy for patient selection Evaluation of the outcome The Phoenix-definition was used to define BF following 1 or 2 FS-HIFU procedures. Data on the outcome and predictors were analyzed by the primary researcher (M.P.) without blinding, due to the objectivity and availability of all factors. Disease progression was defined as a composite endpoint (CE) of either BF or positive localized or distant disease on MRI or positive biopsies or initiation of systemic therapy or metastases or prostate cancer-related death. An intraprostatic recurrences was defined as either in or out of the treatment field Statistical analysis Baseline and survival Determinants with a normal distribution are presented as mean (±standard deviation) and skewed distributions as medians with their interquartile range. Categorical data are presented as frequencies with percentages. Kaplan-Meier analysis was performed to quantify biochemical disease-free survival (bdfs) and CE-free survival (CEFS) for the entire group and for the final risk groups. The log-rank test was used for comparisons between groups Missing data handling Missing data were considered at random (MAR): no relation of missing entries with the variables themselves was assumed (e.g., a missing PSA value is not related to the PSA value itself but to the retrospective nature of data collection). Multiple imputation (MI) with the iterative Markov chain Monte Carlo method with a total of 20 iterations was used to impute missing values [15]. The MI procedure was performed by including all determinants used in the univariable analyses. The outcomes (BF and CE) were also included [15,16] Model development Cox-proportional hazards regression was used for the relation between determinants and outcomes (BF/CE). Hazard ratios (HR) with 95% CI are provided. From univariable analysis, the most significant factors based on the Wald-test statistic were included in the multivariable model. Univariable significance was set at P 0.10 and in multivariable analysis, factors with P 0.25 were retained in the model, as higher P values are recommended in smaller datasets to obtain more valid models [16]. With a backward stepwise approach, the least significant predictors were excluded, starting with the full model. Proportionality of the cumulative hazard functions was visually evaluated by Schoenfeld residuals for continuous variables and loglog curves for categorical variables. Martingale residuals were used to assess linearity of continuous covariates. Interactions were not assessed. With continuous variables the original scale was maintained and no categorization was applied to decrease information loss. A sensitivity analysis was done, excluding patients in which residual low-volume/ low-grade disease was left untreated, to assess if this would affect the model Model performance and validation The C-statistic was calculated as a measure of discriminative ability of the models [17]. Internal validation of the models was performed as follows: 500 bootstrap resamples of the 20 imputed datasets were created, in which all modeling steps were repeated to calculate the optimism/ shrinkage factors of the original models. Subsequently, the apparent C-statistics and the coefficients (β's or natural logarithm of the HRs) could be adjusted. Optimismcorrected estimates were used in further analyses. Predictive accuracy of the final models was visually assessed at 1 to 4 years using calibration plots. No external validation was possible, since no similarly sized datasets were available Risk score construction Biochemical disease-free survival (bdfs) and CE-free survival (CEFS) proportions were calculated using S(t) ¼ S(0) exp(βpredictor1 * predictor1 þ βpredictor2 * predictor2, etc.), with the β's being the natural logarithm/ln of the HRs after multivariable analyses (corrected for optimism after internal validation) [16]. S(0) is the baseline survival proportion at a specified follow-up with the multivariable coefficients equaling 0. Risk scores were calculated by multiplying the optimism-corrected coefficients by 10 and subsequently with the values of the predictors. Finally, points were added to the sum score to obtain positive scores. The final risk groups were based on statistical practicality and clinical applicability.
4 13.e4 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 Table 1 Patient- and treatment-related characteristics of the focal salvage HIFU patients Characteristics before primary radiation treatment Number/median/mean %/IQR/SD Missing (%) Primary therapy EBRT % 0 EBRT þ HDR-BT boost 5 3.3% 0 EBRT dose 64 Gy Range: Gy 39.3 Initial PSA before primary therapy (ng/ml), median (IQR) Primary T-stage T % 50 T % T % Differentiation grade primary tumor Gleason % 12.7 Gleason % Gleason % ADT use (cytoreduction/adjuvantly or neo-adjuvantly) % 1.3 Presalvage characteristics PSA-nadir (ng/ml) after primary treatment, median (IQR) Disease-free survival interval after primary treatment (months), mean (±SD) 85.3 ± Age at focal salvage treatment, mean (±SD) 69.8 ±6.1 0 T-stage presalvage T % 1.3 T % T % MRI volume, median (IQR) Differentiation grade presalvage Gleason % 2.7 Gleason 3 þ % Gleason 4 þ % Gleason % Biopsy type TPM biopsies % 3.3 TRUS-guided biopsies % MRI-guided biopsies 1 0.7% Median cores TRUS Median cores TPM Positive cores presalvage, median (IQR) MCCL (mm), median (IQR) MCCL (%), median (IQR) Invasion on biopsy None % 1.3 Perineural % Lymphovascular 1 0.7% Unknown % PSA presalvage (ng/ml), median (IQR) PSADT, median (IQR) PSA-density (ng/ml/cc), median (IQR) PSAV (ng/ml/y), median (IQR) D'Amico risk group presalvage PSAo10, Gleason 6, T1 2a 4 2.7% 16.7 PSA 10 20, Gleason 7, T2b % PSA420, Gleason 8 10, T2c % ADT presalvage (cytoreduction/adjuvantly or neo-adjuvantly) % 0 Outcome characteristics Method of ablation 0 Focal ablation % Hemi-ablation 51 34% Index lesion ablation (with residual cancer left untreated or treated with second course) % BF (Phoenix-definition: PSA-nadir þ 2 ng/ml) % 0 Composite endpoint (BF, ADT, MRI þ, biopsies þ, systemic treatment þ, metastases þ, prostate cancer specific mortality) % 0
5 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 13.e5 Table 1 Continued Characteristics before primary radiation treatment Number/median/mean %/IQR/SD Missing (%) Death 9 6% 0 Other cause mortality 5 3.3% Prostate cancer specific 4 2.7% Median composite endpoint free survival, months (95% CI) Median biochemical disease-free survival, months (95% CI) PSA-nadir after salvage (ng/ml), median (IQR) Follow-up (mo) from salvage, median (IQR) IQR ¼ interquartile range; SD ¼ standard deviation; MCCL ¼ maximum cancer core length. The R language environment (version 3.1.2) for statistical computing (available at was used for statistical analyses (using the survival, rms, and mice packages [18 20]). All analyses and reporting were performed in accordance with the TRIPOD statement for multivariable prediction models ( [16]. 3. Results 3.1. Baseline characteristics and BF Patient- and treatment-related characteristics are outlined in Table 1. Patients either underwent primary EBRT (n ¼ 145) or EBRT þ HDR (n ¼ 5). Doses from EBRT ranged from 46 to 86 Gy with median 64 Gy. Most underwent quadrant focal ablation (n ¼ 82). Fifty-one underwent hemi-ablation and 17 patients had index-lesion ablation only with clinically insignificant disease left untreated (lowvolume Gleason 6 disease). Seventy-seven experienced BF and 91 reached the CE. Sixty-eight patients (45.3%) received ADT before FS-HIFU, which was discontinued on the day of the procedure Kaplan-Meier survival analysis Fig. 1 depicts the Kaplan-Meier curves for bdfs and CEFS for the entire group, showing a median bdfs of 33 months (95% CI: months) and 24 months (95% CI months), respectively Missing data Data on BF and the CE was complete. Important missing data was on PSADT (n ¼ 43) and PSAV (n ¼ 51) Also, nadir after primary treatment and primary T-stage were often not available. Other variables had acceptable missing data frequencies (Table 1) Cox-proportional hazards models Supplementary Tables 1 and 2 provide the results from uni- and multivariable Cox-regression for BF and the CE, respectively. In univariable anlaysis, 8 predictors were found to be associated with BF (P 0.10), whilst in multivariable analysis 5 factors were identified: DFSI (optimism-corrected HR ¼ [95% CI: ], P ¼ 0.05), T3 (HR ¼ 1.30 [ ], P ¼ 0.21), prostate volume (HR: [ ], P ¼ 0.05), presalvage PSA (HR ¼ [ ], P ¼ 0.02) and presalvage PSADT (HR ¼ [ ], P ¼ 0.13). For the CE, PSADT did not reach significance, but the primary Gleason score did. Otherwise, the same factors were found. In the sensitivity analysis, the same variables were retained in the model for both BF and the CE, with minor deviations in HRs Calibration Fig. 2 depicts calibration curves at 1 to 4 years. Until 4 years strong concordance between predicted probabilities from the multivariable model and observed probabilities is attained Internal validation The mean optimism was 0.22 and 0.24 for the BF model and the CE model, respectively. With a shrinkage factor of 0.78 and 0.76 the coefficients were adjusted. The C-statistic was adjusted from 0.71 to 0.68 and from 0.68 to 0.64 for the BF and CE model, respectively Risk score Table 2 shows the risk scores. Points are given for the value of the predictors from multivariable analysis. The final score is added with a constant value of 22 and 10 points to obtain positive scores (BF and CE model, respectively). Table 3 shows the 3 risk categories corresponding to relevant bdfs and CEFS proportions. The Kaplan-Meier curve in Fig. 3 depicts the difference in bdfs and CEFS between the risk categories. For risk group 1 to 3, the bdfs estimates are 60%, 35% and 7%, respectively and the CEFS estimates are 40%, 24%, and 0% at 4 years.
6 13.e6 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 Fig. 1. Kaplan-Meier curves depicting biochemical disease-free survival and composite endpoint free survival for the entire group. Fig. 2. Calibration plots depicting the observed (y-axis) vs. the predicted probability (x-axis) of biochemical disease-free survival (bdfs) and composite endpoint free survival (CEFS) at 1 to 4 years, respectively. The diagonal line depicts the optimal line for complete concordance between observed and predicted probabilities. The blue crosses indicate the optimism-corrected predicted probabilities after 500 bootstrap resamples.
7 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 13.e7 Table 2 Risk score calculation tool for biochemical failure and the composite endpoint Determinant Corrected coefficient Hazard ratio (95% CI) Risk score contribution (coefficient*10) Score ( ¼ value determinant*risk score contribution) Biochemical failure DFSI, mo ( ) 0.07 T-stage ( ) 2.7 Volume, cm ( ) 0.09 PSA, ng/ml ( ) 0.43 PSADT, mo ( ) 0.26 þ Sum score þ22 Composite endpoint Gleason ( ) 0.83 Gleason ( ) 4.8 DFSI, mo ( ) 0.07 T-stage ( ) 0.31 Volume, cm ( ) 0.07 PSA, ng/ml ( ) 0.42 þ Sum score þ10 DFSI ¼ disease-free survival interval after primary therapy (or time from the end of primary therapy to the MRI date). An individual score can be calculated by multiplying the value of the predictor variables by the value corresponding to the risk score contribution. Patients in the most favorable risk groups can achieve 95%, 80%, and 65% bdfs and 87%, 73%, and 61% CEFS at 1, 2, and 3 years, respectively. 4. Discussion Our results regarding the first multivariable prediction model for FS-HIFU demonstrate that several factors can be used to predict bdfs and CEFS at 4 years. These include the DSFI (time between primary radiation therapy and the recurrence as assessed with MRI), prostate volume (MRI based), T-stage (MRI based), PSA, and PSA-doubling time (BF only) and primary Gleason score (CE only). Some of these factors have been found earlier in whole-gland salvage series: DFSI and PSA in salvage cryosurgery [9], DFSI and PSADT in salvage iodine-125 BT [10], and PSA in salvage radical prostatectomy [7] and salvage HIFU [8]. Predictive models using these variables are not available. We developed 3 risk groups which showed 40% and 60% CEFS and bdfs at 4 years in the most favorable group. As risk group increases, bdfs and CEFS decreases to 24% and 35% (group 2) and 0% and 7%, (group 3), respectively. To date, most FS series have been too limited in size to undertake any univariable or multivariable modeling [5]. In addition, prognostic factors from wholegland salvage modalities might have different predictive values for FS. FS potentially offers curative treatment while minimizing poor functional outcomes from whole-gland salvage. A total of 16 patients (11%) had Clavien 3b complications, requiring surgical, endoscopic or radiological intervention to resolve. IPSS scores increased from median 8 to 11 and IIEF decreased from median 15 to 13, although data were frequently missing. Whole-gland salvage modalities report high rates of incontinence (5 50%), erectile dysfunction (35 70%), bladder neck stricture (up to 20%) and rectal injury (5 10%), among others [4 9]. Our previously published data shows a bdfs of 48% at 3 years [6], comparable to many whole-gland salvage series and FS series, the latter describing 3-year bdfs rates of 50% to 91% [5]. However, FS is not yet considered standard of care and these results will allow better patient selection. Our results also identify groups of patients who do poorly and thus could be better counseled preoperatively. Of particular importance in determining patient suitability for FS is accurate disease localization. MpMRI and TPM biopsies have increasing diagnostic potential, both in the Table 3 Risk score categories and corresponding biochemical disease-free survival (bdfs) and composite endpoint free survival (CEFS) probabilities Risk group Risk score n, % n, % Kaplan-Meier estimates at 48 mo 36 mo 24 mo 12 mo bdfs 1 0 o15 45 (30%) 13 (29%) 60% 65% 80% 95% 2 15 o22 71 (47%) 35 (49%) 35% 54% 59% 77% (23%) 29 (85%) 7% 15% 24% 52% CEFS (27%) 16 (39%) 40% 61% 73% 87% 2 7 o15 82 (55%) 53 (65%) 24% 39% 48% 73% (18%) 22 (81%) 0% 12% 22% 52% The corrected predicted probabilities are after internal validation of the model.
8 13.e8 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 Fig. 3. Differences in biochemical disease-free survival (bdfs) and composite endpoint free survival (CEFS) up to 4 years for the 3 created risk groups. primary as well as in the radiorecurrent setting [21 23]. MpMRI can achieve positive and negative predictive values up to 90% to 100% with TPM biopsies as reference standard. Patient selection using these modalities can therefore provide the right population for true focal ablation, which was mostly achieved in this cohort. Focal therapy can be offered to patients based on either TPM biopsies in patients with a negative mpmri, or targeted cognitive/fusion biopsies when a mpmri lesion is seen. There is much debate whether systematic biopsies are needed or if targeted biopsies will suffice. In the pre-mri era 5 mm TPM biopsies in patients diagnosed with unilateral disease showed 61% actually harbored bilateral disease [24]. In primary disease mpmri when compared to 5 mm TPM biopsies will miss only 10% to 20% of clinically significant disease [14]. Thus, mpmri fusion biopsies may also miss 10% to 20% of clinically significant cancer within MRI negative areas of the prostate. In radiorecurrent disease mpmri targeted biopsies has a similar detection rate compared to TPM biopsies [25]. It would stand to reason that a staged focal therapy protocol used for patients undergoing only mpmri targeted biopsy may lead to an estimated 10% to 20% needing retreatment for MRI occult disease. The benefit of such a protocol would be a reduction in the biopsy burden while still offering the low side-effect profile conveyed by focal therapy. The necessity of these procedures could influence costeffectiveness. Contrary to this, the lower toxicity rates and associated savings in costs could tip cost-effectiveness in the direction of FS. Underlying pathological reasons for recurrence are not fully understood. Residual disease may play an important role and poorer oncological outcomes in some patients may possibly be related to the presence of micrometastatic disease at diagnosis. Even though newer imaging techniques such as prostate-specific membrane antigen (PSMA)-PET/CT have a high diagnostic accuracy for detection of metastatic disease, micrometastases can still be missed [26]. Multivariable prediction models such as ours can guide patient selection by identifying high-risk groups. In relation to this, misclassification bias is possible because of the different PET-tracers used. However, the current models correct for several classical risk characteristics related to failure, therefore, the confounding effect of PET-tracer type was deemed minor. It has been shown extensively that dose escalation whether image guided or using HDR reduces recurrence rates [27,28]. It might be the case that in the era of dose-escalation radiotherapy, smaller secondary tumor foci in the prostate are more adequately treated and that only the index lesion will recur, increasing the validity of FS as a treatment option. However, due to missing data on radiotherapy schedules, assessing this dose relation from the primary setting was not possible in our database. For this reason and the fact that unlike the presence of LDR BT seeds the addition of HDR would not impact on the delivery of salvage HIFU all patients who underwent EBRT and EBRT plus HDR-BT boost were included in the analysis. The study has some limitations. First and foremost, external validation of this model is necessary. The plan for this to occur will be once an on-going prospective multicentre trial has completed and matured [29]. Furthermore,the model is most likely only applicable in patients undergoing similar staging procedures, as MRI is necessary to obtain 3/5 parameters contained within the model. This specific model might have decreased use for centers not using these selection criteria. It is unknown whether the factors assessed with MRI (T-stage,
9 M. Peters et al. / Urologic Oncology: Seminars and Original Investigations 36 (2018) 13.e1 13.e10 13.e9 DFSI, and prostate volume) can be based on other diagnostic modalities as well. Second, testing of multiple factors in a univariable analysis might have introduced a type-i error. Because of the uniqueness of this series, exploratory univariable testing was accepted. Third, when assessing the models' predictors, some aspects need to be considered. There was no relation with biopsy results and outcomes. Presalvage Gleason score has only been significantly associated with failure in the whole-gland salvage radical prostatectomy setting [7], not HIFU and cryosurgery [8,9]. Misclassification of tumor presence is common postradiotherapy, especially in the first 2 to 3 years[30]. However, the mean DFSI in this series was 85 months and thus would reduce the likelihood of misclassification. Fourth, MRI based prostatic volume was used and we found that a larger prostate volume was associated with increased failure rates, indicating the need for caution when treating large prostates. This may be due to poor anterior penetration of HIFU in larger prostates. Our revised local protocols involve the use of FS cryotherapy as an alternative energy modality for disease within the anterior prostate and we feel competency with multiple energy modalities is needed. We also did not assess tumor volume due to nonstandardised reporting and potential misclassification due to interobserver variability and thus increasing model complexity. Further work using tumor contouring of mpmri images may improve this limitation. Sixth, we used both BF and a more expansive composite outcome. Even though the Phoenix-definition is primarily constructed for failure postradiotherapy, BF was mostly verified by MRI (n ¼ 51) and biopsies (n ¼ 11), potentially indicating the validity of BF in this setting. In addition, the definition of failure after prostatectomy would not hold because of the remaining functional prostatic tissue. Lastly, more complete data in parameters such as in the PSA-nadir after primary radiotherapy ( 50% missing) might change a future model. It could also be that models incorporating other predictive factors might increase the suboptimal C-indices found in this study. Because of the multiple CEs, our CEFS outcomes may seem somewhat more unfavorable than studies and models that are based solely on BF. As progression can occur on occasions without BF our composite outcome would capture these patients better than BF alone. Our model did not contain PSA-nadir after treatment, since it cannot be used for patient selection before FS-HIFU. A model with PSA-nadir might be used to individualize follow-up. The frequency of follow-up could be intensified in patients with a high nadir after treatment so as to catch recurrences early and potentially enabling further curative salvage treatment. Overall, our results show that patients in the most favorable risk groups can achieve 95%, 80%, 65%, and 60% bdfs and 87%, 73%, 61%, and 40% CEFS at 1 to 4 years, respectively. This score might help guide patient selection and research into FS-HIFU and might also apply to other FS modalities. 5. Conclusion FS-HIFU has the potential to achieve durable biochemical disease-free survival and CE-free survival in adequately selected patients. Using the pretreatment risk scores bdfs and CEFS up to 4 years could be significantly improved. Conflicts of interest and funding M. Emberton and H.U. Ahmed would like to acknowledge funding from the Medical Research Council (UK), the Pelican Cancer Foundation Charity, Prostate Cancer UK, St Peters Trust Charity, Prostate Cancer Research Center, the Wellcome Trust, National Institute of Health Research- Health Technology Assessment Program, National Institute of Health Research-i4i Program and the US National Institute of Health-National Cancer Institute. M. Emberton receives funding in part from the UK National Institute of Health Research UCLH/UCL Comprehensive Biomedical Research Center. M. Emberton and H.U. Ahmed previously received funding from GSK, Angiodynamics, and Advanced Medical Diagnostics for clinical trials. They currently receive trial funding from Trod Medical and Sophiris Inc. M. Emberton is a paid consultant to Steba Biotech and Sonacare. R.G. Hindley and M. Emberton have share options in Nuada Medical Ltd., UK. Ahmed and Emberton have previously received consultancy payments from Oncura/GE Healthcare and Steba Biotech. Both are paid consultants with Sophiris Inc. T.T. Shah would like to acknowledge funding from the St Peters Trust for clinical research and has received funding for conference attendance from Astellis, Ferring and Galil Medical. Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at References [1] Zumsteg ZS, Spratt DE, Romesser PB, et al. The natural history and predictors of outcome following biochemical relapse in the dose escalation era for prostate cancer patients undergoing definitive external beam radiotherapy. Eur Urol 2015;67: , doi.org/ /j.eururo [2] Pucar D, Hricak H, Shukla-Dave A, et al. Clinically significant prostate cancer local recurrence after radiation therapy occurs at the site of primary tumor: magnetic resonance imaging and step-section pathology evidence. 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Mid-term results demonstrate salvage high-intensity focused ultrasound (HIFU) as an effective and acceptably morbid salvage treatment option for locally radiorecurrent prostate cancer. Eur Urol 2009;55:640 7, org/ /j.eururo [9] Wenske S, Quarrier S, Katz AE. Salvage cryosurgery of the prostate for failure after primary radiotherapy or cryosurgery: long-term clinical, functional, and oncologic outcomes in a large cohort at a tertiary referral centre. Eur Urol 2013;64:1 7, /j.eururo [10] Peters M, van der Voort, van Zyp JR, Moerland MA, et al. Development and internal validation of a multivariable prediction model for biochemical failure after whole-gland salvage iodine-125 prostate brachytherapy for recurrent prostate cancer. Brachytherapy 2016;15: , doi.org/ /j.brachy [11] Peters M, van der Voort van Zyp JR, Moerland MA, et al. Multivariable model development and internal validation for prostate cancer specific survival and overall survival after whole-gland salvage iodine-125 prostate brachytherapy. Radiother Oncol 2016;119:104 10, [12] Spiess PE, Katz AE, Chin JL, et al. A pretreatment nomogram predicting biochemical failure after salvage cryotherapy for locally recurrent prostate cancer. BJU Int 2010;106:194 8, /j X x. [13] Ahmed HU, Cathcart P, McCartan N, et al. Focal salvage therapy for localized prostate cancer recurrence after external beam radiotherapy: a pilot study. Cancer 2012;118: , cncr [14] Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017;389:815 22, doi.org/ /s (16) [15] Moons KG, Donders RA, Stijnen T, Harrell FE Jr. Using the outcome for imputation of missing predictor values was preferred. 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