Salvage Local Treatments After Focal Therapy for Prostate Cancer

E U RO P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

available at www.sciencedirect.com journal homepage: euoncology.europeanurology.com

EUO Collaborative Review – Prostate Cancer Editorial by Aminsharifi and Polascik on pp. 539–540 of this issue

Salvage Local Treatments After Focal Therapy for Prostate Cancer Giancarlo Marra a,1,*, Massimo Valerio b,1, Mark Emberton c, Axel Heidenreich d, Juanita M. Crook e, Alberto Bossi f, Louis L. Pisters g a

Department of Urology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy;

b

Department of Urology,

c

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Division of Surgery and Interventional Science, University College London, London, UK; d

Department of Urology, Uro-Oncology, Robot-Assisted and Reconstructive Urologic Surgery, University Hospital Cologne, Cologne, Germany; e Department

of Surgery, Division of Radiation and Developmental Radiotherapeutics, University of British Columbia, BC Cancer Center for the Southern Interior, Kelowna, Canada; f Department of Urology, Gustave Roussy Cancer Institute, Villejuif, France; g Department of Urology, MD Anderson Cancer Center, TX, USA

Article info

Abstract

Article history: Accepted March 25, 2019

Context: Whether focal therapy (FT) for prostate cancer (PC) jeopardizes outcomes from salvage treatments is a matter of debate still to be resolved. Objective: To review the literature on oncological and functional outcomes and complications for available treatment options for recurrent or residual PC after primary FT. Evidence acquisition: We performed a nonsystematic search of PubMed for articles assessing relevant outcomes for salvage local treatment after FT failure using a manual search. When no evidence could be extracted for the FT domain, records dealing with recurrence after whole-gland ablation were considered. Evidence synthesis: Four retrospective series assessed salvage treatments after FT failure evaluating cases of radical prostatectomy (RP) and repeat ablation (sample size from 12 to 22 patients). The quality of the studies was low, with a high risk of bias. Other options are radiation therapy (RT) and whole-gland or focal repeat ablations, although these have only been described after whole-gland ablation. With some exceptions, including sexual function for RP, overall complications and oncological and functional outcomes do seem to be acceptable and are not much worse than those in the primary setting. Important limitations include the low level of the evidence and the absence of standardized criteria for FT, salvage treatment, and FT failure. Conclusions: Current evidence shows acceptable outcomes for post-FT salvage options, although this is based on retrospective data. While it seems that FT has a minimal impact on salvage treatment results, prospective controlled studies are needed to confirm these preliminary data. Patient summary: We performed a literature search to determine the treatment options available for prostate cancer after failure of focal therapy and their outcomes. Options include radical prostatectomy, repeat whole-gland ablation, focal ablation, and radiotherapy. Overall cancer control, impacts on urinary and sexual function, and complications seem slightly worse but not markedly different compared to primary treatments, but high-quality studies are awaited to confirm these findings. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Associate Editor: Paul Nguyen Keywords: Prostate cancer Recurrence Focal therapy Salvage treatment Surgery Radiotherapy

1

These authors contributed equally to this work. * Corresponding author. Department of Urology, San Giovanni Battista Hospital, Citta` della Salute e della Scienza and University of Turin, C.so Bramante 88/90, 1010 Turin, Italy. Tel.: +39 011 6336594; Fax: +39 011 6335707. E-mail address: [email protected] (G. Marra).

https://doi.org/10.1016/j.euo.2019.03.008 2588-9311/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

E U RO P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

1.

Introduction

Focal therapy (FT) for prostate cancer (PC) has been proposed as a minimally invasive option for treating localized disease with the aim of minimizing the side effects associated with radical treatment while maintaining the oncological benefit of local treatments [1–3]; however, the ideal eligibility criteria for FT are not well defined. Although FT is not generally considered a standard-of-care option, short- to medium-term results are now available and show acceptable oncological outcomes and low toxicity [2,4]. Several concerns remain. First, PC is multifocal in the majority of the cases, documented as approximately 80% of radical prostatectomy (RP) cases in large series; second, despite recent improvements through the use of multiparametric magnetic resonance imaging (mpMRI) for targeted biopsies, inappropriate patient selection may result in disease progression, and thus worse outcomes than for initial radical treatment; and third, no long-term oncological results from prospective cohorts are available at present [1,3–6]. Finally, as for other nonsurgical wholegland treatment (WT) modalities, FT may jeopardize subsequent salvage treatment outcomes in the case of PC recurrence [5]. The latter issue in particular will probably become crucial. Although FT should still be considered experimental, it is considered attractive by patients and by the wide urological community [7]. The rate of clinically significant PC persistence and/or recurrence in short- to medium-term FT series is 17%, with approximately 28% of cases needing additional local treatment [1,2]. As a consequence, the outcome of salvage treatments remains a key issue to be resolved in evaluating the trade-off between initial FT and radical treatment. If an initial FT does not negatively impact subsequent treatment, then many would prefer this approach; however, if an initial FT would have a major detrimental effect on secondary treatments, then it should be reserved for very well-selected patients in whom the chances of recurrence are extremely low. Currently, several salvage options for FT failure can be envisioned. For low-risk disease, active surveillance may be appropriate. In the case of intermediate- to high-risk PC, active treatment with curative intent should be regarded as the standard. Options include: (1) repeat treatments using the same or different energy sources compared to the firstline setting,; (2) salvage RP (sRP); and (3) salvage radiotherapy (sRT) for the whole gland or on a focal basis using external beam RT (EBRT) or brachytherapy. From an oncological perspective, selection of more resistant PC clones may result in more aggressive tumor biology at recurrence; from a functional perspective, welldocumented phenomena including neoangiogenesis, necrosis, and tissue scarring may alter anatomic landmarks, surgical planes, and healing potential, possibly increasing complication risks and impairing recovery [8–13]. Whilst these effects following whole-gland nonsurgical treatments are well documented, there is little evidence for effects after FT, which, by definition, aims to reduce the collateral effects of radical treatment.

527

We performed a literature review with the aim of reporting the impact of prior focal ablation on complications and the functional and oncological outcomes of salvage treatments for recurrent or residual PC. 2.

Data acquisition

A nonsystematic search with no time restrictions was performed independently by two authors (G.M. and M.V.) using PubMed on September 5, 2018 with the search terms “focal therapy” AND “prostate cancer” AND “recurrence”. We included all relevant English language articles dealing with salvage treatments following PC recurrence after primary FT. Additional articles dealing with recurrences after whole-gland ablation were also considered when no evidence was found for primary FT. A manual search strategy for references in the included articles was applied and the senior authors were consulted. When possible, continence was classified according to the number of pads/ day; erectile function according to the International Index of Erectile Function (IIEF-5) or according to patients’ reports of preserved erections (spontaneous or with phosphodiesterase type5 inhibitors) versus others; complications were measured according to the Clavien-Dindo classification [14] and the European Association of Urology (EAU) guidelines [15]. 3.

Data synthesis

We found three series reporting on sRP after FT. Only one series reported repeat ablation results and no series investigated RT after FT; for the purpose of completeness, we report results from the main studies on repeat ablation and sRT after whole-gland RT and/or ablation. We found no series relating to outcomes for active surveillance, watchful waiting, and androgen deprivation therapy (ADT) after initial FT. Evidence concerning their use in a post-FT setting remains mainly based on the experience of expert groups (no published series available) [16,17]. Since these strategies are noninterventional and/or do not have a curative aim and an overall survival endpoint will require many more years to allow results, their evaluation is beyond the scope of the present review. An overview of possible management options and current evidence for recurrent or persistent PC after FT is shown in Figure 1.

3.1.

Salvage repeat ablation

Focal or whole-gland ablation using the same or different energy sources are possible options and have been used after failure in FT series, ranging in incidence up to 33% [1]. Some expert groups support repeat procedures on the basis of their own experience. Nonetheless, results from these institutions have not yet been published [16,17] and direct evidence on the efficacy of repeat ablation following FT remains scarce. Two energy sources have been assessed as repeat options, almost exclusively following whole-gland ablation

528

[(Fig._1)TD$IG]

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Fig. 1 – Treatment options for persistent or recurrent disease after FT for PC. FT = focal therapy; PC = prostate cancer; AS = active surveillance; mpMRI = multiparametric magnetic resonance imaging; PSA = prostate-specific antigen; LE = life expectancy; PSAdt = PSA doubling time; WW = watchful waiting; ADT = androgen deprivation therapy; sRP = salvage radical prostatectomy; sRT = salvage radiotherapy.

(Table 1). Chang and colleagues [18] reported outcomes for salvage whole-gland cryosurgery (CS) for local recurrence in 12 men at a median of 7 mo (range 6–99) after focal CS (fCS). At mean follow-up of 33.5 mo, seven men were diseasefree, three received ADT because of disease progression, and the remaining two underwent another cycle of sCS and were disease-free at subsequent checks. No major complications were reported. One man who underwent repeat CS developed mild incontinence (1–2 pads/d); of the two patients who were potent before the procedure, none experienced permanent erectile dysfunction [18]. This is currently the only study specifically assessing outcomes for a repeat treatment after FT. No large series of salvage CS after FT or whole-gland ablation specifically addressing functional and oncological outcomes is available. Salvage CS outcomes were also assessed for a large cohort from the USA including recurrent cases after primary RT (n = 259), low-dose–rate brachytherapy (n = 49), or CS (n = 20) [19]. At median follow-up of 47.0 mo (range 1.6– 203.5), 160 men (49%) experienced recurrence and 108 (33%) died, 35 (10.7%) due to PC (10-yr disease-free survival 35%, overall survival [OS] 45%, and cancer-specific survival [CSS] 79%). Complications were relatively infrequent, occurring in 46 men (14%); urethral stricture (n = 15) was the most frequent adverse event. Six cases of fistula were recorded. Seven men had severe incontinence and underwent subsequent surgical treatment [19]. Interestingly, a subgroup of 55 men (16.7%) received fsCS, including five cases of primary fCS (results not reported separately). The 10-yr disease-free survival rate was similar to that for whole-gland sCS (42%)

and CSS was 83%; surprisingly, 10-yr OS was much higher in the fsCS group, at 81%. Again, serious complications were uncommon. Nonetheless, three cases (5%) of fistula were noted. As possible explanations, the authors state these cases occurred at the beginning of their fsCS experience, with two of the men also receiving two fsCS sessions each. Repeat high-intensity focused ultrasound (HIFU) is another possible option. Berge and co-workers [20] investigated the effect of repeat whole-gland HIFU compared to a single whole-gland HIFU treatment in terms of complications and functional outcomes. Of 359 men included, 130 (36.2%) underwent one or more repeat HIFU treatments (19 had two repeat and 1 had three repeat HIFU sessions) and the rest had a single whole-gland HIFU session. No major baseline differences were identified with the exception of higher Gleason score before repeat HIFU (p = 0.004). The rate of biochemical recurrence (BCR) was higher for the repeat HIFU group (44.8% vs 26.4%), possibly related to the higher Gleason scores. Intra- and postoperative complications, including a need for additional procedures, were similar for the two cohorts with the exception of urinary tract infection, which was less frequent after repeat treatment (p = 0.009). Moreover, the repeat group had shorter treatment times (p < 0.001), hospital stays (p = 0.002), and catheterization times (p = 0.001) compared to the primary HIFU group. After repeat HIFU there was an increase in urinary leakage (p < 0.001) although this increase was not statistically significant among those using pads (p = 0.07). No significant changes in sexual function (p = 0.9) were observed [20].

Table 1 – Main studies reporting on salvage cryotherapy and/or HIFU following prostate cancer recurrence after focal therapy or after whole-gland treatments including whole-gland ablation Chang et al. [18]

Wenske et al. [19] Overall

Patients (n) First-line Tx Type (n)

Years Gleason score PSA (ng/ml) cT stage

PSA (ng/ml) FU after salvage Tx Time (mo) PSA nadir (ng/ml) BCR, % (n)

PC-related death, % (n)

PC progression, % (n) MRP after sTx

Berge et al.f [20]

fsCS subgroup

First-line HIFU

Redo HIFU

Blana et al. [21] p value

First-line HIFU

Redo HIFU

12

328

55

279

229

130

223

49

fCS (12)

259 EBRT 49 BT 20 CS

44 EBRT 5 fCS 6 CS

HIFU

HIFU

HIFU

HIFU

2008–2012 7 (6–9)* 26.04 (3.81–38.63)* 4 cT2a, 6 cT2b, 2 cT2c 0.08 (0.03–3.12)*

NA 7 (5–10)y 8.0 (0.6–290.0)y NA

NA NA 7 (1.2–185.8)y NA

218 EBRT 32 BT 20 EBRT + BT 9 NA NA NA NA NA

2004–2012 NA NA NA

NA NA NA NA

1997–2003 5.3  1.5 11.3  1.0 NA

1997–2003 NA NA NA

0.5 (0.01–44.5)y

0.5 (<0.1–5.3)y

NA

NA

NA

NA

NA

CS NA 7 (3–42)* 77.5 (56–86)* 7 (6–9)*

273 CS, 55 fCS 1994–2011 67.5 (18–212.7)y 65.8 (45–81)y 43 GS 6 113 GS7 172 GS 8

fCS 1994–2011 67 (8.1–151.1)y 66 (50–79)y NA

– – – 65.9 (46.7–87.4)z 111 GS 6 101 GS7 9 GS 8

Redo HIFU 2004–2012

– – – – –

Redo HIFU NA 7 (1–49)y NA NA

2.5 (0.18–7.28)*

4 (0.1–112.4)y

NA

CS NA NA 70  7.1 45 GS 6 98 GS7 122 GS 8 15 NA 7.6  8.2

NA

NA

–

NA

0.44 (0.04–20.10) 49.1 (27)b

21.6  24.9 NA 41.1 at 5 yr

45 (3.93)y NA 26.4 (60)

27 (3–81)y NA 44.8 (56)

– – –

13 (3–50)y NA NA

NA

NA

NA

NA

–

NA

NA 16 ADT + sRT, 13 ADT, 3 sRT, 2 ADT + sRP, 1 ADT + CT, 1 sCS, 24 AS

NA 18 ADT, 2 ADT + sRT, 1 sRP, 19 redo HIFU, 17 sRT

– –

NA 2 pts third redo HIFU

188.6 (90–340)z 1.7 (1–7)z 17.6 (5–75)z

117.4 (40–285)z 1.4 (1–4)z 12.3 (1–49)z

164  42 NA NA

107  41 NA NA

47.8 (1.6–203.5)y 0.2 (0.01–70.7) Overall 48.2 (160) EBRT 47.1 (122) BT 46.9 (23) CS 65.0 (13) NA Overall 10.7 (35) EBRT 11.2 (29) BT 8.1 (4) CS 10.0 (20) 25.0 (3) NA 3 ADT, 2 repeat fCS NA 33.5 (15–54) 1.32 (0.15–4.14) 41.67 (5)

Functional outcomes Operating time (min) NA Hospital stay (d) NA Catheterization time (d)

NA NA 5 (2–10)y

NA NA 11 repeat fCS after NA y 16 (3.2–33.5) mo

NA NA NA

64.6 (43.6–80.5) 45 GS 6 81 GS7 6 GS 8

0.13 0.004

<0.001 0.002 0.001

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PSA nadir (ng/ml) Salvage Tx Type Years FSTT (mo) Age (yr) Gleason score

Pisters et al.49

529

530

Table 1 (Continued ) Chang et al. [18]

Wenske et al. [19] Overall

Pisters et al.49

fsCS subgroup

Berge et al.f [20] First-line HIFU

0

12.8 (42)a

7.2 (4)c

6.8 (19) AURd 1.2 (NA) rectal fistula

PO continence

1 pt 1–2 pads/d

NA

NA

6 pts using padse 73.3% before ! 55.1% 8 pts UL, no padse after HIFU had no UL (p < 0.001)

PO erectile function

2 pts transient ED

NA

NA

NA

3.8 (5) IO 10.8 (14) UTI 2 (1.5) epididymitis 9.2 (12) ENS 13.8 (18) dilation

No significant # but " in PDE-5i use (p < 0.001)

Redo HIFU 5.4 (7) IO 3.9 (5) UTI 2 (1.6) epididymitis 11.6 (15) ENS 14.0 (18) dilation

p value

First-line HIFU

0.009 UTI – >0.05 all others

97.3% before ! 91.0% after reHIFU had 0 pads (p = 0.07)

–

No significant #, no " in PDE-5i use (p = 0.5)

–

Redo HIFU UTI 4.1 (2) HIFU1, 4.1 (2) HIFU2 (p > 0.99) CPP 0 HIFU1, 4.1 (2) HIFU2, p = 0.5 BOO 22.4 (11) HIFU1, 14.3 (7) HIFU2, p = 0.5 RUF 0 HIFU1, 2.0 (1) HIFU2, p > 0.99 6.1% INC after HIFU1 12.2% INC after HIFU2 p = 0.024 vs baseline p = 0.266 vs HIFU1 38.8% IMP after HIFU1 55.1% IMP after HIFU2 p < 0.01 vs baseline p = 0.039 vs HIFU1

HIFU = high-intensity focused ultrasound; Tx = treatment; sTx = salvage Tx; FU = follow-up; MRP = management of recurrence/persistence after sTx; PO = postoperative; EBRT = external beam RT; BT = brachytherapy; CS = cryosurgery; FSTT = time from first Tx to sTx; PC = prostate cancer; pt = patient; ED = erectile dysfunction; ADT = androgen deprivation therapy; PSA = prostate-specific antigen; AUR = acute urinary retention; BOO = bladder outlet obstruction; UL = urine leak; sRP = salvage radical prostatectomy; CT = chemotherapy; AS = active surveillance; IO = intraoperative complications; UTI = urinary tract infection; ENS = endoscopic surgery; PDE-5i = phosphodiesterase type 5 inhibitor; HIFU1 = first HIFU; HIFU2 = second HIFU; INC = incontinent; IMP = impotent; RUF = rectourethral fistula; CPP = chronic pelvic pain. a Complications included 15 urethral strictures requiring surgery, 11 BOO requiring endoscopic surgery, six AUR (5 spontaneous resolution), six rectourethral or urethroperineal fistula (4 open surgery), three incontinence requiring an artificial sphincter, seven stone removal, and three penile prosthesis cases, b Including 11 men who had two sCS cycles. c Three RUF (of whom 2 had 2 sCS cycles) and one BOO and subsequent transurethral resection of the prostate. d AUR after catheter removal (10 transient and 9 requiring endoscopic surgery). e Of the 137 patients for whom pre-SC data were available. f Ten patients had two redo HIFU and one patient three redo HIFU treatments. * Data reported as mean (interquartile range). y Data reported as median (range). z Data reported as mean (range).

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Complications, % (n)

Blana et al. [21]

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Similar findings were reported by others evaluating 223 men undergoing a single HIFU session and 49 men undergoing two or more repeat HIFU sessions [21]. The repeat procedure had a shorter operating time and a similar complication rate. Overall, the risk of incontinence following two HIFU sessions was higher compared to baseline (12.2%; p = 0.024). However, this was related to first-line whole-gland HIFU, as repeat HIFU did not have a significant impact on continence (p = 0.266). By contrast, there was a higher risk of erectile dysfunction compared to baseline (55%; p < 0.01) that persisted when comparing erectile function before and after second HIFU (p = 0.039) [21]. Guillaumier and colleagues [2] recently published intermediate-term results for focal HIFU in a prospective multicenter cohort of 599 men. At median follow up of 56 mo (interquartile range 35–70), 18.7% (n = 112) had undergone one and 1.5% (n = 9) had undergone two repeat HIFU sessions. Unfortunately, functional and oncological results for the repeat procedures were not specifically addressed, so the impact of repeat HIFU sessions after FT was not determined. Irreversible electroporation and high-dose-rate focal brachytherapy have also been described in a salvage context and do seem to be feasible after FT failure. However, the evidence is scarce and warrants further assessment [22,23]. 3.2.

Salvage surgery

To date, three studies have reported outcomes for sRP after first-line FTs (Table 2). Lebdai and colleagues [24] investigated the outcomes for 19 men undergoing radical prostatectomy for PC recurrence in eight French institutions (12 open, 5 robotic, and 2 laparoscopic) after focal photodynamic therapy. Nine patients (47%) had positive surgical margins (PSMs), with six needing subsequent sRT. At median follow-up of 10 mo (range 1–46) after sRP, prostate-specific antigen (PSA) was undetectable in 16 men (84%). The dissection was considered difficult in seven cases (37%) at the posterior and lateral sides of the prostate due to local fibrosis, precluding nerve-sparing procedures. Continence was achieved postoperatively in the majority (n = 13; 68%); five (26%) had mild incontinence needing 1 pad/d and one man (5%) had severe incontinence needing >2 pads/d. Complications were acceptable; there was one case of accidental intraoperative ureteral transection during lymphadenectomy and one of pelvic hematoma that was treated with radiological evacuation. There were no other major (Clavien III) complications. The median hospital stay, catheterization time, and blood loss were 7 d, 7 d, and 400 cm3, respectively. Interestingly, the authors found that prior bilateral vascular targeted photodynamic (VTP) treatment was significantly correlated with PSMs (p = 0.003) and a “difficult” dissection (p = 0.009) [24]. While this series is heterogeneous by nature with relevant confounders—such as surgical expertise, low number of cases per institution, and heterogeneous surgical technique and ablation—it does show that the procedure is feasible and has an acceptable complication rate, although surgical and genitourinary outcomes might be compromised.

531

The other two series were from the same institution and thus overlap of some patients is likely to have occurred. In the first study, Linares Espinos and colleagues [25] included 28 men undergoing laparoscopic or robot-assisted sRP, half of whom had FT as primary treatment. PSMs were observed for one FT patients versus three WT patients, all of whom had extracapsular disease. Importantly, pathological stage was worse in the WT group (p = 0.008). At median follow-up of 62 mo, seven FT versus four WT patients had BCR (p = 0.8). One cancer-related death occurred in a with pT4a Gleason 4 + 5 R1 disease (WT group). There were no significant differences in continence at 12 mo; one patient (7%) had severe incontinence (>2 pads/d) and seven (50%) were fully continent in the FT group. No intraoperative complications occurred and there were three major complications, including one myocardial infarction and two urinary leaks. There were no differences in overall complications (7 in the FT group; p = 0.68), mean blood loss (550 cm3 in the FT group; p = 0.58), or median hospital stay (4 d in the FT group; p = 0.36). Interestingly, those who had FT as their primary treatment had shorter operating time (133  21 vs 176  34 min; p = 0.001) [25]. In 2018, Nunes-Silva et al. [26] reported on a second study that included 23 men undergoing robotic sRP after FT who were compared with 44 patients undergoing primary robotic RP, selected using a matched-pair analysis from 2775 cases. Baseline pathologic Gleason score (p = 0.256) and stage (p = 0.705) and preoperative PSA (p = 0.691) were comparable. Surgical margins were positive in one sRP case (4%) versus eight (18%) in the primary RARP group, although the difference was not significant (p = 0.253). BCR was comparable between the groups (p = 0.426) occurring in 31.82% of sRP cases. However, the sRP group had a shorter median time to BCR (p = 0.0001) and a lower probability of BCR-free survival (56.3% vs 92.4% at 2 yr; p = 0.001), resulting in a 4.8-fold higher risk of BCR (p = 0.004) compared to the primary RP group. The pad-free probability was comparable, with 73% versus 76.5% being continent at 2 yr (p = 0.8). For patients who were potent before unilateral or bilateral nerve-sparing surgery, those in the sRP group had a lower mean IIEF-5 score (p = 0.008). Overall complications did not differ (p = 0.742), but high-grade complications were found only in the sRP group (n = 3). Operating time (p = 0.625), hospital stay (p = 0.999), catheterization time (p = 0.637), and estimated blood loss (p = 0.596) did not differ significantly [26]. Pelvic lymph node dissection was inconsistent in these two series (29% [25] and 31.8% [26]), whereas a higher percentage of patients underwent the procedure after primary VTP (78.9%) [24]. The latter study also described the sole case of N1 disease observed. 3.3.

sRT

No studies have reported on the use of sRT after FT failure. Nonetheless, several groups have reported retrospectively on outcomes for small sRT series after whole-gland HIFU and/or cryosurgery (CS) (Table 3).

532

Table 2 – Main series reporting salvage radical prostatectomy outcomes for recurrent prostate cancer after focal therapy Lebdai et al. [24]

Nunes-Silva et al. [26] pRRPa

sRRP Baseline features Patients (n) First-line focal treatment

19 Tookad sRP (12 ORP, 2 LRP, 5 RRP) 2009–2014 17 (8–48)* NA 3.65 (NA)

Positive surgical margins (n) Follow-up after RP Time (mo) BCR, % (n)

9

PC progression, % (n) FOs and complications Operation time (min) Blood loss (ml) PO catheterization (d) Hospital stay (d) NSS (n) Complicationsc

4 GS 6, 13 GS7, 1 GS 8, 1 NE 12 pT2c, 6 pT3a, 1 pT3b

10 (1–46) 15.79 (3)

*

22 7 HIFU, 11 Cryo, 1 BT, 1 Tookad, 2 LA sRRP 2000–2016 24 (12.75–31.25) 63.32  4.72z 9.24  5.76z

44

28

– 2000–2016 – 63.02  4.56z 8.73  4.41z

0.691

sRP (16 RRP, 12 LRP) 2001–2015 28 (IQR 16–46)y NA 7.74  4.85z

4 GS 6, 18 GS7 16 pT2, 4 pT3a, 2 pT3b 1

6 GS 6, 37 GS7, 1 GS >7 29 pT2, 12 pT3a, 3 pT3b

0.256 0.705

8

0.253 <0.0001 0.426

7 (2.75–19.5) 31.82 (7)

38.5 (23.5–61.75) 22.73 (10)

0 (0)

NA

NA

150 (90–210)* 400 (100–1000)* 7 (5–18)* 7 (4–21)* 0 Clavien IIIb: 1 IO ureteral section Clavien II: 1 transfusion, 1 UTI Clavien IIIa: 1 pelvic HT Clavien I: 1 wound infection

134.77  19.66z 465.91  227.5z 8.73  1.58z 4.41  2.11z 20 Clavien II: none Clavien III: 2 anastamotic leaks, 1 permanent incontinence 7 pts continent 4 pts 1 pad/d 1 pt 2 pads/d 1 pt >2 pads/d 3  2z

138.41  40.52z 427.27  299.31z 8.36  3.41z 4.41  1.77z 43 Clavien II:4

0.62 0.6 0.63 0.99 0.033 0.7

28 pts continent 9 pts 1 pad/d 4 pts 2 pads/d 2 pts 2 pads/d 9.22  6.55z

0.845

PO continence

13 pts continent 5 pts 1 pad/d 1 pt >2 pads/d

PO erectile functiond

1 8 3 7

no ED complete ED (also preop.) PDE-5i PGE/vacuum

Overall

5 GS 6, 20 GS7, 3 GS 8 14 pT2, 7 pT3a, 6 pT3b, 1 pT4a 4 62 (43–110) 39.29 (11)

Whole-gland

14 3 fHIFU, 9 fCryo, 1 fBT, 1 fTookad

14 7 wgRT, 3 wgHIFU, 3 wgCryo, 1 wgBT

7.0  2.38z

9.39  5.7z,b

4 GS 6, 10 GS7 11 pT2, 2 pT3a, 1 pT3b

1 GS 6, 10 GS7, 3 GS 8 3 pT2, 5 pT3a, 5 pT3b, 1 pT4a 3

1

p value

0.008

y

90.9 5 year CSS

0.008

Focal

154  35z NA NA 20 Clavien II: 4 UTI, 2 HT, 3 UL, 1 PO bleeding Clavien III: 2 UL, 1 MI

12 pts continent 2 pts 1 pad/d 3 pts 2 pads/d 4 pts 2 pads/d 5 PGE/vacuum 1 PDE-5i 2 complete ED 20 NA

50.0 (7) 22 mo (7.75–30.75)z 1 PC related death (GS 4 + 5, pT4a)

28.5 (4) 14 mo (12–16)z 0 PC-related deaths

0.8

133  21z 550z NA 4 (4–5)y NA 4 pts: 2 UL + UTI 1 bleeding + transfusion + MI 1 epididymitis + gross HT 7 pts continent 1 pt 1 pad/d 2 pts 2 pads/d 1 pt 2 pads/d 3 PGE/vacuum 1 PDE-5i 10 NA

176  34z 492z NA 5.5 (4–8)y NA 5 pts: 3 UL 1 gross HT 1 UTI

0.001 0.58 0.36 0.68

5 pts continent 1 pt 1 pad/d 1 pt 2 pads/d 3 pts 2 pads/d 2 PGE/vacuum 2 complete ED 10 NA

FSTT = time from first to salvage treatment; RP = radical prostatectomy; sRP = salvage RP, ORP = open RP; LRP = laparoscopic RP; RRP = robotic RP; pRRP = primary RRP; PSA = prostate-specific antigen; BCR = biochemical recurrence; NSS = nerve-sparing surgery; pt = patient; NE = neuroendocrine; ED = erectile dysfunction; PDE-5i = phosphodiesterase type 5 inhibitor; PGE = prostaglandin; IO = intraoperative; PO = postoperative; UTI = urinary tract infection; HIFU = high-intensity focal ultrasound; BT = brachytherapy; FOs = functional outcomes; UL = urine leak; HT = hematuria; MI = myocardial infarction a

Data for pRRP are reported in the salvage treatment section to simplify data comparison.

b

Data missing for six patients.

c

Timings for the onset of complications were rarely available in the three series. Lebdai et al. [24]: one man had a proximal urethral stenosis complicated with two UTI episodes 1 mo after the procedure. Linares-Espinos et al. [25]: 13 complications within 30 d in nine patients, with no late complications. d Information on erectile function changes for preoperatively potent patients undergoing nerve-sparing procedures was not always available. Linares-Espinos et al. [25]: of the patients who were preoperatively potent (40%), two (20%) had spontaneous or PDE-5i–assisted sexual intercourse and five (50%) had PGE- or vacuum-assisted erections at 12 mo. For Nunes-Silva et al. [26], data in the table are reported for potent patients undergoing NSS. * y z

Data reported as mean (range). Data reported as median (interquartile range). Data reported as mean  standard deviation.

E U R O P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

Salvage treatment Accrual years FSTT (mo) Age at RP (yr) PSA at RP (ng/ml) RP pathological features Gleason score pT stage

Linares-Espinos et al. [25] p value

E U RO P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

Following a feasibility study [27], Riviere and colleagues [28] reported outcomes from the largest sRT series of 100 men with histologically proven recurrence and at least 1-yr follow-up who were treated with EBRT (72 Gy) after one or two HIFU sessions (17 of whom received adjuvant ADT). At median follow-up of 36.5 mo, 15 patients (15%) who received EBRT experienced treatment failure (5-yr progression-free survival 72.5%) and ten (10%) had died, one due to metastatic PC. High-grade toxicities were rare and included three cases of acute urinary retention requiring endoscopic treatment, one case of chronic painful retention requiring urinary diversion, and one death due to multiorgan failure after hemostatic cystectomy. Incontinence did not change significantly (28% before and 32% after sRT; p > 0.05). Erectile dysfunction severity increased following primary HIFU and again after sRT. These results are supported by the second largest postHIFU sRT series, which had the longest follow-up to date (mean 50 mo). Munoz et al. [29] analyzed outcomes for 76Gy three-dimensional conformal sRT after one (n = 17) or two (n = 7) HIFU sessions. Four men (16.6%) underwent pelvic RT (including bilateral ileo-obturator chains) and seven (29%) received adjuvant ADT. BCR occurred in four men (16.6%). High-grade toxicity was relatively rare, and included three cases of acute genitourinary toxicity (2 grade III and 1 grade IV) and five cases of grade III late genitourinary toxicity (3 severe frequency and dysuria; 1 frequent hematuria) or bowel toxicity (1 rectal morbidity). At 1 yr, two men had developed permanent post-sRT incontinence (8%). Another recent series including six patients also showed acceptable functional and oncological results together with relatively low toxicity for sRT after whole-gland HIFU [30]. The largest series of sRT after CS evaluated men undergoing sEBRT (mean dose 62.9 Gy) following one (n = 39), two (n = 8), or three (n = 2) CS sessions between 1990 and 1999 [31]. Four patients received additional pelvic irradiation (8%). At median follow-up of 32 mo, 61% were free from BCR. No acute high-grade toxicities were recorded, while two men experienced subacute late morbidity that was managed conservatively (1 urethral stricture at 10 mo and 1 proctitis at 2 mo). No new-onset incontinence occurred. Hepel et al. [32] reported outcomes for 16 men treated with 72-Gy full-dose intensity-modulated RT (IMRT) either in the adjuvant setting after focal CS (n = 3) or in a salvage context after local failure of standard whole-prostate CS (n = 13) from 1997 to 2007. At median follow-up of 33 mo, BCR had occurred in four patients (25%). No major toxicities were recorded. Other small case series investigated sRT after wholegland CS using dose-escalated IMRT [33], IMRT [34], EBRT [35], and CyberKnife robotic stereotactic body RT [36]. All these series suggest promising results [36]; further investigation in larger prospective studies is warranted. Finally, Holtzman et al. [37] described 74-Gy proton beam sRT in 21 men who experienced recurrence after either HIFU (n = 9) or CS (n = 12). Two cases with a higher risk of positive nodes also received an additional 46 Gy of

533

pelvic IMRT followed by a proton boost to the prostate and seminal vesicles. The 3-yr BCR-free survival was 77%, with five men experiencing recurrence (1 biochemical only, 1 local, 2 regional, and 1 distant; 4 had a Gleason score of 8). The cumulative 3-yr grade 3 toxicity was 17% (95% confidence interval 5–42%; n = 3; CTCAE v4). There was only a mild decline in sexual and urinary functions at 12 mo [37]. No studies on sRT after ablative energy sources other than HIFU or CS are currently available. 3.4.

Discussion

This review shows that the outcomes for salvage treatments after FT failure have to be further elucidated. The literature on second ablation and sRT is scarce and mainly addresses repeat procedures after primary WT, with encouraging complication rates and functional outcomes. A few reports on sRP after FT suggest that although some cases may be technically more challenging, oncological and functional results are promising and do not seem to markedly differ from those after first-line RP. Despite the unresolved debate regarding FT in PC, its implementation in clinical practice is rapidly growing [5] and is likely to further increase in the future. A 2014 systematic review included approximately 2000 patients being treated with tissue-sparing approaches, while just 2 yr later another systematic review on the same subject reported outcomes for more than 3200 men [1,4]. Recently published medium-term FT outcomes suggest acceptable results in a prospective multicenter cohort of 599 men including nine centers in the UK offering off-trial FT under local governance and insurance agreements [2]. The European urological community is highly interested in this option: 52% of respondents in a recent survey stated that they would suggest FT to their patients [7], and 65% confirmed that they had access to FT either in their hospital (44.6%) or in their region (55.4%). While the field is quickly moving forward, a new issue is likely to become more relevant: management of men for whom primary FT fails. If the rate of secondary treatment is estimated to be 20–25% over 5 yr and the number of men being treated with FT is increasing, this means that a substantial group of patients will require further treatment in the near future. In the post-FT setting, RP currently seems to be an acceptable oncological option, with the prior FT having little impact compared to primary surgery. PSMs are reported for 20% and BCR for 33% of cases, with no clinical PC progression or deaths being described. These results do seem to be better than recent series of sRP after WT, with PSM and BCR rates of approximately 50% [11,38], and are not inferior to the primary RP setting [26]. Of note, one series reported that almost one in two men had PSMs [24]. These results may reflect suboptimal expertise of some of the surgeons involved and strengthens the EAU guideline recommendations that sRP, even after FT, should only be carried out by experienced surgeons [39]. On the one hand, aggressive histology and advanced local disease (>pT3a) remain relatively rare in the post-FT

534

Table 3 – Main studies (all retrospective) reporting the role of sRT for prostate cancer recurrence after local ablative HIFU and/or cryotherapy Study Hopper [33] Choi [34] Burton [31] McDonough [35] Hepel [32] Quarrier [36] Riviere [28] Holtzman [37]

Study Hopper [33] Choi [34] Burton [31] McDonough [35] Hepel [32] Quarrier [36] Riviere [28]

8 9 49 6 16a 4 100 83d 21 12 9 24 6 45

pTx

Accrual period

CS CS CS CS CS CS HIFU

CS HIFU HIFU HIFU HIFU

n

pTx

TsRT (mo)

sTx

y

Dose (Gy)

2008–2016 2008–2010 1990–1999 1993–1998 1997–2007 2011–2012 1995–2008

68 (25–195) 20.5 (8.5–56.5)z 19 (3–78)y 36 (18–48)y 50 (40–149)y 44.5 (20–69)y 10 (2–53)z

IG-IMRT IMRT EBRT EBRT EBRT + IMRT boost Cyberknife (SBRT) EBRT

2007–2014

27 (NA)z

EBRTb

77.7 (75.6–81.0) 79.2 (72–81)y 62.9 (50.4–68.4)z 66 (62–70.2)y 73 (–) – 72 (65–78)z NA 74 (74–82)y

2004–2011 2004–2008 1995–2004

19.6 (7.1–79.3)z 10.5 (9–20)y 12 (NA)z

EBRT EBRT EBRT

76 (66.6–78) NA 71 (68–72)y

FU (mo)

BCR, % (n)

Mets, % (n)

CSS, % (n)

OS, % (n)

55 (6–88) 31 (15–40)y 32 (12–85)y 34 (8–46)y 33 (NA)z 4.5 (0.5–7.5)y 33 (5–64)y 36.5 (5–164)

25.0 (2) 22.2 (2) 38.8 (19) 33.3 (2) 25.0 (4) 0 NA 18.0 (15)

12.5 (1) 22.2 (2) 2.0 (1) 16.6 (1) NA 0 NA NA

100 NA NA 100 100 100 NA NA

100 NA NA 100 100 100 NA NA

y

8 9 49 6 16a 4 100 83d

CS CS CS CS CS CS HIFU

Munoz [29]

21 12 9 24

Overall cohort CS HIFU HIFU

37 (6–95)z NA NA 40.3 (24–107)y

23.0 (5) NA NA 25.0 (6)

14.2 (3) NA NA NA

100 (21) 100 (12) 100 (9) NA

Ripert [30] Pasticier [27]g

6 45

HIFU HIFU

36.5 (24–54) 40 (–)

16.6 (1) 25.0 (8)c

NA NA

100 (6) NA

Holtzman [37]

Age (yr) y

(8)

(6) (16) (4)

(8)

PSA (ng/ml) y

74 (62–83) 67e (49–76)z 67 (52–76)z 71 (63–79)z 72 (64–76)z 74 (69–76)z 71 (54–81)z NA 70 (53–80)z 68 (52–78) 70 (53–80) 72 (52–83)z 70.5 (60–79) 70 (–)y

8.4 (4.2–14.38) 4.3 (1.1–15.6)z 2.4 (0.1–7.4)z 2.3 (0.8–4.1)z 6.0 (NA)y 13.3 (4.4–20.9) 1.5 (0–8.95)z NA 7 (3–18)y

y

4.21 (1.17–34.45)y 2.6 2.5–14.8)y 2.79 (NA)z

UF

GS pre-sRT

cT pre-sRT

1 GS6, 4 GS7, 3 GS Unclearf NA 4 GS 6, 1 GS 8, 1 NA NA 2 GS7, 2 GS 8 NA NA 4 GS6, 10 GS7, 7 GS 8

2 cT4; others NA Unclearf NA NA NA NA NA NA 12 cT1, 7 cT2, 2 cT3

NA NA Unclearf

NA cT1 n = 6 Unclearf

EF

NA NA All continent NA NA All continent (3/3)

No changes (all prior ED) NA NA NA NA 1 new-onset ED, 2 no change

DINC 28% ! 32% at 12 mo

NA in detail

100 (21) 100 (12) 100 (9) NA

DINC 9% ! 14% at 12 mo

No change in those who were potent (n = 4)

DINC 8.3% ! 16.6% at 12 mo

NA

85.7 (1) NA

1 PSI DINC 13.3% ! 17.7% at 12 mo

NA NA

(6) (16) (4)

HG complications No G No G No G No G No G No G 4 G3 1 G4 1 G5 3 G3

6 1 1 1

>2 >2 >2 >2 >2 2

G3 G4 G3 G3

Tx = treatment; pTx = primary Tx; sTx = salvage Tx; TsRT = time to salvage radiation therapy; sTx = salvage RT modality; PSA = prostate-specific antigen; GS = Gleason score; cT = cT stage before sRT; FU = follow-up; BCR = biochemical recurrence; Mets = metastasis; CSS = cancer-specific survival; OS = overall survival; UF= urinary function; EF = erectile function; CS = cryosurgery; HIFU = high-intensity focused ultrasound; ED = erectile dysfunction; IG-IMRT = dose-escalated image-guided intensity-modulated RT; EBRT = external beam RT; SBRT = stereotactic body RT; DINC = change in incontinence from before to after sRT; PSI = persistent stress incontinence; NA = not available; G = grade. a Three patients received RT as an adjuvant treatment after cryotherapy. b Proton therapy. c Assessed on 32 patients. d RT without androgen deprivation therapy. e At primary CS. f Not able to define if reported values were before first-line treatment or before sRT. g Feasibility study for the study by Riviere et al. (patients included in the Riviere et al. study). y Data reported as median (range). z Data reported as mean (range).

E U R O P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

Munoz [29] Ripert [30] Pasticier [27]g

n

E U RO P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

scenario compared to surgery following WT, and may explain the higher cancer control rates after FT. In this context, pelvic lymphadenectomy was performed inconsistently, with only one man having N1 disease, and its role remains unclear. On the other hand, FT failures were associated with significant PC upstaging/grading compared to before FT. Whether this is treatment-induced or can be attributed to disease underestimation at first assessment remains to be determined. Nonetheless, in all three series the median time from first to salvage treatment was <30 mo. Despite the absence of standardized criteria for defining FT failure, stringent follow-up after first-line treatment is key. It is possible that greater use of mpMRI and implementation of other imaging modalities, including positron emission tomography with 68Ga-labeled prostatespecific membrane antigen ligands and/or a combination of both, may improve patient selection for FT. Although systemic failure following PC recurrence after FT may be lower than after WTs, there remains the ambiguity that PSA failures do not necessarily imply local recurrence [40,41]. New imaging modalities may facilitate detection of PC recurrence and/or persistence at an early stage and avoid disease mischaracterization, and could thus improve oncological outcomes [42–44]. Approximately 30% of the patients who were classified as having organ-confined disease and were treated with FT had extracapsular extension at the time of salvage surgery. Nonetheless, only four (7%) had pT3b disease, and the others had pT3a. Furthermore, some studies showed higher BCR for sRP after FT compared to the first-line setting [26]. FT and/or a delay in identifying biopsy-proven local recurrence, depending on different institutional protocols, may significantly prolong definitive treatment and alter the prognosis. FT follow-up schedules certainly need to be standardized, and international consensus would be desirable. While the potential impact of diagnostic delays remains to be quantified, especially in light of evidence suggesting no impact of a 6-mo treatment delay, even in high-risk disease, close follow-up after FT is warranted [45]. Toxicity and functional recovery results for sRP are also encouraging. With the exception of erectile function preservation, and despite higher technical difficulty on the treated side, no marked differences are apparent compared to primary RP when the procedure is performed in experienced centers [26]. Excluding cases of previous bilateral FT, surgical complexity is not significantly altered as testified by short operating time and minimal blood loss. Similarly, complications are relatively rare yielding overall reasonable hospital stay and catheterization time. Continence is achieved by the majority of patients with severe incontinence being relatively rare. Interestingly, the sole study comparing sRP after whole- vs focal first-line treatment did not find any major differences with the exception of operating time, shorter for sRP after FT [25]. Absence of randomization or statistical matching and the small study sample prompt further studies to overcome these limitations. Two other salvage alternatives have been described: repeat ablation and sRT. Importantly, evidence is derived

535

almost entirely from post-WT salvage series. Outcomes, especially in terms of functional recovery and comorbidities, may be different after FT. Limiting the treated area to a specific target and leaving unmodified benign surrounding areas produces fewer tissue alterations, as confirmed by post-FT sRP series. Thus, less fibrosis and scarring may help to preserve key structures during firstline treatment, including the striated urethral sphincter and neurovascular-bundles, and theoretically lead to improved outcomes and safety profile following nonsurgical salvage treatments. Repeat ablation is feasible and yields acceptable complications and oncological and functional outcomes. The only study investigating whole-gland salvage CS after FT yielded acceptable cancer control, although patient baseline features included some high-risk cases that would not have been ideal candidates for first-line FT [18]. Continence and erectile function were almost unchanged and no major complications were described, in contrast to salvage cryoablation following whole-gland BT and/or RT where, despite being uncommon, fistulas and strictures did still occur. No complication differences were highlighted between whole-gland re-do and first-line HIFU. Furthermore, the repeat group had shorter treatment and catheterization times and hospital stays [20,21]. As highlighted by some authors, improvements in the learning curve and in technology are likely to play an important role, which needs to be addressed in the coming years [19]. Focal salvage repeat ablation is also a viable solution for suitable candidates, with preliminary results showing noninferior cancer control but better OS compared to whole-gland approaches. As for first-line FT, focal salvage techniques may further reduce salvage treatment–related side effects [19]. sRT is another feasible approach for FT failure according to post-WT ablation series. Disease control is promising, as are treatment-related toxicities, which seem similar to [29] or only slightly greater than [37] those for RT alone. However, owing to the limited follow-up, approximately 3 yr in the majority of published series, late complications remain to be determined. On the contrary, as BCR after RT mainly presents within the third year after radiation [28,46], oncological efficacy can be expected to be relatively high on longer follow-up, even though these outcomes are not available yet. Among the several issues requiring further clarification is the optimal total dose used in a post-FT setting, as several series used a median of <72 Gy [27,28,31,35]. While this dose may not be sufficient in the post-WT setting from an oncological perspective, it may well reduce the burden of treatment-related side effects. Again, there is no evidence of the effects following FT. While the role of active surveillance, watchful waiting, and ADT after FT was not assessed in this review, clinicians should consider these possibilities whenever appropriate [16,17]. In light of the different options and the poor evidence available, multidisciplinary decision-making is paramount in facing the challenge of FT failure [47].

536

E U R O P E A N U R O L O GY O N C O L O GY 2 ( 2 019 ) 5 2 6 – 5 3 8

Overall, although it does not allow any definitive conclusion, the current evidence suggests that FT has a minimal impact on subsequent salvage treatments, and still allows acceptable oncological success with minimal changes in functional outcomes and complications. If confirmed, this would support FT development and its introduction in clinical practice. Nonetheless, high-quality studies are urgently needed to clearly determine many aspects of the impact of FT on subsequent salvage treatments and to optimize the use of FT and the management of FT failures. The experience of Lebdai and colleagues [24], showing greater difficulty after bilateral versus unilateral VTP, favors the intuitive hypothesis that the more limited the initial treatment, the more feasible is salvage surgery with neurovascular bundle preservation more likely to be performed. This is a key point, as FT with margins 8 mm is recommended, but the more extensive the treatment delivery, the more challenging is salvage treatment, when indicated. The impact of different energy sources and focal techniques on any subsequent salvage option needs to be clarified; whether one salvage treatment modality or focal technique proves superior to others may influence the choice of primary FT approach. In addition, the optimal salvage option is far from resolved, as comparisons among different treatments are not feasible without significant selection bias, including a lower PC risk profile for those undergoing repeat ablation rather than surgery or radiotherapy and vice versa. In some series, poor surgical candidates underwent WT ablation because of greater comorbidity [37]. This is distinct from the goal of FT, which should represent an alternative with lower morbidity for potential surgery or RT candidates [3,48]. The same holds true for the absence of universally accepted criteria for FT and for definition of recurrence and/or failure. As a consequence, repeat biopsies are mainly performed on an ad hoc basis rather than according to uniform predefined triggers. These should be required in a clear follow-up schedule that includes a combination of imaging, biomarkers, and the patient’s risk profile. Finally, the most important point is that we are not aware of the nature and natural history of PC recurrence after FT, as FT is still in its infancy. Different energy types act and consequently may tend to fail differently. Similarly, in-field/ edge-of-field and out-of-field recurrences may have different biological origins and behaviors. A UK-based prospective study, the RAFT trial (NCT03011606), is currently enrolling men undergoing robotic salvage surgery following FT failure. Results from this and other high-quality large studies are urgently needed to enhance our understanding of the impact of FT on subsequent salvage treatments so that management of FT failures can be optimized.

series after FT and after WT ablation or sRT series. Available salvage options include RP, repeat whole-gland and focal ablation, and RT. Overall oncological outcomes are acceptable, although BCR is slightly higher than after primary PC treatment, probably because of the higher aggressiveness of recurrent/persistent PC. Functional outcomes and complications are slightly worse but not markedly so compared to primary treatment. This favors the hypothesis that FT may only marginally jeopardize subsequent salvage therapy. Future high-quality prospective studies are needed to specifically address the impact of FT on subsequent salvage treatments and to optimize decision-making in cases with FT failure. Author contributions: Giancarlo Marra had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Marra, Valerio, Pisters. Acquisition of data: Marra, Valerio. Analysis and interpretation of data: Marra, Valerio, Pisters. Drafting of the manuscript: Marra, Valerio. Critical revision of the manuscript for important intellectual content: Emberton, Crook, Bossi, Heidenreich, Pisters. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Pisters. Other: None. Financial disclosures: Giancarlo Marra certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. Acknowledgments: Mark Emberton receives research support from the UK National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre. He has held an NIHR Senior Investigator Award since 2013.

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