Effect of Prior Focal Therapy on Perioperative, Oncologic and Functional Outcomes of Salvage Robotic Assisted Radical Prostatectomy

Author's Accepted Manuscript Effect of Prior Focal Therapy on Perioperative, Oncologic and Functional Outcomes of Salvage Robotic Assisted Radical Prostatectomy Igor Nunes-Silva , Eric Barret , Victor Srougi , Mohammed Baghdadi , Paolo Capogrosso , Silvia Garcia-Barreras , Solange Kanso , Rafael Tourinho-Barbosa , Ariê Carneiro , Rafael Sanchez-Salas , François Rozet , Marc Galiano , Xavier Cathelineau

PII: DOI: Reference:

S0022-5347(17)74439-4 10.1016/j.juro.2017.05.071 JURO 14777

To appear in: The Journal of Urology Accepted Date: 18 May 2017 Please cite this article as: Nunes-Silva I, Barret E, Srougi V, Baghdadi M, Capogrosso P, GarciaBarreras S, Kanso S, Tourinho-Barbosa R, Carneiro A, Sanchez-Salas R, Rozet F, Galiano M, Cathelineau X, Effect of Prior Focal Therapy on Perioperative, Oncologic and Functional Outcomes of Salvage Robotic Assisted Radical Prostatectomy, The Journal of Urology® (2017), doi: 10.1016/ j.juro.2017.05.071. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].

ACCEPTED MANUSCRIPT

Effect of Prior Focal Therapy on Perioperative, Oncologic and Functional Outcomes of Salvage Robotic Assisted Radical Prostatectomy 1,2

1

1,3

1

1,4

RI PT

Igor Nunes-Silva , Eric Barret , Victor Srougi , Mohammed Baghdadi , Paolo Capogrosso , Silvia Garcia1 1 1 1 1 1 Barreras , Solange Kanso , Rafael Tourinho-Barbosa , Ariê Carneiro , Rafael Sanchez-Salas , François Rozet , Marc 1 1 Galiano , Xavier Cathelineau 1

Department of Urology, Institut Mutualiste Montsouris, Université Paris-Descartes, Paris, France. Department of Urology, Arnaldo Vieira de Carvalho Cancer Institute, São Paulo, Brazil. 3 Department of Urology, University of São Paulo Medical School, São Paulo, Brazil. 4 Division of Experimental Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele Università Vita-Salute San Raffaele, Milan, Italy.

M AN U

*Corresponding Author: Eric Barret Institut Mutualiste Montsouris Address: 42 Boulevard Jourdan, 75014, Paris, France Phone: +33 1 56 61 62 63 / Fax: +33 1 45 80 60 41 E-mail address: [email protected]

SC

2

EP

TE D

Email addresses: Igor Nunes-Silva: [email protected] Eric Barret: [email protected] Victor Srougi: [email protected] Mohammed Baghdadi: [email protected] Paolo Capogrosso: [email protected] Silvia Garcia-Barreras: [email protected] Solange Kanso: [email protected] Rafael Tourinho-Barbosa: [email protected] Ariê Carneiro: [email protected] Rafael Sanchez-Salas: [email protected] Francois Rozet: [email protected] Marc Galiano: [email protected] Xavier Cathelineau: [email protected]

AC C

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

Word count:

Abstract: 237

Manuscript: 2281

Tables: 5

Figures: 2

References: 30

Total: 2518

Runninghead: Effect of focal therapy on salvage-RARP outcomes Keywords: Ablation techniques; Robotic Surgical Procedures; Prostate Cancer; Urinary Incontinence; Erectile Dysfunction

ACCEPTED MANUSCRIPT 2

ABSTRACT

47

Purpose: To assess the impact of focal therapy (FT) on perioperative, oncologic, and functional

48

outcomes in men who underwent salvage robotic-assisted radical prostatectomy(S-RARP)

49

compared to primary RARP (P-RARP).

RI PT

46

50

Materials and Methods: FT was performed in patients presenting Gleason score 3+3 or 3+4,

52

clinical stage ≤cT2a, serum prostate-specific antigen(PSA) ≤15ng/ml, unilateral positive biopsy,

53

maximum length of any positive core <10mm and life expectancy >10 years. FT was defined as

54

target ablation of the index lesion plus 1cm of safety margin within the normal ipsilateral

55

prostatic parenchyma. The S-RARP group included 22 men who underwent S-RARP after FT

56

failure. The P-RARP group was defined using matched-pair 1:2 selection of 44 of 2750 P-RARP

57

patients. The primary and secondary end points were between-group differences in functional

58

and oncologic outcomes, respectively.

M AN U

TE D

59

SC

51

Results: Complication rates were comparable (p>0.05). Pad-free probability was comparable

61

between groups at 1 and 2 years(p=0.8). Recovery of erectile function was significantly lower

62

with S-RARP(p=0.008), and S-RARP showed significantly lower probability of cumulative

63

biochemical recurrence(BCR)–free survival (56.3% vs 92.4% at 2 years, p=0.001). S-RARP

64

presented significantly increased risk of BCR (HR 4.8, 95% CI 1.67–13.76, p=0.004). Limitations

65

included the retrospective nature, lack of randomization and short follow-up time.

66

AC C

EP

60

ACCEPTED MANUSCRIPT 3

Conclusions: S-RARP following FT failure is feasible, with acceptable complication rates.

68

However, patients assigned to primary FT should be advised about a poorer prognosis in terms

69

of oncological control and lower erectile recovery rates in case of a future salvage surgery.

RI PT

67

70 71

SC

72 73

M AN U

74 75 76 77

81 82 83 84 85 86 87 88

EP

80

AC C

79

TE D

78

ACCEPTED MANUSCRIPT 4

INTRODUCTION

90

Low-risk prostate cancer(PCa) incidence has substantially increased over time.1,2 In this

91

scenario, focal therapy(FT) has emerged as an experimental treatment option to be offered

92

within ethically-approved clinical trials for selected patients presenting low- to intermediate-risk

93

PCa not suitable for active surveillance(AS).3,4 Although still under long-term evaluation, FT has

94

demonstrated reasonable oncological outcomes while diminishing the drawbacks of radical

95

therapies. 5

96

In contrast, rates of PCa recurrence after primary treatment range from 20% to 60% regardless

97

of local therapy modality.6,7 Recurrence after FT has challenged urologists regarding the best

98

management option for such cases. Although no consensus exists on the optimal salvage

99

treatment, salvage options (subsequent FT, salvage radical prostatectomy(S-RP), radiotherapy,

100

hormonal therapy) have different rates of complications and cancer control.8,9 Although S-RP

101

after radiorecurrent PCa has already been widely described10, only a few reports describing

102

previous experience with S-RP after FT failure are currently available.

TE D

M AN U

SC

RI PT

89

EP

103

This comparative controlled study is the first to assess the impact of FT on surgical outcomes in

105

a cohort of men with low- to high-risk localized PCa who underwent salvage robotic assisted

106

radical prostatectomy(S-RARP) versus primary RARP(P-RARP).

107

AC C

104

108

MATERIALS AND METHODS

109

Selection and Sample size

110

Prospectively collected data from 2775 men who underwent RARP for localized PCa from 2000

ACCEPTED MANUSCRIPT 5

to 2016 were reviewed. Our institutional review board approved the study, and patients

112

provided informed consent. Two cohorts were identified including men with low- to high-risk

113

localized PCa according to D’Amico criteria. In total, 2750 men underwent RARP as primary

114

treatment(overall P-RARP), whereas 25 men underwent S-RARP for PCa recurrence or

115

progression after FT failure (S-RARP group). Three patients had <1-year follow-up and were

116

excluded from the S-RARP group. Propensity score matching (PSM) analysis was applied on the

117

overall P-RARP sample selecting 44 patients(P-RARP group) for between-group comparison.

SC

RI PT

111

M AN U

118

Outcome measurements

120

The primary end point was between-group differences in continence, International Prostate

121

Symptom Score (IPSS), and International Index of Erectile Function (IIEF-5) at 1-year follow-up.

122

Secondary end points were differences in oncologic data.

123

TE D

119

Treatment strategies and protocols

125

- FT definition and Election criteria -

126

FT was defined as target ablation of the index lesion plus 1cm of safety margin within the nor-

127

mal ipsilateral prostatic parenchyma, respecting the apical and rectal security limits. Focal ther-

128

apy(FT) was performed as an experimental treatment for patients not suitable for active sur-

129

veillance(AS) or for those patients that refused AS treatment due to personal reasons. Eligibility

130

criteria for focal treatment were: Gleason score 3+3 or 3+4, clinical stage ≤cT2a, serum pros-

131

tate-specific antigen(PSA) ≤15ng/ml, unilateral positive biopsy, maximum length of any positive

AC C

EP

124

ACCEPTED MANUSCRIPT 6

132

core <10mm and life expectancy >10 years. FT energy source was chosen according to the tu-

133

mor location in the prostate, according to our institution guidelines previously published. 11

RI PT

134

- Biopsy protocol before FT -

136

All the patients underwent multiparametric MRI(mp-MRI) for local staging and transperineal

137

template prostatic biopsy, performed in our institution. Template biopsy was made randomly

138

and targeting lesions previously identified on mp-MRI.

M AN U

139

SC

135

- FT follow-up, failure evaluation and metastatic work-up -

141

Patients were followed with PSA measurements and digital rectal examination at 3, 6, 12, 18,

142

and 24 months and then annually. Prostate template biopsy was routinely performed at 12

143

months and then annually. Two subsequent PSA elevation during follow-up triggered a con-

144

firmatory transperineal template prostatic biopsy.12 FT failure was defined as biopsy-proven

145

PCa at the same site of the primary ablation. Patients who had FT failure had mp-MRI per-

146

formed before salvage treatment to rule out locally advanced disease. Patients presenting up-

147

grade in the biopsy specimen and gland bilateral positive biopsies underwent abdominal-pelvic

148

computed tomography and bone scan to rule out systemic metastatic disease.

EP

AC C

149

TE D

140

150

- Salvage-RARP indication -

151

S-RARP with curative intent was offered, after multidisciplinary committee discussion, to highly

152

motivated patients with localized PCa after FT failure and life expectancy >10 years. Surgeons

153

with experience in RARP performed the procedures. S-RARP was made according to the

ACCEPTED MANUSCRIPT 7

154

previously described standard technique for RP at our institution.13

155

- Functional and Oncological Evaluations -

157

Self-administered validated questionnaires[IIEF-5, IPSS, and the International Continence

158

Society male incontinence symptoms questionnaire (ICSmaleIS)]14 were provided to the patients

159

during preoperative and postoperative consultations at 3, 6 and 12 months. The fulfilled forms

160

were collected and recorded in our database by assistant physicians. Postoperative continence

161

was defined as no use of pads(Pad-free). Mild, moderate, and severe incontinence was

162

classified as the use of one, two, or three or more pads per day, respectively. IIEF-5 ≥22

163

represented normal erectile function. PSA measurements were performed and recorded at 3, 6,

164

and 12 months during the first year, every 6 months during the second year and yearly

165

thereafter. BCR after S-RARP was defined as PSA >0.2 ng/dl. Postoperative 90-day complications

166

were collected, retrospectively revised and graded using the Clavien–Dindo classification.15

167

TE D

M AN U

SC

RI PT

156

Statistical analysis

169

Matching was performed by propensity scores analysis.16 S-RARP(n-22) and P-RARP(n=2750)

170

were defined as treated and control samples, respectively. The covariates age, IPSS and IIEF5

171

were used for balance calculation between-samples. Covariates were preoperatively measured

172

at the time point just before S-RARP and P-RARP surgeries. Propensity scores were calculated by

173

logistic regression model using ‘nearest neighbor’ matching algorithm in a 1:2 ratio. Descriptive

174

statistics were expressed as frequencies and percentages, mean plus or minus standard

175

deviation, or median and interquartile range (IQR). The Student t test or Mann-Whitney test

AC C

EP

168

ACCEPTED MANUSCRIPT 8

was applied for comparison of continuous variables. The Pearson χ2 test or Fisher exact test was

177

used to compare categorical variables. BCR-free and Pad-free survival probability curves were

178

estimated using the Kaplan–Meier method. Cox proportional hazards analysis accessed the risks

179

of BCR and for achieving continence between-groups. A two-sided p<0.05 indicated statistical

180

significance. Data were analyzed using SPSS v.22(IBM Corp, Armonk, NY).

RI PT

176

SC

181

RESULTS

183

Baseline Characteristics

184

The mean number of biopsy series before surgery was higher in the S-RARP group(p<0.0001).

185

Baseline PSA, Gleason score, clinical T stage and D’Amico clinical stage were comparable

186

between groups(p=0.691, p=0.83, p=0.312, p=0.98, respectively). All men were continent at

187

baseline. IPSS and IIEF-5 were comparable between-groups(p=0.757 and p=0.455, respectively).

188

(Table 1).

189

TE D

M AN U

182

Operative outcomes

191

Operative time, hospital stay, catheterization time, and estimated blood loss(EBL) were

192

comparable between groups(p=0.625, p=0.999, p=0.637, and p=0.596, respectively). Bilateral

193

nerve sparing(NS) rates differed significantly between-groups(p=0.016). Complications were

194

comparable between-groups(p=0.742). High-grade complications(Clavien>2) were found only in

195

the S-RARP group. (Table 2).

AC C

EP

190

196 197

Functional outcomes

ACCEPTED MANUSCRIPT 9

Pad-free probability rates(49.5% vs 62.4% at 1 year, p=0.8; 73% vs 76.5% at 2 years, p=0.8) and

199

the chance of achieving continence(hazard ratio [HR] 1.062, 95% CI 0.54–2.08, p=0.861) were

200

comparable between groups(Figure 1). Preoperatively potent patients(IIEF-5≥22) who

201

underwent unilateral or bilateral NS showed significantly lower IIEF-5 means with S-RARP(3 ± 2

202

vs 9.22 ± 6.55, p=0.008). (Table 3).

RI PT

198

SC

203

Oncological outcomes

205

Positive surgical margin(PSM) and overall BCR rates were comparable between groups(p=0.253

206

and p=0.426, respectively). Median time to BCR was significantly lower for S-RARP(p=0.0001). S-

207

RARP showed significantly lower probability of BCR-free survival(67.6% vs 95.1% at 1 year,

208

p=0.001; 56.3% vs 92.4% at 2 years, p=0.001). Cox proportional hazards analysis demonstrated a

209

significantly increased risk of BCR with S-RARP versus P-RARP(HR 4.8, 95% CI 1.67–13.76,

210

p=0.004) (Figure 2). (Table 4).

211

TE D

M AN U

204

DISCUSSION

213

Our data suggest that S-RARP after FT failure is feasible, with acceptable complication rates.

214

However, the S-RARP patients showed a poorer prognosis in terms of biochemical control com-

215

pared to P-RARP patients. The erectile recovery rates tended to be lower in men who under-

216

went S-RARP at 1-year follow-up than those men who underwent P-RARP.

217

Surgical trends have favored a minimally invasive approach, with comparable perioperative

218

outcomes for robotic and open salvage series after radiation failure.17 In our report, between-

219

group analysis on perioperative outcomes did not show significant differences in mean

AC C

EP

212

ACCEPTED MANUSCRIPT 10

operative time, EBL, hospital stay, and catheterization time. Although mean EBL did not differ

221

significantly(p=0.6), contemporary salvage robotic series have shown slightly lower EBL means

222

ranging from 75 to 280 ml.10 Regarding perioperative morbidity, complication rates were

223

comparable between groups(p=0.74). High-grade complications(Clavien>2) were found only in

224

two S-RARP patients, whereas blood transfusion was needed only for two P-RARP

225

patients(4.5%). No rectal injury occurred. Our salvage morbidity outcomes were acceptable and

226

similar to recent P-RARP series that demonstrated overall complication rates of 8.7–20.5% and

227

blood transfusion rates of 2.1–5.3%.18 Furthermore, surgical dissection was not more difficult in

228

the salvage setting compared with P-RARP. Posterior anatomic plans were preserved without

229

signals of fibrosis, and we did not face major difficulties in dissecting the bladder neck, seminal

230

vesicles, rectum–prostatic space, or apex. However, rates of bilateral NS were significantly lower

231

with S-RARP(p=0.016), perhaps suggesting that nerve-bundle tissues presented some level of

232

impairment that compromised adequate preservation. These findings indicate that FT does not

233

completely compromise surgical anatomic status and does not limit subsequent salvage surgery

234

if necessary, although the quality of NS should be considered.

SC

M AN U

TE D

EP

235

RI PT

220

Regarding functional outcomes at 1-year follow-up, most patients achieved continence(no pads

237

per day), and ICSmaleIS, and IPSS mean rates were comparable between groups. Our results are

238

consistent with previous series of S-RP for radio-recurrent PCa that reported incontinence rates

239

of 22–67%.17 Pad-free probability(p=0.8 at 1 and 2 years) and the chance of achieving

240

continence(p=0.861) were comparable between groups. These findings corroborate the

241

hypothesis that FT does not completely compromise surgical anatomy or present difficulty and

AC C

236

ACCEPTED MANUSCRIPT 11

thus does not seem to affect postoperative continence. Conversely, erectile dysfunction

243

outcomes were inferior at 1-year follow-up. Preoperatively potent patients(IIEF-5≥22) who

244

underwent unilateral or bilateral NS during S-RARP developed significantly impaired erectile

245

function(mean 3 ± 2 vs 9.22 ± 6.55, p=0.008). In this context, FT seemed to negatively affect

246

erectile recovery. This effect is likely related either to the FT energy applied directly to the

247

prostate or to the higher number of prostate biopsies these patients underwent during FT

248

follow-up before S-RARP(p=0.0001). In our series, only two patients(9.1%) underwent more

249

than one FT session before surgery; this is another important variable to consider regarding

250

recovery of erectile function. The short follow-up in our series may underestimate the true

251

return of erectile function, although modern S-RP series for radiorecurrent PCa with long-term

252

follow-up have shown low potency rates.10,19,20

M AN U

SC

RI PT

242

TE D

253

Consensus has not yet been achieved regarding the best salvage option. Although treating

255

recurrence with S-RP seems reasonable and feasible, residual disease after primary ablation has

256

typically been treated with active surveillance or subsequent ablations; the threshold limit for S-

257

RP is still an evolving concept.12 Consequently, data on S-RP following FT have been scarce, and

258

little is known about pathologic PCa characteristics and behavior after FT failure. These

259

evidences reinforce the concept that FT may be offered as an experimental treatment option

260

within ethically-approved clinical trials for selected patients. In this context, our between-group

261

analysis found significantly lower probability of BCR-free survival with S-RARP compared with P-

262

RARP. In addition, Cox proportional hazards analysis showed a significantly increased risk of BCR

263

with S-RARP versus P-RARP(p=0.004). The groups were comparable in terms of Gleason score

AC C

EP

254

ACCEPTED MANUSCRIPT 12

upgrading(p=0.59), clinical upstaging(p=0.57), and PSMs(p=0.25), potential confounding factors

265

that could have significantly affected BCR-free survival analysis. The S-RARP group had lower

266

PSM rates than the P-RARP group(p=0.25), congruent with the lower rates of bilateral NS found

267

with S-RARP. Although overall BCR rates did not differ significantly between-groups(p=0.42), the

268

median time to BCR was significantly lower for S-RARP(p=0.0001), denoting shorter time to

269

failure in this group. Notably, the S-RARP group showed even lower 2-year BCR-free survival

270

rates than those reported in previous series of S-RP performed for radiorecurrent PCa(73–

271

87%).10 In contrast, previous reports of P-RARP outcomes described 2-year BCR-free survival

272

and PSM rates of 69–91% and 5–25%, respectively, congruent with our P-RARP group.21

M AN U

SC

RI PT

264

273

Our series demonstrated poor prognosis in terms of biochemical control for patients who

275

underwent S-RARP after FT failure. Consequently, concerns arise regarding one question: How

276

effective have our current FT follow-up methods been in predicting treatment failure? In this

277

context, it is possible that the current lack of clear BCR definition criteria after FT may have

278

contributed to delayed diagnosis of disease failure and allowed local progression during FT

279

follow-up, resulting in the impaired BCR-free survival outcomes found in the S-RARP group.

280

Indeed, we found long median time intervals between FT and S-RARP. This result raises concern,

281

especially when the current trend is to treat FT failure with active surveillance or subsequent

282

ablations. This scenario can remarkably minimize the likelihood of a successful local salvage

283

approach and underscores the importance of appropriate patient selection at the right time

284

during FT follow-up to avoid delaying salvage treatment. In this sense, analysis of potential

285

predictors associated with higher risk of worse evolution in the FT postablation scenario could

AC C

EP

TE D

274

ACCEPTED MANUSCRIPT 13

help identify patients at risk of failure to manage them with a stricter follow-up protocol or

287

prompt early radical treatment when necessary, possibly improving salvage oncologic

288

outcomes. The growing knowledge of MRI and 68Ga-PSMA-11 PET/CT interpretation could be

289

useful to identify PCa lesions with high Gleason score and exclude patients not suitable for FT. 22

290

Nevertheless, the development of a precise definition of FT failure is an outstanding issue and

291

will be a milestone in the future of FT.

SC

RI PT

286

292

To our knowledge, this comparative study is the first and the largest analyzing S-RARP outcomes

294

after FT failure compared with P-RARP as a control group. Furthermore, our cohort included

295

only FT cases. Previously published studies are case reports, small descriptive series, or series

296

that mixed cases of FT failure with external beam radiation.23-30 Limitations included its

297

retrospective nature, the lack of randomization, and a short follow-up time, although our short-

298

to midterm results have been adequately supported.

TE D

M AN U

293

299

CONCLUSIONS

301

S-RARP following FT failure is feasible, with acceptable complication rates. However, patients

302

assigned to primary FT should be advised about a poorer prognosis in terms of oncological

303

control and lower erectile recovery rates in case of a future salvage surgery.

AC C

304

EP

300

305

ACKNOWLEDGMENTS

306

Prof. Marcos Tobias-Machado, PhD. and Prof. Hamilton Zampolli, PhD.

307

Department of Urology, Arnaldo Vieira de Carvalho Cancer Institute - IAVC, São Paulo, Brazil.

ACCEPTED MANUSCRIPT 14

308

REFERENCES

310

1. Klotz L: Active surveillance for prostate cancer: Overview and update. Curr Treat Options

311

Oncol 2013; 14: 97-108.

312

2. van den Bergh RCN, Essink-Bot ML, Roobol MJ et al: Anxiety and distress during active

313

surveillance for early prostate cancer. Cancer 2009; 115: 3868-3878.

314

3. Mottet N, Bellmunt J, Bolla M et al: EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1:

315

Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017; 71: 618-629.

316

4. Perera M, Krishnananthan N, Lindner U et al: An update on focal therapy for prostate cancer.

317

Nat Rev Urol 2016; 13: 641-653.

318

5. Sivaraman A: High intensity focused ultrasound for focal therapy of prostate cancer. Arch Esp

319

Urol 2016; 69: 311-316.

320

6. Agarwal PK, Sadetsky N, Konety BR et al: Treatment failure after primary and salvage therapy

321

for prostate cancer: Likelihood, patterns of care, and outcomes. Cancer 2008; 112: 307-314.

322

7. Zelefsky MJ, Kuban DA, Levy LB et al: Multi-institutional analysis of long-term outcome for

323

stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol

324

Phys 2007; 67: 327-333.

325

8. Kimura M, Mouraviev V, Tsivian M et al: Current salvage methods for recurrent prostate

326

cancer after failure of primary radiotherapy. BJU Int 2010; 105: 191-201.

327

9. van den Bos W, Muller BG, de Bruin DM et al: Salvage ablative therapy in prostate cancer:

328

international multidisciplinary consensus on trial design. Urol Oncol Semin Orig Investig 2015;

329

33: 495.e1-495.e7.

AC C

EP

TE D

M AN U

SC

RI PT

309

ACCEPTED MANUSCRIPT 15

10. Chade DC, Eastham J, Graefen M et al: Cancer control and functional outcomes of salvage

331

radical prostatectomy for radiation-recurrent prostate cancer: A systematic review of the

332

literature. Eur Urol 2012; 61: 961-971.

333

11. Sivaraman A, Barret E: Focal Therapy for Prostate Cancer: An "A la Carte" Approach. Eur

334

Urol 2016; 69: 973-975.

335

12. Barret E, Harvey-Bryan K, Sanchez-Salas R et al: How to diagnose and treat focal therapy

336

failure and recurrence? Curr Opin Urol 2014; 24: 241-246.

337

13. Vallancien G, Gupta R, Cathelineau X et al: Initial results of salvage laparoscopic radical

338

prostatectomy after radiation failure. J Urol 2003; 170: 1838-1840.

339

14. Donovan JL, Peters T, Abrams P et al: Scoring the short form ICSmaleSF questionnaire.

340

International Continence Society. J Urol 2000; 164: 1948-1955.

341

15. Dindo D, Demartines N, Clavien PA: Classification of surgical complications: a new proposal

342

with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: 205-

343

213.

344

16. Rosenbaum PR, Rubin DB: The central role of the propensity score in observational studies

345

for causal effects. Biometrika 1983; 70(1): 41-55.

346

17. Matei DV, Ferro M, Jereczek-Fossa BA et al: Salvage radical prostatectomy after external

347

beam radiation therapy: a systematic review of current approaches. Urol Int 2015; 94: 373-382.

348

18. Agarwal PK, Sammon J, Bhandari A et al. Safety profile of robot-assisted radical

349

prostatectomy: a standardized report of complications in 3317 patients. Eur Urol 2011; 59: 684-

350

698.

AC C

EP

TE D

M AN U

SC

RI PT

330

ACCEPTED MANUSCRIPT 16

19. Heidenreich A, Richter S, Thüer D et al: Prognostic parameters, complications, and oncologic

352

and functional outcome of salvage radical prostatectomy for locally recurrent prostate cancer

353

after 21st-century radiotherapy. Eur Urol 2010; 57: 437-445.

354

20. Stephenson A, Scardino P, Bianco F et al: Morbidity and functional outcomes of salvage

355

radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol 2004;

356

172: 2239-2243.

357

21. Novara G, Ficarra V, Mocellin S et al: Systematic review and meta-analysis of studies

358

reporting oncologic outcome after robot-assisted radical prostatectomy. Eur Urol 2012; 62:

359

382-404.

360

22. Uprimny C, Kroiss AS, Decristoforo C et al: 68Ga-PSMA-11 PET/CT in primary staging of pros-

361

tate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary

362

tumour. Eur J Nucl Med Mol Imaging 2017; 44: 941-949.

363

23. Kaffenberger SD, Keegan KA, Bansal NK et al: Salvage robotic assisted laparoscopic radical

364

prostatectomy: a single institution, 5-year experience. J Urol 2013; 189: 507-513.

365

24. Lawrentschuk N, Finelli A, Van Der Kwast TH et al: Salvage radical prostatectomy following

366

primary high intensity focused ultrasound for treatment of prostate cancer. J Urol 2011; 185:

367

862-868.

368

25. Leonardo C, Franco G, De Nunzio C et al: Salvage laparoscopic radical prostatectomy

369

following high-intensity focused ultrasound for treatment of prostate cancer. Urology 2012; 80:

370

130-133.

371

26. Linares Espinós E, Sánchez-Salas R, Sivaraman A et al: Minimally invasive salvage

372

prostatectomy after primary radiation or ablation treatment. Urology 2016; 94: 111-116.

AC C

EP

TE D

M AN U

SC

RI PT

351

ACCEPTED MANUSCRIPT 17

27. Rodríguez Jr E, Skarecky DW, Ahlering TE: Salvage robot-assisted radical prostatectomy with

374

pelvic lymph node dissection after cryotherapy failure. J Robot Surg 2007; 1: 89-90.

375

28. Liatsikos E, Bynens B, Rabenalt R et al: Treatment of patients after failed high intensity

376

focused ultrasound and radiotherapy for localized prostate cancer: salvage laparoscopic

377

extraperitoneal radical prostatectomy. J Endourol 2008; 22: 2295-2298.

378

29. Murphy DG, Pedersen J, Costello AJ: Salvage robotic-assisted laparoscopic radical

379

prostatectomy following failed primary high-intensity focussed ultrasound treatment for

380

localised prostate cancer. J Robot Surg 2008; 2: 201-203.

381

30. Stolzenburg JU, Bynens B, Do M et al: Salvage laparoscopic extraperitoneal radical

382

prostatectomy after failed high-intensity focused ultrasound and radiotherapy for localized

383

prostate cancer. Urology 2007; 70: 956-960.

AC C

EP

TE D

M AN U

SC

RI PT

373

ACCEPTED MANUSCRIPT 63.32 ± 4.72 25.32 ± 2.49

63.02 ± 4.56 26.07 ± 2.7

14 (63.6) 6 (27.3) 2 (9.1)

27 (61.4) 17 (38.6) 0 (0)

TE D

EP

AC C

p 0.81 0.28 0.103

<0.0001 0 (0) 11 (50) 7 (31.8) 4 (18.2) 2.68 ± 0.78

44 (100) 0 (0) 0 (0) 0 (0) 1.00 ± 0.00

0 (0) 20 (90.9) 2 (9.1)

44 (100) 0 (0) 0 (0)

M AN U

1 2 3 Number of Biopsies Series n (%) 1 2 3 4 Number of Biopsies Series (Mean/SD) Number of Focal Treatments n (%) 0 1 2 FT Energy Applied n (%) High-Intensity Focused Ultrasound - HIFU Cryotherapy Brachytherapy Vascular-Targeted Photodynamic Therapy - VTP Laser Ablation WST11 Prostate size (Mean/SD) PSA (Mean/SD) Gleason Score** n (%) 6 (3+3) 7 (3+4) 7 (4+3) 8 (4+4) Clinical T Staging n (%) T1c T2a Clinical Stage - D'Amico n (%) Low Risk Intermediate Risk High Risk ICSmaleIS (Mean/SD) IPSS (Mean/SD) IIEF5 (Mean/SD) IIEF5 n (%) No ED Mild ED Mild-Moderate ED Moderate ED Severe ED

P-RARP (n=44)

RI PT

Age - year (Mean/SD) BMI - kg/m2 (Mean/SD) ASA n (%)

S-RARP (n=22)

SC

Table 1. Demographic Data*

<0.0001 <0.0001

N/A

7 (31.81) 11 (50) 1 (4.5) 1 (4.5) 2 (9.1) 40.05 ± 11.33 9.24 ± 5.76

0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 50.38 ± 11.12 8.73 ± 4.41

10 (45.5) 7 (31.8) 4 (18.2) 1 (4.5)

17 (38.6) 16 (36.4) 7 (15.9) 4 (9.1)

20 (90.9) 2 (9.1)

35 (79.5) 9 (20.4)

6 (27.3) 13 (59.1) 3 (13.6) 0.41 ± 1.4 6.27 ± 4.55 16.23 ± 8.99

13 (29.5) 25 (56.8) 6 (13.6) 0±0 6.61 ± 4.00 14.43 ± 9.22

9 (40.9) 2 (9.1) 4 (18.2) 2 (9.1) 5 (22.7)

18 (42.9) 4 (9.5) 2 (4.8) 6 (14.3) 12 (28.6)

0.001 0.691 0.873

0.312

0.98

0.186 0.757 0.455 0.511

BMI = Body Mass Index; ASA = American Society of Anesthesiologists Physical Status Classification System; FT = Focal Therapy; PSA = Prostate-Specific Antigen; ICSmaleIS = International Continence Society Male Incontinence Symptoms; IPSS = International Prostate Symptom Score; IIEF5 = International Index of Erectile Function; ED = Erectile Dysfunction; S-RARP = Salvage Robotic-Assisted Radical Prostatectomy; P-RARP = Primary Robotic-Assisted Radical Prostatectomy; N/A = Not Applicable. * Data collected after the last FT and immediately before S-RARP; or just immediately before P-RARP, for the S-RARP and P-RARP groups, respectively. ** Highest Gleason score obtained from the last prostate biopsy performed before S-RARP or P-RARP.

ACCEPTED MANUSCRIPT Table 2. Perioperative Outcomes P-RARP (n=44)

p

134.77 ± 19.66

138.41 ± 40.52

0.62

Hospital Stay - Days (Mean/SD)

4.41 ± 2.11

4.41 ± 1.77

0.99

Catheterization time - Days (Mean/SD)

8.73 ± 1.58

8.36 ± 3.41

0.63

Operative Time - Minutes (Mean/SD)

Estimated Blood Loss - ml (Mean/SD)

RI PT

S-RARP (n=22)

465.91 ± 227.5

Blood Transfusion n (%)

427.27 ± 299.31

0.6

0.54

22 (100) 0

TE D

EP

42 (95.5) 2 (4.5)

SC

0.033

2 (9.1) 8 (36.4) 12 (54.5)

M AN U

No Yes Nerve Sparing Approach n (%) No Unilateral Bilateral Lymphonode Dissection n (%) No Yes Total Number of patients with complications n (%) Number of patients - Complication Clavien > 2 Number of patients - Complication Clavien 1-2 Total Number of complications n (%) Number of complications = clavien >2 Number of complications = clavien 1-2 Complication Type (Clavien >2) n (%) Anastomotic Leak Permanent Incontinence Complication Type (Clavien 1-2) n (%) Urinary Tract Infection Perioperative Bleeding Pelvic Hematoma

1 (2.3) 6 (13.6) 37 (84.1) 0.99

15 (68.2) 7 (31.8) 2 (9.1) 2 0 3 (42.8) 3 0

30 (68.2) 14 (31.8) 3 (6.8) 0 3 4 (57.1) 0 4

2 (66.6) 1 (33.3)

0 (0) 0 (0)

0.7

N/A

N/A 0 (0) 0 (0) 0 (0)

1 (25) 2 (50) 1 (25)

S-RARP = Salvage Robotic-Assisted Radical Prostatectomy; P-RARP = Primary Robotic-Assisted Radical Prostatectomy; N/A = Not Applicable

AC C

0.74

ACCEPTED MANUSCRIPT Table 3. Functional Outcomes S-RARP (n=22)

p 0.462

6 (46.2) 7 (53.8)

15 (34.9) 28 (65.1)

2 (15.4) 11 (84.6)

6 (14) 37 (86)

RI PT

0.897

SC

7 (53.8) 4 (30.8) 1 (7.7) 1 (7.7)

0.845

28 (65.1) 9 (20.9) 4 (9.3) 2 (4.7)

0.41 ± 1.4 4.09 ± 5.43

0±0 4.6 ± 4.28

0.186 0.744

6.27 ± 4.55 5 ± 5.25

6.61 ± 4 4.97 ± 3.42

0.757 0.984

16.23 ± 8.99 3±2

14.43 ± 9.22 9.22 ± 6.55

0.455 0.008

M AN U

Continence at 1-year (Criteria: No pads per day) No Yes Continence at 1-year (Criteria: ≤1 pad/day) No Yes Continence status at 1-year Continence achieved (No pads per day) Mild-incontinence (1 pad/day) Moderate-incontinence (2 pads/day) Severe-incontinence (≥3 pads/day) ICSmaleIS (Mean/SD) Preoperative 1-year Postoperative IPSS (Mean/SD) Preoperative 1-year Postoperative IIEF5 (Mean/SD) Preoperative 1-year Postoperative (IIEF5 ≥22; Unilateral/Bilateral NS)

P-RARP (n=44)

AC C

EP

TE D

ICSmaleIS = International Continence Society Male Incontinence Symptoms; IPSS = International Prostate Symptom Score; IIEF5 = International Index of Erectile Function; NS = Nerve Sparing; S-RARP = Salvage Robotic-Assisted Radical Prostatectomy; P-RARP = Primary Robotic-Assisted Radical Prostatectomy.

ACCEPTED MANUSCRIPT

Table 4. Oncological Outcomes

S-RARP (n=22) n (%)

P-RARP (n=44) n (%)

Pathological T stage

p 0.705

16 (72.7) 4 (18.2) 2 (9.1)

29 (65.9) 12 (27.3) 3 (6.8) 0.256

21 (95.5) 1 (4.5)

TE D

EP

AC C

14 (63.6) 8 (36.4) 6 (75) 1 (12.5) 1 (12.5)

0.35

14 (31.8) 0 (0) 30 (68.2)

SC

6 (27.3) 1 (4.5) 15 (68.2)

6 (13.6) 17 (38.6) 20 (45.5) 1 (2.3)

RI PT

4 (18.2) 13 (59.1) 5 (22.7) 0 (0)

M AN U

pT2a-pT2c pT3a pT3b Pathological Gleason score 6(3+3) 7(3+4) 7(4+3) 8(4+4) Pathological Node status pN0 pN1 pNx Margin status Negative Positive Upgrading status No Yes Type of upgrading 6(3+3) > 7(3+4) 6(3+3) > 7(4+3) 7(3+4) > 7(4+3) Upstaging status No cT1/T2 > pT3/pT4 Upstaging status in patients with upgrading No cT1/T2 > pT3/pT4 Biochemical Recurrence (BCR) BCR in patients with upgrading No Yes BCR in patients with upstaging No Yes Follow-up (months) [median (IQR)] Time to BCR (months) [median (IQR)] Time Interval between FT/S-RARP (months) [median (IQR)]

0.253

36 (81.8) 8 (18.2) 0.595 25 (56.8) 19 (43.2) 0.283 8 (42.1) 4 (21.1) 7 (36.8) 0.575

16 (72.7) 6 (27.3)

29 (65.9) 15 (34.1)

4 (50) 4 (50) 7 (31.8)

10 (52.6) 9 (47.4) 10 (22.7)

3 (37.5) 5 (62.5)

15 (78.9) 4 (21.1)

0.901

0.426 0.037

0.477 3 (50) 3 (50) 7 (2.75-19.5) 7 (3-19)

10 (67.7) 5 (33.3) 38.5 (23.5-61.75) 35 (17.25-44.75)

<0.0001 <0.0001

Overall

24 (12.75 - 31.25)

In patients without upstaging In patients with upstaging

26 (14.25 - 31.75) 12.5 (12 - 31.25)

0.245*

In patients without BCR In patients with BCR

27 (12 - 32) 23 (13 - 31)

0.493**

BCR = Biochemical Recurrence; IQR = Interquartile Range; FT = Focal Therapy; S-RARP = Salvage Robotic-Assisted Radical Prostatectomy; P-RARP = Primary RoboticAssisted Radical Prostatectomy. * p value calculated between patients with versus without upstaging within S-RARP group. ** p value calculated between patients with versus without BCR within S-RARP group.

RI PT SC M AN U TE D EP

A

AC C

Pad-Free Survival Probability

ACCEPTED MANUSCRIPT

B

Figure 1. (A)Kaplan-Meier estimates for Pad-free survival probability: Between-group analysis demonstrated comparable Pad-free probability rates [49.5% versus 62.4% (p=0.8) and 73% versus 76.5% (p=0.8), at 1 and 2 years, respectively]. (B) Cox proportional hazard analysis for achieving continence: Between-group analysis demonstrated comparable chances for achieving continence [HR 1.062, 95%CI 0.54–2.08, p=0.861].

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

A

Figure 2. (A) Kaplan-Meier estimates for BCR-free survival probability: S-RARP presented significant lower rates of cumulative BCR-free survival probability [67.6% versus 95.1% (p=0.001) and 56,3% versus 92,4% (p=0.001), at 1 and 2 years, respectively]. (B) Cox proportional hazard analysis for the risk of BCR between-groups: S-RARP presented a significant increased risk of BCR [HR 4.8, 95%CI 1.67 – 13.76, p=0.004].

B

ACCEPTED MANUSCRIPT

1

ABBREVIATIONS

4

- FT: focal therapy

5

- AS: active surveillance

6

- RARP: robotic assisted radical prostatectomy

7

- S-RARP: salvage robotic assisted radical prostatectomy

8

- P-RARP: primary robotic assisted radical prostatectomy

9

- RP: radical prostatectomy

SC

- PCa: prostate cancer

M AN U

3

RI PT

2

- S-RP: salvage radical prostatectomy

11

- IPSS: International Prostate Symptom Score

12

- IIEF-5: International Index of Erectile Function

13

- PSA: prostate-specific antigen

14

- ICSmaleIS: International Continence Society male Incontinence Symptoms

15

- BCR: biochemical recurrence

16

- IQR: interquartile range

17

- NS: nerve sparing

18

- PSM: positive surgical margin

19

- EBL: estimated blood loss

20

- MRI: magnetic resonance imaging

21

- mpMRI: multiparametric magnetic resonance imaging

22

- PSM: propensity score matching

AC C

EP

TE D

10

ACCEPTED MANUSCRIPT

Table 5. Comparison between-samples: P-RARP (n=44) versus overall P-RARP population (n=2706). P-RARP (n=44)

P-RARP (n=2706)

"p value"

Age (Mean/SD) BMI (Mean/SD) ASA (n/%)

63.02 ± 4.56 26.07 ± 2.7

61.79 ± 5.84 26.073 ± 9.618

0.16 0.99 < 0.005

1 2 3 4 Prostate Size (gr.) (Mean/SD) Preoperative PSA (Mean/SD) Clinical T-Stage (n/%) T1a T1b T1c T2a T2b T2c T3a T3b Preoperative Gleason Score (n/%) 6 (3+3) 7 (3+4) 7 (4+3) 8 (4+4) 9 (5+4) D'Amico Risk Classification (n/%) Low Intermediate High Operative Time (Mean/SD) Hospital Stay (Mean/SD) Estimated Blood Loss (Mean/SD) Blood Transfusion (n/%) No Yes Nerve Sparing Status (n/%) No Unilateral Bilateral Number of Patients with Complication (n/%) No Yes Pathological T-Stage (n/%) pT2a pT2b pT2c pT3a pT3b Pathological Gleason Score (n/%) 6 (3+3) 7 (3+4) 7 (4+3) 8 (4+4) 8 (5+3) 9 (5+4) Margin Status (n/%) Negative Positive Margin Length (mm) (Mean/SD) Biochemical Recurrence (BCR) (n/%) No Yes Preoperative IPSS (Mean/SD) Preoperative IIEF5 (Mean/SD)

27 (61.4) 17 (38.6) 0 (0) 0 (0) 50.38 ± 11.12 8.73 ± 4.41

1386 (51.5) 537 (20) 746 (27.7) 20 (0.7) 52.72 ± 19.72 8.16 ± 4.59

0 (0) 0 (0) 35 (79.5) 9 (20.4) 0 (0) 0 (0) 0 (0) 0 (0)

4 (0.2) 8 (0.3) 1728 (65.1) 631 (23.8) 179 (6.7) 91 (3.4) 11 (0.4) 2 (0.1)

RI PT

SC 1146 (42.9) 1288 (48.2) 236 (8.8) 137.29 ± 34.92 4.49 ± 6.25 438.54 ± 300.6

42 (95.5) 2 (4.5)

2426 (96.7) 84 (3.3)

TE D

13 (29.5) 25 (56.8) 6 (13.6) 138.41 ± 40.52 4.41 ± 1.77 427.27 ± 299.31

1 (2.3) 6 (13.6) 37 (84.1)

0.17

0.83 0.93 0.81 0.66

0.006 342 (12.6) 710 (26.3) 1652 (61.1) 0.47

41 (93.2) 3 (6.8)

2258 (88.7) 288 (11.3)

2 (4.5) 1 (2.3) 26 (59.1) 12 (27.3) 3 (6.8)

126 (4.8) 156 (5.9) 1555 (58.9) 604 (22.9) 199 (7.5)

6 (13.6) 17 (38.6) 20 (45.5) 1 (2.3) 0 (0) 0 (0)

574 (21.7) 1296 (49) 703 (26.6) 43 (1.6) 6 (0.2) 23 (0.9)

36 (81.8) 8 (18.2) 3.63 ± 1.92

2038 (76.9) 612 (23.1) 4.2 ± 5.79

34 (77.3) 10 (22.7) 6.61 ± 4 14.43 ± 9.22

2294 (84.8) 412 (15.2) 6.95 ± 5.81 19.02 ± 6.56

EP

AC C

0.091

1436 (53.5) 868 (32.4) 279 (10.4) 86 (3.2) 13 (0.5)

M AN U

17 (38.6) 16 (36.4) 7 (15.9) 4 (9.1) 0 (0)

0.18 0.41 0.49

0.85

0.13

0.44

0.78 0.17

0.7 0.002