Treatment of High Risk Incontinence After Multimodal Therapy for Prostate Cancer

O. Lenaine Westney, MDProfessorDirector, Urinary Tract and Pelvic Reconstruction

27th Annual USF Advances in UrologyKey West, Florida

April 6, 2017

Objectives

• Discuss the utilization and prevalence of radiation in the treatment of prostate cancer

• Examine the GU toxicity rates associated with radiation

• Review the effect of radiation therapy on the success rates of surgical treatment for postprostatectomy incontinence

• Explain theoretical options for decreasing atrophy and/or erosion

Use of Radiation for Pelvic Tumors

• Highly integrated into the treatment algorithms for pelvic malignancies– Prostate, Rectal, Uterine, Cervical ….

• Mixtures of radiation delivery techniques have proven efficacy in particular disease sites (cervical)

• Multimodality therapy is widely utilized – surgery + chemo and/or radiation

Radiation and Prostate Cancer

American Cancer Society Intramural Research, 2016

Westney Reconstructive /Incontinence Cases 2013

Pelvic RadiationNo Pelvic Radiation

64%

46%

Reconstructive Cases by Primary Cancer Diagnosis

0

20

40

60

80

100

120

Pelvic Radiation

No Pelvic Radiation

Cancer Primary

Radiation: The Reconstructive Urologist View

Radiation Effects in the Lower Urinary Tract

• Acute– Edema (Urothelial, endothelial and smooth

muscle cells)• Chronic

– Normal smooth muscle replaced by fibroblasts >> collagen deposition >> decreasing compliance

• Dose dependent• (Soler, 2011) Significant increase in

collagen:muscle ratio, decrease in vascular density)

– Obliterative endarteritis >> ischemia >> fibrosisMarks LB, Carroll PR, Dugan TC, et al. Int. J. Radiation Oncology Biol. Phys.3:1257‐ 1280. 1995Soler R, Vianello A, Füllhase C, Wang Z, Atala A, et al. Neurourol Urodyn. 2011Mar;30(3):428‐34.

Overall Bladder Dose - Toxicity

Disease Treated Approximate Doseto  > 50 % of the Bladder

ApproximateMaximum Bladder Dose (Gy)

Approximate Clinical Complication Rate

Prostate 40 60‐65 5

Bladder 50‐65 50‐65 5‐20

Cervical 40 65‐75 5‐10

30 ≥ 80 10‐20

Rectum 40‐50 40‐50 0

Marks LB, Carroll PR, Dugan TC, et al. Int. J. Radiation Oncology Biol. Phys.3:1257‐ 1280. 1995

RTOG (Radiation Therapy Oncology Group) Late GU Toxicity Classification

0 1 2 3 4

None Slight epithelial atrophy; minortelangiectasia(microscopichematuria)

Moderate frequency; generalizedtelangiectasia; intermittentmacroscopic hematuria

Severe freq  & dysuria; severetelangiectasia ; frequenthematuria; reduction in bladdercapacity (< 150 cc)

Necrosis/Contracted bladder(capacity < 100 cc)Severe hemorrhagic cystitis

Cox JD, Stetz J, Pajak TF, Int. J. Radiation Oncology Biol. Phys.,  31: 134 I ‐ 1346, 1995.

Brachytherapy

• Early stage organ confined prostate cancer• Dose delivery over the life of the implant

– Isotope half life dependent (I-125: 59.4 days, Pd-103: 16.97 days)

– 75% of dose delivered in first 4 months (I-125)• Expanded definition of acute toxicity• Prescribed dose: 140-145 Gy

Cesaretti J, Stone N, Skouteris V, et al. Brachytherapy for the treatment of prostate cancer. Cancer J. 2007;13:302‐312.Frank SJ, Levy LB, Kuban DA, et al. Prostogram‐predicted brachytherapy outcomes may not be universally accurate: an analysis based on the M.D. Anderson Cancer Center experience with iodine‐125 brachytherapy. J Urol. 2009;181:1658‐1663.

Brachytherapy: Acute and Chronic ToxicityEarly urinary side effects as measuredby EPIC domains

Late side effects as graded by modified RTOGcriteria

Anderson JF, Swanson DA, Levy LB, et al. Urinary side effects and complications after permanent prostate brachytherapy: The MD Anderson Cancer Center experience. Urology 2009;74:601e605.

Post Brachytherapy Imaging:Urinary Symptoms

3D reconstruction from Fused CT‐MRI depicting prostate and adjacent organs with threshold doses for urinary symptoms

Register SP,  Kudchadker RJ, Levy LB, et al. Brachytherapy 12 (2013) 210‐216

Salvage Local Therapy Urinary Complications

Modality # of studies

N Incontinence UrethralStricture

RectourethralFistula

Brachytherapy 10 255 8 (0‐31) ‐ 3 (0‐12)

Cryotherapy 8 473 36 (7‐95) 17 (0‐55) 3 (0‐11)

HIFU 2 102 7 17‐36 3‐6

Ahmed HU, Cathcart P, McCartan N, Kirkham A, Allen C, Freeman A, Emberton M.Focal salvage therapy for localized prostate cancer recurrence after externalbeam radiotherapy: a pilot study. Cancer. 2012 Sep 1;118(17):4148‐55. 

Radiotherapy in Multimodality Settings

• Primary Prostatectomy– Adjuvant Radiation– Salvage Radiation

• Primary Radiation + Salvage Prostatectomy

Incidence of GU Toxicity in External Beam Radiation

• Acute phase toxicity is very common (50-80%)• The incidence of late GU toxicity (> Grade 2) is

considerably less at 10-20% – dosage

• Urinary toxicity stable regardless of technique; – IMRT vs conformal/proton: increased erectile

dysfunction; decreased GI toxicity and hip fractures

Zietman AL, DeSilvio ML, Slater JD, et al. JAMA. 2005 294(10):1233.Dearnaley DP, Sydes MR, Langley RE, et al. Radiother Oncol. 2007 83(1):31.Peeters ST, Heemsbergen WD, van Putten WL, et al.. Int J Radiat Oncol Biol Phys. 2005 61(4):1019. Zelefsky MJ, Levin EJ, Hunt M, et al.. Int J Radiat Oncol Biol Phys. 2008 70(4):1124.Pederson AW, Fricano J, Correa D, et al. Int J Radiat Oncol Biol Phys. 2012 82(1):235. Sheets NC,  Goldin GH, Meyer A‐M, et al. JAMA . 2012 April 18; 307(15): 1611–1620

Adjuvant/Salvage Radiation Therapy: General GU toxicity

• Adjuvant – based on adverse pathological features at RRP: + margin, SV invasion, extraprostaticextension, - PSA

• Salvage Series– Goenka

• IMRT similar to 3DCRT for o > Grade 2 acute GU toxicity (IMRT, 16.8%; 3D-CRT, 15.8%; p = 0.86) and urinary incontinence (IMRT, 13.6%; 3D-CRT, 7.9%; p = 0.25).

– late > Grade 2 GI toxicity was significantly reduced in the IMRT group (IMRT, 1.9%; 3D-CRT, 10.2%; p = 0.02)

• Development of late GU toxicity in the 3-5 year period > primary radiotherapy

Goenka A, Magsanoc JM, Pei X, et al. Improved toxicity profile following high‐dose postprostatectomy salvage radiation therapy with intensity‐modulated radiation therapy. Eur Urol. 2011 60(6):1142.http://www.auanet.org/education/guidelines/radiation‐after‐prostatectomy.cfm

Adjuvant: Urinary Incontinence

• Adjuvant– Randomized trials

• (60Gy,conventional) and observation, reported no difference in continence recovery (Van Cangh, 1998)

– urinary continence endpoint: 1-hour pad test• 60-64 Gy EBRT vs observation – 425 pts (SWOG)

– increased risk of urethral stricture (RR,1.9; 95% CI,1.1-3.1; P=.02) in patients treated with adjuvant radiation (60-64Gy,); higher ‘total incontinence’ in the adjuvant (RR, 2.3; 95% CI, 0.9-5.9; P=.11

» no objective measures or grading of incontinence were performed at baseline or at study completion.

http://www.auanet.org/education/guidelines/radiation‐after‐prostatectomy.cfmP.J. Van Cangh, F. Richard, F. Lorge et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: results of a prospective randomized study. J Urol 1998 159:164.Thompson IM Jr, Tangen CM, Paradelo J, et al: Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006 Nov 15; 296(19): 2329‐35

Adjuvant: Urinary Incontinence

• (Suardi) Significant difference in 3-year urinary continence in non-randomized groups with (Med. Gy: 70.2, IMRT) and without adjuvant radiation– 59 vs 81% (p<0.001), respectively. – Incontinence was quantified based on patient

report of pad usage at scheduled follow-up.

Suardi N, Gallina A, Lista G, et al. Impact of Adjuvant Radiation Therapy on Urinary Continence Recovery After Radical Prostatectomy. Eur Urol. 2013 Feb 4.http://www.auanet.org/education/guidelines/radiation‐after‐prostatectomy.cfm

Adjuvant vs Salvage Radiotherapy

Urinary Complications: Definitive External Beam >> Salvage Prostatectomy

Series: First Author (Yr)

N Anastomotic Stricture (%) Incontinence (%)

Open

Stephenson (2004) 100 30 32

Sanderson (2006) 51 41 30

Leonardo (2009) 32 12 69

Gotto (2010) 98 41 70

Heidenreich (2010) 55 11 29

Robotic

Boris (2009) 11 9 20

Eandi (2010) 18 17 67

Chauhan (2011) 15 - 29

Kaffenberger (2013) 34 9 61

Surgical Options

• Male Sling– Bone-Anchor– Transobturator +/- Prepubic– Adjustable

• Adjustable Balloons• Artificial Urinary Sphincter• Bladder Neck Closure, Catheterizable

Limb +/- Augmentation• Urinary Diversion

The Effect of Radiation on Sling Outcomes

• Bone-Anchor • Transobturator• Transobturator + Pre-pubic• Adjustable

Bone-Anchor SlingReference Mean 

Follow‐up( months)

Total N RadiatedN

Total Success

Radiated Success

Carmel (2010)

36 45 12 (Adj) 76% 66% 

Guimarães(2009)

Up to 48 months

62 18 88% 72%

GallagherBL(2007)

15 31 6* 3.4 > 0.8 pads/day

4.5 >2.5 pads/day

Castle (2005)

18 42 8 47% 13%

Comiter(2005)

48 42 10 (8 adj) 82% 0%

*2 removals due to infectionCarmel M, Hage B, Hanna S, Schmutz G, Tu le M. BJU Int. 2010 Oct;106(7):1012‐6Guimarães M, Oliveira R, Pinto R, Soares A, Maia E, Botelho F, Sousa T, Pina F, Dinis P, Cruz F.BJU Int. 2009 Feb;103(4):500‐4.Gallagher BL, Dwyer NT, Gaynor‐Krupnick DM, Latini JM, Kreder KJ. Urology. 2007 Jun;69(6):1090‐4.Castle EP, Andrews PE, Itano N, Novicki DE, Swanson SK, Ferrigni RG. J Urol. 2005 May;173(5):1657‐60.Comiter CV. Neurourol Urodyn. 2005;24(7):648‐53.

Transobturator SlingsReference (Yr)

Mean Follow‐up (months)

Total (N) Radiated (n) Non‐radiated Success* (%)

Radiated Success* (%)

2‐arm, outside‐in

Rehder(2012)

36 (min) 153 22 65 54

Cornu (2010) 21 136 23 78 P=0.053#

2‐arm inside‐out

Leruth (2012)

24 136 17 91 35

4‐arm Transobturator^

Grise (2012) >12 103 0 87 N/A

*Success= Dry+ Improved# p value for comparison between success rates^Extrinsic to the bulbospongiosus muscle Rehder P, Haab F, Cornu JN, Gozzi C, Bauer RM.

Eur Urol. 2012 Jul;62(1):140‐5Leruth J, Waltregny D, de Leval J. Eur Urol 61(3): 608‐15, 2012Cornu JN, Sebe P, Ciofu C et al. BJU Int 108: 236‐240, 2011Grise P, Vautherin R, Njinou‐Ngninkeu B, et al : Urol 79: 458‐464, 2012

Torrey R, Rajeshuni N, Ruel N, Muldrew S, Chan K. Radiation history affectscontinence outcomes after advance transobturator sling placement in patients withpost‐prostatectomy incontinence. Urology. 2013 Sep;82(3):713‐7.

Radiation and the Artificial Urinary Sphincter

Radiation as a Risk Factor for AUS Complications

Raj GV, Peterson AC, Webster GD. JU 175, 2186‐2190,  2006

The Effect of Radiation on First AUS Revisions

Westney OL, Lai HH, Boone TB, Latini J, McGuire EJ. Abstract  568, AUA 2013

Systematic review and meta-analysis of the artificial urinary sphincter in men undergoing prior

external beam radiotherapy

Anthony Bates, Timothy Terry, Leicester, United Kingdom

NO!!

• Erosion picture

Strategies for Decreasing the Atrophy/Erosion Rate

• Lengthening of post-op Deactivation Period• Nocturnal Deactivation• Transcorporal Cuff Placement• Utilization of Allograft/Xenograft Buttress• Adjustment in Cuff Size and/or Reservoir

Pressure

Elliott DS, Barrett DM, Gohma M, Boone TB. Urology. 2001 Jun;57(6):1051‐4Lee D, Zafirakis H, Shapiro A, Westney OL. Int J Urol. 2012 May 9Trost L, Elliott D. Urology. 2012 Apr;79(4):933‐8

Lengthening Deactivation Period

0

2

4

6

8

10

12

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 91 94 97

Time of Activation (weeks)

Time of Activation (weeks)

Nocturnal Deactivation

• Furlow – Pioneered system capable of deactivation (post-op and nocturnal) (FurlowWL. J Urol 16:741-4, 1981)

• Comparison of atrophy and erosion– No significant difference based on

deactivation (Elliot DS et al. J Urol 57:1051-4, 2001)

• Reasonable in patients dry at night preoperatively– Strongly recommend for radiation/cryotherapy,

prior erosion

Cuff Downsizing Vs. TranscorporalApproach in the High-Risk Patient

Transcorporal Technique

Downsizing to the 3.5 cm cuff

Simhan J, Morey AF, Singla N, Tausch TJ, Scott JF, Lemack GE, Roehrborn CG.  3.5 cm artificial urinary sphincter cuff erosion occurs predominantly in  irradiated patients. J Urol. 2015 Feb;193(2):593‐7.

Risk Factors for Explantation of Artificial Urinary Sphincters: a prospective multicenter analysis

• 386 patients with at least 3 months follow-up treated with AUS

• Retrospective analysis was performed looking for risk factors predictive for explantation using both univariateand multivariate techniques

• Explantation occurred in 31 (8.03%) at a median time of 15.1 +/- 7.8 months

• Multivariable logistic regression of significant univariatepredictors revealed – radiation (OR 4.82, 95% CI 2.02-11.49)– urethral stent placement [OR 5.71 (1.2-27.2)] and – 3.5 cm cuffs [OR 3.2 (1.2 – 8.8)] to be independent

predictors of explantation.

Brant WO, Erickson BA, Elliott SP, Powell C, Alsikafi N, McClung C, Myers JB,  Voelzke BB, Smith TG 3rd, Broghammer JA. Risk factors for erosion of artificial urinary sphincters: a multicenter prospective study. Urology. 2014 Oct;84(4):934‐8.

Pressure Regulating Balloon Gradient Decrease• 61-70 cm H2O >>> 51-60 cm H2O• Proposed as a method for decreasing the risk of

urethral atrophy and erosion in radiated patients• Based on the original work from Brantley Scott

Motley RC, Barrett DM. Urol 36 (3): 215-218, 1990Brito GC, Mulcahy JJ, Mitchell ME, Adams MC. J Urol 149:283-285, 1993Scott FB. Urol Clin N Amer 16 (1): 105 – 117, 1989

Allograft AUS cuff Buttress

• Small Intestinal submucosal (SIS) wrap– 8 patients with history of prior AUS cuff erosion.

At 12 months follow-up: 3/8 dry, 2 erosions, 1 infection (Trost, 2012)

• Placement of dry, equine fibrin, adhesive coated collagen sponge around the urethra– 17 patients; mean follow-up 38 months. 2

revisions for tandem cuff, 1 erosion and 1 pump malfunction.(Margreiter, 2013)

• Pericardium – 20 patients with a mean follow-up of 31.1

months. 40% complication rate. (Powell, Abs. # 94, AUA 2013)

Trost L, Elliott D. Urology. 2012 Apr;79(4):933-8.Margreiter M, Farr A, Sharma V, Schauer I, Klingler HC. J Urol. 2013 May;189(5):1777-81.Powell C, Dhabuwala C, Brant W, Odom B, Vicena J, Windsperger A, Brohammer. Abs. 94, AUA 2013.

Summary

• The utilization of radiation (external beam, brachytherapy) can result in significant urinary symptoms that increase with time from original treatment

• Radiation therapy has been demonstrated to reduce the success rates for the majority of slings

• The rate of complications after placement of Artificial Urinary Sphincter has been demonstrated to be significantly higher in radiated patients.

Thanks for your attention