outcomes and evidence based medicine systematic reviews reviews/apsa-2018... · • udt = failure...

Outcomes and Evidence Based Medicine Systematic Reviews

Meghan A. Arnold, Karen Diefenbach, Robert Gates, Julia Shelton

Management of the Undescended Testicle

APSA Outcomes and Evidence Based Medicine Committee

Disclosures

• We have no disclosures • There is some discussion of non-FDA approved therapies as some

studies outside of the US have evaluated the use of LHRH analogs

Commonalities

• UDT = failure of the testis to descend into a scrotal position

• Extrascrotal (prescrotal, superficial inguinal pouch, external ring, canalicular, abdominal or ectopic) vs absent “vanishing”

• Congenital vs acquired (ascending, entrapped, retractile, atrophic)

• Orchidopexy = Orchiopexy

https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf


Questions posed in this systematic review For children with undescended testicle

1. When is pre-operative imaging indicated and if so, which study is most appropriate?

2. What is the role of medical management in undescended testicle?

3. What is the appropriate timing of intervention and how is this affected by associated clinical factors?

4. What is the evidence supporting type of operative intervention?

5. What are the long term outcomes after orchiopexy? 5

Search Results

• MeSH headings searched back to 2007: • Cryptorchid/cryptorchidism, undescended testicle/testis, orchidopexy/orchiopexy,

intraabdominal testis, impalpable/nonpalpable testis, • Infant, child or adolescent

• 417 articles total • All abstracts reviewed and categorized • Cross referenced between reviewers • Snowballing technique used to obtain additional papers • 388 chosen for full review • 180 included in the review

Question 1 For children with undescended testicle:

When is pre-operative imaging indicated and if so, which study is most

appropriate?

Search Results

• 19 studies obtained from initial search • 5 added after further review • 7 suitable for inclusion

– 3 prospective – 4 retrospective

• Imaging modalities: MRI, CT and US

Consensus Statements •American Urological Association 2014 (http://www.auanet.org/guidelines/cryptorchidism-(published-2014)) Providers should not perform ultrasound (US) or other imaging modalities in the evaluation of boys with cryptorchidism prior to referral, as these studies rarely assist in decision making

•European Association of Urology 2016 (https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf) Use of US, CT or MRI is limited and only recommended in specific and selected clinical scenarios

http://www.auanet.org/guidelines/cryptorchidism-(published-2014))




When is pre-operative imaging indicated?

• Ultrasounds should not be obtained prior to being seen by surgeon (pediatric surgeon or pediatric urologist)

Wayne et al. 2017 (Level II) and Kanaroglou et al. 2017 (Level II) - May not be necessary as >50% referrals were normal on exam by specialist

(Wayne) - Children who had an US prior referral had an approximate 3 month delay in

definitive surgical management (Kanaroglou)

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When pre-operative imaging is indicated, which study is most appropriate?

• Cross-sectional imaging (CT/MRI) – no evidence that this is indicated for locating testes

• May be helpful when evaluating for other anomalies associated with undescended testes


• Ultrasound may be helpful in select patients • Moriya et al. 2017 (Level III) • Berger et al. 2017 (Level II) • Abdulrahman et al. 2016 (Level III) • Vos et al. 2014 (Level II) • Adesanya et al. 2013 (Level II)


• Recommendations • Ultrasound may be helpful in select patients:

• Patients with non-palpable testes (unilateral or bilateral) in which location may alter operative approach or avoid diagnostic laparoscopy (Abdulrahman, Vos, Adesanya)

• Evaluation of volume of contralateral testis may predict viability or increase accuracy of approach (Moriya, Berger)

(Level II-III evidence, Grade B recommendation)


What is the role of medical management?

Search Results


• 4 prospective • 3 retrospective

• Hormonal therapy investigated as • Medical therapy alone to induce descent • Adjuvant to surgery to improve fertility

Consensus Statements

•American Urological Association 2014 (http://www.auanet.org/guidelines/cryptorchidism-(published-2014))

Providers should not use hormonal therapy to induce testicular descent as evidence shows low response rates and lack of evidence for long-term efficacy.

•European Association of Urology 2016 (https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf) Endocrine treatment to achieve testicular descent is not recommended.

•Nordic consensus (Ritzen et al, 2007)

Hormonal treatment following orchiopexy has been proposed to have beneficial effects on sperm count but these findings need confirmation by other groups before being incorporated into clinical practice.

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What is the role of medical management in undescended testicle?

• Hormone therapy to induce descent of testes - Aycan et al. 2006 (Level II), Marchetti et al. 2012 (Level III), Pirgon

et al. 2009 (Level III) - Variable results from >65% successful descent into scrotum (Aycan)

to 25% (Marchetti) - May have side effects including increased left ventricular mass

(Pirgon)

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• Hormone therapy as an adjuvant to surgery to improve fertility - Spinelli et al. 2014 (Level II) – GnRHa effect on TAIn - Thorup et al. 2012 (Level III) – endocrine and histopathology of

testis in determining possible improvement of fertility after orchiopexy

- Jallouli et al. 2009 (Level II) – GnRH effect on fertility index - Hadziselimovic 2008 (Level II) – LH-RH Analogue (GnRH) effect on

sperm concentration after puberty

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• Hormone therapy as an adjuvant to surgery to improve fertility

• Additional clinical information may be required: - Ultrasound of testes to determine volume and calculate TAIn - Endocrine evaluation (serum levels of LH, FSH, and inhibin B) - Histopathologic evaluation of testes (bilateral biopsy of testes)

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• Recommendations

• Reserve consideration of hormonal therapy for select patients as it may improve fertility after orchiopexy

(Level II evidence, Grade C recommendation)


What is the appropriate timing of intervention and how is this affected by

other clinical factors?

Consensus Statements – Timing of Orchiopexy


<18 months

•European Association of Urology 2016 (https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf)

Treatment should be completed by 12 months or 18 months at the latest

•Nordic consensus (Ritzen et al, 2007)

6-12 months 22

Search results • 61 studies obtained from initial search • 22 added after further review • 16 suitable for inclusion

• 6 prospective • 10 retrospective

• Data on timing related to • Outcome

• Testicular growth • Germ cell development • [Sperm count/extraction and testicular cancer discussed elsewhere]

• Laterality • Associated gastroschisis/omphalocele • Concurrent inguinal hernia

• No data on timing related to • Other comorbid conditions; associated torsion; palpable/non-palpable; symptoms; ascending/retractile

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Timing of Orchiopexy – Testicular Growth

• 4 papers representing 3 patient populations • Prospective RCT • Prospective case series • Retrospective

• Kollin et al. 2006, 2007 • Kim et al. 2011 • Tseng et al. 2017

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• Kollin et al. 2006, 2007 • N = 155 boys with unilateral, UDT • Randomized at 6 months to surgery at 9 months or 3 years • Serial ultrasounds

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Testicular volume ratio (undescended/descended)


• Kim et al. 2011 • N = 108 • Divided by age at orchiopexy

• Group 1 = <2 years • Group 2 = ≥2 to <5 years • Group 3 = ≥5 years

• Serial ultrasounds

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• Tseng et al. 2017 • N = 134 • Divided by age at orchiopexy

• ≤ 1 year • >1 to ≤ 2 years • > 2 years

• Serial ultrasounds

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• Recommendation • Orchiopexy should be performed between 9 months and 2

years of age to optimize testicular growth (Level II-III evidence, Grade B recommendation)

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Timing of Orchiopexy – Germ Cell Development

• 3 papers • All prospective • 1 RCT

• Kollin et al. 2012 • Li et al. 2014 • Park et al. 2007

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•Kollin et al. 2012 • 228 biopsies from 225 boys randomized to orchiopexy at 9

months vs 3 years • Those who had surgery at 9 months

• Significantly larger numbers of germ cells and Sertoli cells • Greater diameter of seminiferous cords • Higher ratio of tubular/interstitial tissue

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• Li et al. 2014 • N = 20 • Age at surgery 5-24.5 mo • Testicular biopsy at OR

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• Park et al. 2007 • N = 65 • Mean age at OR 1.95 years • Testicular biopsy at OR • Divided by age at orchiopexy

• ≤1 year • 1-2 years • 2-4 years • >4 years

• 15 age-matched controls

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• Recommendation • Early orchiopexy should be performed to optimize germ cell

number and other markers of histologic normalcy in the cryptorchid testis

(Level II evidence, Grade B recommendation)

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Timing of Orchiopexy – Based on Laterality

• Yardley et al. 2012 • Retrospective

• 32 boys with abdominal wall defect and 46 UDT • Spontaneous descent in 10/17 R UDT = 58.8% • Spontaneous descent in 9/29 L UDT = 31.8%

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p=0.06

Timing of Orchiopexy – Based on Laterality

• Recommendation • Laterality should not determine the timing of orchiopexy

(Level IV evidence, Grade C recommendation)

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Timing of Orchiopexy – Concurrent Inguinal Hernia

• 1 paper • Retrospective

• Wright et al. 2017 • N = 43 • OR in first 6 months of age

• 26% required urgent/emergent repair • 67% required delayed orchiopexy • 18% overall atrophy rate

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67%

19% 9%

Timing of Orchiopexy – Concurrent Ipsilateral Inguinal Hernia

• Recommendation • Both procedures should be performed at the same time and

according to standard guidelines for inguinal hernia repair


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Timing of Orchiopexy – Gastroschisis and Omphalocele

• 3 papers • All retrospective case series

• Gastroschisis • 24 boys with 31 UDT (Hill et al. 2012) • 26 boys with 35 UDT (Yardley et al. 2012) • 7 boys with 9 UDT (Berger et al. 2006)

• Omphalocele • 6 boys wth 11 UDT (Yardley et al. 2012)

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Gastroschisis Omphalocele

Boys (n) 57 6

Undescended testes (n) 75 11

Spontaneous descent 36/75 = 48% 1/11 = 9.1%

Orchiopexy 22/66 = 33% 5/8 = 62.5%


• Recommendation • The decision regarding timing of orchiopexy in gastroschisis

and omphalocele should follow standard orchiopexy guidelines


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What is the evidence supporting type of operative intervention?

Search Results • 179 studies obtained from initial search • 18 added after further review • 98 suitable for inclusion

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Procedure Articles Reviewed Prospective Retrospective

Open Inguinal 27 6 21

Single Scrotal Incision 17 2 15

Single Stage Laparoscopy 42 5 37

1-Stage Fowler Stevens 18 1 17

2-Stage Fowler Stevens 39 6 33

No Closure of Patent Processus 19 3 16

Pathologic evaluation of Nubbin 14 0 14

Consensus Statements – Choice of Operation for Inguinal Testicle


Standard two incision (inguinal, scrotal) and single scrotal incision orchiopexy are both recommended

•European Association of Urology 2016 (https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf) Standard two incision (inguinal, scrotal) and single scrotal incision orchiopexy are both recommended

• Nordic consensus (Ritzen et al, 2007) Standard two incision (inguinal, scrotal) and single scrotal incision orchiopexy are both recommended 43




Single scrotal incision orchiopexy (SSIO)

Ref: Endo M, 2011

Inguinal orchiopexy vs. SSIO

Open Inguinal SSIO

N 640 2130

Atrophy, % (95% CI) 0.31 (0.12, 0.74) 0.23 (0.00, 0.43)

Retraction, % (95% CI) 1.72 (0.71, 2.73) 1.50 (1.45, 1.55)

One RCT showed no difference in atrophy or retraction (Eltayeb 2014)

Inguinal orchiopexy vs. SSIO

Study N SSIO time (minutes)

Inguinal time (minutes)

p

Eltayeb (prospective) 35 18 25 <0.001

Takahashi (retrospective) 49 47 67 <0.0001

Al-Mandil (retrospective) 56 34 64 0.002

• Length of Operation

Inguinal orchiopexy vs. SSIO • Recommendations

• SSIO may be associated with lower incidence of atrophy and retraction (Level II-III Evidence, Grade C Recommendation)

• SSIO is associated with a lower operative time (Level II Evidence, Grade B Recommendation)

Consensus Statements – Choice of Operation for Non-palpable Testicle

• American Urological Association 2014 (http://www.auanet.org/guidelines/cryptorchidism-(published-2014))

Perform examination under anesthesia to reassess for palpability of testes. If nonpalpable, surgical exploration (open or laparoscopy) and, if indicated, abdominal orchidopexy should be performed.

• European Association of Urology 2016 (https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf)

Thorough re-examination under anaesthesia; the easiest and most accurate way to locate an intra-abdominal testis is diagnostic laparoscopy

• Nordic consensus (Ritzen et al, 2007)

Diagnostic laparoscopy through an umbilical port to determine surgical approach. The operative procedure is chosen according to pathoanatomical findings related to the testis and vessels and to the surgeons preferences.

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Abdominal Testis Open Inguinal vs. Primary Laparoscopic

Open Inguinal Primary Laparoscopic

N 313 1434

Atrophy, % (95% CI) 4.47 (2.18, 6.76) 4.15 (3.16, 5.16)

Retraction, % (95% CI) 1.60 (0.21, 2.99) 3.05 (2.19, 3.91)

Factors Affecting Retraction

• Increased incidence of retraction with inguinal orchiopexy in children age greater than 19 months (Sfoungaris 2012)

• For abdominal testis (laparosopic orchiopexy) • Distance from the internal ring, ability to reach contralateral ring

did NOT CONSISTENTLY predict incidence of long-term retraction (Yucel 2007)

• Patient age was an independent risk factor for retraction (Bagga 2013)

Abdominal Testis Open Inguinal vs. Primary Laparoscopic

• Recommendations • Either open or laparoscopic orchiopexy for abdominal

testis is appropriate based upon surgeon’s preference • Perform orchiopexy at 6 to 12 months to achieve a lower

rate of testicular retraction (Level II Evidence, Grade B Recommendation)

Consensus Statements – Choice between one or two stage Fowler Stephens Orchiopexy


The decision to perform a one-stage or two-stage FS orchiopexy is left to the discretion for the surgeon based on the location of the testis, associated vascular supply to the testis, and the anatomy of the peritesticular structures.


The two stage approach may result in less testicular atrophy and better testicular mobility.

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Fowler-Stephens Orchiopexy

1-Stage 2-Stage

N 147 1434

Atrophy, % (95% CI) 14.4 (9.34,19.5) 9.17 (7.49, 10.8)

Retraction, % (95% CI) 3.72 (1.14, 6.30) 2.41 (1.55, 3.28)

Non-comparative data – groups had differing clinical presentations


• One RCT compared One-stage and Two-Stage • Mean age – 21.6 months • Compared Testicular volume before and six months after

surgery

Pre-op Volume Post-op Volume P

1 – stage 0.53 0.50 0.310

2 – stage 0.56 0.54 0.333

(Wang CY. Asian J Surg 2018)


• Recommendations • Both One-stage and Two-stage procedures have similar

rates of retraction therefore choice of approach is left to the surgeon

• One stage procedures may have a higher rate of testicular atrophy (Level II-III Evidence, Grade B Recommendation)

Closure of Patent Processus Vaginalis

• Total Patients without hernia repair: 1677 (19 studies) • Median follow up: 18.75 months • No hernias reported • Ceccanti noted increased incidence of testicular

retraction with closure • 4.3% vs. 1.7% (P = 0.42)

Closure of Patent Processus Vaginalis

• Recommendation • Routine closure of the patent processus vaginalis during

orchiopexy is not indicated (Level II Evidence, Grade B Recommendation)

Resection of Nubbin

• Total units with pathologic evaluation: 329 • Findings

• Calcification 25.4 % • Hemosiderin 23.5% • Seminiferous tubules 6.67%

Resection of Nubbin

• Recommendation • During exploration for non-palpable testicle, a nubbin

should be resected if found (Level II Evidence, Grade A Recommendation)


What are the long term outcomes of orchiopexy?

5. What are the long term outcomes after orchiopexy?

a. What is the failure/recurrence rate? b. Is testicular mass/size affected by orchiopexy? c. What is the effect on fertility? d. What is the risk of testicular cancer?

Search Results


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Sub-question Articles Reviewed

Prospective Retrospective Other

Failure/recurrence rate 8 1 5 2

Testicular mass/size 24 9 7 4 + 4rct

Effect on fertility 18 10 4 4

Risk of Testicular Cancer 10 2 2 6

Search Results


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Failure rate is less than 4%. Monitor for retractile testes and for testicular ascent at every well child check


Overall success rates reported to be 88%-100% 64

Consensus Statements – What is the failure/recurrence rate?





5a -What is the failure/recurrence rate?

Title Level of evidence

Findings

McIntosh, et al. 2013

IV failure rate = 1.6% (uni 1.5%, bil 1.9%)

Alagaratnam, et al. 2014

IV 8.8% ascent rate

Lopes, et al. 2016 IV 1.8% of patients required reoperation

Sijsterman, et al. 2009

II 88.7% unilateral, 88.9% bilateral testes were found to be low scrotal in position

Vikraman, et al. 2017

IV 3.4% of 25,984 orchiopexies required revision

Attalla, et al. 2017 IV 98% success rate of inguinal orchiopexies

5a -What is the failure/recurrence rate?

• Recommendation • Annual testicular exams should be performed until

puberty to assess for retractile or ascending testes that may require operative fixation.

(Level II-IV Evidence, Grade C Recommendation)

Search Results


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Consensus Statements – Is testicular mass/size affected by orchiopexy?


Atrophy rates are less than 2% •European Association of Urology 2016 (https://uroweb.org/wp-content/uploads/EAU-Guidelines-Paediatric-Urology-2016-1.pdf)

Atrophy rates ~1.8% for inguinal orchiopexy, 28.1% for one- stage F-S, and 8.2% for two-stage F-S. 68





5b - Is testicular mass/size affected by orchiopexy? • Jedrzejewski, et al. The role

of ultrasound in the management of undescended testes before and after orchidopexy – an update

• 128 boys with UDT • Annual ultrasound for 3 years • Testicular volume ratio

(operated to scrotal testes volume) was noted to increase when compared to the contralateral testes. Catch up growth was noted to increase overtime

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5b - Is testicular mass/size affected by orchiopexy?

5b - Is testicular mass/size affected by orchiopexy?

• Carson, et al. Undescended testes: does age at orchiopexy affect survival of the testes?

• Retrospective review, 349 testicles, primary outcome = testicular survival without atrophy

• 7.7% atrophy rate • Odds of atrophy were 15.6 times higher for intra-

abdominal testes • Age was not associated with increased atrophy

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5b – Is testicular mass/size affected by orchiopexy?

• Recommendation • Operation does not always reduce volume but is a known

complication (atrophy – reported in less than 2% to as high as 33% in two-stage F-S)

• UDT are smaller than non-cryptorchid controls and contralateral testes in most cases

• Testicular size appears to benefit from earlier operation allowing for catch up growth, increased atrophy risk has not been shown in younger patients

(Level I-IV Evidence, Grade C Recommendation)

Search Results


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Consensus Statements – Effects on fertility?


A 6-fold increase in infertility for bilateral UDT, unilateral infertility is similar to controls, pre-treatment testes location does not affect paternity/sperm count/hormones, biopsy of bilateral UDT may help predict fertility


Medical therapy may increase fertility, biopsy of bilateral UDT may be indicated

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5c - What is the effect on fertility?

•Feyles, et al. Improved Sperm Count and Motility in Young Men Surgically Treated for Cryptorchidism in the First Year of Life

• 51 young men (age 18-26 years) with unilateral or bilateral undescended testicles underwent operation in the 1st or 2nd year of life

• Total Sperm Count and Motility were higher in those patients operated on in the 1st year of life

• Not affected by pre-op hormonal therapy, position of the testes, or bilateral disease

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Feyles, et al


•Hadeziselimovic, et al. Infertility in cryptorchidism is linked to the stage of germ cell development at orchidopexy

• Cryptorchid boys lacking Ad spermatogonia will develop infertility despite

successful orchiopexy in childhood

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Hadeziselimovic, et al

5c - What is the effect on fertility? • Bilius, et al. Incidence of High

Infertility Risk among Unilateral Cryptorchid Boys

• Cryptorchid boys lacking Ad

spermatogonia will develop infertility despite successful orchiopexy in childhood

• 2000-2001: • mean age of surgery = 5.3 years • No Ad spermatogonia were found

in 44% of samples • 2012-2013

• mean age of surgery = 4.1 years • No Ad spermatogonia were found

in 50% of samples

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• Canavese, et al. Sperm Count of Young Men Surgically Treated for Cryptorchidism in the First and Second Year of Life: Fertility is Better in Children Treated at a Younger Age.

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5c – What is the effect on fertility?

• Recommendations • To improve fertility perform orchiopexy between 6 and 12

months • Counsel patients and families that successful orchiopexy

may not mitigate infertility in all patients (Level I-III Evidence, Grade B Recommendation)

Search Results


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Consensus Statements – Risk of testicular cancer?


Orchiopexy before puberty does decrease the risk of testicular cancer Close follow up and monthly self exam is indicated in boys with a history of cryptorchidism


Failed or delayed orchiopexy may increase risk of malignancy, for unilateral UDT in post-pubertal boys or older, orchiectomy should be considered if the contralateral testes is normal 83




What is the risk of testicular cancer?

Timing of Orchiopexy – Risk of Testicular Cancer

• 1 paper • Retrospective, population-based study

• Pettersson et al. 2007 • N = 16,983 • OR between 1964 and 1999 • Mean age of OR 8.6±3.5 years

• Only 4.2% were <2 years of age • 56 cases of testicular cancer

• <13 years = RR 2.23 (95% CI 1.58 – 3.06) • >13 years = RR 5.40 (95% CI 3.20 – 8.53)

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What is the risk of testicular cancer?

• Recommendations • The risk of testicular cancer in cryptorchidism can be

mitigated by prepubertal orchiopexy but is not brought to the level of normal controls

• The risk of malignant degeneration in testicular remnants exists; if in OR, perform nubbinectomy.

(Level II evidence, Grade B Recommendation)

Questions?

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