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ava ilable at www.sciencedirect.com

journa l homepage: euoncology.europeanurology.com

Management of Sporadic Renal : A Systematic

Review of Available Evidence to Guide Recommendations

from the European Association of Renal Cell

Carcinoma Guidelines Panel

a, b c d e

Sergio Ferna´ndez-Pello *, Milan Hora , Teele Kuusk , Rana Tahbaz , Saeed Dabestani ,

f g h i

Yasmin Abu-Ghanem , Laurence Albiges , Rachel H. Giles , Fabian Hofmann ,

j k l m

Markus A. Kuczyk , Thomas B. Lam , Lorenzo Marconi , Axel S. Merseburger ,

n o p q r,s

Thomas Powles , Michael Staehler , Alessandro Volpe , Bo¨rje Ljungberg , Axel Bex , t

Karim Bensalah

a b

Department of Urology, Cabueñes University Hospital, Gijón, Spain; Department of Urology, University Hospital Plzen and Faculty of Medicine in Plzen, Charles

c d

Universtity, Czech Republic; Department of Urology, Royal Free Hospital, Pond Street, London, UK; Department of Urology, University Hospital Hamburg

e f

Eppendorf, Hamburg, Germany; Department of Clinical Sciences Lund, Skåne University Hospital, Lund, Sweden; Department of Urology, Chaim Sheba Medical

g h

Center, Tel-Hashomer, Ramat-Gan, Israel; Department of Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France; Department of

i

and , Patient Advocate International Cancer Coalition (IKCC), University Medical Center Utrecht, Utrecht, The Netherlands; Department of

j k

Urology, Sunderby Hospital, Sunderby, Sweden; Department of Urology and Urologic , Hannover Medical School, Hannover, Germany; Academic

l m

Urology Unit, University of Aberdeen, Aberdeen, UK; Department of Urology, Coimbra University Hospital, Coimbra, Portugal; Department of Urology,

n

University Hospital Schleswig-Holstein, Lübeck, Germany; The Royal Free NHS Trust and Barts Cancer Institute, Queen Mary University of London, London, UK;

o p

Department of Urology, Ludwig-Maximilians University, Munich, Germany; Division of Urology, Maggiore della Carità Hospital, University of Eastern Piedmont,

q r

Novara, Italy; Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden; The Royal Free London NHS

s

Foundation Trust and UCL Division of Surgery and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van

t

Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Urology, University of Rennes, Rennes, France

Article info Abstract

Article history: Context: Little is known about the natural history of sporadic angiomyolipomas

Accepted April 11, 2019 (AMLs); there is uncertainty regarding the indications of treatment and treatment

options.

Associate Editor:

Objective: To evaluate the indications, effectiveness, harms, and follow-up of

Gianluca Giannarini

different management modalities for sporadic AML to provide guidance for clinical practice.

Keywords:

Evidence acquisition: A systematic review of the literature was undertaken, incor-

Kidney

porating Medline, Embase, and the Cochrane Library (from 1 January 1990 to

Angiomyolipoma

30 June 2017), in accordance with Preferred Reporting Items for Systematic

Active surveillance

Reviews and Meta-Analyses guidelines. No restriction on study design was im-

Selective arterial embolisation

posed. Patients with sporadic AML were included. The main interventions included

Nephron-sparing surgery

active surveillance, surgery (nephron-sparing surgery and radical ),

Systematic review selective arterial embolisation, and percutaneous or laparoscopic thermal ablations

(radiofrequency, microwaves, or cryoablation). The outcomes included indications

* Corresponding author. Department of Urology, Cabuen˜es University Hospital, Calle de los Prados

395, Gijo´ n 33394, Spain. Tel. +34 985 185 000; Fax: +34 985 185 028.

E-mail address: [email protected] (S. Ferna´ ndez-Pello).

https://doi.org/10.1016/j.euo.2019.04.005

2588-9311/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

2 E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X

for active treatment, AML growth rate, AML recurrence rate, risk of bleeding, post-

treatment renal function, adverse events of treatments, and modalities of follow-

up. Risk of bias assessment was performed using standard Cochrane methods.

Evidence synthesis: Among 2704 articles identified, 43 were eligible for inclusion

(zero randomised controlled trials, nine nonrandomised comparative retrospective

studies, and 34 single-arm case series). Most studies were retrospective and

uncontrolled, and had a moderate to high risk of bias.

Conclusions: In active surveillance series, spontaneous bleeding was reported in 2%

of patients and active treatment was undertaken in 5%. Active surveillance is the

most chosen option in 48% of the cases, followed by surgery in 31% and selective

arterial embolisation in 17% of the cases. Selective arterial embolisation appeared to

reduce AML volume but required secondary treatment in 30% of the cases. Surgery

(particularly nephron-sparing surgery) was the most effective treatment in terms of

recurrence and need for secondary procedures. Thermal ablation was an infrequent

option. The association between AML size and the risk of bleeding remained unclear;

as such the traditional 4-cm cut-off should not per se trigger active treatment. In

spite of the limitations and uncertainties relating to the evidence base, the findings

may be used to guide and inform clinical practice, until more robust data emerge.

Patient summary: Sporadic (AML) is a benign tumour of the

kidney consisting of a mixture of blood vessels, fat, and muscle. Large tumours

may have a risk of spontaneous bleeding. However, the size beyond which these

tumours need to be treated remains unclear. Most small AMLs can be monitored

without any active treatment. For those who need treatment, options include

surgical removal of the tumour or stopping its blood supply (selective embolisation).

Surgery has a lower recurrence rate and lower need for a repeat surgical procedure.

© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1. Introduction nephron-sparing surgery (NSS) [10], although total

nephrectomy may be necessary for large tumours [2];

Renal angiomyolipoma (AML) is a benign mesenchymal and (4) thermal ablations, which are less frequently used

tumour composed of fat, smooth muscle, and blood vessels. [6,7,11] but can be offered in selected patients.

AMLs belong to the group of perivascular epithelioid cell There is uncertainty regarding how best to manage

tumours [1]. Most AMLs (approximately 80%) are sporadic; patients with AML, and how the different treatment

in the remaining 20%, AMLs are diagnosed in patients with options compare with each other in terms of clinical

tuberous sclerosis (TS) [2]. There are differences regarding effectiveness and harms. Moreover, very little is known

the clinical presentation and management of sporadic and about the natural evolution of AMLs and the risk of

TS AMLs. TS AMLs occur at a younger age, can grow fast, and bleeding. A 4-cm cut-off has traditionally been proposed to

are often bilateral and multilocular. Sporadic AMLs occur trigger active treatment. This 4-cm cut-off is nevertheless

between 50 and 60 yr of age, are more common in women, quite arbitrary and was based on the results of a literature

are frequently unilateral, and have a slow growth rate review in 1986 [12]; however, some recent series suggest

[3,4]. AMLs can be diagnosed on imaging studies when that the risk of bleeding is increased only in much larger

there is evidence of fatty tissue inside the tumour. is tumours [13,14].

rarely needed. However, imaging techniques cannot differ- This systematic review (SR) was undertaken by the

entiate benign fat-poor AMLs from potentially malignant European Association of Urology (EAU) Renal Cell Carcino-

epithelioid AMLs [5,6]. ma (RCC) Guidelines Panel to clarify the evidence available

The main complication of AMLs is spontaneous bleeding on natural evolution, the risk of complications, and

in the retroperitoneum or into the collecting system, which management options of sporadic AMLs. The findings will

can be life threatening [7]. The risk of bleeding is related to be used to formulate guideline recommendations regarding

the angiogenic component of the tumour that includes the management of sporadic AML in our 2019 guidelines

irregular blood vessels [7]. Little is known about the risk (Supplementary material).

factors of bleeding, but it is believed to increase with

tumour size [2]. 2. Evidence acquisition

There are several options for AML management: (1)

active surveillance (AS) based on regular imaging; (2) 2.1. Search strategy and screening of studies

selective arterial embolisation (SAE) that can be used to

devascularise AMLs, which may minimise further risk of This review was undertaken by the EAU RCC Guidelines

bleeding [8,9]; (3) surgical removal, preferably by Panel that includes urologists, oncologists, pathologists,

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

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radiologists, and patient representatives. The review was homogeneity, we considered exclusively series comprising

performed according to Preferred Reporting Items for only sporadic AMLs or with a minimum of 70% of sporadic

Systematic Reviews and Meta-Analyses (PRISMA) guide- AMLs.

lines [15]. The search was conducted in accordance with the

principles outlined in the Cochrane Handbook for System- 2.4. Types of interventions included

atic Reviews of Interventions [16]. Studies were identified

by searching electronic databases and relevant websites. The interventions included were the following: surgery

Highly sensitive electronic searches were conducted to (NSS and radical nephrectomy), SAE, percutaneous or

identify published and on-going comparative studies of laparoscopic thermal ablations (radiofrequency, micro-

AML treatment. Searches were limited to studies published waves, or cryoablation), and AS.

between 1 January 1990 and 30 June 2017, with no language

restriction. The search was complemented by additional 2.5. Types of outcome measures included

sources, including relevant SRs and reference lists of

included studies, which were hand searched to identify The outcomes were as follows:

additional relevant studies.

The searched databases were MEDLINE (from 1946 to 1. Duration and frequency of AS

present), MEDLINE In-Process (from 1946 to present), 2. Indications for active treatment

EMBASE (from 1974 to 11 May 2017), EBM Reviews— 3. Incidence of haemorrhage and active treatment during

Cochrane Central Register of Controlled Trials (April 2017), AS

and EBM Reviews—Cochrane Database of Systematic 4. Success rate of active treatments

Reviews (from 2005 to 10 May 2017). SRs and other 5. Incidence of retreatment after active treatment

background information were identified by searching the 6. Renal function outcome after treatment when available

Cochrane Database of Systematic Reviews (the Cochrane 7. Adverse events of treatments

Library, 2015). Additionally, clinicaltrials.gov and the World

Health Organization (WHO) International Clinical Trials 2.6. Data extraction

Registry were searched to identify on-going trials.

The search terms included the following: kidney/renal A data extraction form was developed a priori to collect

hemangiomyolipoma, and angiomyolipoma or angiomyo adj2 information on study design, participants, interventions,

lipoma or angio adj2 myolipoma or hemangiomyolipoma. Full outcome measures, and risk of bias (RoB) or confounders.

details of the protocol, search strategies, and websites Two reviewers (S.F.P. and R.T.) independently extracted data

consulted are described in the Supplementary material. related to prespecified outcomes.

Two reviewers (S.F.P. and R.T.) screened all abstracts and

full-text articles independently. Abstract screening dis- 2.7. Assessment of RoB and confounders

agreement was resolved by discussion, and when no

agreement was reached, the manuscript was considered RoB in nonrandomised comparative studies was assessed

doubtful and subsequently included for full-text screening. using a modified Cochrane tool. This is a pragmatic

In case of ambiguous studies at full-text screening, the approach from the methodological literature designed to

–

decision on final study inclusion was taken by reviewers report RoB in nonrandomised studies [17 19]. A list of four

with the help of final input by one of the arbitrators (K.B. potential confounders was defined a priori by the panel

and M.H.). group: AML size, emergency cases, TS syndrome, and AML-

related symptoms. Overall judgement regarding each

2.2. Types of studies confounder was based on whether it was measured or

not, it was balanced across groups, and any statistical

Randomised controlled trials (RCTs), quasi-RCTs, and adjustment was made.

nonrandomised comparative studies, with a minimum of RoB in case series was assessed using a pragmatic approach

10 patients and no language restrictions, were eligible for based on external validity (whether study participants were

inclusion. Studies with no comparative elements (ie, single- selected consecutively, application of an a priori protocol, how

arm case series) with 10 patients were also included. attrition bias was dealt with, and whether outcomes were

Studies with mixed populations (ie, sporadic and TS AMLs) properly addressed and measured) [20,21].

were included if the results were reported separately for the

sporadic AML subgroup. Studies in which subgroups were 2.8. Data analysis

not reported separately would still be included if the



sporadic AML subgroup represented 70% of the cohort. Descriptive statistics were used to summarise baseline

characteristics. Owing to the anticipated clinical heteroge-

2.3. Types of participants included neity and the majority of studies being nonrandomised in

design, a narrative (qualitative) synthesis was planned. A

The study population consisted of patients diagnosed with quantitative synthesis (ie, meta-analysis) could not be

sporadic AML with available follow-up (FU) after any performed because of the low level of evidence of the

treatment, including surveillance. In an effort to improve reported results.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

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3.2. Characteristics of included studies

3. Evidence synthesis

Synthesis of the evidence and description of the results

3.1. Quantity of evidence identified

were as follows:

A total of 2704 articles were identified by the literature

search. Of these, 186 studies were eligible for full-text 1. One arm surveillance: n = 4 studies, 899 patients

screening, and after removing duplicates, 163 full-text 2. One arm ablation: n = 5 studies, 68 patients

articles were reviewed. Forty-three studies including 3. One arm surgery (surgery with or without previous SAE):

2377 patients met the inclusion criteria and were evaluated n = 13 studies, 583 patients

for evidence synthesis. No RCT was included. There were no 4. One arm SAE: n = 12 studies, 321 patients

direct comparative studies, only unbalanced comparative 5. Two arms comparative (surgery vs surveillance):

results of different treatments in the same series. Fig. 1 n = 3 studies, 111 patients

represents the PRISMA flow diagram outlining the study 6. Two arms comparative (surgery vs SAE): n = 4 studies,

selection process. 248 patients

Fig. 1 – AML systematic review PRISMA flow diagram. AML = angiomyolipoma; LAM = lymphangioleiomyomatosis; PRISMA = Preferred Reporting Items

for Systematic Reviews and Meta-Analyses; RCC = renal cell carcinoma; SAE = selective arterial embolisation; Surg = surgery; Surv = active surveillance;

a

TSC = tuberous sclerosis complex. Small arms, risk of high heterogeneity on outcomes report.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

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7. Three arms (surgery, surveillance, and SAE): Table 2 represents the RoB summary for the 33 case

n = 2 studies, 147 patients series. In general, these studies were at a high RoB

regarding the selection and detection of patients, and they

The length of FU was not equally reported across studies, were at a low RoB in terms of FU/change of treatment

but when available median FU varied from 4.5 to 96 mo reporting and selective or proper outcome measurement

(37 mo on average). The vast majority of studies were reporting.

monocentric. Twelve studies exclusively contained sporadic

AMLs, 12 had >90% sporadic AMLs, 12 reported 70–90% of 3.4. Comparison of intervention results

sporadic AMLs, whilst seven did not clearly mention the

proportions but met the inclusion criteria. The summary of demographic findings of all included

studies based on different treatment modalities are out-

3.3. RoB assessment of the included studies lined in Table 3. Patients were mostly in the 4th and 5th

decades of their life, and there was a clear predominance of

Overall, the RoB across studies was moderate to high. All female gender (ratio of 4:1). AML size was reported in an

studies had a retrospective and nonrandomised design, inconsistent way, and there was a trend towards choosing

except for two prospective studies. AS for small asymptomatic AMLs and active treatment for

Table 1 presents the RoB summary and confounders for larger symptomatic AMLs. Many studies relied on the 4-cm

nonrandomized comparative studies. All studies had a high cut-off to trigger active treatment.

risk of selection, performance, and detection biases. The risks

of attrition and reporting bias were low, and confounders were 3.4.1. Duration and frequency of AML FU

reported in the majority of studies with a trend towards bigger The FU results of different treatment modalities are

size, emergency situations, and AML-related symptoms. summarised in Table 4.

Table 1 – Risk of bias and confounder assessment for nonrandomised comparative studies (n = 9)

Selection bias Performance bias Detection Attrition Reporting Confounding biases 1, 2, 3, and 4

bias bias bias

Random Allocation Blinding Blinding Blinded Incomplete Selective Size Emergency Pure Symptoms

sequence concealment of patients of personnel outcome outcome outcome sporadic generation assessment reporting reporting AML

Amano (2002)[29]

De Luca (1999)[30]

Delhorme (2017)[31]

Huyghe (2009)[32]

Koo (2010)[33]

Faddegon (2001)[34]

Lee (2009)[35]

Mues (2010) [4]

Seyam (2008)[36]

AML = angiomyolipoma; SAE = selective arterial embolisation.

Green indicates low risk, red indicates high risk, and yellow indicates unclear risk.

Confounders:

1. Is the size equally distributed?

2. Is the emergently treated AML equally distributed?

3. Is the pure sporadic AML equally distributed?

4. Are the symptoms equally distributed?

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

6 E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X

Table 2 – Risk of bias assessment for case series (n = 33)

Selection bias Detection bias Attrition bias Reporting bias

Consecutive A priori Loss of Selective Outcome

patients? protocol? FU accounted outcome appropriately

for? Change of reporting measured?

treatment accounted for?

Surveillance

Bhatt (2016) [3]

Chan (2016) [22]

Mclean (2014) [26]

Ouzaid (2014) [14]

Ablative

Han (2015)[37]

Castle (2012) [11]

Guo (2009)[38]

Makki (2016)[39]

Swanson (2012)[40]

Surgery

Lane (2008) [27]

Boorjian (2007)[41]

Heidenreich (2002)[42]

Minervini (2007)[43]

Golan (2017)[44]

Liu (2016)[45]

Wang (2017) [28]

Yip (2000) [25]

Qin (2017) [23]

Lin (2016)[46]

Ng (2016)[47]

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

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Table 2 (Continued )

Selection bias Detection bias Attrition bias Reporting bias

Consecutive A priori Loss of Selective Outcome

patients? protocol? FU accounted outcome appropriately

for? Change of reporting measured?

treatment accounted for?

Msezane (2010)[48]

SAE

Wang (2017) [28]

Bardin (2017)[49]

Chan (2011)[50]

Chick (2010)[51]

Duan (2016)[52]

Ramon (2009) [7]

Sheth (2016)[53]

Takebayashi (2009)[54]

Urbano (2017)[55]

Tso (2005)[56]

Tillou (2010)[57]

Chatziioannou (2012) [24]

FU = follow-up; SAE = selective arterial embolisation.

Green indicates low risk, red indicates high risk, and yellow indicates unclear risk.

In AS patients, the length of FU varied from 21 to 49 mo. similar to surgery groups, with imaging control every 3–6

Imaging modalities were mostly ultrasound (US) and mo during the 1st year and then annually.

abdominal computed tomography (CT). There was no The ablative series had a mean FU ranging from 6 to

standardised FU protocol throughout the studies. One 25 mo. The initial FU was more frequent with imaging at 3 d,

based its FU on AML size [22]. All the others relied on an 1 mo, 6 mo, and yearly thereafter.

annual schedule, except for the 1st year when patients were

controlled twice. 3.4.2. Indications for active treatment

The mean FU after surgical treatment varied from 8 to The summary of indications for active treatment is shown in

96 mo. Likewise, the imaging FU was mostly based on US Table 5. Indications for active treatment in the majority of

and CT. The frequency was increased during the 1st year, the studies were as follows: bleeding (spontaneous rupture



and then patients were followed annually. or haematuria), larger size (generally 4 cm), and presence

In SAE series, the mean FU varied from 15 to 85 mo. The of symptoms (most commonly pain). In AS studies, the

imaging also relied on US and CT. Two studies alternated CT growth of AML was constantly considered as a criterion for

and magnetic resonance imaging. The frequency was active treatment. On the contrary, AML growth was not

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

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EUO-204; No. of Pages 16

8 E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X

Table 3 – Demographic summary of included studies

Patients Age –average Gender % Sporadic AML Size average (cm) Size range Size other reports Asymptomatic Symptomatic

Active surveillance 899 49.6–59 155 M/599 F 92–96.7 1.124 NR 615 <4 cm 498 69

(1 arm) Min NR 97 >4 cm

Max NR

Surgery 583 40.75–57 135 M/448 F 85–100 6.73 0.3–24.0 33 <4 cm 203 199

(1 arm) Min 2 108 >4 cm

Max 13.3

SAE 321 37–59 79 M/251 F 75–100 8.98 2.0–24.4 112 176

(1 arm) Min 6.68

Max 12.7

Ablative 68 49.2–67 12 M/33 F 100 2.5 1.0–5.5 5 9

(1 arm) Min 1.5

Max 3.4

Active surveillance 111 46.7–56 32 M/79 F 90–97.14 6.75 0.3–30.0 39 <5 cm 59 29

(2 arms) Min 1.5 14 >5 cm

Surgery Max 10 7 <5 cm

(2 arms) 13 >5 cm

SAE 248 45.2–53 28 M/111 F 86–90 6.12 1.2–14.3 5.5 cm SAE 122 55

(2 arms) Min 3.70

Surgery Max 9.40

(2 arms)

4.4 cm Surg

3-arm AS 147 35–59 43 M/134 F 73–75 6.78 0.3–21.0 3 cm AS 89 58

3-arm SAE Min 1.70 9.5 cm SAE

3-arm Surg. Max 11.0 3.8 cm Surg.

AML = angiomyolipoma; F = female; M = male; NR = not reported; SAE = selective arterial embolisation; Surg. = surgery.

considered to trigger active treatment, not even in two- and three because of symptoms. When a secondary treatment

three-arm comparative series. Cancer suspicion on imaging was required, SAE was used in 69 procedures and surgery in

and patient’s preference were also considered an indication 18 procedures. Renal function changes were reported in four

for active treatment in the majority of the studies. studies with various measurements, but renal function

The 4-cm cut-off was considered to trigger active alteration did not seem clinically relevant (Table 6).

treatment in 21%, 41%, and 82% of AS, surgery, and SAE Ablative series comprised patients treated by micro-

patients, respectively. In AS series, the 4-cm cut-off was wave, radiofrequency, and cryotherapy. There was no

retained only in one study (187 out of 899 patients). In reported recurrence. Resolution of symptoms was complete

surgical series, the 4-cm cut-off was taken into account in in the single study that reported it. Secondary treatments

six of 13 studies and concerned 238/583 patients. In SAE were inconsistently reported, and only one patient required

series, the 4-cm of cut-off was applied in eight of nine another thermal ablation for a reason that was not specified.

studies (264/321 patients). There was no change in renal function after treatment

(Table 6).

3.4.3. Outcomes in active treatment groups

Summary of outcomes in active treatment groups are 3.4.4. Outcomes in AS groups

outlined in Table 6. Findings regarding the outcomes are summarised in Table 7.

In all surgical series (except for two without treatment In one-arm AS series, there were a total of 97 patients

modality specifications), there was clear predominance of (11%) with growing AMLs. AML growth was reported in two

NSS. Two NSS series reported the use of SAE before surgery. ways across studies: (1) proportion of growing AMLs

In the majority of the series, there was no recurrence, but (number of growing AMLs/number of total AMLs) and (2)

three publications reported a recurrence rate between 4% annual growth rate (cm/yr). Global proportions of growing

and 15%. Improvement or complete remission of symptoms AMLs ranged from 3% to 20%. Two studies reported annual

was seen in all five series that reported it. Secondary growth rates of 0.02 and 0.01 cm/yr. Other studies reported

treatment after surgery was rare (5/583, 0.85%). Renal growth rates according to AML size: AMLs <2 cm had a

function measurement and reporting were inconsistent growth rate of 0.07 cm/yr, AMLs >2– < 4 cm had a growth

(the results are summarised in Table 6). rate of 0.1 cm/yr, and AMLs >4 cm had a growth rate of

In SAE series, there was a predominant use of polyvinyl 0.92 cm/yr. Twenty patients (2.2%) had spontaneous bleed-

alcohol and coil particles to perform the procedures. The ing or haematuria, and 51 patients (5.7%) required active

recurrence rate varied from 4% to 39%. Two series reported treatment (77% SAE, 19% surgery, and 4% radiofrequency

neither recurrence nor tumour growth. Symptom outcomes ablation).

were reported in eight series including 273 patients and

improvement varied from 41% to 100%. Eighty-four patients 3.4.5. Adverse events in active treatment groups

(30.7%) required secondary AML treatment: 39 for unspeci- Adverse events of active treatment according to the Clavien-

fied reasons, 18 for haemorrhage, 24 for AML growth, and Dindo classification are highlighted in Table 8.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

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Table 4 – Duration, frequency, and imaging modalities performed throughout the different studies

FU Available Frequency Modality Duration, mo ((range))

Active surv. 1 arm

Bhatt (2016) [3] Yes Not reported Not reported 43 (14–144)

Chan (2016) [22] Yes <2 cm: no FU; 2–3 cm: US 5 yr; 3– US 30 (8.66–51.34)

4 cm: US 2 yr; >4 cm: consider surgery

MacLean (2014) [26] Yes 12 mo US and CT 21.8 (6–85.3)

Ouzaid (2014) [14] Yes 6 mo, 6 mo, yearly CT 49 (9–89)

Surgery 1 arm

Lane (2008) [27] Yes Not reported CT 40.8 (0–288)

Boorjian (2007) Yes Not reported Not reported 96 (1–372)

Heidenreich (2002) Yes 3 mo after surgery CT 58 (3–114)

Minervini (2007) Yes 3 mo after surgery, 6 mo, 6 mo, 6 mo, CT/US alternative 56 (10–120)

6 mo, yearly

Golan (2017) Yes Not reported Not reported 8 (1–15)

Lui (2016) Yes 3 mo after surgery Not reported 23.1 (17.7–18.5)

a

Wang (2017) [28] Yes 3 mo, 6 mo CT 8.2 (4–20.5)

Yip (2000) [25] Yes Not reported CT 26 (1–80)

a

Qin (2017) [23] Yes 3 mo, 3 mo, 3 mo, 3 mo, yearly CT Not reported

Lin (2016) Yes 3 mo, 6 mo, 1 yr, yearly US, if abnormality CT 40 (30.5–61.5)

Ng (2016) Not reported – – –

Msezane (2010) Yes Not reported Not reported 29 (SD 20)

Zhang (2016) Yes Not reported Not reported 19.5

SAE 1 arm

Wang (2017) [28] Yes Not reported Not reported 35.9

Bardin (2017) Yes 3 mo after SAE, yearly CT/MRI 20.5 (0.5–56)

Chan (2017) Yes 3 mo after SAE, 3 mo, yearly CT 85.2 (15.6–242.4)

Chick (2010) Yes Not reported CT/US 44.2 (12–116)

Duan (2016) Yes 1 wk after SAE, 6 mo, 12 mo, 24 mo CT 50.2 (24–72)

Ramon (2009) [7] Yes 3 mo after SAE, 3 mo, yearly CT 58 (3–148)

Sheth (2016) Yes Not reported CT 54 (2–266)

Takebayashi (2009) Yes 3 mo after SAE, 6 mo, 12 mo, yearly CT 26.4 (14.64–38.6)

Urbano (2017) Yes 6 mo, 12 mo, 24 mo CT/MRI 36.7 (5–124)

Tso (2005) Yes Not reported CT 48 (2–84)

Tillou (2010) Yes Not reported Not reported 53.2 (5–101)

Chatziioannou (2012) [24] Yes Not reported CT/US 15 (6–15)

Ablative 1 arm

Han (2015) Yes 3 d, 3 d, 1 mo, 3 mo, 3 mo, 3 mo, 3 mo, CT/CE-US/MRI 10 (6–36)

6 mo, each 6 mo

Castle (2012) [11] Yes 1 mo after ablation, 6 mo, 12 mo, yearly CT 21.2 (1.3–71.7)

Guo (2009) Yes 1 mo after ablation, 6 mo CT/CE-US 14.6 (6–23)

Makki (2016) Yes Not reported CT/MRI 25 (12–33)

Swanson (2012) Yes Not reported MRI 6 (3–46)

Surg. vs AS 2 arm

Amano (2002) Not reported – – –

De Luca (1999) Yes 2 yr US (22–164)

Delhorme (2017) Yes 6–12 mo first 5 yr, then yearly CT 43 (1–205)

Surg. vs SAE 2 arm

Huyghe (2009) Not reported – MRI –

Koo (2010) Not reported – – 64.8 (11–97)

Faddegon (2001) Not reported 6 mo after surgery – –

Lee (2009) Not reported – – 21.53 (SD 22.58)

Surg., AS, SAE 3 arm

Mues (2010) [4] Yes 12 mo CT/MRI 54.8(0.2–211.7)

Seyam Yes – – 39.3 (33.9–44.7)

AS = active surveillance; CT = computed tomography; CE-US = contrast-enhanced ultrasound; FU = follow-up; MRI = magnetic resonance imaging;

SAE = selective arterial embolisation; SD = standard deviation; Surg. = surgery; surv. = surveillance; US = ultrasound.

a

Includes an SAE group in addition to surgery.

In surgical series, there were no Clavien 4–5 complica- secondary embolisation because of haemorrhage. Hos-

tions. Minor complications occurred in 19% of the cases. The pital stay was inconsistently reported and varied

hospital stay was inconsistently reported, but on average between 1.5 and 8.5 d.

varied between 2 and 9 d. No major complication was reported in ablative series

In SAE series, there was only one grade 5 complica- (68 patients). Grade 1, 2, and 3 minor complications

tion. Minor complications occurred in 179 (56%) occurred in 12 (17.64%), three (4.41%), and one (1.47%)

patients. The majority of the complications were SAE patients, respectively. There were no reported data regard-

syndromes. Sixteen patients required surgery or ing the length of hospital stay.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

10 E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X

Table 5 – Indication analysis for active treatment and size cut-off

Intervention group General indications for active treatment Size cut-off Size cut-off (cm)

Active surveillance Size growth: yes. 1 study 4 cm: 1 study (187/899)

(n = 4 studies; 899 patients) Bleeding: spontaneous rupture or haematuria (187/899 pts)

Size: >4 cm

Location: no

Pain: yes

Cancer suspicion on imaging: yes

Patient preference: yes

Surgery Size growth: no 9 Studies 4 cm: 6 studies (238/583)

(n = 13 studies; 583 patients) Bleeding: spontaneous rupture or haematuria (325/583 pts) 5 cm: 1 study (28/583)

Size: >4, >5, >7, >10 cm 7 cm: 1 study (36/583)

Location: no 10 cm: 1 study (23/538)

Pain: yes

Cancer suspicion on imaging: yes

Patient preference: yes

SAE Size growth: no 9 Studies 4 cm: 8 studies (264/321)

(n = 12 studies, 321 patients) Bleeding: spontaneous rupture or haematuria (274/321 pts) 8 cm: 1 study (10/321)

Size: >4, >8 cm

Location: no

Pain: no

Cancer suspicion on imaging: no

Patient preference: no

Ablative therapies Size growth: not reported 0 studies –

(n = 5 studies, 68 patients) Bleeding: not reported

Size: not reported

Location: not reported

Pain: yes (9 patients)

Cancer suspicion on imaging: not reported

Patient preference: not reported

Surgery vs AS Size growth: no 1 study (23/111 pts) <2, <4 cm: AS

(n = 3 studies, 111 patients) Bleeding: yes >4 cm: surgery

Size: yes, but not specified

Location: no

Pain: yes

Cancer suspicion on imaging: yes

Patient preference: no

Surgery vs SAE Size growth: no 1 study (129/213 pts) 4 cm: 1 study (129/213 pts)

a

(n = 3 studies, 213 patients) Bleeding: yes

Size: 4 cm

Location: no

Pain: yes

Cancer suspicion on imaging: yes

Patient preference: yes

3-arm AS vs surgery vs SAE Size growth: no 1 study (87/177 pts) 4 cm: 1 study (87/177)

(n = 4 studies, 177 patients) Bleeding: yes

Size: yes, but not specified

Location: no

Pain: yes

Cancer suspicion on imaging: yes

Patient preference: no

AS = active surveillance; pts = patients; SAE = selective arterial embolisation.

a

Only three of five studies in surgery versus SAE report data about “treatment indications”.

3.5. Discussion representing 44% of the total AML population. Some studies

considered a larger size cut-off ranging from 5 to 10 cm [26–

3.5.1. Principal findings 28]. In view of the results of AS series, where a 4-cm cut-off

The main indications for active treatment of AML were as was considered in only 187 of 899 patients (21%), there is a

follows: (1) increased tumour size, (2) presence of valid argument that active treatment should not be decided

symptoms (bleeding and pain), and (3) suspicion of cancer solely on the 4-cm cut-off [13,14]. The average size of the

on imaging. The 4-cm cut-off to trigger active treatment has actively treated AMLs (that did not bleed) in the largest AS

been followed for decades [12], mainly based on the series was 8 cm, ranging from 0.8 to 29 cm [3]. The AML size

assumption that larger tumours have an increased risk of seems to matter, but the limit upon which active treatment

bleeding. However, there is very little evidence to support should be proposed cannot be defined well based on the

the 4-cm threshold. In our SR, the 4-cm cut-off was followed available evidence. Other factors such as AML growth and

in 18 out of 43 studies, which involved 1016 patients patient’s preference should be taken into account [3,12].

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X 11

Table 6 – General outcomes in active treatment modalities

Active Growth/relapse Pain/symptom resolution 2nd Treatment 2nd Renal function treatment requirement Treatment evolution modality modality

Surgery

a

Lane (2008) [27] Not specified 0% relapse Not reported 0, no 2nd – Not reported

treatment

Boorjian (2007) NSS 4% relapse (2 pts) 100% 1, after SAE Preop Cr 1 and

haemorrhage postop 1.1

Heidenreich (2002) Not specified 0% relapse 100% 0, no 2nd – Preop Cr 0.9 and

treatment postop 1.2

Minervini (2007) NSS 0% relapse Not reported 0, no 2nd – Preop Cr 0.95 and

treatment postop 0.99

Golan (2017) NSS 0% relapse 100% 1, after SAE Preop Cr 0.85 and

haemorrhage postop NR

Liu (2016) NSS 0% relapse Not reported 0, no 2nd – Preop eGFR 42.5/

treatment postop 33.5

Wang (2017) [28] NSS Æ SAE 0% relapse Not reported 0, no 2nd – NSS: preop 69.8/

treatment postop 84.2

NSS/SAE: preop 71.1/

postop 70.1

Yip (2000) [25] NSS, RN 4% relapse 100% 1, RCC suspicion on Surgery Not reported

FU

Qin (2017) [23] NSS Æ SAE 0% relapse 100% 0, no 2nd – NSS: <33.05% eGFR treatment postop

NSS/SAE: <15.08%

eGFR postop

Lin (2016) NSS 0% relapse Not reported 0, no 2nd – Preop eGFR 102.4/

treatment postop 99.8

Ng (2016) NSS 15% relapse (3 pts) Not reported Not reported – <11% eGFR postop

Msezane (2010) NSS 0% relapse Not reported 1, contralateral NSS Preop eGFR 99.2/

AML postop 84

1, after SAE

haemorrhage

Zhang (2016) NSS 0% relapse Not reported 0, no 2nd – Preop Cr 92/postop

treatment 92;

Preop eGFR 32/

postop 32

SAE

Wang (2017) [28] PVO, coils 0% 94% 39 (34 “planned”; 39 SAE Not reported

5 “unplanned” for

growth)

5 (4 haemorrhage,

1 growth)

Bardin (2017) 10 agents 13% (3 pts) 91% 8 (7 haemorrhage, 4 SAE, Preop eGFR 78/

1 growth) 1 surgery postop 77

5 (2 symptoms, 4 SAE,

3 growth) 4 surgery

Chan (2011) PVO, coils 6% (1 pts) 81% 2 (1 haemorrhage, 2 SAE, Not reported

1 SAE syndrome) 3 surgery

17 (1 haemorrhage, 2 surgery

16 growth)

Chick (2010) PVO 17% (6 pts) 83% Not reported Not reported

15 SAE,

2 surgery

Duan (2016) PVO, coils 4% (1 pts) 96% Not reported – Preop eGFR 58.5/

postop 73.5

Ramon (2009) [7] PVO 39% (16 pts) 97.5% 2 (2 haemorrhage) – Preop Cr 0.89/postop

0.87

3 (3 growth)

Sheth (2016) Microspheres, 0% relapse Not reported 2 SAE Not reported

coils, gelatin

Alcohol Not reported 1 SAE,

2 surgery

Takebayashi (2009) Not reported Not reported 3 Surgery 4 patients > Cr 0.1–

0.2 mg/dl;

1 patient > Cr 1–

2 mg/dl

EVO 3 (3 haemorrhage) Not reported

Urbano (2017) Lipids and OH 0% relapse 100% 2 SAE, Not reported

1 surgery

Tso (2005) 23% (3 pts) 41%

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

12 E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X

Table 6 (Continued )

Active Growth/relapse Pain/symptom resolution 2nd Treatment 2nd Renal function treatment requirement Treatment evolution modality modality

Microspheres, Not reported

coils

Tillou (2010) 4 agents Not reported 100%

Not reported

Chatziioannou 2002) [24] Not reported Not reported

Ablative

Han (2015) MWA 0 100% 0 – Not reported

Castle (2012) [11] RFA Not reported Not reported Not reported – Not reported

Guo (2009) RFA 0 Not reported Not reported – Not reported

Makki (2016) Cryotherapy Not reported Not reported Not reported – Not reported

Swanson (2012) RFA, 0 Not reported Not reported 1 Ablative Preop eGFR 77/

cryotherapy postop eGFR 75

AML = angiomyolipoma; Cr = serum creatinine; eGFR = estimated glomerular filtration rate; EVO = ethylene vinyl alcohol; FU = follow-up; MWA = microwave

ablation; NSS = nephron-sparing surgery; preop = preoperative; postop = postoperative; pts = patients; PVO = polyvinyl alcohol; RCC = renal cell carcinoma;

RFA = ; RN = radical nephrectomy; SAE = selective arterial embolisation.

a

No specification about the modality of surgery (radical or nephron sparing) or approach.

Table 7 – Success and outcomes in active surveillance groups

Surveillance 1 arm Growth Growth rate Spontaneous Active Active treatment modality

4 studies = 899pts (cm/yr) bleeding/haematuria treatment (treatments)

(patients)

Bhatt (2016) [3] 9% (40 pts) 0.021 12 pts 5.59% (25) SAE 22 (73.3%), surgery 4 (13.3%),

RFA 2 (6.7%); mtor 2 (6.7%)

Chan (2016) [22] 19.78% (37 pts) 0.013 1 pts 3.2% (6) SAE 6 (100%)

Maclean (2014) [26] 11.85% (16 pts) <2 cm (0.07) 3 pts 2.22% (3) SAE 2; surgery 1

2–4 cm (0.1)

Ouzaid (2014) [14] 3% (4 pts) >4 cm (0.92) 4 pts 13.07% (17) SAE 11 (64.7%), partial neph 5

(29.4%), mtor 1 (5.9%)

Not reported

97/899 20/899 51/899 SAE 41, surgery 10, RFA 2, mtor 3

mtor = mammalian target of rapamycin; neph = nephrectomy; pts = patients; RFA = radiofrequency ablation; SAE = selective arterial embolisation.

Some of the most relevant findings in AS series were the definition of recurrence was different throughout SAE studies.

rate of AML growth and the risk of spontaneous bleeding. In Secondary treatment rate was 1% after surgery and 31% after

AS studies, AML size was smaller (only 13.6% of AMLs were SAE. The preferred modality for retreatment was SAE (60%

>4 cm) than the size reported in treated patients. We found after surgery vs 80% after SAE) [27,28]. Based on these data,

that 11% of the patients experienced AML growth and only surgical treatment seems to perform better in terms of

2% a spontaneous rupture or haematuria. The relationship recurrence and requirement for secondary treatment. Both

between AML size and the probability of rupture remains surgery and SAE were comparable in terms of major

unclear based on our findings. However, the probability of complications. One has to acknowledge that the literature

spontaneous rupture in small AML appears to be very low regarding SAE and ablative treatments of AMLs is limited

[26]. Active treatment in AS series was decided in 6% of the compared with surgical treatment. Therefore, although the

patients. Patients were most frequently treated by SAE analysis of data seems to favour surgery in terms of outcomes

(77%) rather than by surgery (19%). As such, AS of small and additional treatment, it might just be related to

AMLs appears to be a safe option. More data are needed publication bias (with surgical series being much more

regarding AS in larger AMLs (>4 cm), as they accounted for frequently reported). Therefore, the message we deliver has

14% of AS patients [3]. to be interpreted with caution. There was no well-defined FU

Owing to the heterogeneity of the data, surgical and SAE scheme. In most series, FU relied on US and CT.

series were hardly comparable. The results of ablative

therapies were scarcely reported in terms of recurrence, 3.5.2. Implications for clinical practice

secondary treatments, and complications. Tumour growth or Despite clinical heterogeneity and uncertainty in the

recurrence occurred in 4–15% of patients treated by surgery evidence base, the following are potentially important

and in 6–39% of patients treated by SAE. However, the findings that might be highlighted.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X 13

Table 8 – Adverse events in active treatment modalities according to Clavien-Dindo system and hospital length stay

CD1 CD1 CD2 CD2 CD3 CD3 CD4 CD4 CD5 CD5 Hosp

explanation explanation explanation explanation explanation stay day av. (range)

Surgery

Lane (2008) [27] – e – – – – –

Boorjian (2007) 5 5—Ileus 14 1—Infection 4 1—Haemorrh-SAE – – 6 [2–13]

13—Transfusion 3—Urinoma-Stent

Heidenreich (2002) – 1—Urinoma 0 3 – – –

1—Ileus 1—Infection 2–3a

Minervini (2007) – 1—Atrial fibr. 2 1—Transfusion 1 1–3b – – 6 [5–11]

2—Infection

Golan (2017) 3 1—Urinoma 4 2—Transfusion 1 1—Infection-drain – – 2 [2,3]

Liu (2016) – 1—Ileus 1 1—Transfusion – 1—Haemorrh-SAE – – –

Wang (2017) [28] 1 4 1—Infection – – – –

2—Pain-SAE sd 1—AV fistula-SAE

Yip (2000) [25] – 1 1—Transfusion 1 – – 9 [6–21]

1—Pseudoan-SAE

Qin (2017) [23] – 4 1—CVA transient – – – 5 (Æ1.3)

Lin (2016) 1 4 4—-Transfusion – – – 8 (Æ1.4)

Ng (2016) – 3 1—Ileus – – –– 3.3 [2–8]

3—Transfusion

Msezane (2010) – 1 1 – – 2.3 (SD 2.6)

Zhang (2016) NR NR 1—Infection NR NR NR 7 (SD 2) 3—Transfusion 1—Transfusion

SAE

Wang (2017) [28] – 69 68—SAE sd – – – NR

1—Infection

Bardin (2017) – 15 1—Infection 6 2—Infection-drain – 1 1—CVA brain NR

14—SAE sd 3—Haemorrh-SAE

Chan (2011) – 11 6 1—Haemorrh-Surg – – 5–7 [5–20]

11—SAE sd

Chick (2010) – 12 – 3—Haemorrh-SAE – – NR

1—Infection 3—Haemorrh-Surg

Duan (2016) – 15 11—SAE sd 2 – – NR

15—SAE sd 1—SAE sd-Surg

Ramon (2009) [7] – 5 1 1—Haemorrh-Surg – – NR

5—SAE sd 1—Haemorrh-Surg

Sheth (2016) – 6 2 – – NR

6—SAE sd 2—Infection-drain

Takebayashi (2009) NR NR NR NR NR [2–4]

5—SAE sd 2—Haemorrh-SAE

Urbano (2017) 0 5 0 1—Haemorrh-Surg 0 0 1.5 [1–3]

6—SAE sd

Tso (2005) 0 6 0 0 0 NR

10—SAE sd

Tillou (2010) NR 11 1—Infection 0 0 0 8.5 [1–28]

4—SAE sd

Chatziioannou (2012) [24] – 4 3 – – 6 [2–8]

Ablative

Han (2015) 11 11—Pain 1 1—Infection-AB 1 1—Colonic injury-Surg – – NR

Castle (2012) [11] NR 1—Skin enfisema NR 2—Transfusion NR NR NR NR

Guo (2009) NR NR NR NR NR NR

Makki (2016) 1 2 – – – NR

Swanson (2012) NR NR NR NR NR NR

Surg vs Surv

3 studies with inconsistent report of adverse events, except one which reports: C1 + C2 = 15; C3 + C4 + C5 = 0

Surg vs SAE

4 studies with inconsistent report of adverse events, except one with more blood loss for SAE and better hospital stay for SAE (16 vs 19 pts)

AB = antibiotic; CD1 = Clavien-Dindo grade 1; CD2 = Clavien-Dindo grade 2; CD3 = Clavien-Dindo grade 3; CD4 = Clavien-Dindo grade 4; CD5 = Clavien-Dindo

grade 5; CVA = cerebrovascular accident; fibr. = fibrillation; Hosp = hospital; NR = nor reported; SAE = selective arterial embolisation; Haemorrh = haemorrhage;

sd = syndrome; SD = standard deviation; Surg = surgery; Surv = surveillance.

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

14 E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X

fi fl

1. The growth rate of sporadic AMLs is low. Financial disclosures: Sergio Fernández-Pello certi es that all con icts of

interest, including specific financial interests and relationships and affilia-

2. The probability of spontaneous rupture is low.

tions relevant to the subject matter or materials discussed in the manuscript

3. The need for active treatment is infrequent.

(eg, employment/affiliation, grants or funding, consultancies, honoraria,

4. There is no high-level evidence to suggest any cut-off size

stock ownership or options, expert testimony, royalties, or patents filed,

for active treatment, and the 4-cm cut-off should be

received, or pending), are the following: Professor Dr. Axel Bex has received

reconsidered.

company speaker honoraria from Pfizer; has participated in trials for Pfizer

5. NSS seems to be the most effective treatment option in

Europe; has participated in advisory boards for GlaxoSmithKline and

order to avoid recurrence and secondary treatments.

Novartis; is a company consultant for Pfizer and Novartis; and has received

grants/research support from Pfizer. Professor Dr. Thomas Powles is a

3.5.3. Strengths and limitations of the review company consultant for Novartis, Pfizer, and GlaxoSmithKline; has received

fi

This review was undertaken in a rigorous manner in company speaker honoraria from Novartis, P zer, GlaxoSmithKline, and

fi

accordance with recognised standards by a multidisciplin- Genentech; has participated in trials for GlaxoSmithKline, P zer, BMS,

Genentech, and Genetech; and has received grants/research support from

ary panel of clinical, methodological, and patient experts

GlaxoSmithKline, Pfizer, and Novartis. Professor Dr. Börje Ljungberg has

(EAU RCC Guidelines Panel) according to PRISMA guidelines.

received company speaker honoraria from GlaxoSmithKline, Roche, Pfizer,

Overall, the certainty of the evidence obtained from this SR

and Novartis; has participated in trials for GlaxoSmithKline, Medivation,

is low, due to the nature of available studies that were

Pfizer, and Janssen R&D; and has been on advisory boards for Pfizer and

retrospective and mostly noncomparative, had high clinical

GlaxoSmithKline. Professor Dr. Laurence Albiges has received consulting/

heterogeneity, and had moderate to high RoB. This nature of

advisory fees from BMS, Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb,

the available evidence made a meta-analysis inappropriate.

Bayer, and Cerulean; and research funding from Pfizer and Novartis. Professor

Dr. Karim Bensalah has received grants/research support from Pfizer, and

4. Conclusions honoraria or consultation fees from Intuitive Surgical. Professor Dr. Michael

Staehler is a company consultant for Pfizer, Novartis, GlaxoSmithKline, Roche,

fi

Our SR found that AMLs are mostly managed by AS (48% of Astellas, and Bayer; has received company speaker honoraria from P zer,

Novartis, GlaxoSmithKline, Roche, Astellas, Bayer, and Aveo; has participated

the cases) and that most of them do not grow (89% of cases).

in trials for Pfizer, Novartis, GlaxoSmithKline, Roche, Bayer, Aveo, Wilex, and

Even if they grow, their size increases very slowly and

Immatics; has received fellowships and travel grants from Pfizer, Novartis,

bleeding is a rare event (2.2%). There is no clear relationship

GlaxoSmithKline, Roche, and Bayer; has received grants/research support

between AML size and the occurrence of bleeding, although

from Pfizer, Novartis, GlaxoSmithKline, Roche, Bayer, and Aveo; and took part

larger AMLs seem to be associated with an increased risk of

in the S-TRAC trial as an investigator and is an author of the S-TRAC

bleeding. Nevertheless, the 4-cm cut-off that has tradition-

publication. Professor Dr. Milan Hora has received company speaker

ally been used as an indication for active treatment may

honoraria from Covidien, Olympus, Janssen, and Astellas; has participated

have to be reconsidered and should not be used in isolation in trials for Janssen; and has received grants/research support from Ipsen.

to trigger active treatment; other factors such as patient age, Professor Dr. Markus A. Kuczyk is a stock shareholder of Bayer Healthcare,

rate of growth, and preference should also be taken into Astellas, Storz, Pfizer, Wyeth, and Novartis; is a company consultant for Karl

account. According to our systematically reviewed data, the Storz, Coloplast, AstraZeneca, Astellas, Storz, and Hexal; has received

company speaker honoraria from Pfizer, Astellas, Bayer, GlaxoSmithKline,

most frequently reported active treatment is surgery (31%),

Pierre Fabre, Janssen Cilag, and Hexal; has participated in trials for the ProtecT

particularly NSS, followed by SAE (17%). Both have similar

Study, Millenium Study C21004, Millenium Study C21005, Astellas, Ipsen, and

morbidity, but there are more recurrences and need for

Janssen; and has received grants/research support from Wyeth and Pfizer. Dr.

secondary treatment in SAE patients (0.85% in surgery vs

Thomas B. Lam is a company consultant for and has received company

31% in SAE). Despite the limitations of the evidence, the

speaker honoraria from Pfizer, GlaxoSmithKline, Astellas, and Ipsen. Professor

findings of this SR may be used to guide and inform clinical

Dr. Axel S. Merseburger is a company consultant for Ipsen Pharma, Bayer,

practice, until more robust data emerge.

Astellas, Janssen Cilag, Novartis, and Pfizer; has received company speaker

honoraria from Ipsen Pharma, Wyeth, Astellas, Novartis, Pfizer, and SEP; has

Author contributions: Sergio Fernández-Pello had full access to all the participated in trials for AstraZeneca, Bayer, Pfizer, TEVA, Novartis, and

data in the study and takes responsibility for the integrity of the data and Astellas; has received grants/research support from Wyeth; and has

the accuracy of the data analysis. participated in a company-sponsored speakers bureau for TEVA, Janssen,

Pfizer, Astellas, Ferring, and Novartis. Dr. Teele Kussk has received company

Study concept and design: Bensalah, Hora, Dabestani, Fernández-Pello.

speaker honoraria from Ipsen. Professor Dr. Rachel H. Giles, Professor Dr.

Acquisition of data: Fernández-Pello, Tahbaz.

Alessandro Volpe, Dr. Saeed Dabestani, Dr. Fabian Hofmann, Dr. Lorenzo

Analysis and interpretation of data: Fernández-Pello, Lam, Marconi, Hora,

Marconi, Dr. Sergio Fernández-Pello, Dr. Rana Tahbaz, and Dr. Yasmin Abu-

Bensalah.

Ghanem have nothing to disclose.

Drafting of the manuscript: Fernández-Pello, Kuusk, Bensalah, Hora.

Critical revision of the manuscript for important intellectual content: Funding/Support and role of the sponsor: None.

Fernández-Pello, Kuusk, Hora, Tahbaz, Dabestani, Abu-Ghanem, Albiges,

Giles, Hofmann, Kuczyk, Lam, Marconi, Merseburger, Powles, Staehler,

Volpe, Ljungberg, Bex, Bensalah.

Statistical analysis: None.

Appendix A. Supplementary data

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Bensalah, Ljungberg, Bex. Supplementary data associated with this article can be

Other: None. found, in the online version, at doi:10.1016/j.euo.2019.04.005

Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005

EUO-204; No. of Pages 16

E U R O P E A N U R O L O G Y O N C O L O G Y X X X ( 2 0 1 9 ) X X X – X X X 15

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Please cite this article in press as: Fernández-Pello S, et al. Management of Sporadic Renal Angiomyolipomas: A Systematic

Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma

Guidelines Panel. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.04.005