Pediatr Blood Cancer 2012;58:833–835

REVIEWWhat is the Evidence for Radical Surgery in the Management of Localized

Embryonal Bladder/Prostate Rhabdomyosarcoma?

Nicholas Alexander, MA MBBS MRCS,1* Sheila Lane, MBBS MRCP PhD,2 and Rowena Hitchcock BChir, MRCS, BM BCh1

INTRODUCTION

Rhabdomyosarcoma (RMS) is the commonest soft tissue

sarcoma in the pediatric population, of which around 25% have

bladder/prostate (BP) as the primary site [1]. The management of

patients with BP RMS has changed radically over the last forty

years, driven by results from the clinical trials carried out by the

international collaborative Intergroup Rhabdomyosarcoma Study

Group (IRSG). The initial trials were aimed at improving survival

[2], but with this goal achieved, the latter trials focused on quality

of life and reduction in treatment related morbidity [1,3,4].

The role aggressive surgery plays in the management of BP

RMS has moved from the primary treatment modality to an

adjunct to chemotherapy [5] as understanding of the chemosensi-

tive nature of RMS improved. The IRSG based on results from

IRS I–IV now recommends where possible a move to definitive

radiotherapy without resection or conservative surgery. However,

a number of groups are still proponents of aggressive surgery to

provide local control of BP RMS [6–9]. Although technically

feasible, the high risk of urinary incontinence [10], denervation

of the neurovascular bundles leading to erectile dysfunction, and

the high complication rates after radical surgery [11,12] have a

large impact of the quality of life of survivors.

We undertook a critical review of the current literature to guide

the management of an infant with a large localized prostatic em-

bryonal RMS, specifically looking for evidence that primary radical

surgery is of benefit following chemotherapy. Using the evidence

available in the current literature, we show that there is no differ-

ence in overall survival (OS) and event free survival (EFS) when

comparing differing modalities utilized in local disease control as

well as demonstrating that microscopic disease clearance does not

necessarily correlate with improved outcomes. Finally, we provide

evidence that the morbidity associated with radical surgery for BP

RMS is significantly greater than for a conservative method of local

control.

It is worth noting at the outset that the data presented in the

literature are not uniform with most series combining data from

bladder dome tumors with those of the BP. There are clear differ-

ences between these tumor locations in terms of surgical clear-

ance and anticipated postoperative morbidity. In the case of

bladder tumors, complete excision can be achieved with minimal

morbidity, with the exception of those requiring an augmentation

procedure to restore bladder volume. However, for BP tumors,

complete excision will likely result in damage to the neurovas-

cular bundles, as well as the need to provide a urinary conduit to

ensure patient dryness, as true continence will be sacrificed.

THERE APPEAR TO BE NO DIFFERENCE IN OS ANDEFS WHEN COMPARING DIFFERING MODALITIESUTILIZED IN LOCAL DISEASE CONTROL

There is general consensus that chemotherapy is the mainstay of

treatment in BP RMS, but the method to be used for local control is

debated. Reviewing the current literature, data are available on the

survival outcomes from both large international studies and indi-

vidual group reports (Table I). However, it is somewhat difficult

to draw direct comparisons between these studies, as the patient

groups are rather heterogeneous in terms of interventions and loca-

tion of tumors. Nevertheless, OS and EFS at 5 years appears to be

remarkably similar between all studies, irrespective of the method

employed for local disease control.

The largest and most recent publication of outcomes from

Rodeberg et al. collates the experience of four large international

consortia in managing BP RMS [13]. The data do not show out-

comes of specific method of local control, but some interesting

conclusions can be gleaned nonetheless. The authors report that in

only 12% of cases was surgical resection attempted at diagnosis,

with the majority receiving biopsy followed by chemotherapy.

The subsequent local control with surgery/radiotherapy was de-

termined by treatment group. Although there was some variability

in the use of radiotherapy, radical resections were recommended

to be avoided. There was no significant difference in the OS or

EFS at 5 years for across all four cohorts of patients. Taking the

As survival outcomes for bladder/prostate rhabdomyosarcomahave improved over the last 40 years, the emphasis has shifted tominimizing treatment related morbidity. We undertook a criticalreview of the current literature to examine the role of radical pelvicsurgery to achieve local control. We illustrate that there appears tobe no difference in overall survival or event free survival when

comparing differing modalities utilized in local disease control,microscopic disease clearance does not correlate with improvedoutcomes, and the morbidity associated with radical surgery forBP RMS is significantly greater than for a conservative method oflocal control. Pediatr Blood Cancer 2012;58:833–835.� 2012 Wiley Periodicals, Inc.

Key words: pediatric bladder/prostate rhabdomyosarcoma; radical surgery; outcomes

1Department of Paediatric Surgery, John Radcliffe Hospital, Oxford,

UK; 2Department of Paediatric Oncology, John Radcliffe Hospital,

Oxford, UK

Conflict of interest: Nothing to declare.

*Correspondence to: Nicholas Alexander, MA MBBS MRCS, Depart-

ment of Paediatric Surgery, John Radcliffe Hospital, Headley Way,

Headington, Oxon, OX3 9DU, UK

E-mail: nicalexander1@gmail.com

Received 21 November 2011; Accepted 4 January 2012

� 2012 Wiley Periodicals, Inc.DOI 10.1002/pbc.24087Published online 23 January 2012 in Wiley Online Library(wileyonlinelibrary.com).

data from Rodeberg et al. as the most current measure of survival

outcomes, it can be seen that groups adopting a radical surgical

approach do not have superior survival outcomes. Similar quite

promising survival outcomes are also seen following a more

conservative surgical approach with additional brachytherapy as

a novel method employed for local control [14]. If one accepts

that there is no survival advantage for the chosen method of local

control, then the treatment related morbidity for survivors must be

the salient factor to consider.

MICROSCOPIC DISEASE CLEARANCE DOES NOTSEEM TO CORRELATE WITH IMPROVED OUTCOMES

The theoretical importance of microscopic disease clearance

for BP RMS has driven those who are proponents of radical

surgery, and was central to the early management goals. Within

the recent literature, data have emerged challenging this assump-

tion. The large data series reported on by Rodeberg et al. provides

some insight into the use of surgery at diagnosis [13]. There are

notable differences in the initial approach reported between

groups (CWS, ICG, IRSG, SIOP), particularly in the proportion

of patients of IRS Group I, i.e., complete resection at diagnosis.

Although, tumors of the bladder dome are certainly amenable to

primary resection this location will only occur in a small percent-

age of BPRMS. Given that one quarter of patients from the IRSG

study group were IRS Group I, and by definition therefore defi-

nitely underwent primary surgical resection, one can conclude

that a number of patients received radical surgery to the bladder

neck/prostate at diagnosis. This is in contrast to CWS, SIOP, and

ICG study groups, where no patients are reported to be IRS I at

diagnosis. Adjusting for tumor size and invasion, there was no

significant difference in OS or EFS between the groups, indicating

that microscopic disease clearance does not appear to convey a

survival advantage.A number of groups continue to practice radical surgery based

on the evidence that 75% of BP RMS arise from the base of the

BP [15] and, therefore, microscopic clearance of disease is only

possible through pelvic exenteration. Authors such as Filipas et al.

[7] report excellent outcomes with radical surgery, stressing the

value of complete surgical clearance. However, the survival out-

comes from centers that perform conservative treatment or radio-

therapy for local control do not support the need for total

microscopic clearance. In spite of residual disease following con-

servative treatment, survival outcomes are comparable to those

with microscopic clearance.

Possibly the most significant evidence suggesting a move away

from the concept of microscopic clearance is the work of Martelli

et al. who have presented a series of cases with BP RMS in whom

local control is achieved with conservative surgery and brachy-

therapy [14]. Their rationale for this approach is the preservation

of the neurovascular bundles and reduced burden of treatment

associated morbidity. Martelli et al. elect to perform a debulking

procedure making no attempt at microscopic clearance, and at the

same operation slinging the bladder neck for the provision of

brachytherapy postoperatively. This strategy shows promising

results that in spite of leaving macroscopic disease at surgery

the patients have an overall survival of 92% and event free sur-

vival of 84%.

THE MORBIDITY ASSOCIATED WITH RADICALSURGERY FOR BP RMS IS SIGNIFICANTLY GREATERTHAN FOR A CONSERVATIVE APPROACH

Advocates of the aggressive approach for treatment of BP

RMS would also point to data presented of high rates of bladder

dysfunction in survivors who have received radiotherapy. Arndt et

al. investigated bladder dysfunction in survivors of BP RMS using

a retrospective questionnaire tool [16]. Results from the question-

naire showed that patients who had received chemotherapy fol-

lowed by radiotherapy had a very high incidence of bladder

dysfunction (approximately 60%). The data presented are limited

by the retrospective nature of the study and are likely to underre-

port the incidence of urinary problems. Alternatively, reporting

bias driven by the questionnaire used may have resulted in an

overestimation of bladder dysfunction. There was no correlation

with urodynamic studies or urinary flow data to support the con-

clusions. A further retrospective study to assess late treatment

related morbidity reported that the incidence of bladder dysfunc-

tion to be was between 27 and 31% [17].

Further to these reports of poor bladder outcome, Filipas et al.

presented their experience as proponents of aggressive surgery to

manage local disease, utilizing a continent diversion pouch [7].

The use of a Mainz pouch is required, as the exenteration proce-

dure will necessarily render the patient incontinent. Although the

patients have controlled urinary outflow they cannot be classed as

being truly continent as they do not have functioning bladders.

The outcomes for this group are not significantly better than those

of the conservative approach but have the additional burden of

procedure related morbidity including ureteric stenosis, pouch

perforation, and pouch stones.

Major treatment related complications/morbidity for radical

surgery is a constant feature and reported to be as high as

25% [11]. Although the surgical techniques are reported to be

technically feasible and sound [6],18],, there are significant

TABLE I. Outcome Data for Retrospective Series of BP RMS (OS/EFS at 5 Years)

Group Number Intervention OS (%) EFS (%)

Duel 1996 [18] 24 CTX þ radical surgery and colonic conduit 96 96

Silvan et al. 1997 [3] 10 CTX þ radiotherapy or conservative surgery 80 80

El-Sherbiny et al. 2000 [9] 30 CTX þ radical surgery 70 63

Stevens et al. 2005 [22] 62 CTX plus surgery/radiotherapy MMT 89 protocol 80 64

Filipas et al. 2004 [7] 14 CTX þ radical Surgery and continent conduit 78 64

Martelli et al. 2009 [14] 26 CTX þ conservative surgery and brachytherapy 92 84

Seitz et al. 2011 [12] 63 CTX þ radiotherapy or radical surgery CWS 90 protocol 76 70

Rodeberg et al. 2011 [13] 322 CTX � surgery/radiotherapy 84 75

834 Alexander et al.

Pediatr Blood Cancer DOI 10.1002/pbc

complications outside of those related to the formation of a con-

tinent pouch, in particular high rates of small bowel obstruction

necessitating reoperation.

With these complications of radical surgery in mind, the in-

ternational results presented by Seitz et al. report that resection

providing negative tumor margins was achievable in about 50% of

cases [12,19]. Therefore, a significant number of patients under-

going radical resection are not cleared of disease but incur the

burden of complications.

CONCLUSIONS

The literature review undertaken has been difficult with re-

spect to analyzing data from different centers, as most series

contain a mixture of patients whose location of tumor site varies

from those which can be easily excised to tumors whose removal

cannot be undertaken without causing significant morbidity.

Local control using definitive radiotherapy without surgery is an

accepted standard treatment modality, providing excellent

treatment outcomes, but treatment related morbidity has been

demonstrated to be a significant problem. The risks of pelvic

radiotherapy are particularly important in younger children, which

is an important consideration given that the median age of pre-

sentation of patients with BPRMS is around 2.4 years [17].

Evidence within the literature point to the bladder as the most

sensitive pelvic organ when subjected to radiotherapy, with long-

term bladder fibrosis and dysfunction contributing to significant

post-treatment morbidity [10,20]. Of more concern with the

younger age group patients is the significant alteration in pelvic

growth plates with full dose pelvic radiotherapy compared to

older children [21].

Thus there appears to be no clear advantage in terms of overall

survival or event free survival for patients undergoing radical

pelvic surgery compared to other methods of local control. Given

the significant morbidities associated with pelvic exenteration, a

less aggressive approach combined with brachytherapy or confor-

mal radiotherapy should be further studied.

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