Current standards of care in bladder and prostate rhabdomyosarcoma

Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

Seminar article

Current standards of care in bladder and prostate rhabdomyosarcoma Kathleen Kieran, M.D., M.S.*, Margarett Shnorhavorian, M.D., M.P.H. Division of Urology, Seattle Children's Hospital, Seattle, WA Received 18 November 2015; received in revised form 21 December 2015; accepted 21 December 2015

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue tumor in children, and 15% to 20% arise from the genitourinary tract. Multicenter collaborative studies have improved survival substantially, and in addition to excellent oncologic control, current treatment focuses on organ preservation and minimization of late treatment effects. The multiple modalities needed to treat RMS dictate that treating physicians must be familiar with the disease as well as the goals and possible sequelae of treatment with chemotherapy, radiotherapy, and surgery. This article discusses the current standards of care for bladder and prostate RMS. r 2016 Elsevier Inc. All rights reserved.

Keywords: Pediatric; Oncology; Bladder; Prostate; Rhabdomyosarcoma

Introduction Rhabdomyosarcoma (RMS) is the most common tumor of skeletal muscle [1]. In this review, we discuss the treatment of genitourinary (GU) RMS; it should be remembered that a multidisciplinary approach improves favorable outcomes in most oncologic conditions, and each subspecialty must be knowledgeable regarding the indications for and expectations of treatment. Although this review focuses on the treatment of bladder and prostate RMS, an understanding of the epidemiology, molecular characteristics, and diagnosis of disease is a necessary component of treatment planning.

Epidemiology and presentation RMS is the most common soft tissue sarcoma (STS). Half of the children who develop RMS will be younger than 10 years of age [2]. GU RMS affects approximately 60 to 70 children in the United States annually, with approximately 75% of index cases occurring in boys and most cases occurring in children aged 5 years and younger [3]. Prostate and bladder RMS are the most common GU manifestations of the disease in men. Typical presenting Corresponding author. Tel.: þ1-206-987-1623; fax: þ1-206-987-3925. E-mail address: [email protected] (K. Kieran). *

http://dx.doi.org/10.1016/j.urolonc.2015.12.012 1078-1439/r 2016 Elsevier Inc. All rights reserved.

symptoms include pain, stranguria, hematuria, and in severe cases, abdominal distension as well as severe constipation and urinary retention secondary to mass effect from the tumor. Although some children may pass small pieces of tissue in the urine, in general tumor tissue is not present externally; girls with a bladder RMS in whom the tumor extends out of the urethral meatus are an exception [4]. In boys, differentiation between a bladder or prostate primary tumor can be difficult because in many cases the tumors are large and symptomatic at presentation; as many bladder RMS arise from the trigone, the location, in conjunction with the associated inflammation, may make identification of the organ of origin challenging (Fig.). Patient demographic factors that have been identified as risk factors for development of RMS or enabling stratification of patients into different prognostic groups have been identified. Numerous congenital syndromes, including Costello Syndrome, Gorlin basal cell nevus syndrome, Rubinstein-Taybi syndrome, Down syndrome, BeckwithWiedemann syndrome, Li-Fraumeni syndrome, neurofibromatosis, and fetal alcohol syndrome are all associated with an increased risk of RMS development [5–7]. As discussed later, children with p53 abnormalities are also more likely to develop secondary and other primary malignancies in addition to RMS, particularly when they have undergone treatment with alkylating agents. RMS development has also been shown to be more common in previously irradiated tissue as well as after exposure to alkylating

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

2

Intergroup Rhabdomyosarcoma Study Group classification

Fig. Bladder and prostate RMS are often large at diagnosis, making identification of the organ of origin difficult. This is a prostatic RMS.

agents, independent of p53 status, and treatment with these modalities should be limited (or at least carefully considered) in populations at high risk for RMS development [8].

Alveolar vs. embryonal subtypes The following 2 major histologic types of RMS arise in the bladder and prostate: alveolar (ARMS; 10%) and embryonal (ERMS; 90%). The latter has a much better prognosis than the former (failure-free survival [FFS] at 5 y of 82% vs. 65%) [9].

Intergroup Rhabdomyosarcoma Study (IRS) Group was formed in 1972 as a multicenter collaborative study group; at that time, survival for patients with RMS was extremely poor, with fewer than 1 in 4 patients alive 5 years after diagnosis [10]. Data collected from the IRS, now contained within the Children's Oncology Group (COG) STS Committee, has enabled classification of RMS to more accurately risk stratify and stage tumors and has also, through the conduct of several large-scale, multicenter randomized trials, helped to tailor the treatment for RMS to optimize oncologic outcome while minimizing treatment-related effects. Current COG studies focus on risk stratification of tumors by biological characteristics to deliver targeted therapies. The current classification (Tables 1 and 2) considers tumor site, size, and extent (nodal or distant metastases). Staging is based on preoperative findings, group on intraoperative findings and pathology, and risk is derived from both stage and group data. The TNM staging system utilized for many adult and pediatric tumors is also used for RMS, with additional information based on biopsyderived pathologic variables also considered in IRS-specific classification. The IRS classification has been shown to reliably and accurately predict patient oncologic outcomes including FFS. Although the distribution of histologic subtypes is known to vary by age, younger children seem to fare better clinically than their older counterparts when controlling for tumor histology: 5-year event-free survival (EFS) was 71% for children aged 1 to 9 years, but only 53% for infants and 51% for children aged older than 10 years [11].

Pathologic diagnosis Histologically, RMS is a small round blue cell tumor with differentiated skeletal muscle [12]. The diagnosis of

Table 1 IRS clinical groups and pretreatment staging Group

Description

I IIA IIB IIC III IV

Completely resected, no evidence of metastatic disease Microscopic residual disease after complete gross resection No residual disease, þ lymph nodes þ Lymph nodes with microscopic residual disease Gross residual disease (includes biopsy) Distant metastases

Stage Stage Stage Stage

1: 2: 3: 4:

orbit, head, and neck (except parameningeal), GU sites other than bladder and prostate, biliary tract; any size or nodal status, no metastases all other sites, r5 cm, no nodal involvement or metastases all other sites, r5 cm with nodal involvement or 45 cm with any nodal status, no metastases metastatic disease

Adapted with permission from Malempati and Hawkins [5].

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]] Table 2 Current COG-STS risk stratification for RMS (all sites) Risk

Stage

Group

Histology

Low

1 1 2 2 1 1 3 3 2 3 1 1 1 2 2 2 3 3 3 4 4

I II I II III III I II III III I II III I II III I II III IV IV

Embryonal Embryonal Embryonal Embryonal Embryonal (orbital only) Embryonal (orbital only) Embryonal Embryonal Embryonal Embryonal Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar Embryonal Alveolar

Intermediate

High

Nota Bene: Bladder and prostate RMS, by virtue of their location, cannot be Stage 1 tumors (Table 1). Adapted with permission from Malempati and Hawkins [5].

RMS necessitates the histologic finding of skeletal muscle, although this may be present in only a small portion of the overall specimen; failure to identify muscle may lead to some RMS being incorrectly categorized as undifferentiated STSs. Recent advances in molecular biology have allowed pathologists to perform specific staining using antibodies to desmin, myogenin, and myoD (all proteins involved in the differentiation of skeletal muscle) [13,14]. Used together, antibody staining for myogenin and myoD is 97% sensitive for the detection of RMS [12,15]. Initial diagnosis is made by obtaining tissue via cystoscopic, transrectal, percutaneous, or open biopsy; if the latter is performed, then suspicious lymph nodes (LNs) should also be sampled. Minimally invasive approaches to tissue acquisition for diagnosis have been reported [16], but are not yet widely used and should be considered only by surgeons experienced with laparoscopic techniques to minimize the risk of tumor spillage or inadequate tissue collection or both.

Tumor biology Clinical outcomes for RMS largely reflect the stratification of disease into low-, intermediate-, and high-risk subtypes; much of this stratification is based on age and general histology of the tumor (ARMS vs. ERMS), with infants and children older than 10 years having poorer outcomes than children aged 1 to 10 years (who are more likely to have ERMS than ARMS).

3

Contemporary research on RMS tumor histology has centered on molecular markers, specifically PAX and FOXO1 fusion anomalies [17–20]. These advances have enabled further stratification of patients with intermediaterisk RMS, and have suggested that some of the observed variability in clinical outcomes in children with different tumor subtypes may reflect the molecular characteristics of the tumor. Of particular recent interest is the finding that over three-quarters of ARMS have one of 2 specific balanced translocations (PAX3/FOXO1 and PAX7/ FOXO1). Using localization data, PAX3 appears to be on chromosome 1 while PAX7 is on chromosome 2, and FOXO1 is on chromosome 13q [21–23]. Children with these translocations fare more poorly clinically than fusionnegative patients, who tend to have clinical outcomes more consistent with ERMS [5]. These chromosomal translocations have not been described in ERMS tumors, which instead appear to have alterations in chromosome number and also loss of heterozygosity at chromosome 11p15.5. A recent review of patients enrolled in the COG D9803 trial found that children with increased expression of 5 genes (EPHA2, EED, NSMF, CBS, and EPB41L4B) had a poorer prognosis than children with decreased expression of these genes [17]. The findings that children with RMS were more likely than controls to have a first-degree relative with a history of cancer suggests that future identification of additional genes is likely [24].

Imaging Cross-sectional imaging of the thorax, abdomen, and pelvis with either computed tomography (CT) or magnetic resonance imaging (MRI) allows evaluation of tumor burden and determines the feasibility of surgical resection. Primary tumors should be evaluated for size as well as for proximity to surrounding structures; nodal disease and the presence of metastases should also be assessed. One in 6 patients with RMS would have metastatic disease or nodal metastases; the most common site of metastatic disease is the lungs [25,26]. In children who have undergone treatment, residual masses may be present, but do not always represent active disease. Fluorodeoxyglucose-positron emission tomography (FDG-PET) CT has been shown to be more precise for the detection of metastatic and nodal disease than conventional cross-sectional imaging with MRI or CT alone [27,28], although the authors did caution that very small tissue metastases may present a detection challenge on both conventional cross-sectional imaging (owing to the small size) and on FDG-PET-CT (because of decreased FDG avidity). In this series, FDG-PET-CT had a sensitivity and specificity for nodal disease of 94% and 100%, respectively. This finding is of particular clinical relevance as nodal disease requires radiotherapy, which increases the risk of late effects. The authors did note that FDG-PET-CT does

4

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

carry an increased radiation dose per image obtained, but refinement of FDG-PET-CT protocols should allow the number of images to be decreased (limiting diagnostic radiation exposure) and for some patients to avoid therapeutic radiation. Similar results were also published by another group [29], and a more recent study comparing FDG-PET-CT and standard cross-sectional imaging also found that although the investigated modalities had similar rates of detection for primary tumors, FDG-PET-CT identified multiple soft tissue metastases that were not visible on CT or MRI [30]. Bone marrow biopsy and bone scan to assess for pathologic and radiographic evidence of marrow involvement is typically performed as part of the metastatic workup for RMS and can be done at the same time as biopsy of the primary tumor. Lumbar puncture is performed in children in whom meningeal involvement is suspected, although this is rare at presentation in patients with bladder and prostate RMS.

Treatment Although surgical staging and excision are the mainstay of treatment for many childhood cancers, in recent years treatment for prostatic and bladder RMS has been increasingly directed toward organ preservation given the adverse effect of prostatectomy and cystectomy on quality-of-life (QOL) measures. The decision to move away from radical surgery was prompted by the excellent survival outcomes seen in IRS-IV (86% 3-year overall survival [OS] and 77% 3-year EFS) [31] as well as the morbidity associated with extensive and often deforming surgeries of the lower urinary tract and reproductive organs. Nonetheless, the importance of excellent surgical technique and complete tumor resection is underscored by a study comparing oncologic outcomes in patients with RMS undergoing surgery, radiotherapy, and chemotherapy in different orders. Children who received upfront chemotherapy or upfront radiochemotherapy and who then underwent tumor resection and those undergoing radiochemotherapy alone (without a residual mass) had the highest 5-year EFS, ranging from 75% to 84%; children undergoing incomplete tumor resection followed by radiotherapy had much poorer outcomes (38.5% 5-year EFS). Overall, children who underwent upfront chemotherapy followed by secondary tumor resection had the best outcomes (89% 5-year EFS) [32]. Contemporary therapy for bladder and prostatic RMS consist of risk-stratified multimodality treatment with chemotherapy and radiotherapy, with surgical intervention reserved for patients with a residual mass following upfront therapy. Both COG and International Society of Pediatric Oncology (SIOP) endorse chemotherapy and radiotherapy, although the latter places more emphasis on surgery and chemotherapy and less on radiotherapy compared with the former. Rodeberg et al. [33] compared oncologic outcomes

in patients with bladder and prostate RMS treated on different pediatric cancer protocols and found that OS and FFS rates were similar across protocols after controlling for tumor characteristics and stratifying patients by tumor histology33. Chemotherapy Vincristine, actinomycin, and cyclophosphamide (VAC) together make up the standard combination of chemotherapeutic agents for RMS treatment in the United States. Although this 3-drug combination has been in place since IRS-I [34], modifications to the regimen including dose intensification, addition of stem-cell rescue [35], and addition of novel chemotherapeutic agents such as etoposide, topotecan, and ifosfamide [31,36], have not resulted in improved survival outcomes compared with VAC alone [37]. Thus, there are continued efforts to modify treatment protocols to limit therapy-related sequelae and to improve outcomes for patients in high-risk groups. ARST0431 compared patients with metastatic RMS receiving a chemotherapy regimen consisting of vincristine/irinotecan (VI), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide, and VAC with historical patients from previous COG studies; over two-thirds of patients with an Oberlin score of 0 to 1 were alive without relapse at 5 years [38]. In addition, the benefit of adding either cixutumumab (an insulin growth factor-1 inhibitor) or temozolomide (an alkylating agent) to standard chemotherapy in high-risk patients is being evaluated [5]. Renal function should be optimized before the initiation of chemotherapy. As percutaneous tracts of any type (e.g., suprapubic or percutaneous nephrostomy tubes) may become seeded with tumor, internal drainage (e.g., ureteral stents) is preferred when possible [4]. If internal or external tube drainage is performed, the potential alterations in urine composition in patients with decreased mobility and on chemotherapy should be kept in mind, and drainage tube changes planned more frequently than usual to prevent encrustation. Radiation therapy Radiation therapy is reserved for children with disease that cannot be resected, with residual disease following surgery, or with nodal disease, regardless of histology, as well as for all patients with alveolar histology [39,40]. The standard maximum radiotherapy dose is 50.4 Gy to the affected areas in patients with macroscopic residual tumor, although the exact radiation dose is determined by the site and extent of the residual tumor; ongoing studies are evaluating the response to lower radiation doses in lowrisk patients. In the past, radiotherapy was administered at the same time as chemotherapy, but the discovery that some

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

chemotherapeutic agents increased tissue radiosensitivity prompted a 6 to 12 week window between chemotherapy and radiotherapy to be instituted. Furthermore, assessment of initial response to chemotherapy and use of conformal and local techniques to deliver targeted radiotherapy have enabled lower radiation doses to be used for treatment. These considerations are particularly important in the management of bladder and prostate RMS given the proximity of the bladder and prostate to reproductive, gastrointestinal, and GU structures, which may function poorly after exposure to radiation [40]. A study found that 9% of radiation-naive patients, compared with 39% of radiation-treated patients on bladder preservation protocols, had lower urinary tract issues related to treatment [41]. Concern about radiation exposure in children, and specifically in areas with potential effect on reproductive function and QOL, have increased the appeal of techniques that focus the delivered dose of radiation to the oncologic area of interest. Brachytherapy, intensity-modulated proton therapy, and photon therapy have all been reported in small series to have acceptable outcomes both in terms of oncologic control and with regard to radiation dose delivery. Small series reporting treatment of bladder and prostate RMS with intensity-modulated proton therapy or brachytherapy have found that radiation dose to adjacent organs was decreased significantly (e.g., rectal radiation exposure decreased by 67% and 33%, respectively) when compared with intensity-modulated radiation therapy [42,43], and similar results were found when comparing radiation exposure to pelvic growth plates. Localized delivery of radiation may translate into better clinical outcomes; a French study reported a diurnal continence rate of 83% in boys aged 4 years and older following treatment with chemotherapy, organ-sparing surgery, and brachytherapy [44]. Fukushima et al. [45] reported their experience with proton-beam therapy for the treatment of GU RMS, with all patients tolerating the proton-beam therapy well and alive at a median 3-year follow-up45. Novel therapies Currently open studies are evaluating the role for monoclonal antibodies such as bevacizumab (a monoclonal antibody to vascular endothelial growth factor) in recurrent disease and cixutumumab in high-risk disease, and of mTOR (mammalian target of rapamycin) inhibitors such as temsirolimus in recurrent RMS. In the currently open studies, these novel biologic agents are administered as adjuncts to, rather than replacements for, standard chemotherapeutic agents [5]. Surgical therapy: Upfront excision vs. second look Unlike extremity tumors, bladder and prostate RMS are often large at presentation. The close proximity of these tumors to the bladder, rectum, and reproductive organs

5

make upfront complete excision with organ preservation challenging. The initial surgical approach to a child with a pelvic mass suspicious for bladder or prostate RMS is acquisition of sufficient tissue for histologic analysis. This can typically be accomplished through transcutaneous or cystoscopic biopsy, although open biopsies may be necessary in some cases. When open biopsy is performed, primary LN assessment and sampling (typically the obturator and internal iliac chains are adequate) should be performed in the same setting. As with any oncologic surgery, orientation of the pathologic specimen using inking or stitches should be performed. After the diagnosis of RMS is confirmed, the decision to proceed with additional surgical resection or upfront chemotherapy and radiotherapy may be initiated. The focus on upfront chemo- and radiotherapy rather than aggressive initial tumor resection was a significant turning point in the treatment of RMS. With the introduction of the IRS cooperative group studies in 1972, the therapeutic focus for RMS shifted from surgical excision as the primary modality of care to achieving oncologic control through the use of chemotherapy and radiotherapy, with surgery resolved for persistent viable disease. Underlying these changes in therapy were not only the results of the initial IRS studies on vaginal RMS, which demonstrated that most RMS were highly sensitive to chemotherapy [46], but also the understanding of the effect of extensive surgery (typically pelvic exenteration) on the QOL and overall health of cancer survivors. IRS-I and IRS-II found that modified treatment regimens enabled 7 of every 8 patients with vaginal RMS to avoid pelvic exenteration and to preserve reproductive organs. In IRS-III and IRS-IV, fewer than one-quarter of patients required hysterectomy, and OS at 5 years was 82%, confirming that although local tumor control was associated with excellent clinical outcomes, disfiguring surgery was not necessary to achieve clinical goals [47]. At present, complete resection of all viable tumors, with a surrounding 0.5 cm margin, is recommended, unless achieving such margins would result in significant structural or functional damage to or loss of organs [48]. Complete resection before the initiation of chemotherapy or radiotherapy is unusual in bladder or prostate RMS unless the primary tumor is found within the bladder at a location amenable to partial cystectomy [49]. Tumors at the bladder dome may be managed with partial cystectomy, although care must be taken to distinguish primary bladder RMS from urachal RMS, which has a significantly poorer prognosis [50]. Thus, although survival was higher in children with localized disease in whom complete tumor excision with negative margins could be achieved, patients in whom upfront tumor resection would result in damage to or loss of organs are instead directed to receive upfront chemotherapy with delayed resection of residual tumor. As noted, the results using this approach have been quite acceptable.

6

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

Pretreatment re-excision (PRE) is a consideration for children who undergo excision of the tumor mass before the diagnosis of RMS being made. In such cases, a “proper” oncologic excision, including excision of the mass in its entirety, examination for distant or metastatic disease, and achievement of proper surgical margins, may not have been performed. In cases where excision of the residual mass can be performed without causing loss of function or damage to adjacent organs, PRE can be considered to minimize tumor burden before initiating adjuvant therapy. As prostatic and bladder RMS are often large at presentation, with associated inflammation and local extension, PRE is less commonly used for GU RMS than for extremity tumors, but should still be considered when technically feasible given the favorable overall and EFS outcomes associated with successful oncologic control using this method [51]. Second-look operations (SLO) may be undertaken following treatment with chemotherapy or radiotherapy or both when imaging studies suggest that resection of tumor may result in complete eradication of tumor burden or when surgical debulking of the tumor may reduce or eliminate the need for additional adjuvant therapy, thus limiting the secondary effects of treatment. Patients in whom the residual tumor cannot be excised entirely should undergo biopsy of the residual mass to assess tumor viability; the presence of mature rhabdomyoblasts is not associated with an increase in adverse outcomes and therefore alone is not an indication for further surgical intervention [52]. In IRSIV, 57% children with bladder and prostate RMS initially classified as partial responders (decrease in tumor size but residual mass) based on cross-sectional imaging were classified as complete responders following SLO (either through confirmation of clinical and pathologic response, or through excision of the residual tumor burden with negative margins resulting in complete tumor excision) [53]. Within all subtypes of RMS, complete responders have markedly better clinical outcomes than partial responders; thus, although SLO (like PRE) is more easily achieved in extremity and head tumors, the role of SLO in the management of pelvic RMS should not be discounted [54]. When performing SLO, the surgeon should be cautious to excise any residual tumor in its entirety when possible, and must also be cognizant of the surgical considerations unique to chemotherapy- and radiotherapy-treated tissue when considering surgical technique as well as potential for healing. In particular, bladder and prostate surgery in a previously irradiated pelvis may be associated with an increased risk of fistula, stricture, or decreased bladder capacity. The decision to pursue aggressive resection of residual tumor should be made in conjunction with the patient, family, and physician. Complete pelvic exenteration should be considered only when there is tumor growth or essential failed response to other therapies; even slow response should prompt deferral of surgery. In some cases where pelvic RMS is small and localized, excision of part or the entire involved organ, without extensive dissection, may be

successful in achieving oncologic control while minimizing morbidity. Although prostatectomy can be a challenging procedure in prepubertal men, some cases of successful prostate resection with reconstruction of the lower GU tract have been reported [55]. Symphysiotomy is a method to increase visualization in the pediatric pelvis [56]. Partial cystectomy for amenable tumors has equivalent survival rates and may decrease the prevalence of treatmentassociated lower urinary tract dysfunction by reducing the total radiation dose delivered [57]. Management of lymph nodes Although LN involvement is known to portend a poorer prognosis, the management of LNs in bladder and prostate RMS is less well defined than in other oncologic diseases or even in paratesticular RMS. It is generally recommended that boys with paratesticular RMS undergo retroperitoneal LN dissection if they are older than 10 years or if they have radiographic findings suggestive of nodal disease. In boys with bladder and prostate RMS, no standard template for nodal dissection has been defined, and nodal evaluation for staging is generally accomplished through sampling of suspicious LNs (typically those that are radiographically enlarged or palpably abnormal at the time of surgery). Sentinel node mapping has been employed in patients with RMS, but is more frequently employed in extremity tumors [58]. Minimally invasive approaches Laparoscopic and robotic approaches to urologic oncologic surgery are considered the standard of care for adults. Although there are scattered case reports of successful minimally invasive approaches for the treatment of bladder and prostate RMS [59,60], the adoption of minimally invasive techniques has been slower in the pediatric population. GU reconstruction The emphasis on organ preservation has underscored the need for medical and surgical oncologists to understand the effects of treatment on native bladder function, as well as the potential early and late effects of urinary diversion. Urinary diversion after cystoprostatectomy is typically accomplished using a segment of small or large bowel as either a conduit or reservoir. The choice of whether to create a continent or incontinent diversion is based on the extent of local disease and of organ resection, as well as the maturity of the child and capability of the family and caregivers. Additionally, upper tract function should be taken into account before planning lower tract reconstruction, as children with poor renal function are more likely to develop metabolic complications following continent

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

urinary diversions. Stomal stenosis is also a risk after reconstruction [61]. Diversions in which segments of bowel are substituted for part of the urinary tract are associated with an increased likelihood of metabolic anomalies. Both ileal and colon interpositions are associated with a hypokalemic, hyperchloremic metabolic acidosis, whereas jejunal substitutions (less common in contemporary series) are associated with an increased likelihood of hypochloremic, hyponatremic metabolic acidosis. Gastrocystoplasty is increasingly rare, but is associated with hypokalemic, hypochloremic metabolic alkalosis as well as hematuria secondary to tissue exposure to acidic urine. These metabolic derangements are more likely when a continent rather than incontinent diversion is used. In children who undergo augmentation cystoplasty or other urinary tract reconstructions in which bowel mucosa and urine have prolonged contact, development of tumors along the anastomosis between the gastrointestinal and GU tracts is possible; these tumors are thought to arise secondary to the development of nitrosamines [62]. These neoplastic changes were first described in children with diversions such as ureterosigmoidostomy, but have since been reported in association with various urinary diversions including augmentation cystoplasty and appendicovesicostomy. Tumors that develop secondary to exposure of bowel mucosa to urinary components typically have an approximately decade-long latency period, and so surveillance cystoscopy (sigmoidoscopy for patients with ureteroscigmoidostomy), as well as cytologic evaluation of the urine is recommended on an annual basis beginning 7 years after reconstruction [62,63]. In addition, as metabolic derangements are systemic, children with urinary diversions should be carefully monitored for the development of abnormalities in other organ systems (for example, issues with bone mineral density in children with chronic acidosis) [64].

Native bladder function With the increased emphasis on native bladder preservation, comes the need to understand the natural history of lower urinary tract function following treatment with surgery, chemotherapy, and radiotherapy, or any combination of these. Postsurgical alterations in native bladder function arise through direct or indirect damage to nerves and muscles controlling lower urinary tract function, or through loss of bladder capacity through partial cystectomy. Procedures that are necessary components of lower urinary tract reconstruction but which are not directly related to oncologic control (e.g., ureteral reimplantation after resection of a tumor near the bladder neck) may also be associated with complications. An increasingly conservative approach to surgery as well as improved understanding of neuromuscular anatomy in the lower urinary tract has limited the direct sequelae of surgical intervention while

7

increasing the number of patients with complications secondary to radiotherapy or chemotherapy. The standard chemotherapeutic regimen for RMS includes VAC; newer regimens involving irinotecan and carboplatin have been successfully employed for selected intermediate-risk patients [65]. Although all the drugs in this chemotherapeutic regimen can increase the likelihood of complications related to immunosuppression, cyclophosphamide in particular has been associated with an increased risk of early and late lower urinary tract issues including hemorrhagic cystitis. The risk of these conditions developing is increased when acrolein, a metabolite of cyclophosphamide, is allowed to come in contact with tissue for prolonged periods [66]. Maintaining excellent hydration in patients receiving cyclophosphamide and administering Mensa (that binds acrolein, rendering it inactive) would reduce the incidence of hemorrhagic cystitis and lower tract complaints in children receiving cyclophosphamide [67]. Patients should be encouraged to void frequently to empty the bladder; the irritant properties of indwelling catheters should be weighed against their ability to achieve complete bladder drainage. Although cyclophosphamide is the chemotherapeutic agent most commonly associated with the development of hemorrhagic cystitis, several publications have suggested that other chemotherapeutic agents and radiotherapy [68,69] may act synergistically with cyclophosphamide to increase the risk of hemorrhagic cystitis. Furthermore, hemorrhagic cystitis is most common while chemotherapy is being administered, but can also arise months or years after chemotherapy is completed and can become a chronic condition [70]. Ionizing radiation has long been known to induce acute and chronic tissue damage. In addition to “burning” the local tissue, radiation is associated with local inflammation and obliteration of blood vessels with subsequent secondary changes in local tissue compliance and oxygenation; bladders exposed to radiation may experience tissue contraction with low functional bladder capacity and subsequent pressure-related upper tract compromise. Despite these deleterious effects on the bladder, radiation therapy remains a mainstay of treatment for RMS. A total of 2 independent studies (SIOP-MMT89 and SIOP-IV) have demonstrated improved local control with higher EFS (although equivalent OS) in boys with bladder and prostate RMS, who receive radiation compared with radiation-naive patients [71,72]. Pelvic radiation is associated with decreased bladder capacity and abnormal urinary flow patterns (presumably owing to sphincter anomalies) [73], although these urodynamic findings do not always correlate strongly with patient-reported elimination habits. Physicians evaluating survivors of childhood cancer who present with seemingly minor voiding complaints such as nocturnal enuresis or frequent voiding should employ a low threshold for objective evaluation of lower urinary tract function (e.g., invasive or noninvasive urodynamics and voiding diary rather than simply assessment of bother), as well as for

8

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

upper tract evaluation (in light of the increased risk of renal damage in patients with high pressure in the lower urinary tract).

mutations (development of pleuropulmonary blastoma), WT1, FOXO1 fusion mutations, RAS, NF1, HRAS (Costello syndrome), and PTPN11 (Noonan syndrome) [2,22,78].

Metastatic disease

Fertility and sexual function

Although children with localized RMS have enjoyed substantial improvements in survival, less success has been realized with metastatic disease. Excluding children younger than 10 years of age with embryonal RMS, the 3-year EFS for metastatic RMS is dismal, ranging from 5% to 50% (depending on the number and location of metastases) [5,26,74]. A recently published COG study (ARST0431) utilized a 3-pronged approach to treat patients with metastatic RMS: dose intensification (by decreasing the intervals between treatment cycles), therapy with the chemotherapeutic agents found to be most effective in prior Phase II upfront window studies, and use of irinotecan (a chemotherapeutic agent that also increases tissue sensitivity to radiation). Participants in this study received 2 cycles of VI, followed by interval-compressed cycles of vincristine/doxorubicin/cyclophosphamide, followed by 4 cycles of VAC and then 2 cycles of VI. The authors reported a 3-year OS of 56% and 5-year EFS of 38% using this regimen, but the success rates were markedly higher in children with good function overall (e.g., Oberlin score of 0 or 1) [26,38].

Although compromised sexual function has been demonstrated in adult oncology patients treated with pelvic surgery and radiation, there are at present very few published data on sexual function following treatment of pediatric pelvic malignancies. A study of only 4 boys with RMS suggested that sexual function was preserved in patients undergoing cystectomy and urinary diversion [79]. Although these results are encouraging, many treatmentrelated sequelae do not become clinically apparent until many years after the completion of therapy. Infertility may arise owing to genital tract reconstruction, other local effects of surgery, radiotherapy, or a sequelae of chemotherapy. Infertility rates are higher in patients receiving radiation and alkylating agents [80]. Patients should be educated on fertility preservation options before initiating treatment.

Late effects Secondary neoplasms Although the survival rates for pediatric malignancies, including RMS, have improved dramatically in recent decades, secondary malignant neoplasms (as opposed to recurrences of the primary tumor) have emerged as a significant consideration for the long-term health care of pediatric cancer survivors. As many as 1 in 5 survivors of childhood cancer would die from a secondary malignancy, making it the most common cause of death in this population [75,76]. Although secondary malignancies are often attributed to late effects from either chemotherapy or radiotherapy, recent publications have highlighted the role of familial predisposition syndromes that may independently increase the risk of secondary neoplasms or increase the sensitivity of chemotherapy- or radiotherapy-treated tissue to mutations leading to neoplasia. The latter is thought to be particularly important in the development of secondary malignancies in RMS survivors, as children with RMS comprise one-fifth of those who develop later secondary neoplasms [77]. The genetic mutations underlying these conditions have been defined in many cases, including TP53 (Li-Fraumeni syndrome that carries an increased risk of breast and adrenal cancers, among others), DICER1

Conclusion Pelvic and bladder RMS remains a therapeutic challenge requiring a multidisciplinary approach. Medical oncologists, radiation oncologists, and surgeons must work together to tailor therapy to individual patient and tumor characteristics. Improved understanding of tumor biology and an emphasis on organ preservation and patient QOL help to identify priorities for care. References [1] Dasgupta R, Rodeberg DA. Update on rhabdomyosarcoma. Semin Pediatr Surg 2012;21:68. [2] Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 2009;115:4218. [3] Perez EA, Kassira N, Cheung MC, et al. Rhabdomyosarcoma in children: a SEER population-based study. J Surg Res 2011;170:e243. [4] Meir DB, Inoue M, Gur U, et al. Urinary diversion in children with pelvic tumors. J Pediatr Surg 2004;39:1787. [5] Malempati S, Hawkins DS. Rhabdomyosarcoma: review of the Children's Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer 2012;59:5. [6] Sung L, Anderson JR, Arndt C, et al. Neurofibromatosis in children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study IV. J Pediatr 2004;144:666. [7] Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:1233. [8] Ruymann FB, Maddux HR, Ragab A, et al. Congenital anomalies associated with rhabdomyosarcoma: an autopsy study of 115 cases. A report from the Intergroup Rhabdomyosarcoma Study Committee (representing the Children's Cancer Study Group, the Pediatric Oncology Group, the United Kingdom Children's Cancer Study

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

[9]

[10] [11]

[12]

[13]

[14] [15]

[16]

[17]

[18] [19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

Group, and the Pediatric Intergroup Statistical Center). Med Pediatr Oncol 1988;16:33. Meza JL, Anderson J, Pappo AS, et al. Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on Intergroup Rhabdomyosarcoma Studies III and IV: the Children's Oncology Group. J Clin Oncol 2006;24:3844. Pappo AS, Shapiro DN, Crist WM, et al. Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123. Joshi D, Anderson JR, Paidas C, et al. Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 2004;42:64. Qualman SJ, Coffin CM, Newton WA, et al. Intergroup Rhabdomyosarcoma Study: update for pathologists. Pediatr Dev Pathol 1998;1:550. Cessna MH, Zhou H, Perkins SL, et al. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol 2001;25:1150. Tsokos M. The role of immunocytochemistry in the diagnosis of rhabdomyosarcoma. Arch Pathol Lab Med 1986;110:776. Morotti RA, Nicol KK, Parham DM, et al. An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Children's Oncology Group experience. Am J Surg Pathol 2006;30:962. England RJ, Al-Adnani M, Cohen MC, et al. Cystoscopy assisted transvesical biopsy of prostatic rhabdomyosarcoma. Pediatr Blood Cancer 2010;55:583. Hingorani P, Missiaglia E, Shipley J, et al. Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma: a report from the Children's Oncology Group. Clin Cancer Res 2015;21:4733. Chen L, Shern JF, Wei JS, et al. Clonality and evolutionary history of rhabdomyosarcoma. PLoS Genet 2015;11:e1005075. Rudzinski ER, Anderson JR, Lyden ER, et al. Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the Children's Oncology Group. Am J Surg Pathol 2014;38:654. Shern JF, Chen L, Chmielecki J, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusionnegative tumors. Cancer Discov 2014;4:216. Davicioni E, Anderson MJ, Finckenstein FG, et al. Molecular classification of rhabdomyosarcoma—genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol 2009;174:550. Lupo PJ, Danysh HE, Plon SE, et al. Family history of cancer and childhood rhabdomyosarcoma: a report from the Children's Oncology Group and the Utah Population Database. Cancer Med 2015;4:781. Galili N, Davis RJ, Fredericks WJ, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993;5:230. Missiaglia E, Williamson D, Chisholm J, et al. PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 2012;30:1670. Wexler LH, Meyer WH, Helman LJ. Rhabdoyosarcoma. In: Pizzo PA, Poplack's DG, editors Priniciples and Practice of Pediatric Oncology. Philadelphia, PA: Lippincott Williams and Wilkins; 2011. Oberlin O, Rey A, Lyden E, et al. Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 2008;26:2384. Federico SM, Spunt SL, Krasin MJ, et al. Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 2013;60:1128. Völker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 2007;25:5435.

9

[29] Ricard F, Cimarelli S, Deshayes E, et al. Additional benefit of F-18 FDG PET/CT in the staging and follow-up of pediatric rhabdomyosarcoma. Clin Nucl Med 2011;36:672. [30] Dong Y, Zhang X, Wang S, et al. 18FFDG PET/CT is useful in initial staging, restaging for pediatric rhabdomyosarcoma. Q J Nucl Med Mol Imaging 2015:[Epub ahead of print]. [31] Crist WM, Anderson JR, Meza JL, et al. Intergroup Rhabdomyosarcoma Study-IV: results for patients with nonmetastatic disease. J Clin Oncol 2001;19:3091–102. [32] Seitz G, Dantonello TM, Int-Veen C, et al. Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: a report from the Cooperative Soft Tissue Sarcoma trial CWS-96. Pediatr Blood Cancer 2011;56:718. [33] Rodeberg DA, Anderson JR, Arndt CA, et al. Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 2011;128: 1232. [34] Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 1988;61:209. [35] Weigel BJ, Breitfeld PP, Hawkins D, et al. Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 2001;23:272. [36] Arndt CA, Stoner JA, Hawkins DS, et al. Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: Children's Oncology Group study D9803. J Clin Oncol 2009;27:5182. [37] Lager JJ, Lyden ER, Anderson JR, et al. Pooled analysis of phase II window studies in children with contemporary high-risk metastatic rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 2006;24: 3415. [38] Weigel BJ, Lyden E, Anderson JR, et al. Intensive multiagent therapy, including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation, in patients with high-risk rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 2015:[Epub ahead of print]. [39] Cecchetto G, Carretto E, Bisogno G, et al. Complete second look operation and radiotherapy in locally advanced non-alveolar rhabdomyosarcoma in children: a report from the AIEOP soft tissue sarcoma committee. Pediatr Blood Cancer 2008;51:593–7. [40] Eaton BR, McDonald MW, Kim S, et al. Radiation therapy target volume reduction in pediatric rhabdomyosarcoma: implications for patterns of disease recurrence and overall survival. Cancer 2013;119:1578. [41] Hays DM, Raney RB, Wharam MD, et al. Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadjuvant or adjuvant chemotherapy, with or without radiotherapy. A report from the Intergroup Rhabdomyosarcoma Study (IRS) Committee. J Pediatr Hematol Oncol 1995;17:46. [42] Heinzelmann F, Thorwarth D, Lamprecht U, et al. Comparison of different adjuvant radiotherapy approaches in childhood bladder/ prostate rhabdomyosarcoma treated with conservative surgery. Strahlenther Onkol 2011;187:715. [43] Cotter SE, Herrup DA, Friedmann A, et al. Proton radiotherapy for pediatric bladder/prostate rhabdomyosarcoma: clinical outcomes and dosimetry compared to intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:1367. [44] Martelli H, Haie-Meder C, Branchereau S, et al. Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience. J Pediatr Surg 2009;44:190.

10

K. Kieran, M. Shnorhavorian / Urologic Oncology: Seminars and Original Investigations ] (]]]]) ]]]–]]]

[45] Fukushima H, Fukushima T, Sakai A, et al. Tailor-made treatment combined with proton beam therapy for children with genitourinary/ pelvic rhabdomyosarcoma. Rep Pract Oncol Radiother 2015;20:217. [46] Hays DM, Shimada H, Raney RB Jr., et al. Sarcomas of the vagina and uterus: the Intergroup Rhabdomyosarcoma Study. J Pediatr Surg 1985;20:718. [47] Arndt CA, Donaldson SS, Anderson JR, et al. What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer 2001;91:2454. [48] Rodeberg DA, Paidas CN, Lobe TL, et al. Surgical principles for children/adolescents with newly diagnosed rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Sarcoma 2002;6:111. [49] Stein R, Frees S, Schröder A, et al. Radical surgery and different types of urinary diversion in patients with rhabdomyosarcoma of bladder or prostate—a single institution experience. J Pediatr Urol 2013;9:932. [50] Cheikhelard A, Irtan S, Orbach D, et al. Urachal rhabdomyosarcoma in childhood: a rare entity with a poor outcome. J Pediatr Surg 2015;50:1329. [51] Hays DM, Lawrence W Jr., Wharam M, et al. Primary reexcision for patients with microscopic residual tumor following initial excision of sarcomas of trunk and extremity sites. J Pediatr Surg 1989;24:5. [52] Harel M, Ferrer FA, Shapiro LH, Makari JH. Future directions in risk stratification and therapy for advanced pediatric genitourinary rhabdomyosarcoma. Urol Oncol 2015, http://dx.doi.org/10.1016/j.urolonc. 2015.09.013 [Epub ahead of print]. [53] Raney B, Stoner J, Anderson J, et al. Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the Children's Oncology Group. J Pediatr Surg 2010;45:2160–8. [54] Wiener E, Lawrence W, Hays D, et al. Complete response or not complete response? Second look operations are the answer in children with rhabdomyosarcoma. Proc Am Soc Clin Oncol 1991;10:316. [55] Hays DM, Raney RB, Wharam MD, et al. Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadjuvant or adjuvant chemotherapy with or without radiotherapy: a report from the Intergroup Rhabdomyosarcoma Study (IRS). J Pediatr Hematol Oncol 1995;17:46. [56] Pieretti RV, Ryan DP, Pieretti A. Symphysiotomy: a valuable approach in children with prostate rhabdomyosarcoma. Pediatr Surg Int 2010;26:341. [57] Silván AM, Gordillo MJ, Lopez AM, et al. Organ-preserving management of rhabdomyosarcoma of the prostate and bladder in children. Med Pediatr Oncol 1997;29:573. [58] Neville HL, Andrassy RJ, Lally KP, et al. Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 2000;35:961. [59] Chalchal H, Tai TH, Tse E, et al. Ifosfamide, doxorubicin and dacarbazine chemotherapy, and adjunctive laparoscopic cystoprostatectomy and external beam radiotherapy for prostatic embryonal rhabdomyosarcoma. J Urol 2002;168:2545. [60] Blackburn S, Smeulders N, Michalski A, Cherian A. Retroperitoneoscopic para-aortic lymph node sampling in bladder rhabdomyosarcoma. J Pediatr Urol 2010;6:18. [61] Szymanski KM, Whittam B, Misseri R, et al. Long-term outcomes of catheterizable continent urinary channels: what do you use, where you put it, and does it matter? J Pediatr Urol 2015;11:e1. [62] Azimuddin K, Khubchandani IT, Stasik JJ, et al. Neoplasia after ureterosigmoidostomy. Dis Colon Rectum 1999;42:1632.

[63] Austen M, Kalble T. Secondary malignancies in different forms of urinary diversion using isolated gut. J Urol 2004;172:831. [64] Incel N, Incel NA, Uygur MC, et al. Effect of stanford pouch and ileal conduit urinary diversions on bone mineral density and metabolism. Int Urol Nephrol 2006;38:447. [65] Dharmarajan KV, Wexler LH, Wolden SL. Concurrent radiation with irinotecan and carboplatin in intermediate- and high-risk rhabdomyosarcoma: a report on toxicity and efficacy from a prospective pilot phase II study. Pediatr Blood Cancer 2013;60:242. [66] Brock N. Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds. Cancer Treat Rep 1976;60:301. [67] Yilmaz N, Emmungil H, Gucenmez S, et al. Incidence of cyclophosphamide-induced urotoxicity and protective effect of Mesna in rheumatic diseases. J Rheumatol 2015;42:1661. [68] Haldar S, Dru C, Bhowmick NA. Mechanisms of hemorrhagic cystitis. Am J Clin Exp Urol 2014;2:199. [69] Riachy E, Krauel L, Rich BS, et al. Risk factors and predictors of severity score and complications of pediatric hemorrhagic cystitis. J Urol 2014;191:186. [70] Klein J, Kuperman M, Haley C, et al. Late presentation of adenovirusinduced hemorrhagic cystitis and ureteral obstruction in a kidneypancreas transplant recipient. Proc (Bayl Univ Med Cent) 2015;28: 488. [71] Stevens MC, Rey A, Bovet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology—SIOP malignant mesenchymal tumor 89. J Clin Oncol 2005;23:2618. [72] Arndt C, Rodeberg D, Breitfeld PP, et al. Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/ prostate rhabdomyosarcoma? Results from Intergroup Rhabdomyosarcoma Study IV. J Urol 2004;171:2396. [73] Yeung CK, Ward HC, Ransley PG, et al. Bladder and kidney function after cure of pelvic rhabdomyosarcoma in childhood. Br J Cancer 1994;70:1000. [74] Breneman JC, Lyden E, Pappo AS, et al. Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 2003;21:78. [75] Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol 2009;27:2328. [76] Meadows AT, Friedman DL, Neglia JP, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol 2009;27:2356. [77] Pinto N, Hawkins DS. Second malignant neoplasms in rhabdomyosarcoma: victims of our own success or an underlying genetic predisposition syndrome? Pediatr Blood Cancer 2016;63:189–90. [78] Doros L, Yang J, Dehner L, et al. DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPBtumor predisposition syndrome. Pediatr Blood Cancer 2012;59: 558–60. [79] Macedo A Jr., Ferreira PV, Barroso U Jr., et al. Sexual function in teenagers after multimodal treatment of pelvic rhabdomyosarcoma: a preliminary report. J Pediatr Urol 2010;6:605. [80] Mansky P, Arai A, Stratton P, et al. Treatment late effects in longterm survivors of pediatric sarcoma. Pediatr Blood Cancer 2007;48: 192.