Pediatric Urology

Oncologic Outcome and Urinary Function after Radical Cystectomy for Rhabdomyosarcoma in Children: Role of the Orthotopic Ileal Neobladder Based on 15-Year Experience at a Single Center Marco Castagnetti,* Lorenzo Angelini, Rita Alaggio, Giovanni Scarzello, Gianni Bisogno and Waifro Rigamonti From the Section of Pediatric Urology, Urology Unit (MC, LA, WR), Pathology Department (RA) and Hematology/Oncology Division, Woman’s and Child’s Health Department (GB), University Hospital of Padova and Radiotherapy Division, Istituto Oncologico Veneto (GS), Padua, Italy

Abbreviations and Acronyms CIC ¼ clean intermittent catheterization fUTI ¼ febrile urinary tract infection RC ¼ radical cystectomy RMS ¼ rhabdomyosarcoma RT ¼ radiotherapy SFU ¼ Society for Fetal Urology VIP ¼ Padua ileal neobladder Accepted for publication December 20, 2013. * Correspondence: Section of Pediatric Urology, Urology Unit, Department of Oncological Sciences, University Hospital of Padova, Monoblocco Ospedaliero, Via Giustiniani 2, 35100 Padua, Italy (telephone: 39-049-8212737; FAX: 39049-8212721; e-mail: marcocastagnetti@hotmail. com).

See Editorial on page 1650.

Purpose: We determined the oncologic and urological outcomes in patients with bladder/prostate rhabdomyosarcoma according to the type and timing of urinary tract surgery, with emphasis on the role of the Padua orthotopic ileal neobladder. Materials and Methods: We retrospectively analyzed oncologic and urological outcomes of 11 consecutive patients treated at our institution between 1998 and 2012. Results: Two patients underwent urethrectomy and placement of a heterotopic catheterizable ileal neobladder. The membranous urethra was preserved in 9 patients, 6 underwent primary Padua ileal neobladder at radical cystectomy, 2 underwent delayed Padua ileal neobladder and 1 underwent bilateral cutaneous ureterostomy. Four of these 9 patients experienced disease recurrence, including local recurrence in 2 despite negative intraoperative biopsies. Survivors undergoing heterotopic catheterizable ileal neobladder or primary Padua ileal neobladder learned to empty the bladder to completion without long-term upper tract deterioration. Both cases managed by delayed Padua ileal neobladder required clean intermittent catheterization eventually. Erections were reported in 5 of 6 surviving males. Conclusions: The Padua ileal neobladder allowed preservation of volitional urethral voiding in all survivors in whom it was placed at radical cystectomy. Nevertheless, local recurrence was noted in 2 of the 9 cases where the membranous urethra was preserved. By comparison, patients undergoing delayed Padua ileal neobladder after attaining disease-free status never achieved voiding per urethra. Therefore, a heterotopic reservoir might be a more reliable choice under these circumstances. Erectile function is preserved in the majority of cases. Key Words: cystectomy, prostate, rhabdomyosarcoma, urinary bladder, urinary diversion

RHABDOMYOSARCOMAS arising from the bladder/prostate account for approximately 25% of all such tumors in children.1 Multidisciplinary protocols including chemotherapy and radiotherapy have improved patient

1850

j

www.jurology.com

survival and increase the chances of bladder preservation.1,2 Radical cystectomy reportedly is required because of failure of medical treatments and inability to accomplish partial resection in about 40% of

0022-5347/14/1916-1850/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2013.12.040 Vol. 191, 1850-1855, June 2014 Printed in U.S.A.

BLADDER SUBSTITUTION IN CHILDREN WITH RHABDOMYOSARCOMA

cases.3 After radical cystectomy a heterotopic intestinal catheterizable reservoir seems to be a viable option.4e6 However, if the membranous urethra is spared, an orthotopic neobladder joined to it might preserve volitional urethral voiding.5,7 Since 1998, we have incorporated the Padua ileal neobladder into our armamentarium for bladder substitution after radical cystectomy in patients with rhabdomyosarcoma.7 This procedure was initially devised at our institution, where it is extensively used in adults requiring radical cystectomy for transitional cell carcinoma of the bladder.8 Despite the putative advantages of orthotopic neobladder, few instances have been reported thus far in patients with RMS, making information about the functional outcomes of this diversion scarce.5,7 A reason for such a small number of cases is also that evidence suggests that the involvement of the membranous urethra could not be ruled out reliably in RMS cases preoperatively or intraoperatively.4 Therefore, few surgeons recommend extensive urethral excision during RC, and some recommend that urinary tract reconstruction be delayed until after the patient has achieved a durable disease-free status.4,9,10 We reviewed our 15-year experience with urinary tract management in cases of RMS requiring RC to determine the oncologic and urological outcomes according to the type and timing of urinary tract surgery.

MATERIALS AND METHODS Inclusion/Exclusion Criteria A total of 64 patients with bladder/prostate RMS were registered in 2 consecutive protocols (RMS96 and RMS2005) coordinated by the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Soft Tissue Sarcoma Committee between January 1998 and December 2012. Of the patients 6 were diagnosed and treated elsewhere and 11 were referred to our institution for surgery. We retrospectively reviewed the records of the latter, which included 9 patients undergoing RC at our institution and 2 referred for continent diversion after RC performed elsewhere. Patients with RMS confined to the genitalia or undergoing other kinds of urinary tract surgery for RMS were excluded.

Case Management Protocol guidelines recommended initial biopsy, normally endoscopic, to establish the histological diagnosis. Biopsy was followed by intensive chemotherapy according to the risk profile and preoperative or postoperative RT generally to a total dose of 45 Gy. RC was considered in instances of persistent disease after RT or to avoid pelvic irradiation in young children.11,12 In general, our policy regarding urinary tract management in individuals undergoing RC was to favor VIP whenever the membranous urethra was deemed salvageable based on preoperative assessment, intraoperative

1851

findings and the presence of free margins on intraoperative histology on frozen sections. Otherwise, urethrectomy was performed (up to the bulbar segment in males and total in females), and a heterotopic continent catheterizable ileal neobladder was placed. VIP was created as described previously.7 A catheterizable conduit was associated with delayed reconstruction. Heterotopic catheterizable ileal neobladders were fashioned by reshaping a 30 to 40 cm long ileal segment in a spherical configuration and placing the catheterizable conduit at the umbilicus. Postoperatively serial imaging (usually magnetic resonance) was performed to rule out disease recurrence every 3 months in the first year and at increasing intervals thereafter. Followup endoscopy was not systematically performed. Ultrasonography was used to monitor bladder emptying and upper tract status. Post-void catheterization was not recommended. Surveillance cystoscopies plus biopsies of the reservoir were recommended starting 10 years after reconstruction.

Outcome Parameters We evaluated patient clinical characteristics, treatment administered, and oncologic and urological functional outcomes. The latter was assessed in patients surviving at least 1 year after urinary tract reconstruction and included the presence of recurrent fUTIs, urinary continence, upper tract dilatation, reservoir capacity, post-void residual, need for CIC and reported erectile, ejaculatory and sexual function. Hydronephrosis was graded according to the SFU system. Upper tract dilatation was defined as severe in cases of SFU grade III or IV hydronephrosis and concomitant ureteral dilatation. In patients with upper tract dilatation obstruction was ruled out by dynamic diuretic renography. Capacity of the reservoir was assessed on a voiding diary or on videourodynamics. VIP emptying as assessed by ultrasonography or videourodynamics was considered complete when the residual was less than 20 ml. Erectile function was assessed by patient or parent inquiry about the presence of erections. Oncologic and urological outcomes were assessed according to the type and timing of urinary tract surgery, ie if urethrectomy was performed at RC and if the reconstruction was simultaneous to RC (primary) or delayed. Given the small sample size, only descriptive statistics were used. Categorical variables were expressed as ratios and continuous variables as medians (ranges).

RESULTS Patients Patient characteristics are summarized in table 1. Nine patients (7 males) were primarily treated at our institution and the membranous urethra was preserved during RC in 7 (6 males). Of the 2 patients undergoing urethrectomy 1 was a female with neurofibromatosis type 1 with disease extending to the vagina and 1 was a male with positive intraoperative biopsies. Two cases were secondary referrals after RC performed elsewhere 3 and 7 years

1852

Pt No.

Tumor Histology

Location

TNM Stage

1

Embryonal

Bladder/ prostate

T2bN0M0

2

Embryonal

Bladder þ vagina

T2bN0M0

3

Embryonal

Bladder/ prostate

T2bN0M0

4

Embryonal

Bladder/ prostate

T2bN0M0

5

Embryonal

Bladder/ prostate

T2aN0M0

6

Botryoid

Bladder

T1aN0M0

7

Botryoid

Bladder

T1bN0M0

8

Botryoid

Bladder

T2aN0M0

9

Embryonal

Bladder

T1bN0M0

10

Not specified

Bladder

T1bN0M0

11

Embryonal

Bladder

T1aN0M0

First-Line Chemotherapy

RT (Gy)

Age at RC (yrs)

Urethrectomy

Definitive Histology

Ifosfamide-vincristineactinomycin D Carboplatin-epirubicinvincristine-actinomycin D-ifosfamide-etoposide Vincristine-actinomycin D-cyclophosphamidecarboplatin-epirubicin Ifosfamide-vincristineactinomycin D Ifosfamide-vincristineactinomycin D Carboplatin-epirubicinvincristine-actinomycin D-ifosfamide-etoposide Vincristine-actinomycin D-ifosfamide-doxorubicin Carboplatin-epirubicinvincristine-actinomycin D-ifosfamide-etoposide Vincristine-actinomycin D-ifosfamide-doxorubicin Vincristine-actinomycin D-ifosfamide-doxorubicin Ifosfamide-vincristineactinomycin D

50.4

11.9

Urethral involvement

Yes

Free margins

Alive

e

32

2

Urethral involvement

Yes

Free margins

Died of secondary tumor

e

No

2

No urethral involvement

No

Free margins

Died with local recurrence

3 Mos

55.8

3.1

No urethral involvement

No

Free margins

6 Mos

55.8

7.2

No urethral involvement

No

Free margins

44.8

6.5

No urethral involvement

No

Free margins

Died with local recurrence Died with metastases Died with metastases

No

1.8

e

No

e

Alive

e

44.8

3.5

No urethral involvement

No

Free margins

Alive

e

No

2.1

e

No

e

Alive

e

44

4.1

No urethral involvement

No

Free margins

Alive

e

50.4

2.1

No urethral involvement

No

Free margins

Alive

e

Intraop Histology

Oncologic Outcome

Time to Recurrence

3 Mos 2.5 Yrs

BLADDER SUBSTITUTION IN CHILDREN WITH RHABDOMYOSARCOMA

Table 1. Patient characteristics, treatment and oncologic outcomes

BLADDER SUBSTITUTION IN CHILDREN WITH RHABDOMYOSARCOMA

earlier in combination with a Mainz pouch and a colon conduit. The membranous urethra was preserved in both. Urinary diversion included a heterotopic catheterizable ileal neobladder in both patients undergoing urethrectomy. Of the 9 patients in whom the membranous urethra was spared (7 treated at our institution and 2 elsewhere) VIP was placed in 8 and bilateral cutaneous ureterostomy in 1. In the latter the cutaneous ureterostomy had been placed elsewhere due to bilateral hydroureteronephrosis with renal failure at presentation, and during RC we elected to wait for delayed reconstruction. No perioperative complications were recorded. In 1 of the 2 patients undergoing delayed reconstruction dissection of the membranous urethra to obtain fresh urethral tissue for the VIP-urethral anastomosis required a combined approach from the abdomen and perineum. Oncologic Outcomes Of the 11 patients 6 were alive without evidence of disease recurrence after a median followup of 6.5 years (range 1 to 15) from RC. Neither of the 2 patients undergoing urethrectomy experienced disease recurrence. One was alive at final followup and the other was the patient with neurofibromatosis type 1, who died of a second malignancy (malignant Schwannoma) 7 years after RC. Of the 9 patients undergoing preservation of the membranous urethra 4 died of metastatic disease at a median of 0.7 years (range 0.4 to 2.5) after RC. Two

1853

patients also had evidence of local recurrence. Both patients had free margins on definitive pathological examination. The remaining 5 patients were alive at final followup, including 3 primarily treated at our institution and 2 who were referred and underwent delayed reconstruction. Table 2 summarizes the characteristics of patients in whom RMS treatment failed or was successful. Urological Outcomes Eight of the 11 patients survived more than 1 year after urinary tract reconstruction allowing for urinary function assessment, including 2 patients with a heterotopic neobladder, 4 with primary VIP and 2 with delayed VIP. Neither patient with a heterotopic neobladder suffered recurrent fUTIs. Capacity of the reservoir in these patients was 400 and 730 cc. One patient had SFU grade II unilateral nonobstructive hydronephrosis. Neither patient experienced incontinence or difficulty with bladder emptying via the catheterizable conduit. One required revision of the cutaneous Mitrofanoff stoma. The 4 patients assessable after primary VIP required a median of 40 days (range 20 to 90) to learn to void volitionally to completion. Only 1 patient (2.1 years old at VIP placement) required a prolonged period with the epicystostomy tube in place to monitor post-void residual during the learning process. Thereafter, no patient suffered episodes of mucous retention or recurrent fUTIs, although 1 is still on antibiotic prophylaxis (12 months after

Table 2. Patient characteristics and treatment outcomes Overall No. gender: Male Female Median yrs age at diagnosis (range) Median yrs age at RC (range) No. location: Bladder trigone Bladder/prostatic urethra No. histological variant: Embryonal Botryoid Not specified No. Intergroup Rhabdomyosarcoma Study clinical group 3 No. TNM stage: T1a T1b T2a T2b No. preop treatment: Chemotherapy Chemotherapy þ radiotherapy No. urinary tract reconstruction: Heterotopic neobladder VIP Cutaneous ureterostomy * Both patients underwent urethrectomy during radical cystectomy.

RMS Treatment Success

RMS Treatment Failure

9 2 2.0 (0.8e8.7) 3.3 (1.8e11.9)

6 1 1.6 (1.4e8.7) 2.8 (1.8e11.9)

3 1 3.7 (0.9e6) 4.8 (2e7.2)

6 5

5 2*

1 3

7 3 1 11

4 2 1 7

3 1 4

2 3 2 4

1 3 1 2

1 0 1 2

3 8

2 5

1 3

2 8 1

2 5 0

0 3 1

1854

BLADDER SUBSTITUTION IN CHILDREN WITH RHABDOMYOSARCOMA

VIP placement). Median reservoir capacity was 430 cc (range 350 to 620). One patient had SFU grade II unilateral nonobstructive upper tract dilatation. No patient required protection for incontinence. The 2 patients undergoing delayed VIP never achieved emptying of the bladder per urethra. Although creatinine levels remained stable, severe upper tract dilatation and fUTIs developed in both patients. A progressive stricture of the VIP-urethral anastomosis was observed in 1 patient, whereas the anastomosis remained patent to a 12Fr catheter in the other. Both patients were started on CIC, which was accepted poorly, and were still attempting to void per urethra for several months. Once regular CIC was established, the clinical condition stabilized, although 1 patient required revision surgery due to ureteral stenosis. At final followup reservoir capacity was 390 and 470 cc. Emptying was complete after CIC. Both patients had nonobstructive upper tract dilatation, which was unilateral in 1 and bilateral in 1. Both were continent day and night and did not wear protection, although 1 complained of occasional episodes of urethral leakage more than 3 hours after last catheterization. At final followup after urinary tract reconstruction (median 3.1 years, range 1 to 15.0) all 6 survivors had normal renal function and no metabolic disturbance. No patient had evidence of stone formation in the reservoir. Two underwent surveillance endoscopy plus biopsy of the reservoir and neither showed abnormal findings. All 6 survivors were male, and the parents or patient reported spontaneous erections in 5. The patient reporting no erections underwent urethrectomy during RC. None of the 4 adolescents reported ejaculation. Two patients claimed to be sexually active, although 1 complained of painful orgasms.

DISCUSSION Our results confirm that a heterotopic catheterizable reservoir is a reliable option for continent diversion after RC. Additionally VIP, if performed simultaneously with RC, can preserve volitional urethral voiding, possibly improving patient quality of life. Compared to other orthotopic neobladders,5 the ileal reconfiguration in the VIP procedure allows creating a round reservoir with a funnel-like outlet that is joined to the membranous urethra. This shape aims to maximize reservoir capacity and optimize emptying, which the patient achieves by squeezing the reservoir by Valsalva maneuver while relaxing the perineal muscles and the rhabdosphincter. Some surgeons have questioned the use of an ileal segment in patients receiving preoperative RT due to the risk of bowel damage, recommending

instead the use of transverse colon, which is located distal to the pelvis.9 We did not observe any macroscopic bowel abnormalities in our patients at surgery or in surveillance biopsies performed in 2 patients more than 10 years postoperatively. A prerequisite for the orthotopic neobladder is that the urethra from the membranous segment onward might be preserved. Unfortunately, ruling out involvement of the membranous urethra in patients with RMS may be difficult, and also intraoperative histology can be fraught with falsenegative results.4 We observed no incongruence between intraoperative histology and definitive pathology, but our 2 cases with local recurrence are worrisome. Our sample size is too small to determine prognostic factors that might help select patients most suitable for VIP but it is noteworthy that patients in whom the disease was deemed confined within the bladder on preoperative or intraoperative assessment had a much better prognosis (5 of 6 survived) than those with evidence of prostatic/posterior urethra involvement (3 of 5 died, and both survivors underwent urethrectomy). Patients undergoing primary VIP always learned to void volitionally. However, the learning process can be long, particularly in young patients, perhaps due to the inherent difficulty of involving these children in a voiding program and the relatively narrow caliber of the urethra, which can impair free passage of thick urine with mucus. Therefore, we recommend leaving a percutaneous suprapubic tube in young patients until the learning process is over. Others recommend a formal catheterizable conduit.5 The latter allows performing post-void catheterization to monitor the residual, and flushing the reservoir in case of mucous retention or to prevent stone formation. In fact, all of our patients undergoing primary VIP learned to empty the reservoir to completion. Moreover, none had episodes of mucous retention or stone formation, or signs of upper tract deterioration during followup. Delayed VIP might allow ruling out any disease recurrence before embarking on urinary tract reconstruction.4,10 On the other hand, the urethral dissection necessary to obtain fresh tissue for the VIP-urethral anastomosis is much more difficult technically than in primary cases, and our results in terms of urinary continence were unsatisfactory. Perhaps scarring secondary to multiple procedures results in a stiff and undynamic segment despite the absence of any anastomotic stricture. Consistent placement of a catheterizable conduit seems mandatory in these cases, and the burden of VIP should be carefully weighed against the possibility of a heterotopic reservoir, which seems an easier procedure that yields more reliable results. The major advantage of an orthotopic reservoir under

BLADDER SUBSTITUTION IN CHILDREN WITH RHABDOMYOSARCOMA

these circumstances might be that it allows for additional access to the neobladder should issues with the Mitrofanoff conduit occur. On the other hand, this approach exposes the patient to the risk of leakage from the nonfunctioning urethra, as in 1 of our patients. It is also noteworthy that both of our patients undergoing delayed reconstruction were reluctant to accept CIC after urethral voiding was planned. Therefore, patients should be warned that urethral voiding is unlikely after this surgery. Consistent with previous reports,4,13 erectile function was generally preserved. The only patient reporting no erections had urethral disease requiring extensive dissection and urethrectomy. One patient specifically complained of painful orgasms.14 Limitations of this study include its retrospective nature, small sample size and long study period. Nevertheless, this condition is rare and only a portion of cases require RC. Moreover, we did not use standardized questionnaires to assess incontinence, urinary symptoms or erectile function, but believed this inappropriate given the heterogeneity and size of our sample and the fact that a formal urodynamic assessment (albeit noninvasive) was performed in all patients. Finally, the present series might not reflect the normal spectrum of patients with RMS as, due to our referral pattern, individuals followed

1855

at our center often include those with poor response to standard treatment and, therefore, a poorer prognosis.

CONCLUSIONS Current multidisciplinary protocols aim to preserve bladder and sexual function in patients with bladder/prostate RMS. When a conservative approach is deemed unfeasible, a heterotopic catheterizable reservoir allows for good oncologic and functional outcomes. However, if the membranous urethra can be salvaged, orthotopic VIP placed at RC can preserve volitional urethral voiding. It is noteworthy that 2 of our 9 patients undergoing VIP experienced local disease recurrence despite negative intraoperative biopsies. Therefore, since preoperative evaluation and intraoperative histology are unreliable to determine disease extension, selection of cases where the membranous urethra is salvageable remains a major challenge. On the other hand, waiting for attainment of disease-free status before embarking on reconstruction does not seem to be a viable strategy, as patients undergoing delayed VIP seem unlikely to achieve voiding per urethra. Finally, erectile function is preserved in the majority of cases.

REFERENCES 1. Crist W, Gehan EA, Ragab AH et al: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 1995; 13: 610. 2. Heyn R, Newton WA, Raney RB et al: Preservation of the bladder in patients with rhabdomyosarcoma. J Clin Oncol 1997; 15: 69. 3. 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. 4. Merguerian PA, Agarwal S, Greenberg M et al: Outcome analysis of rhabdomyosarcoma of the lower urinary tract. J Urol 1998; 160: 1191. 5. Stein R, Frees S, Schr€oder A et al: Radical surgery and different types of urinary diversion in patients with rhabdomyosarcoma of bladder or prostateda single institution experience. J Pediatr Urol 2013; 9: 932.

6. Freitas RG, Nobre YT, Macedo A Jr et al: Continent urinary reconstruction in rhabdomyosarcoma: a new approach. J Pediatr Surg 2004; 39: 1333.

with metastatic soft tissue sarcoma: a pilot study on behalf of the European Pediatric Soft Tissue Sarcoma Study Group. Cancer 2005; 103: 1719.

7. Rigamonti W, Iafrate M, Milani C et al: Orthotopic continent urinary diversion after radical cystectomy in pediatric patients with genitourinary rhabdomyosarcoma. J Urol 2006; 175: 1092.

12. 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.

8. Novara G, Ficarra V, Minja A et al: Functional results following vescica ileale Padovana (VIP) neobladder: midterm follow-up analysis with validated questionnaires. Eur Urol 2010; 57: 1045. 9. Macedo A Jr: Editorial Comment. J Urol 2006; 175: 1096. 10. Duel BP, Hendren WH, Bauer SB et al: Reconstructive options in genitourinary rhabdomyosarcoma. J Urol 1996; 156: 1798. 11. Bisogno G, Ferrari A, Bergeron C et al: The IVADo regimenda pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children

13. 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. 14. Angelini L, Castagnetti M and Rigamonti W: Painful orgasm in an adolescent after seminalsparing cystoprostatectomy: a puzzling symptom. Urol Int 2014; Epub ahead of print.

Oncologic outcome and urinary function after radical cystectomy for rhabdomyosarcoma in children: role of the orthotopic ileal neobladder based on 15-year experience at a single center.

We determined the oncologic and urological outcomes in patients with bladder/prostate rhabdomyosarcoma according to the type and timing of urinary tra...
90KB Sizes 0 Downloads 0 Views