DOES THE LESS AGGRESSIVE MULTIMODAL APPROACH OF TREATING BLADDER-PROSTATE RHABDOMYOSARCOMA PRESERVE BLADDER FUNCTION?

0022-5347/05/1746-2343/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 174, 2343–2346, December 2005 Printed in U.S.A.

DOI: 10.1097/01.ju.0000180644.32615.39

DOES THE LESS AGGRESSIVE MULTIMODAL APPROACH OF TREATING BLADDER-PROSTATE RHABDOMYOSARCOMA PRESERVE BLADDER FUNCTION? ROBERTO SOLER, ANTONIO MACEDO, JR.,* HOMERO BRUSCHINI, FABI´OLA PUTY, ELIANA CARAN, ANTONIO PETRILLI, GILMAR GARRONE, MIGUEL SROUGI AND VALDEMAR ORTIZ From the Department of Urology, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil

ABSTRACT

Purpose: The treatment of bladder-prostate rhabdomyosarcoma has evolved into multimodal therapy, including chemotherapy, radiotherapy and organ sparing surgery with bladder preservation. We investigated bladder function in children who underwent multimodal therapy at our institution and retained the original bladder for at least 6 months after treatment ended. Materials and Methods: We evaluated 8 children with bladder-prostate rhabdomyosarcoma treated at our institution between 1999 and 2003 according to inclusion criteria. All patients underwent history, physical examination and urodynamic study at least 6 months after completion of treatment (range 6 to 39 months). Results: All patients were treated following the same chemotherapy and radiotherapy scheme. Three patients (37.5%) were asymptomatic and had normal urodynamic studies, and 1 had only dysuria (this patient later underwent continent urinary diversion with transverse colon). The 4 remaining patients had urological complaints, and the urodynamic findings were reduced bladder capacity in 4, overactivity plus sensory urgency in 2, sensory urgency only in 1 and suprapubic pain during filling in 1. Conclusions: Among 8 patients 3 had normal urinary function and 4 had minor tolerable alterations. Cystectomy and urinary diversion were later necessary in only 1 patient due to disabling dysuria. The fact that the original functioning bladder was preserved in 7 of 8 patients suggests the feasibility of multimodal therapy. Long-term followup will still be necessary for definite conclusions, since we recognize that the deleterious effects, mainly of radiotherapy, may take longer to become evident. KEY WORDS: bladder, prostate, rhabdomyosarcoma, radiotherapy, drug therapy

Rhabdomyosarcoma is the most common type of tumor in children, representing 4% to 8% of all malignant tumors seen in patients younger than 15 years.1 In the Third Intergroup Rhabdomyosarcoma Study (IRS-III, 1995 to 1990) and IRS-IV (1991 to 1997) approximately 10% of cases had their origins in the bladder/prostate (BP).2, 3 Through multicenter collaborative studies BP rhabdomyosarcoma (RMS) treatment evolved into a multidisciplinary focus comprising chemotherapy, radiotherapy and organ preserving surgery. With better survival rates the objective has become focused on less aggressive treatment of the primary tumor to increase the rate of bladder preservation. However, bladder preservation does not necessarily mean the bladder will maintain its active emptying/filling normal accommodation function. In a series of patients with pelvic RMS Yeung et al reported bladder dysfunction in all of those who had undergone radiotherapy.4 The bladder preserving rates are discrepant in subsequent IRS reports3, 5 due to the lack of patterned objective data, which would allow a more accurate evaluation.6 The purpose of this study was to evaluate, through urodynamic testing, bladder function in children who underwent this treatment modality at our institution and retained the original bladder. Submitted for publication March 24, 2005. *Correspondence: Rua Maestro Cardim, 560/215, 01323– 000, Sa˜o Paulo, Brazil (telephone/FAX: 55 11 32870639; e-mail: Macedo.dcir@ epm.br).

MATERIALS AND METHODS

This study included 10 children with BP RMS who had an intact bladder after treatment at our institution between 1999 and 2003. At the initial evaluation patients were classified according to surgical and pathological extension findings and tumor resectability,7 and clinically, taking into account the primary site, lesion size and presence or absence of clinically detectable lymph nodes and/or metastatic illness according to the Intergroup Rhabdomyosarcoma Study.8 The treatment regimen followed protocol 8750 of the Pediatric Oncology Group (POG) guidelines, which involves the combination of vincristine, actinomycin D and cyclophosphamide plus ifosfamide and etoposide. Treatment duration was 36 weeks, with each cycle taking place every 3 weeks. Patients underwent conventional radiotherapy using linear accelerator with a ⫺6 mV proton beam during the 9th and 12th weeks. Radiation fields comprised anterior and posterior pelvis in all patients, except for 2 girls who had the anterior and posterior abdomen irradiated. At a minimum of 6 months after completion of treatment children were evaluated by history and physical urological examinations, focusing on bladder function, and by urodynamic study (Aquarius™), conducted by the same investigator. The parents were questioned during the interview that preceded urodynamic study about current signs and urinary symptoms, such as urinary incontinence (daytime/nighttime), hematuria, increased daytime frequency, nocturia, urgency, pain or discomfort during voiding, and abnormal void-

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DOES MULTIMODAL THERAPY FOR BLADDER-PROSTATE CANCER PRESERVE BLADDER FUNCTION?

ing pattern (hesitancy, intermittency, straining). If the child experienced any of these symptoms, quality of life was assessed by asking the parents and children about its impact on daily routine activities regarding family, social and school life. Before the examination the physician and nurse explained in detail the technique and steps of the procedure to parents, so that together they could explain it to the child in a confident and reassuring way. No patient received anesthesia or sedation. Children were asked to urinate for uroflowmetry. The examination was followed with insertion of an intravesical 7Fr catheter via the urethra after local anesthesia with lidocaine 2% gel and insertion of a 12Fr rectal balloon catheter. Bladder content was emptied for residual volume verification. Filling of the bladder was accomplished with physiological solution at room temperature at 20 ml per minute. Bladder, abdominal and detrusor pressure, and bladder sensation were continuously evaluated during bladder filling. Bladder capacity was evaluated based on the normal volume for age according to the formula proposed by Koff.9 Detrusor overactivity (DO) was observed through detrusor pressure involuntary increase associated with urgency during the filling phase. Bladder compliance was calculated by dividing the cystometric capacity in ml by detrusor pressure at cystometric capacity in cm H2O. A value of more than 20 ml/cm H2O was considered normal.10, 11 Two boys were excluded from the study, of whom 1 presented with early local recurrence (less than 6 months) and underwent radical salvage surgery and 1 suffered a head injury during evaluation. RESULTS

Four boys and 4 girls were included in the study. All patients were younger than 10 years at the beginning of treatment (range 1.5 to 6) and during bladder function evaluation (3 to 9, table 1). In 7 patients diagnosis was established by biopsy, 4 by laparotomy and 3 by cystoscopy. In 1 patient, who presented with a huge abdominopelvic mass originating on the bladder wall, partial cystectomy (resection of the anterolateral wall of the bladder) was performed as the initial procedure. The primary site of tumor was the bladder in 6 cases, bladder plus prostate in 1 and prostate in 1. The embryonal histological type tumor prevailed over the botryoid type, for the most part being classified as stage 3 and group III (table 2). Bladder function was evaluated during the course of 9 to 36 months (average 17). Most patients had achieved daytime and nighttime urinary control by the time of evaluation, and only one 3-year-old boy had to use diapers at night. Three patients (37.5%) did not present with urinary complaints, 2 (25%) presented with dysuria, 2 (25%) had increased daytime frequency and one 8-year-old girl (12.5%) had nocturnal enuresis. According to informants, symptoms did not impair daily routine activities, except for in a girl who presented with disabling dysuria. All children underwent urodynamic study (table 3). Maximum flow rate varied from 5.5 to 22.7 ml per second, and no patient had post-void residual. Bladder compliance was normal in all examinations, and detrusor pressure at cystometric capacity varied from 1 to 8 cm H2O in all patients. Reduced bladder capacity (RBC, 33% to 52% of expected capacity for age) was observed during 4 examinations (50%) due to overactivity and sensory urgency (SU) in 2 cases, pain

TABLE 1. Patients characteristics No. males No. females Mean yrs age at start of treatment (range) Mean yrs age at bladder function evaluation (range)

4 4 3.4 (1.5–6) 5.6 (3–9)

TABLE 2. Tumor characteristics No. Pts Biopsy: Laparotomy Cystoscopy Partial cystectomy Site: Bladder Bladder ⫹ prostate Prostate Histology: Embryonal Botryoid Stage: 3 4 Group IIC

4 4 3 1 6 1 1 5 3 7 1 1

TABLE 3. Clinical and urodynamic characteristics No. Pts Symptoms: None Frequency Dysuria Nocturnal enuresis Voiding pattern: Normal Dysuria Normal compliance Detrusor overactivity: No Yes Normal bladder capacity Reduced bladder capacity: Pain Sensory urgency Sensory urgency ⫹ detrusor overactivity

3 2 2 1 7 1 8 5 3 4 1 1 2

during bladder filling in 1 and SU in 1. Three examinations (37.5%) were considered normal. One girl presented with intense dysuria during pressure flow phase (table 3). In this case, due to the clinically disabling condition, continent urinary diversion with transverse colon was selected 7 months after completion of treatment.12 Although there was a homogenization of the treatment scheme adopted for all children, due to the small number of patients, it was not possible to establish a correlation between the urodynamic changes and the primary tumor site or the interval from last treatment (table 4). Also, since cystectomy was performed in only 1 case, it was not possible to establish a direct correlation between reduction surgery and urodynamic changes. DISCUSSION

During the last 3 decades multicenter collaborative studies have demonstrated improved results in overall and eventfree survival rates for children with BP RMS. Treatment currently focuses on bladder preservation and quality of life improvement. In IRS-I most patients underwent radical surgery as an initial procedure. In an attempt to avoid such procedures a primary multiagent chemotherapy approach combined with radiotherapy was used in IRS-II. However, during a 3-year period mortality rates (26%, 30%) and bladder preservation rate (22%, 25%) were similar in both studies. In IRS-III the primary chemotherapy approach was intensified and radiotherapy doses were increased. This modality was used in all patients for 6 weeks, except those in whom tumor removal was possible without the need for total cystectomy. In this group bladder preservation rate at 3 years was 60%.5 The objectives of IRS-IV were to increase the global and

DOES MULTIMODAL THERAPY FOR BLADDER-PROSTATE CANCER PRESERVE BLADDER FUNCTION?

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TABLE 4. Tumor, treatment and bladder function characteristics Sex—Age (yrs) M—3 M—3 F —5 F —4 M—9 M—4 F —9 F —8

Tumor Site Bladder (wall/pelvic mass) Bladder (dome) Bladder (wall/abdominopelvic mass) Bladder (base/lateral wall) Bladder (base) ⫹ prostate Prostate Bladder (dome/lateral wall) Bladder (wall/pelvic mass)

Radiotherapy (cGy)

Last Treatment (mos elapsed)

Histology

Stage/ Group

Chemotherapy Protocol

Cystoscopy

Embryonal

3/III

POG 8750

Pelvic (3,990)

6

Laparotomy Partial cystectomy

Botryoid Embryonal

3/III 3/IIC

POG 8750 POG 8750

Pelvic (4,050) Pelvic (3,000)

Cystoscopy

Botryoid

3/III

POG 8750

Cystoscopy

Embryonal

3/III

Laparotomy Laparotomy

Botryoid Embryonal

Laparotomy

Embryonal

Biopsy

Symptoms

Urodynamic Findings

None

Normal

9 10

None Frequency

Normal RBC (pain during filling)

Pelvic (4,500)

16

Normal (dysuria)

POG 8750

Pelvic (4,500)

20

Disabling dysuria Frequency

RBC (SU)

3/III 3/III

POG 8750 POG 8750

21 33

None Dysuria

Normal RBC (SU, DO)

4/IV

High grade sarcoma

Pelvic (4,500) Abdominal (4,500) Abdominal (4,500)

39

Nocturnal enuresis

RBC (SU, DO)

event-free survival rates, and improve bladder function. Arndt et al evaluated bladder function in 88 patients with BP RMS who were included in IRS-IV.3 At 6 years the global survival and event-free survival rates were 82% and 77%, respectively. Patients were evaluated by questionnaire and mailers, and only 1 child underwent urodynamic studies. In that study 40% of patients were classified as failure-free with normal functioning bladder. Compared to previous results, bladder preservation function rate was decreased (60% vs 40%) in IRS-IV. Probable explanations for such a discrepancy would be different definitions for normal bladder function and longer followup (6.1 vs 3 years), since bladder function may deteriorate with time due to the long-term effects of radiotherapy. Yeung et al studied bladder and renal function in 11 children with pelvic (bladder, prostate, pelvic wall, vagina and uterus) RMS, with an average followup of 6.6 years.4 All patients underwent chemotherapy and conservative surgery. Radiotherapy was used in 7 patients, all of whom presented with urinary pattern changes and reduced functional bladder capacity (11% to 48% of bladder capacity expected for age). In contrast, the 4 patients who did not undergo radiation presented with normal bladder behavior. Data were obtained from a frequency-volume chart, and 4 children with urinary changes underwent urodynamic study. Pattered objective data such as symptom questionnaires and urodynamics will be required for better evaluation of bladder function in future multicenter studies. In our experience urodynamic study was an important tool to evaluate the success of treatment. Even taking into account a highly manipulated group of cases, due to the intensity and frequency of the examinations, hospitalization and treatment itself, performance of urodynamic study was not associated with major difficulties. A longer period was required from the beginning of the examination until the child could comprehend, through interventions of the doctor, nurse and parents, how to collaborate. This factor did not represent an obstacle for the safe accomplishment of the examination, which makes it positively feasible. Urodynamic data obtained in our study correlated with patient complaints. However, they reflected with greater objectivity the intensity of the symptoms. Three patients were nonsymptomatic and had a normal study, with followup of 21 months. In the remaining patients the main change was reduced bladder capacity, with varied followup (10 to 39 months). We delineated additional subgroups, ie those who received less (3 patients) or more (5) than 4,500 cGy radiotherapy. Symptoms were present in 1 of the 3 patients receiving less than 4,500 cGy, compared to 4 of 5 of those receiving more than 4,500 cGy. Considering the small number of

patients, it is impossible to draw any conclusions regarding the impact of radiation dose on bladder dysfunction. Reports from IRS-I and IRS-II revealed no correlation between high doses of radiation therapy and bladder dysfunction. On the other hand, IRS-IV did not allow any conclusions concerning this subject because a small number of patients did not undergo irradiation.3, 13 Only 1 patient our series, who presented with disabling dysuria, underwent cystectomy and urinary diversion as a result of treatment effect on the lower urinary tract. According to the questionnaire respondents (parents), the complaints did not constitute an obstacle to daily life activities in the remaining children. This finding supports other studies showing that multimodal therapy is a well tolerated and plausible form of noninvasive intervention that improves quality of life. Longer followup is necessary to assess preservation or deterioration of bladder function, since changes resulting from radiation, such as fibrosis, tend to occur later. Therefore, data collected in the future will provide interesting information concerning this issue. CONCLUSIONS

Treatment of BP RMS has evolved into a multidisciplinary therapeutic modality that is less aggressive and that, in addition to healing, aims to decrease morbidity. Preservation of an anatomical and functional bladder is an important objective regarding this aspect. In our series of 8 patients, who are still undergoing early followup, 3 had normal bladder function, 4 had tolerable changes and 1 required secondary intervention due to treatment complications. These preliminary results suggest the feasibility of this treatment approach and the positive impact on quality of life, although longer followup is required for more definite conclusions. REFERENCES

1. Shapiro, E. and Strother, D.: Pediatric genitourinary rhabdomyosarcoma. J Urol, 148: 1761, 1992 2. Crist, W., Gehan, E. A., Ragab, A. H., Dickman, P. S., Donaldson, S. S., Fryer, C. et al: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol, 13: 610, 1995 3. Arndt, C., Rodeberg, D., Breitfeld, P. P., Raney, R. B., Ullrich, F. and Donaldson, S.: Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/prostate rhabdomyosarcoma? Results from intergroup rhabdomyosarcoma study IV. J Urol, 171: 2396, 2004 4. Yeung, C. K., Ward, H. C., Ransley, P. G., Duffy, P. G. and Pritchard, J.: Bladder and kidney function after cure of pelvic rhabdomyosarcoma in childhood. Br J Cancer, 70: 1000, 1994 5. Hays, D. M., Raney, R. B., Wharam, M. D., Wiener, E., Lobe, T. E., Andrassy, R. J. et al: Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadju-

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DOES MULTIMODAL THERAPY FOR BLADDER-PROSTATE CANCER PRESERVE BLADDER FUNCTION?

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H., Millard, R. et al: The standardization of terminology in neurogenic lower urinary tract dysfunction: with suggestions for diagnostic procedures. International Continence Society Standardization Committee. Neurourol Urodyn, 18: 139, 1999 11. Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U. et al: The standardisation of terminology of lower urinary tract function: report from the Standardisation Subcommittee of the International Continence Society. Neurourol Urodyn, 21: 167, 2002 12. Freitas, R. G., Nobre, Y. T., Macedo, A., Jr., Demarchi, G. T., Ortiz, V. and Srougi, M.: Continent urinary reconstruction in rhabdomyosarcoma: a new approach. J Pediatr Surg, 39: 1333, 2004 13. Raney, B., Jr., Heyn, R., Hays, D. M., Tefft, M., Newton, W. A., Jr., Wharam, M. et al: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study Committee. Cancer, 71: 2387, 1993