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



The purpose of this study was to determine patient characteristics and outcomes for bladder/prostate (BP) rhabdomyosarcoma (RMS) using an international cohort of prospectively treated patients comparing different treatment algorithms. Data were collected from 379 patients (1979–1998) treated on protocol; Intergroup Rhabdomyosarcoma Study, IRS-IV (n = 239 patients), International Society of Pediatric Oncology Malignant Mesenchymal Tumors (MMT) Committee MMT-84 and -89 (n = 74), Italian Cooperative Group, RMS-79 and RMS-88 Studies (n = 37) or German Cooperative Soft Tissue Sarcoma Study CWS-91 protocols (n = 29). A total of 322 (85%) patients had localized embryonal RMS (ERMS) and 27 had metastatic disease. Thirty patients (21 local disease; 9 metastatic) had nonembryonal BP RMS. Patients with localized ERMS had large tumors (64% >5 cm) that were invasive (54%) with uninvolved regional lymph nodes (N0, 93%). The 5-year failure-free survival (FFS) was 75% and the overall survival (OS) was 84%, with 89% of deaths attributed to disease. Treatment failures were usually local disease recurrence (60%). Predictors of FFS included T-stage (invasiveness), size, and histology. FFS was decreased for patients not receiving initial radiotherapy but this did not translate into a decreased OS. The 21 patients with localized nonembryonal BP RMS had a FFS and OS of 47%. The 36 patients with metastatic disease were more likely to be older and had large tumors that were invasive with alveolar histology and regional lymph node involvement. The 5-year FFS and OS were 41 and 44%, respectively. In conclusion, the majority of BP RMS patients had localized ERMS with a resultant good prognosis using current treatment algorithms. There were differences in FFS between treatment protocols but this did not result in an altered OS.

Genitourinary rhabdomyosarcoma (RMS) accounts for ∼25% of RMS.1 In the first Intergroup Rhabdomyosarcoma Study (IRS-I; 1972–1978), most patients with bladder/prostate (BP) RMS were treated with primary pelvic exenteration, 2 years of chemotherapy and local irradiation. The overall survival (OS) for patients with nonmetastatic BP RMS on IRS-I was 78%, but only 22% of patients retained their bladders at 3 years.2, 3 As chemotherapy programs became more intensive, more patients retained the bladder and survived.4 The goals of IRS-IV were to improve the OS and failure-free survival (FFS) of patients and to improve the rate of bladder preservation, by using initial chemotherapy and delayed local therapy with radiation to avoid exenterative surgery. Tumors commonly arose in the bladder (70%), were of favorable histology (embryonal or botryoid: 80%), large (69% >5 cm), unresectable (84% group III) and invasive (56% T2). OS for nonmetastatic BP RMS was 82% and FFS was 77%. The bladder was preserved in 83% but was only functional in 55% of event-free survivors. Of all patients in the study, 40% (36/88) survived event free with apparently normal functioning bladders.5 This percentage of functioning bladders is similar to other recent series.6

Clinical trials organized by the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors Committee (MMT), the German Cooperative Soft Tissue Sarcoma Study (CWS) the and Italian Cooperative Group (ICG) have explored strategies by which the use of local therapy with radiotherapy (RT) can be modified or avoided on the basis of response to chemotherapy and conservative surgery.7 The overall objectives of these protocols were to improve treatment outcomes and to reduce the consequences of local therapy. Efforts to improve treatment outcome included evaluating early tumor response and modifying chemotherapy and dose intensification in poor responders. Systematic use of RT was avoided in patients who achieved complete local tumor control with chemotherapy, with or without surgery.

We describe the results of an international effort begun in 1999. Members of IRSG, SIOP, ICG and the CWS sought to characterize patients and evaluate outcomes using several treatment strategies. This study presents the largest number of prospectively treated BP RMS patients in the literature. Our results provide a firm characterization of BP RMS patients, their presentation, outcomes and prognostic factors. This study also allows a comparison of the treatment plans used by the different study groups including upfront versus salvage RT treatment.

Material and Methods

A standardized data collection form was developed for reviewing records at the respective statistical centers. Data were collected from patients diagnosed between 1979 and 1998.

Patients were treated based on the following protocols: IRS-IV (n = 239 patients),5 SIOP MMT-84 and -89 (n = 74),7, 8 ICG RMS-79 and -88 (n = 37)9, 10 and CWS-91 (n = 29).11 For all protocols, patients were considered to have alveolar RMS if any portion of the tumor was alveolar histology. These studies all complied with the Helsinki Declaration regarding human experimentation, and informed consent was obtained for all participants, or participant's legal guardian, before the initiation of therapy. In addition, each study was conducted after Human Experimentation Review by the relevant institutional committees. All of these protocols used similar chemotherapy regimens, with either VAC (Vincristine, Actinomycin D, Cyclophosphamide), IVA (Ifosphamide), VAIA (Adriamycin), EVAIA (Etoposide), VACA or CEVAIE (Carboplatin, Epirubicin) at approximately equivalent myelotoxic doses. Surgical recommendations all included an avoidance of radical resections. Completeness of initial surgical resection is reported using the IRS Clinical Grouping System.5 The RT protocol was variable between the treatment groups. IRS patients received RT at Week 9 of therapy if the tumor had not been completely resected (41.4 Gy for Group II microscopic residual disease or 50.4 Gy for Group III gross residual disease). Similar to IRS, for CWS patients no RT was performed for complete resections (Group I). All others received postoperative RT with either 32 Gy (good response to chemotherapy or CR 4–10 days after the initiation of RT) or 44.8 Gy. For SIOP and ICG, only those patients who had not achieved complete remission radiographically (SIOP) or histologically confirmed by second-look operation or biopsy (ICG) after initial chemotherapy obtained local control with a combination of resection and/or RT (45 Gy) between week 9 and 12 of therapy.

FFS was defined as the time from the start of treatment to disease progression/relapse or death from any cause. OS was defined as the time from the start of treatment to death from any cause. The Kaplan-Meier method was used to estimate the FFS and OS distributions. Differences between survival curves were analyzed by the log-rank test. The distributions of categorical participant characteristics were compared between the groups using a χ2 test or Fisher's exact test. Multivariate comparisons of time to event distributions were made using the Cox proportional hazards model.


Patient demographics

Of the 379 patients, 74% were less than 5 years of age and 87% were <10 years with a total of 76% of patients between 1 and 10 years of age. Of these patients, 82% were male (as 67% of the subset of patients were with bladder primaries).

Tumor characteristics

A total of 322 of the 379 patients (85%) had localized embryonal rhabdomyosarcoma (ERMS; including botriod and spindle cell variants). Only 27 (7%) patients with ERMS had metastatic disease. In addition, 30 patients (8%, 21 with local disease; 9 with metastases) had nonembryonal [alveolar, RMS not otherwise specified (NOS) and undifferentiated sarcoma] histology tumors.

The characteristics of patients with localized ERMS are described in Table 1. The site of primary tumor was classified by the different study groups as bladder (59%), prostate (29%) and bladder/prostate, not otherwise specified (12%). Seventy-six (24%) of the ERMS tumors showed botryoid features. Patients with localized BP ERMS had large (64% >5 cm), T-2 [invasive] (54%) tumors and uninvolved regional lymph nodes (N0, 93%).

Table 1. Characteristics of the 322 patients with localized embryonal rhabdomyosarcoma of the bladder/prostate
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Treatment of patients with localized BP ERMS

Local tumor control included a combination of operative resection and/or RT. Resection of the primary tumor was attempted in only 12% of cases, with gross complete resection of the tumor in 5% of all cases (40% of the cases where resection was attempted). For the remaining patients, the tumor was thought to be unresectable and was only biopsied.

Of the 344 Group II/III patients, the RT status is unavailable for five patients. There were 51 of 106 SIOP/ICG patients who had not achieved CR by the end of initial chemotherapy and operation resection who subsequently received RT. There were also 37 CWS/IRSG patients scheduled to receive RT who did not and these were usually young patients in whom there were concerns about the long-term effects of RT on growth, development and function. Therefore, 48% of SIOP/ICG patients required RT, compared to approximately 85% of IRS/CWS patients, for the initial treatment of the primary tumor. These figures do not account for subsequent treatment of relapse.

Outcomes of patients with localized BP ERMS

There were 81 treatment failures in 322 patients with localized ERMS to give a 5-year FFS of ∼75% (95% confidence interval [CI]: 70–79%; Fig. 1). About 88% (71/81) of all failures occurred within 3 years from the initiation of treatment. Failure occurred only locally in 60%, 9% involved regional lymph nodes, with or without local recurrence, and 25% involved distant metastatic disease, with or without locoregional disease, and in 6%, the site of failure was unknown.

Figure 1.

Five-year OS and FFS for patients with localized embryonal RMS.

Five-year OS was estimated to be 84% (53 deaths; Fig. 1). In this patient population, 89% (47/53) of the deaths were attributed to disease. Four of the 322 patients (1% of all patients; 5% of all failures) died as a result of an event unrelated to disease progression: three from treatment toxicity and one from second malignancy. Three of the 322 patients were diagnosed with a second malignancy 1.6–8.4 years from the start of therapy.

Prognostic indicators for localized BP ERMS

Prognostic indicators of FFS in patients with localized BP ERMS were evaluated by univariate analysis. Local tumor invasion was prognostic for FFS, with a 5-year survival of 81% for patients with T-1 (noninvasive) tumors versus 69% for those with T-2 (invasive) tumors (p = 0.006) (Fig. 2a). In addition, size of the primary tumor was prognostically significant with 5-year FFS of 85% for patients with tumors <5 cm compared to 70% for those with tumors >5 cm (p = 0.002; Fig. 2b). T-stage and tumor size appear to be independently prognostic (Fig. 2c). Prognostic differences related to histology of the tumor were also present (5-year survival 82% for botryoid tumors versus 73% for other ERMS tumors, p = 0.08). The incidence of regional nodal disease was so low in these patients that the prognostic significance of nodal disease could not be established.

Figure 2.

(a) Five-year FFS for patients with localized embryonal RMS by T-stage (tumor invasion). (b) Five-year FFS for patients with localized embryonal RMS by size of primary tumor. (c) Five-year FFS for patients with localized embryonal RMS by T-stage and size of primary tumor.

For patients with localized BP ERMS, multivariate analysis demonstrated that tumor size >5 cm (relative risk 2.3, p = 0.006) and invasive tumors (T stage 2; relative risk 1.6, p = 0.06) were independently predictive of FFS. Only tumor size >5 cm was predictive of OS (relative risk 2.4, p = 0.002).

Outcomes of localized BP ERMS based on treatment regimen

There were differences in FFS between the different treatment groups with a 5-year FFS of 81% for ICG and 79% for IRS compared to 65% for SIOP and 70% for CWS (Fig. 3a). However, these differences were not statistically significant (p = 0.17 after correction for differences in tumor invasion and size between treatment groups; Table 2). A total of 55 of the 106 SIOP/ICG patients did not receive RT as part of the initial therapy. The 5-year OS for all study groups was also not significantly different between treatment protocols and ranged between 79 and 85% (p = 0.93 after correction for differences in tumor invasion and size between treatment groups; Fig. 3b).

Figure 3.

(a) Five-year FFS for patients with localized embryonal RMS by treatment protocol. (b) Five-year OS for patients with localized embryonal RMS by treatment protocol.

Table 2. Distribution of T-stage and tumor size by treatment group for 322 localized embryonal RMS
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Outcomes of patients with nonembryonal localized BP RMS

There were 21 patients (6% of all BP RMS patients) with nonembryonal (alveolar and undifferentiated) localized BP RMS. The FFS and OS at 5 years were both 47%.

Characterization and outcomes of patients with metastatic BP RMS

Thirty-six patients (9% of all patients with BP RMS) presented with metastatic BP RMS. Tumor characteristics that differentiated patients with metastatic disease versus localized tumors included large tumors (>5 cm 88% metastatic vs. 64% localized) that were more commonly invasive (90% vs. 54%), age <1 year and older than 10 years (32% vs. 10%) and nonembryonal histologies (25% vs. 6%; Table 3). The 5-year FFS for patients with metastatic disease was 41%; the 5-year OS was estimated to be 44%.

Table 3. Comparison of tumor characteristics for localized versus metastatic disease for all patients (n = 379)
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Histology and patient characteristics

This study demonstrated that most of the patients (76%) were between 1 and 10 years old. For patients with bladder tumors only, there was a 2:1 male to female ratio. The reason for this gender bias is unknown but it is very possible that as many of these tumors are so large at presentation that it is clinically difficult to determine the exact site of origin and in boys some “bladder” may actually be prostate. This difficulty is most likely the explanation seen between study groups (Table 1) in allocating tumors between bladder, prostate or BP. Unfavorable histology (alveolar or undifferentiated) was uncommon (5% of cases). Most of the tumors were large and invasive but without nodal involvement. These results are similar to those reported by Arndt et al. and suggest that this international study patient population was not significantly different than previously described patients with BP RMS.2, 3, 5

Local control

Local control of the tumor is established using either operative resection and/or RT. As increasingly effective multimodality treatment regimens have improved survival rates, the treatment approach has moved toward a less aggressive operative management of the primary tumor in an effort to improve bladder conservation and function.12 If this less aggressive operative approach did not eradicate the cancer, delayed cystectomy/prostatectomy could still achieve local tumor control and survival in many patients.13–19 However, not all groups advocate minimal resection. A report by Filipas et al.20 described 20 patients with BP RMS treated with major resection of the primary tumor after neoadjuvant chemotherapy with subsequent RT in selected patients resulting in a 70% OS rate.

This transition to less aggressive operative resection is reflected in our data in which a primary resection of the tumor was only attempted in 12% of patients. As a result of this trend toward less aggressive operative resection, there has been an increased dependence on RT for local tumor control.

RT has been demonstrated to improve local control for patients with RMS. Unfortunately, RT is associated with treatment complications in patients with BP RMS.21 The repercussions of pelvic RT for RMS were profiled by Spunt et al.22 who described 24 of 26 female patients with Grade 3 and 4 complications associated with RT. Several reports have also implicated RT in post-treatment bladder dysfunction. In the series by Yeung et al.,23 only the children who did not receive RT had normal bladder function. Similarly, Raney et al.24 noted that 30% of patients receiving RT had bladder dysfunction compared to 11% without RT. Hays et al.25 reported that 47% of patients who received RT had long-term bladder sequelae compared to 9% who did not. The amount of RT administered impacted functional sequelae with 17% of patients receiving <40 Gy having dysfunction versus 61% receiving >40 Gy.

Radiation sequelae can be divided into acute and long-term consequences and are dependent on RT dosing. Acute consequences are reversible and are caused by an inflammatory response in the bladder wall.26–33 Alternatively, late consequences are permanent and are a result of fibrosis of the bladder wall due to collagen deposition causing urgency, frequency, hematuria, a dysfunctional sphincter and decreased bladder compliance.34

These complications of RT have resulted in a divergence of treatment strategies by the different study groups. Initially, in IRS-II, local control by RT and resection was delayed until after 8 weeks of chemotherapy, and the decision to pursue these therapies was based on tumor response, similar to the protocol currently used by SIOP and ICG. In IRS–II, this treatment strategy resulted in a 5-year FFS of 58% and an OS of 72%; however, patients who received RT had a 10% complication rate related to growth at 1 year.2, 35, 36 The FFS and OS outcomes from IRS-II are similar to the outcomes for patients treated on the SIOP/ICG protocols in whom RT was given later in therapy only if there was a poor response to initial chemotherapy.37 This concern for complications related to external RT has also led to an increased use of brachytherapy. Brachytherapy combined with conservative resection of tumor may afford improved outcomes of local control as well as bladder function in boys with residual mass after chemotherapy.38 However, as this treatment was not directly compared to standard therapy and was performed on masses after chemotherapy, direct comparisons to outcomes in the studies described here are difficult.

Outcomes and prognostic markers

The prognostic markers indicating a worse prognosis (FFS and OS) identified for this international cohort included nonembryonal histology, tumor invasion and tumor size >5 cm. These results are similar to those reported for RMS regardless of tumor site. In IRSG, the main determinates of outcomes for all patients with nonmetastatic RMS were age (<1 or >10 years), invasive tumors, alveolar histology, site of primary tumor and tumors >5 cm.39 In a contemporary study of 503 SIOP patients with RMS, the primary site of tumor, invasion and histologic subtype were all independent predictors of OS by multivariate analysis.7 Similarly, for 951 patients pooled from international studies with RMS from all sites, tumor invasion, site, size and nodal status were also sited as prognostic factors.40 Botryoid histology also has an improved prognosis compared to other histologies including embryonal when looking at all sites combined.39 This observation is supported by our BP RMS data demonstrating that botryoid histology had a better prognosis than localized ERMS.

The OS for patients with nonembryonal localized BP RMS was similar to patients with ERMS metastatic disease (47% vs. 44%). It is possible that the survival rates for embryonal and nonembryonal metastatic RMS patients are different. Previous reports have shown a 3-year OS of 47% for embryonal and 34% for nonembryonal metastatic RMS.41 However, the number of BP RMS patients with metastatic disease in this cohort were too small to make any conclusions. The patient characteristics associated with metastatic BP RMS disease (large invasive tumors, positive nodes, age <1 or >10 years and nonembryonal histologies) are similar to those previously described for RMS at all sites.41

A factor associated with somewhat poorer FFS was the lack of RT as part of the initial therapy; however, this was not associated with a decreased OS. This would suggest that many patients who had progression or relapse of disease due to lack of RT could subsequently be salvaged probably because they had not been exposed to radiation during their initial therapy, and therefore, the tumors were more likely to relapse locally and still be amenable to further therapeutic interventions resulting in a 44% survival for isolated local relapse.7, 42 This delay in local control with RT has previously been associated with a worse prognosis for patients with BP RMS.43, 44 However, both of these studies are based on older treatment regimens and do not reflect current chemotherapy and local control guidelines. However, these results seem to be supported by our own data as well as by a recent review of CWS outcomes from 1980 to 2002, which demonstrated an increased risk of relapse in patients who did not receive initial RT.45 It needs to be remembered that patients with failure require additional aggressive chemotherapy and RT. Therefore, these relapse patients will have a higher burden of therapy than if they had been irradiated initially and not relapsed.42 This is offset by patients who did well with reduced therapy, including lack of RT, and did not relapse. Identifying the patients who require additional therapy and those who can be adequately treated with less intense therapy is a high priority for all study groups.

Outcome results for BP RMS have not significantly changed in the last 20 years and are not significantly different from those described in this international cohort (FFS 75% and OS 84%).5, 24, 46 This would suggest that significant improvements in survival outcomes are not likely if new therapies are not used in these patients. However, it should be noted that attempts at bladder salvage have not resulted in decreased survival.

Treatment recommendations

Delaying RT in an effort to improve functional outcome and prevent the complications of RT has resulted in a somewhat decreased FFS but no impact on OS. Delaying RT may have resulted in a decreased overall “burden of therapy” for some patients, but this is uncertain as it is not possible to determine the number of patients who relapsed and required salvage therapy with intensified chemotherapy and RT from the current data. These questions underscore the major difference in treatment philosophy on the different sides of the Atlantic as has been described by Donaldson and Anderson.47 Of equal importance for patients with BP RMS is their functional outcome after completion of therapy. Raney et al.48 have previously described the functional outcomes for the same international patient cohort used for this study. They did not demonstrate any differences in morbidity or functional outcome for the different treatment philosophies embodied in the Children's Oncology Group, SIOP, CWS and ICG treatment protocols. The results of Raney et al. combined with our results would argue that either treatment paradigm, delayed selective RT versus early broad RT, is equally efficacious with similar survival and functional outcomes. The ultimate determinant of what may be considered the “best” approach will require carefully constructed, comparative long-term follow-up studies of patients treated by the two differing approaches.