Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults.

BACKGROUND: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome. METHODS: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 × 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS). RESULTS: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups. CONCLUSION: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS.

Tumour volume reduction after neoadjuvant chemotherapy impacts outcome in localised embryonal rhabdomyosarcoma.

BACKGROUND: Response (tumour volume reduction) to induction chemotherapy has been used to stratify secondary local and systemic treatment of Intergroup Rhabdomyosarcoma Study Group III (IRSG-III) embryonal rhabdomyosarcoma (RME) in consecutive CWS-trials. To evaluate its actual impact we studied response-related treatment and outcomes. PROCEDURE: Patients with IRSG-III RME <21 years and non-response (NR, <33% volume reduction) in five consecutive CWS-trials were analysed and compared with partial responders (PAR, ≥ 33% reduction). The NR was reviewed and sub-classified as Objective Response (OR, <0%-33% reduction) or Stable/Progressive Disease (SPD). RESULTS: Fifty-nine of 529 patients had NR (n = 34 OR, n = 25 SPD). Primary risk-factors including age, tumour size, and TN-classification did not differ between NR and PAR groups but NR had more patients with unfavourable sites comparatively (P = 0.04). There were no differences in primary risk-factors between OR and SPD. Significant factors associated with poor outcome in multivariate analysis were NR, TN-classification, age >10 years, tumour size >5 cm and therapy in older trials. After response assessment n = 24 NR continued to receive induction chemotherapy, n = 32 received other combinations and n = 3 no further chemotherapy. Forty-two non-responders were irradiated, and the tumours were completely resected in n = 20. After a median follow-up of 8 years, 34 NR are alive. Seventeen of 21 failures leading to disease-related deaths were locoregional. The five-year overall survival rate (OS) was 76 ± 4% for PAR, 79 ± 14% for OR, but only 40 ± 19% for SPD (P < 0.001). CONCLUSION: Response to induction chemotherapy appears to be an important surrogate marker of poor outcome in patients with SPD largely due to ineffective local control.

Challenges in the local treatment of large abdominal embryonal rhabdomyosarcoma.

BACKGROUND: Embryonal rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. The best local treatment in large, nonmetastatic primary unresected nongenitourinary embryonal rhabdomyosarcoma of the abdomen (LARME) is however unclear. METHODS: We analyzed patients with LARME treated in four consecutive CWS trials. All diagnoses were confirmed by reference reviews. Treatment included multiagent chemotherapy and local treatment of the primary tumor with surgery and/or radiotherapy. The impact of primary debulking surgery (PDS) also was studied. RESULTS: One hundred patients <21 years with a median age of 4 years had LARME. Sixty-one of them had a tumor >10 cm in diameter at diagnosis. PDS was performed in 19 of 100 children. The outcomes of patients with PDS were similar to those of the other patients. In 36 children, the tumor was resected after induction chemotherapy; 60 RME were irradiated. The toxic effects of radiochemotherapy were not significantly increased compared with the nonirradiated patients. With a median follow-up of 10 years, the 5-year EFS and OS were 52 ± 10 and 65 ± 9 %, respectively. Significant risk factors in multivariate analysis were age >10 years; no achievement of complete remission; and inadequate secondary local treatment, defined as incomplete secondary resection or no radiation. CONCLUSIONS: Children with LARME have a fair prognosis, despite an often huge tumor size and unfavorable primary site, if the tumors can either be resected or irradiated following induction chemotherapy. PDS was only performed in a small subgroup. Radiation performed concomitantly with chemotherapy did not increase the acute toxicity significantly.

Impact of hemiscrotectomy on outcome of patients with embryonal paratesticular rhabdomyosarcoma: results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P.

PURPOSE: Children with paratesticular rhabdomyosarcoma have a favorable prognosis. Surgical treatment problems include inadequate primary transscrotal approaches, incomplete tumor resections and the need for secondary hemiscrotectomy. We evaluated the need for hemiscrotectomy regarding local relapse and outcome. MATERIALS AND METHODS: A total of 173 patients with a diagnosis of paratesticular rhabdomyosarcoma were enrolled in the Cooperative Soft Tissue Sarcoma Studies between 1986 and 2008. Of the patients 17 were excluded due to an incomplete data set and alveolar histology. Thus, a total of 156 patients with embryonal subtype were analyzed. All patients were treated according to study protocols, which included multiagent chemotherapy, tumor resection and/or radiotherapy. RESULTS: Mean ± SD 5-year overall survival rate was 91.5% ± 2.4% for patients with embryonal rhabdomyosarcoma. A total of 28 patients underwent transscrotal approaches initially. Of these patients 12 were treated with hemiscrotectomy (mean ± SD 5-year event-free survival 91.7% ± 8%) and 16 without hemiscrotectomy (93.8% ± 6.1%). Additionally 13 of 156 patients underwent an inguinal approach with hemiscrotectomy due to suspicious tumor infiltration of the scrotal skin (mean ± SD 5-year event-free survival 84.6% ± 10%). Relapse was observed in 3 of 12 patients after transscrotal approach with hemiscrotectomy (locoregional lymph node in 1 and metastasis in 2). One metastatic relapse was observed in the group undergoing a transscrotal approach without hemiscrotectomy. One of 13 patients treated with an inguinal approach and hemiscrotectomy had locoregional relapse and died of disease. CONCLUSIONS: Hemiscrotectomy seems not to be mandatory in patients after transscrotal approaches regarding outcome and local relapse. Nevertheless, hemiscrotectomy probably should be performed if the scrotal skin is infiltrated.

Treatment and outcome of patients suffering from perineal/perianal rhabdomyosarcoma: results from the CWS trials--retrospective clinical study.

OBJECTIVE: To analyze the clinical course, treatment, complications, outcome, and quality of life (QOL) in patients with perineal/perianal rhabdomyosarcoma (PRMS) treated within the CWS-86, -91, -96, and -2002P trials. BACKGROUND: Although multiple international study trials exist for the treatment of rhabdomyosarcoma, only very limited information is given on treatment, outcome, and QOL in PRMS. METHODS: A total of 35 patients suffering from PRMS were treated with neoadjuvant chemotherapy. Local therapy with radiation and/or surgery was performed, followed by adjuvant chemotherapy. Functional long-term follow-up was evaluated by a gastrointestinal/QOL survey. RESULTS: Thirty-two patients were evaluated (exclusion n = 3). Eight patients had embryonal histology, and 24 patients had alveolar histology. The median age was 108 months (median follow-up: 5.8 years). The 5-year overall survival was 47% (95% confidence interval: 29-64). Sixteen IRS (Intergroup Rhabdomyosarcoma Study) III and IV patients had locoregional lymph node involvement at diagnosis. Seven patients were treated with chemotherapy/surgery alone [5-year event-free survival (EFS): 85.7%]. Eleven patients received only radiochemotherapy (5-year EFS: 27.3%). Combined radiochemotherapy/surgery was used in 12 patients (5-year EFS: 63.6%). Two patients were treated only with chemotherapy and they died. Patients with embryonal histology had a significantly better 5-year EFS (87.5%) than patients with alveolar histology (39.1%; P = 0.013). Some patients reported symptoms of fecal incontinence. The median Wexner fecal incontinence score was 9 (possible range: 0-20), and the median QOL score was 90.5 (applicable range: 0-144). CONCLUSIONS: The outcome of these patients remains unsatisfactory. Prognostic factors for a favorable outcome are tumor size of smaller than 5 cm, negative locoregional lymph nodes, age less than 10 years, low IRS group, and embryonal histology. Fecal incontinence seems to be a problem.