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Background: Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma., Methods: We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m 2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m 2 weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m 2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m 2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up., Findings: Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6-78·9). The 3-year event-free survival was 67·5% (95% CI 61·2-73·1) in the IVA plus doxorubicin group and 63·3% (56·8-69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65-1·16; p=0·33). Grade 3-4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3-5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group., Interpretations: The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe., Funding: Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Extremity rhabdomyosarcomas do not always show satisfactory outcomes. We analyzed data from 643 patients treated in 14 studies conducted by European and North American groups between 1983 and 2004 to identify factors predictive of outcome., Procedure: Clinical factors, including age; histology; site of primary (hand and foot vs. other); size; invasiveness (T stage); nodal involvement (N stage); and treatment factors, including post-surgical group; chemotherapy type and duration; radiotherapy; and treatment (before or after 1995); were evaluated for impact on overall survival (OS)., Results: 5-year OS were 67% (se 1.8). Multivariate analysis showed that lower OS correlated with age >3 years, T2 and N1 stage, incomplete initial surgery, treatment before 1995, and European cooperative group treatment. Patients with gross residual disease after initial incomplete resection/biopsy had similar outcomes in both continental groups. The better global survival of patients treated in American studies was accounted for by differences in outcome in the subset of those with grossly resected tumors (OS 86% [se 3] for COG patients vs. 68% [se 4] for European patients (P = 0.004)). When excluding chemotherapy duration from the model, analysis in this subset of patients showed that cooperative group (P = 0.001), site (P = 0.001), and T stage (P = 0.05) were all significant. However, after adding duration of chemotherapy (≥27 weeks) to the model, only primary site remained significant (P = 0.006)., Conclusion: This meta-analysis confirms the role of many established prognostic factors but identifies for the first time that chemotherapy duration may have an impact on outcome in patients with grossly resected tumors., (© 2015 Wiley Periodicals, Inc.)

Background: The results obtained by protocols for children with rhabdomyosarcoma (RMS) have improved in recent decades. Survival curves usually reach a plateau 3 years after the diagnosis, suggesting that long-term survival can be expected, but late events are known to occur. We analyzed the long-term results of the RMS 79 protocol to investigate the type and impact of such events., Procedure: From 1979 to 1987, 163 children with RMS diagnosed at 21 Italian institutions were registered. Each institution was contacted every year to record patients' status after the end of treatment. When patients were lost to follow-up, their status was checked by inquiring at the Registry Offices of the towns of residence and the cause of death or occurrence of second cancers was investigated by contacting the patients or their family by phone., Results: Overall, 16 patients had late events, that is, 7 tumor recurrences, 6 second tumors, and 3 deaths due to treatment-related complications. The overall survival rates dropped from 62.6 at 3 years to 52.8 at 20 years. By multivariate analysis, the characteristics influencing long-term survival were histology, tumor site and size, and IRS group. Factors predictive of any kind of late event were tumor site and IRS group., Conclusions: Major late events can significantly affect the long-term survival of children with RMS. Modern protocols should provide for a much longer follow-up than is usually considered to confirm the results achieved and enable possible correlations between primary treatment and late events to be investigated., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: In many types of cancer, the survival rates are reported to be less favorable for adolescents compared with younger children. To investigate whether this is true for adolescents with rhabdomyosarcoma (RMS), the results obtained in patients enrolled in protocols run by the Italian Soft Tissue Sarcoma Committee (STSC) were analyzed., Methods: From 1988 through 2005, 643 patients were registered (567 children ages birth-14 years and 76 adolescents ages 15-19 years) and treated in 4 STSC protocols. The number of patients enrolled was compared with the expected number calculated from incidence rates derived from the Italian network of cancer registries., Results: Only 27% of the expected number of adolescents with RMS were enrolled in the STSC trials. Compared with children, adolescents were found to have a longer interval from initial symptoms to diagnosis (8 weeks vs 4.6 weeks), more alveolar RMS (47.4% vs 32.6%), lymph node infiltration (39.1% vs 23.3%), and metastases at the time of diagnosis (30.7% vs 17.8%). The 2 age groups received similar treatments. The 5-year overall survival (OS) rate was 68.9% in children versus 57.2% in adolescents (P = .006), and the progression-free survival (PFS) rate was 64.3% in children versus 48.1% in adolescents (P = .0237). On multivariate analysis, age, tumor site, lymph node involvement, and metastases were found to be significant prognostic factors for OS and PFS., Conclusions: Survival for adolescents with RMS enrolled in STSC protocols appears to be satisfactory. The higher prevalence of unfavorable tumor characteristics noted among adolescents seems to explain their worse outcome compared with children. However, the limited number of adolescents enrolled in STSC studies is worrisome, and cooperation with oncologists who treat adults needs to be improved., (Copyright © 2011 American Cancer Society.)

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., (Copyright © 2010 UICC.)

Background: Breast metastasis from rhabdomyosarcoma (RMS) is an uncommon event but may be problematic in treatment decision-making. Aim of the study was to evaluate clinical characteristics, treatment, and subsequent outcome, of patients with RMS metastasis in the breast, enrolled in four consecutive Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) Soft Tissue Sarcoma Committee protocols during the last 20 years, in order to obtain information to establish a more adequate diagnostic and therapeutic approach., Procedures: Data were derived from the AIEOP STSC database and reviewed for the purpose of this study., Results: From 1988 to 2008, among 189 patients with metastatic RMS, we identified 7 (3.7%) patients with RMS with breast involvement at diagnosis. All patients were females, aged 13-17 years with alveolar histology and multiple metastasis sites (2-5). The primary tumor was located in the extremities in 3/7 patients. In spite of intensive treatment no patient survived. The cause of treatment failure was distant relapse in six patients, including two on the mammary region. Treatment data analysis revealed that local measures to control breast lesions were used in only two patients., Conclusions: Our data suggest that investigations of the mammary region should be part of the usual diagnostic workup in adolescent girls with alveolar RMS, especially if the primary tumor arises in the extremities. New and more effective strategies are needed to improve the outcome of these patients including aggressive local measures to control breast disease., (Copyright © 2010 Wiley-Liss, Inc.)

Aim: The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma., Patients and Methods: Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered., Results: Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years., Conclusion: Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma.

Background: Sentinel Node Biopsy is an established staging technique in many adult malignancies. However, only few reports describe this procedure for the evaluation of regional lymph nodes in childhood and adolescents. Our experience with sentinel node biopsy in soft tissue sarcomas of extremities in children is reported., Methods: Seventeen children were evaluated with sentinel node biopsy between 2002 and 2007: 11 at initial surgery, 5 at primary re-excision, 1 at local relapse. The diagnosis was rhabdomyosarcoma in 5 and other soft tissue sarcomas in 12: Ewing/PNET sarcoma 6, epithelioid sarcoma 1, malignant peripheral-nerve-sheath tumor 1, undifferentiated sarcoma 1, myxoid liposarcoma 2, adult-type fibrosarcoma 1. Primary sites included lower limbs (8), upper limbs (9). Mapping of nodes was performed with lymphoscintigraphy plus intra-operative injections with blue-dye in 14 cases, with lymphoscintigraphy and intra-operative injections alone in 2 and 1, respectively., Results: Of the 17 lymphatic regions (9 axilla, 8 inguinal), 16 were identified with lymphoscintigraphy, 15 by intra-operative injections. Thirty-five lymph nodes were removed. Nodes were positive for metastasis in two patients with alveolar rhabdomyosarcoma and undifferentiated sarcoma. There were no complications. No further lymph node metastases were recognized either at diagnosis or during the follow-up (6-78 months)., Conclusions: Sentinel node biopsy was technically feasible, reliable, and free of complications. It could be an alternative to aggressive or random biopsies for extremity rhabdomyosarcoma and it can contribute to define those non-rhabdomyosarcoma soft tissue sarcomas that spread to regional nodes.

Background: To evaluate the effect of radiotherapy (RT) in association with complete second look operation, histologically confirmed, on outcome of patients with IRS Gr.III non-alveolar RMS., Procedure: We analyzed data from 39 patients (age: 0.5-194 months, median 52) who were enrolled between 1988 and 2005 in 2 consecutive Italian Studies, RMS 88 and RMS 96. All achieved a complete resection of the residual tumor after neoadjuvant chemotherapy; 27 did not receive any other local treatment: pelvic 8, extremities 6, head-neck-non-parameningeal 5, orbit 1, genito-urinary-bladder-prostate 3, trunk 2, abdomen 1, vagina 1; 12 were given RT (32-45 Gy), 5 before and 7 after the operation: genito-urinary-bladder-prostate 3, pelvic 3, abdominal 1, extremities 1, head-neck-parameningeal 1, head-neck-non-parameningeal 1, vagina 1, orbit 1. All received postoperative chemotherapy., Results: Median follow-up was 81 months (range 17-219 months). With RT: 10/12 patients are in first complete remission; 2/12 had a metastatic relapse (1 also local relapse), and both of them died of disease. Without RT: 16/27 maintained the first complete remission, however 1/16 died due to a second tumor; 8 suffered from local relapse (4 pelvic, 1 orbit, 1 vagina, 1 head-neck-non-parameningeal, 1 abdomen) and 3 of them died, 3 showed a metastatic recurrence (2 extremities, 1 pelvic) and 1 died., Conclusions: Local relapses were more frequent for patients without RT, especially in pelvic sites. The two relapses after RT occurred in huge bladder-prostate RMS. Although the limited number of patients does not allow statistically significant conclusions, our experience suggests that RT may have a positive influence on local control for completely resected non-alveolar RMS., ((c) 2008 Wiley-Liss, Inc.)

Background: Parameningeal rhabdomyosarcoma (PM-RMS) is a rare, highly malignant pediatric tumor arising from locations adjacent to the meninges, from where it can spread intracranially., Procedure: We reviewed 109 children with non-metastatic PM-RMS enrolled in the Italian RMS79, RMS88 and RMS96 protocols over a 24-year period. All patients received intensive chemotherapy and standard or hyperfractionated and accelerated radiotherapy. Some had delayed surgery., Results: Five-year overall survival rose from 40% in the RMS79 to 72% in the RMS88 and RMS96 protocols (P = 0.01), where more intensive chemotherapy and hyperfractionated accelerated radiotherapy (HART) was used. Delayed surgery after initial treatment was statistically associated with a better prognosis. Unfavorable tumor characteristics for RMS arising in other sites, for example, histology, invasiveness or node involvement, did not predict outcome for PM-RMS., Conclusion: Outcome in PM-RMS patients enrolled in three consecutive Italian protocols has progressively improved, as a result of intensive chemotherapy, delayed surgery and, possibly, HART, though improved imaging and radiotherapeutic tools may have had a role as well., ((c) 2007 Wiley-Liss, Inc.)

Purpose: To identify risk factors associated with outcome in children with metastatic rhabdomyosarcoma in a large cohort of patients, Patients and Methods: Pooled data were obtained from 788 patients treated in nine studies performed by European and American cooperative groups. Clinical factors, including age, histology, site of primary, and site(s) and number of sites of metastatic disease, were correlated with event-free survival (EFS) and overall survival (OS)., Results: Seven hundred eighty-eight patients were eligible for analysis. The 3-year OS and EFS were 34% (SE, 1.7) and 27% (SE, 1.6), respectively. By univariate analysis, 3-year EFS was significantly and adversely influenced by age, alveolar histology, location of primary tumor in unfavorable site (defined as extremity and "other" sites), presence of three or more sites of metastatic disease, and the presence of bone or bone marrow involvement. By multivariate analysis, EFS was strongly correlated to all factors except histology. Relative risks were 1.6 for age younger than 1 year or at least 10 years, 1.4 for unfavorable site of primary tumor, 1.4 for bone or bone marrow involvement, 1.4 for three or more metastatic sites. EFS was 50% for patients without any of these four adverse factors and was respectively 42%, 18%, 12%, and 5% in patients with one, two, three, or four factors (P < .0001)., Conclusion: This analysis identified subsets of patients with metastatic rhabdomyosarcoma with different outcomes to current therapy and offers a strategy to define patient candidates for experimental approaches to treatment.

Background: The purpose of the current study was to analyze the influence of the initial surgical approach (biopsy vs resection with macroscopic residual tumors) on the outcome of patients with localized Intergroup Rhabdomyosarcoma Study (IRS) Group III rhabdomyosarcoma (RMS) enrolled in the Italian studies between 1979 and 2003., Methods: Among the 394 patients evaluated, 323 underwent biopsy, as recommended by the protocols, and 71 patients underwent surgical resection with macroscopic residual tumors (debulking operation [DO]), although this procedure was discouraged. All these patients were classified at the same risk group and received the same treatment. The different characteristics (patient age, tumor site, T classification and size, histology) and outcome in the 2 groups were considered., Results: The estimated 5-year overall survival (OS) rates were 68.4% and 72.6%, respectively, after biopsy and DO (P=.38), and the rates of progression-free survival (PFS) were 56.5% and 61.7%, respectively, after biopsy and DO (P=.41). The outcome did not differ significantly when considering other variables such as tumor site, size, and histology. Age>10 years appeared to have little benefit in patients with DO; the OS was 62% after biopsy and 83.1% after DO (P=.06); the PFS was 49.7% and 72.8%, respectively after biopsy and DO (P=.04). No surgical complications due to the 2 procedures were reported, but in 2 cases the initial DO resulted in a mutilation., Conclusions: No significant advantages of DO versus biopsy were detected with regard to patient outcome. Biopsy, which is less aggressive, appears to be thebest option for patients with IRS Group III RMS., (Copyright (c) 2007 American Cancer Society.)

Purpose: We determined the late sequelae in children and adolescents with rhabdomyosarcoma of the bladder/prostate treated in the United States, Canada and selected Western European countries, primarily France, Germany, Italy and the United Kingdom, from 1979 to 1998., Materials and Methods: We used a data collection form to record data from patient records available at the group statistical centers., Results: A total of 164 patient charts had sufficient data available to be included in the study. Median patient age at diagnosis was 2.4 years. Median length of followup was approximately 8 years (range 3 to 24). Of the patients with available data 78 did not undergo cystectomy, 49 underwent partial cystectomy and 34 underwent complete cystectomy. Urinary continence was assessed at age 6 years or older in 62 patients who did not undergo cystectomy. Of these patients 43 (69%) were continent, 16 had nocturnal incontinence and 9 had diurnal incontinence. Of 44 patients who underwent partial cystectomy and had pertinent followup data 32 (73%) were continent, and 12 had nocturnal and/or diurnal incontinence. Only 11 patients underwent urodynamic investigation. Other nephrourological complications consisted of 3 or more urinary tract infections in 29 of 53 patients, abnormal renal function in 19 of 48 (tubulopathy 14, increased creatinine/blood urea nitrogen 5), chronic hematuria in 13 of 51 and hydronephrosis in 8 of 54 with available data. Vesicoureteral reflux, urinary stones and bowel problems were infrequent., Conclusions: Of the patients 48% had a relatively intact bladder after biopsy only. However, 31% of patients 6 years or older had some urinary incontinence, as did 27% of patients who had undergone partial cystectomy. In addition, 55% of all patients had 3 or more urinary tract infections, 40% had decreased renal function and 25% had chronic hematuria. Other complications were present in 15% or less of the patients with available data.

Background: Rhabdomyosarcoma (RMS) has 2 major histologic subtypes: alveolar (ARMS) and embryonal (ERMS). ARMS is more aggressive and prone to distant tumor dissemination, whereas ERMS tends to expand and recur locally. Little information is available on bone marrow involvement by RMS., Methods: We determined the sensitivity and specificity of MyoD1, myogenin, and PAX-FKHR transcripts as RMS markers and used them to study prospectively by reverse-transcriptase polymerase chain reaction (RT-PCR) a series of consecutive unselected RMS patients enrolled in the Italian Association of Pediatric Hematology and Oncology national trial. Prevalence of minimal disseminated disease (MDD) and its response kinetics to chemotherapy were assessed., Results: MyoD1 and myogenin were specifically associated with RMS, independently of histologic subtype, whereas PAX3/7-FKHR transcripts were expressed only in ARMS. Sensitivity was higher for MyoD1 compared with myogenin and PAX-FKHR. Out of a cohort of 40 patients, MDD positivity was limited to ARMS, with the sole exception of 1 ERMS. Prevalence of MDD positivity increased when a real-time polymerase chain reaction approach was used on a subgroup of patients. RT-PCR was more sensitive than microscopic examination of bone marrow biopsies. The study of the response kinetics of MDD showed that in approximately half of the cases, bone marrow was cleared of disease after 1 cycle of chemotherapy., Conclusions: MyoD1 and myogenin transcripts can be used as tumor markers for MDD assessment in virtually all RMS cases, whereas PAX-FKHR is specific for ARMS. Sensitivity of RT-PCR methods was superior compared with standard morphologic assays. Our study suggests that bone marrow involvement is more common in ARMS compared with ERMS, and that MDD can be often cleared by the initial chemotherapy cycles., (2006 American Cancer Society)

Purpose: We present our experience with orthotopic continent urinary diversion following radical cystectomy due to genitourinary rhabdomyosarcoma in children not responding to radiotherapy or chemotherapy., Materials and Methods: Four children with persistent genitourinary rhabdomyosarcoma underwent radical cystectomy with reconstruction of an orthotopic ileal neobladder., Results: Average followup was 50.7 months. One patient died at 12 months postoperatively due to pulmonary recurrence. All patients were able to void completely at regular intervals. Renal function was normal in all patients. Average reservoir capacity was 250 ml. Daytime and nighttime urinary continence was achieved in all patients., Conclusions: The orthotopic continent urinary diversion is technically feasible even in small children. It represents a safe long-term option and offers good quality of life after disfiguring surgery. In fact, patients are able to void spontaneously through the urethra.

Background: Although > 90% of children with nonmetastatic rhabdomyosarcoma (RMS) achieve complete remission with current treatment, up to one-third of them experience a recurrence. Survival rates are not always poor in patients who develop recurrences; thus, prognostic factors are needed to tailor salvage treatment., Methods: The current analysis included 125 children who were affected by localized RMS and were enrolled in 3 consecutive Italian protocols (RMS79, RMS88, and RMS96) who developed recurrences after complete remission. Patient, tumor, and treatment characteristics were studied in univariate and multivariate analyses to determine the independent significance of different factors., Results: The median time from diagnosis to recurrence was 17.8 months. Most patients had local recurrences (72%). The 5-year overall survival (OS) rate was 28.3% +/- 8.7%. Multivariate analysis identified 4 factors that were associated with poor survival: 1) alveolar subtype (relative risk [RR], 2.0), 2) parameningeal or "other" sites (RR, 2.6), 3) systemic recurrence (RR, 3.1), and 4) recurrence on therapy (RR, 2.3). The absence of any of these risk factors identified a "favorable risk" group (12% of patients) with a 5-year OS rate of 71.8% +/- 23.5%. Patients with a single risk factor (32%) had an OS rate of 37.5% +/- 17.2%. Combining patients with 0 or 1 risk factor, the OS rate was 66.5% in the subgroup who had not received radiotherapy compared with an OS rate of 30.3% in the subgroup who had received radiotherapy; this difference was significant (P = 0.03)., Conclusions: The results of the current analysis demonstrated that groups with a different prognosis can be identified among patients with recurrent RMS. Patients with a nonalveolar histology, a primary site other than the parameningeal or "other" sites, local recurrence, and recurrence off therapy had a better prognosis. First-line treatment may have an impact on prognostic variables. In fact, patients who had no or only one risk factor and patients who had tumors with a nonalveolar histology benefited more from salvage therapy if they had not received radiotherapy for their initial treatment. These data may be useful in planning risk-adapted salvage protocols.

Background: Following their previous report on the activity of vinorelbine in the treatment of rhabdomyosarcoma, the authors report the results of a pilot study aimed at defining the optimal dose of vinorelbine when this agent is used in conjunction with continuous, orally administered low-dose cyclophosphamide to treat patients with refractory or recurrent sarcoma. It is hoped that the combination of vinorelbine and low-dose cyclophosphamide can be used as a maintenance regimen in an upcoming European trial involving high-risk patients with rhabdomyosarcoma., Methods: In the current pilot study, the cyclophosphamide dose was fixed at 25 mg/m2 per day for 28 days. Vinorelbine was administered intravenously on Days 1, 8, and 15, with trial doses escalated from an initial level of 15 mg/m2 in steps of 5 mg/m2; intrapatient dose escalation was not allowed., Results: Between April 2002 and November 2003, 18 patients ages 2-23 years were treated with the study regimen after having received 1-4 (median, 2) other regimens previously. Ninety cycles were administered in total (median, 5 cycles per patient; range, 1-10 cycles per patient). Two cases of dose-limiting toxicity (Grade 4 neutropenia in both cases) were observed among the 5 patients who received vinorelbine at a dose of 30 mg/m2. Of the 41 cycles in which vinorelbine was administered at a dose of 25 mg/m2, Grade > or = 3 neutropenia was observed in 15 (37%); no other major toxicity was documented in association with these cycles. One complete remission and 6 partial remissions were noted among the 17 patients who had measurable disease. Three of the eight assessable patients with rhabdomyosarcoma (which was embryonal in two cases and alveolar in one) had responses to treatment., Conclusions: Combination therapy involving vinorelbine and low-dose cyclophosphamide was found to be feasible and to possess activity against recurrent sarcomas. The maintenance therapy doses recommended for use in the upcoming European trial are cyclophosphamide 25 mg/m2 per day for 28 days and vinorelbine 25 mg/m2 on Days 1, 8, and 15., ((c) 2004 American Cancer Society.)

Background: The management of rhabdomyosarcoma (RMS) in patients age < 1 year is particularly problematic and requires a tailored therapeutic approach. We report on the Italian Cooperative Group's 20-year study of 50 children with RMS who were age < 1 year at diagnosis., Methods: Patients were treated using multimodality therapeutic approaches that were based on three consecutive protocols. Chemotherapy was administered to all patients, with dosages calculated according to body weight; calculated doses subsequently were reduced by 33-50%. Radiotherapy was administered to 10 patients., Results: With a median follow-up of 76 months, 5-year event-free survival and overall survival rates were 42.3% and 61.7%, respectively. Local recurrence was the major reason for treatment failure. In particular, the local recurrence rate was high in patients who warranted radiotherapy but received none due to their age. Completeness of surgery and nodal involvement were the most significant prognostic factors. After a suitable reduction in dosage was made, acute toxicity was no different from what has been observed in older children. The most relevant toxic event was cardiotoxic death in a newborn (n = 1)., Conclusions: The current study confirmed that the outcome for infants with RMS is less satisfactory than for older children and that infants with RMS require more careful monitoring and specific treatment guidelines. The absence of local control is the major cause of treatment failure; aggressive conservative surgery should be encouraged, but more radiotherapy may be advisable in selected cases. Intensive chemotherapy is essential; a 33% dose reduction may ensure adequate tolerance. In addition, patients age < 3 months should not receive anthracyclines., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11357)

Background: In the current study, the authors aim to evaluate clinical features and treatment results observed in patients from the German and Italian studies who had nonmetastatic abdominal rhabdomyosarcomas (RMS)., Methods: One hundred sixty-one patients were observed; 78 registered in the German studies between October 1980 and August 1995, and 83 registered in the Italian studies between April 1975 and December 1995. The age range of the patients was 0-18 years (median, 4 yrs). The distribution of tumor sites was as follows: 32 intraperitoneal, 42 retroperitoneal, 75 pelvic, and 12 not otherwise specified (NOS). Most patients had a large and invasive primary mass (26 T1b, 114 T2b). The breakdown in histology was as follows: 116 embryonal, 34 alveolar, and 11 other (leiomyomatous, pleomorphic, and NOS); all cases were staged according to the Intergroup Rhabdomyosarcoma Studies (IRS) system. Nine Group I patients were treated after surgery with chemotherapy (CT) (radiotherapy [RT] was delivered to treat alveolar RMS in the 1991 German and 1988 Italian studies); 19 Group II patients received CT + RT (40-44 Gy); 133 Group III patients underwent neoadjuvant CT +/- surgery and/or RT (54 Gy) + CT. Different CT regimens (based primarily on the administration of vincristine, dactinomycin, doxorubicin, and cyclophosphamide or ifosfamide) were adopted. RT was not recommended for patients age < 3 years., Results: The 10-year overall survival (OS) and progression-free survival (PFS) were 47.2% and 43.9%, respectively. The OS was related significantly to the following variables: histology (alveolar, 29.4% vs. nonalveolar, 52.1% [P = 0.0156]), tumor size (> 5 cm, 42.1% vs. < 5 cm, 81% [P = 0.005]), age (< 10 yrs, 51.4% vs. >or= 10 yrs, 27.8% [P = 0.02]), complete surgery at diagnosis or after CT (+/-RT) (70.4% vs. 34.4% without it [P = 0.0015]). Most patients who achieved the delayed local control had responded well to neoadjuvant CT., Conclusions: Tumor size, histology, age, and initial or delayed achievement of local control were important prognostic factors. Most relapsed patients had unfavorable outcomes., (Copyright 2003 American Cancer Society.)

Background: To evaluate the role of primary reexcision (PRE) with scrotal resection in patients with paratesticular rhabdomyosarcoma enrolled in the German-Italian Cooperative Studies. The authors compared patients who underwent this procedure, according to the protocol guidelines, with those who did not., Methods: In 32 of 198 patients with localized disease, the primary surgery was performed through a noncorrect scrotal approach. Twenty-four patients underwent PRE as recommended by the protocol guidelines (Group A) and 8 did not receive this treatment (Group B). The Group B patients were treated with the same chemotherapeutic regimens as the Group A patients and no radiotherapy was given to either group., Results: After PRE, residual tumor was not detected in 21 of the 24 Group A patients. Twenty patients are alive in first complete remission 26-250 months after diagnosis (median, 40 months), 2 are alive in second complete remission at 3 and 9 months from diagnosis of lymph node and lung recurrence, and 2 died of disease after lymph node and distant metastases at 16 and 13 months from diagnosis. Three-fourths of these patients were older than 10 years old and the tumor was larger than 5 cm. The eight Group B patients are all alive in first complete remission 24-250 months since diagnosis., Conclusions: The data on the eight patients who obtained local control without PRE or radiotherapy warrant further investigation. Because of the supposed high risk of contamination with subsequent microscopic residual tumor after a transcrotal approach, we emphasize the utility of PRE with hemiscrotectomy., (Copyright 2003 American Cancer Society.)

The MYCN oncogene encodes a phosphoprotein that acts as a transcription factor and is involved in the regulation of cell proliferation and differentiation in normal as well as in cancer cells.MYCN amplification and expression have been reported in various tumours, including neuroblastoma and lung cancer, but little is known about its expression in human rhabdomyosarcoma. MYCN expression and amplification were studied in five alveolar and five embryonal rhabdomyosarcoma cell lines and in 19 tumour biopsies. All the cell lines studied expressed MYCN RNA, as demonstrated by northern blot analysis and RT-PCR, but the oncogene was amplified in only one. Similarly, MYCN protein was detected in all cell lines by western blot analysis, with higher levels of expression in alveolar than in embryonal rhabdomyosarcoma cells. RT-PCR analysis of tumour samples demonstrated 18/19 cases positive for MYCN RNA. Although MYCN expression was higher in alveolar than in embryonal rhabdomyosarcoma cell lines, no clear relationship between histology and level of MYCN expression could be established in this tumour series. These data suggest that MYCN expression is a common feature of rhabdomyosarcoma, independent of gene amplification and without a clear relationship with specific histological and clinical features., (Copyright 2002 John Wiley & Sons, Ltd.)