Clinicopathologic and survival correlates of embryonal rhabdomyosarcoma driven by RAS/RAF mutations.

Embryonal rhabdomyosarcoma (ERMS) is the most common subtype of rhabdomyosarcoma (RMS). Among RMS subtypes, ERMS is associated with a favorable outcome with an overall survival of 70% at 5 years for localized disease. The molecular profile of ERMS is heterogeneous, including mostly point mutations in various genes. Therapeutic strategies have remained relatively consistent irrespective of the molecular abnormalities. In this study, we focus on a homogeneous RAS/RAF mutated ERMS subset and correlate with clinicopathologic findings. Twenty-six cases (16 males and 10 females) were identified from screening 98 ERMS, either by targeted DNA sequencing (MSK-IMPACT) or by Sanger sequencing. Fourteen (54%) cases had NRAS mutations, 6 (23%) had KRAS mutations, 5 (19%) had HRAS mutations, and 1 case (4%) had BRAF mutation. Median age at diagnosis was 8 years (range 1-70) with two-thirds occurring in the children. Tumor sites varied with H&N and GU sites accounting for 62% of cases. RAS isoform hot spot mutations predominated: NRAS p.Q61K (57%), KRAS p.G12D (67%), and HRAS (codons 12, 14, and 61). Additional genetic abnormalities were identified in 85% of the RAS-mutated cases. At last follow-up, 29% of patients died of disease and 23% were alive with disease. The 3-year and 5-year survival rates were 75% and 61% respectively. In conclusion, RAS mutations occur in 27% of ERMS, with NRAS mutations encompassing half of the cases. Overall RAS-mutant RMS does not correlate with age or site, but most tumors show an undifferentiated and spindle cell morphology.

Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation.

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.

PURPOSE: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS: Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS: DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants < 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data. CONCLUSION: This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.

Disease Control and Patterns of Failure After Proton Beam Therapy for Rhabdomyosarcoma.

PURPOSE: Pediatric patients with rhabdomyosarcoma (RMS) are treated with multimodal therapy, often with radiation therapy (RT) as part of local therapy. We report on the efficacy and patterns of failure after proton beam therapy (PBT) for RMS. METHODS AND MATERIALS: Between January 2006 and February 2017, patients with RMS were enrolled in a prospective institutional review board-approved registry protocol for pediatric patients undergoing PBT. Demographics, clinical characteristics, and treatment related outcomes were reviewed. RESULTS: Ninety-four RMS patients were treated with a combination of chemotherapy (CT) and PBT. The majority of patients had head and neck (49%) and genitourinary (30%) primaries. Median tumor size was 4.1 cm (range, 1.0-16.5 cm); 33 patients (35%) had primary tumors >5 cm. Median cyclophosphamide equivalent dose was 14.4 g/m2 (range, 0-30.8 g/m2). Median time from CT initiation to RT initiation was 13 weeks (range, 1-58 weeks). With median follow-up of 4 years, 4-year overall survival (OS) was 71%, and 4-year progression-free survival (PFS) was 63%. Thirty patients (32%) experienced relapse (13% with local failure [LF]). Four-year local control (LC) was 85% overall; 4-year LC rates were 100% for low-risk, 85% for intermediate-risk, and 55% for high-risk patients (P = .02). Tumor size predicted LC (P = .007), with 7% versus 33% LF rate by tumor size (≤5 cm vs >5 cm). Delayed RT delivery (≥13 weeks from initiation of CT) predicted worse LC (P = .01). Increased tumor size predicted both inferior PFS (P = .02) and OS (P = .01). Delayed RT delivery predicted both inferior PFS (P = .04) and OS (P = .03). CONCLUSIONS: PBT provides LC comparable to prior studies using photon RT. Inferior LC, PFS, and OS rates were observed for patients with larger tumors and those treated with delayed RT. This finding supports ongoing prospective efforts to dose-escalate treatment of tumors >5 cm; however, these data call into question the optimal timing of local therapy, particularly for patients treated with reduced-dose cyclophosphamide.

Embryonal and Alveolar Rhabdomyosarcoma in Adults: Real-Life Data From a Tertiary Sarcoma Centre.

AIMS: Embryonal and alveolar rhabdomyosarcoma (ERMS, ARMS) are subtypes of RMS that mainly occur in children, with relatively good outcomes. The incidence in adults is extremely low and survival is significantly worse compared with children. Data are scarce and literature generally combines all RMS subtypes, including pleomorphic RMS, which primarily occurs in adults and behaves more like undifferentiated pleomorphic sarcoma. The aim of this study was to evaluate patient and tumour characteristics, outcome and prognostic factors in adult patients with ERMS and ARMS. MATERIALS AND METHODS: All adult (18 years or older) ERMS and ARMS patients (presenting 1990-2016) were identified from a prospectively maintained database and were included in this analysis. RESULTS: Overall, 66 patients were included (42 men, 24 women). The median age at presentation was 28 years (range 18-71). The median overall survival for all ARMS (n = 42) and ERMS (n = 24) patients was 18 months, with a 5-year overall survival rate of 27%. Patients presenting with localised disease (n = 38, 58%) and metastatic disease (n = 25, 42%), had a 5-year overall survival rate of 36% and 11%, respectively. In univariate analysis we found alveolar subtype, fusion gene positivity, infiltrative tumour and metastatic presentation to be negative prognostic factors. CONCLUSION: Survival in adult ERMS and ARMS patients is poor and the current data may be useful in the design of trials with novel agents. Ideally, paediatric and adult oncologists should set up trials together to get a better understanding of biological, genetic and clinically relevant factors in this disease.

45 GyRBE for group III orbital embryonal rhabdomyosarcoma.

Purpose: Despite widespread concerns of radiotherapy toxicity in children with head and neck tumors, recent Children's Oncology Group (COG) findings suggest that the use of 45 Gy results in an unacceptably high rate of local recurrences in patients with low-risk orbital rhabdomyosarcoma. We therefore evaluated outcomes in our pediatric patients who received 45 GyRBE using proton therapy. Material and methods: To assess disease control and toxicity, we reviewed the medical records of 30 children (≤21 years old) with COG stage 1, group III embryonal orbital rhabdomyosarcoma enrolled on a prospective outcome study and treated with proton therapy between 2007 and 2018. Results: Median age at the time of radiation was 4.8 years old. Twenty-one and nine patients received ifosfamide- and cyclophosphamide-based chemotherapy according to their respective cooperative group regimens. Median duration between the start of induction chemotherapy and radiation was 12 weeks. Two patients had a complete response to induction chemotherapy and two had stable disease. Twenty-six patients had a partial response to induction chemotherapy, with a median volume reduction of 66%. With a median follow-up of 4.0 years (range, 0.5-9.5 years), we observed 1 local failure 6 months following treatment in a patient who had a partial response to cyclosphophomide-based induction chemotherapy. The 5-year local control, progression-free survival, and overall survival rates were 97%, 97%, and 100%, respectively. Serious late toxicities included 18 patients with cataracts, 4 with exposure keratoconjunctivitis resulting in permanently reduced visual acuity, and 1 with chronic sinusitis. Conclusion: 45 GyRBE offers effective local control for most patients with group III orbital rhabdomyosarcoma. The delivery of proton therapy to the postinduction tumor volume plus a small margin can mitigate early- and intermediate-term toxicity, but side effects still occur and long-term data are needed to demonstrate the dosimetric advantage of proton therapy.

Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma. METHODS: RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing. FINDINGS: Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved. INTERPRETATION: Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials. FUNDING: Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.

Epidemiology, Incidence, and Survival of Rhabdomyosarcoma Subtypes: SEER and ICES Database Analysis.

Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and adolescents and accounts for 3% of all pediatric tumors. Subtypes include alveolar, spindle cell, embryonal, mixed-type, pleomorphic, and rhabdomyosarcoma with ganglionic differentiation. The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was queried for patients diagnosed with any type of rhabdomyosarcoma between 1973 and 2014. Patient demographics, tumor characteristics, and incidence were studied with χ2 analysis. Survival was modeled with Kaplan-Meier survival curves and Cox proportional hazards models were used to assess the effect of age and gender on survival. Pleomorphic subtype had higher grade and larger sized tumors compared to other subtypes (p < 0.05). Pleomorphic and alveolar rhabdomyosarcoma had the worst overall survival with a 26.6% and 28.9% 5-year survival, respectively. Embryonal rhabdomyosarcoma had the highest 5-year survival rate (73.9%). Tumor size was negatively correlated with survival months, indicating patients with larger tumors had shorter survival times (p < 0.05). Presence of higher-grade tumors and metastatic disease at presentation were negatively correlated with survival months (p < 0.05). No significant differences in the survival were found between gender or race between all of the subtypes (p > 0.05). This study highlights key differences in the demographic and survival rates of the different types of rhabdomyosarcoma that can be used for more tailored patient counseling. We also demonstrate that large, population-level databases provide sufficient data that can be used in the analysis of rare tumors. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2226-2230, 2019.

Tumour expressions of hypoxic markers predict the response to neo-adjuvant chemotherapy in children with inoperable rhabdomyosarcoma.

Objective: The study was to assess whether tumour expressions of hypoxia-inducible factor (HIF)-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX and vascular endothelial growth factor (VEGF) predict response to neo-adjuvant chemotherapy (naCHT) in children with inoperable rhabdomyosarcoma (RMS). Methods: Immunohistochemical expressions of hypoxia markers were determined semi-quantitatively in tumour tissue microarray of 46 patients with embryonal RMS (RME) and 20 with alveolar (RMA), treated with CWS protocols (1992-2013). Results: In paediatric RME, response to naCHT was influenced significantly by tumour expression of CA IX and GLUT-1. Patients with RMA with low expressions of analysed markers responded well to naCHT, while all poor-responders expressed highly hypoxia markers. Only 5.88% of RMA and 11.11% of RME tumours did not express any of the proteins. In both RME and RMA subgroups, most poor-responders demonstrated simultaneous high expression of ≥3 markers, while most patients expressing ≤2 markers responded well to naCHT. In the whole cohort, co-expression of ≥3 markers, was the only independent factor predicting poor-response to chemotherapy (odds ratio 14.706; 95% CI 1.72-125.75; p = 0.014). Conclusions: Immunohistochemical expression pattern of four endogenous markers of hypoxia, in tumour tissue at diagnosis, emerges as a promising tool to predict response to naCHT in children with inoperable RMS.

Worse Outcomes for Head and Neck Rhabdomyosarcoma Secondary to Reduced-Dose Cyclophosphamide.

PURPOSE: Recent trends, including the use of proton therapy and administration of reduced doses of cyclophosphamide, have been adapted in head and neck (HN) rhabdomyosarcoma (RMS) to reduce late morbidity. Our primary goal was to analyze local control and survival outcomes after photon versus proton irradiation in pediatric patients with HN-RMS, with the secondary goal of analyzing the effect of cyclophosphamide dose on disease outcomes. METHODS AND MATERIALS: This single-institution cohort study comprised 76 pediatric HN-RMS patients treated with definitive chemoradiation from 2000 to 2018. Fifty-one patients (67%) received intensity modulated photon radiation therapy, and 25 (33%) received proton therapy. RESULTS: Local failure (LF) at 2 years was 12.5% for parameningeal RMS and 0% for orbital RMS and other head and neck sites (P = .24). Patients treated with protons were more likely to have received reduced-dose cyclophosphamide (P < .0001). The 2-year LF was 7.9% in the intensity modulated photon radiation therapy cohort versus 14.6% in the proton cohort (P = .07), with no difference in survival outcomes. Cumulative cyclophosphamide dose was significantly associated with 2-year LF: 0% for cumulative dose of >20 g/m2 versus 15.3% for ≤20 g/m2 (P = .04). In parameningeal RMS patients (n = 59), both cumulative cyclophosphamide dose and dose intensity were associated with LF (P = .01). There was a trend toward worse event-free survival for parameningeal RMS patients who received reduced-dose-intensity cyclophosphamide (59.2% vs 70.6%, P = .11). CONCLUSIONS: Both dose-intensity and cumulative cyclophosphamide dose seem to play an important role in achieving local control for HN-RMS patients treated with either protons or photons. Longer follow-up is needed to further assess disease outcomes with proton therapy.

A review of pediatric middle ear tumors and analysis of the demographics, management, and survival of pediatric rhabdomyosarcomas of the middle ear.

OBJECTIVE: To examine the types of pediatric middle ear tumors and review the demographics, management, and survival of pediatric patients with rhabdomyosarcoma (RMS) of the middle ear. METHODS: Pediatric patients in the Surveillance, Epidemiology, and End Results (SEER) database were included from 1973 to 2014 based on a diagnosis of middle ear tumors using the ICD O-3 code: C30.1: Middle ear primary site. Patients were included from ages 0-18 years. RESULTS: Forty pediatric middle ear tumor cases were identified. Twenty patients were female (50%). Twenty-seven (67.5%) cases were rhabdomyosarcomas (RMS). Pediatric RMS patients tended to be diagnosed in early childhood (mean age 5.30 years, standard deviation 2.9, range 1.00-13.00, 59.3% of patients were ages 5 or below). Most pediatric RMS patients received chemotherapy and radiation therapy as part of the treatment regimen (88.8%). Finally, the 5-year overall and disease-specific survival rates were 59% and 63% respectively. CONCLUSIONS: Pediatric middle ear tumors are rare. Females and male pediatric patients are both at risk for middle ear tumors. RMS is the most common malignant middle ear tumor affecting pediatric patients. Despite the use of multimodality therapies, survival rates for pediatric patients with RMS of the middle ear are low. Physicians may consider including middle ear tumors on the differential diagnosis for pediatric patients with symptoms presenting similarly to non-resolving otitis media.

Outcome of 449 adult patients with rhabdomyosarcoma: an observational ambispective nationwide study.

Five-year overall survival (OS) of localized RMS exceeds 70% in children (<18) but is very poor in adult patients. We analyzed the outcome and prognostic factors (PF) of a national series of adult patients with RMS in a large study. The study population consisted of two different cohorts: a retrospective cohort (157 adult patients treated in 13 reference centers between 05/1981 and 02/2010) and the prospective cohort (292 patients with RMS diagnosed and treated between 01/2010 and 12/2014 in France) included in the NetSarc database. A descriptive analysis of patients' characteristics and prognostic factors was conducted on both series which were compared. In the retrospective series, histological subtypes were embryonal (E-RMS) for 21% of patients, alveolar (A-RMS) for 35% of patients, and "adult-type" P-RMS (pleomorphic, spindle cell RMS, not otherwise specified) (P) for 44% patients. This distribution significantly differed in the prospective cohort: A-RMS: 18%; E-RMS: 17%; and P-RMS 65%. With a median follow-up of 8.5 years, 5-year OS for localized RMS and advanced RMS (with nodes and/or metastases) was 43% and 5%, respectively, (P < 0.0001), and median OS was 51, 33, and 16 months for E-RMS, A-RMS, and P-RMS, respectively, in the retrospective cohort. The median OS was less than 40 months for the prospective nationwide cohort for the entire population. In a multivariate analysis of the retrospective study, independent prognostic factors for OS were A-RMS, R0 resection, and adjuvant radiotherapy (RT). For localized RMS, age and use of pediatric chemotherapy (CT) regimen are independent prognostic factors. Adult patients with RMS have a poorer overall survival than pediatric patients, and survival varies considerably across histological subtypes.

45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Recent Children's Oncology Group (COG) trials tested the efficacy of reduced therapy in an effort to lessen late effects compared to the Intergroup Rhabdomyosarcoma Study (IRS) IV regimen with associated hematologic and hepatic toxicity, and infertility. Here, we analyze the efficacy of 45 Gray (Gy) local radiotherapy (RT) in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the COG low-risk study ARST0331. PROCEDURE: Sixty-two patients with Group III orbital ERMS were treated on ARST0331 with four cycles of vincristine (VCR), dactinomycin (DACT), and cyclophosphamide (CPM; VAC, total cumulative CPM dose 4.8 g/m2 ) followed by four cycles of VCR and DACT over 22 weeks. Forty-five Gray of radiation was administered in 25 fractions beginning at week 13 of therapy. RESULTS: Fifty-three patients were evaluable for this response analysis; seven had missing week 12 response evaluation data and two had progressive disease prior to starting RT. Median follow-up was 7.8 years. None of the 15 patients with radiographic complete response (CR) compared to 6 of the 38 patients with

The prognostic value of early radiographic response in children and adolescents with embryonal rhabdomyosarcoma stage IV, metastases confined to the lungs: A report from the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis apart from children with embryonal RMS whose metastases are confined to the lungs (PRME). The prognostic significance of response in patients with metastatic disease is still unknown and optimal treatment remains to be defined. METHODS: Patient-, tumor- and treatment-related factors of patients with PRME treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (CWS) (1981-2013) were analyzed with a focus on response to induction chemotherapy. Response at week 7-10 was based on anatomic imaging and determined (1) for the primary tumor as complete response (CR), good response (GR), partial response (PR) and no response (NR) and (2) for pulmonary metastases as either complete lack of residual lesions (pCR) or no complete response (no-pCR). Event-free (EFS) and overall survival (OS) were the endpoints. RESULTS: EFS and OS of all 53 eligible patients was 41% (±13 confidence interval [CI] 95%) and 52% (±11 CI 95%), respectively. pCR at week 7-10 and maintenance therapy (MT) were favorable prognostic factors. Interestingly, response of primary tumor at week 7-10 and number of metastases were not prognostic factors. The 5-year OS was 68% (±18 CI 95%) for 26 patients in pCR, but only 36% (±18 CI 95%) for 27 patients not in pCR at week 7-10 (P = 0.004) despite achieving pCR under continuation of chemotherapy or local therapy. CONCLUSION: Achievement of pCR at week 7-10 by induction chemotherapy is a prognostic factor.

Patterns of Failure in Pediatric Rhabdomyosarcoma After Proton Therapy.

PURPOSE: To report on the patterns of failure in children with rhabdomyosarcoma treated with proton therapy. PATIENTS AND METHODS: Between February 2007 and November 2013, 66 children with a median age of 4.1 years (range, 0.6-15.3 years) diagnosed with nonmetastatic rhabdomyosarcoma were treated with proton therapy. Clinical target volume 1 was defined as the prechemotherapy tumor plus a 1-cm anatomically constrained margin. Clinical target volume 2 was defined as the postchemotherapy tumor (or tumor bed) plus a 0.5-cm anatomically constrained margin, further expanded to encompass potential pathways of spread, including soft tissue infiltrated with tumor at diagnosis. RESULTS: Of the 66 children, 11 developed locally progressive disease at a median of 16 months (range, 14-32 months), for an actuarial 2-year local control rate of 88%. Among the children who progressed, median age and tumor size at diagnosis were 6.7 years (range, 0.6-16 years) and 6 cm (range, 2-8 cm), respectively. Of the recurrences, 64% and 36% were embryonal and alveolar, respectively. Disease progression was observed in 7 (64%) parameningeal, 2 (18%) head and neck (other), and 2 (18%) bladder/prostate subsites. At diagnosis, 8 of 11 patients who developed a recurrence were Intergroup Rhabdomyosarcoma Study stage 3, and all 11 were group III. Of the relapses, 100% (11 of 11) were confirmed as in-field within the composite 95% isodose line. One of the 11 patients (9%) developed a new simultaneous regional nodal recurrence outside of the previously treated radiation field. CONCLUSION: Early data suggest that the sharp dosimetric gradient associated with proton therapy is not associated with an increased risk of marginal failure. Routine use of a 0.5- to 1-cm clinical target volume 1/2 margin with highly conformal proton therapy does not compromise local control in children diagnosed with rhabdomyosarcoma with unfavorable risk features.

Embryonal Rhabdomyosarcoma of the Cervix in Young Women.

PURPOSE: Cervical rhabdomyosarcoma (RMS) is an extremely rare disease, and there is no precise criteria related to its treatment. Our aim was to describe the clinical and pathological features of cervical RMS. METHODS: Clinicopathological data of cases with cervical RMS were retrieved from the computerized database of Etlik Zubeyde Hanim Women's Health and Research Hospital. Five patients with the diagnosis of cervical RMS who underwent surgical treatment and had adjuvant chemotherapy between 2003 and 2015 were included in the study. RESULTS: Mean age of patients at the time of diagnosis was 15.8 ± 2 years. Abnormal vaginal bleeding and mass were the most common complaints. All patients had embryonal rhabdomyosarcoma (E-RMS) and Group I disease according to the Intergroup Rhabdomyosarcoma Study Group clinical classification system. Cone biopsy and polypectomy were performed in four patients, and radical abdominal hysterectomy with pelvic-paraaortic lymphadenectomy was performed in one patient. Chemotherapy consisting vincristine, dactinomycin, and cyclophosphamide was given as an adjuvant therapy. Estimated 5-year overall survival and disease-free survival were 40% and 37.5%, respectively. CONCLUSIONS: We report a small series of patients with cervical E-RMS who were treated with surgery and adjuvant chemotherapy. Although all patients in the present study had good prognostic factors, survival was not as good as indicated in the literature. Diminished survival of our patient group may be associated with underlying molecular and pathophysiologic differences other than stage and histological subtype that have not been discovered yet.

Current status of treatment for pediatric rhabdomyosarcoma in the USA and Japan.

This article reviews the current status of treatment for children with rhabdomyosarcoma, according to the four risk groups. Low-risk subgroup A: the Children's Oncology Group in the USA recently performed a clinical trial consisting of a chemotherapy regimen with a shortened treatment period and a reduced drug dosage. Patients in this group received only four cycles of vincristine and actinomycin D (VA) after four cycles of vincristine, actinomycin D, and cyclophosphamide (VAC) with cyclophosphamide (CPM) 1.2 g/m(2) and their outcome was no worse than that obtained with previous regimens. Low-risk subgroup B: although marked improvement in survival was seen with an intensive VAC regimen with CPM 2.2 g/m(2) /cycle (Intergroup Rhabdomyosarcoma Study [IRS]-V, 1997-2004), the total dose of CPM in this regimen caused serious and fatal hepatic veno-occlusive disease during treatment and probably cannot avoid infertility or possible secondary cancer as a late effect. Thereafter, a reduced-dose regimen consisting of four cycles of VAC with CPM 1.2 g/m(2) followed by 12 cycles of VA was investigated in the next study, but the outcome appeared to be worse than in IRS-V. Intermediate-risk group: no significant difference was found between VAC/vincristine, topotecan and cyclophispahamide (VTC) and intensive VAC in IRS-V. The results of a subsequent regimen of VAC with CPM 1.2 g/m(2) alternating with vincristine and irinotecan are awaited. High-risk group: overall survival is approximately 30% and has not improved over the last 25 years. Although 18 month failure-free survival (FFS) was improved with an intensive combination therapy regimen, 36 month FFS dropped to 32% and thus better novel approaches or additive treatments are needed.

Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute.

BACKGROUND: Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES: Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS: With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS: Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.

Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group.

PURPOSE: To determine local control according to clinical variables for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group protocol D9803. PATIENTS AND METHODS: Of 702 patients enrolled, we analyzed 423 patients with central pathology-confirmed group III embryonal (n=280) or alveolar (group III, n=102; group I-II, n=41) RMS. Median age was 5 years. Patients received 42 weeks of VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VTC (T = topotecan). Local therapy with 50.4 Gy radiation therapy with or without delayed primary excision began at week 12 for group III patients. Patients with group I/II alveolar RMS received 36-41.4 Gy. Local failure (LF) was defined as local progression as a first event with or without concurrent regional or distant failure. RESULTS: At a median follow-up of 6.6 years, patients with clinical group I/II alveolar RMS had a 5-year event-free survival rate of 69% and LF of 10%. Among patients with group III RMS, 5-year event-free survival and LF rates were 70% and 19%, respectively. Local failure rates did not differ by histology, nodal status, or primary site, though there was a trend for increased LF for retroperitoneal (RP) tumors (P=.12). Tumors ≥5 cm were more likely to fail locally than tumors <5 cm (25% vs 10%, P=.0004). Almost all (98%) RP tumors were ≥5 cm, with no difference in LF by site when the analysis was restricted to tumors ≥5 cm (P=.86). CONCLUSION: Local control was excellent for clinical group I/II alveolar RMS. Local failure constituted 63% of initial events in clinical group III patients and did not vary by histology or nodal status. The trend for higher LF in RP tumors was related to tumor size. There has been no clear change in local control over RMS studies, including IRS-III and IRS-IV. Novel approaches are warranted for larger tumors (≥5 cm).

Clinicopathological characteristics and treatment outcomes of Chinese patients with genitourinary embryonal rhabdomyosarcoma.

BACKGROUND: Genitourinary embryonal rhabdomyosarcoma is rarely reported in China. This retrospective analysis aimed to characterize the clinicopathologic features and treatment outcomes of genitourinary embryonal rhabdomyosarcoma in a sample of Chinese patients. METHODS: Basic demographic and clinical data of 29 patients, who were diagnosed with genitourinary embryonal rhabdomyosarcoma between January 2000 and December 2011, were retrieved and analyzed. RESULTS: In these patients, 25 were males and 4 were females with a median age of 12 years. Paratesticule was the most common lesion site, followed by the prostate, bladder, and vagina. The median tumor size was 5.80 cm. Six patients had clinically positive regional nodes. At the initial diagnosis, patients had a metastatic disease. According to the TNM staging classification for the IRS-IV, phase I lesions were detected in ten cases, phase II lesions in six cases, phase III lesions in four cases, and phase IV lesions in nine cases. The median survival of all patients was 63 (range from 6 to 118) months. The 1-, 3-, and 5-year survival rates for these patients were 93%, 83%, and 52%, respectively. Multivariate analyses demonstrated that staging and anemia were significant predictors of prognosis. CONCLUSIONS: Our findings suggest that metastasis predicts a poor prognosis. Chemotherapy played an important role in comprehensive treatment. Palliative and neo-adjuvant chemotherapy could increase median survival time.