LRA0401/ LRB0402 protocols for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma based on the central pathological review system: The first report from the Japan Rhabdomyosarcoma Study Group

LRA0401/ LRB0402 protocols for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma based on the central pathological review system: The first report from the Japan Rhabdomyosarcoma Study Group | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article LRA0401/ LRB0402 protocols for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma based on the central pathological review system: The first report from the Japan Rhabdomyosarcoma Study Group Hajime Hosoi, Hiroshi Hojo, Mitsuru Miyachi, Hajime Okita, Jun-Ichi Hata, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3838227/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Aug, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background A retrospective study of pediatric rhabdomyosarcoma patients treated between 1991 and 2002 in Japan revealed that among the two major subtypes, embryonal rhabdomyosarcoma (ERMS), was more prevalent than alveolar rhabdomyosarcoma (ARMS), differing from a United States (US)-based report. Moreover, the survival rate of low-risk ERMS was worse in Japan than in the US. We hypothesized that some patients with ARMS having a poorer prognosis were misdiagnosed and undertreated in Japan. We explored this hypothesis using a nationwide group study, by risk-adopted therapy based upon a central pathological review system to improve the prognosis of patients with “low-risk” rhabdomyosarcoma in Japan. Methods Using the first nationwide Japan Rhabdomyosarcoma Study Group established in 2004, we classified patients into low-risk subgroup A, including ERMS with orbital, grossly resectable, favorable site, and small unfavorable site tumors, who were eligible for JRS-I LRA0401; and low-risk subgroup B, including ERMS with residual, favorable site and grossly resectable, large, unfavorable site tumors, eligible for JRS-I LRB0402. Results ERMS cases decreased from 78–51% before and after the central pathological review. Fusion genes were not detected in ERMS. The overall survival rate was significantly better (p = 0.0015) in ERMS (84.8 ± 4.0%) than in ARMS (57.7 ± 6.1%). The 3-year overall survival rates of low-risk patients in subgroups A and B improved from 86–100% and from 81–94%, respectively. Conclusion By implementing a central pathological review system in Japan and adopting fusion gene analyses for diagnosis, the number of patients with ERMS decreased and their outcomes improved significantly. embryonal rhabdomyosarcoma a nationwide group study risk-adopted therapy central pathological review system Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Before the first nationwide study of all risk groups of children with rhabdomyosarcoma in Japan, children with rhabdomyosarcoma were retrospectively analyzed between 1991 and 2002 [ 1 ]. Patient overall survival (OS) rates in both low-risk groups in Japan were approximately 10% lower than the corresponding populations in the contemporary Intergroup Rhabdomyosarcoma Study (IRS) IV and early IRS-V in the United States of America (US) [ 2 ]. Pathologically, the rate of alveolar rhabdomyosarcoma (ARMS), which is more aggressive and an unfavorable subtype of embryonal rhabdomyosarcoma (ERMS), was much smaller in Japan than in the US [ 1 ]. Furthermore, only 10% of rhabdomyosarcoma patients in Japan were examined for PAX3-FOXO1 and PAX7-FOXO1 fusion genes, which are useful markers for differentiating ARMS. The histology of the tumors in the low-risk groups is ERMS. Therefore, we hypothesized that some ARMS patients were misdiagnosed with ERMS, resulting in low-risk group patients having poorer outcomes in Japan. Moreover, those with ARMS misdiagnosed as ERMS may not have received sufficient therapy. The standard therapy for rhabdomyosarcoma needs to be validated by a nationwide group study that includes a rapid central pathological review (CPR) system. Subsequently, we established the Japan Rhabdomyosarcoma Study Group (JRSG) in 2004 and performed nationwide group studies consisting of four risk groups using the IRS-V risk group classification [ 2 ]. Most patients classified into low-risk subgroup A in the IRS-V could be curable. Therefore, they were expected to have shortened treatment period without a worse outcome, with better QOL and minimal short and long-term toxicity. The toxicity of “the gold standard” intensive vincristine, actinomycin-D, and cyclophosphamide (VAC) therapy is not “minimal.” The IRS data indicated that severe hematologic toxicity and serious infections were experienced by approximately 20% of patients per treatment course. Furthermore, 5% of patients developed veno-occlusive disease (VOD), with four VOD deaths observed in IRS-V study using the VAC therapy, like that of IRS-IV VAC. We believed that intensive VAC therapy in IRS-IV for the low-risk group subset A patients was not yet optimal. For the subset A patients, we believed that the treatment period could be shortened by adding a modest dose of cyclophosphamide to the VA therapy. This was not expected to add substantial toxicity beyond that seen with VA; it even had increased failure-free survival (FFS) compared to that seen with IRS-IV VAC. We validated the shortened treatment period giving the patients only eight cycles of VAC for 24 weeks instead of sixteen cycles of VA for 48 weeks Treatment such as intensive pulsed VAC therapy given in IRS-IV study yielded excellent results in the low-risk subset B patients. The Soft Tissue Sarcoma study committee of Children Oncology Group suspended all STS research involving intensive pulsed VAC therapy because of acute toxicity concerns related to VOD in 2002. In addition, late effects of increased cyclophosphamide dose such as infertility cannot be ignored. We believe that intensive pulsed VAC therapy for subset B patients is not yet optimal in terms of maximizing long-term FFS, while minimizing short and long-term toxicity. For subset B patients, we are convinced that intensive pulsed VAC therapy in IRS-IV or IRS-V is excessive and propose to demonstrate that reducing treatment by giving eight cycles of intensive VAC followed by eight cycles of VA instead of sixteen cycles of intensive VAC for 48 weeks will produce long-term treatment benefits with minimized short and long-term toxicity without reducing the survival rate as seen with intensive pulsed VAC therapy in IRS-IV. We evaluated the validity of reducing chemotherapy by giving eight cycles of intensive VAC for 24 weeks followed by eight cycles of VA for 24 weeks instead of sixteen cycles of intensive VAC for 48 weeks to estimate the progression-free survival (PFS) of ERMS patients in subgroup B, when treated with eight cycles of intensive VAC followed by eight cycles of VA instead of sixteen cycles of intensive VAC for 48 weeks. Here, we report a change in the number of ERMS patients and patient outcomes in the two low-risk tumor subsets, in clinical studies of the Japan Rhabdomyosarcoma Study-I (JRS-I) LRA0401 (Low-risk subgroup A) and JRS-I LRB0402 (Low-risk subgroup B). We demonstrated how a group study using multimodal, risk-adapted therapy based on prognostic factors and CPR of rhabdomyosarcoma patients yielded different results compared to a prior retrospective study in Japan. Patients and Methods The central pathology review committee of the JRSG consisted of pediatric pathologists or specialists in soft tissue sarcoma. The pathological classification of JRS-I was preformed based on the International Classification of Rhabdomyosarcoma (ICR) [ 3 ], independent of the molecular analyses results. Rhabdomyosarcoma not otherwise specified (RMS NOS), with PAX3,7-FOXO1 fusion-positive tumors, were classified as ARMS, RMS NOS with the fusion-negative tumors were classified as ERMS, and tumors with no sample for molecular analysis were classified as ARMS. Molecular analysis of ARMS-associated gene fusions PAX3-FOXO1 and PAX7-FOXO1 was carried out using RT-PCR assays. Gene fusion status was evaluated by two independent laboratories of NCCHD and KPUM blinded to the histopathological subtypes. The patients were registered provisionally at the JRSG registration office at the Department of Pediatric Surgery, Keio University School of Medicine. Each determined risk classification was issued to the registerer of each institution by the person in charge of JRSG after the specimens were submitted and before the protocol therapy was started. Thereafter, the registerer sent the case report form to the data centers of each risk grouped study for the definitive registration. In this non-randomized study, treatments were assigned according to subgroups. We demonstrated the results of the two low-risk groups, low-risk subgroup A (LRA0401) and low-risk subgroup B (LRB0402) studies among the total of four risk groups studied. The remaining two risk groups, intermediate and high risks, are being prepared for submission and publication elsewhere. The primary endpoint was FFS, defined as the time from enrollment to disease progression, recurrence, or death, whichever event occurred first. Secondary endpoints were OS, response rate to chemotherapy (for group III patients), and frequency of adverse events. OS was defined as the time from enrollment to death due to any cause. The FFS and OS of patients who did not experience an event were censored at the patient’s last contact date. The Kaplan–Meier method was used to estimate FFS and OS distributions. Patients aged < 19 years at diagnosis who were previously untreated were eligible for JRS-I LRA0401 and JRS-I LRB0402. The local institutional review board approved both studies for patient registration. The study approval numbers from the administrating center in Kyoto Prefectural University of Medicine are RBMR-C-466 and RBMC-R-465 for JRS-I LRA0401 and JRS-I LRB0402, respectively. All patients or their guardians signed an informed consent form. The trial registration numbers were UMIN000039048 for JRS-I LRA0401 and UMIN000039049 for JRS-I LRB0402. ERMS patients with stage 1 group I/IIA/III orbit or stage 2 group I tumors were classified as low-risk subgroup A, eligible for the JRS-I LRA0401 study. ERMS patients with stage 1 group IIB/IIC/III, stage 2 group IIA, or stage 3 group I/II tumors were classified as low-risk subgroup B, eligible for the JRS-I LRB0402 study. The details of LRA0401 and LRB0402 treatment regimens for patients in subgroup A (Supplementary Table 1) and subgroup B (Supplementary Table 2) including radiotherapy (RT) are described in the supplementary material. Results Histopathology and prognosis By January 2014, 211 patients including all four tumor risk groups were diagnosed with rhabdomyosarcoma by the CPR system of JRSG. There were 108 cases (51%) pathologically diagnosed as ERMS, including botryoid, spindle cell, and “mixed histopathology of ERMS NOS, and spindle cell rhabdomyosarcoma (Mixed E &S),” and 97 cases (46%) of ARMS, including solid variant and “mixed histopathology of ERMS and ARMS (Mixed A & E)”. The last six cases (3%) were diagnosed as RMS NOS because of insufficient information to determine either ERMS or ARMS. Notably, the proportion of ARMS patients increased from 22% in the former retrospective study in the 1990s to 46% in this prospective study (Table 1 ). Table 1 Comparison of numbers of patients by histopathology subtypes between pre- and post-central pathological reviews 1991–2002 (Retro. Stu.) 2004–2013 (JRS-I) ERMS 202 (78%) 108 (51%) ERMS NOS 177 76 Botryoid 21 18 Spindle cell 4 8 Mixed E and S ND 6 ARMS 67 (22%) 97 (46%) ARMS NOS ND 73 Solid variant ND 13 Mixed A & E ND 11 RMS NOS ND 6 (3%) ERMS, Embryonal rhabdomyosarcoma; NOS, not otherwise specified; Mixed E and S, Mixed histopathology including both embryonal rhabdomyosarcoma NOS and spindle cell rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; Mixed A & E, mixed histopathology including both embryonal and alveolar rhabdomyosarcoma; JRS-I, Japan Rhabdomyosarcoma Study-I; ND, not determined (no definition at that time); Retro. Stu, retrospective studies Tissue samples from 153 patients (73%) were available for molecular analysis of ARMS-associated gene fusions. The fusion genes were not detected in samples from the 80 ERMS cases (100%) and 16 (18%) ARMS cases, including Mixed A & E cases. However, 55 out of 71 ARMS patients (77%) expressed PAX3-FOXO1 or PAX7-FOXO1 fusion genes (Table 2 ). Among the six samples from Mixed A & E patients, two expressed PAX3-FOXO1 fusion gene, whereas four did not express any fusion gene (Table 2 ). Two RMS NOS fusion-negative cases were classified as ERMS and four RMS NOS cases with no data of fusion status were classified as ARMS based on the CPR system. As described above, survival was analyzed between the 109 ERMS and 99 ARMS patients, excluding one ERMS and two ARMS patients for whom survival data could not be collected. Table 2 Molecular analysis of histology and fusion status in 153 patients in JRS-I Diagnosis Negative PAX3-FOXO1 PAX7-FOXO1 ERMS (n = 80) 80 0 0 ERMS NOS 59 0 0 Botryoid 12 0 0 Spindle cell 5 0 0 Mixed E and S 4 0 0 ARMS (n = 71) 16 48 7 ARMS NOS 11 38 7 Solid variant 1 8 0 Mixed A & E 4 2 0 RMS NOS (n = 2) 2 0 0 ERMS, Embryonal rhabdomyosarcoma; NOS, not otherwise specified; Mixed E and S, Mixed histopathology including both embryonal rhabdomyosarcoma NOS and spindle cell rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; Mixed A & E, mixed histopathology including both embryonal and alveolar rhabdomyosarcoma; JRS-I, Japan Rhabdomyosarcoma Study-I The PFS rate of ERMS group (n = 109) [76.5 ± 4.4% (95% confidence interval [CI] = 66.5–83.9%)] was significantly better than that of ARMS histology group (n = 99) [59.7 ± 4.9% (95% CI = 49.5–68.6%)] (p = 0.0145) (Fig. 1 ). The OS rate of ERMS group [84.8 ± 4.0% (95% CI = 75.1–91.0%)] was significantly higher than that of ARMS and mixed histology group [57.7 ± 6.1% (95% CI = 44.9–68.5%] (p = 0.0015) (Fig. 2 ). Furthermore, both PFS (p = 0.0022) and OS (p = 0.0001) were significantly different between patients with fusion-negative and fusion-positive tumors. The PFS rate of patients with fusion-negative ERMS (n = 80) was 76.3 ± 4.9% (95% CI = 64.9–84.8%). The PFS rate of patients with fusion-positive ARMS (n = 53), excluding those with mixed histology (n = 2), was 44.2 ± 7.3% (95% CI = 29.6–57.8%). The PFS rate of patients with the fusion-negative ARMS (n = 12), excluding those with mixed histology (n = 4), was 75.0 ± 12.5% (95% CI = 40.8–91.2%). Patients with mixed histology (n = 6), which included fusion-positive (n = 2) and fusion-negative (n = 4) patients, had no event during the observation period (Fig. 3 ). The OS rate of patients with fusion-negative ERMS was 85.4 ± 4.3% (95% CI = 74.3–91.9%). The OS rate of patients with fusion-positive and fusion-negative ARMS, excluding those with mixed histology, was 38.8 ± 8.4% (95% CI = 22.8–54.5%) and 81.5 ± 11.9% (95% CI = 43.5–95.1%), respectively. All six patients with mixed histology and two of 48 patients with tumors expressing PAX3-FOXO1 fusion gene were alive with no evidence of tumors (Fig. 4 ). JRS-I LRA0401 JRS-I LRA0401 included 17 patients treated between May 2004 and July 2010, of whom 12 patients were eligible and four were ineligible for analysis (three with ARMS diagnosis, one with a benign tumor, and one due to specimen not being sent for CPR). The median follow-up duration was 5.6 years (3.0–9.0 years). Seven patients (58%) were aged < 10 years and male (male: female = 1.4:1) (Table 3 ). Eleven (91.7%), five (42%), three (25%), and four (33%) patients had tumors at favorable sites (stage 1), group I tumors, group IIA tumors, and group III tumors, respectively. Ten patients (83%) had non-invasive tumors < 5 cm (widest diameter). None of the cases metastasized to the regional lymph nodes (Table 3 ). For subgroup A patients (n = 12), the 3-year FFS and OS rates were 83% (95% CI = 48–96%) and 100%, respectively (Figs. 5 , 6 ). Table 3 Comparison between subgroups of patients treated according to LRA0401 and LRB0402 Subgroup A n = 12 Subgroup B n = 16 Total n = 28 Age (years) No % No % No % <5 5 41.7 10 62.5 15 53.6 5–9 2 16.7 3 18.8 5 17.9 10–14 3 25 3 18.8 6 21.4 15< 2 16.7 0 0 2 7.1 Sex Male 7 58.3 8 50 15 53.6 Female 5 41.7 8 50 13 46.4 Stage 1 11 91.7 10 62.5 21 75 2 1 8.3 2 12.5 3 10.7 3 0 0 4 25 4 14.3 Group I 5 41.7 2 12.5 7 25 IIA 3 25 4 25 7 25 IIB 0 0 1 6.3 1 3.6 IIC 0 0 1 6.3 1 3.6 III 4 33.3 8 50 12 42.9 Primary site Paratestis 4 33.3 2 12.5 6 21.4 Female genital tract 1 8.3 5 31.3 6 21.4 Head and neck 1 8.3 2 12.5 3 10.7 Orbit 5 41.7 1 6.3 6 21.4 Bladder 0 0 1 6.3 1 3.6 Parameningeal 0 0 1 6.3 1 3.6 Others 1 8.3 4 25 5 17.9 Tumor size <5 cm 10 83.3 2 12.5 12 42.9 ≥5 cm 1 8.3 13 81.3 14 50 N.A. 1 8.3 1 6.3 2 7.1 Invasiveness T1 10 83.3 10 62.5 20 71.4 T2 2 16.7 6 37.5 8 28.6 Nodal state N0 12 100 10 62.5 22 78.6 N1 0 0 3 18.8 3 10.7 Nx 0 0 3 18.8 3 10.7 N.A., not applicable Only one case of isolated local recurrence was observed. Among four patients with group III tumors, two each achieved complete response (CR) and partial response. Grades 3 or 4 adverse events included neutropenia (100%), anemia (67%), thrombocytopenia (58%), nausea (42%), stomatitis (25%), peripheral neuropathy (17%), and constipation (17%). Treatment was discontinued in one patient due to intermediate VOD. Vincristine and dactinomycin doses were reduced in one patient who developed mild VOD. Delayed effects of orbital primary tumors included cataracts in three patients and ptosis and eye movement disorder in two patients. Bladder wall thickening, vesicoureteral reflux, and hydronephrosis were observed in one patient with a para-testicular primary tumor. Cosmetic problems arose in the case of primary head and neck tumors. No unexpected grade 4 toxicities or deaths resulting from the toxicity were observed. One relapse occurred in a 14-year-old male patient in whom the primary site was the nasal flare (stage 1 Group IIA; ≤5 cm and confined [T1a]; N0; no distant metastasis [M0]). In this patient, local relapse occurred four times and was treated with chemotherapy and RT, including brachytherapy. The patient is alive with the fifth CR. JRS-I LRB0402 JRS-I LRB0402 included 22 patients from May 1, 2004, to April 30, 2012, of whom 16 were eligible for inclusion in this study (six patients excluded due to alveolar subtype diagnosis in a CPR). The median follow-up duration was 5.3 years (0.8–8.3 years). Thirteen patients (81%) were aged < 10 years, and eight (50%) were male (male: female = 1:1) (Table 3 ). Ten patients (63%) had tumors at favorable sites (stage 1). Two (13%), six (38%), and eight (50%) patients had group I, II, and III tumors, respectively. Two patients (12.5%) had tumors < 5 cm (widest diameter), and 10 (63%) had non-invasive tumors. Regional lymph node metastasis was observed in three patients (19%) (Table 3 ). For subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI = 59–97%) and 94% (95% CI = 63–99%), respectively (Figs. 7 , 8 ). Four patients with a primary vaginal tumor showed no residual tumor by week 28 and did not experience relapse without RT. Grade 3 or 4 adverse events observed included neutropenia (94%), anemia (94%), thrombocytopenia (50%), nausea (31%), peripheral neuropathy (13%), and constipation (6%). No unexpected grade 4 toxicities or deaths resulting from the toxicity were observed. The doses of dactinomycin and cyclophosphamide were reduced in one patient due to mild VOD. Gonadal failure was observed in one patient with a primary uterine tumor, while growth retardation was observed in one patient with a head and neck tumor. Discussion We hypothesized that in the previous retrospective study in Japan, some ARMS patients were misdiagnosed with ERMS by institutional pathologists. To verify this hypothesis, we established a nationwide study group with a CPR system for pediatric rhabdomyosarcoma patients in Japan. This study shows the relationship between histopathology and survival based on the CPR of the JRS-I and results of two low-risk subgroups A and B rhabdomyosarcoma studies, LRA0401 and LRB04042. In this nationwide group study with a CPR system, the proportion of patients with the two major histopathological subtypes of rhabdomyosarcoma with each subtype in Japan were consistent with those reported in studies conducted in Children’s Oncology Group (COG) [ 4 ] and UKCCSG [ 5 ] which indicate no difference between Japan and US or Europe in the histopathological subtypes of rhabdomyosarcoma and that our CPR system performed well. Using the CPR system, we performed the first nationwide group study for children with rhabdomyosarcoma covering all risk groups including low-risk A and low-risk B, which were not necessarily considered “low-risk” in the previous retrospective study in Japan. The LRA0401 study involved eight cycles of VAC1.2 therapy over 22 weeks. The PFS and OS observed in the present study were comparable with those observed in clinical trials of patients with similar risk groups conducted in the US and Europe [ 6 – 9 ]. In the ARST0331 study by the COG, cyclophosphamide was reduced further compared with our study, and four cycles of VAC were administered, followed by four cycles of VA over 22 weeks (cyclophosphamide cumulative dose of 4.8 g/m 2 ) to low-risk patient subgroup A [ 10 ]. Although the survival rate in the ARST0331 study was comparable to that in the D9602 study that used 16 cycles of VA over 45 weeks, the ARST0331 study incurred fewer costs for the healthcare system than did the D9602 study [ 11 ]. In the US, the standard treatment for patients with localized, grossly resectable para-testicular or gross residual orbital ERMS was comparable to that in the ARST0331 study [ 12 ]. Because the results of the JRS-I LRA0401 study were consistent with those of the ARST0331 study, the feasibility of cyclophosphamide dose reduction is being tested in an ongoing JRS-II on low-risk subgroup A patients in Japan [ 13 ]. The LRB0402 study, which included a reduced dose of cyclophosphamide and RT, did not compromise FFS in low-risk subgroup B ERMS patients. A suboptimal FFS of patients in a similar risk group using a reduced total cyclophosphamide (4.8 g/m 2 ) dose was reported in the COG ARST0331 study due to poor local control of the vaginal primary tumor [ 14 , 15 ]. These results showed that the use of RT could not be safely eliminated in patients with primary vaginal tumors using a cumulative cyclophosphamide dose of 4.8 g/m 2 . However, patients with primary vaginal tumors in complete remission at week 28 were safely treated without RT in the D9602 study using 28.8 g/m 2 cyclophosphamide [ 6 ]. Similarly, we showed that RT can be safely avoided in patients with primary vaginal tumors who have received a cumulative cyclophosphamide dose of 17.6 g/m 2 . Thus, the dose of an alkylating agent is closely related to the local control of rhabdomyosarcoma tumors. Currently, we are investigating whether further reductions in cyclophosphamide dose is possible using irinotecan in low-risk subgroup B patients [ 13 ]. This trial may reduce the risk of infertility due to rhabdomyosarcoma treatment. Patients with localized, grossly resectable para-testicular ERMS and those with gross residual orbital or eyelid ERMS in the IRS-IV [ 9 ] had 3-year FFS rates of 81% and 89%, respectively. These patients received only VA for 36 weeks without cyclophosphamide. The German CWS-86 clinical trials for similar patients suggested that further reduction in the dose intensity or treatment period could be possible by using modest doses of ifosfamide [ 7 ]. Patients with localized, grossly resectable (unfavorable site) or gross residual (favorable site except the orbit) ERMS had 3-year FFS and OS rates of 88% and 96%, respectively, in the IRS-IV study [ 9 ]. The study prescribed a cumulative cyclophosphamide dose of 26.4 g/m 2 , which is sufficiently high, causing infertility. The primary objective of the JRS-I LRB0402 study was to estimate the FFS and OS rates of low-risk subgroup B patients with localized, grossly resectable (unfavorable site) or gross residual (favorable site except the orbit) ERMS using a reduced dose of cyclophosphamide to minimize the risk of acute side effects and infertility. We administered VAC2.2 (cyclophosphamide dose 2.2 g/m 2 ; cumulative cyclophosphamide dose 17.6 g/m 2 ) for 24 weeks, followed by 24 weeks of VA therapy. In the group study, the prognosis of low-risk ERMS patients improved. In the ongoing JRS-II research, we are verifying treatment strategies to avoid long-term complications in low-risk rhabdomyosarcoma patients (subgroup A and B) in Japan [ 13 ]. A limitation of our study is its small sample size. Although these data alone cannot be used to establish an appropriate treatment strategy, a meta-analysis of several clinical trials of low-risk rhabdomyosarcoma, including the present study, may enable researchers to identify treatment strategies for future clinical trials. Researchers from the US and Europe created an international consortium, INSTRuCT, with the goal of establishing a database of information from clinical trials, including those on pediatric rhabdomyosarcoma. Nonetheless, rhabdomyosarcoma is a rare disease, and even results from a clinical trial with a small sample size are important. Therefore, our results will be valuable in collaboration with this database. This prospective clinical study is the first nationwide group study that includes a CPR system for rhabdomyosarcoma patients in Japan. The proportion with the two major histopathological rhabdomyosarcoma subtypes and prognoses of each subtype differed from previous retrospective study results in Japan but were consistent with those reported in similar studies conducted in the US and Europe. Additionally, we show that reduction in the cyclophosphamide dose to 9.6 g/m 2 and shortening of treatment duration to 24 weeks achieved a comparable result to that in historical clinical trials in low-risk subgroup A patients. Moreover, according to the LRB0402 study, a reduced cyclophosphamide dose of 17.6 g/m 2 did not compromise FFS low-risk subgroup B ERMS patients. Declarations Data Availability Statement Data cannot be shared openly but are available on request from authors: The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are in controlled access database at the Childhood Cancer Center, National Center for Child Health and Development. Acknowledgments We would like to express our gratitude to Dr. Peter J. Houghton, Dr. William M. Crist, and William H. Meyer (Intergroup Rhabdomyosarcoma Study Group). Without their guidance, this project would not have materialized. We would also like to thank Dr. Masanori Fukushima (Translational Research Informatics Center) and Hideo Oda (Translational Research Informatics Center) for the protocol development and project management. Finally, we dedicate this work to late Drs. Yoshiaki Tsuchida, Masaaki Kumagai, Takeshi Kusafuka, and Shigeru Ohta as members of the JRSG. This work was supported by the Japan Agency for Medical Research and Development (AMED) under the grant numbers JP19ck0106333 and JP20ck0106610. References Hosoi H, Teramukai S, Matsumoto Y, et al (2007) A review of 331 rhabdomyosarcoma cases in patients treated between 1991 and 2002 in Japan. Int J Clin Oncol 12:137–145 Hosoi H (2016) Current status of treatment for pediatric rhabdomyosarcoma in the USA and Japan. Pediatr Int 58:81–87 Newton WA Jr, Gehan EA, Webber BL, et al (1995) Classification of rhabdomyosarcoma and related sarcomas. Pathologic aspects and proposals for a new classification - an intergroup rhabdomyosarcoma study. Cancer. 76:1073-1085. Sorensen PH, Lynch JC, Qualman SJ, et al (2002) PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children’s Oncology Group. J Clin Oncol 20:2672–2679 Anderson J, Gordon T, McManus A, et al (2001) Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome? Br J Cancer 85:831–835 Raney RB, Walterhouse DO, Meza JL, et al (2011) Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol 29:1312–1318 Koscielniak E, Harms D, Henze G, et al (1999) Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative soft tissue sarcoma Study CWS-86. J Clin Oncol 17:3706–3719 Stewart RJ, Martelli H, Oberlin O, et al (2003) Treatment of children with nonmetastatic paratesticular rhabdomyosarcoma: results of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology. J Clin Oncol 21:793–798 Crist WM, Anderson JR, Meza JL, et al (2001) Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19:3091–3102 Walterhouse DO, Pappo AS, Meza JL, et al (2014) Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol 32:3547–3552 Russell H, Swint JM, Lal L, et al (2014) Cost minimization analysis of two treatment regimens for low-risk rhabdomyosarcoma in children: a report from the Children’s Oncology Group. Pediatr Blood Cancer 61:970–976 Hawkins DS, Spunt SL, Skapek SX et al (2013) Children’s Oncology Group’s 2013 blueprint for research: soft tissue sarcomas. Pediatr Blood Cancer 60:1001–1008 Miyachi M, Tsuchiya K, Hosono A, et al (2019) Phase II study of vincristine, actinomycin-D, cyclophosphamide and irinotecan for patients with newly diagnosed low-risk subset B rhabdomyosarcoma: A study protocol. Medicine (Baltimore) 98:e18344 Walterhouse DO, Meza JL, Breneman JC, et al (2011) Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the Children’s Oncology Group. Pediatr Blood Cancer 57:76–83 Walterhouse DO, Pappo AS, Meza JL, et al (2017) Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. Cancer 123:2368–2375 Supplementary Files Supplements20240103HH.docx Cite Share Download PDF Status: Published Journal Publication published 23 Aug, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 05 Feb, 2024 Reviewers agreed at journal 11 Jan, 2024 Reviewers invited by journal 08 Jan, 2024 Editor assigned by journal 07 Jan, 2024 First submitted to journal 04 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3838227","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266162773,"identity":"7bb30ac1-eab8-44e8-8295-e0ede5ee6d02","order_by":0,"name":"Hajime 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1","display":"","copyAsset":false,"role":"figure","size":119174,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival of patients with ERMS and ARMS histology\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/5cb792bed35b5441d323d597.png"},{"id":49540308,"identity":"7ff1ecb3-a772-4fbd-8f4f-1cf5d7728ea7","added_by":"auto","created_at":"2024-01-12 17:17:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":134836,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival of patients with ERMS and ARMS histology\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/b1d373f7af848c8fb63caff6.png"},{"id":49540310,"identity":"3635618e-06be-4874-b555-1ba4d86bc697","added_by":"auto","created_at":"2024-01-12 17:17:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":168150,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival of patients with the fusion-negative and fusion-positive RMS\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/848c022b9a1f36733bd1f134.png"},{"id":49540312,"identity":"c1920c40-f9cf-498a-8b6f-b2e2917180c0","added_by":"auto","created_at":"2024-01-12 17:17:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":174639,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival of patients with the fusion-negative and fusion-positive RMS\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/769d0405e342ecce78c012ff.png"},{"id":49540314,"identity":"b97e95e8-59a5-48fb-adee-3b75ab0fb874","added_by":"auto","created_at":"2024-01-12 17:17:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":27688,"visible":true,"origin":"","legend":"\u003cp\u003eFailure-free survival (FFS) for low-risk subgroup A patients\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/1730bce0983addf13925461b.png"},{"id":49540309,"identity":"4f191a32-b2ae-4274-9332-4ced8a8b058e","added_by":"auto","created_at":"2024-01-12 17:17:53","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":26824,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (OS) for low-risk subgroup A patients\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/e404fd6685966590e3775ebb.png"},{"id":49541441,"identity":"5557b628-f760-4d69-876d-459f97292f15","added_by":"auto","created_at":"2024-01-12 17:25:53","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":26332,"visible":true,"origin":"","legend":"\u003cp\u003eFailure-free survival (FFS) for low-risk subgroup B patients\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/201705e7a42ee31a49129590.png"},{"id":49541442,"identity":"e44a7579-c165-48ef-b617-d7e6c6528e4c","added_by":"auto","created_at":"2024-01-12 17:25:53","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":26291,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (OS) for low-risk subgroup B patients\u003c/p\u003e","description":"","filename":"Fig8.png","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/763e196eb7b6c4a5987ee2a0.png"},{"id":63300509,"identity":"bde38937-7cec-4758-a3ee-a0b6cb8208ab","added_by":"auto","created_at":"2024-08-26 16:14:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1305563,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/8abf990a-e8f5-4b57-bd8e-5ed1493aacf8.pdf"},{"id":49540307,"identity":"20824403-fecf-4cfd-bf33-6cdbacc6bee2","added_by":"auto","created_at":"2024-01-12 17:17:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":49118,"visible":true,"origin":"","legend":"","description":"","filename":"Supplements20240103HH.docx","url":"https://assets-eu.researchsquare.com/files/rs-3838227/v1/dc420aa09b4f6835755f2d13.docx"}],"financialInterests":"","formattedTitle":"LRA0401/ LRB0402 protocols for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma based on the central pathological review system: The first report from the Japan Rhabdomyosarcoma Study Group","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBefore the first nationwide study of all risk groups of children with rhabdomyosarcoma in Japan, children with rhabdomyosarcoma were retrospectively analyzed between 1991 and 2002 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Patient overall survival (OS) rates in both low-risk groups in Japan were approximately 10% lower than the corresponding populations in the contemporary Intergroup Rhabdomyosarcoma Study (IRS) IV and early IRS-V in the United States of America (US) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Pathologically, the rate of alveolar rhabdomyosarcoma (ARMS), which is more aggressive and an unfavorable subtype of embryonal rhabdomyosarcoma (ERMS), was much smaller in Japan than in the US [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, only 10% of rhabdomyosarcoma patients in Japan were examined for \u003cem\u003ePAX3-FOXO1\u003c/em\u003e and \u003cem\u003ePAX7-FOXO1\u003c/em\u003e fusion genes, which are useful markers for differentiating ARMS. The histology of the tumors in the low-risk groups is ERMS. Therefore, we hypothesized that some ARMS patients were misdiagnosed with ERMS, resulting in low-risk group patients having poorer outcomes in Japan. Moreover, those with ARMS misdiagnosed as ERMS may not have received sufficient therapy.\u003c/p\u003e \u003cp\u003eThe standard therapy for rhabdomyosarcoma needs to be validated by a nationwide group study that includes a rapid central pathological review (CPR) system. Subsequently, we established the Japan Rhabdomyosarcoma Study Group (JRSG) in 2004 and performed nationwide group studies consisting of four risk groups using the IRS-V risk group classification [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMost patients classified into low-risk subgroup A in the IRS-V could be curable. Therefore, they were expected to have shortened treatment period without a worse outcome, with better QOL and minimal short and long-term toxicity. The toxicity of \u0026ldquo;the gold standard\u0026rdquo; intensive vincristine, actinomycin-D, and cyclophosphamide (VAC) therapy is not \u0026ldquo;minimal.\u0026rdquo; The IRS data indicated that severe hematologic toxicity and serious infections were experienced by approximately 20% of patients per treatment course. Furthermore, 5% of patients developed veno-occlusive disease (VOD), with four VOD deaths observed in IRS-V study using the VAC therapy, like that of IRS-IV VAC. We believed that intensive VAC therapy in IRS-IV for the low-risk group subset A patients was not yet optimal. For the subset A patients, we believed that the treatment period could be shortened by adding a modest dose of cyclophosphamide to the VA therapy. This was not expected to add substantial toxicity beyond that seen with VA; it even had increased failure-free survival (FFS) compared to that seen with IRS-IV VAC. We validated the shortened treatment period giving the patients only eight cycles of VAC for 24 weeks instead of sixteen cycles of VA for 48 weeks\u003c/p\u003e \u003cp\u003eTreatment such as intensive pulsed VAC therapy given in IRS-IV study yielded excellent results in the low-risk subset B patients. The Soft Tissue Sarcoma study committee of Children Oncology Group suspended all STS research involving intensive pulsed VAC therapy because of acute toxicity concerns related to VOD in 2002. In addition, late effects of increased cyclophosphamide dose such as infertility cannot be ignored. We believe that intensive pulsed VAC therapy for subset B patients is not yet optimal in terms of maximizing long-term FFS, while minimizing short and long-term toxicity. For subset B patients, we are convinced that intensive pulsed VAC therapy in IRS-IV or IRS-V is excessive and propose to demonstrate that reducing treatment by giving eight cycles of intensive VAC followed by eight cycles of VA instead of sixteen cycles of intensive VAC for 48 weeks will produce long-term treatment benefits with minimized short and long-term toxicity without reducing the survival rate as seen with intensive pulsed VAC therapy in IRS-IV. We evaluated the validity of reducing chemotherapy by giving eight cycles of intensive VAC for 24 weeks followed by eight cycles of VA for 24 weeks instead of sixteen cycles of intensive VAC for 48 weeks to estimate the progression-free survival (PFS) of ERMS patients in subgroup B, when treated with eight cycles of intensive VAC followed by eight cycles of VA instead of sixteen cycles of intensive VAC for 48 weeks.\u003c/p\u003e \u003cp\u003eHere, we report a change in the number of ERMS patients and patient outcomes in the two low-risk tumor subsets, in clinical studies of the Japan Rhabdomyosarcoma Study-I (JRS-I) LRA0401 (Low-risk subgroup A) and JRS-I LRB0402 (Low-risk subgroup B). We demonstrated how a group study using multimodal, risk-adapted therapy based on prognostic factors and CPR of rhabdomyosarcoma patients yielded different results compared to a prior retrospective study in Japan.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e The central pathology review committee of the JRSG consisted of pediatric pathologists or specialists in soft tissue sarcoma. The pathological classification of JRS-I was preformed based on the International Classification of Rhabdomyosarcoma (ICR) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], independent of the molecular analyses results. Rhabdomyosarcoma not otherwise specified (RMS NOS), with \u003cem\u003ePAX3,7-FOXO1\u003c/em\u003e fusion-positive tumors, were classified as ARMS, RMS NOS with the fusion-negative tumors were classified as ERMS, and tumors with no sample for molecular analysis were classified as ARMS.\u003c/p\u003e \u003cp\u003eMolecular analysis of ARMS-associated gene fusions \u003cem\u003ePAX3-FOXO1\u003c/em\u003e and \u003cem\u003ePAX7-FOXO1\u003c/em\u003e was carried out using RT-PCR assays. Gene fusion status was evaluated by two independent laboratories of NCCHD and KPUM blinded to the histopathological subtypes.\u003c/p\u003e \u003cp\u003eThe patients were registered provisionally at the JRSG registration office at the Department of Pediatric Surgery, Keio University School of Medicine. Each determined risk classification was issued to the registerer of each institution by the person in charge of JRSG after the specimens were submitted and before the protocol therapy was started. Thereafter, the registerer sent the case report form to the data centers of each risk grouped study for the definitive registration.\u003c/p\u003e \u003cp\u003eIn this non-randomized study, treatments were assigned according to subgroups. We demonstrated the results of the two low-risk groups, low-risk subgroup A (LRA0401) and low-risk subgroup B (LRB0402) studies among the total of four risk groups studied. The remaining two risk groups, intermediate and high risks, are being prepared for submission and publication elsewhere.\u003c/p\u003e \u003cp\u003eThe primary endpoint was FFS, defined as the time from enrollment to disease progression, recurrence, or death, whichever event occurred first. Secondary endpoints were OS, response rate to chemotherapy (for group III patients), and frequency of adverse events. OS was defined as the time from enrollment to death due to any cause. The FFS and OS of patients who did not experience an event were censored at the patient\u0026rsquo;s last contact date. The Kaplan\u0026ndash;Meier method was used to estimate FFS and OS distributions.\u003c/p\u003e \u003cp\u003ePatients aged\u0026thinsp;\u0026lt;\u0026thinsp;19 years at diagnosis who were previously untreated were eligible for JRS-I LRA0401 and JRS-I LRB0402. The local institutional review board approved both studies for patient registration. The study approval numbers from the administrating center in Kyoto Prefectural University of Medicine are RBMR-C-466 and RBMC-R-465 for JRS-I LRA0401 and JRS-I LRB0402, respectively. All patients or their guardians signed an informed consent form. The trial registration numbers were UMIN000039048 for JRS-I LRA0401 and UMIN000039049 for JRS-I LRB0402. ERMS patients with stage 1 group I/IIA/III orbit or stage 2 group I tumors were classified as low-risk subgroup A, eligible for the JRS-I LRA0401 study. ERMS patients with stage 1 group IIB/IIC/III, stage 2 group IIA, or stage 3 group I/II tumors were classified as low-risk subgroup B, eligible for the JRS-I LRB0402 study.\u003c/p\u003e \u003cp\u003eThe details of LRA0401 and LRB0402 treatment regimens for patients in subgroup A (Supplementary Table\u0026nbsp;1) and subgroup B (Supplementary Table\u0026nbsp;2) including radiotherapy (RT) are described in the supplementary material.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eHistopathology and prognosis\u003c/p\u003e \u003cp\u003eBy January 2014, 211 patients including all four tumor risk groups were diagnosed with rhabdomyosarcoma by the CPR system of JRSG. There were 108 cases (51%) pathologically diagnosed as ERMS, including botryoid, spindle cell, and \u0026ldquo;mixed histopathology of ERMS NOS, and spindle cell rhabdomyosarcoma (Mixed E \u0026amp;S),\u0026rdquo; and 97 cases (46%) of ARMS, including solid variant and \u0026ldquo;mixed histopathology of ERMS and ARMS (Mixed A \u0026amp; E)\u0026rdquo;. The last six cases (3%) were diagnosed as RMS NOS because of insufficient information to determine either ERMS or ARMS. Notably, the proportion of ARMS patients increased from 22% in the former retrospective study in the 1990s to 46% in this prospective study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of numbers of patients by histopathology subtypes between pre- and post-central pathological reviews\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1991\u0026ndash;2002 (Retro. Stu.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2004\u0026ndash;2013 (JRS-I)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eERMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e202 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108 (51%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eERMS NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBotryoid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpindle cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed E and S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97 (46%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARMS NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid variant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed A \u0026amp; E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRMS NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eERMS, Embryonal rhabdomyosarcoma; NOS, not otherwise specified; Mixed E and S, Mixed histopathology including both embryonal rhabdomyosarcoma NOS and spindle cell rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; Mixed A \u0026amp; E, mixed histopathology including both embryonal and alveolar rhabdomyosarcoma; JRS-I, Japan Rhabdomyosarcoma Study-I; ND, not determined (no definition at that time); Retro. Stu, retrospective studies\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTissue samples from 153 patients (73%) were available for molecular analysis of ARMS-associated gene fusions. The fusion genes were not detected in samples from the 80 ERMS cases (100%) and 16 (18%) ARMS cases, including Mixed A \u0026amp; E cases. However, 55 out of 71 ARMS patients (77%) expressed \u003cem\u003ePAX3-FOXO1\u003c/em\u003e or \u003cem\u003ePAX7-FOXO1\u003c/em\u003e fusion genes (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the six samples from Mixed A \u0026amp; E patients, two expressed \u003cem\u003ePAX3-FOXO1\u003c/em\u003e fusion gene, whereas four did not express any fusion gene (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Two RMS NOS fusion-negative cases were classified as ERMS and four RMS NOS cases with no data of fusion status were classified as ARMS based on the CPR system. As described above, survival was analyzed between the 109 ERMS and 99 ARMS patients, excluding one ERMS and two ARMS patients for whom survival data could not be collected.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMolecular analysis of histology and fusion status in 153 patients in JRS-I\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePAX3-FOXO1\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ePAX7-FOXO1\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eERMS (n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eERMS NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBotryoid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpindle cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed E and S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARMS (n\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARMS NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid variant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed A \u0026amp; E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRMS NOS (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eERMS, Embryonal rhabdomyosarcoma; NOS, not otherwise specified; Mixed E and S, Mixed histopathology including both embryonal rhabdomyosarcoma NOS and spindle cell rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; Mixed A \u0026amp; E, mixed histopathology including both embryonal and alveolar rhabdomyosarcoma; JRS-I, Japan Rhabdomyosarcoma Study-I\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe PFS rate of ERMS group (n\u0026thinsp;=\u0026thinsp;109) [76.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4% (95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;66.5\u0026ndash;83.9%)] was significantly better than that of ARMS histology group (n\u0026thinsp;=\u0026thinsp;99) [59.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9% (95% CI\u0026thinsp;=\u0026thinsp;49.5\u0026ndash;68.6%)] (p\u0026thinsp;=\u0026thinsp;0.0145) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The OS rate of ERMS group [84.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0% (95% CI\u0026thinsp;=\u0026thinsp;75.1\u0026ndash;91.0%)] was significantly higher than that of ARMS and mixed histology group [57.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1% (95% CI\u0026thinsp;=\u0026thinsp;44.9\u0026ndash;68.5%] (p\u0026thinsp;=\u0026thinsp;0.0015) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurthermore, both PFS (p\u0026thinsp;=\u0026thinsp;0.0022) and OS (p\u0026thinsp;=\u0026thinsp;0.0001) were significantly different between patients with fusion-negative and fusion-positive tumors. The PFS rate of patients with fusion-negative ERMS (n\u0026thinsp;=\u0026thinsp;80) was 76.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9% (95% CI\u0026thinsp;=\u0026thinsp;64.9\u0026ndash;84.8%). The PFS rate of patients with fusion-positive ARMS (n\u0026thinsp;=\u0026thinsp;53), excluding those with mixed histology (n\u0026thinsp;=\u0026thinsp;2), was 44.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3% (95% CI\u0026thinsp;=\u0026thinsp;29.6\u0026ndash;57.8%). The PFS rate of patients with the fusion-negative ARMS (n\u0026thinsp;=\u0026thinsp;12), excluding those with mixed histology (n\u0026thinsp;=\u0026thinsp;4), was 75.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5% (95% CI\u0026thinsp;=\u0026thinsp;40.8\u0026ndash;91.2%). Patients with mixed histology (n\u0026thinsp;=\u0026thinsp;6), which included fusion-positive (n\u0026thinsp;=\u0026thinsp;2) and fusion-negative (n\u0026thinsp;=\u0026thinsp;4) patients, had no event during the observation period (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe OS rate of patients with fusion-negative ERMS was 85.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3% (95% CI\u0026thinsp;=\u0026thinsp;74.3\u0026ndash;91.9%). The OS rate of patients with fusion-positive and fusion-negative ARMS, excluding those with mixed histology, was 38.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4% (95% CI\u0026thinsp;=\u0026thinsp;22.8\u0026ndash;54.5%) and 81.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9% (95% CI\u0026thinsp;=\u0026thinsp;43.5\u0026ndash;95.1%), respectively. All six patients with mixed histology and two of 48 patients with tumors expressing \u003cem\u003ePAX3-FOXO1\u003c/em\u003e fusion gene were alive with no evidence of tumors (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eJRS-I LRA0401\u003c/h2\u003e \u003cp\u003eJRS-I LRA0401 included 17 patients treated between May 2004 and July 2010, of whom 12 patients were eligible and four were ineligible for analysis (three with ARMS diagnosis, one with a benign tumor, and one due to specimen not being sent for CPR). The median follow-up duration was 5.6 years (3.0\u0026ndash;9.0 years). Seven patients (58%) were aged\u0026thinsp;\u0026lt;\u0026thinsp;10 years and male (male: female\u0026thinsp;=\u0026thinsp;1.4:1) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Eleven (91.7%), five (42%), three (25%), and four (33%) patients had tumors at favorable sites (stage 1), group I tumors, group IIA tumors, and group III tumors, respectively. Ten patients (83%) had non-invasive tumors\u0026thinsp;\u0026lt;\u0026thinsp;5 cm (widest diameter). None of the cases metastasized to the regional lymph nodes (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For subgroup A patients (n\u0026thinsp;=\u0026thinsp;12), the 3-year FFS and OS rates were 83% (95% CI\u0026thinsp;=\u0026thinsp;48\u0026ndash;96%) and 100%, respectively (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison between subgroups of patients treated according to LRA0401 and LRB0402\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubgroup A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSubgroup B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u0026ndash;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u0026ndash;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u0026lt;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e46.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParatestis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale genital tract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHead and neck\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrbit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBladder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameningeal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;5 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;5 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e81.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasiveness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e71.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal state\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e78.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eN.A., not applicable\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOnly one case of isolated local recurrence was observed. Among four patients with group III tumors, two each achieved complete response (CR) and partial response. Grades 3 or 4 adverse events included neutropenia (100%), anemia (67%), thrombocytopenia (58%), nausea (42%), stomatitis (25%), peripheral neuropathy (17%), and constipation (17%). Treatment was discontinued in one patient due to intermediate VOD. Vincristine and dactinomycin doses were reduced in one patient who developed mild VOD. Delayed effects of orbital primary tumors included cataracts in three patients and ptosis and eye movement disorder in two patients. Bladder wall thickening, vesicoureteral reflux, and hydronephrosis were observed in one patient with a para-testicular primary tumor. Cosmetic problems arose in the case of primary head and neck tumors. No unexpected grade 4 toxicities or deaths resulting from the toxicity were observed.\u003c/p\u003e \u003cp\u003eOne relapse occurred in a 14-year-old male patient in whom the primary site was the nasal flare (stage 1 Group IIA; \u0026le;5 cm and confined [T1a]; N0; no distant metastasis [M0]). In this patient, local relapse occurred four times and was treated with chemotherapy and RT, including brachytherapy. The patient is alive with the fifth CR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eJRS-I LRB0402\u003c/h2\u003e \u003cp\u003eJRS-I LRB0402 included 22 patients from May 1, 2004, to April 30, 2012, of whom 16 were eligible for inclusion in this study (six patients excluded due to alveolar subtype diagnosis in a CPR). The median follow-up duration was 5.3 years (0.8\u0026ndash;8.3 years). Thirteen patients (81%) were aged\u0026thinsp;\u0026lt;\u0026thinsp;10 years, and eight (50%) were male (male: female\u0026thinsp;=\u0026thinsp;1:1) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Ten patients (63%) had tumors at favorable sites (stage 1). Two (13%), six (38%), and eight (50%) patients had group I, II, and III tumors, respectively. Two patients (12.5%) had tumors\u0026thinsp;\u0026lt;\u0026thinsp;5 cm (widest diameter), and 10 (63%) had non-invasive tumors. Regional lymph node metastasis was observed in three patients (19%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For subgroup B (n\u0026thinsp;=\u0026thinsp;16), the 3-year FFS and OS rates were 88% (95% CI\u0026thinsp;=\u0026thinsp;59\u0026ndash;97%) and 94% (95% CI\u0026thinsp;=\u0026thinsp;63\u0026ndash;99%), respectively (Figs.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, \u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFour patients with a primary vaginal tumor showed no residual tumor by week 28 and did not experience relapse without RT. Grade 3 or 4 adverse events observed included neutropenia (94%), anemia (94%), thrombocytopenia (50%), nausea (31%), peripheral neuropathy (13%), and constipation (6%). No unexpected grade 4 toxicities or deaths resulting from the toxicity were observed. The doses of dactinomycin and cyclophosphamide were reduced in one patient due to mild VOD. Gonadal failure was observed in one patient with a primary uterine tumor, while growth retardation was observed in one patient with a head and neck tumor.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe hypothesized that in the previous retrospective study in Japan, some ARMS patients were misdiagnosed with ERMS by institutional pathologists. To verify this hypothesis, we established a nationwide study group with a CPR system for pediatric rhabdomyosarcoma patients in Japan. This study shows the relationship between histopathology and survival based on the CPR of the JRS-I and results of two low-risk subgroups A and B rhabdomyosarcoma studies, LRA0401 and LRB04042.\u003c/p\u003e \u003cp\u003eIn this nationwide group study with a CPR system, the proportion of patients with the two major histopathological subtypes of rhabdomyosarcoma with each subtype in Japan were consistent with those reported in studies conducted in Children\u0026rsquo;s Oncology Group (COG) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and UKCCSG [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] which indicate no difference between Japan and US or Europe in the histopathological subtypes of rhabdomyosarcoma and that our CPR system performed well.\u003c/p\u003e \u003cp\u003eUsing the CPR system, we performed the first nationwide group study for children with rhabdomyosarcoma covering all risk groups including low-risk A and low-risk B, which were not necessarily considered \u0026ldquo;low-risk\u0026rdquo; in the previous retrospective study in Japan.\u003c/p\u003e \u003cp\u003eThe LRA0401 study involved eight cycles of VAC1.2 therapy over 22 weeks. The PFS and OS observed in the present study were comparable with those observed in clinical trials of patients with similar risk groups conducted in the US and Europe [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the ARST0331 study by the COG, cyclophosphamide was reduced further compared with our study, and four cycles of VAC were administered, followed by four cycles of VA over 22 weeks (cyclophosphamide cumulative dose of 4.8 g/m\u003csup\u003e2\u003c/sup\u003e) to low-risk patient subgroup A [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although the survival rate in the ARST0331 study was comparable to that in the D9602 study that used 16 cycles of VA over 45 weeks, the ARST0331 study incurred fewer costs for the healthcare system than did the D9602 study [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the US, the standard treatment for patients with localized, grossly resectable para-testicular or gross residual orbital ERMS was comparable to that in the ARST0331 study [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Because the results of the JRS-I LRA0401 study were consistent with those of the ARST0331 study, the feasibility of cyclophosphamide dose reduction is being tested in an ongoing JRS-II on low-risk subgroup A patients in Japan [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe LRB0402 study, which included a reduced dose of cyclophosphamide and RT, did not compromise FFS in low-risk subgroup B ERMS patients. A suboptimal FFS of patients in a similar risk group using a reduced total cyclophosphamide (4.8 g/m\u003csup\u003e2\u003c/sup\u003e) dose was reported in the COG ARST0331 study due to poor local control of the vaginal primary tumor [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These results showed that the use of RT could not be safely eliminated in patients with primary vaginal tumors using a cumulative cyclophosphamide dose of 4.8 g/m\u003csup\u003e2\u003c/sup\u003e. However, patients with primary vaginal tumors in complete remission at week 28 were safely treated without RT in the D9602 study using 28.8 g/m\u003csup\u003e2\u003c/sup\u003e cyclophosphamide [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Similarly, we showed that RT can be safely avoided in patients with primary vaginal tumors who have received a cumulative cyclophosphamide dose of 17.6 g/m\u003csup\u003e2\u003c/sup\u003e. Thus, the dose of an alkylating agent is closely related to the local control of rhabdomyosarcoma tumors. Currently, we are investigating whether further reductions in cyclophosphamide dose is possible using irinotecan in low-risk subgroup B patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This trial may reduce the risk of infertility due to rhabdomyosarcoma treatment.\u003c/p\u003e \u003cp\u003ePatients with localized, grossly resectable para-testicular ERMS and those with gross residual orbital or eyelid ERMS in the IRS-IV [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] had 3-year FFS rates of 81% and 89%, respectively. These patients received only VA for 36 weeks without cyclophosphamide. The German CWS-86 clinical trials for similar patients suggested that further reduction in the dose intensity or treatment period could be possible by using modest doses of ifosfamide [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with localized, grossly resectable (unfavorable site) or gross residual (favorable site except the orbit) ERMS had 3-year FFS and OS rates of 88% and 96%, respectively, in the IRS-IV study [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The study prescribed a cumulative cyclophosphamide dose of 26.4 g/m\u003csup\u003e2\u003c/sup\u003e, which is sufficiently high, causing infertility. The primary objective of the JRS-I LRB0402 study was to estimate the FFS and OS rates of low-risk subgroup B patients with localized, grossly resectable (unfavorable site) or gross residual (favorable site except the orbit) ERMS using a reduced dose of cyclophosphamide to minimize the risk of acute side effects and infertility. We administered VAC2.2 (cyclophosphamide dose 2.2 g/m\u003csup\u003e2\u003c/sup\u003e; cumulative cyclophosphamide dose 17.6 g/m\u003csup\u003e2\u003c/sup\u003e) for 24 weeks, followed by 24 weeks of VA therapy.\u003c/p\u003e \u003cp\u003eIn the group study, the prognosis of low-risk ERMS patients improved. In the ongoing JRS-II research, we are verifying treatment strategies to avoid long-term complications in low-risk rhabdomyosarcoma patients (subgroup A and B) in Japan [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA limitation of our study is its small sample size. Although these data alone cannot be used to establish an appropriate treatment strategy, a meta-analysis of several clinical trials of low-risk rhabdomyosarcoma, including the present study, may enable researchers to identify treatment strategies for future clinical trials. Researchers from the US and Europe created an international consortium, INSTRuCT, with the goal of establishing a database of information from clinical trials, including those on pediatric rhabdomyosarcoma. Nonetheless, rhabdomyosarcoma is a rare disease, and even results from a clinical trial with a small sample size are important. Therefore, our results will be valuable in collaboration with this database.\u003c/p\u003e \u003cp\u003eThis prospective clinical study is the first nationwide group study that includes a CPR system for rhabdomyosarcoma patients in Japan. The proportion with the two major histopathological rhabdomyosarcoma subtypes and prognoses of each subtype differed from previous retrospective study results in Japan but were consistent with those reported in similar studies conducted in the US and Europe.\u003c/p\u003e \u003cp\u003eAdditionally, we show that reduction in the cyclophosphamide dose to 9.6 g/m\u003csup\u003e2\u003c/sup\u003e and shortening of treatment duration to 24 weeks achieved a comparable result to that in historical clinical trials in low-risk subgroup A patients. Moreover, according to the LRB0402 study, a reduced cyclophosphamide dose of 17.6 g/m\u003csup\u003e2\u003c/sup\u003e did not compromise FFS low-risk subgroup B ERMS patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData cannot be shared openly but are available on request from authors:\u0026nbsp;The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are in controlled access database\u0026nbsp;at the Childhood Cancer Center, National Center for Child Health and Development.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to Dr. Peter J. Houghton, Dr. William M. Crist, and William H. Meyer (Intergroup Rhabdomyosarcoma Study Group). Without their guidance, this project would not have materialized. We would also like to thank Dr. Masanori Fukushima (Translational Research Informatics Center) and Hideo Oda \u0026nbsp; (Translational Research Informatics Center) for the protocol development and project management. Finally, we dedicate this work to late Drs. Yoshiaki Tsuchida, Masaaki Kumagai, Takeshi Kusafuka, and Shigeru Ohta as members of the JRSG. This work was supported by the Japan Agency for Medical Research and Development (AMED) under the grant numbers JP19ck0106333 and JP20ck0106610.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHosoi H, Teramukai S, Matsumoto Y, et al\u003cem\u003e \u003c/em\u003e(2007) A review of 331 rhabdomyosarcoma cases in patients treated between 1991 and 2002 in Japan. Int J Clin Oncol 12:137\u0026ndash;145\u003c/li\u003e\n\u003cli\u003eHosoi H (2016) Current status of treatment for pediatric rhabdomyosarcoma in the USA and Japan. Pediatr Int 58:81\u0026ndash;87\u003c/li\u003e\n\u003cli\u003eNewton WA Jr, Gehan EA, Webber BL, et al (1995) Classification of rhabdomyosarcoma and related sarcomas. Pathologic aspects and proposals for a new classification - an intergroup rhabdomyosarcoma study. Cancer. 76:1073-1085.\u003c/li\u003e\n\u003cli\u003eSorensen PH, Lynch JC, Qualman SJ, et al\u003cem\u003e \u003c/em\u003e(2002) PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children\u0026rsquo;s Oncology Group. J Clin Oncol 20:2672\u0026ndash;2679\u003c/li\u003e\n\u003cli\u003eAnderson J, Gordon T, McManus A, et al\u003cem\u003e \u003c/em\u003e(2001) Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome? Br J Cancer 85:831\u0026ndash;835\u003c/li\u003e\n\u003cli\u003eRaney RB, Walterhouse DO, Meza JL, et al\u003cem\u003e \u003c/em\u003e(2011) Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children\u0026rsquo;s Oncology Group. J Clin Oncol 29:1312\u0026ndash;1318\u003c/li\u003e\n\u003cli\u003eKoscielniak E, Harms D, Henze G, et al\u003cem\u003e \u003c/em\u003e(1999) Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative soft tissue sarcoma Study CWS-86. J Clin Oncol 17:3706\u0026ndash;3719\u003c/li\u003e\n\u003cli\u003eStewart RJ, Martelli H, Oberlin O, et al\u003cem\u003e \u003c/em\u003e(2003) Treatment of children with nonmetastatic paratesticular rhabdomyosarcoma: results of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology. J Clin Oncol 21:793\u0026ndash;798\u003c/li\u003e\n\u003cli\u003eCrist WM, Anderson JR, Meza JL, et al\u003cem\u003e \u003c/em\u003e(2001) Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19:3091\u0026ndash;3102\u003c/li\u003e\n\u003cli\u003eWalterhouse DO, Pappo AS, Meza JL, et al\u003cem\u003e \u003c/em\u003e(2014) Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children\u0026rsquo;s Oncology Group. J Clin Oncol 32:3547\u0026ndash;3552\u003c/li\u003e\n\u003cli\u003eRussell H, Swint JM, Lal L, et al\u003cem\u003e \u003c/em\u003e(2014) Cost minimization analysis of two treatment regimens for low-risk rhabdomyosarcoma in children: a report from the Children\u0026rsquo;s Oncology Group. Pediatr Blood Cancer 61:970\u0026ndash;976\u003c/li\u003e\n\u003cli\u003eHawkins DS, Spunt SL, Skapek SX et al\u003cem\u003e \u003c/em\u003e(2013) Children\u0026rsquo;s Oncology Group\u0026rsquo;s 2013 blueprint for research: soft tissue sarcomas. Pediatr Blood Cancer 60:1001\u0026ndash;1008\u003c/li\u003e\n\u003cli\u003eMiyachi M, Tsuchiya K, Hosono A, et al\u003cem\u003e \u003c/em\u003e(2019) Phase II study of vincristine, actinomycin-D, cyclophosphamide and irinotecan for patients with newly diagnosed low-risk subset B rhabdomyosarcoma: A study protocol. Medicine (Baltimore) 98:e18344\u003c/li\u003e\n\u003cli\u003eWalterhouse DO, Meza JL, Breneman JC, et al\u003cem\u003e \u003c/em\u003e(2011) Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the Children\u0026rsquo;s Oncology Group. Pediatr Blood Cancer 57:76\u0026ndash;83\u003c/li\u003e\n\u003cli\u003eWalterhouse DO, Pappo AS, Meza JL, et al\u003cem\u003e \u003c/em\u003e(2017) Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children\u0026rsquo;s Oncology Group. Cancer 123:2368\u0026ndash;2375\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"embryonal rhabdomyosarcoma, a nationwide group study, risk-adopted therapy, central pathological review system","lastPublishedDoi":"10.21203/rs.3.rs-3838227/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3838227/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eA retrospective study of pediatric rhabdomyosarcoma patients treated between 1991 and 2002 in Japan revealed that among the two major subtypes, embryonal rhabdomyosarcoma (ERMS), was more prevalent than alveolar rhabdomyosarcoma (ARMS), differing from a United States (US)-based report. Moreover, the survival rate of low-risk ERMS was worse in Japan than in the US. We hypothesized that some patients with ARMS having a poorer prognosis were misdiagnosed and undertreated in Japan. We explored this hypothesis using a nationwide group study, by risk-adopted therapy based upon a central pathological review system to improve the prognosis of patients with \u0026ldquo;low-risk\u0026rdquo; rhabdomyosarcoma in Japan.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eUsing the first nationwide Japan Rhabdomyosarcoma Study Group established in 2004, we classified patients into low-risk subgroup A, including ERMS with orbital, grossly resectable, favorable site, and small unfavorable site tumors, who were eligible for JRS-I LRA0401; and low-risk subgroup B, including ERMS with residual, favorable site and grossly resectable, large, unfavorable site tumors, eligible for JRS-I LRB0402.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eERMS cases decreased from 78\u0026ndash;51% before and after the central pathological review. Fusion genes were not detected in ERMS. The overall survival rate was significantly better (p\u0026thinsp;=\u0026thinsp;0.0015) in ERMS (84.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0%) than in ARMS (57.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1%). The 3-year overall survival rates of low-risk patients in subgroups A and B improved from 86\u0026ndash;100% and from 81\u0026ndash;94%, respectively.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBy implementing a central pathological review system in Japan and adopting fusion gene analyses for diagnosis, the number of patients with ERMS decreased and their outcomes improved significantly.\u003c/p\u003e","manuscriptTitle":"LRA0401/ LRB0402 protocols for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma based on the central pathological review system: The first report from the Japan Rhabdomyosarcoma Study Group","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-12 17:17:48","doi":"10.21203/rs.3.rs-3838227/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-02-05T20:28:28+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-01-11T11:20:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-09T00:28:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-07T17:15:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-01-04T14:57:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9e78b2ae-f8dc-4571-a1b2-5d26ba840e80","owner":[],"postedDate":"January 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T16:05:53+00:00","versionOfRecord":{"articleIdentity":"rs-3838227","link":"https://doi.org/10.1007/s10147-024-02608-x","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2024-08-23 15:57:56","publishedOnDateReadable":"August 23rd, 2024"},"versionCreatedAt":"2024-01-12 17:17:48","video":"","vorDoi":"10.1007/s10147-024-02608-x","vorDoiUrl":"https://doi.org/10.1007/s10147-024-02608-x","workflowStages":[]},"version":"v1","identity":"rs-3838227","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3838227","identity":"rs-3838227","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}