Results of a phase II trial for intermediate-risk rhabdomyosarcoma treatment protocol JRS-I: A report from the Japan Rhabdomyosarcoma Study Group

Results of a phase II trial for intermediate-risk rhabdomyosarcoma treatment protocol JRS-I: A report from the Japan Rhabdomyosarcoma Study Group | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 4 February 2025 V1 Latest version Share on Results of a phase II trial for intermediate-risk rhabdomyosarcoma treatment protocol JRS-I: A report from the Japan Rhabdomyosarcoma Study Group Authors : Atsushi Kikuta [email protected] , Hidekazu Masaki , Hiroshi Hojo , Jun-ichi Hata , Hajime Okita , Hajime Hosoi , Atsuko Nakazawa , … Show All … , Shiro Hinotsu , Hitoshi Ikeda , Seiji Koshimoto , Michio Kaneko , Akira Kawai , Jun-Ichi Hara , Tetsuya Takimoto , Miho Kato , Takashi Kaneko , Yoshiyuki Kosaka , and Yasuhide Morikawa Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.173867962.23200709/v1 377 views 279 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Purpose: To evaluate the safety and efficacy of multimodality treatment with vincristine, actinomycin-D, and cyclophosphamide (VAC) therapy, surgery, and radiotherapy according to the U.S. Intergroup Rhabdomyosarcoma Study IV (IRS-IV), and to establish a central review system and standard treatment for intermediate-risk pediatric rhabdomyosarcoma in Japan. Patients and methods: The JRS-I was a single-arm, phase II trial for intermediate-risk rhabdomyosarcoma treatment with open enrollment from June 2004 to March 2009. Patients received 12 cycles of VAC every 3 weeks for 42 weeks, with local therapy beginning after week 12. The endpoints were progression-free survival (PFS), overall survival (OS), and incidence of hepatic veno-occlusive disease (VOD). Results: Thirty-one eligible patients were enrolled, and at a median follow-up of 5.2 years, the 3-year PFS and OS for patients were 74.2% ± 7.9% (95% CI 55.0%-86.2%) and 90.3% ± 5.3% (95% CI 72.9%-96.8%), respectively. VOD occurred in 3 (8%) of the 40 evaluable patients, but all recovered, and there were no deaths. Conclusion: The VAC regimen for intermediate-risk rhabdomyosarcoma with the first central review system in Japan is safe and feasible, and these findings can be positioned as basic data for improving treatment outcomes in Japan. not-yet-known not-yet-known not-yet-known unknown Results of a phase II trial for intermediate-risk rhabdomyosarcoma treatment protocol JRS-I: A report from the not-yet-known not-yet-known not-yet-known unknown Japan Rhabdomyosarcoma Study Group Atsushi Kikuta 1 , Hidekazu Masaki 2 , Hiroshi Hojo 3 , Jun-ichi Hata 4 , Hajime Ohkita 5 , not-yet-known not-yet-known not-yet-known unknown Hajime Hosoi6, Atsuko Nakazawa7, Shiro Hinotsu8, Hitoshi Ikeda9, Seiji Kishimoto10, Michio Kaneko 11 , Akira Kawai 12 , Junichi Hara 13 , Tetsuya Takimoto 14 , Miho Kato 14 , Takashi Kaneko 15 , Yoshiyuki Kosaka 16 , Yasuhide Morikawa 17 , For the Japan Rhabdomyosarcoma Study Group (JRSG) 1 Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima, Japan 2 Department of Radiology, National Center for Child Health and Development, Tokyo, Japan 3 Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan 4 Central Institute for Experimental Medicine and Life Science, Tokyo, Japan 5 Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan 6 Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto Japan 7 Department of Pathology, National Center for Child Health and Development, Tokyo, Japan 8 Department of Biostatistics and Data Management, Sapporo Medical University, Sapporo, Japan 9 Department of Pediatric Surgery, Dokkyo Medical University Saitama Medical Center, Saitama, Japan 10 Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan 11 Department of Pediatric Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan 12 Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan 13 Department of Pediatric Hematology/Oncology, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan 14 Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan 15 Department of Hematology/Oncology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan 16 Department of Hematology/Oncology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan 17 Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan Atsushi Kikuta Department of Pediatric Oncology, Fukushima Medical University Hospital, 1 Hikariga-oka, Fukushima City, 960-1295 JAPAN FAX: +81-24-547-1443 TEL: +81-24-547-1437 E-mail: [email protected] Corresponding Author: Atsushi Kikuta Abstract Purpose: To evaluate the safety and efficacy of multimodality treatment with vincristine, actinomycin-D, and cyclophosphamide (VAC) therapy, surgery, and radiotherapy according to the U.S. Intergroup Rhabdomyosarcoma Study IV (IRS-IV), and to establish a central review system and standard treatment for intermediate-risk pediatric rhabdomyosarcoma in Japan. Patients and methods: The JRS-I was a single-arm, phase II trial for intermediate-risk rhabdomyosarcoma treatment with open enrollment from June 2004 to March 2009. Patients received 12 cycles of VAC every 3 weeks for 42 weeks, with local therapy beginning after week 12. The endpoints were progression-free survival (PFS), overall survival (OS), and incidence of hepatic veno-occlusive disease (VOD). Results: Thirty-one eligible patients were enrolled, and at a median follow-up of 5.2 years, the 3-year PFS and OS for patients were 74.2% ± 7.9% (95% CI 55.0%-86.2%) and 90.3% ± 5.3% (95% CI 72.9%-96.8%), respectively. VOD occurred in 3 (8%) of the 40 evaluable patients, but all recovered, and there were no deaths. Conclusion: The VAC regimen for intermediate-risk rhabdomyosarcoma with the first central review system in Japan is safe and feasible, and these findings can be positioned as basic data for improving treatment outcomes in Japan. (192 words) Keywords: Rhabdomyosarcoma, Intermediate-risk, Clinical trial, Central review system, multimodality treatment Running title: phase II trial for intermediate-risk rhabdomyosarcoma Abbreviations: IRSG, Intergroup Rhabdomyosarcoma Study Group; VAC, vincristine, actinomycin D, and cyclophosphamide; VAI, vincristine, actinomycin D, and ifosfamide; VIE, vincristine, ifosfamide, and etoposide; FFS, failure free survival; JRSG, Japan Rhabdomyosarcoma Study Group; LN, lymph node; PFS, progression-free survival; OS, overall survival; VOD, veno-occlusive disease; SIADH, Syndrome of inappropriate secretion of antidiuretic hormone. Introduction The U.S. Intergroup Rhabdomyosarcoma Study Group (IRSG), started in 1972, is one of the largest research groups in the world and has developed a multidisciplinary approach combining surgery, chemotherapy, and radiation therapy. The group’s efforts have been centered on vincristine, actinomycin D, and cyclophosphamide (VAC) therapy. In their studies, patients showed a dramatic improvement in outcomes, with 5-year survival rates of 55% for IRS-I, 63% for IRS-II, and approximately 71% for IRS-III and IRS-IV [1-6]. The IRS lists the following risk factors for rhabdomyosarcoma: (1) distant metastasis at initial presentation; (2) findings in the parameningial head and neck except for the orbit, bladder, and prostate; (3) gross residual tumor; (4) histological type other than embryonal/botryoid; and (5) tumor maximum diameter of ≥5 cm [5,6]. In the IRS-IV conducted from 1991 to 1997, 883 patients had localized rhabdomyosarcoma, of whom 490 were group III cases with large residual tumors [6]. These group III cases, which accounted for 47.3% (490/1035) of all cases, were randomized to receive VAC; vincristine, actinomycin D, and ifosfamide (VAI); or vincristine, ifosfamide, and etoposide (VIE) therapy. The 3-year failure free survival (FFS) was 75% in the VAC group, 77% in the VAI group, and 77% in the VIE group. The IRS is currently conducting further studies with the most feasible VAC therapy as the standard arm. In Japan, there is strong awareness of the need to avoid various negative side effects caused by extensive surgical invasion, and there is a tendency to avoid aggressive surgery and to rely on preoperative chemotherapy. As a result, many cases are classified as belonging to group III, which corresponds to macroscopic residual tumors. Therefore, the survival rate of these cases, which should be classified as either group I or II remains low at 50% to 60% in Japan. Although many cases have been treated with high-dose chemotherapy in Japan, the efficacy of such chemotherapy is unclear based on the results of studies in the USA and Europe [7]. For the intermediate-risk group in Japan, whose outcomes thus far have been inferior to those in the USA IRS, we apply a multimodal treatment approach centered on standard chemotherapy without high-dose chemotherapy. However, the difference in treatment results between Japan and the USA cannot be ignored and should be corrected as soon as possible. To this end, the standard treatment applied in the USA should be actively introduced, and basic data should be accumulated. We have therefore adopted VAC therapy, the standard chemotherapy of the USA IRSG. For radiotherapy and surgery, we decided to use a slightly modified version of the USA IRSG guidelines. The IRS-IV study used higher doses of cyclophosphamide (2.2 g/m 2 /dose) than the IRS-III study, showing a consequently improved 3-year FFS by up to 76%, especially for stage 1, Group III embryonal type. However, the prognosis for stages 2 and 3, group III was 61%, which was not a sufficient improvement. Based on the results of the IRSG, the present study adopted as its study treatment the VAC regimen using 2.2 g/m 2 /dose of cyclophosphamide, as in the IRS-IV study. However, the 3-year FFS for the entire IRSG intermediate-risk group in the IRS-IV study was not markedly different from that in the IRS-III study [8], suggesting that the Japan Rhabdomyosarcoma Study Group (JRSG) intermediate-risk group of patients with alveolar and undifferentiated sarcomas did not have improved outcomes. To limit our study to the group that would benefit most from this chemotherapy regimen, the JRSG study will enroll Group III patients with alveolar and undifferentiated histology and Group IV patients with embryonal histology under 10 years old, for which there is no evidence of a favorable prognosis in Japan, as the high-risk group. This Phase II, single-arm, open study examined the efficacy and safety of multimodality treatment combining VAC, surgery, and radiation therapy, which is considered the standard chemotherapy in the USA, in a population of patients with intermediate-risk rhabdomyosarcoma. This is the first nationwide multicenter study of intermediate-risk pediatric rhabdomyosarcoma. Patients and methods Patients The JRS-I enrolled previously untreated patients younger than 18 years old with a pathologically confirmed diagnosis of rhabdomyosarcoma or undifferentiated sarcoma. Patients enrolled after eligibility determination were confirmed by the data center, with treatment set to begin within seven days of the end of enrollment. The treatment protocol was approved by the Institutional Review Boards of the participating centers, and informed consent for participation was obtained from patients, parents, or legal guardians. The pathology committee of the JRSG centrally reviewed all pathologic specimens, the surgical committee reviewed and confirmed clinical staging, and the radiotherapy committee reviewed the dosimetry and compared the patient’s actual treatment with the protocol requirements. Patients were assigned a presurgical stage based on the tumor site, size, and presence of clinically determined lymph node (LN) involvement (i.e. increased LN size or positive imaging studies) and/or metastatic disease (Table 1) [2]. Patients were also assigned to a group following surgery based on the extent of disease and degree of surgical resection by each participating institution, according to the criteria of the IRS Post-Surgical Grouping Classification (Table 2) [3]. If primary re-excision of the tumor was the definitive operation, the patients were classified into groups after this operation. The target cases of JRS-Ⅰ intermediate risk were as follows: 1. Patients with embryonal-type Group III disease arising in sites with a poor prognosis (stage 2 and 3) 2. Patients with alveolar-type or undifferentiated sarcoma of stage 1, 2, or 3 and group I or II 3. Patients with alveolar-type or undifferentiated sarcoma of stage 1 and group III The primary endpoint for this study was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS) and incidence of hepatic veno-occlusive disease (VOD) and serious adverse events, excluding hepatic VOD. Therapy In this study, the VAC regimen of cyclophosphamide 2.2 g/m 2 used in the IRS-IV study was used as the study treatment. Chemotherapy was administered every 3 weeks for 12 cycles (total of 42 weeks); the details of the regimen are shown in Figure 1. Doses by age are listed in Table 3. Actinomycin-D was administered in a single standard dose, but five divided doses were allowed at the discretion of the institution. Radiotherapy was commenced at week 13 in most patients. However, patients with tumors that extended intracranially or with spinal cord compression began radiotherapy on day 0. When radiotherapy was required on an emergent basis on day 0, the entire treatment course was completed. Actinomycin D was discontinued during radiotherapy. The dose and dose distribution of radiotherapy should be determined according to the extent of residual disease based on the IRSG radiotherapy guidelines [9]. Patients with inoperable lesions in partial remission after chemotherapy received 50.4 Gy, those with postoperative lesions with gross residual disease received 45 Gy, those with postoperative lesions with microscopic residual disease and lesions that achieved complete remission with chemotherapy received 41.4 Gy, and those with lesions completely resected by surgery received 36 Gy. Patients were evaluated for their response at weeks 12 and 24 and at the end of therapy. At week 12, excision of the tumor with negative margins in group III patients was feasible, with organ preservation and without loss of form or function, and the radiation dose was adjusted according to the amount of residual tumor. Selected patients who responded poorly to induction chemotherapy were recommended to undergo preoperative RT followed by a second-look surgery at week 24. Definition of endpoints The PFS was defined as the time from therapy initiation to disease progression, recurrence, or death from any cause. If chemotherapy was discontinued due to toxicity or patient refusal, and another treatment was added as post-treatment, it was not considered an event at that time. The OS was defined as the time from the initiation of therapy to death from any cause. The PFS and OS were censored at the last contact date. Hepatic VOD was defined based on the presence of at least 2 clinical findings (tender hepatomegaly, hyperbilirubinemia >2 mg/dL, ascites or weight gain >2% above baseline). Serious adverse events were defined as grade 3, 4, or higher in the NCI-CTC Version 2.0, excluding abnormal blood values. Statistical analyses The present study evaluated the efficacy and safety of the VAC regimen used by the IRSG, which is used to treat approximately 85% of patients with rhabdomyosarcoma in the USA, in Japan. The primary endpoint was defined as the 3-year PFS based on comparability with existing data. Since 1991, the 3-year PFS for intermediate-risk patients with rhabdomyosarcoma in Japan has been approximately 60%, and it is expected to increase to approximately 75% as a result of the VAC regimen with IRS, which was the treatment modality used in this study. We set our 3-year PFS at 60% under the null hypothesis and at 75% as the expected probability, with a one-sided alpha error rate of 0.025 and a power of 0.80. Hence, the planned sample size was 68 and the accrual period was 3 years. Comparisons of JRS-I patient characteristics were performed using the χ 2 test. The endpoints for this analysis were the PFS and OS, calculated using the Kaplan-Meier method [10]. not-yet-known not-yet-known not-yet-known unknown Patient population Between June 14, 2004, and March 24, 2009, 44 patients were enrolled in 26 institutions. Thirteen (33%) were ineligible for analyses: one had premature chromatid separation syndrome, four were misdiagnosed, and eight were found to have a different risk after starting treatment. A survival analysis was performed on the remaining 31 patients. A safety analysis was performed on the 40 patients who had received at least some of this treatment. Patient or tumor characteristics Table 4 shows the presenting characteristics of the eligible patients. Histopathologic classification of tumors, according to the JRS Pathology Review Committee, was used to determine eligibility. Review Committee data are available for 31 cases (78% of 40 eligible patients). Seven patients were missing institutional pathology information, including four with a central review pathology diagnosis of alveolar disease, one with embryonal disease, one with embryonal/spindle cell disease, and one with embryonal/alveolar disease. According to the central pathology review diagnosis, there were 21 embryonal tumors and 10 alveolar tumors. Group classifications based on institutional data were available for 32 patients, and group classifications based on surgical review data were available for 31 patients. Concordance between the institutional and central review committee group assignments was observed in 97% of all patients (excluding one patient in group III). not-yet-known not-yet-known not-yet-known unknown Treatment outcomes The average percentage of chemotherapy drugs administered as recommended by the protocol was 89% (vincristine: 87%; actinomycin-D: 89%; cyclophosphamide: 92%). Twelve of 40 patients received Actinomycin-D in five divided doses, at the discretion of each institution. At a median follow-up of 5.2 years, the 3-year PFS and OS for patients in JRS-I were 74.2% ± 7.9% (95% confidence interval [CI] 55.0%-86.2%) and 90.3% ± 5.3% (95% CI 72.9%-96.8%), respectively (Figure 2). When compared by histology, the 3-year PFS for the embryonal and alveolar types was 71.4% ± 9.9% (95% CI 47.2%-86.0%) vs. 80.0% ± 12.7% (95% CI 40.9 %-94.6%), and the 3-year OS was 85.7% ± 7.6% (95% CI 62.0%-95.2%) vs. 100%, respectively, with no significant differences noted. With a median follow-up of 5.2 years, there were seven treatment failures. Three patients had progression during treatment, and four relapsed after treatment was completed. Five patients died of primary disease, but none died of infection, organ failure, secondary malignancy, or other causes. Secondary surgery was performed in 17 patients: 13 patients did not undergo secondary surgery, and the situation in one patient was unclear. The reasons for not performing the procedure were as follows: six patients had no residual tumor, six patients had inoperable sites, and the reason was unknown in one patient. Radiotherapy was administered to 27 patients but not to three patients, for reasons of amputation of the affected area, concern about extensive radiation damage, and not wanting it, in one case each. The condition of the remaining patients was unknown. Toxicity Although bone marrow suppression was observed in all patients, the most common adverse events were febrile neutropenia in 28 patients (70%), Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in three (8%), convulsions in two (5%), and tumor hemorrhage, cytomegalovirus retinitis, hemophagocytic syndrome, bacterial endocarditis, and peripheral motor nerve palsy in one (3%) each. Between 4 and 30 months after completion of all treatments, one patient had pneumococcal bacteremia, one patient had ataxia, and one patient had ovarian dysfunction. The observation period for late effects is short, so further long-term observations are required. Hepatic VOD occurred in three (8%) of the 40 evaluable patients, but all recovered by supportive care, and there were no deaths. All three patients who developed VOD received actinomycin-D in five-day divided doses at the discretion of the facility. not-yet-known not-yet-known not-yet-known unknown Discussion In this article, we have reported the results of the first nationwide prospective clinical study of pediatric rhabdomyosarcoma that incorporates a central review pathology system and a prospective evaluation of the clinical stage by a surgical committee and treatment decisions by a radiotherapy committee. The study endeavored to evaluate the feasibility of this system and improve the outcomes of pediatric rhabdomyosarcoma in Japan. The pathological diagnosis differed in seven patients due to institutional and central pathology findings, with five patients (13%) changing from fetal to sporadic type and two (5%) changing from sporadic to fetal type. This resulted in a risk change in these seven patients, so the study was terminated. This rate of risk change was comparable in frequency to that in the IRS-III and IV trials [11], and the central pathology system was deemed to have functioned successfully. However, improvements in the speed of tissue diagnoses need to be devised to further reduce the number of diagnostic differences. One patient had metastasis to the regional lymph nodes and was changed from a group classification of III to IV by the surgical committee, resulting in discontinuation of the study. In these eight total patients, treatment was initiated at the institutional diagnosis and completed with the parents’ consent concerning either continuation of treatment or risk-based modification of treatment. Reducing the number of ineligible cases owing to differences in risk is an important issue. To this end, a future clinical study will address this issue by making the initial treatment the same for all risk categories. An ongoing JRS-II clinical trial is implementing this strategy. The proportion of chemotherapy regimens administered according to protocol was as high as 89%, especially for the 2.2 g/m2/dose cyclophosphamide regimen, which was administered in 92% of courses and judged to be well administered. The 3-year PFS and OS were 74% and 90%, respectively, which were comparable to the values for IRS-IV intermediate risk. These also exceeded the 62% survival rate observed in a retrospective Japanese intermediate risk group analysis by Hosoi et al. [12]. These are the most basic results in Japan, and future treatment strategies will be based on these findings. Radiation therapy was administered in accordance with the IRS-IV guidelines. Radiation oncologists helped determine the appropriate stage and group classification, and subsequent local control with radiation imaging was reviewed for appropriateness of treatment. All cases were reviewed by a radiation oncologist at the time of enrollment. We carefully checked the treatment records of twenty-seven patients who underwent radiation therapy and confirmed that the treatments had been appropriately carried out. Severe myelosuppression due to intensified therapy was observed in all patients; however, subsequent bacteremia and death were undetected. This may be due to the shortened duration of severe neutropenia due to the routine use of granulocyte colony stimulating factor (G-CSF) and the appropriate response to febrile neutropenia at each institution. Specific adverse events, such as cytomegalovirus retinitis and hemophagocytic syndrome, resulted in a temporary interruption of treatment, but patients were able to complete treatment without relapse or progression. Hepatic VOD occurred in 3 of 40 patients (8%) for whom treatment was at least partially administered, which seems more frequent than the rate of 3.1% with VAC in IRS-IV [13]. The ages of onset were 10, 15, and 183 months. One patient developed VOD in cycles 2 and 3, and treatment was discontinued because of progression of the primary disease, although the VOD was mildly relieved. Two other patients developed VOD in cycles 2 and 5 and recovered with treatment interruption and supportive care. In general, known risk factors for the development of hepatic VOD in children include high-dose chemotherapy for neuroblastoma and allogeneic hematopoietic cell transplantation for metabolic diseases [14-16]. In addition to transplantation, it also occurs after chemotherapy, including actinomycin-D, in Wilms tumor and rhabdomyosarcoma [17]. The pathogenesis involves damage to hepatic sinusoidal endothelial cells and hepatocytes caused by anticancer drugs or radiation [18]. The risk of developing hepatic VOD can be reduced but not eliminated by changing actinomycin-D from a single dose to divided dosing [19]. Three patients who developed VOD in our study were administered divided doses. However, due to the limited number of patients involved, comparisons between outcomes may not be statistically meaningful. The risk of developing the disease is particularly high in younger children; however, older children may also develop the disease. When administering chemotherapy, including actinomycin-D, it is always important to diagnose and initiate treatment early while considering the risk of developing hepatic VOD. Several limitations associated with the present study warrant mention. First, the sample size was small, hampering the direct comparison of outcomes. Further analyses using larger cohorts are warranted to verify our findings. Second, the difference in histological diagnoses between the central and institutional diagnoses resulted in risk changes and many dropouts. In the future, it will be necessary to reduce the number of such dropouts. Third, this study was unable to investigate long-term late effects, which should be done in the future. In conclusion, the VAC regimen for intermediate-risk rhabdomyosarcoma with the first central review system in Japan seems safe and feasible, and these findings can be used as basic data for improving treatment outcomes in Japan. Future treatment development should endeavor to maintain the equivalence of treatment results and preserve fertility by introducing irinotecan and reducing the total dose of cyclophosphamide. (3,007 words) [still <3,500] Acknowledgments We thank the late Dr. Shigeru Ohta for conducting this clinical trial. We thank all physicians at the participating institutions for enrolling cases, filling out case report forms, and providing follow-up data. Funding This study was supported by a Grant for Cancer Research by the Ministry of Health, Labour and Welfare Japan, Grant for Scientific Research by the Ministry of Health, Labour and Welfare Japan, and Grant for Research by the Ministry of Education, Culture, Sports, Science and Technology Japan. Authors’ Disclosures of Potential Conflicts of Interest Atsushi Kikuta is affiliated with an endowed chairs sponsored by Alfresa Corporation. Junichi Hara is an advisory role of Ohara Pharmaceutical Co., Ltd. The other authors indicated no potential conflicts of interest. REFERENCES 1. Qualman SJ, Coffin CM, Newton WA, et al (1998) Intergroup Rhabdomyosarcoma Study: Update for pathologists. Pediatr Dev Pathol 1:550-61 2. Lawrence W Jr, Gehan EA, Hays DM, et al (1987) Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5:46-54 3. Maurer H, Beltangady M, Gehan E, et al (1988) The Intergroup Rhabdomyosarcoma Study-I: A final report. Cancer :209-220 4. Crist WM, Gehan EA, Ragab AH et al (1995) The third intergroup rhabdomyosarcoma study. J Clin Oncol 13:610-630 5. 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Cheuk DK, Wang P, Lee TL, et al (2007) Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 40: 935–944 17. Raine J, Bowman A, Wallendszus K, et al (1991) Hepatopathy-thrombocytopenia syndrome: A complication of dactinomycin therapy for Wilms’ tumor: A report from the United Kingdom Children’s Cancer Study Group. J Clin Oncol 9: 268-273 18. Carreras E, Diaz-Ricart M (2011) The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant 46: 1495–1502 19. Green DM, Norkool P, Breslow NE, et al (1990) Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: A report from the National Wilms’ Tumor Study. J Clin Oncol 8:1525-1530 not-yet-known not-yet-known not-yet-known unknown FIGURE 1 Treatment plans for JRS-Ⅰ FIGURE 2 Kaplan-Meier estimates of a progression-free and overall survival for the intermediate-risk group Author contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Atsushi Kikuta, Hidekazu Masaki, Hiroshi Hojo, Junichi Hata, Hajime Ohkita, Hajime Hosoi, Atsuko Nakagawa, Shiro Hinotsu, Hitoshi Ikeda, Seiji Kishimoto, Michio Kaneko, Akira Kawai, Junichi Hara, Tetsuya Takimoto, Miho Kato, Takashi Kaneko, Yoshiyuki Kosaka, and Yasuhide Morikawa. The first draft of the manuscript was written by Atsushi Kikuta and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Supplementary Material File (●jrs-i ir fig 1.docx) Download 21.05 KB File (●jrs-i ir fig 2.docx) Download 207.97 KB File (●jrs-i ir table 1-4.docx) Download 27.51 KB Information & Authors Information Version history V1 Version 1 04 February 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords outcomes research pediatric oncology phase ii clinical trials rhabdomyosarcoma veno-occlusive disease Authors Affiliations Atsushi Kikuta [email protected] Fukushima Kenritsu Ika Daigaku Igakubu Shuyo Naikagaku View all articles by this author Hidekazu Masaki Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Seiiku Iden Kenkyubu View all articles by this author Hiroshi Hojo Fukushima-shi View all articles by this author Jun-ichi Hata International Life Sciences Institute Japan View all articles by this author Hajime Okita Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo View all articles by this author Hajime Hosoi Doshisha Women's College of Liberal Arts View all articles by this author Atsuko Nakazawa Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Byoin View all articles by this author Shiro Hinotsu Sapporo Ika Daigaku Fuzoku Byoin View all articles by this author Hitoshi Ikeda Dokkyo Ika Daigaku Saitama Iryo Center View all articles by this author Seiji Koshimoto Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka Jibi Inkokagaku View all articles by this author Michio Kaneko Tsukuba Daigaku Igaku Iryokei Seikei Geka View all articles by this author Akira Kawai Kokuritsu Gan Kenkyu Center Chuo Byoin Shuyo Naika View all articles by this author Jun-Ichi Hara Osaka Shiritsu Sogo Iryo Center View all articles by this author Tetsuya Takimoto Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo View all articles by this author Miho Kato Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Seiiku Iryo Kenkyu Center Kenkyujo View all articles by this author Takashi Kaneko Tokyo Toritsu Shoni Sogo Iryo Center Shinseijika View all articles by this author Yoshiyuki Kosaka Hyogo Kenritsu Kodomo Byoin View all articles by this author Yasuhide Morikawa Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Gekagaku Kyoshitsu View all articles by this author Metrics & Citations Metrics Article Usage 377 views 279 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Atsushi Kikuta, Hidekazu Masaki, Hiroshi Hojo, et al. Results of a phase II trial for intermediate-risk rhabdomyosarcoma treatment protocol JRS-I: A report from the Japan Rhabdomyosarcoma Study Group. Authorea . 04 February 2025. DOI: https://doi.org/10.22541/au.173867962.23200709/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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