Japanese Journal of Clinical Oncology Advance Access originally published online on January 20, 2009
Japanese Journal of Clinical Oncology 2009 39(4):271-273; doi:10.1093/jjco/hyn153
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© The Author (2009). Published by Oxford University Press. All rights reserved
Preoperative and Postoperative Chemotherapy with Ifosfamide and Adriamycin for Adult High-grade Soft-tissue Sarcomas in the Extremities: Japan Clinical Oncology Group Study JCOG0304
1 Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka
2 Clinical Trials and Practice Support Division, Center for Cancer Control and Information Services, National Cancer Center, Tokyo
3 Department of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo
4 Division of Clinical Trial Management, Translational Research Center, Kyoto University Hospital, Kyoto, Japan
For reprints and all correspondence: Yukihide Iwamoto, Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yiwamoto{at}ortho.med.kyushu-u.ac.jp
Received August 19, 2008; accepted December 16, 2008
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Abstract |
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 TOP Abstract PROTOCOL DIGEST OF THE...INTERIM ANALYSIS AND MONITORINGPARTICIPATING INSTITUTIONS (FROM...FundingConflict of interest statementReferences |
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This phase II clinical trial aims to evaluate the efficacies and toxicities of pre- and postoperative chemotherapy with adriamycin plus ifosfamide on the patients with soft-tissue high-grade sarcomas. Patients who have operable, non-round cell soft-tissue sarcomas [French Federation of Cancer Center (FNCLCC) Grades 2 and 3] arising in the extremities [T2bN0M0, i.e. American Joint Committee on Cancer (AJCC) stage III] are treated by three courses of preoperative chemotherapy consisting of adriamycin and ifosfamide followed by complete resection and additional two courses of the same chemotherapy regimen. The Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) including 26 specialized institutes will accrue 75 patients. The primary endpoint of the study is the 2-year progression-free survival rate, and secondary endpoints are response rate of the preoperative chemotherapy, 3-year progression-free survival rate, progression-free survival, overall survival and adverse events. The JCOG Clinical Trial Review Committee approved the protocol on 11 March 2004, and the study was started on 29 April 2004. Protocol amendment was approved on 18 May 2007.
Key Words: soft-tissue sarcoma • preoperative and postoperative chemotherapy • extremity • high grade • adult • non-round cell tumor
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PROTOCOL DIGEST OF THE JCOG0304 |
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Trial Backgrounds
Soft-tissue sarcomas (STS) in adults can be divided into two groups: round cell sarcomas and non-round cell sarcomas (NRC-STS). The tumors in the former group, including rhabdomyosarcoma and extra-skeletal Ewing's sarcoma, are chemo-sensitive, and efficacy of the intensive chemotherapy on the tumors has been established. On the other hand, the tumors in the latter group, the majority of STS are thought to be relatively chemo-resistant, thus the standard therapeutic modality for NRC-STS is surgical resection. The survival rate of the patients with large (>5 cm), deep, high-grade NRC-STS (American Joint Committee on Cancer AJCC 6th edition, Stage III) is <35% at most, and most of the treatment failure includes distant metastasis suggesting the requirement of systemic therapy for NRC-STS (1,2). Meta-analysis of 14 randomized clinical trials of adriamycin-based adjuvant chemotherapy for NRC-STS showed the possibility of improvement of prognosis by the chemotherapy especially in the patients with stage III NRC-STS arising in the extremities (3). Recently, a randomized controlled trial of the postoperative chemotherapy using epirubicin and ifosfamide versus surgery alone for Stage III NRC-STS in the extremities revealed the significant improvement of survival in the patients with postoperative chemotherapy (4). However, a standard chemotherapy regimen for NRC-STS arising in extremities has not been established yet.
The study protocol was designed by the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG), approved by the Protocol Review Committee of JCOG on 11 March 2004 and started on 29 March 2004. The expected period for accrual completion is 4 years. This trial was registered at the UMIN Clinical Trials Registry as C000000096 [http://www.umin.ac.jp/ctr/index.htm].
Purpose
The trial aims to evaluate the efficacy and feasibility of pre- and postoperative chemotherapy using adriamycin and ifosfamide on the patients with AJCC Stage III NRC-STS in the extremities.
Study Setting
This study is a multi-institutional (26 specialized institutes), phase II trial.
Endpoints
The primary endpoint in the original protocol was response rate of the preoperative chemotherapy. On the basis of the discussion about the credibility of historical response data, it was amended to the 2-year progression-free survival rate, which was approved by the Protocol Review Committee in May 2007. Secondary endpoints are response rate of the preoperative chemotherapy, 3-year progression-free survival rate, progression-free survival, overall survival, adverse events, postoperative complication rate and pathological response rate.
Eligibility Criteria
STS are staged according to AJCC 6th edition of TNM Classification of Malignant Tumours (5). The histological grading of the tumors is carried out according to French Federation of Cancer Center (FNCLCC) system (6).
Inclusion Criteria
(i) A histological diagnosis of NRC-STS as malignant fibrous histiocytoma, fibrosarcoma, leiomyosarcoma, synovial sarcoma, liposarcoma, pleomorphic rhabdomyosarcoma or undifferentiated sarcoma (WHO classification) using open biopsy specimen; (ii) FNCLCC histological grading system: Grade 2 or 3 in the open biopsy specimen; (iii) 10 or more unstained tumor tissue slides are available; (iv) AJCC stage: Stage III (T2bN0M0); (v) localized tumor in the extremities; (vi) measurable lesion on MRI axial section; (vii) resectable tumor; (viii) no history of STS; (ix) no history of treatment for NRC-STS, chemotherapy nor radiation therapy for any cancer; (x) age between 20 and 70 years; (xi) ECOG performance status 0 or 1; (xii) sufficient organ function within 14 days of entry; (xiii) no blood transfusion within 14 days of entry and (xiv) written informed consent.
Exclusion Criteria
(i) Poorly controlled diabetes mellitus; (ii) poorly controlled hypertension; (iii) history of myocardial infarction or angina; (iv) cardiac pacemaker; (v) severe urinary dysfunction; (vi) infectious disease which requires treatment; (vii) mental disease or mental symptoms that would affect the patient's decision to participate; (viii) women in pregnant, possibly pregnant or breast feeding; (ix) active double cancer and (x) continuous systemic medication of steroids.
Treatment Methods
Preoperative chemotherapy
Preoperative chemotherapy consists of adriamycin (30 mg/m2, 2-h d.i.v., Days 1 and 2) and ifosfamide (2 g/m2, 4-h d.i.v., Days 1–5). The chemotherapy is repeated for three courses with 3-week interval.
Surgical treatment
The tumor is resected within 5 weeks of the last course of preoperative chemotherapy. The surgical margin should be wide or marginal. When the surgical margin is judged to be insufficient, local radiation therapy may be added after the protocol treatment.
Postoperative chemotherapy
When the tumor resection is completed, two courses of the same regimen as preoperative chemotherapy with adriamycin and ifosfamide are carried out with 3-week interval.
No additional therapy will be given until the patient has treatment failure including local recurrence and/or distant metastasis.
Follow-up
All patients are followed-up for 3 years after the close of entry to the study. Chest X-ray is carried out every 3 months, and chest CT and local MRI are done every 6 months.
Study Design and Statistical Methods
The single-arm design was used to investigate whether the 2-year progression-free survival rate was sufficient to proceed to Phase III trials. The precision-based sample size calculation was performed so that the 95% confidence interval for the estimated 2-year progression-free survival rate would be no greater than ±15% around 55%. To achieve this, 75 patients are required. The statistical inferences of progression-free survival and overall survival were based on the Kaplan–Meier method. The interval estimation of the response rate was based on the exact binomial distribution.
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INTERIM ANALYSIS AND MONITORING |
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TOPAbstractPROTOCOL DIGEST OF THE...INTERIM ANALYSIS AND MONITORINGPARTICIPATING INSTITUTIONS (FROM...FundingConflict of interest statementReferences |
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An interim analysis is planned to evaluate the futility during the accrual period. The Data and Safety Monitoring Committee (DSMC) of the JCOG independently reviews the interim analysis report. Monitoring is performed by the JCOG Data Center to ensure data submission, patient eligibility, protocol compliance, safety and on-schedule study progress. The monitoring reports are submitted to and reviewed by the BSTTSG and DSMC every 6 months during the study.
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PARTICIPATING INSTITUTIONS (FROM NORTH TO SOUTH) |
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TOPAbstractPROTOCOL DIGEST OF THE...INTERIM ANALYSIS AND MONITORINGPARTICIPATING INSTITUTIONS (FROM...FundingConflict of interest statementReferences |
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Sapporo Medical University, Hokkaido Cancer Center, Tohoku University, Chiba Cancer Center, National Cancer Center Hospital, Nihon University, Kyorin University, Keio University, Cancer Institute Hospital, Teikyo University, Kanagawa Cancer Center, Niigata Cancer Center Hospital, Kanazawa University, University of Yamanashi, Gifu University, Shizuoka Cancer Center, Mie University, Kyoto University, Osaka University, Osaka Medical Center, Tottori University, Okayama University, Hiroshima Prefectural Hospital, Kanmon Medical Center, Kyushu University, National Kyushu Cancer Center.
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Funding |
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TOPAbstractPROTOCOL DIGEST OF THE...INTERIM ANALYSIS AND MONITORINGPARTICIPATING INSTITUTIONS (FROM...FundingConflict of interest statementReferences |
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The study is supported by Grants-in Aid for Clinical Cancer Research and Grants-in Aid for Cancer Research (14S-4, 17S-4, 17S-5, 20S-4 and 20S-6) from the Ministry of Health, Labour and Welfare, Japan.
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Conflict of interest statement |
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TOPAbstractPROTOCOL DIGEST OF THE...INTERIM ANALYSIS AND MONITORINGPARTICIPATING INSTITUTIONS (FROM...FundingConflict of interest statementReferences |
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None declared.
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References |
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1 Benjamin RS. Evidence for using adjuvant chemotherapy as standard treatment of soft tissue sarcoma. Semin Radiat Oncol (1999) 9:349–51.[CrossRef][Web of Science][Medline]
2 Hasegawa T, Yamamoto S, Yokoyama R, Umeda T, Matsuno Y, Hirohashi S. Prognostic significance of grading and staging systems using MIB-1 score in adult patients with soft tissue sarcoma of the extremities and trunk. Cancer (2002) 95:843–51.[CrossRef][Web of Science][Medline]
3 Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet (1997) 350:1647–54.[CrossRef][Web of Science][Medline]
4 Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol (2001) 19:1238–47.
5 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–16.
6 Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol (1997) 15:350–62.
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