Japanese Journal of Clinical Oncology Advance Access originally published online on April 3, 2008
Japanese Journal of Clinical Oncology 2008 38(5):387-389; doi:10.1093/jjco/hyn025
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© The Author (2008). Published by Oxford University Press. All rights reserved
Accelerated Fractionation versus Conventional Fractionation Radiation Therapy for Glottic Cancer of T1-2N0M0 Phase III Study: Japan Clinical Oncology Group Study (JCOG 0701)
1 Clinical Trials and Practice Support Division, Center for Cancer Control and Information Services, National Cancer Center, Tokyo
2 Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya
3 Department of Radiology, Shinshu University School of Medicine, Nagano
4 Radiation Oncology Division, National Cancer Center Hospital, Tokyo
5 Department of Radiation Oncology and Image-applied Therapy, Kyoto University Hospital, Kyoto, Japan
For reprints and all correspondence: Takeshi Kodaira, Department of Radiation Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. E-mail: 109103{at}aichi-cc.jp
Received December 11, 2007; accepted March 1, 2008
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Abstract |
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A randomized Phase III study was started in Japan to demonstrate the non-inferiority of survival of accelerated fractionation radiation therapy (2.4 Gy/fr) with conventional fractionation radiation therapy (2 Gy/fr) in patients with T1-2N0M0 glottic cancer. This study began in September 2007, and a total of 360 patients will be accrued from 22 institutions within 4 years. The primary endpoint is 3-year progression-free survival (PFS). The secondary endpoints are overall survival, local progression-free survival, disease-free survival, survival with preserved voice function, complete response rate, proportion of treatment completion and adverse events.
Key Words: laryngeal neoplasms • radiotherapy • dose fractionation • clinical trials • phase III
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INTRODUCTION |
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Accelerated fractionation radiation therapy has considerable benefits in terms of treatment duration and cost compared with conventional fractionation methods. In addition, some reports suggest that increased single radiation dose and shortened treatment time may improve local control (1–7). However, no multi-institutional randomized study has been conducted to show that accelerated fractionation is equivalent to conventional fractionation in terms of efficacy and safety for early glottic cancer. Various types of fractionation methods are performed in clinical practice, and according to the guidelines of the Head and Neck Cancer Disease Site Group in Canada, an optimal fractionation protocol has not yet been established (8). We therefore designed a study, which investigates whether accelerated fractionation radiotherapy is suitable for T1-2N0M0 glottic cancer in terms of survival, feasibility, voice function and safety.
The Protocol Review Committee of the Japan Clinical Oncology Group (JCOG) approved the protocol in August 2007 and the study was activated in September 2007. This trial was registered at the UMIN Clinical Trials Registry as UMIN000000819 [http://www.umin.ac.jp/ctr/index.htm].
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PROTOCOL DIGEST OF THE JCOG 0701 |
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Purpose
The aim of this study is to demonstrate the non-inferiority of the efficacy of accelerated fractionation radiation therapy (2.4 Gy/fr) with conventional fractionation radiation therapy (2 Gy/fr) in patients with T1-2N0M0 (UICC/TNM, 6th edition) glottic squamous cell carcinoma.
Study Setting
A multi-institutional randomized Phase III study.
Resources
Grants-in-Aid for Cancer Research (17-17, 16-12, 17S-5) from the Ministry of Health, Labour and Welfare of Japan.
Endpoints
The primary endpoint is the 3-year progression-free survival (PFS) proportion in all eligible patients. PFS is defined as days from randomization to first evidence of local progression, distant metastasis or death from any cause. In patients alive without events, PFS will be censored at the last visit. The secondary endpoints are overall survival, local progression-free survival, disease-free survival, survival with preserved voice function, complete response rate, proportion of treatment completion and adverse events.
Overall survival is defined as days from randomization to death from any cause. Local progression-free survival consists of time free from local disease progression or death from any cause, while disease-free survival is defined as duration free of local progression, distant metastasis, secondary cancer or death from any cause. Survival with preserved voice function is defined as days from randomization to first evidence of death from any cause or appearance of voice changes of Grade 3 or more as diagnosed by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The proportion of treatment completion denotes the percentage of patients whose treatment is completed within the recommended length of time: 51 days for T1 and 53 days for T2 in the conventional radiation arm, and 39 days for T1 and 43 days for T2 in the accelerated radiation arm.
Eligibility Criteria
Inclusion Criteria
For inclusion in the study, the patient must fulfill each of the following criteria: (i) primary tumor site lies within the vocal cords; (ii) the tumor consists of histologically proven squamous cell carcinoma; (iii) the extent of the primary tumor is evaluated as T1 or T2 without impaired cord mobility; (iv) the tumor is clinically staged as N0/M0; (v) radiation therapy can be completed within the recommended duration without interruption due to national holidays; (vi) age between 20 and 80 years; (vii) ECOG performance status of 0 or 1; (viii) no prior surgery or radiation therapy of the larynx; (ix) no prior chemotherapy for any malignancies within 5 years; (x) sufficient organ function; (xi) completed written informed consent.
Exclusion Criteria
Patients are excluded if they meet any of the following criteria: (i) active bacterial or fungous infection; (ii) simultaneous or metachronous (within 5 years) double cancers; (iii) women during pregnancy or breast-feeding; (iv) psychosis; (v) treatment with systemic steroids; (vi) history of collagen disease except for rheumatism; (vii) insulin-dependent or poorly controlled diabetes mellitus; (viii) poorly controlled hypertension; (ix) history of severe heart disease, heart failure; (x) myocardial infarction or angina pectoris within the past 6 months.
Randomization
After the confirmation of the inclusion and exclusion criteria by telephone or fax to the JCOG Data Center, the patients are randomized to either conventional radiation arm or accelerated radiation arm, by the minimization method of balancing the arms according to T factor (T1/T2 by UICC/TNM, 6th edition) and institution.
Treatment Method
In conventional radiation arm, conventional fractionation radiotherapy with 2 Gy/fr (1 fr/day and 5 fr/week) is performed 33 times for a total dose of 66 Gy in patients with T1 disease, and 35 times for a total dose of 70 Gy in patients with T2 disease. Irradiation twice daily is permitted, but the maximum number of irradiation sessions per week is limited to five. It is recommended that treatment using the conventional fractionation method is completed within 51 days for T1 disease and 53 days for T2 disease.
In accelerated radiation arm, accelerated fractionation radiotherapy with 2.4 Gy (1 fr/day and 5 fr/week) is delivered 25 times for a total dose of 60 Gy in patients with T1 disease, and 27 times for a total dose of 64.8 Gy in patients with T2 disease. Twice-daily irradiation is prohibited, as is irradiation six or more times per week. Recommended duration of accelerated fractionation radiotherapy is 39 days for T1 disease and 43 days for T2 disease.
In both study arms, the gross tumor volume (GTV) is defined as the GTV of the primary tumor. The clinical target volume (CTV) in T1 disease is the entirety of the vocal cords, while the CTV in T2 disease includes a 1-cm margin surrounding the tumor in addition to the vocal cords. The planning target volume (PTV) is defined as the CTV plus a margin of 0.5-1 cm in the craniocaudal direction and 0.5 cm in the posterioanterior direction.
Follow-up
All enrolled patients are followed-up at least every 6 weeks for the first 6 months and then every 3 months for a duration of 3 years. Laryngeal fiberscope and cervical lymph node exploration by manipulation are carried out at each visit.
Study Design and Statistical Method
This trial is designed to demonstrate that accelerated fractionation radiation therapy is not inferior to the conventional fractionation method in terms of 3-year PFS. If the non-inferiority of accelerated radiation arm is verified, the accelerated fractionation method will be the preferred treatment.
The planned sample size is 360 patients, with 180 cases per arm. We anticipate 3 years of follow-up after 4 years of accrual, ensuring at least 80% power with one-sided alpha of 5% and a non-inferiority margin of 5% for the primary endpoint. This assumes an expected 3-year PFS of 80% in patients treated with the conventional fractionation method, and 85% in those treated with the accelerated fractionation method.
Interim Analysis and Monitoring
We plan on conducting two interim analyses, considering multiplicity according to the method recommended by the Southwest Oncology Group (9). The Data and Safety Monitoring Committee of the JCOG will independently review the interim analysis reports and stop the trial early if necessary. In-house monitoring will be performed every 6 months by the Data Center to evaluate and improve study progress and quality.
Participating Institutions (From North To South)
Sapporo Medical University, Tohoku University, Saitama Cancer Center, National Cancer Center East, National Cancer Center, Tokyo Metropolitan Komagome Hospital, Tokyo Women's Medical University, Tokyo Medical Center, Keio University, Cancer Institute Hospital, University of Tokyo, Kitasato University, Niigata Cancer Center, Yamanashi University, Shinshu University, Aichi Cancer Center, Kyoto University, Osaka University, Kinki University, Osaka Medical Center for Cancer and Cardiovascular Diseases, Hiroshima University, Kyushu University.
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Funding |
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This work is supported by Grant-in-Aid for Cancer Research (17-17, 16-12, 17S-5) from the Ministry of Health, Labour and Welfare of Japan.
Conflict of interest statement
None declared.
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References |
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8 Hodson D, Archibald S, Browman G, Johnston M, Cripps C, Davidson J, et al. Optimum radiation fractionation for T1 N0 glottic (vocal cord) carcinoma evidence summary report #5-4: program in evidence-based care a cancer care ontario program. www.cancercare.on.ca/accsessPEBC.htm.
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