© The Authors (2008). Published by Oxford University Press. All rights reserved
Phase III Trial of Upfront Debulking Surgery Versus Neoadjuvant Chemotherapy for Stage III/IV Ovarian, Tubal and Peritoneal Cancers: Japan Clinical Oncology Group Study JCOG0602
1 Division of Gynecologic Oncology, National Cancer Center Hospital, Tokyo
2 Division of Medical Oncology, Hyogo Cancer Center, Akashi, Hyogo
3 JCOG Data Center, Center for Cancer Control and Information Services, National Cancer Center, Tokyo
4 Department of Obstetrics and Gynecology, Shinshu University, Matsumoto
5 Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka
6 Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan
For reprints and all correspondence: Takashi Onda, Division of Gynecologic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: taonda{at}ncc.go.jp
Received May 11, 2007; accepted October 2, 2007
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Abstract |
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On the basis of promising results of neoadjuvant chemotherapy (NAC) in our previous study (JCOG0206), we have been performing a Phase III study of treatment starting with NAC versus standard treatment starting with primary debulking surgery (PDS) for Stage III/IV müllerian carcinomas (ovarian, tubal and peritoneal carcinomas) since November 2006. The purposes are to prove the non-inferiority of the efficacy and to show the decrease in adverse effects resulting from reduced surgical invasiveness of treatment starting with NAC. Three hundred patients with advanced müllerian carcinomas will be randomized during 3 years. NAC arm patients undergo four cycles of NAC with paclitaxel plus carboplatin followed by interval debulking surgery and an additional four cycles of postsurgical chemotherapy. Standard arm patients undergo PDS and eight cycles of postsurgical chemotherapy with or without interval debulking surgery. The primary endpoint is overall survival. The major secondary endpoints are the incidence of adverse events and parameters representing surgical invasiveness.
Key Words: ovarian neoplasms • neoadjuvant therapy • interval debulking surgery • primary debulking surgery
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INTRODUCTION |
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The current standard treatment for advanced müllerian cancer is primary debulking surgery (PDS) followed by postsurgical chemotherapy. Better prognosis can be expected in cases in which optimal debulking can be achieved. Unfortunately, optimal debulking in the primary surgery can be achieved in only 30–60% of Stage III/IV müllerian cancers in average institutions (1,2), and the prognosis of patients with advanced müllerian cancers is poor. Neoadjuvant chemotherapy (NAC) has been recognized as a possible approach to improve the prognosis of these patients. In initial studies, NAC was chosen for patients with apparently unresectable bulky tumors or poor performance status as an alternative treatment to primary surgical debulking. Retrospective analyses (3–7) revealed that progression-free and overall survival were comparable between patients treated with NAC followed by interval debulking surgery (IDS) and those treated with PDS, though the former group had more advanced disease and poorer performance status. On the basis of these favorable results of NAC for patients with advanced disease or poor performance status, the target disease was extended to all cases of advanced disease, including patients without apparently unresectable tumors and good performance status in prospective studies. The European Organization for Research and Treatment of Cancer (EORTC) is conducting a Phase III study comparing neoadjuvant setting treatment with standard treatment for advanced müllerian cancers (8). We conducted a Phase II study of NAC with paclitaxel plus carboplatin followed by IDS and postsurgical chemotherapy as the study of the Japan Clinical Oncology Group (JCOG0206) (9). In the study, we assessed the safety and efficacy of NAC treatment, and also assessed whether we can accurately diagnose advanced müllerian cancer based on clinical findings, including imaging studies, cytologic findings and tumor markers. Although the final survival results of this Phase II study are awaited, we have started the Phase III trial on the basis of the efficacy and diagnostic accuracy shown in the study (10). Our study is basically similar to the EORTC study, with the aim of comparing NAC treatment with standard treatment for advanced müllerian cancer. One of the distinct points of our study is omitting the diagnostic surgical procedure, such as laparoscopy or laparotomy, based on the results of our above-mentioned previous study. This means the elimination of an extra procedure for the purpose of the clinical trial in both treatment arms and it has the advantage of making it possible to start NAC treatment earlier. In our study, it is possible to compare the two treatment protocols under clinically relevant conditions. Another distinct point is the number of cycles of chemotherapy. Since the study subjects are patients with evidently advanced disease according to clinical findings, we administer a total of eight cycles of chemotherapy in both treatment arms instead of the standard of six cycles.
The study protocol was designed by the Gynecologic Cancer Study Group (GCSG) of the Japan Clinical Oncology Group (JCOG), approved by the Protocol Review Committee of JCOG on 18 October 2006 and activated on 17 November 2006. This trial was registered at the UMIN Clinical Trials Registry as UMIN000000523 (http://www.umin.ac.jp/ctr/index.htm).
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PROTOCOL DIGEST OF THE JCOG0602 |
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Purpose
The purposes are to prove the non-inferiority of the efficacy and to show the decrease in adverse effects due to reduced surgical invasiveness of treatment starting with NAC with paclitaxel plus carboplatin compared with standard treatment starting with PDS for stage III/IV müllerian carcinomas.
Study Setting
A multi-institutional (30 centers) randomized Phase III trial.
Resources
Health Sciences Research Grants for the Third Term Comprehensive Control Research for Cancer (Nos. h16-035, h19-028) and Grants-in Aid for Cancer Research (Nos. 17S-1, 17S-5, 17-12), from the Ministry of Health, Labor and Welfare, Japan.
Endpoints
The primary endpoint is overall survival among all eligible patients. Secondary endpoints concerning the efficacy of the treatments are as follows: (i) proportion of clinical complete remission (%cCR) among all eligible patients, (ii) progression-free survival among all eligible patients, (iii) response rate to NAC among patients assigned to the NAC arm. Clinical complete remission is defined as the disappearance of all lesions by computed tomography (CT) or magnetic resonance imaging (MRI), no pleural effusions by chest radiography and normal serum CA125 level (<20 U/ml) after completion of the protocol treatment. Secondary endpoints concerning the safety and surgical invasiveness of the treatments are as follows: (i) adverse events, (ii) number of times of surgery, (iii) total duration of the surgery, (iv) total amount of blood loss, (v) amount of blood transfusion during protocol treatment, (vi) amount of blood plasma, plasma expander and albumin infusion during protocol treatment, among all treated patients.
Eligibility Criteria
Inclusion Criteria
The study subjects are patients diagnosed with Stage III or IV ovarian, tubal or peritoneal carcinoma. The diagnosis is based on both imaging studies (CT or MRI, and chest radiography) and cytology/histology of ascites, pleural effusion or fluid/tissue obtained by tumor centesis. Malignancies of other origins, such as breast and digestive tract, should be excluded by endoscopy, opaque enema, or ultrasonography when these malignancies are suspected from symptoms, physical examination or imaging diagnosis. To rule out malignancies of digestive tract origin, the criteria for tumor markers are set to be CA125 >200 U/ml and CEA <20 ng/ml.
Further inclusion criteria are (i) the patient is clinically deemed to be a candidate for debulking surgery without evidence of brain, bone or bone marrow metastases, (ii) previously untreated for these malignancies and have no history of treatment with chemotherapy or radiotherapy for other diseases, (iii) age 20–75 years, (iv) Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, (v) adequate bone marrow, hepatic, renal, cardiac and respiratory functions and (vi) written informed consent.
Exclusion Criteria
Exclusion criteria are (i) synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ, (ii) pregnant or nursing, (iii) severe mental disorder, (iv) systemic and continuous use of steroidal drugs, (v) positive for serum hepatitis B surface antigen, (vi) active infections, (vii) uncontrolled hypertension, (viii) diabetes mellitus, uncontrolled or controlled with insulin, (ix) history of cardiac failure, unstable angina, myocardial infarction within 6 months prior to registration, (x) intestinal occlusion requiring surgical treatment, (xi) hypersensitivity to polyoxyethylated castor oil and (xii) hypersensitivity to alcohol.
Treatment Methods
Standard Treatment Arm
Primary debulking surgery. PDS is performed within 4 weeks of study enrollment. Standard procedures for PDS consist of total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and maximal debulking of metastatic tumors. Systematic pelvic and/or aortic lymphadenectomies are allowed.
Postsurgical chemotherapy. Eight cycles of a combination of paclitaxel (175 mg/m2, Day 1) and carboplatin (AUC = 6, Day 1), namely the TC regimen, are administered every 3 weeks. Postsurgical chemotherapy is initiated within 3–5 weeks after PDS, according to the invasiveness of the surgery.
Interval debulking surgery. IDS is required when any of the standard procedures is not completed at PDS. IDS is allowed, as an option, when residual tumor larger than 1 cm is left at PDS. In such cases, IDS is performed 4–7 weeks after administration of the fourth cycle of postsurgical chemotherapy unless there is disease progression. The standard goal of IDS is completion of all standard procedures of PDS and maximal debulking of metastatic tumors. Systematic pelvic and/or aortic lymphadenectomies are allowed, but not included in the standard goal of IDS. Following IDS, four additional cycles of chemotherapy (TC regimen) is administered (eight cycles of chemotherapy in total). The chemotherapy is initiated within 3–5 weeks after IDS, according to the invasiveness of the surgery.
NAC Arm
Neoadjuvant chemotherapy. Four cycles of a combination of paclitaxel (175 mg/m2, Day 1) and carboplatin (AUC = 6, Day 1) are administered every 3 weeks. NAC is initiated within 2 weeks of study enrollment.
Interval debulking surgery. IDS is performed 4–7 weeks after administration of the fourth cycle of NAC unless disease progression occurs during NAC. Standard procedures of IDS consist of total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and maximal debulking of metastatic tumors. Systematic pelvic and/or aortic lymphadenectomies are allowed, but not included in standard procedures.
Postsurgical chemotherapy. Four additional cycles of chemotherapy (TC regimen) are administered (8 cycles of chemotherapy in total). Postsurgical chemotherapy is initiated within 3 to 5 weeks after IDS, according to the invasiveness of the surgery.
Study Design and Statistical Methods
The study is designed as a randomized Phase III non-inferiority study. Patients are randomized to each treatment arm by a minimization method with institution, Stage (III or IV), PS (0, 1 or 2, 3) and age (<60 or 
60) as balancing factors at the JCOG Data Center. The planned accrual period is 3 years and the follow-up period is set as 5 years after completion of accrual. The hazard ratio between treatment arms and its confidence interval, estimated by the Cox proportional hazard model stratified with stage, PS and age is used to test the non-inferiority of the NAC treatment regarding overall survival. The significance level is set as 0.05 in a one-sided test because of the non-inferiority design of the study. Two hundred seventy-six events would provide a statistical power of 80%, to conclude that the NAC arm is not inferior to the standard arm in 3-year overall survival with a non-inferiority margin of 5%, and non-inferiority is concluded if the upper limit of the confidence interval of the hazard ratio does not exceed the limit of 1.161, which is in accord with the non-inferiority margin. A sample size of 298 patients is necessary to observe 276 events, considering the accrual and follow-up period, an estimated 3-year overall survival of 25% in the standard treatment arm and an expected 3-year overall survival of 30.3% in the NAC arm. Thus, the target sample size of 300 patients (150 patients per regimen) was set. Interim analysis is planned after half of the patients are enrolled, taking into account the multiplicity with the O'Brien Fleming type alpha spending function.
Study Monitoring
In-house interim monitoring is performed by the JCOG Data Center to ensure data submission, patient eligibility, protocol compliance, safety and on-schedule study progress according to standard JCOG procedures. Monitoring reports are submitted to the investigators in GCSG and the JCOG Data and Safety Monitoring Committee every 6 months.
Participating Institutions
Hokkaido University, Sapporo Medical University, Tohoku University, University of Tsukuba, National Defense Medical College, Saitama Cancer Center, Saitama Medical Center, National Cancer Center Hospital, The Jikei University School of Medicine, Cancer Institute Hospital, University of Tokyo, Juntendo University, Kitasato University, Niigata Cancer Center Hospital, Shinshu University, Aichi Cancer Center, National Hospital Organization Nagoya Medical Center, Kinki University, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka City General Hospital, Osaka City University, Hyogo Cancer Center, Tottori University, National Hospital Organization Kure Medical Center, National Hospital Organization Shikoku Cancer Center, National Hospital Organization Kyushu Cancer Center, University of Kurume, Kyushu University, Saga University and Kagoshima City Hospital.
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