Japanese Journal of Clinical Oncology 34:43-45 (2004)
© 2004 Foundation for Promotion of Cancer Research
Feasibility Study of Neoadjuvant Chemotherapy Followed by Interval Cytoreductive Surgery for Stage III/IV Ovarian, Tubal and Peritoneal Cancers: Japan Clinical Oncology Group Study JCOG0206
1 Division of Gynecologic Oncology, National Cancer Center Hospital, Tokyo, 2 Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka, 3 Japan Clinical Oncology Group Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, 4 Department of Medical Oncology, National Cancer Center Hospital, Tokyo and 5 Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONPROTOCOL DIGEST OF THE...REFERENCES |
|---|
A feasibility study was started in January 2003 on neoadjuvant chemotherapy (NAC) followed by interval cytoreductive surgery (ICS) and postoperative chemotherapy for stage III/IV müllerian carcinomas such as ovarian, tubal and peritoneal carcinomas. The purpose is to assess the safety and efficacy of the treatment starting with NAC and also to know whether we can accurately diagnose these advanced carcinomas by imaging studies, cytologic findings and tumor markers without staging laparotomy or laparoscopy. Fifty-six patients with advanced müllerian carcinomas will be recruited to the study. After confirmation of diagnosis by laparoscopic inspection and biopsies, patients undergo four cycles of chemotherapy as NAC, followed by ICS and an additional four cycles of post-surgical chemotherapy. The primary endpoint is proportion of clinical complete remission after accomplishment of the protocol treatment, while the major secondary endpoint is positive predictive value of diagnosis before laparoscopy regarding tumor origin, histology and stage. Based on the results of this study, we will conduct a phase III study to compare the treatment starting with NAC and primary cytoreductive surgery followed by post-surgical chemotherapy.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONPROTOCOL DIGEST OF THE...REFERENCES |
|---|
Prognosis of patients with advanced epithelial ovarian, tubal and peritoneal carcinomas is known to be poor. Even using platinum compound regimens, the 5-year survival rate of stage III/IV ovarian cancer is still around 20% (1). The current standard treatment for advanced ovarian cancer is primary cytoreductive surgery followed by post-surgical chemotherapy. However, optimal cytoreduction in primary surgery can be achieved only in 40% of stage III/IV ovarian cancer patients (2). An alternative to primary surgical cytoreduction in patients with unresectable bulky tumors or poor performance status is the use of chemotherapy in the neoadjuvant setting. Recent retrospective analyses (3–6) have revealed that progression-free and overall survival were comparable between patients treated with neoadjuvant chemotherapy (NAC) followed by interval cytoreductive surgery (ICS) and those treated by primary cytoreductive surgery, though the former group was older and had a poorer performance status. Phase II and III trials have not been performed on the role of neoadjuvant-setting treatment for advanced ovarian, tubal and peritoneal cancers. Therefore, we started a phase II study to assess the safety and efficacy of NAC followed by ICS and post-surgical chemotherapy before comparing with the current standard treatment including primary cytoreductive surgery in randomized controlled trial. Neoadjuvant setting has the advantage of earlier treatment start and lower invasiveness. However, according to the current general rules for the management of ovarian cancer, it is necessary to confirm the origin, histology and stage before starting treatment by staging laparotomy or laparoscopy. Thus, we also determine whether we can omit the ‘extra procedure’ of staging laparotomy or laparoscopy before the neoadjuvant-setting treatment in the majority of patients with advanced ovarian, tubal or peritoneal cancer.
The study protocol was designed by Gynecologic Cancer Study Group (GCSG) of the Japan Clinical Oncology Group (JCOG), approved by the Clinical Trial Review Committee of JCOG on December 6, 2002, and activated on January 14, 2003.
|
PROTOCOL DIGEST OF THE JCOG0206 |
|---|
|
TOPABSTRACTINTRODUCTIONPROTOCOL DIGEST OF THE...REFERENCES |
|---|
Purpose
The purposes are to assess the safety and efficacy of the treatment starting with NAC with paclitaxel and CBDCA for phase III study, comparing NAC therapy with current standard procedure, and to know whether we can accurately diagnose these advanced carcinomas by imaging studies, cytologic findings and tumor markers without staging laparotomy or laparoscopy.
Study Setting
A multi-institutional (26 centers) non-randomized phase II trial.
Resources
Health Sciences Research Grants for Clinical Research for Evidenced Based Medicine and Grants-in Aid for Cancer Research (nos 14S-4, 14-12), from the Ministry of Health, Labor and Welfare, Japan.
Endpoints
Primary endpoint is proportion of clinical complete remission (%cCR) among all stage III or IV müllerian carcinoma confirmed by laparoscopic inspection and histopathology of biopsy specimens. Clinical complete remission is defined as 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 are as follows: (i) positive predictive value (PPV) of pre-laparoscopic diagnosis concerning the origin and histology—proportion of the patients diagnosed as müllerian carcinoma by laparoscopic inspection and histopathology of biopsy specimen among those diagnosed by pre-laparoscopic findings; (ii) PPV of prelaparoscopic diagnosis concerning clinical stage—proportion of the patients diagnosed as stage III or IV by laparoscopic inspection among those diagnosed by pre-laparoscopic findings; (iii) PPV of overall pre-laparoscopic diagnosis—proportion of the patients diagnosed as stage III or IV müllerian carcinoma by laparoscopic inspection and histopathology of biopsy specimen among those diagnosed by pre-laparoscopic findings.
Other secondary endpoints are: (iv) response rate to NAC among patients whose clinical diagnosis is confirmed by laparoscopy; (v) proportion of patients who received ICS among patients whose clinical diagnosis is confirmed by laparoscopy; (vi) progression-free survival among patients whose clinical diagnosis is confirmed by laparoscopy; (vii) operative morbidity among all enrolled patients; (viii) adverse events among all enrolled patients: and (ix) overall survival among all enrolled patients.
Eligibility Criteria
Inclusion criteria
The study subjects are patients diagnosed as stage III or IV müllerian carcinoma by pre-laparoscopic clinical findings including imaging studies (CT, MRI or ultrasonography) and cytology of ascites, pleural effusions or fluids 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 malignancy of digestive tract origin, criteria for tumor markers are set to be CA125 >200 U/ml and CEA <20 ng/ml.
Further inclusion criteria are: (i) clinically deemed to be a candidate for debulking surgery without evidence of brain, bone, bone marrow metastases, multiple lung or multiple liver metastases; (ii) presence of at least one measurable lesion; (iii) previously untreated for these malignancies and no history of treatment with chemotherapy nor radiotherapy even for other diseases; (iv) age 20–75 years; (v) Eastern Cooperative Oncology Group (ECOG) performance status of 0–3; (vi) adequate bone marrow, hepatic, renal, cardiac and respiratory functions; and (vii) written informed consent.
Exclusion criteria
These are: (i) synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ; (ii) pregnant or nursing; (iii) severe mental disorders; (iv) systemic and continuous use of steroidal drugs; (v) active infections; (vi) uncontrolled hypertension; (vii) diabetes mellitus, uncontrolled or controlled with insulin; (viii) history of cardiac failure, unstable angina, myocardial infarction within 6 months prior to the registration; (ix) liver cirrhosis or bleeding tendency contraindicating debulking surgery; (x) intestinal occlusion necessary for surgical treatment; and (xi) hypersensitivity to alcohol.
Treatment Methods
Diagnostic laparoscopy
After enrolment, diagnostic laparoscopy is performed within 2 weeks. To confirm pre-laparoscopic clinical diagnosis of origin, histology and stage, inspection of peritoneal cavity and biopsy from the main tumor or metastatic tumors are performed. Resection of any organs or tumors attempting to reduce tumor volume is not allowed.
Neoadjuvant chemotherapy (NAC)
Four cycles of combination of paclitaxel (175 mg/m2, day 1) and carboplatin (AUC = 6, day 1) are administered every 3 weeks. NAC is initiated within 1 week after laparoscopy.
Interval cytoreductive surgery (ICS)
ICS is performed in 4–7 weeks after administration of the fourth cycle of NAC unless disease progression occurs during NAC. Standard procedures of ICS 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.
Post-surgical chemotherapy
An additional four cycles of chemotherapy (same regimen as NAC) is administered (eight cycles of chemotherapy in total). Post-surgical chemotherapy is initiated within 3 weeks after ICS.
Study Design and Statistical Methods
The study is planned as a single-stage safety and efficacy study. Sample size calculation was primarily based on binominal test for the primary endpoint, %cCR. Forty-four eligible patients are required when expected %cCR of 40% and an acceptable lowest %cCR of 20% with alpha error level of 0.05 and beta error level of 0.1. Additionally, PPV is to be confident enough to omit laparoscopy before NAC in the following phase III study. It is not possible to use sensitivity or specificity to evaluate accuracy of clinical diagnoses, because laparoscopy is performed only in patients diagnosed as stage III/IV müllerian carcinomas by clinical findings in this study setting. Thus, Bayesian monitoring PPV is planned, which requires 56 patients to have the 10% or lower Bayesian posterior probability that PPV is <90% in case of three false positive patients assuming prior distribution of beta (9,1). The target sample size was determined to be 56, which also can be expected sufficient for primary endpoint. The planned accrual period is 1 year and the follow-up period is set as 3 years after the completion of accrual.
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 the JCOG standard procedures. The monitoring reports are submitted to the JCOG Data and Safety Monitoring Committee every 6 months.
Participating Institutions
Hokkaido University, Sapporo Medical University, Tohoku University, University of Tsukuba, Gunma Prefectural Cancer Center, Shinshu University, National Defense Medical College, Saitama Cancer Center, National Cancer Center Hospital, The Jikei University School of Medicine, Cancer Institute Hospital, University of Tokyo, Juntendo University, Nagaoka Red Cross Hospital, Aichi Cancer Center, National Nagoya Hospital, Osaka Medical Center for Cancer and Cardiovascular Diseases, Kinki University, Niigata Cancer Center, Kure National Hospital (Chugoku District Cancer Center), National Shikoku Cancer Center, National Kyushu Cancer Center, University of Kurume, Kyushu University, Saga Medical School and Kagoshima City Hospital.
|
FOOTNOTES |
|---|
+ 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
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPROTOCOL DIGEST OF THE...REFERENCES |
|---|
1 Nguyen HN, Averette HE, Hoskins W, Sevin BU, Penalver M, Steren A. National survey of ovarian carcinoma. VI. Critical assessment of current International Federation of Gynecology and Obstetrics staging system. Cancer 1993;72:3007–11.[CrossRef][Web of Science][Medline]
2 Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269–74.[CrossRef][Medline]
3 Jacob JH, Gershenson DM, Morris M, Copeland LJ, Burke TW, Wharton JT. Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer. Gynecol Oncol 1991;42:146–50.[CrossRef][Medline]
4 Onnis A, Marchetti M, Padovan P, Castellan L. Neoadjuvant chemotherapy in advanced ovarian cancer. Eur J Gynaecol Oncol 1996;17:393–6.[Medline]
5 Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EI, Thiel RP. Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 1999;72:93–9.[CrossRef][Web of Science][Medline]
6 Vergote I, De Wever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71:431–6.[CrossRef][Medline]
Received October 7, 2003; accepted December 3, 2003
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Onda, H. Yoshikawa, T. Yasugi, K. Matsumoto, and Y. Taketani The Optimal Debulking after Neoadjuvant Chemotherapy in Ovarian Cancer: Proposal based on Interval Look During Upfront Surgery Setting Treatment Jpn. J. Clin. Oncol., October 10, 2009; (2009) hyp127v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Onda, K. Matsumoto, T. Shibata, A. Sato, H. Fukuda, I. Konishi, T. Kamura, and H. Yoshikawa 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 Jpn. J. Clin. Oncol., January 1, 2008; 38(1): 74 - 77. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||