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The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents.

Introduction: Ovarian clear cell carcinoma (CCC) is regarded as grade 3 tumor, and the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend adjuvant chemotherapy for the tumor even at stage IA. However, CCC often showed chemo-resistant phenotype, and the effect of adjuvant chemotherapy still remained uncertain., Methods: Clear cell carcinoma cases treated at collaborating institutions during the period 1992-2005 were retrospectively identified. After a central pathological review, survival analysis was estimated by the Kaplan-Meier method, and prognostic factors were evaluated using a Cox regression model., Results: Among 219 patients with stage I CCC, 195 patients received adjuvant chemotherapy (C+) and 24 patients (C-) did not. The C+ group had 77 pT1a and 118 pT1c cases, and the C- group included 18 pT1a and 6 pT1c tumors (P < 0.001). The median age was 52 years in the C+ group and 57 years in C- group (P = 0.04). During the median follow-up period of 48 months (range, 7-160 years), relapse was observed in one patient (4%) in the C- group and in 35 patients (18%) in the C+ group. There were no statistical differences of progression-free survival and overall survival between the C+ and the C- groups. Multivariate analysis revealed that peritoneal cytology status (P = 0.02) and pT status (P = 0.04) were independent prognostic factors for progression-free survival; however, adjuvant chemotherapy was not a prognostic factor (P = 0.80)., Conclusions: Although the present study was a limited retrospective investigation, it suggested that adjuvant chemotherapy had little impact on the survival of stage I CCC patients. Further strategy, such as a molecular targeting agent, is needed to improve survival of CCC, especially in cases with positive peritoneal washing.

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing resistance to conventional platinum-based chemotherapy and resulting in poor prognosis. The aim of the study was to evaluate the effects of complete surgical staging procedures for early-stage CCC patients in a retrospective multi-institutional analysis. During the period 1992 to 2002, a total of 199 patients with pT1 M0 CCC were identified. Survival analysis was estimated by Kaplan-Meier methods, and prognostic factors were evaluated using a Cox regression model. Among pT1 M0 tumors, retroperitoneal lymph node status was negative in 125 cases (pN0, 63%), positive in 10 cases (pN1, 5%), and unknown in 64 cases (pNx, 32%). Progression-free survival of pN1 was significantly worse than that of pN0 (P < 0.05), whereas there was no significant difference between pN1 and pNx. There was no significant difference of overall survival (OS) among the 3 groups. Multivariate analysis revealed that peritoneal cytology status was the only independent prognostic factor for progression-free survival (P = 0.04), but completion of surgical staging procedures was not a prognostic factor. There was no significant prognostic factor for OS. Our study implied that complete surgical staging enabled us to distinguish a high-risk group of recurrence in pT1 M0 CCC; however, the procedure could not improve OS. Although the study was a limited retrospective study, the impact of peritoneal cytology status was more important than complete surgical staging procedure in CCC patients. More effective treatment modality was warranted, especially for CCC cases positive for malignant peritoneal cytology.

Background: The long-term efficacy and safety of docetaxel/cisplatin as first-line chemotherapy in Japanese patients was evaluated in order to find an optional regimen for ovarian cancer., Patients and Methods: Women with surgically resected stage Ic-IV epithelial ovarian cancer were treated with docetaxel 70 mg/m2 and cisplatin 60 mg/m2 every 4 weeks., Results: Ninety women were enrolled of whom 89 (median age, 54 years) received a median of 6 cycles (range 1 to 9). With a median 38 months'follow-up, median progression-free survival was 28 months (95% lower confidence interval, 24 months) in 60 patients with stage III-IV disease. The overall response rate for 20 patients was 45%. Neutropenia was the most common (67%) grade 3/4 toxicity. Major grade 3/4 nonhaematological toxicities were gastrointestinal toxicities (< or = 11%) and fatigue (8%). No grade 3/4 neurotoxicity was observed., Conclusion: The combination of docetaxel/cisplatin is a regimen with favourable progression-free survival for ovarian cancer.

Background: Irinotecan hydrochloride, a topoisomerase I inhibitor, has been preliminarily recognized as an effective agent against clear cell carcinoma of the ovary (CCC), but there are few clinical data. Our aim was to compare progression-free survival (PFS) between patients treated with irinotecan hydrochloride and cisplatin (CPT-P) and those with treated with paclitaxel and carboplatin (TC)., Methods: One hundred and seventeen patients at International Federation of Gynecology and Obstetrics (FIGO) stages Ic (ascites/malignant washing) - IV were identified by scanning the medical records of ten Japanese hospitals. After complete surgical staging procedures including lymphadenectomy, 35 patients received CPT-P and 82 patients received TC. The PFS and overall survival of the two groups were compared using the Kaplan-Meier method., Results: There was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, or follow-up period between the CPT-P and TC groups. Two-year and 5-year PFS was 48% and 40%, respectively, in the TC group and 55% and 55%, respectively, in the CPT-P group (P = 0.31). Multiple regression analysis revealed that only residual tumor was an independent prognostic factor for PFS (P < 0.01)., Conclusion: CPT-P showed a potential therapeutic effect, at least no less than that of TC therapy. Although there was no significant survival benefit in the present retrospective analysis, we recommend that the CPT-P regimen be evaluated in a larger, prospective, clinical trial.

Clear cell carcinoma (CCC) of the ovary has distinct characteristics showing resistance to conventional platinum-based regimen. Our aim was to evaluate the effects of combination therapy with irinotecan hydrochloride and cisplatin (CPT-P), comparing to regimen with paclitaxel and platinum (TP). We retrospective reviewed 172 patients with complete surgical staging procedures including lymphadenenctomy. Forty-six patients received CPT-P and 126 patients were treated with TP. Survival of the two groups was compared. Between CPT-P group and TP group, there was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, and follow-up period. There was no significant difference in progression-free survival of patients with stage I tumors (p=0.95) and suboptimally debulked stage II-IV tumors (p=0.92). Although there was no significant difference of overall survival, progression-free survival of CPT-P group was significantly better than that of TP group in optimally debulked stage II-IV (p=0.03). Multiple regression survival analysis revealed CPT-P regimen (p=0.02) and residual tumor diameter (p<0.01) were both independent prognostic factors in stage II-IV tumors. The combination of CPT-P was shown to have a potential therapeutic benefit for advanced CCC of the ovary, especially for cases with optimal debulking surgery. However, this is a limited retrospective study, therefore we recommend that the CPT-P regimen be evaluated in a larger prospective study.

Purpose: The purpose of this work was to explore the role of epigenetic inactivation of apoptotic pathways in ovarian cancer by examining the DNA methylation and expression status of four proapoptotic genes in primary ovarian cancers and cancer cell lines and to correlate those findings with the clinicopathological features of ovarian cancer patients., Experimental Design: Genomic DNA was isolated from 15 ovarian cancer cell lines, 80 primary ovarian cancer specimens, and 4 normal ovary specimens using phenol-chloroform extraction. The methylation status of the DNA was evaluated using combined bisulfite restriction analysis, gene expression was evaluated using reverse transcription-PCR, and histone acetylation was evaluated using chromatin immunoprecipitation., Results: Of the four proapoptotic genes studied, expression of TMS1/ASC was absent in six ovarian cancer cell lines. Dense methylation of the 5' region of TMS1/ASC was detected in cells not expressing TMS1/ASC. Treating methylated cells with 5-aza-deoxycytidine restored gene expression, confirming the role of methylation in silencing the gene. Chromatin immunoprecipitation revealed histone to be deacetylated in cells not expressing TMS1/ASC, indicating that histone deacetylation is also involved in silencing TMS1/ASC. Aberrant methylation of TMS1/ASC was detected in 15 of 80 ovarian cancer tissues (19%) but in none of the normal ovary specimens. Aberrant methylation of TMS1/ASC was observed significantly more often in clear cell-type ovarian cancers than in other tumor types (P < 0.0001)., Conclusions: Methylation-mediated silencing of TMS1/ASC confers a survival advantage to tumor cells by enabling them to escape apoptosis. The role for aberrant methylation in human ovarian tumorigenesis may be particularly important for ovarian cancers with the clear cell phenotype.

Ultrastructural characteristics of benign, low-malignant potential (LMP), and malignant ovarian tumors were investigated, considering the aspects of histologic subtypes and histologic grading. In addition, the histogenesis of ovarian cancer was histologically investigated in an attempt to elucidate whether malignant tumor was generated from benign or LMP tumor, or whether it was generated de novo from normal tissues. Although all the benign, LMP, and malignant tumors appeared to be derived from Mullerian duct in serous tumors, the origin of endometrioid or mucinous tumor could not be ultrastructurally clarified. However, there was ultrastructural similarity between benign and malignant tumors among serous, endometrioid, and mucinous tumors, and it was suggested that benign adenoma may be the developmental origin of malignant tumors regardless of the histologic subtype. In addition, the investigation of endometrioid tumors revealed that the differences of histologic grading in malignant tumors reflected the ultrastructural differences, and that G1 tumor had an ultrastructure that was more similar to that of benign and LMP tumors than to that of G2 tumor.

Background: To understand the complicated network of paclitaxel (PTX)-induced apoptosis pathways and to elucidate mechanisms of drug resistance in ovarian cancer, we looked at PTX-induced apoptosis by using cDNA microarray. We also quantitated the changes in apoptosis-related proteins in the process of apoptosis., Methods: An ovarian cancer cell line KF, and its PTX-resistant clone KFTX, were treated with PTX or carboplatin (CBDCA). After exposure to PTX or CBDCA, the induction of apoptosis was examined by internucleosomal DNA fragmentation. Changes in mRNA expression after 12 h of exposure to PTX were studied using cDNA microarray and RT-PCR. Changes in P53 and Bcl-2 levels were also measured over 24 h by ELISA., Results: With increased doses of PTX or CBDCA, an increase in apoptosis was noted in both cell lines. cDNA microarray revealed that PTX treatment upregulated expression of caspase 1, 2, 3, 4, 6, 9, 10, their activator apaf-1, and stress reaction-related genes, gadd34, gadd153 in KF, although most of them were unchanged or downregulated in KFTX. bag-1 and hsc70 were markedly upregulated in KFTX. p53 and bcl-2 were not upregulated in either cell line. Results from protein studies also supported the cDNA microarray data., Conclusions: p53-independent mitochondrial pathways and stress-reaction-induced pathways play critical roles in PTX-induced apoptosis in ovarian cancer cells. Suppression of those pathways and upregulation of bag-1 and hsp-70 played an important role in acquiring resistance to PTX., (Copyright 2004 S. Karger AG, Basel)

Objective: The aim of this study was to compare the usefulness of a new universal grading system for ovarian cancer proposed by Shimizu et al. (Cancer 82 (1998), 893; Gynecol. Oncol. 70 (1998), 2) with that of the FIGO grading system as a prognostic factor of ovarian cancer., Methods: We reviewed all paraffin-embedded tissues of epithelial ovarian cancer obtained from 130 women who underwent initial treatment including primary surgery in our hospital between January 1990 and December 2000. The scores of the specimens were obtained according to both the universal grading system and the FIGO grading system., Results: Both the FIGO grading system and the universal grading system worked as significant prognostic indicators. Patients with Grades 1 and 3 of the universal grading system had high and low 5-year survival rates, respectively, compared to those of the FIGO grading system. Inconsistencies in histologic grade between the FIGO and universal grading systems were observed in 22 patients. The positive rate of lymph node metastasis in patients with Grade 3 of the universal grading system was significantly high compared to those of the FIGO grading system (P = 0.03). Patients with Grade 3 of the universal grading system with residual tumor of not less than 2 cm in diameter were observed more frequently than those of the FIGO grading system. C4ONCLUSION: The universal grading system was superior to the FIGO grading system in terms of the prediction of malignancies such as the potential of lymph node metastasis and invasion and the adaptability to clear cell cancer.

The outcome and reproductive function were examined among patients with malignant ovarian germ cell tumors treated since 1980. Between 1980 and 2001, fertility-sparing surgery was performed in 26 women, 23 of whom received adjuvant chemotherapy. With a median follow-up of 66.6 months, all patients have been alive, with histological types of 6 immature teratomas, 8 dysgerminomas, 6 yolk sac tumors, and 6 mixed types. Clinical stages were involved of 17 early stage and 9 advanced stage patients. After treatment, 20 women out of 26 recovered menstruation within 6 months. During follow-up, two chemotherapy-untreated and one treated patients experienced 4 conceptions in total. A treated patient conceived but selected artificial termination by affection of chemotherapy. Conservative surgery with adjuvant chemotherapy is the standard approach to treat patients with malignant ovarian germ cell tumors. In these 20 years, we experienced no delivery, so that fertility seems to be seriously affected by treatments.

Objective: To better control both acute and delayed emesis resulting from cisplatin(CDDP)-based chemotherapy for gynecological malignancies, we designed a 'cocktail therapy' (CCT) using granisetron (GRN) in combination with methylprednisolone (MPD) plus droperidol (DRP)., Methods: Two crossover clinical trials were carried out to compare the efficacy and safety of (a) GRN alone (3 mg/patient) with that of GRN, MPD (250 mg/patient) and DRP (0.5 ml/patient) in 42 patients (CCT group) and (b) GRN and MPD (CMB group) with that of the CCT group in 27 patients during the first 7 days of chemotherapy, independent of the weight/body surface of the patients. One of these regimens was administered intravenously for the first 3 days of chemotherapy, in case of failure for a maximum of 5 days., Results: For acute emesis, complete protection from nausea and vomiting by the end of the 1st day was achieved in 64.3% receiving GRN and in 92.9% receiving CCT (p < 0.01). For delayed emesis, complete protection was best achieved in CCT on days 2-3, showing statistical significance compared to GRN treatment (p < 0.01). Comparing the three kinds of treatment during 7 days, the lowest protection was 38.1% in the GRN group, 51.9% in the CMB group and 72.5% in the CCT group, especially on days 2 or 3., Conclusions: The CCT combination is useful for the control of delayed and/or anticipatory emesis resulting from CDDP-based chemotherapy for women with gynecological malignancies., (Copyright 2003 S. Karger AG, Basel)