Fumitoshi Terauchi

Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial

BACKGROUND The primary analysis of the JGOG 3016 trial showed that a dose-dense paclitaxel and carboplatin regimen significantly improves progression-free and overall survival compared with the conventional regimen as first-line chemotherapy for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. We report the long-term follow-up results for survival. METHODS This randomised controlled trial was done at 85 centres in Japan. Patients with stage II-IV ovarian cancer were randomly assigned to receive conventional treatment (carboplatin area under the curve [AUC] 6 mg/mL per min and paclitaxel 180 mg/m(2) on day 1) or dose-dense treatment (carboplatin AUC 6 mg/mL per min on day 1 and paclitaxel 80 mg/m(2) on days 1, 8, and 15). The treatments were repeated every 3 weeks for six cycles; responding patients had three additional cycles. The randomisation was done centrally by telephone or fax, stratified by residual disease, stage, and histological type. The primary endpoint was progression-free survival; overall survival was a secondary endpoint. Long-term information on adverse events was not collected. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS 637 patients were enrolled, of whom 631 were analysed (312 assigned to the dose-dense regimen, 319 to the conventional regimen). Median follow-up was 76·8 months (IQR 68·9-85·6). Median progression-free survival was significantly longer in the dose-dense treatment group than in the conventional treatment group (28·2 months [95% CI 22·3-33·8] vs 17·5 months [15·7-21·7]; hazard ratio [HR] 0·76, 95% CI 0·62-0·91; p=0·0037). Median overall survival was 100·5 months (95% CI 65·2-∞) in the dose-dense treatment group and 62·2 months (52·1-82·6) in the conventional treatment group (HR 0·79, 95% CI 0·63-0·99; p=0·039). INTERPRETATION Dose-dense treatment offers better survival than conventional treatment and is a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer.

Randomized phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first-line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG trial

PURPOSE Clear cell carcinoma (CCC) is a rare histologic subtype that demonstrates poor outcomes in epithelial ovarian cancer. The Japanese Gynecologic Oncology Group conducted the first randomized phase III, CCC-specific clinical trial that compared irinotecan and cisplatin (CPT-P) with paclitaxel plus carboplatin (TC) in patients with CCC. PATIENTS AND METHODS Six hundred sixty-seven patients with stage I to IV CCC of the ovary were randomly assigned to receive irinotecan 60 mg/m(2) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1 (CPT-P group) every 4 weeks for six cycles or paclitaxel 175 mg/m(2) plus carboplatin area under the curve 6.0 mg/mL/min on day 1 every 3 weeks for six cycles (TC group). The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, and adverse events. RESULTS Six hundred nineteen patients were clinically and pathologically eligible for evaluation. With a median follow-up of 44.3 months, 2-year progression-free survival rates were 73.0% in the CPT-P group and 77.6% in TC group (hazard ratio, 1.17; 95% CI, 0.87 to 1.58; P = .85). Two-year overall survival rates were 85.5% with CPT-P and 87.4% with TC (hazard ratio, 1.13; 95% CI, 0.80 to 1.61; one-sided P = .76). Grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently with CPT-P, whereas grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently with TC. CONCLUSION No significant survival benefit was found for CPT-P. Both regimens were well tolerated, but the toxicity profiles differed significantly. Treatment with existing anticancer agents has limitations to improving the prognosis of CCC.

Early growth response-1 mediates downregulation of telomerase in cervical cancer

Early growth response (Egr)‐1 is a transcription factor that triggers transcription of downstream genes within 15–30 min of various stimulations. These genes are expressed rapidly through specific promoter activation and mediate cell growth and angiogenesis. Following the previous computational identification of a site that was thought to be an Egr‐1 consensus binding site at –273 to –281 in the human telomerase reverse transcriptase (hTERT) promoter region, the present study was conducted to evaluate the role of Egr‐1 in the regulation of hTERT and telomerase in uterine cervical cancer. First, the expression of Egr‐1 and hTERT at the mRNA level was examined in cervical cancer tissues. Egr‐1 and hTERT were expressed much higher in cervical cancer tissues than in the normal cervix. However, a negative correlation was noted in the expression between Egr‐1 and hTERT. By luciferase assay using hTERT promoter constructs, hTERT transcriptional activation was shown to be inhibited when Egr‐1 was overexpressed. Furthermore, Egr‐1 overexpression decreased hTERT protein production as well as hTERT mRNA as observed by western blotting analysis and real‐time reverse transcription–polymerase chain reaction, respectively. The present study suggests that Egr‐1 plays an important regulatory role in the transcriptional activation of hTERT. (Cancer Sci 2008; 99: 1401–1406)

Sclerosing stromal tumor of the ovary with elevated CA125

The case is reported herein of an 18‐year‐old woman who developed sclerosing stromal tumor of the ovary. Although she was suspected to have a malignant tumor due to magnetic resonance imaging findings and an abnormal blood CA125 value, the tumor was benign. The immunohistochemical staining by CA125 antibody was negative. She had an uneventful postoperative course, with no postoperative recurrence of the tumor.

Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment for stage II–IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016)

BACKGROUND Dose-dense weekly paclitaxel (Taxol) and carboplatin (dd-TC) improved survival compared with conventional tri-weekly paclitaxel and carboplatin (c-TC) as a first-line chemotherapy for newly diagnosed stage II-IV ovarian cancer in the Japanese Gynecologic Oncology Group 3016 trial. We report the quality-of-life (QoL) results from this trial. PATIENTS AND METHODS A total of 637 patients were randomly assigned to receive c-TC or dd-TC (c-TC, n = 319; dd-TC, n = 312) and were asked to complete a QoL assessment at baseline, just after the third and sixth chemotherapy cycles, and at 12 months after randomization. QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-general (FACT-G), FACT-taxane subscale (FACT-T), and FACT-ovary subscale (FACT-Ov). The overall QoL and that according to each subscale were analyzed using mixed-effects models adjusted for treatment and time. RESULTS Baseline QoL assessment was completed by 204 out of 319 (63.9%) and 200 out of 312 (64.1%) patients in the c-TC and dd-TC groups, respectively. In these groups, the compliance rates with regard to QoL assessment were 74.5% and 73.0%, respectively, after three chemotherapy cycles; 86.8% and 86.9%, respectively, after six chemotherapy cycles; and 74.2% and 71.6%, respectively, at 12 months after randomization. The overall QoL did not differ significantly between the two treatment groups up to 12 months after randomization (P = 0.46). However, QoL according to the FACT-T subscale was significantly lower in the dd-TC group than in the c-TC group (P = 0.02). CONCLUSION dd-TC does not decrease overall QoL compared with c-TC.

Pilot study on transdiaphragmatic thoracoscopic-assisted pleural biopsy and intrathoracic washing cytology for Stage IIIc ovarian cancer with diaphragmatic metastases.

Purpose: The significance of investigations of thoracic cavities as well as pleural biopsy and intrathoracic washing cytology through transdiaphragmatic thoracoscopy for stage IIIc ovarian cancer with diaphragmatic metastases was assessed as a prospective pilot study. Subjects and Methods: Eligibility criteria were established to include patients with stage IIIc ovarian cancer in whom pleural effusions were not detected preoperationally, but prominent diaphragmatic metastases were observed when the abdomen was opened and those who submitted consent. Transdiaphragmatic thoracoscopy was performed after diaphragm stripping. Then, biopsy of the lesion suspected to be disseminated or the plural membrane of the thoracic opening was performed followed by washing cytology using physiological saline. Results: Ten subjects were enrolled. Disseminated lesions were observed on plural membranes, and positive results were obtained in biopsy and washing cytology in 3 subjects. In addition, positive results were seen with biopsy alone in 2 subjects and with washing cytology alone in 2 subjects. Hence, a total of 7 subjects (70.0%) were up-staged to the level of stage IV. Postoperational complications were not observed in any of these cases. Conclusions: It was suggested that stage IIIc ovarian cancer with prominent diaphragmatic metastasis may advance to the level of stage IV from a clinical point of view even if carcinomatous pleural effusions are not detected pre-operationally. Therefore, it is thought that this operational method is useful in the management of progressive ovarian cancer.

Does severe anemia caused by dose-dense paclitaxel-carboplatin combination therapy have an effect on the survival of patients with epithelial ovarian cancer? Retrospective analysis of the Japanese gynecologic oncology group 3016 trial

Introduction To evaluate the incidence of anemia in patients with epithelial ovarian cancer receiving paclitaxel-carboplatin combination therapy (TC) using data from the Japanese Gynecologic Oncology Group (JGOG) 3016 trial, and to examine the effect of severe anemia on survival during dose-dense TC. Methods Retrospective analysis was conducted in patients enrolled in the JGOG 3016 trial who underwent at least one cycle of the protocol therapy (n = 622). Hemoglobin values at enrollment and during each cycle of TC were collected. One-to-one matching was performed between patients with and patients without grade 3/4 anemia during TC (anemia and nonanemia groups) to adjust the baseline characteristics of the patients. The cumulative survival curve and median progression-free survival were estimated using the Kaplan-Meier method. Results Grades 2 to 4 anemia was observed in 19.8% of patients before first-line TC. The incidence of grade 3/4 anemia rapidly increased to 56.1% after the fourth cycle of dose-dense TC. After matching, the median progression-free survival in the anemia (hemoglobin <8.0 g/dL) and nonanemia (hemoglobin >8.0 g/dL) groups was 777 and 1100 days, respectively (P = 0.3493) for patients receiving dose-dense TC. The median progression-free survival in patients receiving conventional TC was similar between the 2 groups. Conclusions The difference in progression-free survival between patients with epithelial ovarian cancer with and those without severe anemia during TC was not statistically significant, but for patients receiving dose-dense TC, severe anemia seems to have prognostic relevance. Prospective trials are needed to investigate whether the optimal management of chemotherapy-induced anemia, including appropriate use of erythropoiesis-stimulating agents, would further improve the survival of patients with ovarian cancer receiving dose-dense TC.

Prognostic factor on optimal debulking surgery by maximum effort for stage IIIC epithelial ovarian cancer

Objectives:  The aim of this study was to assess the prognostic factor of radical surgery in patients with stage IIIc ovarian cancer.

A case of advanced ovarian cancer upstaged on the bases of pleural washing cytology.

We encountered a case of ovarian cancer that had positive pleural washing cytology diagnosed by thoracoscopy. A 65‐year‐old woman was referred to our hospital with a sensation of abdominal fullness. A whole‐body examination revealed a solid tumor of the ovary and accumulation of ascites. Neither pleural effusion nor lung metastasis was found at the time. Laparotomy showed extensive dissemination and we classified the stage as IIIc. As the diaphragm was thickened with dissemination, we tried to strip the diaphragm and used thoracoscopy to identify the thoracic area. No tumor or pleural effusion was detected. We performed pleural biopsy and pleural washing cytology. Finally, malignant cells were found in the pleural washing cytology. Pathological findings showed serous papillary adenocarcinoma of the ovary in this stage IV case. We suggest in this report that thoracoscopy is a useful method for making the correct surgical staging.

Hypoxia inducible factor-1 mediates upregulation of urokinase-type plasminogen activator receptor gene transcription during hypoxia in cervical cancer cells.

Hypoxia occurs during development of cervical cancer and is considered to correlate with its invasion. Hypoxia mediates tumor cells to have more invasive property in a variety of cancers. Urokinase plasminogen activator receptor (uPAR) which mediates invasion is considered to be induced by hypoxia. We sought to determine the regulators of uPAR expression during hypoxia in cervical cancer. We showed that cervical cancer cell lines, CaSki and CA, were more invasive under hypoxic condition (1% O2) than under normoxic condition (20% O2) by invasion assays. Using western blot analysis, hypoxia enhanced the endogenous hypoxia-inducible factor (HIF)-1α and uPAR protein expression. uPAR mRNA level was also upregulated by hypoxia using real-time RT-PCR. Overexpression of HIF-1α which is induced by hypoxia activated the transcriptional activity of the uPAR promoter by luciferase assays. HIF-1 protein bound the putative HIF-1 response element on the uPAR promoter using electrophoretic mobility shift analysis, and additional luciferase assays show that this is essential for uPAR transactivation by HIF-1. HIF-1 overexpression enhanced the endogenous uPAR expression and introduction of siRNA for HIF-1α diminishes uPAR expression during hypoxia. These results indicate the upregulation of uPAR by hypoxia in cervical cancer cells is mediated through HIF-1. In cervical cancer tissues, we also demonstrated that uPAR protein expression was detected in cervical cancer but not in normal cervix or cervical intraepithelial neoplasia (CIN) by immunohistopathological staining. Our results provide evidence that regulation of uPAR expression by HIF-1 represents a mechanism for cervical cancer invasion during hypoxia.