Summary 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/m2 on day 1) or dose-dense treatment (carboplatin AUC 6 mg/mL per min on day 1 and paclitaxel 80 mg/m2 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. Funding Japanese Gynecologic Oncology Group, Bristol-Myers Squibb.
Summary Background Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded ...disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer. Methods Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m2 ; 3-h intravenous infusion) plus carboplatin (area under the curve AUC 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m2 ; 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov , number NCT00226915. Findings 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28·0 months, 95% CI 22·3–35·4) than in the conventional treatment group (17·2 months, 15·7–21·1; hazard ratio HR 0·71; 95% CI 0·58–0·88; p=0·0015). Overall survival at 3 years was higher in the dose-dense regimen group (72·1%) than in the conventional treatment group (65·1%; HR 0·75, 0·57–0·98; p=0·03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 92% of 312; conventional regimen, 276 88% of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 69%) than in the conventional treatment group (137 44%; p<0·0001). The frequencies of other toxic effects were similar between groups. Interpretation Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer. Funding Bristol-Myers Squibb.
The objective of this study was to assess clinical outcomes and fertility in patients treated conservatively for unilateral stage I invasive epithelial ovarian cancer (EOC).
A multi-institutional ...retrospective investigation was undertaken to identify patients with unilateral stage I EOC treated with fertility-sparing surgery. Favorable histology was defined as grade 1 or grade 2 adenocarcinoma, excluding clear cell histology.
A total of 211 patients (stage IA, n = 126; stage IC, n = 85) were identified from 30 institutions. Median duration of follow-up was 78 months. Five-year overall survival and recurrence-free survival were 100% corrected and 97.8% for stage IA and favorable histology (n = 108), 100% and 100% for stage IA and clear cell histology (n = 15), 100% and 33.3% for stage IA and grade 3 (n = 3), 96.9% and 92.1% for stage IC and favorable histology (n = 67), 93.3% and 66.0% for stage IC and clear cell histology (n = 15), and 66.7% and 66.7% for stage IC and grade 3 (n = 3). Forty-five (53.6%) of 84 patients who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 56 healthy children.
Our data confirm that fertility-sparing surgery is a safe treatment for stage IA patients with favorable histology and suggest that stage IA patients with clear cell histology and stage IC patients with favorable histology can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy.
We aimed to find key molecules associated with chemoresistance in ovarian cancer using gene expression profiling as a screening tool.
Using two newly established paclitaxel-resistant ovarian cancer ...cell lines from an original paclitaxel-sensitive cell line and four supersensitive and four refractory surgical ovarian cancer specimens from paclitaxel-based chemotherapy, molecules associated with chemoresistance were screened with gene expression profiling arrays containing 39,000 genes. We further analyzed 44 genes that showed significantly different expressions between paclitaxel-sensitive samples and paclitaxel-resistant samples with permutation tests, which were common in cell lines and patients' tumors.
Eight of these genes showed reproducible results with real-time reverse transcription-PCR, of which indoleamine 2,3-dioxygenase gene expression was the most prominent and consistent. Moreover, by immunohistochemical analysis using a total of 24 serous-type ovarian cancer surgical specimens (stage III, n = 21; stage IV, n = 7), excluding samples used for GeneChip analysis, the Kaplan-Meier survival curve showed a clear relationship between indoleamine 2,3-dioxygenase staining patterns and overall survival (log-rank test, P = 0.0001). All patients classified as negative survived without relapse. The 50% survival of patients classified as sporadic, focal, and diffuse was 41, 17, and 11 months, respectively.
The indoleamine 2,3-dioxygenase screened with the GeneChip was positively associated with paclitaxel resistance and with impaired survival in patients with serous-type ovarian cancer.
Human epididymis protein 4 (HE4) levels and the Risk of Ovarian Malignancy Algorithm (ROMA) have recently been shown to improve the sensitivity and specificity of epithelial ovarian cancer (EOC) ...diagnosis. We evaluated HE4 levels and ROMA as diagnostic tools of type I and type II EOC in Japanese women. Women who had a pelvic mass on imaging and were scheduled to undergo surgery were enrolled as ovarian mass patients. Serum levels of carbohydrate antigen 125 (CA125) and HE4 were tested in 319 women (131 benign, 19 borderline, 75 malignant, and 94 healthy controls). CA125, HE4, and ROMA were evaluated for sensitivity and by receiver operating characteristics (ROC) in type I and type II EOC. The results showed that, at 75 % specificity, the sensitivity of CA125 and HE4 for type II was 92.1 % for both markers and for type I was 51.5 % and 78.8 %, respectively. The sensitivities of ROMA (type I, 84.8 % and type II, 97.4 %) were better than those of CA125 and HE4. CA125, HE4, and ROMA were all highly accurate markers for type II. For type I, HE4 and ROMA showed better sensitivity than CA125. ROMA displayed the best diagnostic power for type I and type II including for the early stage of type I. In conclusion, HE4, CA125, and ROMA are valuable markers for type II EOC diagnosis. HE4 and ROMA analyses may improve differentiation between type I EOC and a benign mass. Measurement of combined HE4 and CA125 levels provides a more accurate method for EOC diagnosis.
When compared with other epithelial ovarian cancers, the clinical characteristics of ovarian clear cell adenocarcinoma (CCC) include 1) a higher incidence among Japanese, 2) an association with ...endometriosis, 3) poor prognosis in advanced stages, and 4) a higher incidence of thrombosis as a complication. We used high resolution comparative genomic hybridization (CGH) to identify somatic copy number alterations (SCNAs) associated with each of these clinical characteristics of CCC. The Human Genome CGH 244A Oligo Microarray was used to examine 144 samples obtained from 120 Japanese, 15 Korean, and nine German patients with CCC. The entire 8q chromosome (minimum corrected p-value: q = 0.0001) and chromosome 20q13.2 including the ZNF217 locus (q = 0.0078) were amplified significantly more in Japanese than in Korean or German samples. This copy number amplification of the ZNF217 gene was confirmed by quantitative real-time polymerase chain reaction (Q-PCR). ZNF217 RNA levels were also higher in Japanese tumor samples than in non-Japanese samples (P = 0.027). Moreover, endometriosis was associated with amplification of EGFR gene (q = 0.047), which was again confirmed by Q-PCR and correlated with EGFR RNA expression. However, no SCNAs were significantly associated with prognosis or thrombosis. These results indicated that there may be an association between CCC and ZNF217 amplification among Japanese patients as well as between endometriosis and EGFR gene amplifications.
The purpose of this study was to construct a simple and powerful prognostic index (PI) of epithelial ovarian cancer, the PIEPOC.
In a retrospective review, data from 768 women with stage III or IV ...epithelial ovarian cancer from 24 institutions in Japan were evaluated for clinical features predictive of overall survival. A PI and risk groups to predict overall survival after initial surgery were developed using the proportional hazards regression model.
Of six factors, the four prognostic factors that remained independently significant in the analysis of a training sample (538 randomly selected patients) were age, performance status (PS), histologic cell type, and residual tumor size. From the regression function, we derived a PI = 1 (if age 70 and above) + 1 (if PS 1 or 2) + 2 (if PS 3 or 4) + 1 (if mucinous or clear-cell) + 2 (if residual size 0.1 cm and above). Patients were classified into three risk groups (PIEPOC): low risk (PI 0-2), intermediate risk (PI 3), and high risk (PI 4-6). The PIEPOC was equally predictive in a validation sample (n = 230), identifying three groups (5-year survival: 0.67 in low, 0.43 in intermediate, 0.17 in high risk).
Our proposed PI, the PIEPOC, was predictive in our patient population and may have utility in clinical practice. Prospective studies would be needed to confirm the prognostic predictive ability of the PIEPOC for patients with advanced epithelial ovarian cancer.
Background
The aim of this phase II study was to evaluate the efficacy and toxicity of docetaxel and irinotecan combination chemotherapy in patients with ovarian cancer refractory and resistant to ...both platinum and taxan treatment.
Patients and methods
Patients who had been treated with platinum and paclitaxel but whose ovarian cancer progressed or recurred within 6 months of treatment (
n
= 41) received docetaxel 60 mg/m
2
(day 1) and irinotecan 60 mg/m
2
(days 1, 8), repeated every 21 days Japan Gynecologic Oncology Group (JGOG) study 3015 or every 28 days West Japan Gynecologic Oncology Group (WJGOG) study 002 until disease progression was observed or unacceptable toxicity. Sixteen patients had platinum/paclitaxel-refractory disease, and 25 patients had platinum/paclitaxel-resistant disease.
Results
Thirty-two patients were available for determination of the clinical response. The overall response rate complete response (CR) + partial response (PR) was 6.3%, and the disease control rate (CR + PR + stable disease) was 34.4%. Among the 23 patients with resistant tumor, the disease control rate was 47.8%. Ten patients with refractory tumor showed a 10% disease control rate. The median progression-free interval was 12.1 weeks and the median overall survival time was 45.3 weeks. The major toxic adverse effect was neutropenia (grade 4, 56.1%), but the incidence of neutropenic fever was less frequent (4.9%). Neurotoxicity and gastro-intestinal toxicity were mild.
Conclusion
Among our patients, a combination of docetaxel and irinotecan was well tolerated. However, this combination may not be a beneficial option for patients with platinum-refractory and -resistant ovarian cancer in terms of response rate and survival.
Background
p16
INK4a
immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous ...Terminology Standardization project proposed p16
INK4a
immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16
INK4a
and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16
INK4a
/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system.
Methods
From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16
INK4a
/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared.
Results
p16
INK4a
/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16
INK4a
/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0–93.8 %) and 76.4 % (71.6–80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6–54.0 %) and 96.4 % (93.4–98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16
INK4a
/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test
Conclusions
Compared with high-risk HPV genotyping, p16
INK4a
/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.
ABSTRACT
Introduction
Herbal medicine containing
Vitex agnus
-
castus
(VAC) extract is widely used by women with premenstrual syndrome (PMS) in Europe, however, in Japan, clinical evidence remains to ...be determined. This study attempted to investigate the efficacy and safety profiles of VAC extract in Japanese patients with PMS.
Methods
A multi-center, prospective, open-label, single-arm, phase 3 study was performed in Japanese women with PMS and aged 18–44 years. The patients received Prefemin
®
(Max Zeller Söhne AG, Romanshorn, Switzerland), containing 20 mg of VAC extract, once daily for three menstrual cycles. The efficacy profile was examined based on the intensity of ten PMS symptoms—irritability, depressed mood, anger, headache, bloating, breast fullness, skin disorder, fatigue, drowsiness, and sleeplessness—recorded by patients via a visual analog scale (VAS). In addition, the responder rate was calculated based on the total VAS score defined by the sum of the VAS scores of the first six symptoms mentioned above. Furthermore, physician’s global assessment (PGA) scores were recorded. Adverse events including vital signs and laboratory test values were monitored as safety evaluation.
Results
Sixty-nine patients received Prefemin
®
. After the first menstrual cycle, a statistically significant decrease in total VAS score was observed (
P
< 0.001), and the score continued to diminish for the following two cycles. Each of the ten symptom scores decreased significantly in this manner. In addition, the responder rate increased in a time-dependent manner; the rate at the third menstrual cycle was 91.0%, and almost all of the patients were without symptoms or exhibited only mild symptoms based on PGA. Eight patients exhibited non-serious adverse events, one of which was allergic dermatitis whose causal relationship with VAC was not ruled out.
Conclusion
VAC extract improved PMS symptoms in Japanese patients, with no substantial adverse events. This is the first study to report the effect of VAC extract in Japanese patients.
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