Kimio Ushijima

Multicenter Phase II Study of Fertility-Sparing Treatment With Medroxyprogesterone Acetate for Endometrial Carcinoma and Atypical Hyperplasia in Young Women

PURPOSE To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. PATIENTS AND METHODS This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. RESULTS CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. CONCLUSION The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.

Current status of gynecologic cancer in Japan.

To make an overview of the current status of gynecologic cancer in Japan, we reviewed the recent incidence of cervical, endometrial, and ovarian cancer in Japanese women. The incidence of all three cancers has increased, but trends differ respectively. In age specific cancer site distribution data, the uterus and ovary are leading sites of high incidence among Japanese women younger than 40 years of age. Therefore, fertility sparing cancer treatment has received much attention. Several multicenter clinical trials have been done by Japanese groups, and some excellent evidence has been collected for endometrial and ovarian cancer. A promising international collaboration trial for ovarian clear cell carcinoma is also underway at the present time.

High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway

Purpose: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. Experimental Design: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. Results: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10−20). We validated its predictive ability with five other data sets using multivariate analysis (Tothills data set, P = 1 × 10−5; Bonomes data set, P = 0.0033; Dressmans data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response–related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. Conclusions: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. Clin Cancer Res; 18(5); 1374–85. ©2012 AACR.

Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505

PURPOSE In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma

Background:Stat3 is a member of the Janus-activated kinase/STAT signalling pathway. It normally resides in the cytoplasm and can be activated through phosphorylation. Activated Stat3 (p-Stat3) translocates to the nucleus to activate the transcription of several molecules involved in cell survival and proliferation. The constitutive activation of Stat3 has been shown in various types of malignancies, and its expression has been reported to indicate a poor prognosis. However, the correlation between the constitutive activation of Stat3 and the prognosis of cervical cancer patients has not been reported.Methods:The immunohistochemical analysis of p-Stat3 expression was performed on tissues from 125 cervical squamous-cell carcinoma patients who underwent extended hysterectomy and pelvic lymphadenectomy, and the association of p-Stat3 expression with several clinicopathological factors and survival was investigated.Results:Positive p-Stat3 expression was observed in 71 of 125 (56.8%) cases and was significantly correlated with lymph node metastasis, lymph vascular space invasion, and large tumour diameter (>4 cm) by Fishers exact test. Kaplan–Meier survival analysis showed that p-Stat3 expression was statistically indicative of a poor prognosis for overall survival (P=0.006) and disease-free survival (P=0.010) by log-rank test.Conclusion:These data showed that p-Stat3 expression in cervical cancer acts as a predictor of poor prognosis.

Vaccination with predesignated or evidence-based peptides for patients with recurrent gynecologic cancers.

Two different trials of peptide vaccination were conducted for patients with recurrent gynecologic cancers. In the first regimen, four HLA-A24+ patients (two with cervical cancer and two with ovarian cancer) were vaccinated with peptides that were predesignated before vaccination. Three patients exhibited with a grade 1 adverse effect, and no clinical response was observed in any patients. In the second regimen, six HLA-A24+ and four HLA-A2+ patients (five with cervical cancer, one with endometrial cancer, one with uterine sarcoma, and three with ovarian cancer) were vaccinated with peptides (maximum four) to which preexisting cytotoxic T lymphocyte precursors in the periphery were confirmed before vaccination. With this regimen, grade 1 adverse effects were observed in eight patients, a grade 2 adverse effect in one patient, and a grade 3 adverse effect (ie, rectal bleeding) in one patient. However, this regimen was able to enhance peptide-specific cytotoxic T lymphocytes in seven of ten patients, and three of five cervical cancer patients showed objective tumor regression. Analysis of immunoglobulin G -reactive to administered peptides suggested that the induction of peptide-specific immunoglobulin G was correlated with clinical responses. Overall, these results suggest that peptide vaccination of patients showing evidence of preexisting peptide-specific cytotoxic T lymphocyte precursors could be superior to vaccination with predesignated peptides, and that the evidence-based regimen is applicable for clinical trials in treatment of patients with recurrent gynecologic cancers.

Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer

Irinotecan hydrochloride (CPT-11) is reportedly effective for the treatment of refractory or recurrent ovarian cancer. We investigated the antitumor efficacy and toxicity of combination therapy with CPT-11 and cisplatin in 25 patients (mean age 55 years, range 35-73 years) with refractory or recurrent ovarian cancer who had previously undergone platinum-based combination chemotherapy. Patients received two or more courses of treatment consisting of 50 or 60 mg/m2 of CPT-11 on days 1, 8 and 15 and 50 or 60 mg/m2 of cisplatin on day 1 administered intravenously. All patients were evaluable for the response and the toxicity profile. Complete responses were obtained in two (8.0%) patients and partial responses were obtained in eight (32.0%) patients, giving an overall response rate of 40% (10 of 25 patients) (95% CI 23.0-59.0%). The median duration of response was 5.5 months (range 2-27 months), the median time to tumor progression was 6 months (range 3-28 months) and the median overall survival was 12 months (range 3-39+ months). Grade 3 or 4 neutropenia, which was the most frequent and severe toxic effect, occurred in 36 (54.5%) of the 66 treatment courses and in 16 (64.0%) of 25 patients. The nadir of the leukocyte count occurred on days 18-19. Neutropenia was reversed by short-term administration of granulocyte colony-stimulating factor for 2-10 days. Less serious hematologic effects and non-hematologic effects, such as diarrhea, were also observed. This preliminary study showed that this regimen of CPT-11 and cisplatin was effective in patients with recurrent ovarian cancer.

Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma.

Cap43 is a nickel- and calcium-inducible gene that plays important roles in the primary growth of malignant tumors, as well as in invasion and metastasis, most likely through its ability to induce cellular differentiation. This study investigated associations of Cap43 expression with angiogenesis and other clinicopathological factors in cervical adenocarcinoma. The clinical records of 100 women who underwent surgery for cervical adenocarcinoma were reviewed retrospectively. Microvessel density and the expression of Cap43 and VEGF in the surgical specimens were evaluated immunohistochemically. The Cap43 expression level was significantly associated with angiogenesis, tumor diameter, stromal invasion, lymphovascular space invasion, lymph node metastasis, and histopathological differentiation. Kaplan-Meier analysis showed a significant association between the Cap43 expression level and survival: high Cap43 expression was related to poor survival. Our results suggest that increased expression of Cap43 is associated with angiogenesis and may be a poor prognostic indicator in women with cervical adenocarcinoma.

Treatment for Recurrent Ovarian Cancer—At First Relapse

Recurrent ovarian cancer is a lethal disease, and few patients can be cured. Although most patients receive standardized surgery and chemotherapy, the status of recurrent disease is heterogeneous. The site of recurrence and the survival intervals after recurrence are also widely distributed. Among a number of factors, many clinical trials identified time to recurrence was the factor most related to chemosensitivity at first relapse. The current recommendation for platinum sensitive ovarian cancer is a carboplatin containing combination chemotherapy. Generally, a single agent is chosen for platinum resistant ovarian cancer. Patients with single site recurrence and a long disease free interval are candidates for secondary cytoreduction, which may provide longer survival. There are several treatment choices at first relapse, and disease status, chemotherapy-free interval, and the patients condition play a major role in the decision making process.

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species

OBJECTIVE In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.