Comparison of treatment outcomes between first-line chemotherapy with or without bevacizumab for advanced ovarian, fallopian tube, and primary peritoneal cancer (Tohoku gynecologic cancer unit: TGCU-RS001 study).

BACKGROUND: Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit. PATIENTS AND METHODS: The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events. RESULTS: The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P < 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P < 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P < 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group. CONCLUSION: Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.

Aggressive neuroendocrine tumor of the ovary with multiple metastases treated with everolimus: A case report.

•Neuroendocrine tumors (NETs) frequently occur in the lungs or the gastrointestinal tract; they are uncommon in the ovary.•The mammalian target of rapamycin (mTOR) pathway has been reported as a treatment for advanced NETs.•We describe a patient with an aggressive primary ovarian NET, successfully treated with everolimus (an mTOR inhibitor).

Clinical outcome of pelvic exenteration in patients with advanced or recurrent uterine cervical cancer.

BACKGROUND: Pelvic exenteration has attained an important role in the treatment of advanced or recurrent cervical cancer for obtaining a complete cure or longer disease-free survival. The purpose of this study was to evaluate patients undergoing pelvic exenteration and to determine the clinical features associated with outcome and survival. METHODS: We retrospectively analyzed the records of 12 patients who underwent pelvic exenteration for uterine cervical cancer between July 2002 and August 2011. RESULTS: Two patients had primary stage IVA cervical adenocarcinoma and 10 patients had recurrent cervical cancer. Eight patients underwent anterior pelvic exenteration, 3 patients underwent total pelvic exenteration, and 1 patient underwent posterior pelvic exenteration. With a median duration of follow-up of 22 months (range 3-116 months), 5 patients were alive without recurrence. Of 5 patients with no evidence of disease, 4 were recurrent or residual tumor, all of whom had common factors, such as a tumor size ≤ 30 mm, negative surgical margins, complete resection, and no lymph node involvement. The 5-year overall survival rate for 12 patients was 42.2 %. Ileus was the most common complication (42 %) and post-operative intestinal anastomosis leaks developed in 3 patients, but no ureteral anastomosis leaks occurred. CONCLUSIONS: Pelvic exenteration is a feasible surgical procedure in advanced and/or recurrent cervical cancer patients with no associated post-operative mortality, and the only therapeutic option for complete cure or long-term survival; however, post-operative complications frequently occur.

Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan.

BACKGROUND: Uterine leiomyosarcoma (LMS) and undifferentiated endometrial sarcoma (UES) are rare, aggressive malignancies. Both are treated similarly; however, few chemotherapy agents are effective. Recently, the combination of gemcitabine (900 mg/m(2), days 1 and 8) plus docetaxel (100 mg/m(2), day 8) with granulocyte colony-stimulating factor (G-CSF, 150 µg/m(2), days 9-15) has been shown to have activity in LMS. In Japan, neither prophylactic G-CSF at a dose of 150 µg/m(2) nor docetaxel at a dose of 100 mg/m(2) are approved for use. For this reason, we evaluated the combination of 900 mg/m(2) gemcitabine plus 70 mg/m(2) docetaxel regimen without prophylactic G-CSF support in advanced or recurrent LMS and UES in Japanese patients. METHODS: Eligible women with advanced or recurrent LMS and UES were treated with 900 mg/m(2) gemcitabine on days 1 and 8, plus 70 mg/m(2) docetaxel on day 8, every 3 weeks. The primary endpoint was overall response rate, defined as a complete or partial response. RESULTS: Of the eleven women enrolled, 10 were evaluated for a response. One complete response and 2 partial responses were observed (30 %) with an additional 4 (40 %) having stable disease. Mean progression-free survival was 5.4 months (range 1.3-24.8 months), and overall survival was 14 months (range 5.3-38.4 months). Grade 4 neutropenia was the major toxicity (50 %). The median number of cycles was 5 (range 2-18). Twenty-two cycles (44 %) employed G-CSF. CONCLUSION: The gemcitabine plus docetaxel regimen without prophylactic G-CSF support was tolerable and highly efficacious in Japanese patients with advanced or recurrent LMS and UES.

Tracer injection sites and combinations for sentinel lymph node detection in patients with endometrial cancer.

OBJECTIVE: The aim of the present study was to clarify the most effective combination of injected tracer types and injection sites in order to detect sentinel lymph nodes (SLNs) in early endometrial cancer. PATIENTS AND METHODS: The study included 100 consecutive patients with endometrial cancer treated at Tohoku University Hospital between June 2001 and December 2012. The procedure for SLN identification entailed either radioisotope (RI) injection into the endometrium during hysteroscopy (55 cases) or direct RI injection into the uterine cervix (45 cases). A combination of blue dye injected into the uterine cervix or uterine body intraoperatively in addition to preoperative RI injection occurred in 69 of 100 cases. All detected SLNs were recorded according to the individual tracer and the resultant staging from this method was compared to the final pathology of lymph node metastases including para-aortic nodes. RESULTS: SLN detection rate was highest (96%) by cervical RI injection; however, no SLNs were detected in para-aortic area. Para-aortic SLNs were detected only by hysteroscopic RI injection (56%). All cases with pelvic lymph node metastases were detected by pelvic SLN biopsy. Isolated positive para-aortic lymph nodes were detected in 3 patients. Bilateral SLN detection rate was high (96%; 26 of 27 cases) by cervical RI injection combined with dye. CONCLUSION: RI injection into the uterine cervix is highly sensitive in detection of SLN metastasis in early stage endometrial cancer. It is a useful and safe modality when combined with blue dye injection into the uterine body.

Small cell carcinoma of the uterine cervix: clinical outcome of concurrent chemoradiotherapy with a multidrug regimen.

Small cell carcinoma of the uterine cervix (SCCC) is a rare subtype of cervical cancer with an aggressive behavior. Although SCCC has a worse prognosis than other histological types of uterine cervical cancer such as squamous cell carcinoma or adenocarcinoma, standard therapy for SCCC remains to be established due to its rarity. The purpose of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) using a regimen consisting of vincristine, adriamycin, and cyclophosphamide alternating with cisplatin and etoposide (VAC/PE). We analyzed a series of 9 patients with SCCC. Five patients with stage IB disease underwent radical hysterectomy followed by CCRT. Four patients with advanced stage disease received CCRT primarily. With a median follow-up duration of 47.4 months (range, 10.5 to 86.4 months), 4 out of 5 patients with stage IB disease were alive without recurrence. In 4 patients with advanced stage disease, the response rate was 75% (complete response, 1; partial response, 2; progressive disease, 1). One patient with stage IVB disease remained without recurrence for 89.5 months. At 5 years, overall survival (OS) and progression-free survival for all patients was 52% and 56%, respectively. Patients with early-stage disease had an 80% 5-year OS rate compared to 25% for patients with advanced stage disease. Although all patients developed grade 3-4 neutropenia, CCRT using VAC/PE is feasible in both the primary and adjuvant settings for SCCC. In particular, this combined modality therapy may improve both local control and survival as postoperative treatment in patients with early-stage disease.

Malignant transformation arising from mature cystic teratoma of the ovary: a retrospective study of 20 cases.

OBJECTIVES: Mature cystic teratoma (MCT) of the ovary rarely undergoes malignant transformation (MT). Malignant transformation carries a significantly worse prognosis than epithelial ovarian cancer, regardless of whether postoperative chemotherapy or radiotherapy is applied. The rarity of this tumor has posed a significant challenge to developing standardized postoperative management protocols. The aim of this study was to review our experience with MT and to describe our current treatment practices. METHODS: A retrospective chart review of these patients was performed that identified 20 women treated for MT of MCT at our centers between 1988 and 2008. RESULTS: The median age was 52.5 (range, 29-77) years. Fifteen patients had squamous cell carcinoma (SCC), and 5 patients had other histological subtypes. The International Federation of Gynecology and Obstetrics stage distribution was as follows: 11 were stage I, 4 were stage II, 4 were stage III, and 1 was stage IV. All patients underwent an initial laparotomy. Eleven patients received adjuvant treatment: 8 were treated with chemotherapy, 2 with concurrent chemoradiation therapy, and 1 with radiation therapy. Platinum-based chemotherapy was the first-line regimen. The overall 1-year survival rate was 70%. Significant correlations between overall survival and age, stage, and residual tumor were presented (P = 0.044, P = 0.0107, P < 0.0001, respectively). Eight patients with advanced stage died of their disease. Four patients, however, were treated with adjuvant chemotherapy or concurrent chemoradiation therapy and survived more than 1 year. One stage III patient had a disease-free interval of 2 years. Two cases of SCC treated with combination platinum/taxane chemotherapy temporarily responded. In the other 2 cases of SCC, concurrent chemoradiation therapy with nedaplatin also resulted in tumor regression. CONCLUSIONS: The prognosis of MT is highly dependent on age, stage, and optimal cytoreduction. Adjuvant treatment has not been standardized, although our experience supports the use of combination platinum/taxane chemotherapy.

Evidence-based guidelines for treatment of cervical cancer in Japan: Japan Society of Gynecologic Oncology (JSGO) 2007 edition.

Clinical practice guidelines for gynecologic cancers have been published by the National Comprehensive Cancer Network and the National Cancer Institute. Whereas these guidelines form the basis for the standard of care for gynecologic malignancies in the United States, it has proven difficult to institute them in Japan due to differences in patient characteristics, health-care delivery systems, and insurance programs. Therefore, evidence-based guidelines for treating cervical cancer specifically in Japan have been under development. The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer. Opinions from within and outside the Japan Society of Gynecologic Oncology (JSGO) were incorporated into the final draft, and the guidelines were published after approval by the JSGO. These guidelines are composed of ten chapters and comprise three algorithms. Each chapter consists of a clinical question, recommendations, background, objectives, explanations, and references. The objective of these guidelines is to clearly delineate the standard of care for cervical cancer treatment in Japan in order to ensure equitable care for all Japanese women diagnosed with cervical cancer.

Promoter methylation status of the Cyclin D2 gene is associated with poor prognosis in human epithelial ovarian cancer.

Gene silencing associated with aberrant DNA methylation of promoter CpG islands is one mechanism through which several genes may be inactivated in human cancers. Cyclin D2, a member of the D-type cyclins, implicated in cell cycle regulation, differentiation and malignant transformation, is inactivated due to aberrant DNA methylation in several human cancers. In the present study, we examined the promoter methylation status and expression of Cyclin D2 in human epithelial ovarian cancer, and then determined the relationship between methylation status and various clinicopathological variables. Twelve ovarian cancer cell lines and 71 surgical specimens were examined by methylation-specific polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction to evaluate the methylation status and expression of the Cyclin D2 gene. The relationship between methylation status and various clinicopathological variables was evaluated using statistical analysis. Aberrant methylation of Cyclin D2 was present in five of 12 ovarian cancer cell lines and 16 of 71 primary ovarian cancer tissues. In five cell lines with methylation, expression of the Cyclin D2 gene tended to be lower than in cell lines without methylation. In ovarian cancer tissues, methylation bands were detected in 16 of 71 cases. The methylation status of Cyclin D2 was associated with advanced stage and a residual tumor size (>2 cm) (P = 0.027 and P = 0.031, respectively). Based on univariate analysis, patients with aberrant methylation of the Cyclin D2 promoter had a significantly worse chance of disease-free survival than those without methylation (P = 0.021). Our results suggest that aberrant promoter methylation of the Cyclin D2 gene is significantly associated with patient prognosis in epithelial ovarian cancer.

14-3-3sigma in endometrial cancer--a possible prognostic marker in early-stage cancer.

PURPOSE: We examined expression of 14-3-3sigma, a regulator of cell proliferation, and evaluated its clinical significance in endometrioid endometrial carcinoma. EXPERIMENTAL DESIGN: One hundred three endometrioid endometrial adenocarcinoma cases were examined using immunohistochemistry with archival specimens. We correlated this finding with various clinicopathologic variables, including the status of estrogen receptor, progesterone receptor, and MIB-1 (Ki-57). RESULTS: 14-3-3sigma Immunoreactivity was detected in 78 of 103 (75.3%) of carcinoma cases. No statistically significant correlation was detected between status of 14-3-3sigma and any of clinicopathologic variables examined. There was, however, a statistically significant correlation between loss of 14-3-3sigma expression and adverse clinical outcome of the patients (P = 0.0007). In the early stages of cancer (stages I and II), 14-3-3sigma immunoreactivity was absent in 5 of 10 (50.0%) patients who showed recurrence during follow-up, whereas its absence was detected in only 13 of 68 (19.1%) disease-free patients in the same period. In addition, 14-3-3sigma immunoreactivity was absent in 4 of 5 (80.0%) patients who died, whereas its absence was detected in only 14 of 73 (19.2%) patients who had lived during the same period. Patients whose tumors were negative for 14-3-3sigma were at much greater risk to develop recurrent and/or mortal disease (P = 0.0372 and 0.0067). In multivariate analysis using the Cox proportional hazards model, absence of 14-3-3sigma turned out to be statistically independent risk factor in disease-free survival and overall survival even in patients with early-stage disease (P = 0.0321 and 0.0191). CONCLUSIONS: Results of our study showed that loss or absence of 14-3-3sigma determined by immunohistochemistry may be an important tool to identify endometrial carcinoma cases at high risk of recurrence and/or death, who are otherwise not detected by current clinical and pathologic evaluation, especially in the early stages of the disease. In addition, results of 14-3-3sigma immunohistochemistry in the early stage of endometrial carcinoma could contribute to planning postoperative follow-up and adjuvant therapy.

Expression of estrogen-responsive finger protein (Efp) is associated with advanced disease in human epithelial ovarian cancer.

OBJECTIVE: The estrogen-responsive ring finger protein (Efp) gene, one of estrogen receptor (ER) target genes, is considered to be essential for estrogen-dependent cell proliferation. To understand the estrogenic action on ovarian cancer, we studied the relationships between Efp and ERs expressions and the correlations of Efp expression with clinicopathological parameters in epithelial ovarian cancer. METHODS: The protein expressions for Efp, ERalpha and ERbeta were examined by immunoblotting in 12 ovarian cancer cell lines. Efp mRNA expressions were evaluated by quantitative RT-PCR in 12 ovarian cancer cell lines. A total of 100 surgical specimens diagnosed as epithelial ovarian cancer were examined immunohistochemically using antibodies for Efp, ERalpha and ERbeta. RESULTS: Efp protein was detected in 8 out of 12 cell lines. In Efp protein-positive cell lines, Efp mRNA was expressed higher than that in negative (P=0.021). All of the Efp protein-positive cell lines simultaneously expressed either ERalpha or ERbeta protein. By immunohistochemical staining, Efp immunoreactivity was detected in 63 out of 100 ovarian cancer specimens and positive signals were in the cytoplasm of carcinoma cells. There were significant correlations between Efp and ERalpha, ERbeta immunoreactivity (Efp and ERalpha, P=0.022; Efp and ERbeta, P=0.032). Efp expression was significantly higher in a subgroup with serous adenocarcinoma (P=0.010) and with advanced disease (P=0.026). No significant relationship was detected between Efp immunoreactivity and overall survival. CONCLUSION: The expression of Efp was detected in human epithelial ovarian cancer and high expression of Efp was correlated with advanced disease and serous adenocarcinoma, and ERs status.