Byoung Gie Kim

Incorporation of Pazopanib in Maintenance Therapy of Ovarian Cancer

PURPOSE Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy. PATIENTS AND METHODS Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators. RESULTS Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%). CONCLUSION Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).

A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma

OBJECTIVES Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented. METHODS Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS). RESULTS Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ≥ grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%). CONCLUSIONS Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations.

AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration

Ovarian cancer is a leading cause of death in women. Early detection of ovarian cancer is essential to decrease mortality. However, the early diagnosis of ovarian cancer is difficult due to a lack of clinical symptoms and suitable molecular diagnostic markers. Thus, identification of meaningful tumor biomarkers with potential clinical application is clearly needed. To search for a biomarker for the early detection of ovarian cancer, we identified human anterior gradient 2 (AGR2) from our systematic analysis of paired normal and ovarian tumor tissue cDNA microarray. We noted a marked overexpression of AGR2 mRNA and protein in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors by Western blot analysis and immunohistochemistry. To further elucidate the role of AGR2 in ovarian tumorigenesis, stable 2774 human ovarian cancer cell lines overexpressing AGR2 were established. Forced expression of AGR2 in 2774 cells enhanced the growth and migration of ovarian cancer cells. AGR2 protein was detected in the serum of mucinous ovarian cancer patients by Western blot and ELISA analysis. Thus, AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer and an ELISA assay may facilitate the early detection of mucinous ovarian cancer using patient serum.

Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. METHODS The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851. FINDINGS Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1]). INTERPRETATION The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. FUNDING National Cancer Institute and Genentech.

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.

The interactions between MicroRNA-200c and BRD7 in endometrial carcinoma

OBJECTIVE Increased expression of miR-200c was recently reported in endometrial carcinoma compared with normal tissues. In this study, we evaluated the role of miR-200c in cell growth and drug sensitivity in endometrial carcinoma and investigated the underlying mechanisms. METHODS The expression of miR-200c in human endometrial tissues was detected by quantitative RT-PCR. The transfection with anti-miRNA (anti-miR) or the premature form of miRNA (pre-miR) was performed to regulate the level of expression of miRNA-200c in endometrial carcinoma cells, HEC-1A and Ishikawa. To identify the target genes for miR-200c, we performed mRNA microarray after pre-miR-200c transfection in HEC-1A cells. RESULTS We found that miR-200c expression was increased in endometrial carcinoma compared with normal endometrial tissues. Anti-miR or pre-miR-200c could regulate cell survival, proliferation, and apoptosis and affect cytotoxicity in endometrial cancer cells. Through mRNA microarray analysis, we found that miR-200c inhibits the expression of BRD7, which was recently reported as a potential tumor suppressor gene. MiR-200c regulated the translocation of β-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc. CONCLUSION The interaction between miR-200c and BRD7 might have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.

Ovarian preservation during the surgical treatment of early stage endometrial cancer: A nation-wide study conducted by the Korean Gynecologic Oncology Group

OBJECTIVES The objective of this study was to determine whether ovarian preservation is feasible in younger endometrial cancer patients. METHODS Endometrial cancer patients who underwent ovary-saving surgery were recruited from the tumor registries of 14 tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG). Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. RESULTS One hundred and seventy five patients were eligible for this study. Mean patient age at the time of surgery was 38.5+/-8.3 years (range 25-57). Ovary-preserving surgery was performed in 101 (57.7%) patients who desired to preserve their ovaries, incidentally in 69 (39.4%) patients with preoperative diagnoses other than endometrial carcinoma, and in 5 patients (2.9%) with unknown reasons. Median duration of follow-up was 55.0 months (range 6.2-180.0 months). Recurrence free survival and overall survival rates were 94.3 and 93.3%, respectively. Seven of the 175 (4.0%) patients had documented recurrence, and no recurrences were observed in stage I patients with endometrioid histology. All 7 recurrences had risk factors that could have reasonably explained recurrence, namely, non-endometrioid histology (4/7), deep myometrial invasion (5/7), cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). No metachronous ovarian malignancy occurred during follow-up. Ten (5.8%) deaths occurred during follow-up; five resulted from disease recurrence, and 5 from non-disease related causes. CONCLUSION Our findings suggest that ovarian preservation does not adversely impact the recurrence of early stage endometrial cancer.

Epidemiological characteristics of ovarian cancer in Korea.

OBJECTIVE This study was conducted to examine recent trends in ovarian cancer incidence and mortality and secular trends in demographic factors in Korea. METHODS With the data from Korea Central Cancer Registry, International Agency for Research on Cancer, Korean Death Registry, and World Health Organizations Statistical Information System, we calculated age-standardized incidence and mortality rates for ovarian cancer. Also we estimated future incidence of ovarian and cervical cancer using linear regression model. To assess the demographic trend, data from national surveys in Korea or results from published papers were searched. RESULTS Ovarian cancer incidence rate was similar to that in women worldwide but lower than those in Western countries, and the trend has been increased steadily. Ovarian cancer-related mortality rates have been increasing in Korea, even though those in western and some Asian countries, such as China, have been decreasing. Age-specific incidence rate and mortality rate showed steep increases with advancing age. The incidence rate of ovarian cancer was estimated to surpass that of uterine cervix cancer in 2015. Korea showed rapid changes in nutritional, reproductive, and anthropometric factors. CONCLUSION These recent trends in ovarian cancer incidence and mortality may be partly attributed to gradual westernizing of life styles and to changes in socio-demographic behavior factors. In particular, the increasing trend in ovarian cancer mortality in Korea may be attributed to a real rise in mortality as well as, in part, a decline in misclassification bias related to an increase in the proportion of deaths confirmed by physician diagnosis.

Increased expression of ICAM-3 is associated with radiation resistance in cervical cancer

To search for a marker that predicts the efficacy of radiation therapy in human cervical cancer, gene expression profiles between parental SiHa cervical cancer cells and radiation‐resistant SiHa/R cells have been compared by the microarray technique. Microarray and Northern blot analyses demonstrated that the ICAM‐3 expression was upregulated in SiHa/R cells. This increased expression of ICAM‐3 in SiHa cells enhanced cell survival by about 34.3% after a 2 Gy dosage of radiation. In addition, SiHa/ICAM‐3 cells showed a 2.45‐fold higher level of FAK phosphorylation than that of the control cells. In tumor specimens, ICAM‐3 staining was restricted to tumor stromal endothelial cells and lymphocytes. The overexpression of ICAM‐3 was significantly more frequent in radiation‐resistant cervical cancer specimens when compared with radiation‐sensitive specimens (83.3% vs. 35.3%; p = 0.015). With these observations, we can suggest that an increased expression of ICAM‐3 is associated with radiation resistance in cervical cancer cells and the expression of ICAM‐3 can be used as a valuable biomarker to predict the radiation resistance in cervical cancer that occurs during radiotherapy.

Benign Metastasizing Leiomyoma with Multiple Lymph Node Metastasis: A Case Report

This is a case report about benign metastasizing leiomyoma with multiple lymph node metastasis. A 34-year-old woman received an abdominal myomectomy for a suspicious leiomyoma. On the pathology report, atypical leiomyoma was suspected. Due to the suspicion of multiple lymph node metastasis on pelvis computed tomography (CT) 1 year after the operation, she was transferred to the Samsung Medical Center on October, 2009 for further work up. According to original slide review, it was determined to be a benign leiomyoma with a mitotic count <5/10 high-power fields, little cytological atypia and no tumor cell necrosis. Additional immunostaining was done. Multiple lymph node metastasis and a small lung nodule were identified on positron emission tomogarphy-CT and chest CT. Extensive debulking surgery and diagnostic video-assisted thoracoscopic surgery (VATS) wedge resection were subsequently done. Metastatic lesions were reported to have a histology similar to that of the original mass. VATS right upper lobectomy with mediastinal lymph node dissection was performed because of the pathology result of VATS (adenocarcinoma). She started taking an aromatase inhibitor (Letrozole®) and there was no evidence of recurrence of disease on an imaging study and no post-operative complications until recently.