Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.
Adenosine Diphosphate Ribose ; Anti-Inflammatory Agents, Non-Steroidal ; Antibodies, Monoclonal ; Drug Repositioning* ; Drug Therapy ; Dyslipidemias ; Endothelial Growth Factors ; Female ; Health Care Costs ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Itraconazole ; Ivermectin ; Metformin ; Mortality ; Osteoporosis ; Ovarian Neoplasms* ; Pharmacokinetics ; Prognosis

OBJECTIVES: We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer. METHODS: From October 2015 to May 2018, 65 patients with stages IIIC–IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m2) for 90 minutes, only in cases of optimal cytoreduction. RESULTS: Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score ≥8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0–915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC. CONCLUSIONS: According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits.
Cohort Studies ; Disease-Free Survival ; Drug Therapy* ; Humans ; Laparoscopy ; Mortality ; Neoplasm Metastasis ; Ovarian Neoplasms* ; Paclitaxel ; Pilot Projects* ; Tumor Burden

Ovarian cancer is one of the leading causes of cancer-related deaths in gynecological malignancies. Over 70% of ovarian cancer cases are high-grade serous ovarian cancers and have high death rates due to their resistance to chemotherapy. Despite advances in surgical and pharmaceutical therapies, overall survival rates are not good, and making an accurate prediction of the prognosis is not easy because of the highly heterogeneous nature of ovarian cancer. To improve the patient's prognosis through proper treatment, we present a prognostic prediction model by integrating high-dimensional RNA sequencing data with their clinical data through the following steps: gene filtration, pre-screening, gene marker selection, integrated study of selected gene markers and prediction model building. These steps of the prognostic prediction model can be applied to other types of cancer besides ovarian cancer.
Drug Therapy ; Filtration ; Mortality ; Ovarian Neoplasms ; Prognosis ; RNA ; Sequence Analysis, RNA ; Survival Rate

OBJECTIVE: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed as a treatment in ovarian cancer. A recently published RCT demonstrated that HIPEC prolongs disease-free survival (DFS) and overall survival (OS) in ovarian cancer. The aim of the study was to investigate oncologic results of cytoreductive surgery+HIPEC compared with cytoreductive surgery alone in advanced primary ovarian cancer with a particular attention to the pattern of recurrence. METHODS: This is a retrospective case control study with a propensity score (PS) matching of the patients. All the patients treated for primary advanced ovarian cancer who underwent interval surgery with or without HIPEC were collected; a PS was calculated in order to match cases to controls. RESULTS: Among 77 eligible patients 56 patients were included in the study. Preoperative patients' characteristics were homogeneous. No difference in morbidity and mortality after surgery were recorded. DFS was not different among the 2 groups (13.2 vs. 13.9 months, p=0.454) but OS was better in patients treated with HIPEC with no median reached vs. 35.5 months (p=0.048). Patients treated with cytoreductive surgery alone were more likely to have a peritoneal recurrence (43% vs. 14%). CONCLUSION: HIPEC seems to affect the relapse pattern with lesser peritoneal recurrence. This difference in relapse pattern seems to affect the OS with better results in patients treated with HIPEC. Further studies are needed to confirm these findings.
Case-Control Studies* ; Disease-Free Survival ; Drug Therapy* ; Humans ; Hyperthermia, Induced ; Mortality ; Ovarian Neoplasms* ; Propensity Score* ; Recurrence* ; Retrospective Studies

Cervical, endometrial, and ovarian cancers, have both high morbidity and mortality among the gynecologic malignant tumors in Japan. The present study was conducted using both the population-based cancer registry and the gynecologic cancer registry to elucidate the characteristics of gynecologic malignant tumors in Japan. Based on nationwide estimates from the population-based cancer registry in Japan, the morbidities and mortality of cervical, endometrial, and ovarian cancers were obtained and used for analysis. Clinicopathologic factors for cervical cancer, endometrial cancer, ovarian cancer, including age, clinical stage, postsurgical stage, histological type, therapeutic strategy, and prognosis were retrieved from the gynecologic cancer registry published by the Japan Society of Obstetrics and Gynecology and used for analysis. The morbidities of cervical, endometrial, and ovarian cancers were 10,908, 13,606, and 9,384 women in 2012, respectively. The prevalence of endometrial cancer has significantly and consistently been increasing and represents the most common gynecologic malignant tumor in Japan. The mortalities of cervical, endometrial, and ovarian cancers were 2.1, 1.3, and 3.2 per 100,000 in 2012, respectively. In 2014, 52.2% of cervical cancer patients were classified as stage I, 22.5% as stage II, 10.2% as stage III, and 11.2% as stage IV. In addition, 71.9% of endometrial cancer patients were classified as stage I, 6.0% as stage II, 13.3% as stage III, and 7.5% as stage IV. Finally, 43.2% of ovarian cancer patients were classified as stage I, 9.1% as stage II, 27.6% as stage III, and 7.2% as stage IV. Twelve point five percent of ovarian cancer patients received neoadjuvant chemotherapy.
Drug Therapy ; Endometrial Neoplasms ; Female ; Genital Neoplasms, Female ; Gynecology ; Humans ; Japan* ; Mortality ; Obstetrics ; Ovarian Neoplasms ; Prevalence ; Prognosis ; Registries ; Uterine Cervical Neoplasms

Epithelial ovarian carcinoma is a high mortality neoplasm in gynecologic malignancy. It usually can metastasize to distant organs such as pleura, liver, lung, and lymph nodes. However, the skin metastases are not common and related to very poor prognosis. Here we report a 54-year-old patient with ovarian clear cell carcinoma with skin metastases on the anterior chest at 11 months after initial diagnosis. Although she received palliative chemotherapy, she expired due to disease progression 2 months later after the diagnosis of skin metastases.
Adenocarcinoma, Clear Cell* ; Diagnosis ; Disease Progression ; Drug Therapy ; Humans ; Liver ; Lung ; Lymph Nodes ; Middle Aged ; Mortality ; Neoplasm Metastasis* ; Ovarian Neoplasms ; Pleura ; Prognosis ; Skin Neoplasms ; Skin* ; Thorax

PURPOSE: To determine the most powerful cancer antigen 125 (CA125)-related prognostic factor for advanced epithelial ovarian cancer (EOC) and to identify cut-off values that distinguish patients with a poor prognosis from those with a good prognosis. MATERIALS AND METHODS: We included 223 patients who received staging laparotomy and were diagnosed with stage IIC-IV serous EOC. Cox regression analysis was used to determine the most significant prognostic factor among the following variables: serum CA125 before surgery and after the first, second, and sixth cycles of chemotherapy; the nadir CA125 value; the relative percentage change in CA125 levels after the first and second cycles of chemotherapy compared to baseline CA125; CA125 half-life; time to nadir; and time to normalization of the CA125 level. RESULTS: The CA125 level after the first chemotherapy cycle was the most significant independent prognostic factor for overall survival (OS). Time to normalization (p=0.028) and relative percentage change between CA125 levels at baseline and after the first chemotherapy cycle (p=0.021) were additional independent prognostic factors in terms of OS. The CA125 level after the first chemotherapy cycle (p=0.001) and time to normalization (p<0.001) were identified as independent prognostic factors for progression free survival (PFS). CONCLUSION: Among well-established CA125-related prognostic factors, serum CA125 levels after the first cycle of chemotherapy and time to normalization were the most significant prognostic factors for both OS and PFS.
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/*therapeutic use ; CA-125 Antigen/*blood/metabolism ; Disease-Free Survival ; Female ; Humans ; Middle Aged ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial/*blood/*drug therapy/mortality ; Ovarian Neoplasms/*blood/*drug therapy/mortality ; Prognosis ; Regression Analysis

The aim of this trial was to investigate the efficacy and toxicity of combination chemotherapy with etoposide and ifosfamide (ETI) in the management of heavily pretreated recurrent or persistent epithelial ovarian cancer (EOC). Patients with recurrent or persistent EOC who had measurable disease and at least two prior chemotherapy participating in this phase II trial were to receive etoposide at a dose of 100 mg/m2/day intravenously (IV) on days 1 to 3 in combination with ifosfamide 1 g/m2/day IV on days 1 to 5, every 21 days. Thirty-seven patients were treated; about 78% had previously received more than two separate regimens. The response rate (RR) was 18.9% and median duration of response was 7 months (range, 1-15). Treatment free interval prior to ETI (TFI) has significant correlation with RR rate (P=0.034). Patients (n=6) with TFI > or =6 months had 50% of RR, while patients (n=31) with TFI <6 months had 12.9%. Median survival was 9 months at a median follow-up of 9.2 months. Grade 3 or 4 toxicities included neutropenia in 20.1% of the 139 cycles of ETI, anemia in 7.2% and thrombocytopenia in 8.6%. The ETI produces relatively low toxicity and modest activity in heavily pretreated recurrent or persistent EOC. This is significant in patients with TFI > or =6 months.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Etoposide/administration & dosage/*therapeutic use ; Female ; Humans ; Ifosfamide/administration & dosage/*therapeutic use ; Middle Aged ; Neoplasm Recurrence, Local/*drug therapy ; Ovarian Neoplasms/*drug therapy/mortality ; Survival Rate ; Treatment Outcome

BACKGROUNDCorrect drug selection, the key to successful chemotherapy, is one of the most difficult clinical decisions for the treatment of platinum-resistant recurrent ovarian cancer worldwide. The exact procedures for choosing drugs are undefined, currently relying on clinical trials and personal experience, which often results in disappointing outcomes. Here, we propose a new drug selection method, the "predictive molecule targeted routine chemotherapy", to choose relatively sensitive routine drugs and avoid relatively resistant routine drugs based on the specific predictive molecule expression of the individual tumor tissue.

METHODSFrom January 2004 to June 2008, 26 cases of platinum-resistant recurrent ovarian cancer were prospectively recruited. Their routine chemotherapy drug choice was based on the expression of 6 predictive molecules (including p53) as determined by immunohistochemistry (the predictive molecule targeted routine chemotherapy group). A further 18 cases of platinum-resistant recurrent ovarian cancer were treated by experience and formed the control group. The response rate and the overall survival were compared between the two groups.

RESULTSThe response rate to second-line chemotherapy was 28% in the control group and 77% in the predictive molecule targeted routine chemotherapy group (P = 0.002). The response rate to third-line chemotherapy was 14% in the control group and 33% in the predictive molecule targeted routine chemotherapy group (P = 0.268). The median overall survival of the predictive molecule targeted routine chemotherapy group (88 weeks) was significantly longer than the median overall survival of the control group (56 weeks) (P = 0.0315).

CONCLUSIONThe predictive molecule targeted routine chemotherapy is a new effective protocol for choosing drugs when treating platinum-resistant recurrent ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Drug Resistance, Neoplasm ; Female ; Humans ; Middle Aged ; Organoplatinum Compounds ; therapeutic use ; Ovarian Neoplasms ; drug therapy ; mortality ; Prospective Studies

The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.
Altretamine/*therapeutic use ; Antineoplastic Agents, Alkylating/*therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Disease-Free Survival ; Female ; Humans ; Middle Aged ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial/*drug therapy/mortality ; Ovarian Neoplasms/*drug therapy/mortality ; Retrospective Studies