belotecan and Ovarian-Neoplasms

This study was designed to determine the maximum tolerated dose and toxicity profile of belotecan in combination with oral etoposide in patients with platinum-resistant or heavily treated ovarian cancer, fallopian tubal cancer, and primary peritoneal cancer. Belotecan (0.5 mg/m/day) was administered daily (days 1-5) followed by etoposide (50, 75 mg/day) for up to 5 days (days 6-10) every 3 weeks. Dose-limiting toxicities (DLT) were defined as follows: grade 4 neutropenia less than 1 week; either neutropenic fever less than 24 h or sepsis; grade 4 thrombocytopenia; and grade of at least 3 nonhematologic toxicity except alopecia. At the first dose level (50 mg) of etoposide, none of the three patients developed DLT, whereas DLT was observed in two of three patients at the next dose level. Thus, the dose level was reduced to 50 mg, and another three patients were enrolled. DLT was found in one of six patients who received etoposide at the dose level of 50 mg/m. Thus, the maximum tolerated dose was reached (50 mg of oral etoposide) and the trial was terminated. The response was evaluable in nine patients and an objective response was observed in four patients (44%) including two complete responses. The combined regimen of belotecan followed by oral etoposide showed promising activity in platinum-resistant or heavily pretreated ovarian cancer patients at the dose level of 50 mg of oral etoposide.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Resistance, Neoplasm; Etoposide; Fallopian Tube Neoplasms; Female; Humans; Maximum Tolerated Dose; Middle Aged; Neutropenia; Ovarian Neoplasms; Peritoneal Neoplasms; Thrombocytopenia; Treatment Outcome

Belotecan (CKD602; Camtobell, Chong Keun Dang Corp., Seoul, Korea) is a recently developed camptothecin derivative with antitumor properties. This phase II study was designed to evaluate the toxicity and efficacy of belotecan combined with carboplatin in patients with recurrent epithelial ovarian cancer (EOC).. Thirty-eight patients with recurrent EOC were treated with belotecan 0.3 mg/m(2) /day (days 1-5) and carboplatin AUC 5 (day 5) every 3 weeks for 6 cycles. The primary objective was to determine the response rate as defined by Response Evaluation Criteria in Solid Tumors and CA-125 response. Other end points included toxicities and progression-free survival (PFS).. All 38 patients were assessed for toxicity, and 35 patients were assessed for response. The overall response rate was 57.1%; there were 7 complete responses (20.0%), 13 partial responses (37.1%), 6 patients with stable disease (17.1%), and 9 patients with progressive disease (25.7%). Grades 3 and 4 hematologic toxicities included neutropenia (28.8%), thrombocytopenia (19.8%), and anemia (14.4%), and there were 2 episodes of febrile neutropenia. Median PFS was 7 months, with a median follow-up of 12 months.. The newly developed topoisomerase I inhibitor belotecan (CKD-602) combined with carboplatin is a well-tolerated regimen with activity in recurrent EOC. Further testing of this regimen is warranted to further characterize efficacy and indications for use.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carboplatin; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms

This study was performed to determine the safety and efficacy of belotecan, a new camptothecin analogue and potent topoisomerase I inhibitor, with and without platinum in patients with recurrent ovarian cancer.. Fifty-three patients with recurrent or persistent ovarian cancer were enrolled between March 2005 and March 2008. Eligible patients received 0.5 mg/m of intravenous (IV) belotecan on days 1 to 5, every 3 weeks belotecan monotherapy (B) or 50 mg/m of IV cisplatin on day 1 plus 0.3 mg/m of IV belotecan on days 1 to 5, every 3 weeks (belotecan plus cisplatin combination therapy [BP]).. Of the 53 treated patients, 34 received BP and 19 received B. Thirty-four patients had platinum-sensitive (PS) disease and 19 had platinum-resistant disease. The overall response of the 53 patients was 37.7% (20/53). According to regimen, the response rate in the BP group was 47.1% (16/34) and that of the B group was 21.1% (4/19). BP had better response (66.7%, 14/21) than B (15.4%, 2/13) for PS disease (P = 0.004), but it was not superior in terms of progression-free survival (BP, 6 month; B, 7 months). Grade 3 or 4 toxicity was less common in B than in BP.. Both BP and B seems to be effective and safe regimens for patients with PS or platinum-resistant recurrent ovarian cancer. These results warrant further prospective randomized trials. Both BP and B seems to be effective and safe regimens for patients with PS or platinum-resistant recurrent ovarian cancer.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Cisplatin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Ovarian Neoplasms; Salvage Therapy; Survival Analysis; Treatment Outcome

The aim of this study was to determine the maximum tolerated dose (MTD) and therapeutic efficacy of a newly developed CKD-602 topoisomerase I inhibitor and cisplatin in patients with recurrent epithelial ovarian cancer. CKD-602 (0.30 mg/m(2) daily for 5 days) and cisplatin (60 mg/m(2) on day 5) were administered to patients every 3 weeks with dose adjustment of CKD-602 by 0.05 mg/m(2) daily until the MTD was reached. Dose-limiting toxicity was defined as grade >or= 3 neutropenia or thrombocytopenia for more than 4 days or accompanied by fever >or= 38.5 degrees C, infection, hemorrhage, or transfusion; grade >or= 3 nonhematological toxicity except for alopecia, nausea, and vomiting. We enrolled 26 patients with recurrent epithelial ovarian cancer who had measurable disease (MD) estimated by computed tomography scan (n= 12) and nonmeasurable disease (NMD) evaluated by serum CA-125 levels (n= 14). All patients received 188 cycles of CKD-602 and cisplatin with a median number of six cycles per patient (range, 2 to 12). MTD of CKD-602 was 0.30 mg/m(2) daily. The overall response rate was 69.2% (18/26) with 58.3% (7/12) and 78.6% (11/14) in MD and NMD, respectively. Among the responsive patients, 14 were platinum sensitive (14/18, 77.7%) and four were platinum resistant (4/8, 50.0%). The most common toxicity was grade >or= 3 neutropenia developing in 17 patients (65.4%) and 72 cycles (38.3%). Grade 3 nausea and anorexia were the most common gastrointestinal toxicities, developing in 15 cycles (8.0%) of four patients (15.4%) and 10 cycles (5.3%) of five patients (19.3%), respectively. The median disease-free interval was 6 months (range 0-26 months). CKD-602 at a concentration of 0.3 mg/m(2) daily for 5 days and cisplatin at 60 mg/m(2) on day 5 every 3 weeks showed high efficacy, with acceptable toxicity, against platinum-sensitive/resistant recurrent epithelial ovarian cancer.

Topics: Adult; Aged; Anemia; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Epithelial Cells; Female; Humans; Leukopenia; Middle Aged; Nausea; Neoplasm Recurrence, Local; Neoplasm Staging; Neutropenia; Ovarian Neoplasms; Treatment Outcome

To evaluate the toxicity and efficacy of a newly developed topoisomerase I inhibitor, CKD-602 in second-line therapy of ovarian cancer.. We enrolled 24 patients with recurrent ovarian cancer, of median age 54 years (range, 39-64). Eleven patients had measurable lesions on CT scan, and the other 13 had increased serum CA-125 levels. Eighteen patients had platinum-sensitive disease (minimum treatment free interval > or =6 months) and 6 had platinum-resistant disease (minimum treatment free interval <6 months). CKD-602 (0.5 mg/m(2)/day) was administered intravenously for 5 days every 3 weeks. The median number of courses per patient was 6 (range, 1 to 12). Response was evaluated by the evaluation of the size of the mass by CT scan and CA-125 response.. The overall response rate was 45.0% (9/20), with 4 patients exhibiting partial responses and 5 patients exhibiting 75% CA-125 responses in 20 evaluable patients. Of the 9 responsive patients, 8 were platinum-sensitive (8/15, 53.3%) and 1 was platinum-resistant (1/5, 20.0%). An additional 5 patients showed stable disease, whereas 6 patients exhibited progressive lesions. Of 24 patients, the most common toxicity was hematological, with grades 3 or 4 neutropenia developing in all 24 patients (100%) and in 94 cycles (71.7%). Grade 3 thrombocytopenia developed in 4 patients (16.7%) and 6 cycles (4.6%). None of the patients experienced grades 3 and 4 gastrointestinal toxicities, including nausea, vomiting, and anorexia.. The newly developed topoisomerase I inhibitor, CKD-602, showed activity against both platinum-sensitive and -resistant ovarian cancer, with acceptable toxicity.

Topics: Adult; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Administration Schedule; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Ovarian Neoplasms; Topoisomerase I Inhibitors

Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2/M decrease, representing the release of G2/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Camptothecin; Carcinoma, Ovarian Epithelial; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Checkpoint Kinase 1; Drug Synergism; Female; G2 Phase Cell Cycle Checkpoints; Humans; Immunohistochemistry; Indoles; Mice; Mice, Inbred BALB C; Mice, Nude; Morpholines; Ovarian Neoplasms; Phosphorylation; Pyrimidines; Sulfonamides; Sulfoxides; Xenograft Model Antitumor Assays

Evidence on recurrence patterns after bevacizumab in epithelial ovarian cancer is still insufficient. The aim of this study was to evaluate recurrence patterns after treatment with bevacizumab as second-line treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer.. We retrospectively identified epithelial ovarian cancer patients who relapsed ≥6 months after primary treatment consisting of surgery and platinum-based chemotherapy between January 2008 and June 2019. Only those who received platinum-based doublet chemotherapy with bevacizumab or without bevacizumab as second-line treatment were included (n=192). To adjust confounders, we conducted 1:2 propensity score matching for platinum-free interval and secondary debulking surgery. Imaging studies were performed to locate newly developed or enlarged pre-existing tumors. Recurrence patterns were compared between bevacizumab users (study group) and non-users (control group).. After matching, the study group (n=52) and control group (n=104) showed similar baseline clinicopathologic characteristics including platinum-free interval (median (range) 15.3 (6.2-87.3) vs 14.0 (6.2-143.5) months; p=0.29) and patient age at the time of first recurrence (median (range) 55.5 (33.7-72.4) vs 55.0 (35.7-84.2) years; p=0.56). Initially, FIGO stage III disease was the most common in both two groups (55.8% vs 66.3%; p=0.20). Bevacizumab users were less likely to develop disease recurrence in the retroperitoneal lymph nodes (13.5% vs 34.6%; p=0.005), pelvis (17.3% vs 35.6%; p=0.018), and abdomen (40.4% vs 61.5%; p=0.012). However, no difference in distant metastasis was observed between the groups (23.1% vs 24.0%; p>0.99). Multivariate analyses adjusting for stage, histologic type, grade, platinum-free interval, and secondary debulking surgery revealed that the use of bevacizumab significantly reduced risks of nodal (adjusted HR (aHR) 0.24; 95% CI 0.10 to 0.56; p=0.001), pelvic (aHR 0.32; 95% CI 0.15 to 0.68; p=0.003), and abdominal recurrences (aHR 0.43; 95% CI 0.26 to 0.71; p=0.001). Nevertheless, use of bevacizumab did not influence risk of distant metastasis (aHR 0.70; 95% CI 0.35 to 1.40; p=0.32).. In patients with platinum-sensitive, recurrent epithelial ovarian cancer, second-line chemotherapy with bevacizumab is associated with reduced risks of nodal, pelvic, and abdominal recurrences, but similar risks of distant metastases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carboplatin; Carcinoma, Ovarian Epithelial; Cisplatin; Cohort Studies; Deoxycytidine; Docetaxel; Female; Gemcitabine; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Retrospective Studies; Topotecan

To compare the efficacy and toxicity between topotecan- and belotecan-based chemotherapies in recurrent epithelial ovarian cancer (EOC).. The clinical data of 80 patients treated with topotecan- (n = 45) or belotecan- (n = 35) based chemotherapy as at least a second-line chemotherapy were reviewed retrospectively between July 2001 and December 2007. Response was evaluated using the Response Evaluation Criteria in Solid Tumours (RECIST) and serum CA-125 levels. Hematological toxicity was examined according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. Time to progressive disease (TTPD), chemotherapy-specific survival (CSS) and overall survival (OS) according to the 2 chemotherapies were evaluated by the Kaplan-Meier analysis with the log-rank test.. Overall response rate (ORR) was 24.4% in patients treated with topotecan-based chemotherapy, while it was 45.7% in those treated with belotecan-based chemotherapy (P = 0.046). Moreover, ORR was higher in platinum-sensitive patients treated with belotecan-based chemotherapy (58.8%) than those treated with topotecan-based chemotherapy (22.2%) (P = 0.041) although it was not significantly different in platinum-resistant patients (P = 0.471). Grade 3 or 4 anemia, neutropenia and thrombocytopenia developed in 14.8% vs 3.6%, 43.1% vs 55.6%, and 20.0% vs 12.8% of cycles in topotecan- and belotecan-based chemotherapies, respectively (P < 0.05). There were no significant difference in survival between the 2 chemotherapies.. In our experience, belotecan-based chemotherapy seemed to be efficient with acceptable toxicity, compared to topotecan-based chemotherapy in recurrent EOC. However, randomized controlled trials are required for the comparison of the efficacy and toxicity between topotecan- and belotecan-based chemotherapies in recurrent EOC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Cisplatin; Epithelium; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Retrospective Studies; Survival Analysis; Topotecan

This study evaluated the efficacy and toxicity of belotecan (CKD-602), a new camptothecin analogue topoisomerase i inhibitor, in patients with recurrent or refractory epithelial ovarian cancer. Data from 63 patients who had been treated with intravenous belotecan (0.5 mg/m(2)/day), administered for 5 days every 3 weeks at a single institute in Seoul, Korea, were collected retrospectively. The overall response rate was 30.2% including 9 patients with complete remission (CR) and the progression free survival was a median of 6.5 (0.7 - 29.7) months. The platinumsensitive group had a significantly higher response rate and longer progression-free survival more than the platinum-resistant group. The most common adverse effect of belotecan was hematologic toxicity which was tolerable. As a single chemotherapy agent, belotecan was effective in treating recurrent or refractory epithelial ovarian cancer, and had acceptable toxicity. Further studies of the efficacy of belotecan in combination with platinum or the other agents are warranted.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Salvage Therapy; Survival Rate; Topoisomerase I Inhibitors; Treatment Outcome