belotecan and Carcinoma--Ovarian-Epithelial

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 prospectively correlate clinical responses to second-line chemotherapy for recurrent epithelial ovarian cancer (EOC) with in vitro integrative tumor-response assay (ITRA) results.. Forty-four patients with advanced EOC were enrolled from 2015-2017 at the Asan Medical Center, Seoul, Korea. ITRA comprised of two sequential histoculture drug response assays (HDRAs) of the tumor tissues. The first stage was HDRA with paclitaxel-carboplatin, paclitaxel, and carboplatin chemotherapy. The second stage was performed with surviving tumor cells from the first stage using topotecan, belotecan, gemcitabine, doxorubicin, ifosfamide, vinorelbine, and etoposide.. The median follow-up period was 23.35 (range=4-35.35) months. Eighteen patients (40.9%) completed the second-line chemotherapy, based on the ITRA results. The objective response rate was 38.9%. The clinical response rate was 50%; two patients (11.1%) had stable disease. The sensitivity of ITRA for predicting response was 85.7% (specificity=18.2%; accuracy=44.44%).. ITRAs had acceptable applicability and may help choose second-line chemotherapy for patients with advanced EOC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carboplatin; Carcinoma, Ovarian Epithelial; Doxorubicin; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Republic of Korea; Topotecan