Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE.Trial Registration: JRCT Identifier: jRCTs031180124

In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005–2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progressionfree survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55–4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20–8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs.50.6%, aHR=4.54, 95% CI=2.60–7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.

Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE.Trial Registration: JRCT Identifier: jRCTs031180124

In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005–2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progressionfree survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55–4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20–8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs.50.6%, aHR=4.54, 95% CI=2.60–7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.

Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE.Trial Registration: JRCT Identifier: jRCTs031180124

In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005–2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progressionfree survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55–4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20–8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs.50.6%, aHR=4.54, 95% CI=2.60–7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.

The fifth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was published in 2020. The guidelines contain 6 chapters—namely, (1) overview of the guidelines; (2) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (4) borderline epithelial tumors of the ovary; (5) malignant germ cell tumors of the ovary; and (6) malignant sex cord-stromal tumors. Furthermore, the guidelines comprise 5 algorithms—namely, (1) initial treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (2) treatment for recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) initial treatment for borderline epithelial ovarian tumor; (4) treatment for malignant germ cell tumor; and (5) treatment for sex cord-stromal tumor. Major changes in the new edition include the following: (1) revision of the title to “guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer”; (2) involvement of patients and general (male/female) participants in addition to physicians, pharmacists, and nurses; (3) clinical questions (CQs) in the PICO format; (4) change in the expression of grades of recommendation and level of evidence in accordance with the GRADE system; (5) introduction of the idea of a body of evidence; (6) categorization of references according to research design; (7) performance of systematic reviews and meta-analysis for three CQs; and (8) voting for each CQ/recommendation and description of the consensus.

Objectives: This review aims to introduce preoperative scoring systems to predict lymph node metastasis (LNM) and ongoing clinical trials to investigate the therapeutic role of lymphadenectomy for endometrial cancer. Methods: We summarized previous reports on the preoperative prediction models for LNM and evaluated their validity to omit lymphadenectomy in our recent cohorts. Next, we compared characteristics of two ongoing lymphadenectomy trials (JCOG1412, ECLAT) to examine the survival benefit of lymphadenectomy in endometrial cancer, and described the details of JCOG1412. Results: Lymphadenectomy has been omitted for 64 endometrial cancer patients who met lowrisk criteria to omit lymphadenectomy using our scoring system (LNM score) and no lymphatic failure has been observed. Other two models also produced comparable results. Two randomized phase III trials to evaluate survival benefit of lymphadenectomy are ongoing for endometrial cancer. JCOG1412 compares pelvic lymphadenectomy alone with pelvic and para-aortic lymphadenectomy to evaluate the therapeutic role of para-aortic lymphadenectomy for patients at risk of LNM. For quality assurance of lymphadenectomy, we defined several regulations, including lower limit of the number of resected nodes, and submission of photos of dissected area to evaluate thoroughness of lymphadenectomy in the protocol. The latest monitoring report showed that the quality of lymphadenectomy has been well-controlled in JCOG1412. Conclusion Our strategy seems reasonable to omit lymphadenectomy and could be generalized in clinical practice. JCOG1412 is a high-quality lymphadenectomy trial in terms of the quality of surgical procedures, which would draw the bona-fide conclusions regarding the therapeutic role of lymphadenectomy for endometrial cancer.

Objective: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1. Methods: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint). Results: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11–1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16–2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab. Conclusion: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer.

Objective: To assess the effectiveness of lymphadenectomy at primary debulking surgery (PDS) on the survival of patients with epithelial ovarian cancer (EOC). Methods: We searched PubMed, Ichushi, and the Cochrane Library. Randomized controlled trials (RCTs) and retrospective cohort studies comparing survival of women with EOC undergoing lymphadenectomy at PDS with that of women without lymphadenectomy were included. We performed a meta-analysis of overall survival (OS), progression-free survival (PFS), and adverse events. Results: For advanced-stage EOC, 2 RCTs including 1,074 women and 7 cohort studies comprising 3,161 women were evaluated. Meta-analysis revealed that lymphadenectomy was associated with improved OS (hazard ratio [HR]=0.80; 95% confidence interval [CI]=0.70– 0.90). However, meta-analysis of 2 RCTs revealed no significant difference in OS between the lymphadenectomy and no-lymphadenectomy groups (OS: HR=1.02; 95% CI=0.85–1.22).For early-stage EOC, 1 RCT comprising 268 women and 4 cohort studies comprising 14,228 women were evaluated. Meta-analysis showed that lymphadenectomy was associated with improved OS (HR=0.75; 95% CI=0.68–0.82). A RCT of early-stage EOC reported that lymphadenectomy was not associated with improved OS (HR=0.85; 95% CI=0.49–1.47).Surgery-related deaths were similar in both groups (risk ratio [RR]=1.00; 95% CI=0.99–1.01);however, blood transfusion was required less frequently in the no-lymphadenectomy group (RR=0.74; 95% CI=0.63–0.86). Conclusions Meta-analysis of RCTs and observational studies suggest that lymphadenectomy was associated with improved OS in advanced- and early-stage EOC.However, results from RCTs demonstrate that lymphadenectomy was not associated with improved OS in advanced- and early-stage EOC.