Hiroko Machida

Intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer: association for pathological factors and oncologic outcomes

To examine the association between intrauterine manipulator use and pathological factors and oncologic outcomes in patients with endometrial cancer who had laparoscopic hysterectomy in Japan. This was a nationwide retrospective cohort study of the tumor registry of the Japan Society of Obstetrics and Gynecology. Study population was 3846 patients who had laparoscopic hysterectomy for endometrial cancer from January 2015 to December 2017. An automated 1-to-1 propensity score matching with preoperative and intraoperative demographics was performed to assess postoperative pathological factors associated with the intrauterine manipulator. Survival outcomes were assessed by accounting for possible pathological mediators related to intrauterine manipulator use. Most patients had preoperative stage I disease (96.5%) and grade 1-2 endometrioid tumors (81.9%). During the study period, 1607 (41.8%) patients had intrauterine manipulator use and 2239 (58.2%) patients did not. In the matched cohort, the incidences of lymphovascular space invasion in the hysterectomy specimen were 17.8% in the intrauterine manipulator group and 13.3% in the non-manipulator group. Intrauterine manipulator use was associated with a 35% increased odds of lymphovascular space invasion (adjusted odds ratio 1.35, 95% confidence interval (CI) 1.08 to 1.69). The incidences of malignant cells identified in the pelvic peritoneal cytologic sample at hysterectomy were 10.8% for the intrauterine manipulator group and 6.4% for the non-manipulator group. Intrauterine manipulator use was associated with a 77% increased odds of malignant peritoneal cytology (adjusted odds ratio 1.77, 95% Cl 1.29 to 2.31). The 5 year overall survival rates were 94.2% for the intrauterine manipulator group and 96.6% for the non-manipulator group (hazard ratio (HR) 1.64, 95% Cl 1.12 to 2.39). Possible pathological mediators accounted HR was 1.36 (95%Cl 0.93 to 2.00). This nationwide analysis of predominantly early stage, low-grade endometrial cancer in Japan suggested that intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer may be associated with an increased risk of lymphovascular space invasion and malignant peritoneal cytology. Possible mediator effects of intrauterine manipulator use on survival warrant further investigation, especially with a prospective setting.

Trend and characteristics of minimally invasive surgery for patients with endometrial cancer in Japan

Owing to the potential benefits of minimally invasive hysterectomy for endometrial cancer, the practice pattern has recently shifted in Japan. This study examined the trends in minimally invasive surgery (MIS) in patients with endometrial cancer in Japan. This retrospective observational study examined the Japan Society of Obstetrics and Gynecology Tumor Registry database between 2015-2019. This study examined the time-specific proportion change and predictors of MIS use in initial endometrial cancer treatment in Japan, and compared it with the use of abdominal surgery. Additionally, the association between hospital surgical treatment volume and MIS use was examined. A total of 14,059 patients (26.5%) underwent minimally invasive hysterectomy, and 39,070 patients (73.5%) underwent abdominal hysterectomy in the study period. Patients who underwent MIS were more likely to be treated at high-volume centers, younger, central, or western Japan residents, registered in recent years, and had a tumor with stage I disease, type 1 histology, and less myometrial invasion (all adjusted p<0.05). The proportion of MIS treatments increased from 19.1% in 2015 to 34.3% in 2019 (p<0.001). On multivariable analysis, treatment at high-volume centers was a contributing factor for MIS (adjusted odds ratio=3.85; 95% confidence interval=3.44-4.30). MIS at high-volume centers increased significantly from 24.8% to 41.0% (p<0.001) during the study period, whereas MIS at low-volume centers remained at median 8.8%. MIS has increased significantly in recent years, accounting for nearly 34% of surgical management of endometrial cancer in Japan. High-volume treatment centers take the lead in performing MIS.

Effects of a fertility-sparing re-treatment for recurrent atypical endometrial hyperplasia and endometrial cancer: a systematic literature review

To examine the effectiveness of progestin re-treatment for recurrent endometrial intraepithelial neoplasia (EIN), atypical endometrial hyperplasia (AH) and endometrial cancer (EC) following initial fertility-sparing treatment. A comprehensive systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Endometrial Cancer Committee. Multiple search engines, including PubMed/MEDLINE and the Cochrane Database, were searched in December 2021 using the keywords "Endometrial neoplasms," "Endometrial hyperplasia," "Endometrial intraepithelial neoplasia," "Fertility preservation," "Progestins," AND "Recurrence." Cases describing progestin re-treatment for recurrent EIN, AH and EC were compared with cases that underwent conventional hysterectomy. The primary outcomes were survival and disease recurrence, and the secondary outcome was pregnancy. After screening 238 studies, 32 with results for recurrent treatment were identified. These studies included 365 patients (270 received progestin re-treatment and 95 underwent hysterectomy). Most progestin re-treatment involved medroxyprogesterone acetate or megestrol acetate (94.5%). Complete remission (CR) following progestin re-treatment was achieved in 219 (81.1%) cases, with 3-, 6- and 9-month cumulative CR rates of 22.8%, 51.7% and 82.6%, respectively. Progestin re-treatment was associated with higher risk of disease recurrence than conventional hysterectomy was (odds ratio [OR]=6.78; 95% confidence interval [CI]=1.99-23.10), and one patient (0.4%) died of disease. Fifty-one (14.0%) women became pregnant after recurrence, and progestin re-treatment demonstrated a possibility of pregnancy (OR=2.48; 95% CI=0.94-6.58). This meta-analysis suggests that repeat progestin therapy is an effective option for women with recurrent EIN, AH and EC, who wish to retain their fertility.

Diagnosis-shift between low-grade serous ovarian cancer and serous borderline ovarian tumor: A population-based study

To determine changes in the characteristics of low-grade serous ovarian cancer (LGSOC) and serous borderline ovarian tumor (serous-BOT) in a time-specific manner. We conducted a population-based retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2000. Trends, demographics, and outcomes of 775 women with well-differentiated serous ovarian cancer, used as a surrogate for LGSOC, were compared to 3937 women with serous-BOT. In the multivariable analysis, women with LGSOC were more likely to be older, have stage II-IV disease, and have undergone hysterectomy at surgery, but less likely to be a Western U.S. resident compared to those with serous-BOT (all, adjusted-P < 0.05). During the study period, the number of LGSOCs decreased by 25.9%, particularly stage I disease (37.6% relative decrease) compared to stage II-IV disease (21.1% relative decrease) (all, P < 0.05). With a median follow-up of 16.9 years, there was a decreasing trend in the 15-year overall survival rates among LGSOC (28.7% relative decrease, P = 0.056) but not in serous-BOT (2.5% relative increase, P = 0.416) as a whole cohort. The magnitude of hazard risk from all-cause death for women with LGSOC compared to those with serous-BOT increased by 68.9% from 1988 to 2000 (P < 0.001). LGSOC remained an independent prognostic factor for decreased overall survival compared to serous-BOT (adjusted-P < 0.05). Our study suggests that the decreasing number and survival of LGSOC over time may be due to a diagnosis-shift from LGSOC to serous-BOT. Given the distinct characteristics and outcomes of LGSOC compared to serous-BOT, our study endorses the importance of making the correct diagnosis upfront. Whether this diagnostic-shift supports a hypothesis that serous-BOT is a precursor lesion of LGSOC merits further investigation.

Evolving population-based statistics for rare epithelial ovarian cancers

To describe how population-based statistics for rare epithelial ovarian cancers are evolving. This is a retrospective observational study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2016. Overall survival (OS) of clear cell (OCCC), mucinous (MOC), and low-grade serous (LGSOC) ovarian cancers were compared to high-grade serous ovarian cancer (HGSOC) by fitting a propensity score matching. Among 113,365 ovarian malignancies, 5780 OCCCs (5.1%), 7561 MOCs (6.7%), and 2021 LGSOCs (1.8%) were compared to 38,199 HGSOCs. OCCCs and MOCs were more likely to be diagnosed with stage I disease compared to HGSOC (57.0-59.5% versus 8.6%, P<0.001). For early-stage disease, OCCC (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.82-1.01) and MOC (HR 0.94, 95%CI 0.85-1.04) had similar OS to HGSOC whereas LGSOC had superior OS (HR 0.93, 95%CI 0.89-0.97) versus HGSOC. Conversely, for advanced-stage disease, OCCC (HR 1.42, 95%CI 1.32-1.53) and MOC (HR 1.11, 95%CI 1.09-1.13) had poorer OS whereas LGSOC (HR 0.86, 95%CI 0.84-0.89) had superior OS compared to HGSOC. OCCC (HR range, 1.92-2.45) and MOC (HR range, 1.73-2.22) had particularly poorer OS in the first three years following diagnosis compared to HGSOC. Population-level statistics for advanced-stage disease showed that 5-year OS rates have increased in HGSOC (16.9% to 36.8%, P<0.001) and LGSOC (50.8% to 66.4%, P=0.010); but remain unchanged for OCCC (21.0% to 28.2%, P=0.174) and MOC (21.4% to 16.5%, P=0.102). OCCC, MOC, and LGSOC comprise 2-7% of ovarian malignancies, have distinct characteristics and survival compared to HGSOC. While these rare tumors have a favorable to comparable prognosis in early-stage disease, disproportionally poor survival in advanced-stage OCCC and MOC highlights the need for further research into novel treatment strategies.

Fertility-sparing trachelectomy for early-stage cervical cancer: A proposal of an ideal candidate

To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged <45 years with clinical stage I-II cervical cancer who had planned fertility-sparing trachelectomy and pelvic lymphadenectomy between 2009 and 2013 (n = 393). Ideal candidates were defined to have a tumor size of ≤2 cm, no lymph node metastasis, no deep stromal invasion, and no high-risk histology (n = 284, 69.6%). Less-ideal candidates were defined to have any one of these four characteristics (n = 109, 30.4%). Propensity score inverse probability of treatment weighting was used to assess survival outcomes. Less-ideal candidates were more likely to undergo hysterectomy conversion (22.9% versus 3.2%), receive postoperative radiotherapy (11.9% versus 0.4%), or chemotherapy (32.1% versus 3.2%) compared with ideal candidates (all, P < 0.05). The weighted model revealed that among those who underwent trachelectomy (ideal candidates, n = 275 and less-ideal candidates, n = 84), less-ideal candidates had significantly decreased disease-free survival (5-year rates: 85.5% versus 95.5%; HR 3.93, 95% CI 1.99-7.74; P < 0.001) and cause-specific survival (92.5% versus 98.6%; HR 5.47, 95% CI 1.68-17.8, P = 0.001) compared with ideal candidates. Similarly, less-ideal candidates were significantly associated with decreased disease-free survival compared with ideal candidates among those who were young age, had small tumors or squamous histology, and underwent surgery alone (all, P < 0.05). Less-ideal candidates had approximately four-fold higher recurrence risk and cancer mortality compared with ideal candidates. Ideal candidates for fertility-sparing trachelectomy for early-stage cervical cancer proposed in our study may be useful as the future framework for developing guidelines for fertility-sparing trachelectomy in Japan.

Association between hospital treatment volume and survival of women with gynecologic malignancy in Japan: a JSOG tumor registry-based data extraction study

Associations between hospital treatment volume and survival outcomes for women with 3 types of gynecologic malignancies, and the trends and contributing factors for high-volume centers were examined. The Japan Society of Obstetrics and Gynecology tumor registry databased retrospective study examined 206,845 women with 80,741, 73,647, and 52,457 of endometrial, cervical, and ovarian tumor, respectively, who underwent primary treatment in Japan between 2004 and 2015. Associations between the annual treatment volume and overall survival (OS) for each tumor type were examined using a multivariable Cox proportional hazards model with restricted cubic splines. Institutions were categorized into 3 groups (low-, moderate-, and high-volume centers) based on hazard risks. Hazard ratio (HR) for OS each the 3 tumors decreased with hospital treatment volume. The cut-off points of treatment volume were defined for high- (≥50, ≥51, and ≥27), moderate- (20-49, 20-50, and 17-26), and low-volume centers (≤19, ≤19, and ≤16) by cases/year for endometrial, cervical, and ovarian tumors, respectively. Multivariate analysis revealed younger age, rare tumor histology, and initial surgical management as contributing factors for women at high-volume centers (all, p<0.001). The proportion of high-volume center treatments decreased, whereas low-volume center treatments increased (all p<0.001). Treatment at high-volume centers improved OS than that at other centers (adjusted HR [aHR]=0.83, 95% confidence interval [CI]=0.78-0.88; aHR=0.78, 95% CI=0.75-0.83; and aHR=0.90, 95% CI=0.86-0.95 for endometrial, cervical, and ovarian tumors). Hospital treatment volume impacted survival outcomes. Treatments at high-volume centers conferred survival benefits for women with gynecologic malignancies. The proportion of treatments at high-volume centers have been decreasing recently.

Comparison of treatment outcomes of surgery and radiotherapy, including concurrent chemoradiotherapy for stage Ib2-IIb cervical adenocarcinoma patients: a retrospective study

The study compared the treatment outcomes of surgery versus radiotherapy, including concurrent chemoradiotherapy, in stage Ib2-IIb cervical adenocarcinoma patients in Japan. Of 57,470 patients diagnosed with stage I-IV cervical cancer from January 2001-December 2011, 1,932 patients with stage Ib2-IIb cervical adenocarcinoma were initially treated by surgery or radiotherapy. The primary endpoint was 5-year overall survival (OS) in all and 614 propensity score-matched (PSM) patients (307 per group). We compared OS and prognosis factors based on age, primary stage, and treatment arm. In Japan, >80% (n=1,573) of stage Ib2-IIb cervical adenocarcinoma patients underwent surgery. The 5-year OS of surgery vs. radiotherapy groups were 82.1% (n=704) vs. 79.7% (n=59) (hazard ratio [HR]=1.494; 95% confidence interval [CI]=0.826-2.702; p=0.181) for stage Ib2, 76.6% (n=239) vs. 66.7% (n=54) (HR=1.679; 95% CI=0.986-2.858; p=0.053) for stage IIa, and 71.1% (n=630) vs. 58.9% (n=246) (HR=1.711; 95% CI=1.341-2.184; p65 years), treatment arm (radiotherapy), and stage IIb significantly affect OS in cervical adenocarcinoma patients. Surgery may be considered for <65-year-old patients with stage IIb adenocarcinoma.

Significance of histology and nodal status on the survival of women with early-stage cervical cancer: validation of the 2018 FIGO cervical cancer staging system

To assess the efficacy of the FIGO 2018 classification system for nodal-specific classifications for early-stage cervical cancer; specifically, to examine the impact of nodal metastasis on survival and the effect of postoperative treatments, according to histological subtypes. This society-based retrospective observational study in Japan examined 16,539 women with the 2009 FIGO stage IB1 cervical cancer who underwent primary surgical treatment from 2004 to 2015. Associations of cause-specific survival (CSS) with nodal metastasis and postoperative adjuvant therapy were examined according to histology type (squamous cell carcinoma [SCC], n=10,315; and non-SCC, n=6,224). The nodal metastasis rate for SCC was higher than that for non-SCC (10.7% vs. 8.3%, p<0.001). In multivariable analysis, the impact of nodal metastasis on CSS was greater for non-SCC tumors (adjusted-hazard ratio [HR], 3.11; 95% confidence interval [CI], 2.40-4.02) than for SCC tumors (adjusted-HR, 2.20; 95% CI, 1.70-2.84; p<0.001). Propensity score matching analysis showed significantly lower CSS rates for women with pelvic nodal metastasis from non-SCC tumors than from SCC tumors (5-year CSS rate, 75.4% vs. 90.3%, p<0.001). The CSS rates for women with nodal metastasis in SCC histology were similar between the postoperative concurrent chemoradiotherapy/radiotherapy and chemotherapy groups (89.2% vs. 86.1%, p=0.42), whereas those in non-SCC histology who received postoperative chemotherapy improved the CSS (74.1% vs. 67.7%, p=0.043). The node-specific staging system in the 2018 FIGO cervical cancer classification is applicable to both non-SCC tumors and SCC tumors; however, the prognostic significance of nodal metastases and efficacy of postoperative therapies vary according to histology.

Validation of the 2023 FIGO staging system and its concordance with the JSGO guidelines in endometrial cancer: A multi‐institutional retrospective study in Japan

Abstract Aim To validate the prognostic accuracy of the 2023 FIGO staging system and assess its alignment with the Japan Society of Gynecologic Oncology (JSGO) guidelines for endometrial cancer treatment. Methods This retrospective cohort study included 1207 patients with endometrial cancer treated at four academic hospitals in Kanagawa, Japan, between 2018 and 2022. Patients were reclassified according to the FIGO 2023 system and the JSGO recurrence risk categories. Primary endpoints included stage migration, recurrence risk (RR), overall survival (OS), and concordance between the two classification systems. Results Under FIGO 2023, the stage distribution was: I, 741 (61.4%); II, 203 (16.8%); III, 149 (12.3%); and IV, 114 (9.4%), with stage migration observed in 36.3% of cases. The FIGO 2023 system provided clearer stratification of 3‐year RR than FIGO 2009, with the RR gap widening from 80.0% to 90.1%. Sixteen patients (3.5%) with stage IA3 were classified as high risk by JSGO criteria, while 14.4% of patients considered high risk by JSGO were downstaged under FIGO 2023. Additionally, 46 patients (19.6%) with FIGO stage IA were reclassified as intermediate risk owing to focal lymphovascular space invasion (LVSI). Substantial LVSI was significantly associated with recurrence and poor prognosis (3‐year OS rates: none 94.3%, focal 89.9%, and substantial 40.7%; p  &lt; 0.05). Molecular testing was limited: p53 in 30.2%, MSI in 5.9%, and POLE was not available. Conclusions FIGO 2023 improves prognostic precision. Incorporating LVSI extent and molecular data may refine JSGO classifications and support more individualized adjuvant therapy strategies.

Cost-effectiveness analysis of hospital treatment volume and survival outcomes in endometrial cancer in Japan

Hospital treatment volume affects survival in patients with endometrial cancer; notably, initial treatment at high-volume centers improves survival outcomes. Our study assessed the effect of hospital treatment volume on cost-effectiveness and survival outcomes in patients with endometrial cancer in Japan. A decision-analytic model was evaluated using the following variables and their impact on cost-effectiveness: 1) hospital treatment volume (low-, intermediate-, and high-volume centers) and 2) postoperative recurrent risk factors based on pathological findings (high- and intermediate-risk or low-risk). Data were obtained from the Japan Society of Obstetrics and Gynecology database, systematic literature searches, and the Japanese Diagnosis Procedure Combination database. Quality-adjusted life years (QALY) was used as a measure of effectiveness. The model was built from a public healthcare perspective and the impact of uncertainty was assessed using sensitivity analyses. A base-case analysis showed that the incremental cost-effectiveness ratio at high-volume centers was below a willingness-to-pay (WTP) threshold of ¥5,000,000 with a maximum of ¥3,777,830/4.28 QALY for the high- and intermediate-risk group, and ¥2,316,695/4.57 QALY for the low-risk group. Treatment at the high-volume centers showed better efficiency and cost-effectiveness in both strategies compared to intermediate- or low-volume centers. Sensitivity analyses showed that the model outcome was robust to changes in input values. With the WTP threshold, treatment at high-volume centers remained cost-effective in at least 73.6% and 78.2% of iterations for high- and intermediate-risk, and low-risk groups, respectively. Treatment at high-volume centers is the most cost-effective strategy for guiding treatment centralization in patients with endometrial cancer.