Comparison of Outcomes in Bowel Resections by Gynecologic Oncologists Versus General Surgeons During Maximal Cytoreductive Surgery for Advanced Ovarian Cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA-3006).

BACKGROUND: This report describes the oncologic outcomes for patients with advanced ovarian cancer who had bowel surgery performed by gynecologic oncologists (GOs) and compares the outcomes with those for bowel surgery performed by general surgeons (GSs) during maximal cytoreductive surgery. METHODS: Patients from six academic institutions who had FIGO stage III or IV ovarian cancer and underwent any bowel surgeries during maximal cytoreductive surgery were eligible for the study. The patients were divided into two groups according to whether bowel surgery was performed by a GO or a GS. In both groups, the GOs were mainly involved in extra bowel debulking procedures. Perioperative and survival outcomes were compared between the two groups. RESULTS: The 761 patients in this study included 113 patients who underwent bowel surgery by a GO and 648 who had bowel surgery by a GS. No discernible differences were observed in age, American Society of Anesthesiology (ASA) score, FIGO stage, histologic type, timing of cytoreductive surgery (primary or interval debulking surgery), or complications between the two groups. The GO group exhibited a shorter operation time than the GS group. Kaplan-Meier analysis showed no survival differences between the two groups. In the Cox analysis, non-serous cell types and gross residual diseases were associated with adverse effects on overall survival. However, performance of bowel surgery by a GO did not have an impact on survival. CONCLUSION: Performance of bowel surgery by a GO during maximal cytoreductive surgery is both feasible and safe. These results should be reflected in the training system for GOs regarding bowel surgery, and further research is needed to confirm that GOs can play a more leading role in performing extra-uterine procedures.

Is minimally invasive radical surgery safe for patients with cervical cancer ≤2 cm in size? (MISAFE): Gynecologic Oncology Research Investigators coLLborAtion study (GORILLA-1003).

OBJECTIVE: To identify clinicopathological factors associated with disease recurrence for patients with 2018 FIGO stage IA with lymphovascular invasion to IB1 cervical cancer treated with minimally invasive surgery (MIS). METHODS: A total of 722 patients with cervical cancer between January 2010 and February 2021 were identified. Clinicopathological factors related to disease recurrence were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. To determine prognostic factors for DFS, a Cox proportional hazard regression model was used. RESULTS: Of 722 patients, 49 (6.8%) experienced disease recurrence (37 pelvis, 1 para-aortic lymph node, and 11 peritoneum). Five-year DFS and OS rates were 90.7% and 98.1%, respectively. In multivariate analysis, risk factors associated with disease recurrence were residual disease in the remaining cervix (OR, 3.122; 95% CI, 1.152-8.461; p = 0.025), intracorporeal colpotomy (OR, 3.252; 95% CI, 1.507-7.017; p = 0.003), and positive resection margin (OR, 3.078; 95% CI, 1.031-9.193; p = 0.044). The non-conization group had a higher percentage of stage IB1 (77.4% vs. 64.6%; p = 0.004) and larger tumor (10 mm vs. 7 mm; p < 0.001) than the conization group. Intracorporeal colpotomy and residual disease in the remaining cervix were independent variables associated with disease recurrence in patients undergoing MIS following conization. CONCLUSION: During MIS, patients with cervical cancer ≤2 cm in size can be vulnerable to peritoneal recurrences. Patients diagnosed with invasive cancer through conization often have low-risk pathological features, which may affect their survival outcomes.

Fertility-sparing hormonal treatment in patients with stage I endometrial cancer of grade 2 without myometrial invasion and grade 1-2 with superficial myometrial invasion: Gynecologic Oncology Research Investigators coLLaborAtion study (GORILLA-2001).

OBJECTIVES: To evaluate oncologic and pregnancy outcomes of fertility-sparing treatment (FST) using progestin in patients with stage I grade 2 endometrioid endometrial cancer (EC) without myometrial invasion (MI) or grade 1-2 with superficial MI. METHODS: Multicenter data of patients with stage I grade 2 EC without MI or grade 1-2 EC with superficial MI, who received FST between 2005 and 2021, were analyzed. Cox regression analysis identified independent factors for progressive disease (PD) during the FST. RESULTS: Altogether, 54 patients received FST [medroxyprogesterone acetate (500-1000 mg) in 44, megestrol acetate (40-800 mg) in 10] with concurrent levonorgestrel-releasing intrauterine devices use in 31. With median time to achieve a complete response (CR) of 10 (3-24) months, 39 patients (72.2%) achieved CR. Of the 15 patients who attempted to conceive after achieving CR, 7 (46.7%) became pregnant (2 abortions, 5 live births). During a median FST duration of 6 (3-12) months, nine patients (16.6%) were diagnosed with PD. Fifteen (38.5%) experienced recurrence with a median recurrence-free survival of 23 (3-101) months. In the multivariable analysis, tumor size before FST ≥2 cm (HR 5.456, 95% CI 1.34 to 22.14; p = 0.018) was significantly associated with a high PD rate during FST. CONCLUSION: The overall response rate to FST was promising, however, the PD rate was significant during the first 12 months of FST. Therefore, performing thorough endometrial biopsy and imaging studies is essential to strictly evaluate the extent of the disease every 3 months from FST initiation.

Optimum selection criteria for secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer: A multicenter study from the Gynecologic Oncology Research Investigators coLLaborAtion group (GORILLA-3001).

BACKGROUND: To identify those most likely to benefit from secondary cytoreductive surgery (SCS), we evaluated the survival outcomes and factors predictive of prognosis in patients with recurrent ovarian cancer. METHODS: We retrospectively reviewed the medical records of patients with recurrent ovarian cancer treated at five high-volume Korean hospitals between 2010 and 2021. Recurrence characteristics, treatment methods, and potential predictors of survival were compared between the chemotherapy and surgery groups. RESULTS: Among all 670 patients, 88.1% had initial stage III/IV disease, and 215 (32.1%) underwent SCS. Among patients who underwent SCS, only those who achieved complete resection exhibited improved survival. Even in patients with residual disease < 1 cm after SCS, we observed no significant survival benefit (p = 0.942). In the multivariate Cox analysis, residual disease at primary surgery, progression-free interval, recurrence sites (≤3 regions or limited carcinomatosis), ascites, and SCS were significant predictors of survival. Meanwhile, the only factor predictive of complete resection after SCS was recurrence sites (p < 0.001). CONCLUSIONS: The benefits of SCS appear to be exclusive to cases of complete resection. We propose limited regional platinum-sensitive recurrence (≤3 regions or limited carcinomatosis) without ascites as the optimum selection criteria for SCS.

Risk of adverse obstetric outcomes in patients with a history of endometrial cancer: A nationwide population-based cohort study.

OBJECTIVE: To evaluate adverse obstetric outcomes in women with a history of endometrial cancer (EC). DESIGN: Population-based cohort study. SETTING: The Korean National Health Insurance (KNHI) claims database. POPULATION: Women who gave birth between 2009 and 2016, with a history of EC prior to pregnancy. METHODS: The KNHI database was used to compare obstetric outcomes of women with and without a history of EC, using the ICD-10 codes. Multivariable logistic regression models were used to determine the associations between a history of EC and adverse obstetric outcomes. MAIN OUTCOMES MEASURES: Adverse obstetric outcomes. RESULTS: Overall, 248 and 3 335 359 women with and without a history of EC, respectively, gave birth. When adjusted for age, primiparity and comorbidities, an increased risk of multiple gestations (odds ratio [OR] 4.925, 95% confidence interval [CI] 3.394-7.147), caesarean delivery (OR 2.005, 95% CI 1.535-2.62) and preterm birth (OR 1.941, 95% CI 1.107-3.404) was observed among women with a history of EC. We were unable to demonstrate significant differences in the risk of pre-eclampsia, gestational diabetes, vacuum delivery, placenta praevia, placenta accreta spectrum, placental abruption and postpartum haemorrhage between the groups. In the sensitivity analyses excluding multiple gestations, an increased risk of preterm birth was not observed among women with a history of EC (OR 1.276, 95% CI 0.565-2.881). CONCLUSIONS: There is no convincing evidence of an increased risk of adverse obstetric outcomes among women with a history of EC. Our findings would be useful in counselling of patients with EC who are undergoing fertility-sparing treatment.

Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047).

Through the wide adaptation of next-generation sequencing (NGS) technology within clinical practice, molecular profiling of the tumor has been the principal component of personalized treatment. In our study, we have generated a large collection of cancer genomes on East Asian epithelial ovarian carcinoma (EOC) patients and demonstrate the feasibility and utility of NGS platforms to explore the dynamic interrelations of major cancer driver alterations and their impacts on clinical prognosis and management. A total of 652 EOC patients have undergone clinical NGS panels to determine the prevalence of germline and somatic mutations. Notably, TP53 was the most frequently altered event (73%), followed by both BRCA1 and BRCA2 (22% each) and MYC (19%) through pan-EOC analysis. When analyzed based on individual histopathological levels, TP53 mutation was highly dominant in high-grade serous and mucinous histology, whereas mutations in PIK3CA and ARID1A were mostly observed in clear cell carcinoma, and KRAS, BRAF, and CDKN2A mutations were enriched in endometrioid, low-grade serous, and mucinous tumors, respectively. The network-based probabilistic model showed significant co-occurrences of TP53 with BRCA1 and ALK with BRCA2, NOTCH1, and ROS1, whereas mutual exclusivity of TP53 with KRAS and PIK3CA was evident. Furthermore, we utilized machine-learning algorithms to identify molecular correlates that conferred increased sensitivity to platinum and olaparib treatments including somatic mutations in BRCA1, ATM, and MYC. Conversely, patients with ALK mutation were considerably resistant to both treatment modalities. Collectively, our results demonstrate the clinical feasibility of prospective genetic sequencing to facilitate personalized treatment opportunities for patients with EOC.

Gastrointestinal/genitourinary perforation and fistula formation with or without bevacizumab in patients with previously irradiated recurrent cervical cancer: a Korean multicenter retrospective study of the Gynecologic Oncology Research Investigators Collaboration (GORILLA) group (GORILLA-1001).

BACKGROUND: This study aims to evaluate the incidence of and identify risk factors for gastrointestinal (GI) and genitourinary (GU) fistula or perforation formation with or without bevacizumab in patients with recurrent cervical cancer who underwent pelvic radiation therapy (RT). METHODS: Medical records of patients with recurrent cervical cancer who previously underwent pelvic RT between 2007 and 2020 were retrospectively reviewed. Clinicopathological factors were compared between groups that are stratified according to: 1) fistula/perforation (+) versus (-); and 2) bevacizumab plus conventional chemotherapy (BC) versus chemotherapy alone (C). Univariate and multivariate regression analyses were performed to identify risk factors for fistula/perforation. Overall survival (OS) was compared between the different groups. RESULTS: Of 219 participants, fistula/perforation of any grade occurred in 36 patients (16.4%); 27 fistulas and 9 perforations. Bevacizumab was more frequently used in Bevacizumab was more frequently used ( +) group than fistula/perforation (-) group (p = 0.015). Multivariate analysis showed that bevacizumab administration was the only independent risk factor for fistula or perforation (HR, 3.27; 95% CI, 1.18-9.10; P = 0.023). F/P was observed more frequently in women receiving BC (n = 144) than those receiving C (n = 75) (20.8% vs. 8.0%; P = 0.019). During median follow-up of 33.7 months (1.2-185.6 months), no significant OS difference was observed between fistula/perforation ( +) vs. (-) (hazards ratio [HR], 1.78; median 84.2 months [95% CI, 59.3-109.0] vs. 129.5 months [95% CI, 114.1-144.9]; P = 0.065) or BC vs. C (HR, 1.03; median 119.8 months [95% CI, 97.3-142.3] vs. 115.7 months [95% CI, 96.0-135.4]; P = 0.928). CONCLUSIONS: This study suggests that incorporation of bevacizumab in chemotherapy regimens for treating recurrent cervical cancer in patients who underwent pelvic RT incurs considerable risk for GI/GU fistula or perforation. There were no other independent risk factors for developing GI/GU fistula or perforation in this study population.

Safety and efficacy study of laparoscopic or robotic radical surgery using an endoscopic stapler for inhibiting tumour spillage of cervical malignant neoplasms evaluating survival (SOLUTION): a multi-centre, open-label, single-arm, phase II trial protocol.

BACKGROUND: The Laparoscopic Approach to Cervical Cancer trial and Surveillance, Epidemiology, and End Results program database study demonstrated that minimally invasive radical hysterectomy was inferior to abdominal radical hysterectomy in terms of disease recurrence and survival. Among risk factors related to poor prognosis after minimally invasive surgery (MIS), tumour spillage during intracorporeal colpotomy became a significant issue. Thus, we designed this trial to evaluate the efficacy and safety of minimally invasive radical hysterectomy using an endoscopic stapler for early-stage cervical cancer. METHODS: This trial is a prospective, multi-centre, open-label, single-arm, non-inferiority phase II study. The nine organisations will participate in this trial after the approval of the institutional review board. Major eligibility criteria include women aged 20 years or older with cervical cancer stage IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma according to the revised 2009 FIGO staging system who will undergo type B2 or C hysterectomy by MIS. The primary endpoint is the 4.5-year disease-free survival (DFS) rate between abdominal radical hysterectomy and MIS using an endoscopic stapler. For calculating the sample size, we hypothesised that the 4.5-year DFS rate after MIS using an endoscopic stapler is assumed to be the same after abdominal radical hysterectomy at 90.9%, and the non-inferiority margin was 7.2%. When we consider a three-year accrual and 4.5-year follow-up, at least 13 events must happen, requiring a total of 111 patients assuming a statistical power of 80% and the one-tailed test of 5% significance. A total of 124 patients is needed, considering a drop-out rate of 10%. DISCUSSION: We expect intracorporeal colpotomy using an endoscopic stapler may prevent tumour spillage during MIS for stage IB1 cervical cancer, showing a comparable prognosis with abdominal radical surgery. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04370496 ; registration date, May 2020.

Minimally invasive surgery versus open surgery in high-risk histologic endometrial cancer patients: A meta-analysis.

OBJECTIVE: To compare the effects of minimally invasive surgery (MIS) and open surgery (OPS) on the risk of recurrence and mortality in patients with endometrial cancer (EC) of high-risk histology (grade 3 endometrioid adenocarcinoma, papillary serous carcinoma [PS], clear cell carcinoma [CC], and carcinosarcoma) using meta-analysis. MATERIAL AND METHODS: We systematically reviewed published studies comparing MIS and OPS in EC patients with high-risk histology until January 2022. The endpoints were recurrence and mortality rate. Study design features that may have affected participant selection, recurrence/death detection, and manuscript publication were assessed. For pooled estimates of the effect of MIS on recurrence/mortality, the random- or fixed-effects meta-analytical models were used after assessing the cross-study heterogeneity. RESULT: Nine observational studies (eight retrospective and one prospective) fulfilled our search criteria (MIS, 8877 patients; OPS, 5751 patients). The fixed-effects model-based meta-analysis indicated that MIS did not significantly increase the risk of recurrence (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.71-1.05; p = 0.13) and mortality (HR, 0.86; 95% CI, 0.79-0.93; p < 0.001) when compared with OPS. This pattern was also observed in the subgroup analyses based on the stage (early stage vs. all stage), histology (PS and CC), and MIS type (laparoscopy vs. robotic). There was no evidence of publication bias. CONCLUSION: This meta-analysis of observational studies revealed that MIS did not compromise the prognosis of EC patients with high-risk histology. Well-designed randomized controlled trials could verify the results of this uncommon but deadly tumor.

Retreatment with progestin for recurrence after complete response with fertility-sparing treatment in patients with endometrial cancer.

OBJECTIVE: To assess the outcomes of retreatment using progestin for recurrence after a complete response with fertility-sparing treatment in patients with early endometrial cancer. METHODS: We retrospectively reviewed the data of patients with presumed stage IA, grade 1 endometrioid endometrial cancer who developed intra-uterine recurrence after a complete response with fertility-sparing treatment using progestin. Oncological and pregnancy outcomes were analyzed after repeated fertility-sparing treatment. Logistic and Cox regression analyses were performed to analyze the prognostic factors associated with a complete response with secondary fertility-sparing treatment and recurrence-free survival after secondary fertility-sparing treatment, respectively. RESULTS: Fifty patients with a median age of 31 years (range 23-40) underwent secondary fertility-sparing treatment. With a median secondary progestin treatment duration of 9 months (range 3-55), the complete response rate was 78% (39/50) and no patients had extra-uterine spread of disease. Among the 26 (67%) patients who attempted to conceive after complete response, 10 became pregnant (3 spontaneous abortions, 7 live births). Eighteen (46.1%) patients had a second recurrence, with a median recurrence-free survival after secondary fertility-sparing treatment of 14 months (range 3-36); 15 patients received tertiary fertility-sparing treatment and nine (60%) achieved a complete response. Polycystic ovary on ultrasound (OR 5.82, 95% CI 1.1 to 30.6, p=0.037) was associated with an increased complete response rate with secondary fertility-sparing treatment. Multivariable analysis revealed that recurrence-free survival after initial hormonal treatment >6 months (HR 0.11, 95% CI 0.02 to 0.51, p=0.005) and pregnancy after secondary fertility-sparing treatment (HR 0.27, 95% CI 0.08 to 0.98; p=0.047) were significantly associated with longer recurrence-free survival after secondary fertility-sparing treatment. CONCLUSIONS: Repeated progestin treatment was associated with a 78% response rate and it was safe in patients with intra-uterine recurrent endometrial cancer. Thus, it might help preserve fertility after first and second recurrences.

Comparative performance of various human papillomavirus assays available in Korea for detecting cervical intraepithelial neoplasia.

AIM: The aim of this study was to evaluate the clinical performance for detecting cervical intraepithelial neoplasia (CIN) 2 or higher lesions among available human papillomavirus infection (HPV) genotyping tests in Korea. METHODS: Eligible patients visited 13 tertiary hospitals for colposcopic biopsy following cervical cytology and HPV genotyping test between January and December 2018. Baseline characteristics including age, body mass index (BMI), and parity were collected from 3798 patients. The performance of the Roche Cobas HPV 4800 was evaluated against other domestic HPV assays to detect CIN2 or higher. RESULTS: A total of seven types of HPV genotyping tests were analyzed in the research institutes. A total of 1358 patients (35.8%) tested Anyplex II HPV 28 and 701 patients (18.5%) tested Cobas 4800 HPV. The overall sensitivity in the detection of CIN2 or higher was 41.5% (38.9-44.1) in patients positive for HPV 16/18. The Cobas test for HPV 16/18 was concordant with other assays evaluated for detection of CIN2 or higher and showed sensitivity of 46.6%, which was not significantly different from other assays. Although Anyplex II HPV28 (Seegene) showed slightly decreased sensitivity for detecting CIN2 or higher lesion with HPV 16/18 positive (39.8%, p < 0.05) compared to Cobas 4800, in aspect of high-risk HPV positive, Anyplex II HPV28 showed increased sensitivity (96.9%, p < 0.05). CONCLUSION: The performance of the HPV genotype test that were commonly used in Korea was concordant with Cobas HPV test. Further studies are needed to evaluate the safety, efficiency, and cost-effectiveness of the various commercially available domestic HPV assays.

Optimal duration of fertility-sparing hormonal treatment for early-stage endometrioid endometrial cancer.

OBJECTIVES: To analyze the oncologic outcomes of long-term fertility-sparing treatment (FST) in patients with early-stage endometrial cancer (EC) and to determine the optimal duration of FST that would not hamper survival outcomes. METHODS: Patients undergoing FST for presumed stage IA, grade 1 EC between 2005 and 2018 were retrospectively analyzed. Oncologic outcomes were compared between the group with ≤6 months of FST and the group with >6 months of FST. Segmented regression analysis was used to estimate the dynamic changes in cumulative complete response (CR) rates according to FST duration. RESULTS: A total of 122 patients received oral progestin, with concurrent levonorgestrel-releasing intrauterine device use in 108 (88.5%) and 105 (86.1%) achieved CR with a median time to achieve CR of 10 (3-42) months. Of the patients not achieving CR at 6 months of FST, 95.1% (78/82) continued further FST. The overall CR rate (88.9% [32/36] vs. 84.9% [73/86], P = 0.436] was not significantly different between the groups with ≤6 and > 6 months of FST. The changes in cumulative CR rates were significantly different between the two segments divided by 15 months from the initial FST (P = 0.0015, segmented regression analysis). The overall progressive disease (PD) rate was 3.3% (4/122), and PD was first detected during 9-12 months of FST. CONCLUSION: Patients not achieving CR and not showing PD at 6 months of FST could continue further FST. If disease progression is excluded, 15 months of FST can be considered as the cutoff for the optimal FST duration.

Sarcopenia as a Predictor of Prognosis in Early Stage Ovarian Cancer.

BACKGROUND: To identify sarcopenia as a predictive prognostic factor of ovarian cancer in terms of survival outcome in patients with early-stage ovarian cancer. METHODS: Data of Konkuk University Medical Center from March 2002 to December 2017 were reviewed retrospectively. Eighty-two patients who underwent surgery due to early-stage (International Federation of Gynecology and Obstetrics stage I/II) ovarian cancer and had computed tomography (CT) images taken at the initial diagnosis were included. The initial CT scan images were analyzed with SliceOmatic software (TomoVision). A sarcopenia cutoff value was defined as a skeletal muscle index of ≤ 38.7 cm²/m². Overall survival (OS) times were compared according to the existence of sarcopenia, and subgroup analyses were performed. RESULTS: A Kaplan-Meier analysis showed a significant survival disadvantage for patients with early-stage ovarian cancer when they had sarcopenia (P < 0.001; log-rank test). Sarcopenia remained a significant prognostic factor for OS in early-stage ovarian cancer, in a Cox proportional hazards model regression analysis (HR, 21.9; 95% CI, 2.0-199.9; P = 0.006). CONCLUSION: This study demonstrated that sarcopenia was predictive of OS in patients with early-stage ovarian cancer. Further prospective studies with a larger number of patients are warranted to determine the extent to which sarcopenia can be used as a prognostic factor in ovarian cancer.

Discrepancy between Cytology and Histology in Cervical Cancer Screening: a Multicenter Retrospective Study (KGOG 1040).

BACKGROUND: Cervical cancer is the fourth common cancer in women worldwide. The Papanicolau test is the primary screening procedure to detect abnormal cervical cells. Colposcopy is the main procedure for discriminating high-grade cervical lesions. The study aimed at clarifying the discrepancy between cervical cytology and colposcopic biopsy histology as well as confounding factors. METHODS: Eligible patients visited thirteen tertiary hospitals for colposcopic biopsy following cervical cytology and human papillomavirus (HPV) genotypes between January and December 2018. Baseline characteristics including age, body mass index (BMI), and parity were collected. RESULTS: In our study, 3,798 eligible patients were included. Mean age of patients was 42.7 (19-88) years and mean BMI was 22.5 (16.9-34.1) kg/m². The referred cervical cytologic findings consisted of 495 normal, 1,390 atypical squamous cells of undetermined significance, 380 atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion, 792 low-grade squamous intraepithelial lesion, 593 high-grade squamous intraepithelial lesion, 79 atypical glandular cells, 46 squamous cell carcinoma, and 23 adenocarcinoma. HPV-positive findings were found in 3,008 (79.2%) patients and were not detected in 914 (24.1%) cases. The risk of unexpected low-grade lesions from histology was higher in patients > 45 years (odds ratio [OR], 2.137; 95% confidence intervals [CIs], 1.475-3.096). In contrast, the risk of unexpected high-grade lesions from colposcopic biopsy was lower in patients ≥ 45 years (OR, 0.530; 95% CI, 0.367-0.747) and HPV 16/18 infection was higher than other HPV (OR, 1.848; 95% CI, 1.385-2.469). CONCLUSION: Age and HPV genotypes were responsible for the discrepancies between cytology and histology. Precautions should be taken for women over the age of 45 in triage for colposcopy in order to avoid unnecessary testing.

Reduction of cycles of neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian or primary peritoneal cancer (ROCOCO): study protocol for a phase III randomized controlled trial.

BACKGROUND: Primary debulking surgery (PDS) and adjuvant chemotherapy is the standard treatment for advanced ovarian, fallopian or primary peritoneal cancer. However, neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been introduced as an alternative, showing similar efficacy and decreased postoperative complications compared with PDS. Although there is still no evidence for whether three or four cycles of NAC used clinically could be adequate, reducing one cycle of NAC is expected to remove more visible tumours and thereby improve prognosis. Thus, we proposed with this study to evaluate the efficacy and safety of reducing one cycle of NAC for advanced ovarian, fallopian or primary peritoneal cancer. METHODS: This study is a prospective, multi-centre, open-label, randomized phase III trial. A total of 298 patients with advanced ovarian, fallopian or primary peritoneal cancer will be recruited and randomly assigned to either three (control group) or two cycles of NAC (experimental group). After the NAC, we will conduct IDS with maximal cytoreduction and then administer the remaining three or four cycles for a total of six cycles of adjuvant chemotherapy. The primary end point is progression-free survival, and the secondary end points are time to tumour progression, overall survival, tumour response after NAC, IDS and adjuvant chemotherapy, radiologic investigation after IDS, tumour response by positron emission tomography-computed tomography after NAC, quality of life, adverse events, success rate of optimal cytoreduction, surgical complexity, postoperative complications and safety of IDS. We will assess these factors at screening, at every cycle of chemotherapy, at IDS, after the completion of chemotherapy, every 3 months for the first 2 years after the planned treatment and every 6 months thereafter for 3 years. DISCUSSION: We hypothesize that reducing one cycle of NAC will contribute to more resection of visible tumours despite 10% reduction of optimal cytoreduction, which could improve survival. Moreover, two cycles of NAC may increase postoperative complications by 5% compared with three cycles, which may be acceptable. TRIAL REGISTRATION: This study has been prospectively registered at ClinicalTrials.gov on Oct. 2nd, 2018 (NCT03693248, URL: https://clinicaltrials.gov/ct2/show/NCT03693248).

Prognostic Factors and Impact of Minimally Invasive Surgery in Early-stage Neuroendocrine Carcinoma of the Cervix.

STUDY OBJECTIVE: To investigate the prognostic factors and impact of minimally invasive surgery (MIS) in surgically treated early-stage high-grade (HG) neuroendocrine cervical carcinoma (NECC). DESIGN: Retrospective cohort study. SETTING: Asan Medical Center, Seoul, Korea. PATIENTS: Patients with International Federation of Obstetrics and Gynecology (2009) stages IB1 to IIA HG NECC. INTERVENTIONS: All patients underwent radical hysterectomy (RH) with a laparotomy or an MIS approach. MEASUREMENTS AND MAIN RESULTS: Between 1993 and 2017, 47 patients with International Federation of Obstetrics and Gynecology stages IB1 to IIA1 HG NECC were initially treated with RH. Clinicopathologic variables of patients were retrospectively reviewed from electronic medical records. The median follow-up period was 28.2 months (interquartile range, 17.1-42). Stage IB1 disease was the most common (70.2%). Twenty-nine patients (61.7%) underwent RH by MIS. The overall survival (OS) and disease-free survival (DFS) rates were 63.8% and 38.3%, respectively. Lymph node metastasis and resection margin involvement were significant risk factors for DFS (hazard ratio [HR], 2.227; 95% confidence interval [CI], 1.018-4.871; p =.045 and HR, 6.494; 95% CI, 1.415-29.809; p =.016, respectively) and OS (HR, 3.236; 95% CI, 1.188-8.815; p =.022 and HR, 12.710; 95% CI, 1.128-143.152; p =.040, respectively). The Kaplan-Meier survival curves revealed no significant differences in OS and DFS between the laparotomy and MIS groups (50% vs 72.4% log-rank p =.196, 38.9% vs 37.9% p =.975). CONCLUSION: Lymph node metastasis and resection margin involvement were poor prognostic factors of survival outcomes in initially surgically treated early-stage HG NECC. No difference was observed in the survival outcomes between the MIS and laparotomy approaches.

Outcomes of non-high grade serous carcinoma after neoadjuvant chemotherapy for advanced-stage ovarian cancer: a Korean gynecologic oncology group study (OV 1708).

BACKGROUND: Outcomes of patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied, but there is limited information on the outcomes of patients with non-HGSC. This study aimed to evaluate the outcomes of NAC in non-HGSC patients with advanced-stage ovarian cancer. METHODS: We conducted a retrospective cohort study of patients who underwent NAC for advanced stage non-HGSC between 2002 and 2017 in 17 institutions. Demographics, surgical outcomes, and survival rates were evaluated according to histological subtypes. RESULTS: A total of 154 patients were included in this study, comprising 20 cases (13.0%) of mucinous adenocarcinoma, 31 cases (20.1%) of endometrioid adenocarcinoma, 28 (18.2%) cases of clear cell carcinoma, 29 (18.8%) cases of low-grade serous carcinoma and 12 cases (7.8%) of carcinosarcoma. Complete remission/partial remission after the third cycle of NAC was achieved in 100 (64.9%) patients and optimal debulking surgery (residual disease ≤1 cm) at interval debulking surgery was achieved in 103 (66.9%) patients. The most common reason for performing NAC was high tumor burden (n = 106, 68.8%). The median progression-free survival (PFS) was 14.3 months and median overall survival (OS) was 52.9 months. In multivariate analyses, mucinous and clear cell carcinoma were negative prognostic factors for both PFS (p = 0.007 and p = 0.017, respectively) and OS (p = 0.002 and p = 0.013, respectively). CONCLUSIONS: In this study, poor survival outcomes were observed in patients with mucinous and clear cell carcinoma undergoing NAC. Different treatment strategies are urgently required to improve survival outcomes for this disease subset.

Effect of adjuvant therapy on the risk of recurrence in early-stage leiomyosarcoma: A meta-analysis.

OBJECTIVES: To assess the effect of adjuvant chemotherapy (AC) or radiotherapy (AR) on the risk of recurrence in surgically treated patients with early-stage uterine leiomyosarcoma (uLMS). METHODS: We searched the PubMed, EMBASE, and MEDLINE, and Cochrane databases for publications up to March 2019, which compared patients with early-stage uLMS who received AC or AR with those who did not. The primary endpoint was recurrence rate. Random- or fixed-effects models were used for pooled estimates of the effect of adjuvant treatments on recurrence rates. Subgroup analyses were conducted based on study design, surgical staging, AC regimen (gemcitabine/docetaxel regimen), and type of AR. RESULTS: Three randomized trials and 9 observational studies (9 studies for AC vs. observation, n = 496; 9 studies for AR vs. observation, n = 425) were included. The meta-analysis indicated that AC did not decrease the risk of recurrence compared with observation (odds ratio [OR] = 0.65, 95% confidence interval [CI] = 0.37-1.15, P = 0.14; P = 0.09 and I2 = 42.1). Similarly, AR did not decrease the risk of recurrence compared with observation (OR = 1.11, 95% CI = 0.56-2.21, P = 0.76; P = 0.10 and I2 = 40.4). Meta-regression analyses revealed no significant association between median follow-up time and recurrence. In subgroup analyses (study design, surgical staging, gemcitabine/docetaxel regimen, type of AR), neither AC nor AR decreased the risk of recurrence significantly. CONCLUSION: AC, including gemcitabine/docetaxel regimen, or AR did not reduce the recurrence rate in patients with early-stage uLMS.

Pregnancy and oncologic outcomes after fertility-sparing management for early stage endometrioid endometrial cancer.

OBJECTIVE: Hormonal management is an alternative treatment for preserving fertility in patients with presumed early stage endometrioid endometrial cancer. This study aimed to define the pregnancy and oncologic outcomes and factors of successful conception after hormone therapy for endometrioid endometrial cancer. METHODS: We retrospectively analyzed patients presumed to have stage IA, grade 1-2 endometrioid endometrial cancer who underwent fertility-sparing treatment. Concurrent medroxyprogesterone and levonorgestrel-release intra-uterine devices were used for treatment. The pregnancy outcomes and oncologic outcomes were compared between the pregnant and non-pregnant groups. RESULTS: Seventy-one patients presumed to have stage IA, grade 1-2 endometrioid endometrial cancer had complete remission, and 49 of them tried to conceive. Twenty-two (44.9%) patients became pregnant; the total number of pregnancies was 30. These pregnancies resulted in seven abortions (23.3%), one pre-term birth (3.3%), and 20 full-term births (66.6%). The total live birth rate was 66.6 % (20/30). The median duration of hormonal treatment was 11.9 months (range 4-49) and 12.0 months (range 3-35) in the pregnant and non-pregnant groups, respectively. On multivariate analysis, age, body mass index, treatment duration, medroxyprogesterone dose, and number of dilatation and curettage biopsies were not significantly associated with pregnancy failure, but the association with grade (OR 6.2, 95% CI 1.0 to 38.9; P<0.05) was statistically significant. The median disease-free survival duration was 26 months (range 20-38) and 12 months (range 4-48) in the pregnant and non-pregnant groups, respectively (P<0.05, log-rank test). CONCLUSIONS: A lower grade might be a positive factor for future pregnancy. Moreover, successful pregnancy might be a factor in preventing recurrence.

Prediction model for para-aortic lymph node metastasis in patients with locally advanced cervical cancer.

OBJECTIVE: Concurrent chemoradiotherapy is usually administered to patients with locally advanced cervical cancer (LACC). Extended-field chemoradiotherapy is required if para-aortic lymph node (PALN) metastasis is detected. This study aimed to construct a prediction model for PALN metastasis in patients with LACC before definitive treatment. METHODS: Between 2009 and 2016, all consecutive patients with LACC who underwent para-aortic lymphadenectomy at two tertiary centers were retrospectively analyzed. A multivariate logistic model was constructed, from which a prediction model for PALN metastasis was developed and internally validated. Before analysis, risk grouping was predefined based on the likelihood ratio. RESULTS: In total, 245 patients satisfied the eligibility criteria. Thirty-four patients (13.9%) had pathologically proven PALN metastases. Additionally, 16/222 (7.2%) patients with negative PALNs on positron emission tomography/computed tomography (PET/CT) had PALN metastasis. Moreover, 11/105 (10.5%) patients with both negative PALNs and positive pelvic lymph nodes on PET/CT had PALN metastasis. Tumor size on magnetic resonance imaging and PALN status on PET/CT were independent predictors of PALN metastasis. The model incorporating these two predictors displayed good discrimination and calibration (bootstrap-corrected concordance index=0.886; 95% confidence interval=0.825-0.947). The model categorized 169 (69%), 52 (22%), and 23 (9%) patients into low-, intermediate-, and high-risk groups, respectively. The predicted probabilities of PALN metastasis for these groups were 2.9, 20.8, and 76.2%, respectively. CONCLUSION: We constructed a robust model predicting PALN metastasis in patients with LACC that may improve clinical trial design and help clinicians determine whether nodal-staging surgery should be performed.