Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer.

BACKGROUND: Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS: We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS: Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS: In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).

Proteomic Discovery of Plasma Protein Biomarkers and Development of Models Predicting Prognosis of High-Grade Serous Ovarian Carcinoma.

Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry-based proteomics methods. We conducted label-free liquid chromatography-tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073-2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.

Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer.

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Durvalumab with or without tremelimumab plus chemotherapy in HRR non-mutated, platinum-resistant ovarian cancer (KGOG 3045): A phase II umbrella trial.

AIM: We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. PATIENTS AND METHODS: KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). RESULTS: Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3-4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229-0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. CONCLUSIONS: Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation.

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045.

Choosing an optimal concomitant drug for combination with poly-ADP ribose polymerase (PARP) inhibitor based on patient-specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor-based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub-study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib-based combinations and biomarkers of patients with platinum-resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment-related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD-L1 expression [CPS ≥10], CD8, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole-exome and RNA sequencing and whole blood-based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.

Prognostic significance of L1CAM expression in addition to ProMisE in endometrial cancer.

OBJECTIVE: To investigate the prognostic significance of L1 cell-adhesion molecule (L1CAM), ß-catenin, and programmed death-ligand 1 (PD-L1) in endometrial cancer (EC) patients, with a focus on p53 wild-type subgroup, for additional risk stratification. METHODS: This retrospective cohort study included EC patients classified according to Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) who underwent primary surgical treatment at the single center between January 2014 and December 2018. Immunohistochemical staining was performed for four mismatch repair (MMR) proteins, p53, L1CAM, ß-catenin, and PD-L1. DNA polymerase epsilon (POLE) mutation was detected by hot spot sequencing via droplet digital polymerase chain reaction. Survival outcome of each subgroup of L1CAM, ß-catenin, and PD-L1 was measured according to their expression. RESULTS: A total of 162 EC patients were included. Endometrioid histologic type and early-stage disease were 140 (86.4%) and 109 (67.3%), respectively. ProMisE classification assigned 48 (29.6%), 16 (9.9%), 72 (44.4%), and 26 (16.0%) patients to MMR-deficient, POLE-mutated, p53 wild-type, and p53 abnormal subgroups, respectively. L1CAM was identified as an independent poor prognostic factor for progression-free survival (PFS; adjusted hazard ratio [aHR], 3.207; 95% confidence interval (CI), 1.432-7.187; P = 0.005), whereas ß-catenin and PD-L1 positivity were not associated with recurrence (P = 0.462 and P = 0.152, respectively). In p53 wild-type subgroup, L1CAM positivity was associated with worse PFS (aHR, 4.906; 95% CI, 1.685-14.287; P = 0.004). CONCLUSION: L1CAM positivity was associated with poor prognosis in EC and further stratified the risk of recurrence in p53 wild-type subgroup, whereas ß-catenin and PD-L1 were not informative for risk stratification.

Clinical implications of histologic subtypes on survival outcomes in primary mucinous ovarian carcinoma.

OBJECTIVE: In 2014, the World Health Organization introduced a new histologic classification by dividing primary mucinous ovarian carcinoma (PMOC) into two: expansile (ES) or infiltrative subtypes (IS). This study investigated the clinical implications of these histological subtypes on survival outcomes. METHODS: Data from 131 patients with PMOC who underwent primary surgery between 2003 and 2021 were analyzed. The patients baseline characteristics, surgical and pathological information were collected. Survival outcomes were calculated, while factors affecting them were also investigated. RESULTS: During 55.9 months of median follow-up, 27 (20.6%) patients experienced recurrence and 20 (15.3%) died. Among 131 patients, 113 patients were classified into 87 (77%) ES and 26 (23%) IS after a slide review. Advanced stage, lymph node involvement, and residual tumors after surgery were more common in the IS, showing poorer prognosis. In multivariate analyses, advanced stage and residual tumors after surgery were associated with worse survival, while the IS showed no statistical significance. In subgroup analysis for stage I disease, survival did not vary between subtypes. Nevertheless, patients in the IS group who underwent fertility-sparing surgeries demonstrated a 5-year progression-free survival (PFS) rate of 83.3%, significantly lower than patients without fertility preservation, irrespective of histologic subtypes (5-year PFS rate: 97.9%; P = 0.002 for the ES, 5-year PFS rate: 100%; P = 0.001 for the IS). CONCLUSIONS: The IS of PMOC had poorer survival outcomes and a higher proportion of advanced-stage tumors. Although its independent prognostic significance remains uncertain, adjuvant chemotherapy should be considered for patients with fertility preservation in the IS group.

Conization before radical hysterectomy in patients with early-stage cervical cancer: A Korean multicenter study (COBRA-R).

OBJECTIVE: To investigate the impact of conization on survival outcomes and to identify a specific population that might benefit from conization before radical hysterectomy (RH) in patients with early-stage cervical cancer. METHODS: From six institutions in Korea, we identified node-negative, margin-negative, parametria-negative, 2009 FIGO stage IB1 cervical cancer patients who underwent primary type C RH between 2006 and 2021. The patients were divided into multiple groups based on tumor size, surgical approach, and histology. We performed a series of independent 1:1 propensity score matching and compared the survival outcomes between the conization and non-conization groups. RESULTS: In total, 1254 patients were included: conization (n = 355) and non-conization (n = 899). Among the matched patients with a tumor size of >2 cm, the conization group showed a significantly better 3-year disease-free survival (DFS) rate compared with the non-conization group when RH was conducted via minimally invasive surgery (MIS), in those with squamous cell carcinoma (96.3% vs. 87.4%, P = 0.007) and non-squamous cell carcinoma (97.0% vs. 74.8%, P = 0.021). However, no difference in DFS was observed between the two groups among the matched patients with a tumor size of ≤2 cm, regardless of surgical approach or histological type. In patients who underwent MIS RH, DFS significantly worsened as the residual tumor size increased (P < 0.001). CONCLUSION: Cervical conization was associated with a lower recurrence rate in patients with early-stage cervical cancer with a tumor size of >2 cm who underwent primary MIS RH. Cervical conization may be performed prior to MIS RH to minimize the uterine residual tumor.

Survival outcomes of laparoscopic versus open radical hysterectomy in early cervical cancer with incidentally identified high-risk factors.

OBJECTIVE: Previously, we suggested that patients with cervical cancer (CC) with tumors ≤2 cm on preoperative magnetic resonance imaging (MRI) are safe candidates for laparoscopic radical hysterectomy (LRH). Here, we aim to investigate whether LRH deteriorates the prognosis of patients with incidentally identified high-risk factors; lymph node metastasis (LNM) or parametrial invasion (PMI). METHODS: We identified patients with 2009 FIGO stage IB1 CC who underwent Type C LRH or open radical hysterectomy (ORH) at three tertiary hospitals between 2000 and 2019. Those with a tumor ≤2 cm on preoperative MRI who were not suspicious of LNM or PMI preoperatively were included, while those who were indicated to receive adjuvant treatment but did not actually receive it were excluded. Survival outcomes were compared between the LRH and ORH groups in the overall population, then narrowed down to those with LNM, and then to those with PMI. RESULTS: In total, 498 patients were included: 299 in the LRH group and 199 in the ORH group. The LRH and ORH groups showed similar 3-year progression-free survival (PFS) (94.0% vs. 93.6%; P = 0.615) and 5-year overall survival (OS) rates (97.2% vs. 96.8%; P = 0.439). On pathologic examination, 49 (9.8%) and 16 (3.2%) patients had LNM and PMI, respectively, and 10 (2.0%) had both. In the LNM subgroup, 5-year PFS rate was not significantly different between the LRH and ORH groups (73.2% vs. 91.7%; P = 0.169). In the PMI subgroup, no difference in PFS was observed between the two groups (P = 0.893). CONCLUSIONS: LRH might not deteriorate recurrence and mortality rates in CC patients with tumors ≤2 cm when adjuvant treatment is appropriately administered, even if pathologic LNM and PMI are incidentally identified.

Endometrial carcinosarcoma.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

Gestational choriocarcinoma.

Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.

Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer.

BACKGROUND: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation. METHODS: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival. RESULTS: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery. CONCLUSIONS: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).

A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms.

BACKGROUND: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival. RESULTS: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]). CONCLUSIONS: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).

Clinical implications of neoadjuvant chemotherapy in advanced endometrial cancer: a multi-center retrospective cohort study.

BACKGROUND: The mainstay of endometrial cancer treatment is surgical resection of tumors and postoperative adjuvant treatment is recommended if necessary. However, there is no consensus on the management of unresectable metastatic endometrial cancer. This study aimed to assess the feasibility and effectiveness of neoadjuvant chemotherapy followed by interval debulking surgery (NAC-IDS) in unresectable, metastatic endometrial cancer. METHODS: From the endometrial cancer cohorts of four institutions in Korea, we identified patients with International Federation of Gynecology and Obstetrics stages IIIC-IVB endometrial cancer who received NAC-IDS between January 2008 and December 2020. Through a medical record review, we collected patients' clinicopathological data. Progression-free survival (PFS), overall survival (OS), and the factors affecting survival outcomes were analyzed. RESULTS: Overall, 32 patients were included with endometrioid (n = 18), serous (n = 5), carcinosarcoma (n = 6), and other histological types (n = 3). Among them, 28 (87.5%) patients had stage IVB disease. The most common neoadjuvant chemotherapy (NAC) regimen was paclitaxel-carboplatin (n = 25, 78.1%), which was administered for a median of six cycles. While 26 (81.3%) patients showed an objective response, two (6.3%) progressed despite NAC. At the time of interval debulking surgery (IDS), 23 (71.9%) patients achieved complete cytoreduction. During 31.0 months of the median follow-up, there were 23 recurrences and 11 deaths, corresponding to a median PFS of 19.7 months and a 3-year OS rate of 69.7%. In multivariate analyses, non-endometrioid histology and residual tumor after IDS were identified as independent poor prognostic factors for PFS (adjusted hazard ratio [HR], 7.322; P < 0.001 and 5.934; P = 0.001, respectively). Multivariate analysis for OS could not be conducted because of the small number of events, although non-endometrioid histology was the only factor associated with worse OS in univariate analysis (adjusted HR, 4.523; P = 0.032). CONCLUSIONS: NAC-IDS may be a treatment option for unresectable metastatic endometrial cancer. Tumor histology and the possibility of complete cytoreduction are the primary considerations for NAC-IDS.

A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer.

BACKGROUND: PHI-101 is an orally available, selective checkpoint kinase 2 (Chk2) inhibitor. PHI-101 has shown anti-tumour activity in ovarian cancer cell lines and impaired DNA repair pathways in preclinical experiments. Furthermore, the in vivo study suggests the synergistic effect of PHI-101 through combination with PARP inhibitors for ovarian cancer treatment. The primary objective of this study is to evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent ovarian cancer. METHODS: Chk2 inhibitor for Recurrent EpitheliAl periToneal, fallopIan, or oVarian cancEr (CREATIVE) trial is a prospective, multi-centre, phase IA dose-escalation study. Six cohorts of dose levels are planned, and six to 36 patients are expected to be enrolled in this trial. Major inclusion criteria include ≥ 19 years with histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Also, patients who showed disease progression during platinum-based chemotherapy or disease progression within 24 weeks from completion of platinum-based chemotherapy will be included, and prior chemotherapy lines of more than five will be excluded. The primary endpoint of this study is to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of PHI-101. DISCUSSION: PHI-101 is the first orally available Chk2 inhibitor, expected to show effectiveness in treating recurrent ovarian cancer. Through this CREATIVE trial, DLT and MTD of this new targeted therapy can be confirmed to find the recommended dose for the phase II clinical trial. This study may contribute to developing a new combination regimen for the treatment of ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04678102 .

Impact of hemodynamic instability during cytoreductive surgery on survival in high-grade serous ovarian carcinoma.

BACKGROUND: To evaluate the impact of intraoperative hypotension and hemodynamic instability on survival outcomes in patients with high-grade serous ovarian carcinoma (HGSOC). METHODS: We retrospectively identified patients with HGSOC, who underwent primary or interval debulking surgery between August 2013 and December 2019. We collected anesthesia-related variables, including the arterial blood pressure measurements (at 1-min intervals) during the surgery of patients. The cumulative duration of mean arterial blood pressure (MAP) readings under 65 mmHg and two performance measurements (median performance error [MDPE] and wobble) were calculated. We investigated associations between the factors indicating hemodynamic instability and prognosis. RESULTS: In total, 338 patients were included. Based on the cumulative duration of MAP under 65 mmHg, we divided patients into two groups: ≥30 min and <30 min. The progression-free survival (PFS) was worse in the ≥30 min group (n = 107) than the <30 min group (n = 231) (median, 18.2 vs. 23.7 months; P = 0.014). In multivariate analysis adjusting for confounders, a duration of ≥30 min of MAP under 65 mmHg was identified as an independent poor prognostic factor for PFS (adjusted HR, 1.376; 95% CI, 1.035-1.830; P = 0.028). Shorter PFS was observed in the group with a MDPE <-4.0% (adjusted HR, 1.351; 95% CI, 1.024-1.783; P = 0.033) and a wobble ≥7.5% (adjusted HR, 1.445; 95% CI, 1.100-1.899; P = 0.008). However, no differences were observed in overall survival. CONCLUSION: This study suggests that the three intraoperative variables for hemodynamic instability, cumulative duration of MAP <65 mmHg, MDPE, and wobble, might be novel prognostic biomarkers for disease recurrence in patients with HGSOC.

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea.

OBJECTIVE: To investigate the effectiveness and safety of pembrolizumab and lenvatinib (PEMBRO+LEN) for recurrent endometrial cancer (EC) in a real-world setting. METHODS: This multicenter retrospective cohort study included patients with recurrent EC who received PEMBRO+LEN between March 2020 and May 2021 at three tertiary hospitals in Korea. We summarized patient characteristics and evaluated the response rates, survival outcomes, and treatment-related adverse events (AEs). RESULTS: In total, 48 patients were included in the study. The median age of the patients was 62.5 (range, 42-78) years. The most common histologic subtype was endometrioid adenocarcinoma (43.8%), followed by serous adenocarcinoma (25.0%). Most patients (91.7%) had mismatch repair-proficient tumors. Patients received PEMBRO+LEN for a median of 4.5 cycles, during which the best objective response rate and disease control rate were 23.8% (95% CI, 11.9-38.1) and 76.2% (95% CI, 61.9-88.1), respectively. Overall, 56.2% of patients experienced LEN dose reduction once or more and 16.7% experienced LEN interruption. The most common treatment-related AEs were fatigue (18.8%), hypertension (16.7%), and hypothyroidism (14.6%). Total of 8 patients (16.7%) discontinued LEN during the treatment because of treatment-related AEs. Serum CA-125 level was the only prognostic factor for progression-free survival (adjusted hazard ratio, 4.41; 95% confidence interval, 1.19-16.36; p = 0.03). CONCLUSIONS: In our real-world study, Korean patients with recurrent EC who received PEMBRO+LEN showed lower treatment response rate and similar treatment discontinuation rate, compared to clinical trials.

Second-line olaparib maintenance therapy is associated with poor response to subsequent chemotherapy in BRCA1/2-mutated epithelial ovarian cancer: A multicentre retrospective study.

INTRODUCTION: With expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi), there is a potential impact of PARPi resistance on platinum resistance. A post-hoc analysis of SOLO2 demonstrated a reduction in response to subsequent platinum-based therapy among patients who received prior olaparib but not placebo. The present multicentre, retrospective, observational study was conducted to determine the effects of olaparib on subsequent therapy for recurrent epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Data on EOC patients with BRCA1/2-mutated tumours who received second-line platinum-based chemotherapy between January 2012 and June 2020, at three South Korean institutions (n = 197) were collected. Patients who received olaparib as maintenance therapy after second-line chemotherapy were assigned to the olaparib group (n = 105), and subjects who did not receive olaparib maintenance therapy were assigned to the control group (n = 92). The primary endpoint was time intervals from the date of second disease progression (PFS1) to the date of third disease progression (PFS2), expressed as PFS2 - PFS1. RESULTS: As expected, PFS1 in the olaparib group was longer than the control group. However, PFS2 - PFS1 in the olaparib group was significantly shorter than that of the control group (median 7.9 vs. 13.6 m; p = 0.0005). Even when the third-line PARPi maintenance (cross-over) patients were excluded from the control group, the response to subsequent therapy in the olaparib group remained poor (median 7.7 vs. 11.5; p = 0.0422). DISCUSSIONS: Patients with platinum-sensitive BRCA1/2 mutated tumours who progressed during olaparib maintenance after second-line chemotherapy were less likely to respond to third-line chemotherapy compared to controls who did not receive olaparib, suggesting that resistance to olaparib may contribute to chemotherapy resistance.

Impact of bevacizumab and secondary cytoreductive surgery on survival outcomes in platinum-sensitive relapsed ovarian clear cell carcinoma: A multicenter study in Korea.

OBJECTIVE: This study investigated survival outcomes for platinum-sensitive relapsed ovarian clear cell carcinoma (OCCC) by treatment method. METHODS: OCCC patients with platinum-sensitive recurrence that received secondary treatment at five institutions between July 2007 and June 2021 were included. Patient characteristics and survival outcomes were compared according to the use of bevacizumab (BEV) during second-line chemotherapy and secondary cytoreductive surgery (CRS). RESULTS: 138 patients were included. The BEV (n = 36) and non-BEV (n = 102) groups had similar initial FIGO stages and proportions of secondary CRS. The BEV group showed improved progression-free survival (PFS; median, 15.4 vs. 7.5 months; P = 0.042) and overall survival (OS; P = 0.043) compared to the non-BEV group. In multivariate analyses, BEV was identified as an independent prognostic factor for PFS (adjusted hazard ratio [aHR], 0.571; 95% confidence interval [CI], 0.354-0.921; P = 0.022) and OS (aHR, 0.435; 95%CI, 0.195-0.970; P = 0.042). The secondary CRS group (n = 42) had early-stage disease at diagnosis more frequently (P = 0.009) and multi-site metastasis (P < 0.001) at recurrence less frequently than the no surgery group (n = 96). The secondary CRS group showed significantly better PFS (median, 33.7 vs. 7.2 months; P < 0.001) and OS (P < 0.001). Secondary CRS was associated with a significantly improved PFS (aHR, 0.297; 95% CI, 0.183-0.481; P < 0.001) and OS (aHR, 0.276; 95% CI, 0.133-0.576; P = 0.001). The BEV and non-BEV groups showed similar PFS and OS among the patients who underwent secondary CRS. In contrast, the BEV group showed improved PFS and OS among patients who did not undergo surgery. CONCLUSIONS: The use of BEV during second-line chemotherapy and secondary CRS may improve PFS and OS in patients with platinum-sensitive relapsed OCCC. Further prospective studies are warranted.

Cervical conization before primary radical hysterectomy has a protective effect on disease recurrence in early cervical cancer: A two-center matched cohort study according to surgical approach.

OBJECTIVE: To ascertain whether cervical conization before radical hysterectomy (RH) has a protective effect on survival outcomes in early cervical cancer, taking into account the surgical approach. METHODS: From cervical cancer cohorts of two institutions, we identified node-negative, margin-negative, parametria-negative, 2009 FIGO stage IB1 cervical cancer patients who received primary Type C RH between July 2006 and June 2020. Patients were divided into conization group (n = 144) and control group (n = 434). We conducted three independent 1:1 propensity score matching processes for histology, lymphovascular space invasion, cervical tumor size, and surgical approach (all patients, those who underwent open surgery, and those who underwent minimally invasive surgery [MIS]). Survival outcomes were compared. RESULTS: Overall, the conization group had less cervical tumor size and received MIS more frequently (P = 0.010) and adjuvant treatment less often (P = 0.002) versus the controls. After matching, the conization group showed significantly better disease-free survival (DFS) versus control (3-year DFS rate, 94.2% vs. 86.3%; P = 0.012), but similar overall survival. Among the open RH matched patients (n = 96), no difference in DFS was observed between the conization and control groups (P = 0.984). In contrast, among the MIS RH matched patients (n = 192), the conization group showed significantly better DFS versus control (3-year DFS rate, 95.7% vs. 82.9%; P = 0.005). In multivariate analysis adjusting for cervical tumor size and adjuvant treatment, conization was identified as an independent favorable prognostic factor for DFS (adjusted HR, 0.318; 95% CI, 0.134-0.754; P = 0.009). CONCLUSIONS: Preoperative cervical conization might reduce the disease recurrence rate in early cervical cancer patients who undergo primary MIS RH.