Objective: In the phase 3 KEYNOTE-826 study (NCT03635567), pembrolizumab plus chemotherapy with or without bevacizumab significantly improved progression-free survival (PFS) and overall survival (OS) in participants with persistent, recurrent, or metastatic cervical cancer. We report an exploratory analysis of outcomes for participants enrolled in East Asia based on the final analysis of KEYNOTE-826. Methods: Participants were randomized 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles. All participants received chemotherapy with paclitaxel and cisplatin or carboplatin for up to 6 cycles, and optionally received bevacizumab at the investigator’s discretion. PFS and OS were dual primary endpoints. Results: Ninety-seven participants from East Asia were enrolled in the intention-to-treat population. At data cutoff (October 3, 2022), in the intention-to-treat population, median PFS in the pembrolizumab plus chemotherapy and placebo plus chemotherapy groups was 18.0 and 10.4 months, respectively (hazard ratio [HR]=0.42; 95% confidence interval [CI]=0.23−0.77); median OS was not reached and 20.4 months, respectively (HR=0.53;95% CI=0.28−0.99). In the programmed cell death ligand 1 combined positive score (CPS) ≥1 population, median PFS was 29.3 and 10.9 months, respectively (HR=0.36; 95% CI=0.19−0.68); median OS was not reached and 17.4 months, respectively (HR=0.43; 95% CI=0.22−0.86). The most common adverse events with pembrolizumab plus chemotherapy versus placebo plus chemotherapy were alopecia (75% vs. 68%) and anemia (67% vs. 65%). Conclusion These data support the use of pembrolizumab plus chemotherapy with or without bevacizumab for the treatment of persistent, recurrent, or metastatic cervical cancer in East Asian patients.

Background: Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinumresistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoidreceptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol’s antiapoptotic effects, enhancing chemotherapy’s efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. Methods ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nabpaclitaxel or nab-paclitaxel monotherapy. The study’s primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes.Trial Registration: ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18

Background: Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinumresistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoidreceptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol’s antiapoptotic effects, enhancing chemotherapy’s efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. Methods ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nabpaclitaxel or nab-paclitaxel monotherapy. The study’s primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes.Trial Registration: ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18

Background: Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinumresistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoidreceptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol’s antiapoptotic effects, enhancing chemotherapy’s efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. Methods ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nabpaclitaxel or nab-paclitaxel monotherapy. The study’s primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes.Trial Registration: ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18

OBJECTIVE: immunotherapy with immune checkpoint inhibitors has become one of the standard therapeutic modalities for patients with advanced melanoma. Melanoma of the female lower genital tract is a rare and aggressive disease, with poor long-term clinical outcomes. To date, no study evaluated the role of immunotherapy in metastatic melanoma of the lower genital tract. METHODS: Data of women with metastatic melanoma of the lower genital tract were prospectively collected. Survival outcomes over time was assessed using Kaplan-Meier model. RESULTS: Seven cases of metastatic melanoma of the lower genital tract (vulva [n=2], vagina [n=4], and uterine cervix [n=1]) treated with immune checkpoint inhibitors are reviewed. Two patients had metastatic disease at diagnosis, while 5 patients developed metastatic disease at a mean (standard deviation) time of 9.9 (±3.0) months from primary diagnosis. Four patients received an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) (ipilimumab) and 3 received an anti-programmed cell death 1 (PD-1) (pembrolizumab [n=2], nivolumab [n=1]) therapy. The response rate to immunotherapy was 28.5%. Patients receiving an anti-PD-1 experienced a better progression-free survival than patients treated with anti-CTLA4 (p=0.01, log-rank test). Although not reaching statistical significance, overall survival was better in patients having an anti-PD-1 therapy in comparison to anti-CTLA4 (p=0.15, log-rank test). CONCLUSION: Results from our series confirm the poor prognosis of women with metastatic melanoma of the lower genital tract, thus supporting the need of exploring new treatment modalities. Further studies are warranted to improve knowledge on the role of immunotherapy in metastatic melanoma of the lower genital tract.
Cell Death ; Cervix Uteri ; Diagnosis ; Disease-Free Survival ; Female ; Humans ; Immunotherapy ; Melanoma ; Prognosis ; Prospective Studies ; Vagina

OBJECTIVES: Nerve-sparing radical hysterectomy has been implemented in order to reduce pelvic floor dysfunctions in women undergoing radical surgery for cervical cancer. Here, we aimed to investigate if the adoption of laparoscopic surgery impacts on patients' outcomes. METHODS: Data of consecutive patients affected by cervical cancer who had laparoscopic nerve-sparing radical hysterectomy were matched 1:1 with an historical cohort of patients undergoing open procedure. A propensity-score matched algorithm was applied. RESULTS: Thirty-five patients' pairs (70 patients: 35 undergoing laparoscopic vs. 35 undergoing open abdominal nerve-sparing radical hysterectomy) were included. Demographic and baseline oncologic characteristics were balanced between groups. Patients undergoing laparoscopic surgery had similar operative time than patients undergoing open abdominal procedures (249 [±91.5] vs. 223 [±65.0] minutes; p=0.066). Laparoscopic approach correlated with lower blood loss (30.5 [±11.0] vs. 190 [90.4] mL; p < 0.001) and shorter hospital stay (3.2 [±1.2] vs. 5.4 [2.0] days; p=0.023). Patients undergoing laparoscopy experienced a lower 30-day pelvic floor dysfunction rate than patients having open surgery. Moreover, they experienced shorter recovery of bladder function than patients having open procedures (median, 7 vs. 9 days; p=0.004, log-rank test). CONCLUSIONS: Laparoscopic approach resulted in a faster recovery of bladder function in comparison to open surgery for patients undergoing nerve-sparing radical hysterectomy.
Cohort Studies ; Female ; Humans ; Hysterectomy ; Laparoscopy ; Length of Stay ; Minimally Invasive Surgical Procedures ; Operative Time ; Pelvic Floor ; Urinary Bladder ; Urination Disorders ; Uterine Cervical Neoplasms

OBJECTIVE: To examine outcomes of patients having treatments for newly diagnosed advanced stage low-grade serous ovarian cancer (LGSC). METHODS: We conducted a retrospective case series of women affected by advanced stage (stage IIIB or more) LGSC undergoing surgery in a single oncologic center between January 2000 and December 2017. Survival outcomes were assessed using Kaplan-Meier and Cox models. RESULTS: Data of 72 patients were retrieved. Primary cytoreductive surgery was attempted in 68 (94.4%) patients: 19 (27.9%) had residual disease (RD) >1 cm after primary surgery. Interval debulking surgery (IDS) was attempted in 15 of these 19 (78.9%) patients and the remaining 4 patients having not primary debulking surgery. Twelve out of 19 (63.1%) patients having IDS had RD. After a mean (±standard deviation) follow-up was 61.6 (±37.2) months, 50 (69.4%) and 22 (30.5%) patients recurred and died of disease, respectively. Via multivariate analysis, non-optimal cytoreduction (hazard ratio [HR]=2.79; 95% confidence interval [CI]=1.16–6.70; p=0.021) and International Federation of Obstetrics and Gynecologists (FIGO) stage IV (HR=3.15; 95% CI=1.29–7.66; p=0.011) were associated with worse disease-free survival. Via multivariate analysis, absence of significant comorbidities (HR=0.56; 95% CI=0.29–1.10; p=0.093) and primary instead of IDS (HR=2.95; 95% CI=1.12–7.74; p=0.027) were independently associated with an improved overall survival. CONCLUSION: LGSC is at high risk of early recurrence. However, owing to the indolent nature of the disease, the majority of patients are long-term survivors. Further prospective studies and innovative treatment modalities are warranted to improve patients care.
Comorbidity ; Cytoreduction Surgical Procedures ; Disease-Free Survival ; Drug Therapy ; Female ; Follow-Up Studies ; Gynecologic Surgical Procedures ; Humans ; Multivariate Analysis ; Neoplasm Metastasis ; Obstetrics ; Ovarian Neoplasms* ; Proportional Hazards Models ; Prospective Studies ; Recurrence ; Retrospective Studies ; Survivors

OBJECTIVE: Nerve-sparing radical hysterectomy (NSRH) was introduced with the aim to reduce pelvic dysfunctions related to conventional radical hysterectomy (RH). Here, we sought to assess the effectiveness and safety of NSRH in a relatively large number of the patients of cervical cancer (CC) patients undergoing either primary surgery or neoadjuvant chemotherapy (NACT) followed by surgery. METHODS: Outcomes of consecutive patients undergoing NSRH and of a historical cohort of patients undergoing conventional RH were retrospectively reviewed. RESULTS: This study included 325 (49.8%) and 327 (50.2%) undergoing NSRH and RH, respectively. Via a multivariable model, nodal status was the only factor predicting for DFS (hazard ratio [HR]=2.09; 95% confidence interval [CI]=1.17–3.73; p=0.01). A trend towards high risk of recurrence was observed for patients affected by locally advanced cervical cancer (LACC) undergoing NACT followed by surgery (HR=2.57; 95% CI=0.95–6.96; p=0.06). Type of surgical procedures (NSRH vs. RH) did not influence risk of recurrence (p=0.47). Similarly, we observed that the execution of NSRH rather than RH had not a detrimental effect on OS (HR=1.19; 95% CI=0.16–9.01; p=0.87). Via multivariable model, no factor directly correlated with OS. No difference in early complication rates was observed between the study groups. Conversely, a significant higher number of late complications was reported in RH versus NSRH groups (p=0.02). CONCLUSION: Our data suggested that NSRH upholds effectiveness of conventional RH, without increasing recurrence and complication rates but improving pelvic dysfunction rates.
Cohort Studies ; Drug Therapy ; Humans ; Hysterectomy* ; Recurrence ; Retrospective Studies ; Uterine Cervical Neoplasms*

OBJECTIVE: To test the applicability of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) and Memorial Sloan Kettering (MSK) criteria in predicting complete cytoreduction (CC) in patients undergoing secondary cytoreductive surgery (SCS) for recurrent ovarian cancer (ROC). METHODS: Data of consecutive patients undergoing SCS were reviewed. The Arbeitsgemeinschaft Gynäkologische Onkologie OVARian cancer study group (AGO-OVAR) and MSK criteria were retrospectively applied. Nomograms, based on AGO criteria, MSK criteria and both AGO and MSK criteria were built in order to assess the probability to achieve CC at SCS. RESULTS: Overall, 194 patients met the inclusion criteria. CC was achieved in 161 (82.9%) patients. According to the AGO-OVAR criteria, we observed that CC was achieved in 87.0% of patients with positive AGO score. However, 45 out of 71 (63.4%) patients who did not fulfilled the AGO score had CC. Similarly, CC was achieved in 87.1%, 61.9% and 66.7% of patients for whom SCS was recommended, had to be considered and was not recommended, respectively. In order to evaluate the predictive value of the AGO-OVAR and MSK criteria we built 2 separate nomograms (c-index: 0.5900 and 0.5989, respectively) to test the probability to achieve CC at SCS. Additionally, we built a nomogram using both the aforementioned criteria (c-index: 0.5857). CONCLUSION: The AGO and MSK criteria help identifying patients deserving SCS. However, these criteria might be strict, thus prohibiting a beneficial treatment in patients who do not met these criteria. Further studies are needed to clarify factors predicting CC at SCS.
Cytoreduction Surgical Procedures ; Humans ; Nomograms ; Ovarian Neoplasms* ; Recurrence ; Retrospective Studies

OBJECTIVE: Accumulating evidence support that complete cytoreduction (CC) at the time of secondary cytoreductive surgery (SCS) improves survival in patients affected by recurrent ovarian cancer (ROC). Here, we aimed to determine whether artificial intelligence (AI) might be useful in weighting the importance of clinical variables predicting CC and survival. METHODS: This is a retrospective study evaluating 194 patients having SCS for ROC. Using artificial neuronal network (ANN) analysis was estimated the importance of different variables, used in predicting CC and survival. ANN simulates a biological neuronal system. Like neurons, ANN acquires knowledge through a learning-phase process and allows weighting the importance of covariates, thus establishing how much a variable influences a multifactor phenomenon. RESULTS: Overall, 82.9% of patients had CC at the time of SCS. Using ANN, we observed that the 3 main factors driving the ability of achieve CC included: disease-free interval (DFI) (importance: 0.231), retroperitoneal recurrence (importance: 0.178), residual disease at primary surgical treatment (importance: 0.138), and International Federation of Gynecology and Obstetrics (FIGO) stage at presentation (importance: 0.088). Looking at connections between different covariates and overall survival (OS), we observed that DFI is the most important variable influencing OS (importance: 0.306). Other important variables included: CC (importance: 0.217), and FIGO stage at presentation (importance: 0.100). CONCLUSION: According to our results, DFI should be considered as the most important factor predicting both CC and OS. Further studies are needed to estimate the clinical utility of AI in providing help in decision making process.
Artificial Intelligence* ; Decision Making ; Gynecology ; Humans ; Neurons ; Obstetrics ; Ovarian Neoplasms* ; Recurrence ; Retrospective Studies ; Weights and Measures*