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Purpose: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical–surgical treatment. Experimental Design: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin–paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests. Results: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03–0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11–0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery. Conclusions: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance. See related commentary by May and Oza, p. 4432

Introduction/Background* As stated by ESGO-ESMO, there is a need for indicators of chemotherapy efficacy in ovarian carcinoma patients treated in first-line setting (Colombo et al, IGCS, 2020). The pathological chemotherapy response score (CRS) and the modeled CA-125 KELIM during neo-adjuvant chemotherapy were reported as potential markers. Moreover, changes in tumor infiltrating lymphocytes (TILs) after neo-adjuvant chemotherapy were reported as a prognostic factor (Leary et al, Cancer Immunol Immunother, 2021). We studied the relationships between changes in TILs, the pathological response (pR) and KELIM in patients treated with neo-adjuvant chemotherapy +/- interval debulking surgery (IDS) from CHIVA phase II trial. Methodology The patients were enrolled in the randomized phase II trial CHIVA (NCT01583322, neo-adjuvant carboplatin-paclitaxel +/- nintedanib, +/- IDS, n=188 patients). KELIM were previously calculated (You et al CCR 2020). The 30 patients with the highest KELIM (very chemosensitive) or the lowest KELIM (poorly chemosensitive) were selected. HE-stained sections from available tissue blocks at baseline and after chemotherapy were analyzed for stromal TILs (sTILs, surface of the tumor stroma occupied by lymphocytes) and intra-epithelial TILs (ieTILs, brisk or non-brisk). The pathological response (pR) was assessed on the most tumoral available tissue block obtained after chemotherapy (good response if extensive fibrous changes with no or isolated tumor cells, or Result(s)* No relationships between KELIM and TILs infiltrates on baseline tumor samples were found. However, strong associations were found between KELIM and TIL infiltrates after neo-adjuvant chemotherapy for sTILs (median KELIM for sTILs 0-5% vs >5%: 0.28 versus 1.32, P Conclusion* High consistency was found between the modeled CA125 KELIM calculated during the first 100 days of neo-adjuvant chemotherapy and the pathological response, consistent with their values as indicators of the tumor chemosensitivity in first-line setting. Moreover, TILs changes were strongly associated with chemosensitivity, opening hypotheses about the mechanisms of chemosensitivity, and immunotherapy opportunity.

International audience; Objective: MicroRNAs (miRNAs) are promising biomarkers in ovarian cancer. Their kinetics during treatment might be useful for monitoring disease burden, and guiding treatments in patients treated with peri-operative chemotherapy and interval debulking surgery (IDS).Methods: Serial blood samples of patients enrolled in the randomized phase II CHIVA trial, comparing first line carboplatin-paclitaxel +/- nintedanib (NCT01583322) and IDS, were investigated to assess the kinetics of 11 relevant miRNAs. Their prognostic/predictive values regarding the likelihood of complete IDS, and the patient survival, were assessed and compared to those of CA125 kinetics. The selection of the miRNAs (miR-15b-5p, miR-16-5p, miR-20a-5p, miR-21-5p, miR-93-5p, miR-122-5p, miR-150-5p, miR-195-5p, miR-200b-3p, miR-148b-5p and miR-34a-5p) was based on the expression levels found with a large explorative panel, and on the literature data.Results: 756 serial blood samples from 119 patients were analyzed for a total of 8172 miRNA assays, and 1299 CA125 values. The longitudinal kinetics of the miRNA expressions were highly inconsistent, and were not related to CA125 dynamics. The miRNA changes during neoadjuvant treatment were not found associated with RECIST tumor response or IDS outcomes. Decreases of miR-34a-5p and miR-93-5p were associated with PFS benefit (p = .009) and OS benefits (p < .001), respectively, using univariate tests.Conclusions: The longitudinal kinetics of miRNA expressions during neoadjuvant treatment in ovarian cancer patients were inconsistent, and were not found to be associated with tumor burden changes. Although some prognostic value could be discussed, no predictive value regarding tumor responses or IDS quality could be identified.

Importance To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting. Objective To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate. Design, setting, and participants This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months). Interventions Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone. Main outcomes and measures Six-month progression-free rate. Results Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity. Conclusions and relevance Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit. Trial registration ClinicalTrials.gov Identifier: NCT01770301.

In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy. Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS). Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib. In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.

Objectives The aim of this phase II study was to assess the benefits of a weekly administration of topotecan and gemcitabine in patients with ovarian carcinoma having relapsed after platinum/taxane-based first-line chemotherapy. Methods Seventy-seven patients with progression of disease ≤12 months after first-line chemotherapy were enrolled to receive topotecan (2.5 mg/m 2 ) and gemcitabine (1000 mg/m 2 ) on days 1, 8 and 15 (q 28 d). Primary endpoint was the response rate. Stabilization rate and symptom improvement were also assessed. Results All patients received the combination and 66 were evaluable (≥2 cycles administered). The only major severe toxicity was neutropenia grades 3 (17%) and 4 (6%). Approximately 60% of the patients received the complete schedule of treatment, dose interruptions/delays being mainly due to moderate thrombocytopenia or neutropenia. The objective response rate was 14%, the values for patients having relapsed within 6 ( n =30) and 6–12 ( n =36) months being 7% and 20%, respectively. Median durations of response were 4.9 and 6.4 months and clinical benefit rates including stabilizations reached 63% and 69% in patients having relapsed within 6 or 6–12 months, respectively. Corresponding median overall survival was 7.5 and 15.6 months. Symptoms and pain were reduced in 64% and 39% of the patients concerned, respectively. Conclusion In early relapse ovarian cancer, weekly combination of gemcitabine and topotecan has a modest objective response rate. However, a high proportion of patients experienced stable disease and symptom control leading to acceptable quality of life.

Context The National French Federation of Comprehensive Cancer Centres (FNCLCC) initiated the update of clinical practice guideline for the management of patients with soft tissue sarcoma in collaboration with the French Sarcoma Group (GSF-GETO), specialists from French public universities, general hospitals and private clinics and with the French National Cancer Institute. This work is based on the methodology developed in the "Standards, Options and Recommendations" (SOR) project. Objectives To update SOR guidelines for the management of patients with soft tissue sarcoma previously validated in 1995. Methods The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGsaccording to the definitions of the Standards, Options and Recommendations project. Once the guidelines have been developed, they are reviewed by independent reviewers. Results This article presents the updated recommendations for radiotherapeutic management. The main recommendations are: 1) irradiation before or after surgical treatment is the standard for soft tissue sarcoma of the extremity and uterine sarcoma; 2) no systematic irradiation should be done in case of retroperitoneal sarcoma.

Small cell carcinoma of the ovary of the hypercalcemic type is a rare tumour, usually lethal and occurring almost exclusively in young patients. In the majority of described cases, signs of this lesion were revealed by the associated hypercalcemia or by virtue of the physical tumour bulk alone. We report the first case of ovarian small cell carcinoma of the hypercalcemic revealed by a severe acute pancreatitis in a 19-year-old patient.

Four main clinicopathologic features of neuroendocrine tumors (NETs) of the cervix may be stressed: primary diagnosis at an advanced stage, early nodal metastasis even for low disease, early failure of appropriate local treatment (surgery and/or radiation therapy) and aggressive clinical treatment. Five patients with NET of the uterine cervix (small cell carcinoma type) are reported (one stage I, two stages II, one stage III and one stage IV). One patient was treated by surgery combined with radiation therapy, one by surgery combined with chemotherapy and one by surgery with radiation therapy and chemotherapy. Two patients received radiation therapy alone. Three early stage patients are alive with no evidence of disease 8, 26 and 41 months after diagnosis. The two patients with advanced stage died of disease, 3 and 12 months respectively, after diagnosis. Combination chemotherapy (cisplatin and etoposide) is warranted in disseminated NETs. Neoadjuvant or adjuvant chemotherapy should be combined with radiation therapy and surgery even in early stages.

16016 Background: A weekly association of gemcitabine and topotecan was tested with the aim of evaluating its efficacy and tolerance in patients recurring after first line platinum and taxane-based chemotherapy. Methods: From December 2004 to April 2006, 77 patients whose disease has progressed within 12 months (time-free interval, TFI) after first line chemotherapy were enrolled in a multicenter phase II study. Primary endpoint was overall response rate (ORR). Gemcitabine (1000 mg/m2) and topotecan (2.5 mg/m2) were given day 1, 8 and 15 (q 28 d) for 6 to 9 cycles. Tumor response was assessed according to RECIST or Rustin criteria. Clinical response was assessed using symptoms improvement in responders and patients with stable disease. Follow-up was updated December 2006. Results: Initial characteristics were: median age 63 years (38 to 80), WHO PS 0–1 93%, serous histology 85%, TFI < 6 months 45%, measurable disease 71%. Four cycles (1 to 8) were administered in average. The only major toxicity was neutropenia (Grade 3 and 4 in 17% and 6% of patients) with one febrile neutropenia; one toxic death (pneumopathy) was observed. 34% of cycles were incomplete (d8 and/or d15 not administered) because of grade 1–2 thrombopenia or grade 1–4 neutropenia. Lenograstim and erythropoietin were administered in 14% and 34% of patients, respectively. Sixty-six (86%) patients were evaluable for response (2 cycles administered). The ORR was 14% (CR=3%, PR=11%); there were 53% of stable disease. ORR was 7% and 20% in patients with TFI < 6 months and = 6 months, respectively. Symptoms were improved in 18 (64%) of 28 patients and pain in 11 (39%) of 28 patients. Median event-free survival time was 3.7 months. Median overall survival time was 12.3 months (7.5 and 15.6 months in patients with TFI < 6 months and = 6 months, respectively; p=0.0244). Conclusions: In resistant/refractory ovarian cancer, weekly gemcitabine and topotecan is associated with low objective response rate but with a high proportion of stable disease and symptoms control leading to acceptable quality of life. No significant financial relationships to disclose.