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ObjectiveAdvanced or recurrent endometrial carcinoma (EC) represents a significant clinical challenge. This study aimed to evaluate patient (age and comorbidities) and disease (histological subtypes and stages) characteristics, treatment patterns and survival outcomes in a real-world French healthcare setting.Methods and analysisIn this national, multi-centre, retrospective observational cohort study, 200 patients with advanced or recurrent EC receiving first- or second-line chemotherapy during the year 2019 were analysed. Data collected included baseline characteristics, treatment regimens, real-world progression-free survival (rwPFS) and overall survival (OS).Results127 and 73 were included in the first and second lines, respectively. Endometrioid carcinoma was the most represented histological subtype (62.0%). Patients in the first line, of whom 31.5% had FIGO (Fédération Internationale de Gynécologie Obstétrique) IVB disease, mainly received a combination of carboplatin and paclitaxel (78.0%), while 131 patients receiving second-line therapy were mainly administered anthracycline (54.2%). Median rwPFS and OS were, respectively, 8.5 and 13.2 months for patients receiving first-line therapy and 4.0 and 9.4 months for patients receiving second-line therapy. In Cox analyses, a diagnosis of carcinosarcoma, the presence of liver metastases and stage IVB disease were associated with worse survival outcomes for patients recieving first-line chemotherapy. Non-platinum chemotherapy and liver metastases were associated with poorer survival in patients receiving second-line chemotherapy.ConclusionsThis study highlights the landscape of metastatic EC treatment in a real-world French setting before the availability of PD1 inhibitors, emphasising the discrepancy between clinical trial data and real-world outcomes. It underscores the necessity for further real-world studies to complement clinical trials for a comprehensive understanding of metastatic EC management.

Background On November 13, 2015, terrorist attacks took place in Paris. One hundred and twenty-nine people were immediately killed and 302 needed emergency care. Many resident physicians were on the front line of the medical response. Our aim was to report the frequency of symptoms of post-traumatic stress disorder (PTSD), anxiety and depression among resident physicians after the Paris terrorist attacks. Methods Anonymous questionnaires, including the Impact of Event Scale- Revised (IES-R) and the Hospital Anxiety and Depression Scale (HADS), were emailed two months after the attacks to 2413 Parisian resident physicians. Exposure to the attacks was defined as having direct clinical contact with one of the victims up to one week after the attacks, being one of the victims, or having one among close relatives. Results The questionnaire was completed by 680 (28.2%) residents. Eighty-four (12.4%) reported symptoms of PTSD (IES-R ≥ 33), 76 (11.2%) reported symptoms of anxiety (HADS anxiety score > 10) and 16 (2.4%) reported symptoms of depression (HADS depression score > 10). Exposed residents had higher IES-R scores than non-exposed residents (18.8 ± 16.6 versus 14.2 ± 12.0, p  = 0.001), and 40 (18.5%) of them reported symptoms of PTSD, compared to 44 (9.5%) of the non-exposed residents ( p  = 0.001). Conclusions There was a high frequency of symptoms of mental distress among our respondents. Dedicated screening and care strategies must be considered in the event of new attacks.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing. Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3–16·6) with atezolizumab and 10·4 months (9·7–11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49–0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3–36·8) versus 22·8 months (20·3–28·0), respectively (HR 0·68 [95% CI 0·52–0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1–2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. F Hoffmann-La Roche.

There is a lack of biomarkers to predict outcome following initial treatment in patients with high-grade ovarian cancer. We hypothesized that monitoring TP53 mutation (TP53m) in circulating tumor DNA (ctDNA) could be a tumor-specific biomarker. Patients enrolled in a prospective study (NCT03010124) consented to analysis of biological samples through the disease course. ctDNA was extracted and analyzed to detect the presence of TP53m. Next-generation sequencing was performed on tumor tissue to detect TP53m and on whole blood to detect clonal hematopoiesis of indeterminate potential (CHIP).A total of 102 samples were sequentially collected from 26 patients. ctDNA was detected in all patients at diagnosis. The same TP53m was found in ctDNA and tumor tissue in 77% of patients. TP53m in ctDNA was not CHIP related. During neoadjuvant chemotherapy, increasing ctDNA was associated with failure to achieve complete interval cytoreductive surgery in 60% of patients. Rising ctDNA or de novo TP53m seemed to be associated with a trend for worst survival compared with decrease or complete clearance: progression-free survival 10 versus 26.5 months, HR 3.2. Despite macroscopically complete surgery, 30% of patients had detectable ctDNA post-operatively and had worse survival than those with undetectable ctDNA. Monitoring TP53m in ctDNA during chemotherapy or after surgery could help guide the best adjuvant therapy.

BackgroundMolecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD.MethodsGenes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan–Meier curves and Cox models.ResultsIn total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4–0.7, Pearson correlation = 0.64–0.86, all P < 10−11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I–III BRCA (interaction test, P < 0.001).ConclusionsUCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.

ObjectiveAdult ovarian sex cord–stromal tumors (SCSTs) are a rare histological subtype of ovarian cancer associated with a favorable prognosis. Bleomycin-containing regimens are standards of care, although pneumonitis may cause potentially fatal dose-limiting toxicity. We aimed to evaluate the safety of bleomycin in SCST treatment.MethodsWe performed a systematic literature review of all studies of bleomycin therapy for SCSTs that were referenced in MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials and published from 1986 to 2014.ResultsEight studies totaling 221 patients were included. Rates of pneumonitis (7.7%; 95% confidence interval, 4.2–11.2) and mortality (1.8%; 95% confidence interval, 0.1–3.6) related to bleomycin were significant. However, these results were very similar to those reported for men who were treated with bleomycin for a male germ cell tumor, suggesting that women with ovarian SCSTs are not particularly vulnerable to bleomycin lung toxicity. The main risk factors of bleomycin-induced pneumonitis are high cumulative bleomycin dose (>400 U or mg), age older than 40 years, and impaired renal function. Whether granulocyte colony-stimulating factor is a risk factor remains controversial.ConclusionsBleomycin-induced pneumonitis frequently occurs in patients with SCSTs and lacks effective treatment. Prevention lies in limiting cumulative bleomycin dose, monitoring pulmonary function during treatment, discontinuing bleomycin at the onset of pulmonary symptoms or if pulmonary function is impaired, and avoiding bleomycin in older patients.

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.

International Federation of Gynecology and Obstetrics (FIGO) staging classification for stage IV epithelial ovarian cancer (EOC) separates stages IVA (pleural effusion) and IVB (parenchymal and/or extra-abdominal lymph node metastases). We aimed to evaluate its prognostic impact and to compare survival according to the initial metastatic location. We conducted a multicenter study between 2000 and 2020, including patients with a FIGO stage IV EOC. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and recurrence rates. We included 307 patients: 98 (32%) had FIGO stage IVA and 209 (68%) had FIGO stage IVB. The median OS and PFS of stage IVA patients were significantly lower than those of stage IVB patients (31 versus 45 months (p = 0.02) and 18 versus 25 months (p = 0.01), respectively). Recurrence rate was higher in stage IVA than IVB patients (65% versus 47% (p = 0.004)). Initial pleural involvement was a poor prognostic factor with a median OS of 35 months versus 49 months for patients without initial pleural involvement (p = 0.024). Patients with FIGO stage IVA had a worse prognosis than patients with FIGO stage IVB EOC. Pleural involvement appears to be relevant for predicting survival. We suggest a modification of the current FIGO staging classification.

Recent robust data allow for omitting lymph node dissection for patients with advanced epithelial ovarian cancer (EOC) and without any suspicion of lymph node metastases, without compromising recurrence-free survival (RFS), nor overall survival (OS), in the setting of primary surgical treatment. Evidence supporting the same postulate for patients undergoing complete cytoreductive surgery after neoadjuvant chemotherapy (NACT) is lacking. Throughout a systematic literature review, the aim of our study was to evaluate the impact of lymph node dissection in patients undergoing surgery for advanced-stage EOC after NACT. A total of 1094 patients, included in six retrospective series, underwent either systematic, selective or no lymph node dissection. Only one study reveals a positive effect of lymphadenectomy on OS, and two on RFS. The four remaining series fail to demonstrate any beneficial effect on survival, neither for RFS nor OS. All of them highlight the higher peri- and post-operative complication rate associated with systematic lymph node dissection. Despite heterogeneity in the design of the studies included, there seems to be a trend showing no improvement on OS for systematic lymph node dissection in node negative patients. A well-conducted prospective trial is mandatory to evaluate this matter.