Complete resection significantly improves survival in ovarian cancer patients with a platinum sensitive recurrence who fulfil the AGO score. We assessed the association of levels of CA125 at relapse with surgical and oncological outcome. CA125 at the time of surgery was classified as normal (Group A: <35 U/ml) versus elevated (Group B: 35 U/ml - 350 U/ml) versus strongly elevated (Group C: > 350 U/ml). We assessed surgical outcome by CA125 and explored the prognostic value of CA125. Baseline CA125 was available in 91% (370/407) of randomized patients, 181 randomized to chemotherapy alone and 189 to additional surgery. Median CA125 values and classified cohorts did not differ significantly between patients in the chemotherapy arm vs patients in the surgical arm. The complete resection rate in the 176 patients undergoing surgery was 74% (group A versus B versus C: 83% (48/58) and 72% (74/103) and 53% (8/15) (p=0.053), respectively). There were no relevant differences regarding surgical procedures, but there was a slightly longer duration of surgery (210 vs 223 vs 240 minutes), higher blood loss (195 vs 275 vs 350 ml), higher rate of infections (16 vs 17 vs 47%) in group A vs B vs C. Rate of relaparotomy was low in all cohorts (0%, 6%, and 7%, resp.). Higher CA125 levels were associated with shorter OS in the entire population (median OS: group A 59 months vs group B 52 months, HR 1.26 (95%CI: 0.92-1.71) versus group C 35 months, HR 2.05 (95% CI: 1.33-3.16); log-rank p=0.002). Similarly, in the chemotherapy alone arm (median OS: group A 53 months vs group B 48 months, HR 1.24 (95% CI: 0.81-1.90) versus group C 35 months, HR 1.90 (95% CI: 1.09-3.30)) and in the surgical arm (median OS: group A 61 months vs group B 52 months, HR 1.32 (95% CI: 0.84-2.05) versus group C 35 months, HR 2.06 (95% CI: 1.00-4.26)). Median OS in group C from surgical arm favoured complete resection compared to incomplete resection (HR 0.22 (95% CI: 0.04-1.31); log-rank p=0.049). CA 125 levels at the time of relapse are associated with overall survival independent of treatment strategy. In this AGO score preselected population, the benefit from complete resection is independent from CA125.

BACKGROUND:Older patients with ovarian cancer represent a heterogeneous population. The French National Group of Investigators for the Study of Ovarian and Breast Cancer developed the geriatric vulnerability score (GVS) to identify geriatric parameters predictive of poor outcomes. A prospective validation of the GVS was needed. METHODS:The EWOC-1 study (NCT02001272) was an international, open-label, phase 2, three-arm trial designed according to a two-step process. Patients aged 70 years or older with newly diagnosed stage III or IV ovarian cancer were identified and the GVS determined. Those with a GVS of 3 or greater were randomly assigned to the EWOC-1 trial, stratified by country and surgical outcome, to receive three different carboplatin with or without paclitaxel regimens; those not included in the EWOC-1 trial were followed up in the EWOC-1 registry. External validation of the GVS was a secondary endpoint of the trial. Three validation cohorts were identified: the total population (validation cohort 1 [V1], n=447), the registry-only population (validation cohort 2 [V2], n=327), and the carboplatin-paclitaxel-treated population (validation cohort 3 [V3], n=320). FINDINGS:From Dec 11, 2013, to Nov 16, 2018, 447 patients were included in 48 academic centres in six countries; 120 in the EWOC-1 trial and 327 in the EWOC-1 registry. Median follow-up was 19·7 (95% CI 8·5-29·7) months for the total cohort; missing values were low (<2%). According to the maximum likelihood analysis, the hazard ratio (HR) of death in V1 was 1·8 (95% CI 1·1-3·1, p=0·029) for those with a GVS of 1; 2·4 (1·4-4·0, p=0·0009) with a GVS of 2; 4·1 (2·5-7·0, p<0·0001) for a GVS of 3; 5·5 (3·3-9·3, p<0·0001) for a GVS of 4; and 9·1 (4·7-17·5, p<0·0001) for a GVS of 5 compared with a score of 0. Whatever the validation cohort, GVS of 3 or more significantly segregated two groups with different overall survival: V1 (median 13·2 [95% CI: 10·8-18·7] vs 40·8 [32·0-45·6] months; HR 2·8 [95% CI 2·2-3·7]; p<0·0001); V2 (11·9 [95% CI 8·8-18·1] vs 40·8 [32·0-45·6] months, HR 3·5 [2·5-4·9]; p<0·0001); and V3 (18·1 [95% CI 15·8-31·8] vs 43·0 [40·6-49·7] months, HR 2·6 [1·9 to 3·7]; p<0·0001). INTERPRETATION:The GVS has high prognostic performance for overall survival in patients with advanced ovarian cancer, independently of geographic and historic effect (V1), as well as treatment patterns (V3), validated in an international population. Even though the GVS is time consuming it will allow the stratification of populations for clinical research and might permit the orientation of the geriatric intervention to specific domains. FUNDING:French National Cancer Institute. TRANSLATION:For the French translation of the abstract see Supplementary Materials section.

Between 17 to 25% of recurrent or metastatic endometrial carcinoma (EC) are MSI-H which results in improved response to immune checkpoint inhibitors (ICI). However, little is known regarding chemotherapy sensitivity in MSI-H EC, especially response to first-line platinum-based treatment.

Darolutamide (Daro) and enzalutamide (Enza) are next generation androgen receptor inhibitors. Daro does not significantly penetrate the blood-brain barrier, which may reduce cognitive impairment. ODENZA is a prospective, cross-over, preference, randomized phase II trial of Daro and Enza in patients (pts) with mCRPC. Pts (n=249) were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks or the reverse sequence. Numerically more pts with early mCRPC preferred Daro over Enza, although the difference did not reach significance (Colomba et al, ASCO 2021).

Background: Here is no convincing active treatment for patients with PROC. Anti-apoptotic bcl-2 proteins have been implicated in chemotherapy (CT) resistance. In preclinical studies, we demonstrated promising activity of Navitoclax, an anti-apoptotic inhibitor of Bcl-2 family, in ROC tumors, suggesting a potential action in platinum resistant pts. We conducted a multicentric phase II trial of Navitoclax monotherapy and reported modest efficacy (ESMO 2017, abstract #2269). Here we aimed to describe the relationship between Bcl-2 protein expression and response to Navitoclax; we also reported response to subsequent line of CT. Methods: Pts (N = 46) with high grade serous PROC received oral Navitoclax (150 mg daily for 7 days followed by 250 mg daily) until disease progression or toxicity. All pts had a biopsy of relapsed disease before navitoclax initiation to assess the expression level of Bcl-2 proteins by histoimmunochemistry (IHC), as low, medium or high. We first evaluated the efficacy of Navitoclax for pts with high BIM level, then with high BIM expression combined with low Mcl-1 and/or phospho-ERK. Response to subsequent CT was also described. Results: 44 pts (with median of 4 prior lines) were assessable for efficacy: PFS was 50 days [6-234] with 1 partial response (PR), 15 stable diseases (SD). IHC data were available for 35 pts. BIM was highly expressed in 9 pts, 4 of them with PR/SD (p = 0.68). Among them, 7 had a low expression of Mcl-1 and/or phospho-ERK, of whom 4 with PR/SD, showing no evidence of relation with clinical response. After Navitoclax, 32 pts were retreated with CT: 4PR and 9SD were noted, including 11 pts with long response (6-13 months). Median delay from previous platinum-based treatment to subsequent CT was 9 months [2-23] for PR/SD pts. Especially, 12 pts received platinum after Navitoclax with high response rate (3PR/4SD, 58%), median delay from previous platinum-CT was 18 months. Conclusions: BIM expression, alone or combined with Mcl-1 and/or pERK, is not predictive of Navitoclax benefit. High proportion of PROC pts response to platinum rechallenge; the potential implication of Navitoclax needs further explorations. Other Bcl-2 family proteins (activator BH3-only BID and PUMA) expression may be more relevant. This trial is granted by the French Cancer Research Hospital Program in 2011 and the Mariapia Bressan award in GINEGEPS 2014. Clinical trial identification: Eudract: 2015-000193-35. Legal entity responsible for the study: Centre François Baclesse. Funding: Abbvie. Disclosure: All authors have declared no conflicts of interest.

Background: The Stupp protocol is the standard treatment of glioblastoma multiform (GBM). The non-dividing nature of normal brain cells is an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways such PARP inhibitors as olaparib. PARP inhibition also increases cellular sensitivity to radiation and may be higher in tumor than in normal tissue. Progress in technical imaging and intensity-modulated-radiotherapy (IMRT) techniques provide new possibilities for sparing healthy tissues. We propose a phase 1/2a trial to assess the safety and efficacy of Olaparib combined with TMZ plus fractionated IMRT as a first line treatment in unresectable GBM patients (pts). Trial design: Based on the Stupp phase 2 design, 2 treatment periods are considered. The radiotherapy (RT) period occurs after the last surgery: the pt receives IMRT, daily TMZ during IMRT and olaparib, given at the same dose until 4 weeks after the end of IMRT. For the maintenance (MT) period, the pt receives TMZ (days 1-5 every 28 days, for 6 cycles) plus olaparib (at the MT dose level up to disease progression or unacceptable toxicity). The phase 1 includes 2 consecutive dose escalations to separate both periods for DLT (Dose Limiting Toxicities) assessment. First 15 pts will receive olaparib only during the RT period to determine the MTD1 (Maximum-Tolerated Dose) among 7 dose levels, by assessing DLT on this period. Next 15 pts will all receive MTD1 during the RT period, and a new dose-escalation will determine MTD2 (≤MTD1) during the MT period, assessing DLT from the first 2 cycles. For phase 2a, IMRT and TMZ are given according to the Stupp protocol. Olaparib is given at the MTD1 during the RT period and at the MTD2 during the MT period. Brain disease is assessed using RANO criteria. The trial includes ancillary studies on tumor biopsies, spectro-MRI and neurocognitive and quality of life assessment. Up to 79 pts will be enrolled: 30 pts in the phase 1 and 49 pts in the phase 2a (Case&Morgan two-stage design). This trial (NCT03212742) is granted by the French Cancer Institute and Health Ministry (PHRC-K15-135) and Astra-Zeneca for olaparib provision. First pt was enrolled on Oct 2017. Legal entity responsible for the study: Comprehensive Cancer Centre François Baclesse. Funding: AstraZeneca. Disclosure: All authors have declared no conflicts of interest.

Background: Among ovarian cancer patients with early relapse after platinum chemotherapy, there is no convincing active treatment. In preclinical studies, we previously demonstrated promising activity of Navitoclax (ABT-263), an anti-apoptotic inhibitor of Bcl-2 family, in ROC tumors, suggesting a potential action in platinum resistant patients. In this prospective multicentric phase II study, we evaluated the efficacy of Navitoclax monotherapy in heavily pretreated ROC patients. Methods: This study included high grade serous patients with platinum resistance. Navitoclax was orally administered at 150 mg/day during a lead in period (7 to 14 days) and then increased to 250 mg in the absence of dose-limiting thrombocytopenia (

BACKGROUND:Molecular targeted therapies have improved progression-free survival (PFS) without translating systematically into overall survival (OS) for patients with metastatic renal cell carcinoma (mRCC). In this population, patient-reported outcomes (PROs) have become a significant outcome. We evaluated the methodological quality of the assessment of PROs in randomized controlled trials (RCTs) and the clinical benefit of the different treatments including survival and quality of life (QoL). METHODS:A systematic review identified RCTs published between January 2005 and July 2014. They were evaluated according to 11 items derived from the 2013 CONSORT PROs reporting guidelines. Survival outcomes and PROs main results were analyzed and the magnitude of clinical benefit was assessed with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). RESULTS:12 RCTs were included with a total of 22 publications. The mean CONSORT score for all items was 4.5 on an 11-point scale. No publication reported the power of the PROs analysis and only one reported a PRO hypothesis. 50% of studies did not interpret PROs in relation to clinical outcomes and only 18% discussed specific limitations of PROs and their implications for generalizability. By adding the QoL criterion to PFS, 4 trials (36.4%) obtained a high level of proven clinical benefit according to the ESMO-MCBS. CONCLUSION:The methodology for assessing PROs in mRCC is not optimal. Efforts should focus on defining PROs endpoint and increasing the quality of reporting of QoL. New-generation therapies in mRCC should demonstrate a gain not only in survival but also in QoL to be included in the therapeutic arsenal.

Les progrès en biologie moléculaire et les traitements par thérapies ciblées ont révolutionné la prise en charge des cancers. Ces traitements diffèrent des chimiothérapies cytotoxiques classiques en agissant sur une ou plusieurs cibles moléculaires impliquées dans l’oncogenèse. Ces molécules ont des effets secondaires spécifiques, dont certains peuvent agir sur les fonctions thymiques. Certaines thérapies ciblées, comme les antiangiogéniques oraux, engendrent souvent un état de fatigue profond et peuvent avoir un effet direct sur le psychisme en affectant la cognition et la mémoire. Des effets secondaires d’ordre psychiatrique ont aussi été rapportés mais restent anecdotiques. Délivrées souvent sous forme orale, ces thérapies modifient l’implication et l’autonomie du patient dans son traitement ainsi que la représentation qu’il a de sa maladie et peuvent avoir un retentissement psychique indirect. De même, ces traitements sont donnés sur de longues périodes, et la gestion chronique des effets secondaires comme les troubles digestifs et cutanés devient rapidement difficile sur le plan psychologique. Pour un nombre croissant de ces nouvelles thérapies, l’indication de traitement est fondée sur la recherche d’une anomalie moléculaire qui ne sera retrouvée que pour un nombre restreint de patients induisant souvent des espoirs déçus de la part des patients. De manière contemporaine aux progrès de la biologie moléculaire, les thérapies ciblant des mutations constitutionnelles impliquent de nouvelles problématiques entrecroisant oncogénétique, nécessité thérapeutique et contraintes techniques. Ainsi, dans ce contexte scientifique nouveau, le patient est souvent déstabilisé par un parcours de plus en plus complexe de sa prise en charge.

ABSTRACT Aim: The announcement device was an emblematic measure of the first French Plan Cancer aiming at enabling patients to have a listening and information time after diagnosis announcement and treatment proposition: the different aspects of the treatments including side effects are discussed during these specific clinics. This procedure includes a medical and paramedical consultation. Nausea and vomiting (CINV) are still one of the most common side effects of the chemotherapy (CT) despite of known risk factors and efficient supportive treatments. Hypothesizing patients with good information on CINV and preventive supportive treatments may have less CINV, our study aimed to assess the relation between the patient's satisfaction of information delivered during the diagnosis announcement procedure and the incidence of CINV after the first cycle of chemotherapy. Methods: This prospective multicentric study assessed the frequency and intensity of CINV among patients naive of CT after the first cycle of treatment, using the MASCC Antiemesis Tool (MAT). CINV were defined by≥1 emetic episode or reported nausea intensity≥3 on a 0-10 scale. Multivariate analysis was used to identify various factors related to overall CINV onset, including satisfaction defined as a satisfaction score equal or above median on a 0-10 scale for≥1 announcement consultation. Results: Data from 291 patients (women: 85.2%; mean age: 57 years) from 4 centers were analyzed. Median satisfaction score were 9 and 10 for medical/paramedical consultations (1st quartile: 8 and 9, respectively): 67% of patients were satisfied of announcement device. 40.4% of patients reported acute CINV, 34.8% delayed CINV and 52.4% overall CINV. Four independent predictive factors of CINV were found: motion sickness history (OR 2.73), highly emetogenic CT (OR 2.12), anxiety (OR 2.09) and age under 57 (OR 1.99). No relation was noted between announcement consultation satisfaction and risk of CINV. Conclusions: The announcement consultation satisfaction was not linked to lower CINV frequency. In fact, even "unsatisfied" patients gave a high score, not allowing to clearly identify the impact of satisfaction on CINV. Disclosure: All authors have declared no conflicts of interest.

ABSTRACT Aim: Glandular metastasis (GM) as defined by pancreas, breast, parotid, thyroid and contralateral adrenal metastasis are rare in clear cell renal cell carcinoma. We have performed a multicenter comparison of metastatic clear cell RCC (mRCC) with GM and non-GM to determine if GM impacts on overall survival (OS). Methods: Data were collected from mRCC pts with GM or non-GM at metastatic presentation. GM: pts with at least one GM with or without other sites. Non-GM: pts without GM at metastatic presentation. Pts were treated in 5 French, 1 Belgian and 3 UK centers between January 2004 and October 2013. Association between OS and site of metastasis was assessed using the log-rank test for univariate analysis and the chi-square test for multivariable Cox regression. Results: 188 GM and 453 non-GM mRCC pts were analyzed. The majority were male (70.2%), median age was 59y, with no difference between the GM and non-GM groups. Interval from diagnosis to metastasis was 25.7 months (mo) (0.03-272.8)for GM and 4.8 mo (0.03-334) for non-GM (p 60y), delay between renal tumor and metastatic diagnosis, MSKCC risk group and GM or non-GM group were significant parameters in univariate OS analysis (p Conclusions: This large retrospective study shows that the presence of at least one GM at metastatic presentation of clear cell mRCC was associated with a significantly longer OS compared to non-GM pts. The presence of GM vs non-GM disease was an independent prognostic factor for OS. Further translational studies will be performed on matched primary tumor and metastasis samples to assess molecular differences between GM and non-GM. Disclosure: All authors have declared no conflicts of interest.

La souffrance des médecins, notamment celle des internes, reste peu abordée bien que le syndrome de burnout soit une réalité. L’Association des jeunes oncologues basnormands (Ajon) a mis en place un groupe de réflexion afin de créer un espace d’échange. Ces réunions, animées par un oncologue ou un psychologue, assurent un soutien et permettent de prendre du recul par rapport à des situations difficiles. Cela constitue une aide et une formation pour mieux gérer le stress inhérent à notre pratique clinique auprès des malades et/ou de leurs proches.