Search

Introduction/Background* In patients with gestational trophoblastic tumors (GTT) with a FIGO score ≥ 7, or GTT resistant to both standard monotherapies, the recommended polychemotherapy regimen is EMA-CO. In case of resistance to polychemotherapy, the prognosis is poor. The anti-PD-L1 monoclonal antibody avelumab may be effective for GTT resistant to monochemotherapy (You et al JCO 2020). The efficacy data of avelumab in patients with GTT resistant to polychemotherapy enrolled in cohort B of TROPHIMMUN trial (NCT03135769) are presented. Methodology In cohort B, patients with GTT resistant to polychemotherapy received avelumab 10 mg/kg Q2W until hCG normalization, and for 3 additional cycles thereafter. The primary endpoint was the rate of patients with hCG normalization, following a 2-step Simon design. The cohort was closed prematurely for futility. Result(s)* 2017-2020 : seven patients were treated with the French Gestational Trophoblastic Center (median age was 37 ; choriocarcinoma: 4; placental-site: 1; epithelioid: 1; other: 1) ; stage I/III: 43%/57%; FIGO score 8-10: 43%; score 11-15: 57%. Patients had experienced previous failures to monochemotherapy (n=5), pelvis surgery (n=2), and polychemotherapy (EMA-CO, n=5; EMA-EP, n=1; TP/TE, n=1; APE; n=1). They received a median of 6 avelumab cycles (range: 3-13). Six (85.7%) patients achieved initial hCG stabilization/decline, and one patient (14.2%) had successful hCG normalization after 13 cycles. Another patient experienced favorable hCG decline, but avelumab was discontinued for hemostatic hysterectomy, followed by sustained hCG normalization. The 5 other patients (71.4%) experienced hCG re-increase suggesting avelumab resistance, including two patients who developed brain hemorrhage after 4 cycles (brain metastases in one patient; arteriovenous malformation in one patient who died). The 4 remaining patients were subsequently treated with hysterectomy, other polychemotherapy, including high-dose/bone-marrow-transplant for two; pembrolizumab for one (who died). Conclusion* TROPHIMMUN is the first trial of immunotherapy in GTT. Contrarily to avelumab suggested effectiveness in patients with monotherapy resistance (Cohort A), avelumab activity was limited in patients with polychemotherapy resistance. Despite initial changes in hCG kinetics in most patients, eventual hCG normalization was rare (14%). The prognosis of patients experiencing polychemotherapy resistance remains poor. Combination treatments with immunotherapy should be considered.

Background: An intact homologous repair (HR) pathway is essential for error-free repair of DNA double strand breaks (DSB). Preclinical and clinical data have shown that breast cancer (BC) cells with a defect in the HR pathway are a target for DNA DSB inducing agents and PARP inhibition. HR deficiency (HRD) causes genomic instability with a typical profile of DNA copy number aberrations (CNA) as seen in tumors of patients with a BRCA1 germline mutation. In the Netherlands Cancer Institute (NKI) the BRCA1-like test, a biomarker for HRD, was developed. The test calculates the probability that the genomic profile of DNA CNA of a breast tumor is similar to that of BRCA1 mutated BCs. When this probability is above a certain cutoff, depending on the platform, the test is positive in a small percentage of estrogen receptor positive and over 50% of triple negative BCs. In retrospective analyses, the test appeared to be a predictive biomarker for sensitivity to adjuvant intensified alkylating chemotherapy with autologous stem cell rescue (IA-CT). For example in stage III HER2-negative BRCA1-like BC, the 7-year recurrence free survival improved from 30% with 5 cycles of 5-fluorouracil-epirubicin-cyclophosphamide (FEC) to 78% when treated with 4 cycles of FEC followed by IA-CT (adjusted hazard rate 0.12; p=0.001). There was no benefit in non-BRCA1-like patients. Prospective validation in a randomized phase III trial is eagerly awaited and will possibly result in a practice changing outcome. We hypothesize that, although treatment with IA-CT is controversial, by selecting the right patients, we may substantially improve survival in high risk BRCA1-like BC. Eligibility criteria: Patients, 18 to 66 years old, with HER2-negative BRCA1-like or germline BRCA1 or BRCA 2 related stage III BC, who are fit to undergo IA-CT. Trial Design: In this phase III trial, patients will be randomized to (neo)adjuvant treatment with 4 cycles of dose dense doxorubicin-cyclophosphamide (ddAC) followed by two cycles of IA-CT or followed by 4 cycles of carboplatin(q3)-paclitaxel(q1) and one year of olaparib (300mg twice daily). Adjuvant endocrine treatment is added according to guidelines. Primary outcome is overall survival (OS), analyzed with the intention to treat principle. To detect an improvement of 35% OS (40% vs 75%) with a 2-sided alpha of 0.05 and a power of 0.8 at 10 years, 174 patients should be enrolled. Secondary outcomes are toxicity, quality of life, cost-effectiveness and cognitive function. Additionally we plan to analyze potential biomarkers, like 53BP1 and cancer-immune interaction. The SUBITO trial is part of a Coverage with Evidence Development program, which is a policy which allows conditional funding of a promising health intervention while more conclusive evidence is gathered to prove its (cost-)effectiveness. Since January 2017 we recruited 8 patients in 2 hospitals. Ten other hospitals, including two in France and one in Germany, are expected to start enrollment soon. The Medical Ethical Committee approved the trial. The trial is registered at clinicaltrials.gov (NCT02810743). Contact information for people with a specific interest in the trial: e-mail: subito@nki.nl Citation Format: Vliek S, Jager A, Jonge-Lavrencic M, Lotz J-P, Gonçalves A, Graeser M, Nitz U, Mandjes IAM, Holtkamp MJ, Schot M, Retel VP, Kuip EJ, Wymenga MN, Konings IR, Tjan-Heijnen VCG, Kroep JR, Schroeder CP, Van der Wall E, Linn SC. Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-08.

Les modeles precliniques en cancerologie sont generalement utilises pour tester des hypotheses generees grâce a la recherche fondamentale. Les experiences sur les modeles murins sont ainsi realisees avant qu’un essai clinique ne soit entrepris chez l’homme. Bien que cette strategie ait conduit a de nombreuses decouvertes dans le domaine de l’immunotherapie, elle presente neanmoins plusieurs inconvenients. Pour cette raison, une approche bidirectionnelle iterative doit aujourd’hui etre prise en consideration. Dans un article recemment publie dans la revue Cancer Immunol Res, les defis de l’utilisation des modeles murins en immuno-oncologie ont ete abordes. En meme temps que les etudes precliniques participent au developpement clinique, les donnees obtenues sur l’humain doivent egalement etre utilisees pour generer de nouvelles hypotheses a tester sur les modeles animaux.

Environ 40 000 professionnels etaient presents cette annee encore au plus grand congres international d’oncologie, l’American Society of Clinical Oncology (ASCO) annual meeting, qui s’est deroule du 2 au 6 juin 2017 a Chicago. Dans ce numero de la revue Oncologie, nous presentons une selection de conferences et de posters qui meritent une attention particuliere en raison de leur contribution a une meilleure prise en charge des patients atteints de cancers. Parmi les etudes positives presentees, une etude randomisee portant sur la prise en charge en temps reel des symptomes et la mise en place d’un suivi personnalise des patients atteints de pathologies a un stade avance a montre une amelioration des taux de survie globale. Ainsi, il a ete demontre que le maintien ou l’amelioration de la qualite de vie des patients lors de leur traitement est un element determinant pour le succes des soins. Une avancee importante presentee egalement cette annee a concerne la reconnaissance par les autorites de sante americaines du role de plus en plus important des donnees obtenues lors des etudes observationnelles retrospectives (ou prospectives). Ces donnees de vie reelle presentent en effet une importance qui s’accroit chaque annee, notamment en matiere de pharmacovigilance. Bien que ces donnees ne soient pas encore utilisees dans les processus d’approbation des nouveaux medicaments, leur place et reconnaissance pourraient changer dans un futur proche.

Le but ultime qui conduit a l’utilisation de medicaments antiangiogeniques pour traiter le cancer est celui d’inhiber l’angiogenese et, par voie de consequence, de bloquer la dissemination metastatique. Neanmoins, le traitement par cette classe de medicaments se revele peu efficace en monotherapie. En effet, le blocage du VEGF pourrait accroitre l’hypoxie et ainsi limiter leur bonne delivrance au sein des tumeurs. A l’inverse, il a ete observe que l’association des antiangiogeniques avec les chimiotherapies potentialise l’efficacite de celles-ci au travers de ce que l’on pense etre la normalisation de la vasculature tumorale. Ce mecanisme dependrait fortement des doses administrees de medicaments antiangiogeniques, des doses reduites favorisant la normalisation de la structure vasculaire. Dans un article recent publie dans la revue Nature, le mecanisme de regulation du processus de normalisation de vaisseaux a ete en partie devoile. Dans ce modele, la normalisation des vaisseaux sanguins impliquerait une augmentation de l’activite des pericytes qui serait un processus regule par les cellules immunitaires T-helper de type 1 CD4. Cette regulation serait specifique des tumeurs, car aucune difference dans les structures vasculaires n’a ete observee dans les tissus normaux. Cette decouverte, tres interessante, ouvre la voie a l’utilisation de therapies combinatoires (antiangiogeniques et inhibiteurs de point de controle immunitaire) qui, a la fois, permettraient d’ameliorer la vascularisation de la tumeur, facilitant ainsi l’infiltration des cellules immunitaires en son sein, puis de desinhiber les points de controle de la reponse immunitaire.

La therapie cellulaire par le transfert adoptif de cellules T consiste a amplifier ex vivo des populations lymphocytaires infiltrant la tumeur ou tumor infiltrating lymphocytes. Dans un rapport de cas clinique recent, cette technique a ete utilisee pour cibler une mutation driver chez un patient atteint de cancer colorectal. Le ciblage du produit de la mutation non synonyme KRAS G12D s’est montre tres efficace, avec regression de toutes les metastases pulmonaires du patient. Neanmoins, neuf mois apres la fin du traitement, une lesion pulmonaire a evolue. L’analyse genomique de la lesion a revele une mutation dans HLA-C*08:02. Or, la presence de cette molecule est essentielle pour la reconnaissance de la tumeur par les cellules T specifiques KRAS G12D. Il s’agissait d’un mecanisme d’echappement immunitaire par la tumeur.

Background: Cancer genetics clinics are struggling to cope with increasing referrals of breast and ovarian cancer (BC/OC) patients The approval of anti-PARP for cases with germline BRCA1/2 pathogenic variants (PV) and the associated necessity for the oncologist to receive results rapidly are compounding these difficulties Mainstreamed genetic testing (MGT) via oncologists and gynecologists obviates the need for a genetics consultation for most patients, as only complex cases and PV carriers are referred We report results from an MGT project involving a Paris University hospital and two regional hospitals, and show how MGT guaranteed care continuity during the COVID-19 pandemic Methods: Oncologists and gynecologists participated voluntarily They were sent an e-learning module summarizing the principles of genetic susceptibility to BC/OC, patient selection, consent, carrier management, and highlighting the importance of cascade testing in relatives A computerized and adapted version of the Manchester Scoring System was used for patient selection Only index cases with cancer and aged > 30 were included The oncologist or gynecologist provided basic genetic counseling and gave patients an information sheet A single academic laboratory performed all analyses Results: During the 01 2018 – 05 2020 period, MGT was carried out in 244 patients with an average age of 51 PV detection rate in the BRCA1/2, PALB2, and RAD51C/D major genes was 11% All carriers were subsequently seen by a cancer geneticist Whenever possible, patients with negative results were discussed at a multidisciplinary meeting involving a geneticist or a genetic counselor 27 of the reported patients had MGT during the 8-week COVID-19 lockdown Conclusions: We report the successful implementation of MGT in France for BC/OC patients It allowed for immediate testing at their point of care of eligible patients Results were rapidly returned, and all PV carriers were seen by a cancer geneticist The PV detection rate was similar to rates observed using traditional testing pathways Of note, MGT guaranteed continuity of care during the COVID-19 lockdown, when all medical activity considered nonessential, including cancer genetics, was drastically reduced Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

Background Pharmaceutical consultations are organised in the Department of Oncology when new oral anticancer drugs are prescribed. Drug-drug interactions (DDI) and drug-food interactions are frequent with these new drugs and can produce serious adverse events (SAE). Due to the chronicity of the disease and the fact that patients are taking their medication at home, consultations and phone calls are carried out by a pharmacist. Patient education is a determinant key of clinical outcomes. Purpose To evaluate the impact of pharmaceutical consultation (PC) in the Oncology Department. Material and methods Physicians send patients who initiate a new oral oncology agent to the pharmacist. Information about patient background and treatments are collected from the general doctors and drugstore. In order to verify the DDI, patient history, biological tests and medication review are checked. A plan of adherence and advice for the prevention of SAE are explained to the patient. Every 15 days, phone calls to patients are also made to avoid adverse events and not only SAE. At any moment the oncologist can be notified. Results Over a 5 month period, 16 patients have been followed, including 18 interviews and 52 phone calls. After treatment collecting, 61% of DDI were avoided during the PC. Among these interactions, 12% were contraindications, 34% warnings and 54% precautions. The average for grades 1–2 toxicity is 84%, and 16% for grades 3–4. Three patients were directed to other health professionals, and five patients came as a matter of urgency to see the oncologist after phone calls to the pharmacist. Conclusion Clinical pharmacy consultations performed in our institution reduced the risk of DDI and improved patients’ observance to treatment. Grades 3–4 toxicity is avoided as much as possible by regular phone calls and coordination with medical staff. Pharmaceutical consultation could be an unavoidable step for a better use of this new type of treatment. This resulted in better patient care. The clinical pharmacy could also influence teamwork between pharmacists and other health professionals to assist patients in improving their outcomes. In the future, this enhanced health attention resulting in better use of treatments should also contribute to a decline in healthcare costs. No conflict of interest

Background Nintedanib is a multikinase inhibitor whose main targets are VEGFR 1/2/3, PDGFR and FGFR1. It is approved for idiopathic pulmonary fibrosis and non-small-cell lung cancer. The randomized phase II CHIVA trial tested it as an add-on to chemotherapy in the neo-adjuvant/adjuvant setting in advanced ovarian cancer eligible for debulking surgery. We report a nintedanib exposure-response relationship in the nintedanib arm. Methods Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar model-building strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings. Results The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found. Conclusions An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM. Clinical trial identification 2011-006288-23. Legal entity responsible for the study ARCAGY-GINECO. Funding Boehringer Ingelheim. Disclosure N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.

Background Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel–5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin–cyclophosphamide (EC) and locoregional treatment in IBC patients. Patients and methods PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m2 and C 4000 mg/m2 every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m2, day 1 and 5FU 750 mg/m2/day continuous infusion, days 1–5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). Results Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4–60.3] in arm A and 60.5 months (95% CI 58.3–61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9–64.7) in arm A and 55.5% (95% CI 44.3–65.3) in arm B [hazard ratio (HR) = 0.94 (0.61–1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1–78.8) in arm A and 70% (95% CI 58.8–78.7) in arm B [HR = 0.93 (0.55–1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. Conclusion The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. Clinical trial number ClinicalTrials.gov identifier: NCT02324088.

International audience; Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.

This year the American association for cancer research meeting was held in San Diego. “Harnessing breakthroughs and targeting cures” was the title of this meeting where the major recent scientific data on cancer research were discussed. This year was undoubtedly the year of immunotherapy and immunology of tumors. With the aim of sharing the data presented at this congress, AERIO (Association d’Enseignement et de Recherche des Internes d’Oncologie) and Oncologie joined to propose a digest of this outstanding congress. Of course, exhaustivity is not an objective of this type of digest which reflects the choices of young researchers and physicians, with the help of the editorial board, among the multiple themes and researches presented and discussed during this meeting. Tumor immunology and immunotherapy data from the congress are reported. Moreover, autophagy, microbiome, liquid biopsy, tumoral heterogeneity, and cancer stem cells data from this congress are reported, as a reflection of the diversity of this meeting and cancer research. From a clinical point of view, new targets and molecules and the new design of clinical trial are also reported.

Le traitement de premiere ligne pour les tumeurs trophoblastiques gestationnelles (TTG) a haut risque consiste en une polychimiotherapie a base de methotrexate, le protocole EMA/CO. Les recommandations francaises preconisent l’utilisation d’un protocole a base de platine en cas de contreindication au methotrexate, et du EMA/CO a fortes doses si des metastases cerebrales sont diagnostiquees d’emblee. Chez les patientes resistantes aux therapies de premiere ligne, differentes strategies de rattrapage ont ete developpees ou adaptees, notamment a partir de traitements deja utilises pour les tumeurs d’origine germinale. La principale therapie de rattrapage implique l’utilisation de l’etoposide et du cisplatine (protocole EMA/EP). Dans le protocole EMA/EP, l’etoposide et le cisplatine sont utilises a la place de cyclophosphamide et de la vincristine (CO; dans le regime EMA/CO) dans le but de contourner les mecanismes de resistance aux medicaments precedemment utilises. Neanmoins, aujourd’hui, les efforts sont a poursuivre pour identifier de nouvelles molecules actives chez les patientes resistantes aux traitements de premiere ligne afin d’optimiser leur prise en charge.

Non

La place de la chimiotherapie a haute dose, dans la prise en charge des cancers du sein, a fait l’objet d’un grand nombre d’essais randomises depuis 15 ans. Les donnees actuellement disponibles ne permettent pas de proposer une intensification therapeutique hors essai clinique, que ce soit en situation adjuvante ou metastatique. Des etudes plus recentes, en situation adjuvante, ont montre le profil de tolerance acceptable d’une chimiotherapie dose-densifiee sous couvert de facteurs de croissance hematopoietiques. Le benefice observe, meme modeste sur la survie sans rechute et la survie globale, consacre la densite de dose comme une des options therapeutiques dans le traitement adjuvant des patientes a haut risque de rechute. Dans les cancers du sein inflammatoires, nous ne disposons pas de donnees comparatives et prospectives.

Le mauvais pronostic du cancer de l'ovaire est etroitement lie au stade au moment du diagnostic et justifie de developper des strategies de depistage et de prevention efficaces en terme d'impact sur la mortalite. De grandes etudes randomisees utilisant le depistage combine et/ou sequentiel base sur le dosage serique du CA125 et l'echographie nous renseignerons dans 10 ans de cet impact sur la population generale et a haut risque. Pour les femmes a risque hereditaire de cancer de l'ovaire, le depistage actuellement base sur l'echographie avec ou sans CA-125 reste decevant avec des actes chirurgicaux inutiles. Seule l'annexectomie bilaterale prophylactique confere un haut niveau de protection. La contraception orale a montre son role protecteur mais ne peut etre recommandee notamment dans la population a haut risque en raison d'un risque d'augmentation du risque de cancer du sein. Il n'y a pas d'autre chimio-prevention efficace a ce jour.

Les tumeurs rares de la sphere ovarienne adulte representent moins de 10 % des tumeurs ovariennes de l’adulte. Le traitement des tumeurs rares de l’ovaire est actuellement etabli comme suit: —la chirurgie est calquee sur la chirurgie des adenocarcinomes ovariens, avec une difference majeure: l’objectif d’etre conservateur de la fonction genitale chez les femmes en âge de procreer (cas habituel dans ce type de tumeur); —la chimiotherapie basee sur les donnees de la litterature est calquee sur celle des tumeurs germinales testiculaires; —la chirurgie, la chimiotherapie et une eventuelle chirurgie des lesions residuelles sont fortement intriquees. Cependant, les tumeurs non epitheliales malignes de l’ovaire sont des cancers rares dont l’histoire naturelle est mal connue et dont les facteurs pronostiques ne sont pas precises; pour ces raisons tous les malades devraient etre adresses a des centres specialises ayant un interet specifique pour ce type de tumeur et disposant d’un departement d’anatomopathologie adequat. En effet, les etudes recentes decrivent comme facteurs pronostiques, outre le stade de la maladie, le nombre de patientes pris en charge tant d’un point de vue chirurgical que medical, temoin de la necessite d’une experience importante dans ce domaine. Du fait de l’extreme rarete de ces tumeurs, un site Internet dedie a la prise en charge de ces tumeurs rares a ete elabore puis installe pour mettre a disposition de tous, des avis concernant la prise en charge chirurgicale, oncologique en premiere, deuxieme, etc. ligne de traitement par l’intermediaire d’un forum de discussion accessible par Internet. D’autre part des programmes de recherche cliniques et de l’information pour le public ont ete developpe dans le meme temps. Ce protocole de prise en charge concerne les tumeurs malignes ovariennes germinales, et les tumeurs malignes stromales des cordons sexuels (tumeurs de la granulosa et cellules de Sertoli Leydig).

Since gemcitabine-oxaliplatin (GEMOX) has been used in pancreatic adenocarcinoma, we studied its activity and tolerability in advanced biliary tract adenocarcinoma (ABTA).Consecutive adult patients with confirmed ABTA were recruited from four centers. Those in group A had performance status (PS) 0-2, bilirubin2.5x normal and received GEMOX as first-line chemotherapy. Those in group B had PS2 and/or bilirubin2.5x normal and/or prior chemotherapy. All received gemcitabine 1000 mg/m2 as a 10 mg/m2/min infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2, every 2 weeks.Tumor sites were gallbladder (19), extrahepatic bile ducts (5), ampulla of vater (3) and intrahepatic bile ducts (29). Results for group A (n = 3) were: objective response 36% [95% confidence interval (CI) 18.7% to 52.3%], stable disease 26%, progressive disease 39%, median progression-free survival (PFS) 5.7 months and overall survival (OS) 15.4 months. Results for group B (n = 23) were: objective response 22% (95% CI 6.5% to 37.4%), stable disease 30%, progressive disease 48%, PFS 3.9 months and OS 7.6 months. National Cancer Institute Common Toxicity Criteria grade 3-4 toxicities were neutropenia 14% of patients, thrombocytopenia 9%, nausea/vomiting 5% and peripheral neuropathy 7%.The GEMOX combination is active and well tolerated in ABTA.

L’interet des biomarqueurs circulants a ete largement discute au congres de l’AACR de 2016. En effet, le sang est le seul tissu qui est en contact avec tous les organes. Depuis plusieurs annees, des tests cliniques qui detectent des proteines circulantes comme biomarqueurs sont utilises, par exemple, pour detecter et suivre le cancer de la prostate (PSA) ou pour monitorer le cancer de l’ovaire (CA-125). Tandis qu’un niveau eleve de ces proteines est secrete par ces types de tumeurs ; elles sont aussi produites par les tissus normaux, ce qui complique l’interpretation des resultats et peut, parfois, conduire a des procedures inutiles. La derniere generation des tests sanguins detecte des biomarqueurs circulants qui sont exclusivement produits par les cellules cancereuses. La premiere classe de ce type de test, approuvee par le FDA en 2004, est le systeme CellSearch, utilise pour le comptage du nombre de cellules tumorales circulantes (CTCs). La detection des CTCs est utilisee, en plus d’autres methodes, pour monitorer les patients ayant un cancer colorectal, du sein ou de la prostate dans leur reponse au traitement : une reduction de CTCs apres therapie indique une reponse positive, tandis qu’une augmentation est correlee avec une survie sans progression plus courte. Dix ans plus tard, des biomarqueurs circulants tels que l’ADN, l’ARN et les exosomes sont en cours de developpement, et certains d’entre eux ont deja apporte la preuve de leur utilite. La plupart des tumeurs solides liberent en effet des fragments d’ADN dans le sang. Cependant, non seulement les cellules cancereuses mais aussi les cellules normales liberent de l’ADN. De ce fait, la detection de mutations somatiques dans l’ADN est l’application la plus importante en tant que biomarqueur. L’analyse de variantes somatiques (mutations exclusives dans les fragments d’ADN issus des cellules cancereuses mais qui ne sont pas presentes dans l’ADN des cellules normales extraites du sang) peut etre utilisee pour monitorer de maniere non invasive la reponse au traitement.

Summary Background: studies of bimonthly 48-hour regimens of highdose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6). Patients and methods: Data on 126/161 patients were analyzed. FOLFOX2 included oxaliplatin 100 mg/m 2 ; FOLFOX3, 85 mg/m 2 ; and FOLFOX6, 100 mg/m 2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: J£ 85 mg/m 12 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m 2 /2 weeks). Results: Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients {P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regimens for treating LV-5-FU-resistant metastatic colorectal cancer. Conclusions: This study shows that oxaliplatin dose intensification significantly improves response rate and PFS in pretreated metastatic disease without increasing severe toxicity.

Differentes conferences de consensus et recommandations nationales et internationales ont tente de definir les indications des traitements neoadjuvants des cancers du sein [1, 2, 3, 4]. Nous aborderons ici essentiellement les indications et modalites de ces traitements en excluant une partie de la question des traitements antihormonaux neoadjuvants pour lesquels a ce jour le niveau de preuve d’interet reste moindre malgre un interet en recherche [1, 2, 3] clinique [5]. Les dernieres recommandations pour la pratique clinique de Nice Sain-Paul-de-Vence ont permis d’etablir trois indications qui sont [6] : les tumeurs initialement inoperables d’emblee d’un point de vue carcinologique; les tumeurs initialement operables mais non accessibles a un traitement chirurgical conservateur d’emblee; l’utilisation de l’approche neoadjuvante comme modele de recherche clinique pour la personnalisation des traitements medicaux.

ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P0.0001; HR = 0.61; 95% confidence interval (CI): 0.49-0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56-0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53-0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71-1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.

Background Mandibular osteosarcomas (MOS) mostly affect young adults. Their treatment is extrapolated from that of extragnathic osteosarcomas. Material and methods A retrospective multicooperative group study was conducted to determine the impact of chemotherapy, adjuvant radiation therapy and surgery on outcomes and to identify prognostic factors. This ethical committee-approved study included a centralized review of histology slides and operative reports. Results Of 111 patients, 58.6% were male, median age 35 years (13%, ≤18 years). Histology was osteoblastic, chondroblastic, fibroblastic, conventional not otherwise specified and others in 39.6%, 30.6%, 8.1%, 12.6% and 8.0%, respectively. Pathological World Health Organisation grades were low, intermediate and high grade in 6.4%, 11.8% and 81.8%, respectively. Surgery was carried out for 94.5% of patients. Neoadjuvant chemotherapy (mixed protocols) was carried out in 93.1% of patients. Postoperative chemotherapy and radiotherapy were carried out in 54.7% and 23.8%, respectively. Median follow-up was 59.6 months (range). Five-year local control, metastasis-free, disease-free and overall survival rates were 64.6%, 68.9%, 53.2% and 69.2%, respectively. Survival was significantly associated with age, tumor size and surgery. Wide surgery with clear margins and free flap reconstruction was the strongest prognostic factor. Neoadjuvant chemotherapy improved disease-free and metastatic-free survival and increased clear margins rates from 50% to 68%. Intermediate grades behaved like high grades in terms of metastatic-free and disease-free survival. Conclusion This homogeneous series is the largest to date and emphasizes the major impact of clear margins and multidisciplinary management. Neoadjuvant chemotherapy improves disease-free survival and should be recommended for both high and intermediate grade MOS.

Summary Background Potentiation of the antitumor activity of 5-fluorouracil (5-FU) by folinic acid has been demonstrated in patients with colorectal adenocarcinoma. Modulation is due to the interaction of thymidylate synthase (TS), fluorodeoxyuridylate (FdUMP), and methylene tetrahydrofolate (5,10-CH2-FH4), which leads to the formation of a stable ternary complex with concomitant enzyme inactivation. Folinic acid consists of a mixture of equal parts of two stereoisomers differing in chirality at the C6 carbon of the pteridine ring. Only the levorotatory [6S]-folinic acid is transformed into active folate cofactors. However, the [6R]-stereoisomer is not inert; it was shown to interfere with the [6S] form at the cellular level. The possibility of a deleterious effect of the unnatural stereoisomer on the modulation of 5-FU led us to carry out 2 consecutive phase I-II studies of 5-FU combined with the [6S]-stereoisomer of folinic acid given in high doses for treatment of patients with advanced colorectal carcinoma. Patients and methods Treatment comprised 5-FU by i.v. infusion for 2 hours (the initial dose was 350 mg/m2/d; it was incremented by 25 mg/m2/d until a maximal dose of 550 mg/m2/d) and [6S]-folinic acid (100 mg/m2/d by rapid i.v. injection in Regimen 1, and 100 mg/m2 by rapid i.v. injection followed by a 2-hour infusion of 250 mg/m2 in Regimen 2) for 5 days, every 21 days. Twenty-five pts and 27 pts were assessed in Regimen 1 and in Regimen 2, respectively. They had had no prior chemotherapy. The median follow-up time was 9 months and 15.5 months for patients treated with Regimen 1 and Regimen 2, respectively. For pts treated with Regimen 1, the response rate was 52% (CR, 12%; PR, 40%). The median time to disease progression was 9.2 months. The probability of survival at 12 months was 73%. For pts treated with Regimen 2, the response rate was 37% (CR, 7%; PR, 30%). The median time to disease progression was 8.9 months. The probability of survival at 12 months was 67%. Improvement in quality of life was achieved in most patients who had symptoms due to the tumor before the start of treatment. The dose-limiting toxic effects (WHO grades ≥ 3) were diarrhea, dermatitis, and mucositis. One single episode of grade 4 diarrhea occurred. After injection according to the schema in Regimen 1, [6S]-folinic acid was rapidly cleared from plasma (mean t 1/2 a and t ½ α and t ½ β of 7.2 and 126 minutes, respectively). The mean concentration of the [6S]-stereoisomer two hours after injection was 5.8 mmol/L. After a rapid i.v. injection of 100 mg/m2 followed by a 2-hour infusion of 250 mg/m2, the mean concentration of [6S]-folinic acid two hours after the injection was 57.5 mmol/L. Pharmacokinetic data suggests saturation of the metabolic conversion of [6S]-foli-nic acid when large doses are administered. Conclusions The [6S]-form of folinic acid potentiates the antitumor effect of 5-FU given concomitantly. However, increase of the daily dose of the folate did not result in a therapeutic improvement. The present results justify a more complete exploration of the pure active stereoisomer as a modulator of the fluoropyrimidines.

CA 125 is the most sensitive and the most used marker in the management of ovarian cancer at various stages of the disease. CA 125 is used at the time of diagnosis of the disease, to evaluate the possibility of complete resection during surgery, to estimate sensibility for adjuvant or neo-adjuvant chemotherapy and for diagnosis of recurrences. CA 125 has a diagnostic and therapeutic value and could be of help during therapeutic evaluation. CA 125 has been the topic of many studies for optimizing the management of epithelial ovarian cancers. Mandatory before any ovarian surgery, serum CA 125 levels is a help for the determination of the appropriate surgery. It appears to be a help in choosing therapeutic strategy, to predict optimal surgery and also global and progression-free survival. Low preoperative rates, half-life and fast normalization of CA 125 during the adjuvant chemotherapy are correlated with an optimal surgery and a better global and progression-free survival. The normal range of CA 125 is a strong predictive factor for disease recurrence even if its role in survival has not yet been determined. The dosage of CA 125 and its dynamic interpretation is an indispensable approach to the diagnosis, therapeutics and follow-up of ovarian cancer. Simple serum CA 125 concentration is a very important prognostic and predictive factor for a personalized care.

Tumours of the ovary represent about 30% of all cancers of the female genital system. Ovarian cancer is the fifth leading cause of death from cancer in women and the leading cause of death from gynaecological cancer. The annual worldwide estimated incidence is about 200.000 new cases and the annual mortality rate is about 115.000 [5].

We describe a phase I-II study of two consecutive 5-day courses of a three-drug regimen of ifosfamide (IFM), carboplatin (CBDCA), and either etoposide (VP-16) (regimen 1) or teniposide (VM-26) (regimen 2) in high doses together with autologous bone marrow transplantation (ABMT), for previously treated patients with ovarian carcinoma (OC), germ cell tumors (GCT), gestational trophoblastic disease (GTD), or oat cell carcinoma (OCC). Forty-four patients entered the study. Two patients with OC received regimen 1, and 22 were given regimen 2. Sixteen patients with GCT, two with GTD, and two with OCC were treated with regimen 1. Six patients (13%) died of toxicity. Nephropathy and esophagitis were the dose-limiting toxic effects. The maximum-tolerated doses (MTDs) were 1,500 and 200 mg/m2/d for 5 days for IFM and CBDCA, respectively, in combination with VP-16 250 mg/m2/d for 5 days (regimen 1), and 150, 1,500, and 200 mg/m2/d for 5 days for VM-26, IFM, and CBDCA, respectively (regimen 2). The response rate of patients with OC was 78% (complete response [CR], 14%). For patients previously resistant to chemotherapy, the response rate was 70%. There were no long-term disease-free survivors among patients with OC. The response rate of patients with GCT was 60% (CR, 33%). All responders with GCT were resistant to previous chemotherapy. Unmaintained CRs lasted 2, 6, 8+, 27+, and 37+ months. Of the two patients with GTD, one with previous resistance to chemotherapy attained a CR of 18+ months. One patient with OCC attained a CR lasting 6 months. The regimen possesses great antitumor activity. It produced CRs of long duration in a number of patients with GCT and GTD who were previously resistant to chemotherapy.

International audience; BACKGROUND: XRP6258 is a novel taxoid with a low affinity for P-glycoprotein. This multicenter phase II study assessed the activity of XRP6258 in the treatment of taxane-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: XRP6258 was administered as a 1-h i.v. infusion every 3 weeks at 20 mg/m(2) (then, in the absence of severe toxicity, at 25 mg/m(2) from cycle 2). The primary end point was the objective response rate (ORR) assessed according to response evaluation criteria in solid tumours (RECIST) guidelines. RESULTS: Seventy-one patients were enrolled. The median relative dose intensity was 0.98. The ORR was 14% (two complete, eight partial responses). Eighteen patients (25%) had stable disease of >3 months duration. At a median follow-up of 20.0 months, the median time to progression was 2.7 months, and the median overall survival 12.3 months. The most common grade 3/4 adverse events (AEs) were neutropenia (73%) and leucopenia (55%), with a low febrile neutropenia rate (3%) and infrequent grade 3/4, treatment-related, non-hematological AEs (

Background The aim of this study is to determine feasibility and efficacy of the combination regimen oxaliplatin and paclitaxel in patients with cisplatin (CDDP)-refractory germ-cell tumors (GCT). Patients and methods Patients with either a cisplatin absolute-refractory GCT defined as progressive disease (PD) during or within 1 month of CDDP administration or with a poor prognosis relapse, defined as PD between the second and the sixth month after CDDP administration, were treated with a combination of oxaliplatin (130 mg/m2) and paclitaxel (175 mg/m2) administered every 21 days. Primary end point was efficacy. Results Twenty-seven patients were included. Patients were pretreated with a median of two lines of cisplatin-based chemotherapy (range 1–5). Sixteen patients were absolute refractory. Five patients had relapsed after high-dose chemotherapy plus stem-cell support. There were no complete responses but there was one marker-positive partial response and nine disease stabilization (34, 6%). After a median follow-up of 65 months, two patients are disease-free survivors. Main toxicity was leucocytopenia grade 3/4 in 30% of the patients. Conclusion Combination chemotherapy with oxaliplatin and paclitaxel is feasible with acceptable toxicity and may be effective if combined with additional treatment in patients with CDDP-refractory GCT.

We studied concurrent bevacizumab and sequential cycles of high-dose gemcitabine/docetaxel/melphalan/carboplatin and ifosfamide/carboplatin/etoposide with autologous stem-cell support, in 43 patients with poor-risk relapsed or refractory germ-cell tumors. This resulted in an encouraging 4-year 56% relapse-free survival, exceeding the results expected in this heavily pretreated population.

La question qui m’a ete posee est avant tout celle d’un bilan. L’origine italienne de ce mot, remontant au XVIe siecle et provenant de bilancio (voulant dire balance), m’amene donc a « peser » l’apport des therapies ciblees dans la prise en charge du cancer du sein metastatique.

Purpose A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer. Patients and methods Patients received 175 mg/m2 paclitaxel (over 3 h) followed by 130 mg/m2 oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval ≥6 months. Results Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2–64.2) the median progression-free survival was 10.2 months (range 0.3–21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3–4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3–4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity. Conclusions The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.

Le geste chirurgical initial est primordial dans les tumeurs rares ovariennes puisqu’il permet le diagnostic, le bilan d’extension de la maladie et le premier acte therapeutique. Il n’est pas different techniquement de celui des autres tumeurs malignes ovariennes ; cependant certaines particularites doivent etre soulignees qui modifient l’esprit dans lequel la chirurgie doit etre abordee : – les tumeurs germinales malignes de l’ovaire sont des neoplasmes a croissance rapide qui peuvent atteindre des dimensions volumineuses en peu de temps ; – la premiere intervention est souvent pratiquee par un chirurgien non specialise en cancerologie gynecologique. En effet, soit la pathologie a ete consideree comme benigne, soit la patiente a ete operee en situation d’urgence (torsion ou rupture du neoplasme) ; – les tumeurs rares malignes de l’ovaire surviennent le plus souvent chez des femmes jeunes (âge median : 20 ans) avant meme la premiere grossesse et il est primordial de respecter au maximum l’appareil genital pour preserver la fertilite.