Epicure: a European epidemiological study of patients with an advanced or metastatic Urothelial Carcinoma (UC) having progressed to a platinum-based chemotherapy

Background: Platinum-based systemic chemotherapy is considered the backbone for management of advanced urothelial carcinomas. However there is a lack of real world data on the use of such chemotherapy regimens, on patient profiles and on management after treatment failure. Methods: Fifty-one randomly selected physicians from 4 European countries registered 218 consecutive patients in progression or relapse following a first platinum-based chemotherapy. Patient characteristics, tumor history and treatment regimens, as well as the considerations of physicians on the management of urothelial carcinoma were recorded. Results: A systemic platinum-based regimen had been administered as the initial chemotherapy in 216 patients: 15 in the neoadjuvant setting, 61 in adjuvant therapy conditions, 137 in first-line advanced setting and 3 in other conditions. Of these patients, 76 (35 %) were initially considered as cisplatin-unfit, mainly because of renal impairment (52 patients). After platinum failure, renal impairment was observed in 44 % of patients, ECOG Performance Status ≥ 2 in 17 %, hemoglobinemia 30 % patients). The most frequent all-settings second anticancer therapy regimen was vinflunine (70 % of single-agent and 42 % of all subsequent treatments), the main reasons evoked by physicians (>1 out of 4) being survival benefit, safety and phase III evidence. Conclusion: In this daily practice experience, a majority of patients with urothelial carcinoma previously treated with a platinum-based therapy received a second chemotherapy regimen, most often a single agent after an initial chemotherapy in the advanced setting and preferably a cytotoxic combination after a neoadjuvant or adjuvant chemotherapy. Performance Status and prior response to chemotherapy were the main drivers of further treatment decisions

Tumor Heterogeneity of Fibroblast Growth Factor Receptor 3 (FGFR3) Mutations in Invasive Bladder Cancer: Implications for Peri-Operative anti-FGFR3 Treatment

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. Patients: and methods We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting

Does chemotherapy-induced neutropaenia result in a postponement of adjuvant or neoadjuvant regimens in breast cancer patients? Results of a retrospective analysis

In 2005, 224 patients received adjuvant/neoadjuvant chemotherapy for breast cancer in a single institution according to daily practices. Regimens consisted of epirubicin-based chemotherapy (FEC100, four or six cycles), or three cycles of FEC100 followed by three cycles of docetaxel. An absolute blood count was carried out every 3 weeks, 1–3 days before planned chemotherapy cycle. Overall, 1238 cycles were delivered. An absolute neutrophil count (ANC) <1.5 × 109 l−1 before planned chemotherapy was found in 171 cycles. Of these, 130 cycles (76%) were delivered as planned regardless of whether ANC levels recovered, and 41 (24%) were delayed. None of these patients developed a febrile neutropaenia. Haematopoietic support (granulocyte colony-stimulating factor (G-CSF)) was required in 12 cycles. We found that the majority of patients with an ANC <1.5 × 109 l−1 before planned chemotherapy received planned doses, without complications and need for G-CSF

Tasquinimod : ou comment agir sur le microenvironnement dans le cancer métastatique de la prostate

International audienceDespite the recent introduction of new drugs, castration-resistant metastatic prostate cancer, (mCRPC) remains a poor prognosis disease, with a crucial need for new therapeutic approaches. Tasquinimod is a newly developed molecule, orally administered, currently evaluated in phase III studies. Tasquinimod targets the tumor microenvironment, focusing on the angiogenic and immune components. Its specific action on the S100A9 protein restores immunity and reduces angiogenesis. A phase II double-blind randomized study against placebo showed an improvement of more than 50% of progression free survival in the group of mCRPC patients treated with tasquinimod, as compared to the placebo group. At a dose of 1mg/day, the tolerance of tasquinimod appeared acceptable. This review presents the available preclinical and clinical results of tasquinimod, with a particular focus on the originality of its mode of action

Statistical controversies in clinical research: should schedules of tumor size assessments be changed?

International audienceBACKGROUND:Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules.DESIGN:A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule.RESULTS:For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks.CONCLUSIONS:Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing

Ultrasons focalisés de haute intensité vs prostatectomie totale dans le traitement à visée curative du cancer localisé de la prostate ISUP 1 et 2 : EIG et résultats fonctionnels à 12 mois

International audienceObjectifs : étude prospective multicentrique ouverte comparant l’efficacité carcinologique et les conséquences fonctionnelles d’un traitement conservateur par ultrasons focalisés de haute intensité (HIFU) à la prostatectomie totale (PT) pour adénocarcinome prostatique localisé de stades ISUP 1 (non éligibles à la surveillance active) et ISUP 2. Nous rapportons ici les EIG et résultats fonctionnels à 12 mois.Méthodes : de février 2015 à septembre 2019, 3364 patients (HIFU : 1988, PT : 1376) ont été inclus de façon prospective dans 42 centres. Âge médian : 74,6 vs 65 ; PSA médian : 7,11 vs 6,97 (p = 0,4). Les EIG ont été transmis à l’Agence nationale selon les standards internationaux.Objectifs fonctionnels de l’étude : IPSS, continence (USP), fonction érectile (IIEF5), qualité de vie (EORTC QLQ-C30) à 12 mois.Résultats : les durées médianes d’hospitalisation initiale ont été respectivement de 1 et 4 jours. Cinquante-trois EIG Clavien–Dindo ≥ IIIa : 32 HIFU (1,6 %) et 21 PT (1,5 %). Aucun risque préalablement inconnu n’a été mis en évidence. Onze cas de fistules ont été rapportés : bras HIFU : 3/1988 (1,5/1000) fistules (2 uro-digestives, 1 urinaire) ; bras PT : 8/1376 (5,8/1000) fistules (7 urinaires, 1 digestive). Tous les cas ont été guéris. Vingt-trois décès ont été enregistrés et sont non imputables. Résultats fonctionnels (HIFU vs PT) : IPSS médian : 4 vs 3, IPSS QdV médian : 1 vs 1 ; continence score médian : 0 vs 1 (p < 0,005) ; IIEF5 (Δ médianes pré- et postopératoires) 1 vs −9 (p < 0,0001) ; EORTC QLQ-C30 : 90,7 vs 93,4.Conclusion : une proportion supérieure de réhospitalisations a été constatée après HIFU. Plusieurs explications sont suggérées : l’âge plus élevé des patients, la durée d’hospitalisation initiale très brève et la gestion non standardisée des accidents rétentionnels. En dehors de l’IPSS, les conséquences fonctionnelles (incontinence, dysfonction érectile) sont significativement moins importantes pour l’HIFU que pour la prostatectomie à 12 mois postopératoires. La qualité de vie post-thérapeutique des deux groupes reste élevée, et malgré une différence d’âge de près de dix ans, est comparable

Comparaison ultrasons focalisés de haute intensité vs prostatectomie totale dans le traitement à visée curative du cancer localisé de la prostate ISUP 1 et 2 : données carcinologiques intermédiaires

International audienceObjectifs : étude prospective multicentrique ouverte comparant l’efficacité carcinologique d’un traitement conservateur par ultrasons focalisés de haute intensité (HIFU) à la prostatectomie totale (PT) pour adénocarcinome prostatique localisé de stades ISUP 1 (non éligibles à la surveillance active) et ISUP 2. Nous communiquons des données carcinologiques intermédiaires à 18 mois.Méthodes : de février 2015 à septembre 2019, 3 364 patients (HIFU : 1 988, PT : 1 376) ont été inclus de façon prospective dans 42 centres. Âge médian : 74,6 vs 65 ; PSA médian : 7,11 vs 6,97 (p = 0,4) ; ISUP 1 : 0,39 ; ISUP 2 : 0,61. Objectif principal : survie sans traitement de rattrapage. Objectifs secondaires : bras HIFU : récidive biologique (RB) = PSA > Nadir + 2, PBP contrôle ; bras PT : R1, RB = PSA > 0,2 ng/mL.Résultats : objectif principal : à 18 mois, la probabilité de survie sans traitement de rattrapage est plus importante dans le bras HIFU comparé au bras prostatectomie HR = 0,31 IC95 % [0,23–0,42] soit un risque 3 fois plus élevé dans le groupe prostatectomie (p < 0,01). Objectifs secondaires : bras HIFU : récidives biologiques : 141 (10,6 %), PBP positives : 99 (7 %) ; bras PT : R1 = 25 % ; RB : 77 (9 %) à 18 mois.Conclusion : ces données intermédiaires à 18 mois ne permettent pas encore une comparaison équitable des deux bras en raison d’un profil évolutif spécifique à chaque groupe. Concernant l’objectif principal, la radiothérapie de rattrapage est probablement indiquée plus précocement après PT en raison de décisions de principe en RCP face à des marges positives. Le suivi des données carcinologiques pendant 30 mois, prévu dans l’étude, est justifié