Is ovarian recovery after chemotherapy in young patients with early breast cancer influenced by controlled ovarian hyperstimulation for fertility preservation or tumor characteristics? Results of a prospective study in 126 patients.

Young individuals, aged <40 years, represent 7% of all patients with early breast cancer (EBC), most of whom receive chemotherapy. Preserving future fertility in these patients has become a major concern. This prospective study assessed ovarian function during and after chemotherapy according to patient and tumor characteristics and evaluated the outcome of controlled ovarian hyperstimulation (COH). Ovarian reserve was evaluated in terms of amenorrhea duration and by longitudinal serum anti-Müllerian hormone (AMH) level variations measured at study entry, during treatment and until 24 months thereafter. COH has been proposed for patients receiving adjuvant chemotherapy. We studied the association between clinical factors and ovarian function using Cox models and logistic regression. In this young population (age < 38 years, median = 32), 85 of 90 evaluable patients (94%) experienced chemo-induced amenorrhea, including six persistent amenorrhea and one chemotherapy-induced definitive ovarian failure. Overall, 33% of patients still had undetectable AMH values 12 months after the end of chemotherapy, although most had recovered spontaneous and regular menstrual function. No specific factor was associated with clinical or biological late ovarian dysfunction, except for age and baseline AMH value. Overall, 58 patients underwent COH. The mean number of total retrieved oocytes and metaphase II oocytes were of 11.7 and 6.9, respectively. Thus, our study confirms the importance of fertility preservation in young patients with EBC. Our findings indicate that sequential chemotherapy is associated with a higher risk of persistent amenorrhea. There was no significant association between tumor characteristics, fertility preservation or recovery of ovarian reserve.

A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib in non-adipocytic sarcoma patients previously treated with both chemotherapy and pazopanib.

BACKGROUND: Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. PATIENTS AND METHODS: This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). RESULTS: From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). CONCLUSION: The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

[Evolution of the regulatory framework in clinical research]. / Évolution du cadre réglementaire de la recherche clinique.

The regulatory framework of clinical research is necessary to ensure the protection of participants and to define the actors and their responsibilities. Although main principles have been set up in 1947 with the Nuremberg Code, this regulatory framework is relatively recent in Europe: development of national regulations in the years 1980-1990, first European Directive regarding clinical trials in 2001. In France, as 2006 was marked by the implementation of this first "Clinical trials Directive", the end of the year 2016 and the following months were marked by the enforcement of the Jardé law (previously modified in order to reinforce the regulatory requirements following the death of an healthy volunteer in a clinical trial). As clinical researches involve processing of personal data, the entry into force, on 25 May 2018, of the General Data Protection Regulation (GDPR) had also consequences on their implementation. Finally, regarding clinical trials on drugs, the "Clinical trials Regulation" repealing the Directive, voted in 2014, should come into force in the coming months.

Reappraisal of eligibility criteria in cancer clinical trials.

PURPOSE OF REVIEW: We aimed to summarize the recent reflections and collaborative initiatives pertaining to the definition of more appropriate eligibility criteria in cancer clinical trials. RECENT FINDINGS: There is an intrinsic tension between two opposite purposes when it comes to defining eligibility criteria: on the one hand, participants must be protected, and on the other, the study population must be defined as accurately as possible. However, stringent eligibility criteria jeopardize the feasibility of trials, and, consequently, the generalizability of trial results. Therefore, interdisciplinary working groups under the auspices of the American Society of Clinical Oncology and Friends of Cancer Research propose to adapt/relax some of the classical eligibility criteria. SUMMARY: In-depth reflection of the existing eligibility criteria, and implementation of recent recommendations are needed.

Reporting adverse events in cancer surgery randomized trials: A systematic review of published trials in oesophago-gastric and gynecological cancer patients.

BACKGROUND: Few reports describe how adverse events (AEs) are reported in cancer surgery trials. MATERIALS AND METHODS: We systematically reviewed 179 consecutive study reports issued between January 1, 1990 and November 15, 2014, which investigated surgery in oesophago-gastric (OG) or gynecologic (GY) cancer patients. Based on the reviewed reports, we assessed how AEs were reported according to CONSORT statement. RESULTS: Morbidity assessment was the primary objective of 56 studies (31.3%). Postoperative AEs were described in 161 studies (90%). Definition of AEs and grading scale (NCI-CTC AE, Dindo-Clavien scale, etc …) were given in 27.3% and 16.8% of studies, respectively. AEs were reported by event and grade in 8.3% of studies. Definition of expectedness, seriousness, causality and safety population were present in 0.5%, 1.1%, 7.8%, and 7.2% of the studies, respectively. Reporting of AEs did not improve over time nor better in high-impact factor journals. CONCLUSION: The reporting of AEs in cancer trials investigating surgery needs to be improved.

Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial.

BACKGROUND: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial. METHODS/DESIGN: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients. DISCUSSION: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012).

Prognostic factors among cancer patients with good performance status screened for phase I trials.

BACKGROUND: Selecting patients for phase I trials in order to investigate cytotoxic agents is challenging, since there is no clear and reliable guidance to estimate life expectancy among these patients. We retrospectively assessed prognostic factors in cancer patients screened for Phase1 trials between October 1997 and October 2002. METHODS: 148 consecutive patients, screened for inclusion in phase I trials investigating cytotoxic agents, were included in the present study. 70 out of them actually received phase I trial regimens. Univariate and multivariate analysis were undertaken to determine the prognostic factors for overall survival (OS) from the date of screening. RESULTS: The median OS of the 148 patients was 5.7 months. Ninety-two percent of them had PS