Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma.

BACKGROUND: BRAF inhibitors are approved in BRAFV600-mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAFV600-mutated melanoma and NSCLC. PATIENTS AND METHODS: Patients with advanced tumours other than BRAFV600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety. RESULTS: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAFV600 mutations and 10 with BRAFnonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib. CONCLUSION: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers.

Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

[RHESOU (Registry in HErault Specialized in Onco-Urology) : the first French Registry specialized in Onco-Urology. One-year experience]. / RHESOU (Registre de l'Hérault spécialisé en onco-urologie) : le premier registre français spécialisé en onco-urologie. Un outil méthodologique de recueil de données en onco-urologie. Bilan de faisabilité sur un an d'expérience.

PURPOSE: In 2016, the Herault tumor registry collected 1961cancers in urology (21.4 % from all Herault cancers this year). RHESOU was created to complete RTH' data with specific parameters in onco-urology. The aim of this study is to describe RHESOU and to give some examples with our first results. MATERIAL AND METHODS: In November 2018, RHESOU (Registry HErault Specialised in Onco-Urology) was founded with the same registry recommendations. It collects specific oncologic parameters and also complete RTH's data. For each urological cancer, a specific survey with different choices was performed to collect a maximum of data which could be present in patients' file. These surveys were used for urological cancers cases that live in Herault in 2017. RESULTS: In 2017, we collected 970 prostate cancers, 581 bladder cancers, 212 kidney cancers, 51 upper excretory tract cancers, 28 testicle cancers and 9 penil cancers. Our urological data collection gives many possibilities to create many requests for detailed analysis in urological cancers. In this article, we reported data from kidney, bladder and prostate cancers. CONCLUSIONS: RHESOU is a new tool opened to the different urologic corporations (urologists, pathologists, oncologists, radiotherapists, radiologists) that permits an overview in urological cancers in Herault. Finally, one important aim is that this tool will be adapted when new treatments or new important parameters appear in the years ahead. LEVEL OF EVIDENCE: 3.

Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study.

BACKGROUND: A minority of early breast cancer (EBC) patients treated with adjuvant or neoadjuvant chemotherapy have sufficient baseline vitamin D (vitD) level. This randomized phase III study assessed the safety and efficacy of a tailored, high-dose, oral vitD supplementation in restoring a normal 25-hydroxy vitD (25OHD) level in this population. PATIENTS AND METHODS: Participants received a 6-month conventional (C) vitD and calcium supplementation or a 6-month high-dose oral vitD regimen tailored on the deficiency (T) and a conventional calcium supplementation. The primary end point was the 6-month percentage of 25OHD serum level normalization. RESULTS: A total of 215 patients including 197 patients with vitD deficiency were recruited, and 195 patients were randomized (T, 100; C, 95). Compliance to the daily oral supplementation was 68.4% and 67% in the C and T arms, respectively. Discontinuous high-dose vitD compliance appeared higher in the T arm (77%). At 6 months, more patients presented with a normalized vitD level in the T arm (30% versus 12.6%; P = 0.003). Supplementation was well tolerated, and no significant difference in the treatment-related toxicity between the two arms was reported. Fifty-two patients without vitD normalization from the C arm switched to the T arm after 6 months. At 12 months, 44% of these patients achieved vitD normalization. CONCLUSION: A tailored high-dose oral vitD supplementation safely allows a higher percentage of the serum 25OHD level normalization compared with a conventional regimen in chemotherapy-treated EBC patients. As compliance to a daily oral supplementation remains poor in this setting, an adaptation of the treatment schedule is warranted. CLINICAL TRIAL NUMBER: NCT01480869.

Severe autoimmune hemolytic anemia following rituximab therapy in a patient with a lymphoproliferative disorder.

Rituximab (chimeric anti-CD20 IgG1 monoclonal antibody) is effective in the treatment of relapsed/refractory low-grade lymphomas of B-cell origin as well as in diffuse large B-cell lymphoma. Several reports also demonstrated the efficacy of rituximab for the treatment of autoimmune cytopenia, especially for cold agglutinin disease. We report the first case, to our knowledge, of rituximab-related autoimmune hemolytic anemia. The pathophysiological mechanisms remain unknown, although the drug could act through massive cytokines liberation after destruction of CD20 positive cells by rituximab.

Evaluation of imipenem 1.5 g daily in febrile patients with short duration neutropenia after chemotherapy for non-leukemic hematologic malignancies and solid tumors: personal experience and review of the literature.

Numerous studies have demonstrated efficacy of imipenem-cilastatin, 50 mg/kg/day, as first line therapy in febrile patients with neutropenia of short duration consecutive to cytostatic chemotherapy. However, only two studies used low dosage of this antibiotic as 1.5 g/day, in prospective, double blind, randomized clinical trials, in this indication. Efficacy and tolerability of imipenem-cilastatin 0.5 g three times daily IV in 30-min infusions, as first-line empiric therapy, were retrospectively evaluated in our hematological unit. From January 1996 to September 2000, 30 neutropenic patients (12 females) with 45 febrile episodes were included. Median age was 57.5 years (31-75). Twenty-four of them had lymphomas, 4 solid tumors and 2 myelomas. There were 13 clinically documented infections, (CD, 28.8%), 16 microbiologically documented infections, (MD, 35.6%) and 16 febrile episodes corresponding to fever of unknown origin, (FUO, 35.6%). The median neutrophils count on nadir (n = 44), was 67/mm3 (8-369). The median duration of neutropenia was 5 days (3-15). Bacteremia was observed in 10 patients, urinary tract infection in 3 patients. The most frequently isolated microorganism was Escherichia coli. The overall success rate of the first line therapy was 66.7%. Adverse events were observed in 11.1% of the patients without necessity to stop treatment. The MD infections showed a lower rate of success compared with CD infections and FUO. These data were in accordance with the previous studies. The importance of number of microorganisms (p = 0.007) and of infected sites (p = 0.01) appeared as prognostic factors (univariate analysis). Although imipenem-cilastatin has been used in numerous studies as empiric broad-spectrum antibiotic therapy in the treatment of febrile neutropenic cancer patients, the exact dosage of this antibiotic is still not standardized. However, utilization of this antibiotic in monotherapy at low dosage seems to us to be safe and effective as usual dosage in the antimicrobial treatment ofthe febrile patients with post chemotherapy neutropenia of short duration.

Individual 5FU-dose adaptation schedule using bimonthly pharmacokinetically modulated LV5FU2 regimen: a feasibility study in patients with advanced colorectal cancer.

AIM OF THE STUDY: SFU-dose adaptation optimal schedule using bimonthly LV5FU2 regimen was modulated by previously validated individual pharmacokinetic parameters, in 38 patients with advanced colorectal cancer. METHODS: At the 1st cure, 5F-U pharmacokinetic parameters (particularly the area under curve (AUC) in mg.h/l.m2) were calculated in all patients. In 19 patients (A), 5FU infusion doses were progressively increased from 25 to 50% (at every cycle), according to AUC levels from 2nd to 6th; in 19 consecutive patients (B), 5FU infusion doses were increased, at the same time, at the 2nd cure, according to a protocol taking in account AUC at the 1st cure: increase of 150% it AUC < 5, of 100% if 5 < AUC < 10, of 50% if 10 < AUC < 15, of 25% if 15 < AUC < 20 in case of toxicity < grade 3. RESULTS: a) AUC in all patients, at the beginning of the treatment averaged 9.05 +/- 3.115 (range from 3.9 to 16.41). Large interindividual variability was observed. b) FU infusion doses at the 2nd cure, increased 40% in group A and 82% in group B. Corresponding AUC increased respectively of 42% and 96%. 3-WHO toxicity 23 (per cycle) occurred not very frequently (8% haematological, 6% digestive and 2% cutaneous toxicity) and remained acceptable. CONCLUSION: This feasibility study established a 5FU-dose intensification optimal strategy within the bimonthly LV5FU2 schedule with a control for the risk of toxicity. This study constitutes the basis for a multicentre phase II trial to evaluate the importance of this approach in terms of efficacy and survival.

Pharmacokinetics of 5-fluorouracil (5-FUra) in patients with metastatic colorectal cancer receiving 5-FUra bolus plus continuous infusion with high dose folinic acid (LV5FU2).

The pharmacokinetics of 5-fluorouracil (5-FUra) were investigated in 16 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV 200 mg/m2) followed by 5-FUra bolus (400 mg/m2) and continuous infusion (600 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. The concentrations of 5-FUra at the end of the loading dose averaged 30.7 +/- 13.2 micrograms/ml (i.e., 236 microM). The steady-state plasma concentration averaged 0.31 +/- 0.11 microgram/ml (i.e., 2.4 microM). 5-FUra plasma levels declined rapidly after the end of infusion with an apparent elimination half-life of 7.08 +/- 3.21 minutes. Clearance ranged from 776 to 3023 ml/min/m2. Large patient-to-patient variations in plasma 5-FUra concentrations were observed. No toxicity greater than WHO grade 2 was seen. One patient experienced grade 1 stomatitis and two others experienced grade 1 and 2 myelosuppression. One patient developed diarrhoea and another suffered asthenia. Nausea and vomiting were observed in 5 patients.