Search

Background and Objective: 177 Lu-Dotatate is a radio-labeled analog of somatostatin used in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. In order to prevent nephrotoxic effects of 177 Lu-Dotatate a co-infusion of amino acids (AA) is administered, resulting in a decrease in tubular renal reabsorption of 177 Lu-Dotatate. This study aimed to quantify the impact of AA co-infusion on the pharmacokinetics of 177 Lu-Dotatate in cancer patients and to evaluate its relationship with toxicity during the first treatment cycle (C1)., Methods: 7.4 GBq of 177 Lu-Dotatate was administered to 42 patients over a 30-min intravenous infusion. Infusion of AA started 2 h before and continued for 6 h after the infusion of 177 Lu-Dotatate. Radioactivity-time data (n = 346) were analyzed using NONMEM ® (version 7.2.0)., Results: 177 Lu-Dotatate pharmacokinetics was best described by a three-compartment model with first-order elimination. AA co-infusion had a significant effect ('fixed effect') on 177 Lu-Dotatate pharmacokinetics, with a mean value of 1.5-fold (95% confidence interval 1.03-1.97) increase in the elimination rate constant (k 10 ) from 0.204 to 0.306 h -1 , but this AA co-infusion effect was associated with a large inter-individual variability (IIV) of 104%. The individual k 10 values increased during concomitant AA infusion by a factor ranging from 1.01 to 21.3 for 27 patients, whereas the opposite effect was observed in 15 patients (range 0.36-0.99) of whom seven had a k 10 value lower than 0.85. This variability in AA effect contributed to the variability in 177 Lu-Dotatate plasma exposure (area under the concentration-time curve from time zero to Day 15 for C1 [AUC Day15 ]) that correlated with lymphopenia observed at Day 15 (p = 0.004)., Conclusions: A substantial effect of AA co-infusion on 177 Lu-Dotatate pharmacokinetics was shown but was associated with high IIV, contributing to IIV in hematological toxicity.

Vemurafenib improves the management of advanced melanoma due to selective inhibition of the mutated BRAF V600E kinase. FDG-PET-CT is a tool for the evaluation of the biologic impact of inhibiting mutant BRAF. With vemurafenib at day 15, all the patients had at least partial metabolic response. Reductions in uptake correlate with longer progression free survival. In this case, incomplete information provided by the patient led to the performance of his third PET 85 hours after the introduction of vemurafenib. This early case of complete metabolic response suggests that FDG-PET-CT is a useful marker of early biologic response to vemurafenib.

Innovative cancer therapies and advances in drug development have created new hopes for patients and health providers. The purpose of this article was to evaluate the discrepancies in the assessment of the magnitude of benefit of four new drugs (abiraterone acetate, enzalutamide, cabazitaxel, radium-223 dichloride) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The comparison was done among three European countries (UK, Germany and France) and Canada, according to the statement of each country and to the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale. Whereas those drugs are authorized by the European Medical Agency, one can observed that clear discrepancies in the magnitude of benefit assessment exist between selected countries, as well as between national pricing evaluation agencies and ESMO. However, price setting and reimbursement decisions remain national responsibility with differences in assessment of the medical value of new treatment across countries, leading to a heterogeneous accessibility to cancer treatments. In conclusion, several procedures have to be implemented to overcome the patchwork of administrative assessments. Among them, the assessment of medical value should be based on independent statements of learned societies, and the harmonization of access to cancer therapy in Europe has to be driven by a common European reimbursement and pricing policy., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy. Unlike breast cancer, the prognostic role of the human epidermal growth factor receptor-2 (HER-2) in ovarian carcinoma remains controversial., Methods: The aim of this preclinical study was to further characterise the biological, molecular and cellular effects of trastuzumab (Herceptin) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo., Results: In vitro assessments have shown that trastuzumab treatment inhibited total and phosphorylated HER-2. This was associated with inhibition of the phosphorylated form of phosphatase and tensin homologue (PTEN), mitogen-activated protein kinase and AKT, and the total level of p27(kip). Inhibition of PTEN is associated with phosphorylated MEK1/2 upregulation, suggesting a specific inhibition of the protein phosphatase function of PTEN. Moreover, trastuzumab induced the upregulation of RhoB. These molecular modifications promote inhibition of cell migration and potentially restoration of tumour cell contact inhibition. RhoB induction in NIH-OVCAR-3 control cell lines mimics the molecular and cellular trastuzumab long-time exposition effects. RhoB inhibition in NIH-OVCAR-3 long-time exposed to trastuzumab cell line reverses the cellular and molecular effects observed in this model. In vivo examinations have shown that these changes are also associated with the restoration of structural, morphological and normal functions of the peritoneum of an ovarian carcinoma mouse model., Conclusion: These results provide an indication of the mechanisms underlying the anti-tumour activity of trastuzumab that strongly implicate RhoB in an ovarian carcinoma model that does not show HER-2 amplification or overexpression. These findings highlight that trastuzumab effects involve a possible cross-talk between RhoB and PTEN in the early stages of tumour re-growth in a model of micrometastatic ovarian cancer.

Background The long-term efficacy of somatostatin analogues on insulinomas has not been studied. Design A prospective study to evaluate the response of octreotide in 21 patients with hypoglycaemia related to endogenous hyperinsulinism who were not treated by surgery. Results Reasons for not undergoing surgery were: refusal ( n = 3), old age with multiple diseases ( n = 5), unlocalized insulinomas ( n = 2), malignant unresectable insulinomas ( n = 5), multiple insulinomas ( n = 3) and diffuse β-cell disease ( n = 3). Hypoglycaemia was responsive to octreotide in 14 of the 21 patients. A short 100-µg octreotide test correctly predicted the efficacy of treatment in six patients with benign insulinomas. Octreoscan scintigraphy was positive in 6 of the 16 patients of whom three were responsive and three unresponsive to octreotide. Octreoscan scintigraphy was negative in 10 of the 16 patients, eight of whom were responsive to octreotide. Subcutaneous octreotide treatment was prolonged for > 6 months (7–144 months, 67 ± 47 months) in 11 responsive patients. No tachyphylaxis was observed. However, the octreotide dose had to be increased in two patients after 3 and 18 months, respectively. Only one patient suffered from symptomatic biliary lithiasis after 3 years of treatment. Conclusion Long-term octreotide treatment can be used to control hypoglycaemia in patients with endogenous hyperinsulinism who are not eligible for surgery; octreotide efficacy on hypoglycaemia could be predicted by a short 100 µg-octreotide test in patients with benign insulinomas, but was not correctly predicted by Octreoscan scintigraphy. [ABSTRACT FROM AUTHOR]