Daily Oral Everolimus Activity in Patients with Metastatic Pancreatic Neuroendocrine Tumors after Failure of Cytotoxic Chemotherapy

Abstract

Background: Vatalanib inhibits endothelial growth factor receptor (VEGFR) by binding to the intracellular kinase domain of all 3 VEGFRs. Neuroendocrine tumors (NETs) express VEGF receptors. Inhibiting VEGF with bevacizumab, sorafenib, and sunitinib reduced time to progression or tumor size in some NET patients (pts). To determine vatalanib_s tolerability and efficacy in NET pts, a trial was performed.Methods: Eligibility criteria included NET pts with biopsy-proven metastatic disease and rising biomarkers on somatostatin analog therapy. Eligible pts had measurable lesions, a KPS 9 60%, and normal hematologic, renal, and hepatic functions. A stable octreotide LAR dose, not exceeding 30 mg monthly, was required. Initial total daily dosing of vatalanib was 1,250 mg. Biochemical responses within a 90 day interval were the primary response criteria. Secondary endpoints included radiographic/scintigraphic scan changes and safety.Results: Twenty-four pts (12 males) were enrolled between 5/20/05 to 5/28/09.The median age (range) was 60.4 (25Y74). Eighteen pts were evaluable for efficacy and safety. Four pts continue on therapy. One pt withdrew consent; 2 pts died of disease prior to first cycle initiation; 1 pt was allergic to vatalanib. Six pts required a 10Y28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase, G2 proteinuria, G2 headache, and G3 nausea/vomiting. Resumption of vatalanib at 1,000 mg daily was well tolerated in 2 pts and 750 mg in another. One pt developed carcinoid crisis with fever, flushing, and rising 5HIAA. Grade 1 nausea occurred in 15 pts with antiemetics required for 4 pts. A partial (9 50% decrease) biochemical response occurred in 4 pts. The observed radiographic and scintigraphic responses in 16 pts have shown progressive disease in 6 and stable/minimal response in 10 pts. Accrual continues.Conclusions: Vatalanib is well tolerated in most pts and results in a 24% biochemical partial response rate in NET pts with rising biochemical markers on somatostatin analog therapy.Background: Health-related quality of life (HRQL) can be disrupted in patients with chronic illnesses such as cancer. The study evaluated the HRQL burden of patients with neuroendocrine tumor (NET), testing the hypothesis that NET patients have reduced HRQL compared to the general United States population.Methods: NET patients were invited via email to participate in an online, anonymous survey. This survey consisted of a brief set of demographic and disease-related items, the RAND-36 and the PROMIS-29, the latter two of which are standardized measures of HRQL with general population normative values available for comparison. Norm-based scores were calculated for all subscales, such that a score of 50 represents the mean of the general population (standard deviation = 10). For the anxiety and fatigue subscale, higher scores (9 50) represent worse outcome. Results are presented as means and 95% confidence intervals.Results: Data collection is currently ongoing but at the time of this writing 565 eligible participants ...

Autophagy as a mediator of chemotherapy-induced cell death in cancer

“…Specific mTOR inhibitors have been developed and validated, and two of them (Everolimus and Temsirolimus) are now approved for the treatment of renal cell carcinoma and mantle cell lymphoma [75]. Everolimus indeed induces massive autophagy in vivo, with reduced tumoral mass, for example in leukemia [76], in advanced pancreatic tumors [77] and in many other tumors [78]. Concomitant combinations of etoposide, cisplatin or doxorubicin with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity [79].…”

Pancreatic neuroendocrine neoplasms: Updates on genomic changes in inherited tumour syndromes and sporadic tumours based on WHO classification

“…Other phase II trials evaluated numerous new strategies using targeted agents, e.g. temsirolimus (mTORC1 inhibitor), pazopanib (multi-target tyrosine kinase inhibitor), erlotinib (EGFR inhibitor), surufatinib (multi-target tyrosine kinase inhibitor), MK-2206 (Akt inhibitor), BEZ235 (mTORC1/PI3K inhibitor) or X-82 (VEGFR/PDGFR inhibitor) have been completed or are currently underway [97,99,[101][102][103][104][105][106][107][108] (Table 2).…”

The contribution of antiangiogenic agents and mTOR inhibitors to the treatment of endocrine tumours of the gastro-intestinal tract

“…L'étude RADIANT I était un essai de phase 2 internationale multicentrique étudiant l'effet de l'everolimus (10 mg/j) chez des patients porteurs d'un CEBD pancréatique métastatique en progression après chimiothérapie [19]. Cet essai comprenait deux bras : avec ou sans octréotide LP30 mg/28j, permettant d'inclure les patients qui étaient antérieurement sous analogue de la somatostatine retard.…”

“…Le profil de tolérance de l'everolimus est tout à fait acceptable et est rapporté dans le Tableau 2 pour l'étude RADIANT I[19].…”

“…Effets indésirables de l'everolimus en monothérapie dans l'étude de phase 2, RADIANT I[19] et du sunitinib dans l'étude de phase 3[10] chez des patients ayant un CEBD du pancréas ND : non disponible.…”