BackgroundVitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity.MethodsPatients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777).FindingsIn 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels.InterpretationVEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer.

Background: Although radiation-induced mesenteritis or peritonitis can potentially exacerbate the risk of bowel obstruction, there are no data in the literature on the incidence of intestinal obstruction related to peptide receptor radionuclide therapy (PRRT). Methods: Records of all patients treated with 177 Lu-Dotatate at Moffitt Cancer Center between 4/2018 and 10/2019 were evaluated. The number of patients who developed bowel obstruction within 3 months of a 177 Lu-Dotatate treatment was divided by the total number of patients with preexisting peritoneal or mesenteric disease. Management strategies and outcomes were evaluated. Results: Out of a total of 159 patients treated, 81 had baseline mesenteric and/or peritoneal disease, among whom 5 patients (6%) experienced at least one episode of bowel obstruction within 3 months of treatment. Two of the patients underwent surgical exploration during obstruction describing a 'frozen abdomen'. All 5 responded at least temporarily to high-dose corticosteroid treatment and regained bowel function, but two patients eventually succumbed to progressive peritoneal disease. Conclusion: PRRT can lead to bowel obstruction in patients with mesenteric and/or peritoneal disease, likely by inducing inflammation. Corticosteroids can potentially play a role in treatment and prophylaxis.

The study demonstrated high rates for neoajduvant therapy completion (93.1 %) and pancreatectomy (54.5 %). After pancreatectomy, DSS was significantly improved (43 months), with a pathologic response demonstrated by 81.8 % and a complete response by 14.5 % of the patients. The results support further study of this borderline resectable pancreatic adenocarcinoma clinical pathway.

Background: Δ-Tocotrienol, a natural Vitamin-E analog, which significantly inhibits the growth and survival of pancreatic neoplastic cells by inhibiting signal transduction pathways which are altered in pancreatic neoplasia such as those driven by mutant K-ras. It is hypothesized that this micronutrient may have a role in the prevention and treatment of subjects with pancreatic exocrine neoplasia for which no effective chemoprevention treatment strategy currently exists. We have initiated a phase 1 dose escalation trial of Δ-tocotrienol in order to determine the recommended phase 2 dose and to characterize the safety, tolerability and biologically effective dose. Methods: Eligible patients must have a resectable tumor or cyst arising from the exocrine pancreas for which they are about to undergo resection. This pre-surgical trial design was chosen to allow for acquisition of sufficient tissue for detailed analysis of Δ-tocotrienol's biological effect on signaling within the patient's tumor. Between October 2009 and August 2010, 12 subjects were accrued to the first 4 of 6 planned dose escalation levels. Three patients each were treated at a total of 200, 400, 600 and 800 mg/day divided into 2 doses. Each dose is taken with meals. Treatment was daily for 13-15 days. Blood samples were collected for pharmacokinetic (PK) analysis pre-dose on day 1 and then at 30 min., 1,2,4,6,8 and 12 hours after dosing. Additional samples were obtained pre-dose on day 8 and on the day of surgery. Toxicity assessments were on days 1, 8, the day of surgery and 3-6 weeks after surgery. Study endpoints are to determine 1) safety and tolerability, 2) plasma PK, 3) to evaluate pharmacodynamic markers of Δ-tocotrienol activity such as apoptisis, Ki-67 and p27 expression and 4) the distribution of Δ-tocotrienol in normal and neoplastic pancreatic tissue. Results: Thus far no drug related toxicities have been observed. No elevation in the post-operative complication rate has been observed. To date, the first 12 patients enrolled were evaluated for PK parameters. Interpatient variability within and amongst cohorts was observed. This may be due to varying light breakfast intake amongst subjects leading to differing absorption. The data has been modeled by non-compartmental analysis and the dose independent PK parameters are as follows: Terminal half-life – 3.4 (+/-1.7)hrs; Tmax – 4.9 (+/-2.0) hrs; Volume of Distribution – 229.9 (+/-169.6) L; Clearance – 39.1 (+/-22.5) L/hr. Conclusion: Δ-tocotrienol is well tolerated at doses up to 800 mg daily. Further dose escalation to 3200 mg/day is planned. PD biomarker analysis will be presented. This study demonstrates the feasibility of employing a pre-surgical trial design for determination of biologically effective doses to modulate signaling pathways in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2011-1299

Cancer-related fatigue is one of the most important untreated symptoms of cancer, with a prevalence between 60 and 100%, but there has been a reluctance to prioritize fatigue and develop effective management strategies. The development of standards and guidelines will encourage a more systematic approach and help to stimulate further research. The Mersey Palliative Care Audit Group has developed guidelines for the assessment and management of fatigue. These guidelines were produced following a regional survey, which looked at both the educational needs of nurses, and the impact of fatigue on patients with advanced cancer.