Phase I Study of Lenvatinib and Capecitabine with External Radiation Therapy in Locally Advanced Rectal Adenocarcinoma

BackgroundNeoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation.MethodsIn this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer.ResultsA total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes.ConclusionThe combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified.Clinical Trial Registration {"type":"clinical-trial","attrs":{"text":"NCT02935309","term_id":"NCT02935309"}}NCT02935309     

Intrahepatic Cholangiocarcinoma Treated with Transarterial Yttrium-90 Glass Microsphere Radioembolization: Results of a Single Institution Retrospective Study

Purpose

To evaluate the efficacy and safety of transarterial yttrium-90 glass microsphere radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC).

MK-2206, an Akt inhibitor,enhances carboplatinum/paclitaxel efficacy in gastric cancer cell lines

Background Several molecularly-targeted agents are being evaluated in gastric cancer cell lines. In this study we evaluated the synergistic potential of MK-2206, an oral potent allosteric Akt inhibitor, in combination with chemotherapeutic agents in human gastric cancer cell lines. Materials and Methods We evaluated effects of MK-2206 on cell growth and cell signaling using a panel of gastric cancer cell lines AGS, SNU-1 and SNU 16. The analysis of drug combinations was conducted by using CellTiter-Blue™ Cell Viability Assay which yielded the combination index (CI). MK-2206 and representative chemotherapy agent were further evaluated regarding their effects on Akt inhibition and downstream targets using western blots probed with the appropriate antibodies. We assessed the combination of MK-2206 and chemotherapy in three different treatment sequences. Results We demonstrated in vitro synergistic efficacy of MK-2206 when combined with carboplatinum and paclitaxel in the three cell lines examined. Efficacy was dose dependent. We assessed the combination of MK-2206 and carboplatinum/paclitaxel in three different treatment sequences; 24 h of exposure to combination chemotherapy followed by a 48 h exposure to MK-2206 resulted in the highest synergistic antiproliferative effect in all cell lines. On the other hand, the reverse sequence (MK-2206 followed by chemotherapy) and the concurrent treatment schedule were slightly synergistic or additive as well. The effects of MK-2206 on p-Akt and other downstream targets was reported. Conclusions Our findings suggest that Akt inhibition augments the efficacy of existing gastric cancer therapeutics (carboplatinum and paclitaxel); thus, MK-2206 is a promising agent to treat gastric cancer patients who receive these cytotoxic agents. The magnitude of synergy depended on the treatment sequence; a schedule of MK-2206 dosed before or concurrently with chemotherapy was not as effective as being dosed after chemotherapy. Further experiments addressing MK-2206’s mechanism of action in combination with chemotherapy are needed.     

PET/CT Fusion Scan Enhances CT Staging in Patients with Pancreatic Neoplasms

Background  The role of fusion positron emission tomography/computed tomography scans (PET/CT) in staging of patients with pancreatic neoplasms (PN) is poorly defined. PET/CT may serve as an adjunct to standard imaging by increasing occult metastases detection. The purpose of this study was to assess the additional value, in relation to computed tomography (CT), of PET/CT imaging for patients with PN. Methods  Eighty-two patients with potentially resectable PN underwent staging with PET/CT and CT of the chest and abdomen. Sensitivity of diagnosing pancreatic cancer by PET/CT avidity was evaluated. The sensitivity of detecting metastases was compared between PET/CT, standard CT, and the combination of PET/CT and CT. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered due to PET/CT. Results  The sensitivity and specificity of PET/CT in diagnosing pancreatic cancer were 89% and 88%, respectively. Sensitivity of detecting metastatic disease for PET/CT alone, standard CT alone, and the combination of PET/CT and CT were 61%, 57%, and 87%, respectively. Findings on PET/CT influenced the clinical management in seven patients (11%), two with a supraclavicular lymph node (LN), two occult liver lesions, two peritoneal implants, and one peri-esophageal LN. Conclusion  This study evaluated PET/CT in the initial work-up of patients with PN. PET/CT increased sensitivity (87%) for detection of metastatic disease when combined with standard CT. In invasive cancer, PET/CT changed the management in 11% of our patients. PET/CT should be considered in the initial work-up of patients with potentially resectable pancreatic lesions.     

Biomarkers Predict Outcomes Following Cytoreductive Surgery for Hepatic Metastases from Functional Carcinoid Tumors

BACKGROUND: Cytoreductive therapy for metastatic carcinoid provides symptomatic relief and improvement in overall survival. We evaluated whether CgA and 5HIAA could predict symptomatic relief and control of disease progression after cytoreductive surgery. METHODS: We retrospectively reviewed 70 patients who underwent cytoreductive surgery for neuroendocrine hepatic metastases between 1996 and 2005. Twenty-two patients had pre and post-operative CgA and/or 5HIAA levels measured. Reduction of biomarkers following cytoreduction was correlated with patient symptoms and progression of disease following surgery. RESULTS: Our study consisted of 14 males and 8 females with a mean age of 55 (+/-12 years). Median follow-up was 18 months (range 5-64 months). Six patients (26.1%) had complete (R0) cytoreduction, while 4 (17.4%) and 13 (56.5%) had microscopic (R1) and gross (R2) disease remaining. All patients reported improvements in their symptoms, with 12 (54.5%) reporting complete resolution (CR) and 10 (45.5%) reporting partial resolution (PR). Reduction of CgA of >or= 80% was highly predictive of complete resolution of symptoms (P = 0.007) and stabilization of disease (P = 0.034). Reduction of 5HIAA levels of >or= 80% (or normalization) was predictive of symptomatic relief, but not progression of disease (P = 0.026 and P = 0.725). Five of six patients who had R0 resections had CR and were free of disease at last follow-up (median 24.5 months, range: 11-48, P = 0.002). CONCLUSIONS: We conclude that >or= 80% reduction in CgA level following cytoreductive surgery for carcinoid tumors is predictive of subsequent symptom relief and disease control. Substantial reduction in CgA is associated with improved patient outcomes, even after incomplete cytoreduction.