review of literature on clinical pancreatology - The Pancreapedia

ate in patients with pancreatic cancer [539].Gemcitabine and iridotecanSingle-agent gemcitabine has been established as standard treatment for advancedpancreatic cancer since clinical studies have shown an improvement in overall survival andsignificant clinical benefit when compared to the best supportive care despite low overallobjective response. Several phase II studies have tested other single agents and differentgemcitabine-based regimens in pancreatic cancer, but both response and survival rates haveremained low. Irinotecan, a topoisomerase I inhibitor currently approved for the treatment <strong>of</strong>metastatic colon cancer, has also demonstrated improved response rate in patients withpancreatic cancer. Our purpose was to determine the activity and toxicity <strong>of</strong> this regimen inpatients with The or metastatic pancreatic cancer. Patients with histologically confirmedpancreatic adenocarcinoma received gemcitabine 1000 mg/m 2 plus irinotecan 100 mg/m 2intravenously on days 1, 8, and 15 <strong>of</strong> a 28-day cycle for 6-8 months. From 2004 to 2006, 33patients were entered into this study, 32 <strong>of</strong> whom were evaluable for treatment response,toxicity, median time to progression, and median survival. Characteristics included a medianage <strong>of</strong> 63 years (range 41-79). One patient discontinued treatment due to adverse effects.The total number <strong>of</strong> cycles administered was 188 and the median number <strong>of</strong> cycles forpatients was 6 (range 2-7). Thirty-two patients were assessable for toxicity and response.Grade 3 hematological toxicity occurred in 9 percent <strong>of</strong> patients and was primarilyneutropenia. No grade >2 gastrointestinal toxicities or death due to treatment were observed.The most frequent nonhematological adverse event was fatigue. Ten patients responded totreatment with two complete responses (6 %) and eight partial responses (25 %), for anoverall response rate <strong>of</strong> 31 percent; 11 patients achieved stable disease (34 %). The mediantime to tumor progression and the median survival were 9 (95 % confidence interval 6.0 to12.4) and 12 (95 % confidence interval 7.7 to 15.9) months, respectively, with a 2-yearsurvival <strong>of</strong> 22 percent. On the basis <strong>of</strong> this trial, the combination <strong>of</strong> gemcitabine plusirinotecan, administered in a weekly schedule and at this dose, is well tolerated and <strong>of</strong>fersencouraging activity in the treatment <strong>of</strong> advanced and/or metastatic pancreatic cancer [540].Gemcitabine and proton irradiationOne study evaluated the efficacy <strong>of</strong> combining proton irradiation with gemcitabine, and therole the inhibitor <strong>of</strong> apoptosis proteins survivin and X-linked inhibitor <strong>of</strong> apoptosis protein(XIAP) play in the radiosensitive versus radioresistant status <strong>of</strong> pancreatic cancer. Theradioresistant (PANC-1) and radiosensitive (MIA PaCa-2) pancreatic carcinoma cells'response to combined gemcitabine and proton irradiation was compared. Gemcitabine andproton irradiation resulted in increased survivin levels with little apoptosis. However,combination therapy resulted in robust apoptotic induction with a concomitant survivin andXIAP reduction in the MIA PaCa-2 cells with little effect in the PANC-1 cells. Small interferingRNA studies confirmed a role for XIAP in the radioresistance <strong>of</strong> PANC-1 cells. The datademonstrate that combining gemcitabine and proton irradiation enhances apoptosis inhuman pancreatic cancer cells when XIAP levels decrease. Therefore, XIAP may play animportant role in human pancreatic cancer proton radioresistance [541].Gemcitabine experimentallyA test the efficacy <strong>of</strong> liposomal gemcitabine (GemLip) on primary tumor and metastasesusing the pancreatic tumor cell line AsPC1 implanted orthotopically into nude mice wasmade. In vitro, the IC 50 s for GemLip and gemcitabine were 20 nM and 140 nM, respectively.However, when applied against established tumors, GemLip (8 mg/kg) blocked tumor growthfor 5 consecutive weeks according to bioluminescence measurements in vivo. Gemcitabine(240 mg/kg) had no effect on luciferase-monitored tumor growth. When analyzed at the time<strong>of</strong> necropsy, GemLip strongly reduced tumor size, whereas gemcitabine only weakly affectedtumor size. Empty liposomes had no effect on the tumor size. GemLip and empty liposomesboth significantly interfered with the metastatic spread to the liver, as measured usingluciferase assays. In addition, they showed effects against spleen, as well as peritoneal