motexafin-gadolinium and Pancreatic-Neoplasms

To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated.. Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography.. Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion.. Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

Topics: Aged; Antineoplastic Agents; Area Under Curve; Biliary Tract Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Liver Function Tests; Male; Metalloporphyrins; Middle Aged; Pancreatic Neoplasms

Unresectable pancreatic cancer (UPC) has low survival. With improving staging techniques and systemic therapy, local control in patients without metastatic disease may have increasing importance. We investigated whether the radiation dose used in chemoradiation (CRT) as definitive treatment for UPC and the CA 19-9 response to therapy have an impact on overall survival (OS).. From 1997-2009 46 patients were treated with CRT for non-metastatic UPC. Median prescribed RT dose was 54 Gy (range 50.4-59.4 Gy). All patients received concurrent chemotherapy (41: 5-fluorouracil, 5: other) and 24 received adjuvant chemotherapy.. 41 patients were inoperable due to T4 disease and 5 patients with T3 disease were medically inoperable. Five patients did not complete CRT due to progressive disease or treatment-related toxicity (median RT dose 43.2 Gy). Overall, 42 patients were dead of disease at the time of last follow-up. The median and 12 month OS were 8.8 months and 35%, respectively. By univariate analysis, minimum CA 19-9 post-CRT <90 U/mL was favorably associated with OS (12.3 versus 8.8 months, p = 0.012). Radiotherapy dose ≥54 Gy trended towards improved OS (11.3 versus 6.8 months, p = 0.089). By multivariable analysis, a delivered RT dose of ≥54 Gy (HR 0.47, p = 0.028) and minimum CA 19-9 post-CRT of <90 U/mL (HR 0.35, p = 0.008) were associated with OS.. CRT as definitive treatment for UPC had low survival. However, our retrospective data suggest that patients treated to ≥54 Gy or observed to have a minimum post-CRT CA 19-9 <90 U/mL had improved likelihood of long-term survival.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; CA-19-9 Antigen; Capecitabine; Carcinoma; Chemoradiotherapy; Chemotherapy, Adjuvant; Deoxycytidine; Disease Progression; Dose-Response Relationship, Radiation; Female; Fluorouracil; Gemcitabine; Genetic Therapy; Genetic Vectors; Humans; Kaplan-Meier Estimate; Male; Metalloporphyrins; Middle Aged; Pancreatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha