Efficient Loading of cisplatin into Superabsorbent Polymer Microsphere in the treatment of hepatocellular carcinoma.

Background: Although Superabsorbent Polymer (SAP) microsphere has been useful in treatment of multiple and large hepatocellular carcinoma, efficient loading procedure of cisplatin onto SAP was not established. Loading efficiency of cisplatin was evaluated from the viewpoint of passive concentration gradient and ionic strength. Methods: To load cisplatin into SAP particle, 50mg of cisplatin powder was dissolved in three manners of aqueous solutions: (a) 50mg of cisplatin powder plus 35ml of warmed physiological saline solution (0.9%), (b) 5ml of physiological saline solution (0.9%) plus a half of solution (5ml) of the product made from 50mg of cisplatin powder in 10ml of iohexol 350mgI/ml, and (c) 10ml of iohexol 350mgI/ml plus 0.25ml of 10% NaCl solution Results: Cisplatin dissolved sufficiently in all the three methods. Average amounts of loaded cisplatin into SAP particles were 1.7mg in solution (a), 6.6mg in solution (b), and 11.8mg in solution (c). Since alteration of ionic strength in the method (c) significantly affect the extent of SAP swelling, addition of 0.25ml of 10% NaCl was unquestionably necessary. Release of cisplatin from SAP was evidently gradual, showing 83.1% after 6 hours in static elution experiment and 68.6% after 1 hour in dynamic elution experiment. Conclusions: Cisplatin-loaded SAP may act as a drug delivery system for treatment of liver cancer, and loading of cisplatin should be consciously performed considering cisplatin concentration and ionic strength. (225words)

Phase I/II study of transcatheter arterial chemoembolization with cisplatin powder and degradable starch microspheres for unresectable hepatic metastases from colorectal cancer refractory to systemic standard chemotherapy.

577 Background: We conducted a phase I/II study of novel transcatheter arterial chemoembolization with cisplatin powder and degradable starch microspheres (DSM) to determine the recommended dose (RD) and to assess the efficacy and safety. Methods: Cisplatin powder and DSM mixing solution was administered followed by the injection of DSM alone via hepatic artery every 4 weeks. In phase I, cohorts of 3 patients received escalating dose of cisplatin (50, 65 and 80mg/m2), and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response, toxicity, hepatic progression free survival (H-PFS) and 6-month overall survival (OS) rate. Results: A total of 24 patients (male 16, female 8; mean age 63.0, range 45-79; colon 15, rectal 9) were enrolled in this study. FOLFOX had previously been administered to all patients, irinotecan-containing regimen to 12 and bevacizumab and/or cetuximab to 14. During phase I (n= 9 patients), maximum tolerated dose was not reached and cisplatin 80 mg/m2 was recommended for a phase II. Phase II enrolled 15 patients. The following grade 3 toxicities were observed: platelets reduction 16.6%, aspartate transaminase elevation 38.8%, alanine transaminase elevation 16.6%, hyponatremia 11.1%, cholecystitis 5.5%. The tumor response rate was 53.3% (CR 0, PR 8, SD 6, and PD 1). The median H-PFS was 6.3 months (95% CI; 2.71 to 9.88) and 6 -month OS rate was 86.7%. Conclusions: This phase I/II study demonstrates that novel transcatheter arterial chemoembolization with 80 mg/m2 cisplatin powder and DSM is well tolerable, and can produce a high response rate with encouraging survival duration. Further clinical trials are warranted. No significant financial relationships to disclose.

Phase II study of segmental transcatheter arterial chemoembolization using ethiodized oil mixed with cisplatin powder for unresectable hepatocellular carcinoma.

292 Background: Conventional transcatheter arterial chemoembolization (TACE) using with ethiodized oil mixed with epirubicin or doxorubicin hydrochloride mainly has been widely adapted for intermediate-stage hepatocellular carcinoma (HCC). However, cisplatin has stronger effect for HCC than epirubicin and in the recent years cisplatin powder was commercially available in Japan and then we can use cisplatin powder mixed with ethiodized oil for HCC. We conducted a phase II study to assess the safety and efficacy of segmental or subsegmental (Seg/Subseg) TACE using a suspension of cisplatin powder mixed with ethiodized oil for unresectable HCC. Methods: Twenty patients with single-nodule HCC that was not indicated for surgical treatment or local ablation therapy were enrolled in this study. Seg/Subseg-TACE was performed by using a 2-F tip microcatheter at a distal portion of the subsegmental artery supplying the tumor. Subsequently, the feeding artery was embolized with gelatin sponge particles. The suspension was prepared by mixing 100 mg of cisplatin powder with 10 ml of ethiodized oil. Primary endpoint of this phase II trial was 2-year local disease free survival (DFS); secondary endpoints evaluated were the safety, time to progression (TTP), and 2-year overall survival (OS) rate. Results: A total of 20 patients (male 15, female 5; mean age 72.4, range 62-83; Child Pugh's A 20) were treated single nodule HCC with Seg/subseg TACE. Median tumor size was 2.6cm (range1.2-5.0cm). The 2-year local DFS was 63.2 %. The following grade 3 or 4 toxicities were observed: platelets reduction 5%, aspartate transaminase elevation 55%, alanine transaminase elevation 40% and alkaline phosphatase elevation 5%. The median TTP was 17.6 months (95%CI, 5.25 to 29.9) and the 2-year OS rate was 94.7%. Conclusions: This phase II study demonstrates that segmental or subsegmental transcatheter arterial chemoembolization using a suspension of cisplatin powder mixed with ethiodized oil is well tolerable, and may achieve significant local tumor control and prolong survival. Further clinical trials are warranted. No significant financial relationships to disclose.