Phase I study of miriplatin combined with transarterial chemotherapy using CDDP powder in patients with hepatocellular carcinoma

BMC Gastroenterology

Yutaka Aoyagi¹  Minoru Nomoto¹  Satoshi Yamagiwa¹  Hirokazu Kawai¹  Masato Igarashi¹  Takeshi Yokoo¹  Masaaki Takamura¹  Yasushi Tamura¹  Takeshi Suda¹  Kenya Kamimura¹ 

[1] Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

关键词: Phase I clinical trial;    Cisplatin powder;    Hepatocellular carcinoma;    Miriplatin;   

Others  :  1088664
DOI  :  10.1186/1471-230X-12-127

 received in 2012-05-14, accepted in 2012-09-17,  发布年份 2012

【 摘 要 】

Background

There is no standard therapeutic procedure for the hepatocellular carcinoma (HCC) in patients with poor hepatic reserve function. With the approval of newly developed chemotherapeutic agent of miriplatin, we have firstly conducted the phase I study of CDDP powder (DDP-H) and miriplatin combination therapy and reported its safety and efficacy for treating unresectable HCC in such cases. To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for the combination of transarterial oily chemoembolization (TOCE) and transarterial chemotherapy (TAC) using miriplatin and DDP-H for treating unresectable hepatocellular carcinoma (HCC).

Methods

Transarterial chemotherapy using DDP-H was performed through the proper hepatic artery targeting the HCC nodules by increasing the dose of DDP-H (35–65 mg/m²) followed by targeting the HCC nodules by transarterial oily chemoembolization with miriplatin.

Results

A total of nine patients were enrolled in this study and no DLT was observed with any dose of DDP-H in all cases in whom 80 mg (median, 18–120) miriplatin was administered. An anti-tumour efficacy rating for partial response was obtained in one patient, while a total of four patients (among eight evaluated) showed stable disease response, leading to 62.5% of disease control rate. The pharmacokinetic results showed no further increase in plasma platinum concentration following miriplatin administration.

Conclusion

Our results suggest that a combination of DDP-H and miriplatin can be safely administered up to their respective MTD for treating HCC.

Trial registration

This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003541).

【 授权许可】

   
2012 Kamimura et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 2003, 362:1907-1917.
• [2]Villanueva A, Llovet JM: Targeted therapies for hepatocellular carcinoma. Gastroenterology 2011, 140:1410-1426.
• [3]Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, Tibballs J, Meyer T, Patch DW, Burroughs AK: Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007, 30:6-25.
• [4]Lencioni R: Loco-regional treatment of hepatocellular carcinoma. Hepatology 2010, 52:762-773.
• [5]Ishikawa T: Future perspectives on the treatment of hepatocellular carcinoma with cisplatin. World J Hepatol 2009, 1:8-16.
• [6]Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003, 37:429-442.
• [7]Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J: Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002, 359:1734-1739.
• [8]Oliveri RS, Wetterslev J, Gluud C: Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011, 16:CD004787.
• [9]Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, Ayuso C, Castells L, Montana X, Llovet JM, Bruix J: Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007, 46:474-481.
• [10]Groupe dEtude et de Traitement du Carcinome Hepatocellulaire: A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire. N Engl J Med 1995, 332:1256-1261.
• [11]Chan AO, Yuen MF, Hui CK, Tso WK, Lai CL: A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma. Cancer 2002, 94:1747-1752.
• [12]Okusaka T, Kasugai H, Shioyama Y, Tanaka K, Kudo M, Saisho H, Osaki Y, Sata M, Fujiyama S, Kumada T, Sato K, Yamamoto S, Hinotsu S, Sato T: Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J Hepatol 2009, 51:1030-1036.
• [13]Yoshikawa M, Ono N, Yodono H, Ichida T, Nakamura H: Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 2008, 38:474-483.
• [14]Kinami Y, Miyazaki I: The superselective and the selective one shot methods for treating inoperable cancer of the liver. Cancer 1978, 41:1720-1727.
• [15]Nagasue N, Yukaya H, Okamura J, Kuroda C, Kubo Y, Hirai K, Tanikawa K, Okita K, Ando K, Tamura K: Intra-arterial administration of epirubicin in the treatment of non-resectable hepatocellular carcinoma. Epirubicin Study Group for Hepatocellular Carcinoma. Gan To Kagaku Ryoho 1986, 13:2786-2792.
• [16]Kishimoto S, Noguchi T, Yamaoka T, Fukushima S, Takeuchi Y: Antitumor effects of a novel lipophilic platinum complex (SM-11355) against a slowly-growing rat hepatic tumor after intra-hepatic arterial administration. Biol Pharm Bull 2000, 23:344-348.
• [17]Shimakura J, Fujimoto K, Komuro S, Nakano M, Kanamaru H: Long-term disposition of a novel lipophilic platinum complex SM-11355 in dog after intrahepatic arterial administration: highly sensitive detection of platinum and radioactivity. Xenobiotica 2002, 32:399-409.
• [18]Kishimoto S, Ohtani A, Fukuda H, Fukushima S, Takeuchi Y: Relation between intracellular accumulation and cytotoxic activity of cis-[((1R, 2R)-1, 2-cyclohexanediamine-N, N')bis(myristato)]platinum(II) suspended in Lipiodol. Biol Pharm Bull 2003, 26:683-686.
• [19]Hanada M, Baba A, Tsutsumishita Y, Noguchi T, Yamaoka T, Chiba N, Nishikaku F: Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis. Cancer Chemother Pharmacol 2009, 64:473-483.
• [20]Hanada M, Baba A, Tsutsumishita Y, Noguchi T, Yamaoka T: Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude rats. Cancer Sci 2009, 100:189-194.
• [21]Hanada M, Takasu H, Kitaura M: Acquired resistance to miriplatin in rat hepatoma AH109A/MP10 is associated with increased Bcl-2 expression, leading to defects in inducing apoptosis. Oncol Rep 2010, 24:1011-1018.
• [22]Fujiyama S, Shibata J, Maeda S, Tanaka M, Noumaru S, Sato K, Tomita K: Phase I clinical study of a novel lipophilic platinum complex (SM-11355) in patients with hepatocellular carcinoma refractory to cisplatin/lipiodol. Br J Cancer 2003, 89:1614-1619.
• [23]Okusaka T, Okada S, Nakanishi T, Fujiyama S, Kubo Y: Phase II trial of intra-arterial chemotherapy using a novel lipophilic platinum derivative (SM-11355) in patients with hepatocellular carcinoma. Invest New Drugs 2004, 22:169-176.
• [24]Nishikawa H, Inuzuka T, Takeda H, Nakajima J, Sakamoto A, Henmi S, Ishikawa T, Saito S, Kita R, Kimura T, Osaki Y, Koshikawa Y: A case of advanced hepatocellular carcinoma with portal vein tumor thrombus refractory to epirubicin that showed marked decrease in tumor markers after transcatheter arterial infusion with miriplatin. Case Rep Oncol 2011, 4:327-335.
• [25]Court WS, Order SE, Siegel JA, Johnson E, DeNittis AS, Principato R, Martz K, Zeiger LS: Remission and survival following monthly intraarterial cisplatinum in nonresectable hepatoma. Cancer Invest 2002, 20:613-625.
• [26]Niguma T, Mimura T, Tutui N: Adjuvant arterial infusion chemotherapy after resection of hepatocellular carcinoma with portal thrombosis: a pilot study. J Hepatobiliary Pancreat Surg 2005, 12:249-253.
• [27]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [28]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
• [29]Watanabe S, Nitta N, Ohta S, Sonoda A, Otani H, Tomozawa Y, Nitta Seko A, Tsuchiya K, Tanka T, Takahashi M, Murata K: Comparison of the Anti-tumor Effects of Two Platinum Agents (Miriplatin and Fine-Powder Cisplatin). Cardiovasc Intervent Radiol 2012, 35:399-405.