Abstract
Aim: To evaluate the therapeutic efficacy of transcatheter arterial chemoembolization (TACE) using miriplatin emulsion in unresectable hepatocellular carcinoma (HCC). Patients and Methods: The efficacy of TACE was evaluated by dynamic computed tomography or magnetic resonance imaging three months after TACE, according to the Response Evaluation Criteria in Cancer Study Group of Japan (RECICL). Adverse events were assessed using Common Terminology Criteria, version 4.0. Results: Eighteen patients with 48 lesions received TACE with miriplatin-lipiodol (LPD) suspension (miriplatin suspension) and 53 patients with 114 HCC tumors received TACE with miriplatin-LPD water-soluble contrast agent emulsion (miriplatin emulsion). TACE with miriplatin emulsion enabled for administration of a higher dose of miriplatin compared to TACE with miriplatin suspension (p=0.016), although there were no significant differences in the frequency of adverse events between the two groups. The treatment effect per tumor was significantly higher in the emulsion group than in the suspension group (p=0.001). The time-to-progression per tumor was significantly shorter in the suspension group than in the emulsion group (p=0.001). Conclusion: TACE with miriplatin emulsion is more effective than that with miriplatin suspension.
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide (1). For patients ineligible for surgical resection, liver transplantation and local ablation, transcatheter arterial chemoembolization (TACE) is recognized as an effective treatment option (2-4). Although several chemotherapeutic agents, such as doxorubicin, epirubicin, mitomycin C, and cisplatin, are used with oily lymphographic agents (Lipiodol Ultra-Fluide, LPD; Laboratoire Guerbet, Aulnay-Sous-bois, France), it is not known which drug is the best option as first- or second-line treatment with TACE (5-7).
Miriplatin, cis-[((1R, 2R)-1, 2-cyclohexanediamine-N,N') bis (myristate)] platinum (II) monohydrate (Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan), is a novel lipophilic platinum derivative that can be suspended in LPD (8-10). A miriplatin-LPD suspension deposited within HCC nodules will gradually release active platinum compounds into tumor tissue. Intra-arterial administration of miriplatin, which was well-tolerated, showed promising antitumor activity in patients with HCC (11). In January 2010, transarterial infusion (TAI) with miriplatin was launched for HCC treatment, following approval by the Ministry of Health, Labour, and Welfare of Japan. Recent reports revealed the safety and efficacy of TACE with this miriplatin suspension (12-14). It was shown that TACE with suspended miriplatin had equal therapeutic efficacy compared to TACE with cisplatin or epirubicin (15). On the other hand, Oguro et al. suggested that TACE with suspended miriplatin was significantly worse in terms of treatment response compared with cisplatin; the response rates at one to three months after TACE were 56% in the miriplatin-treated group and 86% in the cisplatin-treated group (16).
In general, mixtures of anticancer drugs and LPD are classified as suspensions (drugs in oil) or emulsions (oil with saline and drugs) (17, 18). Several studies have demonstrated the efficacy of TACE using anticancer drug emulsion (18, 19), although the therapeutic effect of miriplatin emulsion remains unclear. In the current retrospective study, we sought to investigate the antitumor efficacy of miriplatin suspension and miriplatin emulsion in TACE against unresectable HCC.
Patients and Methods
Patients and tumors. Medical records were retrieved for patients treated with TACE with miriplatin for the first time at two institutions in Japan, the Chiba University Hospital and Kimitsu-chuo Hospital, between January 2010 and December 2011. Patients were included if they met the following criteria: (i) HCC proven pathologically or diagnosed according to the current American Association for the Study of Liver Diseases (AASLD) practice guidelines (20); (ii) not treated with local therapy such as percutaneous ethanol infusion (PEI) or radio frequency ablation; (iii) classified as Child-Pugh A or B; (iv) baseline dynamic computed tomography (CT) or dynamic magnetic resonance imaging (MRI) were performed within one month before TACE; (v) treatment effect was evaluated by CT or dynamic MRI at three months after TACE; (vi) without macroscopic vascular invasion, (vii) without extrahepatic metastasis; and (viii) at least one target lesion at baseline CT or MRI with a diameter of not less than 10 mm. All patients provided written informed consent before TACE. This study was approved by Research Ethics Committees of Graduate School of Medicine, Chiba University (approval number 1,594) and Kimitsu Chuo Hospital (approval number 191).
TACE procedure. The femoral artery was catheterized under local anesthesia, and a 4- or 5-Fr Shepherd Hook catheter was inserted. All patients underwent angiography of the celiac artery and superior mesenteric artery to reconfirm the site of HCC. Prior to TACE, highly selective catheterization was performed using a 2.0- or 2.5-Fr microcatheter to obtain complete occlusion of the nourishing arteries. Miriplatin suspension was prepared by suspending miriplatin with LPD according to the package insert. The final concentration of miriplatin was 20 mg/ml. Miriplatin emulsion was prepared by mixing miriplatin-LPD suspension and water-soluble contrast agent (Omnipaque; Daiichi Sankyo, Tokyo, Japan) at a ratio of one to one; the final concentration of miriplatin was 10 mg/ml. The miriplatin suspension and Omnipaque were agitated 20 times to make an emulsion immediately before administration into the tumor feeding artery using a pair of 10-ml syringes and a three-way stopcock (Sensytec Syringe Kit; Top, Tokyo, Japan). The maximum dose of miriplatin per patient was 120 mg in both groups. After miriplatin suspension or miriplatin emulsion was administered, the embolization of feeding arteries was conducted using 1-mm gelatin cubes (Gelpart; Nippon Kayaku, Tokyo, Japan).
Adverse events. Treatment-related toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). Adverse events included clinical symptom assessment (increased fever, anorexia, nausea, abdominal pain), hematological assessments (leukocytopenia, neutropenia, anemia, thrombocytopenia, eosinophilia), and blood chemistry assessments [serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), total bilirubin (T-bil), serum creatinine and albumin].
Summary of patient selection for this study. PEI, Percutaneous ethanol injection; RFA, radiofrequency ablation.
Treatment efficacy evaluation. The efficacy of TACE was evaluated by LPD-CT within one week as early treatment efficacy (TE) and dynamic CT or dynamic MRI at three months after TACE as late TE. Evaluation was performed according to the “Response Evaluation Criteria in Cancer Study Group of Japan” (RECICL) (21). For each patient, a maximum of five delineated tumor target lesions were identified. The longest diameter of the tumor lesions was ≥10 mm. TE was assessed on the basis of the tumor size or disappearance of hypervascularity from the tumor using bi-dimensional measurements. It was categorized as follows: TE1, enlargement of the tumor by more than 25% regardless of tumor-necrosis effect; TE2, tumor necrosis rate other than TE1, TE3 or TE4; TE3, tumor-necrosis effect or tumor size reduction rate of 50–100%; TE4, tumor disappearance or 100% tumor-necrosis effect. In addition, the treatment effect per patient was evaluated as follows: progressive disease (PD), total tumor size enlarged by more than 25%; partial response (PR), overall tumor-necrosis effect or overall tumor size reduction rate of 50-100%; complete remission (CR), complete tumor disappearance or 100% tumor necrosis; stable disease (SD), not classified as PD, PR or CR. Local recurrence was also classified as intratumoral recurrence and peritumoral recurrence (22). Follow-up dynamic CT or dynamic MRI was performed every 3-4 months. The time-to-progression (TTP) per tumor was also evaluated. We assessed TTP for all target lesions. The TTP per tumor was defined as the time between the day on which TACE was performed and the day on which the target lesion was judged as TE1. Target lesions in which additional treatment was performed before progression were censored. The target lesions of patients who were lost during follow-up or died before progression were also censored.
Microscopic observation of suspension and emulsion. We observed the miriplatin suspension and miriplatin emulsion by optical microscopy (BX51; Olympus, Tokyo, Japan) at ×200 magnification immediately following preparation. Miriplatin suspension and miriplatin emulsion were prepared as described above. The emulsion was observed every 15 min up to 60 min after preparation using optical polarizing and polarizing microscopes.
Characteristics of patients and tumors.
Statistical analysis. All analyses were carried out using the PASW Statistics software (ver. 18.0) (IBM corporation, NY, USA). Patients, tumor characteristics, adverse events, treatment effect per patient were compared using unpaired t-test or χ2 test. The median time-to-the first follow-up dynamic CT or MRI was evaluated using an unpaired t-test. TTP per tumor was estimated using the Kaplan Meier method, and comparisons were made by log-rank test. p-Values less than 0.05 were considered statistically significant.
Results
Characteristics of patients and tumors. Out of the 131 patients who underwent TACE with miriplatin at two institutions, 71 with 162 HCC lesions were included in the present study (Figure 1). Sixty patients were excluded, of whom 2 had been treated with local ablation, one was classified with Child-Pugh C, 37 had not undergone CT or MRI during the appropriate time period, 13 had macroscopic vascular invasion, and seven had extrahepatic metastasis. Finally, of these 71 patients, 18 with 48 HCC lesions received TACE with miriplatin suspension (suspension group) and 53 with 114 HCC lesions received TACE with miriplatin emulsion (emulsion group). The median time-to-first follow-up dynamic CT or MRI was 3.2 months in the suspension group and 2.8 months in the emulsion group, with no significant differences (p=0.467).
Patients' characteristics are shown in Table I. The proportion of male patients was significantly higher in the suspension group than in the emulsion group (p=0.043). There was no significant difference between the two groups with respect to age, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), Child-Pugh class, etiology of liver cirrhosis, Barcelona Clinic Liver Cancer (BCLC) stage, number of previous TACE, α-fetoprotein, or des-γ-carboxy prothrombin. Of importance, the median dosage of miriplatin was significantly higher in the emulsion group than in the suspension group (emulsion group, 70 mg; suspension group, 50 mg; p=0.016). The median number of tumors per patient was two in both groups. There were no significant differences in tumor sizes between the suspension group and the emulsion group.
Adverse events. Adverse events observed in patients are summarized in Table II. In both groups, clinical symptoms such as increased fever, anorexia, nausea, and abdominal pain were observed. However, there were no significant differences between the groups for any of these factors. All adverse events were reversible.
Treatment efficacy. Next, late TE per tumor and patient was evaluated three months after TACE (Table III). In the suspension group, only 4 lesions (8%) achieved TE4. In contrast, 46 lesions (40%) in the emulsion group achieved TE4. The rate of TE4 was significantly higher in the emulsion group than in the suspension group (p=0.001). Regarding treatment efficacy per patient, three (17%) and two patients (11%) achieved CR and PR in the suspension group, respectively, and 10 (19%) and 32 patients (60%) achieved CR and PR, in the emulsion group, respectively. As expected, the response rate (CR+PR) was also significantly higher in the emulsion group (p=0.001). We then examined the relationship between early TE and late TE in both groups (Table IV). Only three lesions (3%) in the emulsion group, but 12 (25%) in the suspension group were evaluated as TE4 in early LPD-CT and TE1 in dynamic CT or MRI three months after TACE. Of importance, 11 out of 12 lesions (92%) displayed intratumoral recurrence. Representative CT images for the suspension and emulsion groups are shown in Figure 2.
Adverse events.
Concordant with these findings, the TTP per tumor in the suspension group was significantly shorter than that in the emulsion group (p=0.001) (Figure 3). The median TTP per tumor in the suspension and emulsion groups were 3.3 months and undefined, respectively.
Observation of emulsion particles. Microscopic observation revealed the presence of a water phase within the oil phase in the miriplatin emulsion (Figure 4). Miriplatin particles were clearly identified as white dots in the oil phase under a polarizing microscope (Figure 4). As time passed, the oil and water phases of the emulsion became completely separated.
Discussion
In the present study, we sought to investigate the treatment efficacy of TACE using miriplatin suspension and miriplatin emulsion. The treatment effect in both groups was assessed according to TE4 rate, response rate, and TTP per tumor. The efficacy of TACE with miriplatin emulsion was superior to that of TACE with miriplatin suspension. It has been reported that the viscosity of miriplatin emulsion is lower than that of miriplatin suspension (23). Additionally, droplets of miriplatin emulsion were found to be smaller than those of miriplatin suspension. Indeed, the present microscopic examination successfully demonstrated that miriplatin emulsion comprised a great deal of water phase within the oil phase.
Late treatment effect per tumor and patient.
Relationship between early (one week after) and late treatment effect (three months after transcatheter arterial chemoembolization).
Consistent with these findings, our data showed that the miriplatin dose in the emulsion group was significantly higher than that in the suspension group. Although there was no significant difference in the TE4 rate of early LPD-CT between the suspension and emulsion groups, the TE4 rate of the emulsion group after three months was significantly higher than that of the suspension group. These findings may reflect the inability of particles of suspended miriplatin to reach the peripheral portion of the tumor compared with the particles of miriplatin emulsion. Additionally, miriplatin suspension accumulated in the tumor releases 1,2-diaminocyclohexane platinum (II) dichloride, an active platinum compound that binds to nuclear DNA, causing for gradual cytotoxicity (24, 25). The treatment efficacy of this drug form seems to be increased by retention of miriplatin-LPD particles in the peripheral portion of the tumor.
Representative computed tomography (CT) scans in hepatocellular carcinoma (HCC) cases of the suspension and emulsion groups. A-C: A 79-year-old man with hepatitis C cirrhosis and HCC measuring 17 mm in diameter who was treated with TACE with miriplatin-lipiodol (LPD) suspension. The early treatment effect (TE) of the patient was TE4, but the late TE was TE1. Arterial phase image before TACE (A), LPD-CT at one week after TACE (B), and an arterial phase image three months after TACE (C). D-F: A 78-year-old man with hepatitis C cirrhosis and HCC measuring 65 mm in diameter who was treated with TACE with miriplatin-LPD water-soluble contrast agent emulsion. Both the early TE and the late TE were TE4. Arterial phase image before TACE (D), LPD-CT at one week after TACE (E), and an arterial phase image three months after TACE (F).
Time-to-progression per tumor in the miriplatin suspension- and emulsion-treated transcatheter arterial chemoembolization groups.
Microscopic observation of miriplatin emulsion (×200). Bright-field images (left panels) and polarizing microscope images (middle panels) of miriplatin-LPD water-soluble contrast agent 0 (A), 15 (B), 30 (C), and 60 (D) min after preparation. The white line traces the particles of water-soluble contrast agent as observed by optical microscopy (right panels).
It is known that LPD particles flow into the surrounding portal venules and hepatic sinusoids through the peribiliary plexus and the drainage route from the hypervascular HCC (26). Therefore, the reversed flow from the hepatic sinusoids and portal venules to the peripheral portion of the tumor and daughter nodules can be blocked. The effect of TACE with miriplatin might be attributed to the accumulation and continuous presence of particles of miriplatin-LPD in the peripheral portion of the tumor. Consistent with this, 11/12 (92%) of the lesions evaluated as TE4 in early LPD-CT and as TE1 in follow-up dynamic CT or MRI in the suspension group exhibited intratumoral recurrence. In addition, it is possible that the larger surface area of the droplets in the miriplatin emulsion may lead to the enhanced drug release.
Recently, Seko et al. reported that warming miriplatin decreased its viscosity and allowed the miriptain-LPD to reach the peripheral portion of the tumor in TACE (27). Because the present study did not compare miriplatin-LPD water-soluble contrast agent emulsion against TACE with warmed miriplatin, we cannot conclude at which method is better. However, improved medication methods should be devised to increase the treatment efficacy of TACE with miriplatin. Miriplatin has low toxicity and seems to offer effective treatment when miriplatin-LPD reaches the peripheral portion of the tumor. Further studies are needed to clarify the efficacy of TACE with existing drugs versus TACE with miriplatin, after verifying the optimal administration method.
Because miriplatin causes less vascular damage, it is considered that hepatic arterial administration of miriplatin can be repeatedly performed. However, it is likely that lack of vascular damage often results in early intratumoral recurrence because of the restoration of blood supply to the tumor (28). Considering that TACE with miriplatin plus low-dose epirubicin exhibited favorable therapeutic efficacy (23), emulsion with miriplatin and angiopathic anticancer drugs might contribute to additional therapeutic efficacy in TACE.
In conclusion, the current findings suggest that TACE with miriplatin emulsion was well-tolerated and more effective than TACE with miriplatin suspension. This approach could be considered as a standard method of TACE with miriplatin.
Acknowledgements
The Authors thank Dr. Fumihiko Kanai (Medical Corporation Eikenkai) for valuable discussions.
Footnotes
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↵* These Authors contributed equally to this work.
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Conflicts of Interest
Osamu Yokosuka received grant support (scholarship contribution) from Dainippon Sumitomo Pharma Co, Ltd. (Osaka, Japan).
- Received September 25, 2013.
- Revision received November 2, 2013.
- Accepted November 4, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
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