The aim of this study was to evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) using warmed and nonwarmed miriplatin for hepatocellular carcinoma. Eighty patients (117 nodules), treated between January 2010 and June 2013, were evaluated. Thirty-two and 85 nodules were treated with nonwarmed and warmed miriplatin, respectively. The efficacy of TACE was evaluated on a per nodule basis according to treatment effect (TE). Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. TE grades were significantly improved in the warmed group compared to the nonwarmed group (nonwarmed: TE 4, 12.5%; TE 3, 0%; TE 2, 15.6%; TE 1, 71.9%; warmed: TE 4, 34.1%; TE 3, 5.9%; TE 2, 9.4%; TE 1, 50.6%;
Transcatheter arterial chemoembolization (TACE) is a standard therapy for intermediate stage unresectable hepatocellular carcinoma (HCC) [
Doxorubicin, epirubicin, cisplatin, and mitomycin C have been widely used as chemotherapeutic agents, either alone or in combination [
A new platinum agent, miriplatin ((
Another advantage of miriplatin is its less severe toxicity profile compared to other agents, resulting from gradual release of platinum into serum [
Less damage to feeding arteries and less severe adverse effects make miriplatin suitable for TACE; however, when compared to other agents, the clinical outcomes of TACE using miriplatin have not been satisfactory [
Thus, the purpose of this study was to evaluate and compare the efficacy of nonwarmed miriplatin versus warmed miriplatin in TACE and to review the adverse events in both treatment groups.
This study was approved by the local institutional review board. The review board waived the need for informed consent given the retrospective design of the study.
Patients were eligible for this retrospective study if they were diagnosed with HCC by either contrast-enhanced dynamic computed tomography or dynamic magnetic resonance imaging using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid. A total of 100 patients (140 nodules) were initially selected and met all the following requirements: 1 nodule per hepatic segment and a well-demarcated and hypervascular lesion (Figure
Patient enrollment. Gray boxes indicate patients excluded from the study. TACE: transcatheter arterial chemoembolization; A-P: arterioportal.
A total of 80 patients (117 nodules) were finally selected (Figure
Profile of patients and nodules.
Nonwarmed group ( |
Warmed group ( |
| |
---|---|---|---|
Age, years | 68 (51–83) | 73 (50–91) | 0.086 |
Sex, |
|||
Male/female | 17/5 (77.3/22.7%) | 34/24 (58.6/41.4%) | 0.10 |
Etiology, |
0.093 | ||
HCV | 14 (63.6%) | 44 (75.9%) | |
HBV | 1 (4.5%) | 7 (12.1%) | |
Alcohol | 5 (22.7%) | 3 (5.2%) | |
Others | 2 (9.2%) | 4 (6.8%) | |
Child-Pugh, |
0.73 | ||
5-6 (Class A) | 13 (59.1%) | 33 (56.9%) | |
7–9 (Class B) | 8 (36.4%) | 23 (39.7%) | |
10 (Class C) | 1 (4.5%) | 2 (3.4%) | |
Median score | 6.4 | 6.5 | |
BCLC stage, |
0.72 | ||
0 (very early) | 0 (0%) | 0 (0%) | |
A (early) | 0 (0%) | 0 (0%) | |
B (intermediate) | 8 (36.4%) | 21 (36.2%) | |
C (advanced) | 12 (54.5%) | 36 (62.1%) | |
D (terminal) | 2 (9.1%) | 1 (1.7%) | |
PS, |
0.15 | ||
0 | 6 (27.3%) | 23 (39.7%) | |
1 | 13 (59.1%) | 33 (56.9%) | |
2 | 2 (9.1%) | 2 (3.4%) | |
3 | 1 (4.5%) | 0 (0%) | |
AFP (ng/mL) | 282.8 ± 723.1 | 415.5 ± 1454.3 | 0.80 |
DCP (mAU/mL) | 1562.6 ± 5241.2 | 581.3 ± 2913.8 | 0.15 |
Nodule size (mm2) | 388.6 ± 398.0 | 383.1 ± 468.0 | 0.72 |
History of TACE | 18 (81.8%) | 32 (55.2%) | 0.038* |
Agent | |||
EPI alone | 8/18 (44.4%) | 4/32 (12.5%) | |
CDDP alone | 6/18 (33.3%) | 12/32 (37.5%) | |
MPT alone | 0/18 (0%) | 5/32 (15.6%) | |
Multiple agents | 4/18 (22.3%) | 11/32 (34.4%) | |
Number of sessions | 0.087 | ||
1 | 11/18 (61.1%) | 17/32 (53.1%) | |
2 | 4/18 (22.2%) | 9/32 (28.1%) | |
3 | 1/18 (5.6%) | 4/32 (12.5%) | |
4–6 | 2/18 (11.1%) | 2/32 (6.3%) | |
Preoperative severe arterial damage | 7 (31.8%) | 6 (10.3%) | 0.037* |
Follow-up period (months) | 8.5 ± 7.6 (2–36) | 7.7 ± 6.0 (2–29) | 0.68 |
≥3 months | 19 (86.4%) | 49 (84.5%) | 1.00 |
≥6 months | 11 (50%) | 31 (53.4%) | 0.81 |
Interval between image and TACE (months)† | 0.084 | ||
<1 month | 26/29 (89.7%) | 62/87 (71.3%) | |
1-2 months | 1/29 (3.4%) | 18/87 (20.7%) | |
2-3 months | 2/29 (6.9%) | 7/87 (8.0%) |
Age is presented as median (range).
AFP, DCP, nodule size, and follow-up period are presented as mean ± standard deviation.
Range of follow-up period is shown in the parentheses.
†Interval between preoperative image and treatment was evaluated on a per treatment session basis.
HCV: hepatitis C virus; HBV: hepatitis B virus; AFP: alpha-fetoprotein; DCP: des-gamma-carboxyprothrombin; BCLC: Barcelona Clinic Liver Cancer; PS: performance status (Eastern Cooperative Oncology Group classification); TACE: transcatheter arterial chemoembolization; EPI: epirubicin; CDDP: cisplatin; MPT: miriplatin.
The entire treatment procedure was performed under local anesthesia by administering lidocaine subcutaneously. A 4-French sheath (Super Sheath; Medikit, Miyazaki, Japan) was inserted via the femoral artery. Feeding arteries were routinely selected beyond the second branch of the proper hepatic artery and were cannulated with 2.0-French microcatheters (Gold Crest-MRT; Koshin medical, Tokyo, Japan). The miriplatin suspension was prepared by directly mixing miriplatin powder with lipiodol. The miriplatin/lipiodol suspension was prepared at 25°C for the nonwarmed miriplatin group. For preparing warmed miriplatin, lipiodol was mixed with miriplatin powder first and then the miriplatin/lipiodol suspension was immersed in a hot water bath for more than 5 minutes, which was kept at 55°C as measured using a thermometer inside a clean container placed in an electric range. The stability of miriplatin/lipiodol suspension at this temperature was confirmed by the manufacturer. The standard full dosage of the TACE protocol was miriplatin 120 mg. The miriplatin/lipiodol suspension was administered slowly under fluoroscopic guidance immediately after preparation without causing reflux, until the vascular bed of the target nodule was fully filled with the suspension, as confirmed under fluoroscopy. Thus, the amount of the miriplatin/lipiodol suspension was not predetermined, but rather decided by angiographic findings. Finally, the feeding arteries were embolized with ready-made 2 mm pieces of gelatin sponge (Gelpart; Nippon Kayaku, Tokyo, Japan), until complete stasis of the feeding arteries was obtained.
The response to TACE was evaluated on a per nodule basis, according to the 4-grade system: treatment effect (TE) grades 1–4 [
Arterial damage to the hepatic artery was defined as vessel irregularity, stenosis, or occlusion. It was evaluated on a per regimen basis, independent of other analyses. All patients were assigned to three groups according to anticancer agent used in TACE: epirubicin/cisplatin, nonwarmed miriplatin, and warmed miriplatin, considering both past treatment and the treatment included in this study. Therefore, patients with multiple treatment history using different agents were assigned to more than one group. Preoperative arterial damage was evaluated with celiac arteriography prior to the treatment using each agent. Postoperative celiac arteriography before the usage of other agents was compared with the preoperative one. Damage to the hepatic artery was evaluated according to the 5-grade system: grade 0, no obvious damage; grade 1, irregular vessel wall; grade 2, vessel narrowing; grade 3, stenosis; and grade 4, occlusion. Severe damage was defined as grade 3 and grade 4. The level of arterial damage was classified into 4 levels: level 1, the proper hepatic artery; level 2, lobar branches; level 3, segmental branches; and level 4, subsegmental branches. Development of A-P shunt was also evaluated. The evaluation was performed by two observers (D.Y and T.M), independently and blinded to each other. After individual evaluation, the findings were disclosed and discrepancy in the findings was discussed by 2 observers.
Either contrast-enhanced computed tomography or magnetic resonance imaging was performed every 3 to 6 months after TACE. The end of the follow-up period was defined as either the last patient visit or the addition of other treatments: TACE with other agents, radiofrequency ablation, or surgery. The entire follow-up period was completed in September 2013.
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to evaluate the safety of TACE using warmed miriplatin. Adverse events were evaluated on a per treatment session basis. Levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, and complete blood counts were measured, and pre- and postoperative values were compared between the 2 groups. Eosinophilia, which is among the characteristic adverse events of miriplatin (defined as more than 450 cells/
Statistical analysis was performed using R 2.15.1 (CRAN: the Comprehensive R Archive Network at
Demographic data and parameters related to the patients and nodules are summarized in Table
Eighteen cases (81.8%) and 32 cases (55.2%) had a previous history of TACE in the nonwarmed and warmed miriplatin groups, respectively (Table
No significant difference was observed in follow-up period (
Warming miriplatin had an impact on TE grades. TE grades were significantly higher in the warmed miriplatin group than in the nonwarmed miriplatin group (
Treatment effect. The bar graph shows the distribution of treatment effect (TE) grades.
A case of hepatocellular carcinoma treated with warmed miriplatin. (a) Arterial phase of contrast-enhanced computed tomography (CT) before treatment. The white circle shows an enhanced lesion compatible with hepatocellular carcinoma. (b) Common hepatic arteriography showing a tumor stain (black circle). Occlusion and aneurysm formation are noted in the hepatic arterial branch, presumably caused by previous transcatheter arterial chemoembolization (TACE) using cisplatin (black arrow). (c) Early phase of CT during arteriography with the catheter tip placed in the common hepatic artery, 6 months after the first session of TACE using nonwarmed miriplatin. Obvious enhancement was observed, which indicated recurrence (white circle). (d) Celiac arteriography showing tumor stain (black circle). (e) Selective angiography with a microcatheter placed in a feeding artery. TACE was performed using warmed miriplatin in this session. (f) Arterial phase of contrast-enhanced CT, 4 months after the second session of TACE. Lipiodol accumulated densely in the target lesion, and the tumor size was decreased with no evidence of recurrence.
Logistic regression analysis revealed that warming miriplatin had a significant impact on ORR (odds ratio, 12.35; 95% confidence interval, 2.90–90.0;
Results of logistic regression analysis.
Factors | Odds ratio (95% CI) |
|
---|---|---|
Sex (female) | 0.39 (0.12–1.17) | 0.10 |
HBV infection | 0.30 (0.046–1.49) | 0.16 |
Tumor size (mm2) | 1.00 (1.00-1.00) | 0.13 |
AFP (ng/mL) | 1.00 (1.00-1.00) | 0.16 |
DCP (mAU/mL) | 1.00 (1.00-1.00) | 0.14 |
BCLC stage C | 0.77 (0.24–2.43) | 0.66 |
BCLC stage D | 36.55 (0.70–3635.77) | 0.078 |
History of TACE | 0.78 (0.27–2.24) | 0.64 |
Warming miriplatin | 12.35 (2.90–90.0) | 0.0028** |
Miriplatin dose (mg) | 0.99 (0.96–1.01) | 0.43 |
Severe hepatic arterial damage | 0.59 (0.10–2.73) | 0.52 |
CI: confidence interval; HBV: hepatitis B virus; AFP: alpha-fetoprotein; DCP: des-gamma-carboxyprothrombin; BCLC: Barcelona Clinic Liver Cancer; TACE: transcatheter arterial chemoembolization.
Since significant difference was observed in previous treatment history and preoperative severe arterial damage, two-way ANOVA test was performed to reveal interaction between these factors and warming miriplatin. No significant interaction was observed between previous treatment history and warming miriplatin (
Forty-three cases were included in the epirubicin/cisplatin treatment group. Thirty cases were included in the nonwarmed miriplatin group, considering 8 cases in the warmed miriplatin group with past treatment history using nonwarmed miriplatin. Postoperative angiography was not available in 12 cases in the warmed miriplatin group; therefore, 46 cases were included.
Discrepancy in arterial damage grade evaluation was observed in 7 cases, while that in arterial damage level evaluation was observed in 2 cases with the epirubicin/cisplatin group (
According to the consensus, severe arterial damage was observed in 12 of 43 cases (27.9%) with the epirubicin/cisplatin group, in 2 of 30 cases (6.7%) with the nonwarmed miriplatin group, and in 0 of 46 cases (0%) with the warmed miriplatin group (Table
Evaluation of the effect of anticancer agents on the hepatic artery.
Epirubicin/cisplatin ( |
Nonwarmed miriplatin ( |
Warmed miriplatin ( |
|
---|---|---|---|
Damage grade | |||
0 (no damage) | 25 (58.1%) | 22 (73.3%) | 44 (95.7%) |
1 (irregularity) | 5 (11.6%) | 6 (20.0%) | 2 (4.3%) |
2 (narrowing) | 1 (2.4%) | 0 (0%) | 0 (0%) |
3 (stenosis) | 3 (7.0%) | 0 (0%) | 0 (0%) |
4 (occlusion) | 9 (20.9%) | 2 (6.7%) | 0 (0%) |
Damage level | |||
1 (PHA) | 1/18 (5.6%) | 0/8 (0%) | 0/2 (0%) |
2 (lobar branch) | 3/18 (16.7%) | 0/8 (0%) | 0/2 (0%) |
3 (segmental branch) | 6/18 (33.3%) | 3/8 (37.5%) | 1/2 (50%) |
4 (subsegmental branch) | 8/18 (44.4%) | 5/8 (62.5%) | 1/2 (50%) |
A-P shunt formation | |||
Yes | 2 (4.7%) | 3 (10.0%) | 0 (0%) |
No | 41 (95.3%) | 27 (90.0%) | 46 (100%) |
Number of sessions | |||
1 | 28 (65.1%) | 24 (80.0%) | 27 (58.7%) |
2 | 10 (23.3%) | 5 (16.7%) | 14 (30.4%) |
3 | 1 (2.3%) | 1 (3.3%) | 4 (8.7%) |
4–6 | 4 (9.3%) | 0 (0%) | 1 (2.2%) |
Data in this table were obtained from consensus of two radiologists.
PHA: proper hepatic artery; A-P shunt: arterioportal shunt.
Severe complications, such as liver abscess, bile duct necrosis, and liver infarction, and complications above CTCAE grade 4 were not observed in either group. There was no 30-day mortality.
Grades of AST and ALT elevation after treatment were significantly higher in the warmed miriplatin group (
Adverse events.
Nonwarmed group (29 sessions) | Warmed group (87 sessions) |
| |
---|---|---|---|
AST (IU/L), |
46.8 ± 22.4 | 59.1 ± 50.0 | 0.14 |
Grade 1 | 10 (34.5%) | 24 (27.6%) | |
Grade 2 | 5 (17.2%) | 20 (23.0%) | |
Grade 3 | 3 (10.3%) | 26 (29.9%) | |
Grades 4-5 | 0 (0) | 0 (0) | 0.0083** |
ALT (IU/L), |
35.9 ± 15.6 | 50.6 ± 56.2 | 0.32 |
Grade 1 | 8 (27.6%) | 27 (31.0%) | |
Grade 2 | 1 (3.4%) | 14 (16.1%) | |
Grade 3 | 4 (13.8%) | 22 (25.3%) | |
Grades 4-5 | 0 (0) | 0 (0) | 0.0068** |
T-Bil (mg/dL), |
1.03 ± 0.75 | 0.81 ± 0.39 | 0.25 |
Grade 1 | 5 (17.2%) | 29 (33.3%) | |
Grade 2 | 3 (10.3%) | 8 (9.2%) | |
Grade 3 | 0 (0) | 0 (0) | |
Grades 4-5 | 0 (0) | 0 (0) | 0.22 |
WBC (/ |
3666 ± 1477 | 3840 ± 1604 | 0.59 |
Grade 1 | 1 (3.4%) | 7 (8.0%) | |
Grade 2 | 1 (3.4%) | 7 (8.0%) | |
Grade 3 | 3 (10.3%) | 9 (10.3%) | |
Grades 4-5 | 0 (0) | 0 (0) | 0.38 |
Hb (g/dL), |
12.0 ± 2.0 | 11.6 ± 1.9 | 0.32 |
Grade 1 | 3 (10.3%) | 19 (21.8%) | |
Grade 2 | 1 (3.4%) | 10 (11.5%) | |
Grade 3 | 1 (3.4%) | 3 (3.4%) | |
Grades 4-5 | 0 (0) | 0 (0) | 0.060 |
Plt (×104/ |
9.2 ± 4.5 | 10.8 ± 5.0 | 0.20 |
Grade 1 | 5 (17.2%) | 26 (29.9%) | |
Grade 2 | 7 (24.1%) | 19 (21.8%) | |
Grade 3 | 2 (6.9%) | 14 (16.1%) | |
Grades 4-5 | 0 (0) | 0 (0) | 0.11 |
Eosinophilia† | 13/27 (48.1%) | 22/62 (35.5%) | 0.26 |
Pyrexia, |
|||
Grade 1 | 11 (37.9%) | 35 (40.2%) | |
Grade 2 | 0 (0) | 7 (8.0%) | |
Grades 3–5 | 0 (0) | 0 (0) | 0.22 |
Vomiting, |
|||
Grade 1 | 1 (3.4%) | 3 (3.4%) | |
Grade 2 | 1 (3.4%) | 0 (0) | |
Grades 3–5 | 0 (0) | 0 (0) | 0.42 |
Liver infarction | 0 | 0 | — |
Liver abscess | 0 | 0 | — |
Bile duct necrosis | 0 | 0 | — |
Preoperative values of AST, ALT, T-Bil, WBC, Hb, and Plt are presented as mean ± standard deviation in the first row.
†Data on eosinophilia were missing in 2 sessions with the nonwarmed group and in 25 sessions with the warmed group.
AST: aspartate transaminase; ALT: alanine transaminase; T-Bil: total bilirubin; WBC: white blood cell; Hb: hemoglobin; Plt: platelets.
No significant difference was observed in grades of anemia (
In this study, the improved efficacy of warmed miriplatin compared to nonwarmed miriplatin when used in TACE for HCC was demonstrated; both TE and ORR were improved in the warmed miriplatin group. DCR was also better in the warmed miriplatin group, although this difference was not significant. No significant difference was observed in patient profiles or parameters related to each nodule, except history of TACE and preoperative severe hepatic arterial damage, which was more frequent in the nonwarmed miriplatin group. However, logistic regression analysis revealed that these parameters had no significant impact on objective response. Two-way ANOVA tests also revealed that there was no significant interaction between these parameters and warming miriplatin. On the contrary, Seko et al. reported that history of TACE had significant impact on tumor response [
TACE-induced hepatic arterial damage is a factor that limits the efficacy of this treatment. Good interobserver agreement was obtained in evaluation of the hepatic arterial damage grade and level. Severe arterial damage, which can interfere with injection of anticancer agents and lipiodol, was less frequent with nonwarmed and warmed miriplatin, compared to epirubicin/cisplatin (6.7% and 0% versus 27.9%). More proximal arterial damage was observed with epirubicin/cisplatin. These facts suggest that miriplatin is more suitable for TACE due to its less severe arterial insult.
However, previous studies have shown inferior local tumor control of TACE using miriplatin compared to other agents, including cisplatin and epirubicin [
The reason why local tumor control can be improved when using warmed miriplatin remains unclear. According to the hypothesis that agents with high viscosity cause proximal occlusion of feeding arteries, warmed miriplatin, which is therefore less viscous, can be injected to more distal parts of feeding arteries. Distal vessels usually have more vascular beds than proximal vessels, and thus the amount of injected miriplatin suspension may be assumed to increase; however, there was no significant difference in the miriplatin dose between the nonwarmed and warmed miriplatin groups in our study. Additional studies should be performed to reveal the mechanism underlying the improved efficacy of TACE using warmed miriplatin.
Despite the promising results, local tumor control in this study was not comparable to that found in previous studies on TACE using miriplatin [
With regard to adverse events, CTCAE grades of AST and ALT elevation were significantly higher in the warmed group. There is no consensus on whether elevation of transaminase levels after treatment is caused by damage to normal liver parenchyma or tumor necrosis, so it is difficult to interpret these data. Elevation of transaminase levels was only transient and was managed conservatively. No significant difference was observed in other parameters. Moreover, no serious complications, such as liver infarction, liver abscess, and bile duct necrosis, were observed in either group. These findings indicate that adverse events of TACE using warmed miriplatin are only transient.
Our findings provide evidence that warmed miriplatin can improve the efficacy of TACE; however, this study has some limitations. First, it is a retrospective study, and a randomized controlled study should be considered to further support these findings. There was asymmetry in the numbers of nodules treated in the nonwarmed and warmed groups, which was inevitable given the nature of a retrospective study. This study presented preliminary results on the efficacy of TACE using warmed miriplatin, and a prospective clinical trial is going to be conducted. Second, in order to establish the advantage of using miriplatin, the relationship between survival benefit and repeatability of TACE should be demonstrated. Moreover, the efficacy of TACE using warmed miriplatin should be compared with TACE using other agents or microspheres.
This study demonstrated the safety and improved efficacy of TACE using warmed miriplatin compared to nonwarmed miriplatin for the treatment of HCC.
The authors declare that there is no conflict of interests regarding the publication of this paper.