Oily chemoembolization of hepatoma

Since 1983 we have performed transcatheter oily chemoembolization (TOCE) using adriamycin (40-100 mg), Lipiodol (5-20 ml) and Gelfoam in the treatment of 100 cases with unresectable hepatocellular carcinoma. Adriamycin was dissolved in a fluid equal in specific gravity to Lipiodol and the adriamycin solution was mixed with 3 volumes of Lipiodol, making an adriamycin-in-oil emulsion (AOE). After TOCE, the blood concentration of adriamycin was obviously lower than that after one-shot injection because of the slow release of adriamycin from the AOE. Also, in cases of hepatic resection after TOCE, there was a clear difference in the adriamycin concentration between the tumor and the normal hepatic tissue. The cumulative survival rates for the 100 patients treated by TOCE were: 6 months 81.9%, 1 year 53.8% and 2 years 36.5%. Thus, improvement was found in comparison with the cumulative survival rates for 104 patients who underwent hepatic embolization without Lipiodol, which were 6 months 67.4%, 1 year 45.2% and 2 years 16.3%. AOE retained in the tumor as microemboli brings about the slow-releasing effect of adriamycin. Furthermore, by adding the effect of Gelfoam embolization, TOCE has a strong antitumor effect.     

A randomized trial of intrahepatic arterial infusion of 4′-epidoxorubicin with Lipiodol versus 4′-epidoxorubicin alone in the treatment of hepatocellular carcinoma

We conducted a prospective randomized trial to evaluate the efficacy of Lipiodol in intrahepatic arterial infusion chemotherapy for patients with hepatocellular carcinoma (HCC). A total of 38 patients with unresectable HCCs and underlying cirrhosis were entered in this trial, and 36 of them were evaluable. Every 4 weeks, 17 patients received 70 mg of 4-epidoxorubicin (epirubicin) alone (group A), whereas 19 patients received a Lipiodol emulsion containing the same dose of epirubicin (group B) through the hepatic artery. A tumor response (CR+PR) was observed in 12% of group A patients and in 42% of group B patients. The group B patients showed a significantly higher response rate than the group A patients. There was a tendency for an increased duration of survival (P=0.09) in the group B patients. These results suggested that the infusion of the Lipiodol emulsion with epirubicin was more effective than epirubicin alone for the treatment of these patients with HCC.Work presented at the Third International Symposium on Treatment of Liver Cancer, Scoul, Korea, 12–13 February 1993     

In vitro Antitumor Activity, Intracellular Accumulation, and DNA Adduct Formation of cis-[((1R, 2R)-1,2-Cyclohexanediamine-N, N')bis(myristato)] Platinum (II) Suspended in Lipiodol

SM-11355, cis -[((1 R ,2 R )-1,2-cyclohexanediamine- N , N' )bis(myristato)] platinum (II), is a lipophilic platinum complex under clinical development that targets primary hepatocellular carcinoma using Lipiodol as a carrier. SM-11355 was compared with cisplatin (CDDP) using an in vitro evaluation system capable of examining the release characteristics and the cytotoxicity of drugs suspended in Lipiodol. SM-11355 suspended in Lipiodol (SM-11355/Lipiodol) and CDDP suspended in Lipiodol (CDDP/Lipiodol) showed cytotoxic activity against rat ascites hepatoma AH-109A cells in a dosedependent manner. Their IC₅₀ values following 7-day exposure were 22.3 and 0.40 μg/ml, respectively. Following the subsequent 7-day exposure, from day 7 to day 14 after preparation of the suspension, SM-11355/Lipiodol showed an almost equivalent activity, but CDDP/Lipiodol did not show any activity at all. SM-11355/Lipiodol showed a sustained release into the culture medium over the course of a 14-day exposure. Following the exposure to CDDP/Lipiodol, the platinum concentration in the medium was at its maximum on the first day and remained constant thereafter. Intracellular platinum uptake and formation of platinum-DNA adducts were dependent on the release characteristics of each drug suspension. For SM-11355/Lipiodol, the drug release, intracellular drug uptake, and formation of platinum-DNA adducts over the course of the subsequent 7-day exposure were similar to those observed during the first 7 days. DPC, one of the compounds released from SM-11355/Lipiodol, was taken up by cells and showed formation of platinum-DNA adducts. Thus, this study suggests that SM-11355/Lipiodol may release active platinum compound(s) that bind to nuclear DNA and mediate the cytotoxic activity of SM-11355/Lipiodol.     

Therapeutic effect of a CDDP-epirubicin-Lipiodol emulsion on advanced hepatocellular carcinoma

Prior injection of an anticancer agent and Lipiodol mixture is a key point for the treatment of hepatocellular carcinoma (HCC). We therefore prepared a new, improved emulsion of Lipiodol containing a high dose ofcis-diamminedichloroplatinum (CDDP) and epirubicin by replacing the ionic contrast medium (Urografin 67) with a nonionic contrast medium (Iopamidol; Iopamiron 300) and adding phosphatidyl choline. This CDDP-epirubicin-Lipiodol emulsion (CELE) was examined pharmacologically and chemically with the following results. The size of these particles is less than 10 m (diameter) for up to 24 h; the release of 28%–34% of the CDDP and 80%–90% of the epirubicin was estimated in the dissolution test, and 85% of the CDDP and 35% of the epirubicin was retained in the organs in the moment calculation. CELE was injected into 58 HCC patients via a celiac angiographic catheter. In 36 of these patients, the CELE injection was followed by transcatheter arterial embolization (TAE) therapy. Following the administration of CELE as one-shot injection therapy for stage IV HCC, the 1-year survival rate was 59% and the 2-year survival rate was 27%. Moreover, in patients (stage II, 12; stage III, 8; stage IV, 16) who received CELE and subsequently underwent TAE therapy, the 1-year survival rate was 90% and the 2-year survival rate was 67%. The nonionic contrast medium with Lipiodol forms finer emulsified particles, and these particles are more capable of penetrating into the tumor. In addition, the greater pharmacological stability of these particles provides a slow-release effect and prolonged stability of their shape. Finally, theoretically, the use of two major anticancer agents such as CDDP and epirubicin showed a greater clinical effect in the treatment of HCC than either our earlier suspension or a single anticancer agent.Work presented at the Third International Symposium on Treatment of Liver Cancer, Seoul, Korea, 12–13 February 1993     

Targeting chemotherapy of hepatocellular carcinoma by arterial administration of anticancer agents dissolved in lipiodol

The lipid lymphographic agent, Lipiodol ultrafluid has been found to remain selectively in hepatocellular carcinoma. Using this characteristic nature of Lipiodol, a new targeting anticancer chemotherapy was devised. In order to achieve targeting anticancer chemotherapy and useful anticancer effects, anticancer drugs must be dissolved or suspended in Lipiodol and diffuse out from the Lipiodol gradually. Oily anticancer agents such as SMANCS dissolved in Lipiodol (SMANCS/Lipiodol), Mitomycin C in Lipiodol (MMC/Lipiodol), Aclarubicin in Lipiodol (ACR/Lipiodol) and a mixture of these were administered by catheterizing the celiac or hepatic artery under X-ray monitoring in 216 patients with hepatocellular carcinoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in 91% of cases. The survival period of patients with unresectable hepatoma treated with the present protocol was definitely longer than the comparison group.     

Selective effects of Lipiodolized antitumor agents

Lipiodol Ultra-Fluid (Lipiodol) remains selectively in the tumor for an extended time when applied through arteries feeding the tumor. Although lipophilic antitumor drugs are selective when combined with Lipiodol, wide application of common hydrophilic agents is limited, as these compounds are insoluble in oil. We propose "Lipiodolization" of water-soluble agents using as an intermediate Urografin, a water-soluble contrast medium. Thirteen patients with primary hepatocellular carcinoma were treated with this Lipiodol-Urografin system containing antitumor agents. Marked decrease in serum alpha-fetoprotein (AFP) levels, decrease in tumor size in the hepatic imaging, and histologic studies of the resected specimen revealed this mode of therapy to be effective in 10 of 13 patients (77%) with hepatocellular carcinoma. Lipiodolization of antitumor agents is a new approach to selective cancer chemotherapy.     

Treatment of hepatocellular carcinoma with a CDDP-epirubicin-lipiodol suspension: a pilot clinico-pharmacological study

Lipiodol injection is a useful method for detecting liver tumors, especially hepatocellular carcinoma (HCC). We therefore prepared and tested a new emulsion of lipiodol containing epirubicin andcis-diamminedichloroplatinum (CDDP), drugs that are very effective against HCC. This CDDP-epirubicin-lipiodol suspension (CELS) was injected into 18 HCC patients via a celiac angiographic catheter. In 11 of these patients, CELS was followed by transcatheter arterial embolization (TAE) therapy. Clinical and pharmacological investigations were performed in all 18 patients, and the following results were obtained. CELS is pharmacologicall and chemically stable, and both the results of the dissolution test and the serum levels of these two drugs indicate that slow release can be obtained. After the injection of CELS, serum levels of AFP and PIVKA-II decreased immediately, and no fatal clinical side effects were encountered. Although no statistically significant difference was observed, the survival (Kaplan-Meier method) of patients injected with CELS in the presence or absence of TAE therapy can be estimated to be much longer than that of patients receiving CDDP-lipiodol suspension injection in the presence (16 patients) or absence (6 patients) of TAE therapy. A combination of CELS injection and TAE therapy might be effective and useful for the treatment of HCC.Presented at the Second International Symposium on Treatment of Liver Cancer. Taipei, 3–4 February 1991     

Basic study of anti-cancer agents suspended in lipiodol

Anti-cancer agents suspended in Lipiodol have been proved to be effective in the targeting of chemotherapy for cancer of the digestive organs. 5-FU, ADM and MMC were suspended both separately and collectively in Lipiodol. These preparations were terned FULIP, ADRLIP, MMCLIP and FAMLIP, respectively. Forty percent 5-FU was released from FULIP within 24 hours. ADM and MMC were released more slowly from ADRLIP and MMCLIP when compared with FULIP. ADM W/O type emulsion (ADM was dissolved in 60% Urographin/Lipiodol) released ADM so rapidly that 37% of the drug was detected in the water phase within 10 hours. However, the ADM W/O emulsion with Arlacel-A was much slower. From these results, it was suggested that the release speed of anti-cancer agents can be controlled by modifying the drug dosage and form. FAMLIP released 5-FU, ADM and MMC independently and the release speeds were equal to FULIP, ADRLIP and MMCLIP. It was also suggested that the biological activities of 5-FU, ADM and MMC in FAMLIP were stable in FULIP, ADRLIP and MMCLIP. It should therefore be possible to use a large amount of anti-cancer agent suspended in Lipiodol, as a combined drug cancer therapy.     

A case of recurrent hepatocellular carcinoma after hepatic resection surviving over five years by hepatic arterial infusion of lipiodol-anticancer drug suspension]

A 63-year-old male with four intrahepatic recurrences of surgically resected hepatocellular carcinoma was admitted to our hospital in June 1985. He underwent lateral segmentectomy of the liver in November 1983. Pathologic finding of Edmondson II with liver cirrhosis had been confirmed by the operative specimen. Sizes of four recurrent tumors were assessed by CT as 3.5 x 2.2 cm, 2.6 x 2.2 cm, 2.2 x 2.2 cm and 2.2 x 2.2 cm, respectively. During five years until July 1990, the patient was treated with hepatic arterial infusion of Lipiodol-anticancer drug suspension eight times (total 5-FU 900 mg, ADM 77 mg, MMC 73 mg, and Lipiodol 36 ml) and hepatic arterial chemoembolization of MMC microcapsules one time. In addition, two hepatic arterial infusions of CDDP (total 70 mg) were given and 5-FU (total 10 g) was administered intravenously. Partial response (PR) was obtained for 19 months. Hepatic arterial infusion of Lipiodol-anticancer drug suspension was given only once every 6 months, and he maintained a good quality of life for over four and half years. The man died in July 1990. In general, multiple intrahepatic recurrence of surgical resected hepatocellular carcinoma has a poor prognosis. Therefore it was considered that hepatic arterial infusion of this drug brought about the relatively long survival of more than five years.     

Intra-arterial infusion chemotherapy for advanced cancer--40 years of experience

During the period of 1990-2005, 701 patients with the hepatocellular carcinoma were treated with intra-arterial infusion of 5-FU and epi-adriamycin with or without Lipiodol chemoembolization employing an implantable infusion port system. In 70% of the patients treated, an objective response was observed with marked regression of tumor and decrease in tumor marker (AFP and PIVKA-II). Also 1,091 patients with the metastatic liver cancer of colon, rectum, stomach and pancreas were treated with the same procedure employing 5-FU, mitomycin C, adriamycin, or epi-adriamycin. In more than 80% of the patients treated, an objective response was observed with marked regression of tumor and decrease in tumor marker (CEA, CA19-9, TPA, DUPAN-2, SPan-1). Intra-arterial infusion chemotherapy employing an implantable port system also proved to be a promising treatment modality for most of the intractable head and neck cancer, breast cancer and a few of the pancreas cancer.     

A new method of preparation of doxorubicin-in-oil suspension using ultrasonificator attached with Cuphorn

The property of selective deposition of oily contrast medium, Lipiodol (LPD), in tumor tissue was utilized for targetting intraarterial infusion chemotherapy for hepatic cancers. For this therapy anti-cancer agents need to be suspended in LPD. In this report the new suspension device using ultrasonificator attached with Cuphorn was studied. Doxorubicin (Dx) was stable to ultrasonification for 1 hour. Ten mg/ml of Dx was mixed with LPD and this mixture was treated 2 times for 5 minutes with the ultrasonification method. This procedure was simple and sterile, as the commercially used Dx vials into which LPD was injected were set in the Cuphorn and ultrasonificated just as sealed. Microscopic examination of the suspension showed uniform dispersion of Dx particles without formation of aggregates. Dx particles were finely and regularly fragmented. In vitro the suspensions showed a gradual release of Dx from LPD to water phase. In one case with hepatocellular carcinoma received intraarterial infusion of this suspension, the size of the tumor and serum level of alpha-fetoprotein was prominently decreased. This ultrasonification method was simple and convenient to prepare Dx-in-oil suspension.     

Reduction of hepatic metastases in rabbits by administration of an oily anticancer agent into the portal vein

We studied a prophylactic chemotherapy against hepatic metastases arising from the shedding of tumor cells into the portal circulation. The therapy was done with a lymphographic oily contrast medium, Lipiodol, and a high molecular weight anticancer agent named poly(styrene-maleic acid) copolymer conjugated neocarzinostatin (SMANCS), developed in our laboratory. SMANCS was dissolved in Lipiodol by sonication (SMANCS/Lipiodol, 1 mg of SMANCS in 1 ml of Lipiodol). Twelve rabbits were simply inoculated with the highly malignant carcinoma VX-2. Fifteen rabbits were given injections of SMANCS in glucose and Lipiodol into the portal vein and were subsequently inoculated with the tumor cells. Eighteen were given injections of SMANCS/Lipiodol and then the tumor cells. These rabbits were killed 12 days later. Thirteen were given injections of the tumor cells alone and were allowed to survive. Sixteen were given injections of SMANCS/Lipiodol and then with the tumor cells; they were allowed to survive. Rabbits given injections of SMANCS/Lipiodol before tumor inoculation had significantly fewer (P less than 0.001) metastases than those not treated or those given SMANCS in glucose and Lipiodol. Survival was significantly longer [P less than 0.005; 36.0 +/- 7.7 (SD) days] with SMANCS/Lipiodol before tumor inoculation than without treatment [23.5 +/- 3.0 days]. SMANCS/Lipiodol has a prolonged anticancer effect because it remains in the portal vein and allows sustained drug release from the oil (Lipiodol) to aqueous spaces. Hepatic metastases might be prevented by portal administration of the appropriate oily anticancer agent.     

Long-term outcome of advanced hepatocellular carcinoma that received transarterial hepatic chemotherapy

Nineteen patients with far advanced hepatocellular carcinoma received transarterial hepatic chemotherapy. Twelve patients were Child-Pugh A, 2 were B, and 2 were C. Seventeen patients had portal vein thrombus, and 2 patients had extra-hepatic metastasis. Among the 19 patients, 13 received low-dose CDDP and 5-FU, and 5-FU with interferon was performed in 2. Lipiodol chemotherapy with epirubicin and MMC was performed after first-line chemotherapy, following the evaluation of the progressive disease. The 1- and 3-year survival rates in all cases were 42.5% and 18.2%, respectively. Of the 18 patients evaluated for response, 1 showed complete response, 2 showed partial responses, 8 had stable disease, and 7 progressed. Median survival time of CR, PR and SD patients was 14.2 months. A multivariate analysis identified CLIP score and therapeutic effect as independent predictors for mortality. It is concluded that transarterial hepatic chemotherapy was very useful for far advanced hepatocellular carcinoma.     

阿霉素不同剂型经肝动脉给药治疗肝癌的体内药动力学研究

观察阿霉素以不同剂型肝动脉给药后的药代动力学和生物学分布。方法：２３例肝癌经肝动脉分别注入单纯阿霉素；阿霉素与碘油混合液，阿霉素与碘混混合并制成乳剂，或Ｃ组之乳剂加用明胶海绵栓塞。用高效液相色谱仪测定阿霉素外周血浓度，对其中１２例，用ＥＣＴ测定肝脏的放射性强度。     

Serum alpha fetoprotein kinetics in hepatocellular carcinoma

Summary As chemotherapy with adriamycin is accompanied by toxic side effects, early recognition of ineffective treatment is important. Marker kinetics, apparent half-life (AFL) and doubling time (DT), showed that in five patients with advanced hepatocellular carcinoma, adriamycin was ineffective. Failure of the chemotherapeutic regimen was apparent by the third course of treatment.     

Intraarterial infusion of 5-fluoro-2-deoxyuridine-C8 dissolved in a lymphographic agent in malignant liver tumors. A preliminary report

The drug 5-fluoro-2-deoxyuridine-C8 (FUdR-C8), one of the lipophilic prodrugs of FUdR, was dissolved in an oily lymphographic agent (Lipiodol Ultra Fluid, Andre Gelbe Laboratory, Paris, France; Ethiodol, Savage Laboratories, Melville, NY) and used for the intraarterial treatment of malignant liver tumors. From August 1985 to June 1988, 33 patients with hepatocellular carcinoma and 13 patients with metastatic liver tumors were treated with this agent at the Kumamoto University Hospital and its affiliated hospitals. The response rate (complete remission [CR] and partial remission [PR]) was 27.6% for hepatocellular carcinomas and 46.1% for metastatic liver tumors. The cumulative 1-year survival rate was 55.1% for hepatocellular carcinomas and 70.0% for metastatic liver tumors. More than a 50% decrease in the tumor marker level was observed in ten of 21 patients with hepatocellular carcinoma and in two of eight patients with metastatic liver tumors. The side effects, which were transient and controlled with conservative treatment, included fever, abdominal pain, nausea, vomiting, and acute gastritis.     

吉西他滨超液化碘油乳剂治疗晚期肝肿瘤初步研究

目的：探讨吉西他滨超液化碘油乳剂治疗晚期肝肿瘤的可行性及毒副反应。方法：31例肝晚期肿瘤，用吉西他滨超液化碘油乳剂栓塞治疗，部分直接灌注化疗，首次治疗后初步评估早期疗效及毒性反应。结果：31例中，4例肺癌肝转移，8例胰腺癌肝转移，7例结肠癌肝转移，12例巨块型肝癌。首次治疗后，腹痛症状及食欲情况明显好转，而且其毒副作用不明显。结论：吉西他滨超液化碘油乳剂栓塞、灌注治疗肝肿瘤，是安全的，而且能改善病人的生活质量，并且未见不可耐受副反应。     

The clinical research of elemene emulsion combined with FOLFOX4 regimen in the treatment of advanced gastric carcinoma

Objective

The aim of this study was to observe the effects and adverse reactions of elemene emulsion added to the chemotherapy in the treatment of advanced gastric carcinoma (AGC).

Methods

Forty-nine patients were divided randomly into two groups, elemene emulsion group (25 cases, treated with chemotherapy and elemene emulsion) and chemotherapy group (24 cases, treated with chemotherapy only). All patients received chemotherapy. The clinical effects and adverse reactions were evaluated after four cycles.

Results

The response rate (RR) were 60% in elemene emulsion group and 41.7% in chemotherapy group respectively (P < 0.05). The median time to progression and overall survival in elemene emulsion group and in chemotherapy group were 7.1 months and 11.0 months vs 5.2 months and 9.3 months (P < 0.05). A lower rate of neutropenia, nausea, vomiting and diarrhea occurred in elemene emulsion group compared with chemotherapy group (P < 0.05), and there was significant difference in the elevation of life quality as well (48% vs 25%; P < 0.05).

Conclusion

Elemene emulsion in combination with FOLFOX4 regimen can improve the efficacy, decrease the incidence of side effects of chemotherapy and elevate the life quality and prolong the survival time in AGC.     

Pharmacokinetic study of adriamycin in the emulsion mixed with lipiodol-difference resulting from composition and methods of preparation, and behavior after mesenteric arterial injection in rat]

We experimentally investigated the pharmacokinetics of adriamycin (ADM) in a similar of transcatheter arterial chemoembolization therapy (TAE) of hepatocellular carcinoma using emulsion of lipiodol (Lp) mixed with ADM followed by gelatin sponge, and the difference resulting from composition and method of preparation of the emulsion as well as behavior after mesenteric arterial injection in rat. In in vitro study, the emulsion with iopamidol (iopamiron 300 : IP) was more stable than with amidotrizoic acid (60% Urografin : UG). The highest stability was found in the mixing ratio of Lp. IP and distilled water at 1 : 0.42 : 0.08. Frequent pumping also made the emulsion more stable. But in optimally composed emulsion, pumping 20 or 50 times made no difference in the stability during 30 min. which may be longer than the time from preparation to injection time of the emulsion in clinical application. After injection of the emulsion into the mesenteric artery which may simulate injection into the hepatic artery in hepatocellular carcinoma, the arterial blood flow was suspended. In the peripheral arteries the emulsion separated into two phases of Lp and ADM solution, forming striped pattern, and Lp embolization of the peripheral artery persisted for over 45 min. while ADM extravasated. These findings suggest that after Lp-TAE, Lp maintains an embolizing effect while ADM penetrates into the surrounding tumor tissue, and that this is an underlying mechanism for the anti-cancer effect of Lp-TAE.     

Distribution of tumor stage and initial treatment modality in patients with primary hepatocellular carcinoma

Objective

This study reviewed the distribution of each tumor stage and each type of initial treatment modality among patients with primary hepatocellular carcinoma (HCC) treated at a tertiary tumor hospital between January 2003 and October 2013.

Methods

Baseline data of patients with primary hepatocellular carcinoma treated between January 2003 and October 2013 were retrospectively collected. Tumor stage was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system and Hong Kong Clinic Liver Cancer (HKLC) staging system.

Results

A total of 6241 patients with primary hepatocellular carcinoma were included in the analysis. In accordance with the BCLC, 28.9% of patients were in stage 0/A, 16.2% in stage B, 53.6% in stage C, and 1.3% in stage D. According to the HKLC stage system, 8.4% patients were in stage I, 1.5% in stage IIa, 29.0% in stage IIb, 10.0% in stage IIIa, 33.6% in stage IIIb, 3.4% in stage IVa, 2.5% in stage IVb, 0.2% in stage Va, and 11.4% in stage Vb. Treatment modalities applied to this patient group were as follows: 33.3% of patients underwent hepatic resection, 36.7% underwent transarterial chemoembolization (TACE), 2.2% underwent radiotherapy, 0.9% underwent local ablated therapy, 8.8% underwent systemic chemotherapy, 4.2% underwent traditional herbal medicine therapy, 0.1% underwent targeted drug therapy, and 13.8% received no treatment. Hepatic resection was the most frequent therapy for patients with BCLC 0/A/B disease, and TACE was the initial therapy for patients with BCLC C disease. In the Hong Kong Clinic Liver Cancer staging system, the main treatments for HKLC I to IIIb disease is hepatic resection and TACE. Systemic chemotherapy was the initial therapy for patients with HKLC IVa/IVb disease. Most HKLC Va/Vb patients received traditional Chinese medicine treatment.

Conclusion

Prevalence of stage BCLC B and C disease was high among our hepatocellular carcinoma patients. In Hong Kong Clinic Liver Cancer staging system, HKLC I to IIIb disease was high among our HCC patients. Hepatic resection and TACE are initial therapies.