Three cases of multiple liver metastases of carcinoid tumor responding to hepatic arterial infusion chemotherapy using degradable starch microspheres

We describe three patients with multiple liver metastases of carcinoid tumor who received hepatic arterial infusion chemotherapy using degradable starch microspheres (DSM). A partial response was obtained in all cases, and no side effects were observed. We believe that this chemotherapy was an effective treatment for unresectable liver metastases of carcinoid tumor.     

A case of hepatic metastases from uveal melanoma treated effectively by transcatheter arterial chemoembolization with cisplatin and degradable starch microspheres

A 37-year-old male presented with hepatic metastases from uveal melanoma after the enucleation of an affected eye. Hepatic metastases were thought to be the critical factors determining prognosis, so transcatheter arterial chemoembolization (TACE) was performed for local control of the hepatic metastases. The first TACE with cisplatin (CDDP) and gelatin sponge (GS) did not have much success because fine feeding arteries to the main hepatic tumor on the caudate lobe branched out from the hepatic artery, and GS particles were not distributed in the tumor vessels. We used degradable starch microspheres (DSM) as finer obstructing material for the next treatment, and hepatic metastases were treated effectively with repeated CDDP/DSM-TACE.     

Phase I study of hepatic arterial degradable starch microspheres and mitomycin

Intraarterial administration of 40-microns degradable starch microspheres (DSM) in a drug solution can temporarily retard flow of the drug-blood column through the arteriolar-capillary bed and lead to increased local drug deposition. Premonitory to Phase II-III efficacy studies applying this concept to regional therapy, it was necessary to determine the DSM dose to use. Patients with hepatic cancers were treated with varying doses of DSM with mitomycin C coadministered into the hepatic artery to define a dose of DSM which produces acceptable toxicity with maximal hepatic drug deposition as determined by a reduction in systemic mitomycin C exposure. Comparison of six patients receiving 6 ml of DSM (6 X 10(6) particles/ml) with ten patients receiving 15 ml showed a lower incidence and decreased severity of acute toxicity in terms of nausea/vomiting (16% versus 50%) and right upper quadrant hepatic pain (none versus 40%) with 6 ml of DSM. Reduction in systemic mitomycin C exposure evaluated by decrements in the area under the concentration curve in peripheral blood with time due to DSM was similar in both groups. Another seven patients were treated with escalating doses of DSM concurrently with 5 mg of mitomycin C. Although all seven patients tolerated 6 ml of DSM, higher doses (9 ml, 12 ml, 15 ml) led to incremental patient drop-out due to severe, acute right upper quadrant pain with only two patients able to receive 15 ml of DSM. In these patients, 6 ml of DSM appeared nearly equivalent to higher doses in terms of systemic exposure to mitomycin C. Eleven additional patients were evaluated for tolerance to repeated 6-ml dosing of DSM. Four patients had epigastric pain correlating with flow to the stomach demonstrated by nuclide angiography. The seven patients with no pain and no flow to stomach were treated with good tolerance for three-plus courses. Thus, 6 ml of DSM appear to be appropriate for Phase II-III studies.     

Successful resection of multiple liver metastases from rectal cancer following initial treatment using hepatic arterial infusion chemotherapy and radiotherapy

A 69-year-old-man was referred to our hospital because of rectal cancer with multiple liver metastases. He was initially treated by hepatic arterial chemotherapy using an infusion reservoir (HACR) and radiotherapy for the rectal cancer. An abdomino-perineal resection and extended left lobectomy of the liver were performed and resulted in a reduction in size of the liver tumor. He was diagnosed as having a recurrent liver metastasis (S7) at 3 months after the operation, and was retreated by HACR in the outpatient clinic. A partial hepatectomy was reperformed at 6 months after the operation. Adjuvant hepatic arterial infusion chemotherapy (HAIC) was performed on an outpatient basis and the patient is doing well without recurrence or relapse. Preoperative arterial chemotherapy for metastatic liver tumor may be of some benefit for certain patients with far advanced colorectal carcinoma.     

Hepatic arterial infusion chemotherapy with continuous low dose administration of cisplatin and 5-fluorouracil for multiple recurrence of hepatocellular carcinoma after surgical treatment

To date, conventional treatments for multiple intrahepatic recurrence of hepatocellular carcinoma (HCC) after surgery are unsuccessful. The aim of this retrospective study was to evaluate the prognostic effectiveness of a new infusion chemotherapy of cisplatin (CDDP) and 5-fluorouracil (5-FU) via hepatic artery for HCC with multiple intrahepatic recurrence. Fifty-two patients, who had postoperative multiple recurrence of HCC (more than 3 tumors), were enrolled in this study. Thirty-one patients were treated by hepatic arterial infusion chemotherapy via a subcutaneously implanted injection port. A one-week course of this treatment consisted of daily administration of cisplatin (10 mg for 1 h on days 1-5) and subsequent daily administration of 5-fluorouracil (250 mg for 5 h on days 1-5). Three to six sequential one-week courses were performed (the CDDP,5-FU group). Twenty-one patients underwent conventional interventional therapies including transcatheter arterial chemoembolization, lipiodolization (the conventional group). The complete response rate and the effective response rate in the CDDP,5-FU group were 29.0% and 71.0%, respectively. The 5-year survival rate in this group was 45.7%, which was significantly better than that in the conventional group. Based on multivariate analysis, CDDP,5-FU hepatic arterial infusion chemotherapy was found to be significant in prolonging survival, and this treatment achieved favorable therapeutic results for multiple recurrence of HCC. As part of a multidisciplinary approach this treatment is expected to improve the prognosis of patients with advanced HCC.     

Increasing hepatic arterial flow to hypovascular hepatic tumours using degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the intrahepatic distribution of a low molecular weight marker, 99Tcm-labelled methylene diphosphonate (MDP), was studied in rats with hypovascular HSN liver tumours. MDP was injected regionally, via the hepatic artery, alone or co-administered with DSM, with or without subsequent occlusion of either the hepatic artery or the portal vein. Tumour vascularity was measured with 57Co-labelled microspheres. Co-injection with DSM immediately significantly increased hepatic retention of marker in both tumour (T) (median 22.40 (range 16.82-39.58)% injected dose) and normal liver (N) (9.08 (4.85-12.59) %ID) the greater effect seen in T (P < 0.01). After DSM degradation, very little MDP remained in N (0.61 (0.28-1.40) %ID) but there was significant retention in T (10.01 (6.73-20.28) %ID, P < 0.01). Clamping the hepatic artery had minimal effect on the retention of MDP when administered alone. Regional injection of 16.5 microM 57Co microspheres resulted in a N:T ratio of 2.25:1. Concomitant injection of the 40 microM DSM was 57Co microspheres reversed this ratio to 1:2. The results indicate that DSM selectively enhances the retention of MDP to a hypovascular hepatic tumour, not by causing intra-tumour stasis, but by directing a greater arterial flow to hypovascular areas in the liver.     

Histological evaluation of liver metastasis of colorectal cancer following hepatic arterial infusion with degradable starch microspheres and adriamycin/mitomycin C]

Little is known about the histological effect of hepatic arterial infusion with degradable starch microspheres (DSM), adriamycin (ADM), and mitomycin C (MMC) on liver metastasis of colorectal cancer. We histologically examined hepatic metastases resected following this therapy and investigated their relation to macroscopic changes in size. Neither a histological nor macroscopic effect was found in 2 patients receiving this therapy only one time. A 57-year-old woman with a solitary liver metastasis who received this therapy repeatedly (five times every 3 to 4 weeks) subsequently showed a partial response. She underwent hepatic metastasectomy 5 months after the end of the therapy. Histological examination showed that the greater part of the metastatic lesion was composed of fibrous tissues without any viable cancer cells. In conclusion, it should be noted that repeated infusions of DSM.ADM.MMC for liver metastases of colorectal cancer can have a marked histological effect even though the lesion does not show a complete response.     

A case of postoperative multiple hepatic metastasis from esophageal cancer successfully treated by surgical resection and hepatic arterial infusion chemotherapy]

A 66-year-old male who underwent radical resection for esophageal cancer (stage IV) was diagnosed with multiple hepatic metastasis 1 year and 3 months after the surgery. He underwent hepatic resection and received systemic chemotherapy (FAP: 5-FU, ADR, CDDP), as the post-operative adjuvant therapy. One year and 3 months later, there was a huge recurrence in the residual liver and hepatic arterial infusion chemotherapy (FAP) was performed. The recurrent lesion disappeared completely after 3 sessions of arterial infusion chemotherapy. The arterial infusion chemotherapy was continued in the outpatient clinic and the recurrent lesion is well controlled. At present, this patient has returned to social life, 2 years and 3 months after the hepatic resection. The utility of hepatic arterial infusion chemotherapy and hepatectomy for postoperative multiple hepatic metastasis from esophageal cancer was shown in the present case.     

Successful treatment for advanced hepatocellular carcinoma by hepatic arterial infusion of CDDP powder as second-line chemotherapy

A 72-year-old man with type C liver cirrhosis had suffered from hepatocellular carcinoma (HCC) since April, 2001. HCC spread diffusely all over the right lobe of his liver, and the serum alpha-fetoprotein (AFP) value increased up to 42,696 ng/ml in June of 2004. He was implanted with a port-catheter system, and hepatic arterial infusion chemotherapy (HAIC) using low-dose of CDDP and 5-FU was started. However, it was not effective and after 4 months, the serum AFP level increased up to 755,030 ng/ml, ascites appeared, and gastro-esophageal varices also spread. No definite metastasis was detected, then we started to second-line chemotherapy. He was then given HAIC using CDDP powder for intraarterial use (CDDP 50 mg/m(2)/20 min, monthly). After 3 courses, the serum AFP level decreased to 9 10 ng/ml, and abdominal CT revealed that the main tumor had regressed and ascites had disappeared. After one more course, the serum AFP value decreased to 8 ng/ml and complete response was achieved on abdominal CT imaging. There was no major complication related to the chemotherapy. HAIC for advanced HCC using LFP has been reported to achieve favorable results, but no other regimens have been proved to the standard for HCC. HAIC using CDDP powder for advanced HCC may be beneficial as the second-line chemotherapy.     

Long-term survival case after liver resection and postoperative hepatic arterial infusion for multiple liver metastases from rectal cancer

A 45-year-old man underwent a low anterior resection for rectal cancer [T3, N1, M0, Stage IIa: UICC]. He received a postoperative systemic chemotherapy with 5-FU and LV. Five months after the operation, multiple liver metastases were detected in the right hepatic lobe (S5, 6, 8). Right hepatectomy was performed. Seventeen courses of postoperative hepatic arterial infusion (HAI) chemotherapy (weekly high-dose 5-FU regimen) were performed without severe adverse events. He was still alive with no sign of recurrence for 69 months after hepatectomy. After liver resection for metastases of colorectal cancer, although a systemic chemotherapy has been mainly performed, HAI chemotherapy is one of the important options for prevention of local recurrence.     

Cases of postoperative hepatic metastasis from gastric cancer in which hepatic arterial infusion chemotherapy with 5-FU, adriamycin and cisplatin was performed after TS-1 chemotherapy

The prognosis of patients with hepatic metastasis of gastric cancer is poor, and standard therapies for patients are not established. Here we present two cases of hepatic metastasis from gastric cancer. In both cases, no other organ metastasis except the liver was confirmed, in which hepatic arterial infusion chemotherapy with 5-FU, adriamycin and cisplatin (FAP) were performed because TS-1 chemotherapy was not an effective chemotherapy. Case 1: An 80-year-old man had distal gastrectomy for type 2 gastric cancer (Stage II) in January 2001. A liver S8 metastatic recurrence was discovered in the 18th month post operation. After chemotherapy with TS-1 for 5 courses, a hepatic arterial infusion treatment was performed for 7 courses. The effect was PR, but the treatment was canceled because of a catheter obstruction. The patient is living without recurrence. Case 2: This case was a 73-year-old man who had distal gastrectomy for type 0 IIc gastric cancer (Stage IA) in May 1999. Multiple hepatic metastases recurred in the 32nd month post operation. After chemotherapy with TS-1 for 2 courses, a hepatic arterial infusion treatment was performed for 10 courses. The effect was CR, but a peritoneal recurrence was discovered, and a systemic chemotherapy was performed. The patient is living without recrudescence of hepatic metastasis. The hepatic arterial infusion chemotherapy with FAP was effective for gastric cancer patients with liver metastasis because TS-1 chemotherapy was not an effective chemotherapy. It is necessary to consider combined chemotherapy in addition to systemic chemotherapy.     

Arterial infusion therapy with low-dose cisplatin and continuous 5-fluorouracil for isolated hepatic recurrence of gastric carcinoma

Patients with metachronous liver metastasis after curative resection of gastric carcinoma generally have a poor prognosis, even when recurrence is confined to the liver. We report a patient in whom hepatic arterial infusion therapy with bolus low-dose cisplatin (CDDP) and continuous 5-fluorouracil (5-FU) was effective against large metastases confined to the liver. An 83-year-old man was admitted with huge liver metastases from gastric carcinoma. Intra-arterial bolus injection of low-dose CDDP (5 mg) and continuous intra-arterial infusion of 5-FU (250 mg/day for 7 days) was started. After four courses of this arterial infusion therapy, computed tomography scans revealed shrinkage of the liver metastases. He was followed-up as an outpatient and continued to receive the arterial infusion therapy once every 4 weeks. Throughout the course of the chemotherapy, a partial response of the liver metastases was maintained. The patient had an improved quality of life after starting the chemotherapy, and he survived for 16 months from the commencement of the therapy. Arterial infusion therapy with bolus low-dose CDDP and continuous 5-FU may be recommended for patients with isolated hepatic recurrence of gastric carcinoma. Received: September 6, 1999 / Accepted: January 31, 2000     

A case of postoperative multiple hepatic metastasis from gastric cancer successfully treated by percutaneous microwave coagulation therapy and hepatic arterial infusion chemotherapy

A 61-year-old male who underwent radical resection for gastric cancer was diagnosed with multiple hepatic metastasis 2 years and 2 months after the surgery. He first underwent percutaneous microwave hepatic coagulation therapy with segmental hepatic blood flow occlusion and obtained complete coagulation of the main tumor. Consecutively, he received hepatic arterial infusion chemotherapy (FAP: 5-FU, cisplatin, adriamycin) against residual multiple hepatic tumors. These hepatic recurrent lesions disappeared completely after 3 sessions of arterial infusion chemotherapy. At present, this patient is alive with no recurrent lesions, 1 year and 6 months from the beginning of treatment for hepatic metastasis. Recently, we tried hepatic arterial infusion chemotherapy (FAP) in four cases in which the recurrence from gastric cancer was not only in the liver but elsewhere. The response rate (CR and PR) was 75% and no major side effects were observed. In conclusion, some cases can obtain longer survival if the multimoderate therapy including hepatic arterial infusion chemotherapy (FAP) and microwave coagulation therapy are effective.     

Successful treatment of liver metastasis and extrahepatic metastasis with hepatic arterial infusion of CDDP, CPT-11, and 5-FU

A 63-year-old man, who had been operated with right hemicolectomy 1 year and 3 months ago, had giant liver metastasis, lung metastasis, and local dissemination tumor due to ascending colon cancer. He was treated by systemic chemotherapy with 5-FU and the treatment evaluation was PD on CT. After admission to our hospital, he was treated by hepatic arterial infusion chemotherapy with CDDP, CPT-11, and 5-FU. After 3 courses of the treatment, each recurrent lesion decreased on CT and the CEA level decreased. There were no side effects except mild diarrhea. We believe hepatic arterial infusion chemotherapy with CDDP, CPT-11, and 5-FU may be an effective strategy against liver metastasis and extrahepatic metastsis due to colon cancer.     

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with an without coadministration of 600 mg degradable starch microspheres (DSM). Mean (+/- standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 +/- 0.69 micrograms/ml) than after DDP alone (2.13 +/- 0.43 micrograms/ml, P less than 0.05), with the area under the curve (AUC0-30 min) values of 15.8 +/- 5.5 and 25.1 +/- 3.8 micrograms x min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 +/- 1.60 micrograms/g) than after DDP alone (0.67 +/- 0.49 micrograms/ml, P less than 0.05). Liver concentrations and tumor-liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole-liver extraction of the drug and a redistribution of blood flow and flow-dependent tissue uptake of platinum.     

Histological examination of the effect of hepatic arterial infusion of degradable starch microspheres mixed with adriamycin and mitomycin C for liver metastases of colorectal cancer--second report

We histologically examined the effect of hepatic arterial infusion of degradable starch microspheres mixed with adriamycin and mitomycin C (DSM therapy) for liver metastases of colorectal cancer. The subjects were 15 liver metastatic lesions from 9 patients with colorectal cancer who underwent potentially curative hepatectomy after DSM therapy. Ages were ranged from 36 to 71 years old (mean, 57). The ratio of male to female was 4 to 5. Six patients had synchronous lesion(s). A single injection dosage of the DSM therapy was comprised of 300-600 mg degradable starch microspheres, 30 mg ADM, and 10 mg MMC. Three lesions from the two patients who were given a single DSM therapy did not show any radiographical changes. In addition, histological examination of these lesions demonstrated a grade 1 effect. The radiographical effect of the 12 lesions from the 7 patients, who were given the DSM therapy at least three times, showed SD in 4 lesions, PR in 6 lesions, and PD in two lesions. Histological examination of these lesions demonstrated Grade 2 in 4 lesions and Grade 3 in 5 lesions. In conclusion, it was histologically confirmed that a repeated DSM therapy could cause satisfactory effects beyond expectations by radiographic imaging in patients with liver metastases of colorectal cancer.