The progress of hepatic arterial infusion chemotherapy for hepatocellular carcinoma

Hepatic arterial infusion (HAI) chemotherapy has been selected as a therapeutic option for highly advanced hepatocellular carcinoma (HCC) with tumor thrombi in major portal branches or intrahepatic metastases. Conventional therapies have no clinical effect on highly advanced HCC. Recent advances of an implanted portcatheter system have facilitated repeated arterial infusion of chemotherapeutic agents, and HAI chemotherapy with several anticancer drugs provides a useful choice for advanced HCC. In various regimens of HAI chemotherapy, low-dose cisplatin and 5-fluorouracil (5-FU) therapy or combination therapy of interferon (IFN)-alpha/5-FU have been reported to improve the response rates for advanced HCC. However, the survival benefit of HAI chemotherapy may be affected by liver function. None of these regimens have been proved to be the standard for HAI chemotherapy. We previously reported that the beneficial effects of combination therapy of IFN-alpha/5-FU for advanced HCC. IFN-alpha/5-FU combination therapy may be a promising treatment modality for advanced HCC.     

A case of recurrent hepatocellular carcinoma successfully treated with a combination therapy of interferon-alpha and intravenous continuous infusion of 5-fluorouracil

We report a case of recurrent hepatocellular carcinoma (HCC) successfully treated with a combination therapy of interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU), which was administered intravenously. A 49-year-old Japanese man who underwent a right hepatectomy for HCC developed tumor recurrence in the liver 19 months after surgery. Abdominal CT revealed multiple metastatic lesions in the liver. He received a combination therapy of 500 mg/day of 5-FU that was given intravenously by continuous infusion and 5 x 10(6) units of IFN-alpha, given three times weekly. The treatment resulted in a fall in serum PIVKA-II (protein induced by vitamin K antagonism) levels from 337 mAU/ml to 65 mAU/ml and disappearance of tumor stain in enhanced CT. 5-FU is usually administered by arterial infusion in a combination therapy of IFN-alpha and 5-FU. However, 5-FU infusion may be possible intravenously in the combination therapy of IFN-alpha and 5-FU for the treatment of advanced HCC.     

A report of two cases--two patients of the extremely advanced hepatocellular carcinoma have responded completely for a long time after a combination therapy consisting of arterial chemotherapy and injection of interferon-alpha

The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor. Patient 1 was a 43-year-old male with major portal tumor thrombi. He received combination therapy consisting of continuous arterial infusion (MTX 30 mg/m2, day 1, CDDP/5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Patient 2 was a 66-year-old male with major hepatic venous tumor thrombi. He received combination therapy consisting of continuous arterial infusion (5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Decrease in tumor was observed in both patients markers and marked regression of tumor was observed in both patients. They are still in complete response. This combination therapy is an effective strategy for advanced HCC.     

A case of successful second look operation for hepatocellular carcinoma with right atrial tumor thrombus

We report a case of advanced hepatocellular carcinoma (HCC) with right atrial tumor thrombus treated by interferon (IFN)-combinated chemotherapies and second look operation. A case was a 56-year-old man who had right upper abdominal and back pain. The abdominal CT revealed an early enhanced lesion in the posterior segment of the liver with right atrial tumor thrombus. The patient underwent 2 courses of IFN-β/adriamycin combination therapy and followed by surgical resection. Due to severe congestive live, we only surgically resected tumor thrombi at right atrium, inferior vena cava, and right hepatic vein. Additionally, we closed posterior branch and right hepatic vein to prevent from a tumor progression. Following 16 months of IFN/5-FU and IFN/S-1 therapy, we performed a right posterior sectionectomy of the liver. Twelve months after the second operation, liver tumor relapsed and we performed transcatheter arterial chemoembolizatin, followed by IFN-combinateted chemotherapies. Thereafter, we continued chemotherapy for 14 months. The tumor progressed into the bile duct, and he died after 3 years and 8 months from the initial treatment. The case suggests that some patients with HCC with major vascular invasion and tumor thrombus can gain a long-term survival by multifocal treatment including surgery and chemotherapy.     

A case of hepatocellular carcinoma effectively treated by intraarterial infusion of CDDP and other agents

It is very common for intraarterial infusion therapy of some anticancer agent to be effective against hepatocellular carcinoma. In this case, the patient was a 74-year-old man who suffered from very advanced hepatocellular carcinoma with tumor thrombus of the intrahepatic portal vein and IVC. He was treated with intraarterial infusion of CDDP, Etoposide, 5-FU, through a catheter placed in the proper hepatic artery. CDDP (30 mg/day) and Etoposide (60 mg/day) were given once every 5 days, and then 5-FU(250 mg/day) was infused daily for 26 days. The patient underwent this protocol study twice in 3 months. After the intraarterial infusion, transarterial embolization using CDDP (100 mg) powder added to lipiodol and aluminum stearate as suspension was done a month later. The tumor regression rate was 84% after intraarterial infusion of CDDP, Etoposide and 5-FU. The tumor thrombus in the intrahepatic portal vein and IVC had completely disappeared. We could not find lipiodol accumulated in the tumor after TAE. Thus, we assumed that the remaining tumor was a necrotic scar and that a complete response was obtained in the patient. There were some side effects, such as nausea, vomiting, pancytopenia and gastritis but no severe complication occurred.     

Hepatic arterial infusion chemotherapy (HAIC)--hepatocellular carcinoma

Hepatic arterial infusion chemotherapy (HAIC) has been often selected as a therapeutic option for advanced hepatocellular carcinoma (HCC) with intrahepatic metastases or portal vein thrombosis, which is not eligible for hepatic resection, tumor ablation, or embolization. Among various regimens, HAIC, consisting of 5-fluorouracil (5-FU) in combination with either low-doses of cisplatin (CDDP) or interferon-alpha has been reported to improve the response rates for advanced HCC. As both regimens require the use of an implanted port-catheter system, maintaining the patency of hepatic arteries is an important factor for the intrahepatic drug distribution and the efficacy of HAIC. Recently, a new product, CDDP powder has been also developed for intraarterial use, which adds a new option to HAIC. However, the long-term outcome or the survival benefit remains unclear with HAIC, and it may be significantly affected by liver function and cirrhosis. None of the regimens have been proved to be the standard for HAIC, and prospective multi-center clinical studies with standardized protocol are needed in the future.     

Good response in case of hepatocellular carcinoma with portal tumor thrombs--a case report of interdisciplinary local therapy]

A 56-year-old male patient with chronic C type hepatitis had HCC which invaded right portal vein trunk (Vp3). In August 2000, we performed intrahepatic artery infusion chemotherapy with CDDP and 5-FU under subcutaneous interferon alpha treatment. In addition, we used chemoradiation therapy for portal tumor thrombus in HCC. As the result of such therapy, the size of HCC and portal tumor thrombus reduced and the level of PIVKA-II decreased. There were no side effects except fever due to interferon alpha treatment. In February 2001, we performed devascularization and RFA therapy for HCC in S7 of liver under laparoscope. The level of PIVKA-II was within the normal range. It is important to perform interdisciplinary therapy appropriate for the HCC status.     

A case report of hepatocellular carcinoma with hepatic and portal venous tumor thrombus and multiple intrahepatic metastasis who survived over 1 year after the operation with combined locoregional chemotherapy

Hepatocellular carcinoma (HCC) with vascular invasion and/or intrahepatic metastasis (IM) has a poor prognosis, so advanced HCC may be considered as a contraindication for hepatectomy. We experienced a case of HCC with hepatic venous and portal venous tumor thrombus and multiple IM who survived over 1 year after the operation with combined locoregional chemotherapy. (Case): A 67-year-old male patient was diagnosed with HCC with extracapsular invasion after transarterial embolization (TAE). CT scan revealed the HCC had a right portal venous tumor thrombus and multiple IM. Posterior lobectomy and thrombectomy of hepatic venous and portal venous tumor thrombus and placement of portal venous catheter ware performed. From the first day after operation the patient received continuous intravenous and intraportal 5-FU for 3 weeks. At the first month after operation, TAE and PEIT were given against residual IM. After discharge the patient received hepatic arterial infusion chemotherapy (MTX/CDDP/5-FU/Leucovorin). Fourteen months after operation, the patient is surviving in good physical condition.     

Significance of reduction surgery for giant hepatocellular carcinoma with diffuse lung metastases and multiple intrahepatic metastases

Continuous systemic infusion of low-dose cisplatin (CDDP) (10 mg/body/day) and 5-fluorouracil (5-FU) (500 mg/body/day) was performed for advanced hepatocellular carcinoma (HCC) after hepatectomy with diffuse lung metastases and multiple intrahepatic metastases. This infusion chemotherapy, cisplatin was continued for five days, and discontinued for two days, whereas 5-fluorouracil was administered every day and repeated four weeks as one course basally. Remnant metastases had almost disappeared after systemic chemotherapy for 10 weeks. In our experience, the response rate in 13 patients who underwent reduction surgery for multiple HCC was 84.6%. Continuous infusion of low-dose CDDP/5-FU may be effective in patients having absolute non-curative resection.     

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.     

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.     

A case of advanced pancreatic cancer with multiple liver metastasis that improved remarkably with use of low-dose cisplatin and TS-1

The prognosis and QOL of unresectable pancreatic cancer are very poor. A symptomless 60-year-old male was admitted for examination of a high serum CA19-9 level. Following ultrasound and abdominal CT, we diagnosed unresectable advanced pancreatic cancer with multiple liver metastasis. After we obtained his informed consent, we administered continuous infusion of 5-FU and low-dose cisplatin (CDDP) infusion (low-dose FP therapy) for 3 weeks. He then underwent combination chemotherapy with low-dose CDDP and TS-1 on an outpatient basis. During the chemotherapy, he did not experience any major adverse event and his QOL was relatively good. On follow-up CT 3 months later, the primary tumor in the pancreas was found to be stable. However, the size and number of liver tumors were remarkably reduced. The serum CA19-9 level had also remarkably decreased from 48,300 U/ml to 1,480 U/ml. In conclusion, the combination chemotherapy using low-dose CDDP and TS-1 can be effective in cases of unresectable pancreatic cancer with multiple liver metastasis.     

A case of successful treatment by interferon-α and 5-fluorouracil combination therapy (FAIT) and transcatheter arterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus

We report a case of successful treatment by interferon-α (IFN) and 5-fluorouracil (5-FU) combination therapy and transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). A 70-year-old woman, who was diagnosed as unresectable HCC with PVTT in the main trunk of portal vein and multiple intrahepatic metastases, was admitted to our hospital for further treatment for HCC. First, she was treated by 3 courses of IFN and 5-FU combination therapy. Three courses after the combination therapy, PVTT was shrunken and portal flow to the liver was reperfused. Therefore, she was treated by TACE for intrahepatic tumors. She received a repeat treatment of the combination therapy and TACE. Four years after the initial treatment, she is still alive with good condition with intrahepatic tumors. This case suggested that some patient of HCC with PVTT could get a long-term survival if an initial treatment was succeeded and could apply further treatment such as TACE.     

A case of gastric cancer with synchronous hepatic metastases which enforced the intra hepatic arterial chemotherapy showed a reduction of both tumors

This is a case report of the intrahepatic arterial chemotherapy showing an effective reduction of tumors without an operation. The patient was a 68-year-old female. Instead of having an operation to gastric cancer with synchronous hepatic metastases, an intrahepatic arterial embolization of MMC and CPT-11 with DSM was enforced in the right-and-left hepatic arteries, and intrahepatic arterial infusions of 5-FU and CDDP were enforced after that. After intrahepatic infusion, the tumor size and marker of the gastric cancer and synchronous hepatic metastases decreased, and it was diagnosed as partial response (PR). Since the tumor marker showed an increase after thirteen times of the intrahepatic arterial infusions of 5-FU and CDDP, intrahepatic arterial embolization of CPT-11 and MMC with DSM was performed again and the intrahepatic arterial infusions of 5-FU and CDDP were enforced fourteen times after that. Although the tumor marker showed a small range of fluctuation, PR was kept observed and the patient has been stable for fifteen months since the chemotherapy began. She continuously received the combination chemotherapy as an outpatient.     

Study of continuous arterial infusion chemotherapy with low-dose cisplatin and 5-fluorouracil for patients with hepatocellular carcinoma

Seven patients with postoperative recurrence of hepatocellular carcinoma (HCC) and four patients who underwent absolute non curative resection for HCC were treated with continuous arterial infusion of low-dose cisplatin (CDDP) (10 mg/body/day) and 5-fluorouracil (5-FU) (250 mg/body/day). This infusion chemotherapy was continued for five days and discontinued for two days, repeated over four weeks as one course. The response rate in patients with postoperative recurrence was 42.9%, while that in patients who underwent reduction surgery for multiple HCC was 75%. Continuous arterial infusion of low-dose CDDP/5-FU may be effective in patients with multiple small intrahepatic metastases.     

A case of hepatocellular carcinoma responding to hepatic arterial infusion chemotherapy with low-dose cisplatin and 5-fluorouracil]

A 74-year-old man had multiple liver recurrence of hepatocellular carcinoma (HCC) after extended left hepatectomy. He was treated by continuous hepatic arterial infusion (HAI) chemotherapy with low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) via an implanted reservoir. A catheter was inserted percutaneously into the hepatic artery using the Seldinger technique. The patient was administered 10 mg of CDDP on day 1 and 500 mg/day of 5-FU for 4 days as one course. Four courses were administered and the PIVKA-II level decreased from 427 to 216 mAU/ml. However, infusion port problems led to interruption of chemotherapy and PIVKA-II increased to 798 mAU/ml. His chemotherapy was changed to 10 mg of CDDP on day 1 and 750 mg/day of 5-FU for 2 days. After five courses were administered, PIVKA-II decreased to 540 mAU/ml. This patient is still alive 15 months after the start of therapy. This case suggests that HAI with low-dose CDDP and 5-FU might be useful for prolonging the survival of HCC patients with a good quality of life.     

A case of cecal cancer with multiple liver metastases responding to irinotecan (CPT-11)/cisplatin (CDDP) combination therapy for elevation of CA19-9 after complete response (CR) by l-leucovorin(LV)/5-fluorouracil(5-FU) therapy

A 62-year-old woman complained of abdominal pain and diarrhea from February 2, 2002. She was diagnosed with advanced cecal cancer with simultaneous multiple liver metastases. The serum level of CA 19-9 was 420 U/ ml. Ileoceal resection with D3 lymphnode dissection. The replacement of reservoir for hepatic arterial infusion (HAI) was performed on February 2, 2002. As the dissemination was seen near the mesocolon at laparotomy, we could resect all together. Pathological examination demonstrated II, 5.0 x 2.5 cm, mod, se, INFgamma, ly(1), v(1), n(2), stage IV. Systemic l-leucovorin/5-fluorouracil (l-LV/5-FU) + HAI of weekly high-dose 5-FU combination therapy was initiated at postoperative 14 days. The serum CA 19-9 level decreased immediately but was not within the normal range. On abdominal computed tomography (CT), liver metastatic lesions decreased 9 9% on May 27, 2002 and disappeared on August 26, 2002. Though there were no signs of recurrence, the serum CA 19-9 level elevated as of October, 2002. Since the hepatic artery was occluded, HAI was discontinued on November 28, 2002. The serum CA 19-9 level elevated inspite of the continuation of the l-LV/5-FU therapy which we increased an amount of 5- FU. Thus, we changed low-dose irinotecan (CPT-11)/cisplatin (CDDP) therapy. The serum level of CA 19-9 decreased gradually and got with in normal range on March, 2004. It did not elevate since then. Low-dose CPT-11/CDDP therapy may be useful for patients with advanced colon cancer thought to be resistant to 5-FU as second-line chemotherapy.     

Debulking surgery followed by intraarterial 5-fluorouracil chemotherapy plus subcutaneous interferon alfa for massive hepatocellular carcinoma with multiple intrahepatic metastases: A pilot study

Background

The prognosis in advanced hepatocellular carcinoma (HCC) with multiple intrahepatic metastases is extremely poor. Combination therapy with subcutaneous interferon (IFN) alfa and intraarterial 5-fluorouracil was reported to be effective against such advanced HCC. We describe results of debulking surgery followed by combination therapy with IFN alfa and 5-FU for massive HCC with multiple intrahepatic metastases.

Methods

In 27 HCC patients with massive tumors and multiple intrahepatic metastases, we performed combination therapy with IFN alfa and 5-FU after maximal liver tumor resection.

Results

Mean patient age was 63.3 years. Including intrahepatic metastases, tumors numbered 5 or more in 17 patients (63%). Portal or hepatic vein branches were invaded in 22 (81%). The mean maximum tumor diameter was 102 mm. Among 24 patients whose results were analyzed, an objective response by residual intrahepatic metastases was observed in 13 (54%; complete response in 12, and partial response in 1). Overall 1-, 3-, and 5-year survival was 73.2%, 38.7%, and 38.7%, respectively; 1-, 3-, and 5-year progression-free rates were 38.2%, 22.3%, and 22.3%.

Conclusions

Debulking surgery followed by IFN alfa and 5-FU combination chemotherapy offers possibility of long-term survival despite massive HCC with multiple intrahepatic metastases.     

A case of liver metastasis of pancreatic cancer that was resistant to S-1 and gemcitabine successfully treated by 5-FU and cisplatin hepatic arterial infusion

We report a case of postoperative liver metastasis of pancreatic cancer that was resistant to S-1 and gemcitabine (GEM) successfully treated by hepatic arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP). A 70s woman was referred to our hospital for treatment of a pancreatic head cancer in November 2007. Pancreaticoduodenectomy with a regional lymphadectomy was performed in December 2007 and the pathological stage was Stage IVa. Adjuvant chemotherapy of UFT was administered one month after operation. However, a second chemotherapy of S-1 was administered because DUPAN-2 levels showed a high range 8 months after operation. Ten months after operation, abdominal computed tomography demonstrated a 2 cm tumor in the liver. Although, we performed a systemic GEM infusion and a combination of GEM and S-1, the liver metastasis had progressed. Then, hepatic arterial infusion (HAI) chemotherapy of 5-FU/CDDP was instituted weekly. This efficacy maintained a Partial Response from the start of HAI to the fifth month. She is alive to date, maintaining a stable tumor growth of 30 months after surgery. We suggest that HAI chemotherapy of 5-FU+CDDP might be an effective treatment to liver metastasis of pancreatic cancer and prolong prognosis of those patients.     

Interferon-alpha and 5-fluorouracil combination therapy after palliative hepatic resection in patients with advanced hepatocellular carcinoma, portal venous tumor thrombus in the major trunk, and multiple nodules

BACKGROUND: The authors reported previously the beneficial effects of interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy for patients with advanced hepatocellular carcinoma (HCC) who have tumor thrombi in the major portal branches. In this report, the authors describe the results from IFN/5-FU chemotherapy for patients who underwent palliative hepatic resection for advanced HCC with tumor thrombus in the main trunk of the portal vein and multiple nodules in the whole liver. In addition, they evaluated the correlation between the response to such therapy and expression of IFN-alpha type 2 receptor (IFNAR2). METHODS: From October 1999 to December 2004, 30 patients with advanced HCC, tumor thrombi in the main trunk of the portal vein, and multiple nodules in the whole liver (Vp4 and grade 3 intrahepatic metastases) were recruited for this study. They underwent palliative hepatic resection followed by at least 2 courses of IFN/5-FU. IFNAR2 expression levels were determined by immunohistochemistry. RESULTS: No major treatment-related complications were noted. An objective response was noted in 10 patients (33.3%) and included a complete response in 6 patients (20%), a partial response in 4 patients (13.3%), no response in 1 patient (3.3%), and progressive disease in 19 patients (63.4%). IFNAR2 expression was detected in 20 of 30 patients (66.7%). There was a significant difference in overall survival between patients with positive and negative IFNAR2 expression cases (P<.0025), and a significant correlation was observed between IFNAR2 expression and response to IFN/5-FU combination therapy (P=.0199). CONCLUSIONS: Adjunct IFN/5-FU therapy is a promising modality for patients with advanced HCC, tumor thrombi in the major trunk, and multiple nodules after palliative hepatic resection. The results from this study indicated that the response to such therapy seemed to be correlated with IFNAR2 expression.