Intra arterial infusion chemotherapy combined with interferon-alpha following palliative hepatic resection against advanced hepatoma with portal venous tumor thrombus in the major trunk and multiple nodules--a preliminary study

Recently, we reported the beneficial effects of intra arterial 5-FU infusion chemotherapy combined with interferon-alpha (IFN-alpha/5-FU combined chemotherapy) for advanced hepatocellular carcinoma (HCC). This report describes the preliminary results of treatment of IFN-alpha/5-FU combined chemotherapy following palliative hepatic resection for advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein with multiple nodules in the whole liver. The 15 patients of HCC with portal venous tumour thrombi (PVTT) and multiple intra-hepatic multiple nodules (IM3) were treated with IFN-alpha/5-FU combined chemotherapy following palliative surgery in this study. No leukopenia, thrombocytopenia, or myelosuppression was observed in any of the 15 patients. Other adverse effects were, in general, clinically manageable. Concerning the anti-tumor effect, 6 showed an objective response and 9 showed a progressive disease; the response rate was 40.0% (6/15). The 1-year and 3-year survival rates were 48% and 21% in all 15 cases, respectively. In conclusion, IFN-alpha/5-FU combined therapy may be a promising modality for advanced HCC with tumor thrombi in the major trunk with multiple nodules after following palliative surgery.     

A case of Vp4 hepatocellular carcinoma treated with surgical resection and continuous intrahepatic artery infusion chemotherapy of low-dose cisplatin and 5-fluorouracil

A 49-year-old woman was admitted to our hospital because of hepatocellular carcinoma (HCC). She had no hepatitis virus. Serum AFP and PIVKA-II levels were as high as AFP 329.4 ng/ml (AFP-L3% 73.1%) and 281 AU, respectively. Portal venous thrombus was observed from the right portal branch to left portal branch and superior mesenteric vein. An extended right hemihepatectomy with extraction of portal venous thrombus was performed. On postoperative day 8, low-dose cisplatin (10 mg/day for 5 days/week) and 5-fluorouracil (250 mg/day for 5 days/week) were administered through the hepatic artery for 4 weeks. After chemotherapy, one intrahepatic metastasis appeared and RFA was performed for this tumor. At 16 months after surgery, she had multiple lymph node metastases and died at 20 months after the surgery without intrahepatic metastasis. Low-dose CDDP/5-FU intra-hepatic artery infusion chemotherapy was effective for prevention of intrahepatic recurrence after resection of HCC with portal venous thrombus.     

Effectiveness of radiation therapy to the venous thrombosis between the inferior vena cava and right ventricle

In the management of hepatocellular carcinoma (HCC), a tumor thrombus occurrence between the hepatic vein and right ventricle is life threatening. We studied the effectiveness of radiation therapy to the venous thrombosis between the inferior vena cava and right ventricle. CASE 1: A 66-year-old man who suffered from no hepatic viral infection had hepatectomy of the huge HCC (over 20 cm) and recurrence at the post dperated liver and lung. After transarterial embolization, he suffered from dispnea and was found with tumor thrombus from the left hepatic vein to right atrium. Radiation therapy to the tumor thrombus was done and dispnea disappeared. He died by pneumonia at 5 months after the radiation. CASE 2: A 74-year-old woman who had hepatecomy and RFA for multiple HCC. For the recurrence of HCC, TAE and RFA were performed. After the tumor thrombus in the inferior vena cava, mammarian cancer was found and radiation therapy was performed. She died after 4 months from lung edema, but no growth of tumor thrombus was found. CASE 3: A 79-year-old man who had TAE, hepatectomy, RFA and MCT for multiple hepatoma. After these treatments, tumor thrombus at the right ventricle was found. Although he suffered from portal tumor thrombosis, lung metastases, bone metastases and colon cancer after the radiation therapy, he is still alive at the 19 month of treatments. Radiation therapy is safe and effective for venous tumor thrombosis of HCC.     

Modified pharmacokinetic modulation chemotherapy (PMC) with medication of UFT and intraarterial infusion of 5-FU for advanced unresectable HCC

Advanced unresectable hepatocellular carcinoma (HCC) was treated with modified pharmacokinetic modulation chemotherapy (PMC). METHOD: Modified PMC consists of medication with UFT and intraarterial infusion of 5-FU. The dose of UFT is 300 or 400 mg/day. The infusion to hepatic artery of 5-FU is performed with 500 mg/body in an outpatient clinic once a week from reservoir port for 5 hours. RESULTS: The number of recurrent cases after hepatectomy was 5, and that of initial cases with unresectable HCC was 3. Three cases had tumor thrombus in the main portal branch. One patient had tumor thrombus in the inferior vena cava, which reached to the right atrium. The mean number of infusions in all cases was 21. One case showed PR, and 3 cases NC. Three of 6 mortality cases died from liver failure without tumor progression. One year survival rates of the patients with tumor thrombus in the portal trunk or IVC were 75.0%. The mean survival period of these cases was 12.5 +/- 4.2 months. CONCLUSION: Modified PMC had no severe side effect and was effective for advanced unresectable HCC.     

Successful treatment of postoperative multiple hepatic recurrence with hepatic arterial infusion of cisplatin and degrable starch microspheres

A 38-year-old man had multiple recurrence of hepatocellular carcinoma (HCC) with portal vein thrombosis after hepatectomy and postoperative transcatheter arterial chemotherapy with 5-fluorouracil (5-FU). He was treated by trans hepatic arterial embolization (TAE) with 100 mg of cisplatin (CDDP) and degrable starch microspheres (DSM). After 3 courses were administered, the recurrent lesions almost disappeared on CT, and the postoperative rise in PIVKA-II level and AFP level normalized. There were no side effects except slight fever and general fatigue. We recognized a partial response, and the patient is still alive 14 months after hepatectomy. This case suggests that TAE with CDDP and DSM might be useful for prolonging the survival of advanced HCC 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.     

A case report of hepatocellular carcinoma (Vp4)--an attempt to reduce residual tumor thrombus using combination therapy (hepatic arterial infusion, hepatic arterial embolization and radiation)

A 57-year-old man was found to have elevated levels of HCC markers during an observation of chronic hepatitis C. Diffused hepatoma was involved in the posterior lobe, and tumor thrombus extended into the main portal vein (Vp4). Posterior segmentectomy and tumor thrombectomy were performed. But, CT scan 45 days after the operation showed an enhancement at the residual tumor thrombus in the posterior branch. The patient received a hepatic arterial infusion of 5-FU, followed by hepatic arterial embolization. Then, we chose radiation therapy to the tumor thrombus. The most recent CT showed no enhancement at the reduced tumor thrombus. There have been almost no reports of treatment for residual portal thrombus. Careful observations are necessary in such patients.     

A case of successful treatment of advanced hepatocellular carcinoma with tumor thrombi in the major portal branches and inferior vena cava with combined intraarterial 5-fluorouracil, adriamycin and cisplatin therapy

The patient is a 75-year-old male. Abdominal ultrasound tomography in June 2002 revealed hepatocellular carcinoma with intrahepatic metastasis (IM3) and tumor thrombi (Vp4, Vv3) at S4 in the major portal and hepatic vein. From July 2002, he received hepatic arterial infusion therapy (FAP: 5-fluorouracil, CDDP and adriamycin) for these lesions. In December 2002, these lesions had disappeared completely after 6 sessions of arterial infusion therapy. The patient is still alive with no recurrence after 2 years since the beginning of this treatment. Recently, we treated 9 patients with combined arterial infusion chemotherapy (FAP), and the response rate (CR and PR) was 44% and no major side effect was observed. In conclusion, some patients may obtain longer survival through this treatment, even in cases of advanced HCC with tumor thrombus in the major trunks of portal vein and/or hepatic vein.     

A case of hepatocellular carcinoma with tumor thrombi in the first branch of the portal vein and hepatic vein trunks treated by transcatheter hepatic arterial chemoembolization and hepatic arterial infusion chemotherapy--two years and six months follow-up

The patient was a 73-year-old man. In March 2002, abdominal computed tomography revealed hepatocellular carcinoma (HCC) with tumor thrombi in the first branch of the portal vein (Vp3) and two hepatic vein trunks (Vv2). He had no hepatitis virus. Serum AFP and PIVKA-II levels were as high as 6,919 ng/ml and 91,700 mAU/ ml, respectively. He was treated by transcatheter hepatic arterial chemoembolization (TACE) 3 times. On post 1st TACE week 8, he received hepatic arterial infusion chemotherapy (low-dose cisplatin and 5-FU) for Vp3 Vv2 HCC. The patient is still alive with no recurrence after two years and six months since the initial TACE treatment.     

A complete response to one-shot hepatic arterial infusion of epirubicin in a patient with highly advanced hepatocellular carcinoma

A 61-year-old male was admitted for advanced hepatocellular carcinoma (HCC) with multiple lung metastases and tumor thrombus in the portal vein and superior vena cava. At first, we planned to perform transcatheter arterial embolization (TAE) to avoid the rupture of the liver tumor. But, due to the severe liver dysfunction, ie Child-Pugh C and 36% ICG R15, hepatic arterial infusion (HAI) of epirubicin 40 mg was performed. After that, the patient was followed at the outpatient ward and his general condition has gradually improved without a special treatment. At the present, one year and ten month after HAI, the serum alpha-fetoprotein (AFP) is almost within normal limits and CT scans show that HCC with multiple lung metastases, and tumor thrombus in the portal vein and superior vena cava almost disappeared. Although, spontaneous regression of HCC was a rare phenomenon, it might have played a major role in the good anticancer efficacy of this patient as well as high anti-cancer agent sensitivity of his liver tumor.     

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 long-term survival case of hepatocellular carcinoma with portal vein and inferior vena cava tumor thrombi

We report a case of advanced hepatocellular carcinoma (HCC) successfully treated by hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic administration of interferon (IFN)-α and trans-arterial infusion (TAI) therapy of cisplatin (CDDP). A case was a 60-year-old man who had right upper abdominal pain and back pain. The abdominal CT revealed an early enhanced lesion in the posterior segment of the liver with portal vein and inferior vena caval tumor thrombi and multiple intrahepatic metastases. Tumor markers were elevated, AFP 2,480 ng/mL, PIVKA-II 31,900 mAU/mL. The patient underwent 4 courses of IFN-α/5-FU combination therapy and 8 times of TAI therapy of CDDP. After these therapies, tumors in the liver disappeared and tumor markers returned to the normal range. The patient is alive more than 58 months after the initial treatment. This case suggests that some patients with advanced HCC with tumor thrombus can get a long-term survival when intrahepatic lesions are controlled by various therapies including IFN-α/5-FU combination therapy.     

Successful treatment of multiple hepatocellular carcinoma with tumor thrombi in the major portal branches by intraarterial 5-fluorouracil perfusion chemotherapy combined with subcutaneous interferon-alpha and hepatectomy

We experienced a patient who received successful treatment for multiple hepatocellular carcinoma (HCC) nodules, with tumor thrombi in the major portal branches, with intraarterial 5-fluorouracil perfusion chemotherapy combined with subcutaneous interferon-alpha administration. The patient was a 50-year-old man with hepatitis C virus and HCC. The tumors consisted of a 5-cm main nodule in the right lobe (segment 8) and multiple intrahepatic metastases. The tumor also involved portal vein thrombosis throughout the right portal branch. After two cycles of interferon-alpha/5-fluorouracil combination chemotherapy, tumor markers demonstrated a decreasing tendency. Nine months after the initiation of this therapy, the tumors were limited to the right lobe and were surgically removed by S8 subsegmentectomy, S5 partial hepatectomy, and portal thrombectomy. The serum levels of both alpha-fetoprotein and protein induced by vitamin K absence II fell to normal levels after hepatic resection. Fifty-eight months after the first treatment, he is alive with several recurrent nodules in the liver. In conclusion, the interferon-alpha/5-fluorouracil combination therapy is a useful treatment for HCC in patients who have multiple intrahepatic metastases and portal vein thrombosis. In addition to this therapy, combined modality therapy including, for example, surgical resection, can sometimes have a dramatic therapeutic effect, shown by tumor markers reverting to normal levels.     

A case of HCC with inferior caval vein tumor thrombus and multiple pulmonary metastases that remarkably responded to combination therapy of TS-1 and interferon-alpha

A 56-year-old male was admitted to our hospital for hepatoma with portal vein thrombus and multiple intrahepatic metastases. He underwent an extended left lobectomy and a partial resection of the liver in May 2002. After two weeks from the surgery, he received intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat the lesions in the residual liver. Four months after the surgery, hepatic vein tumor thrombus appeared in the remnant liver and it extended to the inferior caval vein. And another 4 months later, multiple pulmonary metastases were detected with computed tomography and they grew rapidly in the view of their sizes and numbers. Because the combined therapy of 5-FU/interferon-alpha was not effective to distant metastases, we started a new regimen of oral administration of TS-1 and a subcutaneous interferon-alpha injection. After 1 treatment cool, hepatic vein thrombus was markedly reduced the size and vascularity in the CT. Multiple pulmonary metastases also decreased in their sizes and numbers. No adverse effect was seen during this treatment. It was suggested that a combination therapy of TS-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastasis.     

A successful case of systemic chemotherapy followed by liver resection for advanced hepatocellular carcinoma with highly vascular invasion and multiple pulmonary metastases

The prognosis for hepatocellular carcinoma with extrahepatic metastasis or vascular invasion is very poor. We treated a case successfully by combining chemotherapy and liver resection for hepatocellular carcinoma with multiple pulmonary metastases and vascular invasion. A 56-year-old man who complained of abdominal pain in his right side was transported to the hospital by ambulance. Because CT scan revealed the rupture of hepatocellular carcinoma, he underwent emergency transcatheter arterial embolization (TAE). A close examination revealed tumor thrombus in the inferior vena cava and posterior segment of the portal vein branch, with multiple pulmonary metastases. We conducted right hepatic lobectomy and removal of the inferior vena cava tumor thrombus. After the operation, pulmonary metastatic lesions gradually grew larger, so the oral administration of S-1 at 120 mg per day was started. At the end of the first course, the CT scan revealed that multiple pulmonary metastases were significantly reduced, and treatment was maintained until the end of 4 courses. A prolongation of survival could be expected by combining systemic chemotherapy and liver resection for advanced hepatocellular carcinoma such as the present case.     

A successful case of more than 5 years of disease free survival in hepatocellular carcinoma with tumor thrombus to the right main branch of portal vein after repeated hepatic resection following transhepatic arterial embolization (TAE)

A case is a male in his 50's. He received hepatic resections twice for hepatocellular carcinoma. Recurrence was pointed out in the residual liver with tumor thrombus to the right branch of the portal vein. The serum level of AFP was 648 ng/ml. We performed transhepatic arterial embolization (TAE) with Epi-ADM, CDDP, Lipiodol and spongel through the right hepatic artery before re-hepatectomy. Posterior segmentectomy with an extraction of portal vein thrombus was performed. Pathological findings showed complete necrosis not only in the main tumor but in the portal vein thrombus also. He is alive for more than 5 years without recurrence after surgeries following pre-operative TAE.     

Temporary placement of inferior vena cava filter prior to transcatheter arterial embolization (TAE) for hepatocellular carcinoma with IVC tumor thrombus--prevention of pulmonary tumor emboli after TAE]

A 66-year-old-man with a right huge hepatocellular carcinoma (HCC) extending into both the right portal vein and the right atrium underwent transcatheter arterial embolization (TAE) via the right hepatic artery. Prior to the TAE, a temporary inferior vena cava (IVC) filter was placed suprarenally for prevention of pulmonary tumor emboli. When we replaced the temporary IVC filter with a new one 7 days after the TAE, the filter which was pulled out of the IVC captured a fragment of the tumor thrombus. A histopathological specimen demonstrated only ghost cells. The patient has been followed at our outpatient clinic without any tumor thrombus or pulmonary infarction for 13 months after this procedure.     

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.     

Four cases of successful multidisciplinary treatment for hepatocellular carcinoma with portal venous thrombus

CASE 1: TAI and radiation therapy were performed for a lateral segment and tumor thrombus extended into the left portal branch. Then, we diagnosed a tumor thrombus that extended into the right portal branch and TAI and operation were performed. The patient died about 9 months after the diagnosis of tumor thrombus. CASE 2: An operation was performed for hepatoma involving the right lobe and the tumor thrombus extended into the right portal branch. TAI and TAE were performed for residual tumor. The patient died about 12 months after diagnosis of tumor thrombus. CASE 3: An operation was performed for hepatoma involving an anterior segment and tumor thrombus extended into the right portal branch. Then, TAI, TAE and PMCT were performed for residual tumor. The patient is alive for 33 months with recurrence after the diagnosis of tumor thrombus. CASE 4: An operation was performed for hepatoma involving a posterior segment and tumor thrombus extended into the right portal branch. For recurrent TAI and TAE, radiation therapy was performed. The patient is alive for 20 months without recurrence after the diagnosis of tumor thrombus.     

A case of Vp3 hepatocellular carcinoma with a good QOL after multidisciplinary treatments

A 74-year-old male was examined with abdominal CT scan because of general fatigue. Abdominal CT scan indicated enhanced tumors, 9x8 cm in size in subsegment 6/7 and 5 mm in size in subsegment 3. Tumor thrombus was observed in the right portal branch to the main portal vein. We diagnosed the patient with Vp3 hepatocellular carcinoma. A right hepatectomy with extraction of portal venous thrombus was performed. Unresectable tumor was treated with one shot arterial infusion (epi-ADM 40 mg) and TAE 3 times at an interval of three months. The side effect was only a fever and the QOL was good under the treatment. But a tumor in S1 had developed, and the patient died at about 12 months after the operation.