Randomized controlled Phase III study comparing hepatic arterial infusion with systemic chemotherapy after curative resection for liver metastasis of colorectal carcinoma: JFMC 29-0003.

BACKGROUND: The feasibility and efficacy of adjuvant hepatic arterial infusion (HAI) in preventing the development of liver metastases in patients with advanced colon carcinoma have not been validated. The aim of this randomized controlled study was to compare the feasibility of HAI and the protective effect against liver metastasis after curative resection to those of systemic chemotherapy. METHODS: Between July 2000 and June 2003, 91 patients were enrolled. Patients were randomly assigned to receive 5-fluorouracil (5-FU) via continuous venous infusion (CVI) or intra-hepatic arterial weekly high-dose 5-FU (WHF). The primary endpoint was overall survival (OS). RESULTS: In the WHF group, the cumulative failure rate of hepatic arterial catheterization was 16.7% at 6 months. The occurrence of grade 3 adverse events was comparable between the groups. The 5-year OS rates were 59.0% in the CVI group and 34.9% in the WHF group (P = 0.164). CVI tended to show a protective effect against liver metastasis regarding the 5-year liver-specific cumulative recurrence rate: CVI, 45.0% vs. WHF, 68.3%; P = 0.037). CONCLUSION: HAI therapy has a certain protective effect against liver metastasis after curative resection in patients with colorectal cancer. However, this therapy did not contribute to any marked improvement in their overall survival.

Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma.

OBJECTIVES: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government-sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child-Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis. METHODS: Altogether 177 patients with advanced HCC at Child-Pugh class A who were free of extrahepatic metastasis were retrospectively enrolled. The patients were divided into the HAIC group (n = 136) and the sorafenib group (n = 41), and were followed up until their death or withdrawal of therapy. Responses to treatment and overall survival were determined and compared between the two groups. RESULTS: The proportion of patients with complete response, partial response, stable disease and progressive disease were 5.9%, 25.0%, 40.4% and 21.3% in the HAIC and 2.4%, 2.4%, 43.9% and 41.5% in the sorafenib group, respectively. The response rate was higher in the HAIC group than in the sorafenib group (30.9% vs 4.8%). The median survival time was 10 months in both HAIC and sorafenib groups. In patients with macroscopic vascular invasion (MVI) by the case-control method, the response rate was higher in the HAIC group than in the sorafenib group. Overall survival was longer in the HAIC group than in the sorafenib group (14 months vs 7 months, P = 0.005). Multivariate analysis identified MVI (hazard ratio 2.4, P = 0.018) as an independent prognostic factor of survival in the sorafenib group. CONCLUSIONS: Response rate to HAIC was higher than that to sorafenib monotherapy. Prognosis was favorable in HAIC responders despite MVI. HAIC might be a potential treatment option for advanced HCC without extrahepatic metastasis.

Comparison of two transarterial chemoembolization strategies for hepatocellular carcinoma.

AIM: This retrospective study aimed to compare the efficacy of and tolerance to two center-related conventional transarterial chemoembolization (TACE) strategies in the management of unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: All HCC patients in whom TACE was initiated in the two centers from June 2008 to July 2011 were included. The TACE strategy performed in center 1 was "on demand" with selective injections of idarubicin, whereas the TACE strategy in center 2 was based "on scheduled" non-selective injections of epirubicin. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: One hundred and fifty HCC patients were included. Median time to treatment failure was significantly higher in center 1, 13.1 months vs. 7.9 months in center 2 (hazard ratio, 2.32; p<10-3 in multivariate analysis). Median overall survival was 21.1 months in center 1 vs. 18.4 months in center 2 (p=NS). The proportion of grade ≥ 3 adverse events and mean hospitalisation duration for the overall TACE treatment were significantly greater in center 2 than in center 1: 56% vs. 32% (p<0.01) and 14.2 ± 7.2 days vs. 10.3 ± 7.0 days (p<0.01), respectively. CONCLUSION: Our results failed to show any significant survival differences between two center-related TACE strategies but showed a significantly smaller proportion of grade ≥ 3 adverse events and shorter hospitalisation for the overall treatment when the "on-demand" strategy was used.

Isolated limb infusion with melphalan and actinomycin D in melanoma patients: factors predictive of acute regional toxicity.

IMPORTANCE OF THE FIELD: Isolated limb infusion (ILI) is a simple, minimally invasive technique of delivering high concentrations of cytotoxic drugs to a diseased limb for achieving disease control in that limb. Recent studies have suggested that mild hyperthermic (38 degrees C) ILI might be the best initial treatment for extensively recurrent limb melanoma given its simplicity, low morbidity and a complete response rate of 30 - 40%. AREAS COVERED IN THIS REVIEW: Since 1994 when ILI was first described by Thompson et al., the procedure has been adopted by several centres around the world; research and improvements in the technique have resulted in reduction in limb toxicity without reducing its clinical efficacy. The pharmacokinetics of melphalan and the clinical efficacy and adverse effects of ILI from various centres are summarised. Minor but possibly important differences in the ILI techniques used in different institutions may be important in improving its efficacy and reducing the toxic effects. WHAT THE READER WILL GAIN: An understanding of the efficacy and toxicity associated with ILI with cytotoxic drugs in melanoma patients and of methods to optimise regional therapy for malignant disease in a limb. TAKE HOME MESSAGE: ILI with mild hyperthermia (38 degrees C) is well tolerated with tumour remission rates in melanoma patients similar to those achieved by isolated limb perfusion. Mild (grade I - II) and moderate/severe (grade > or = III) limb toxicities occur in 58 - 68% and 32 - 41% of patients, respectively, but long-term morbidity is rare. A high peak and high final melphalan concentration in the infusate, the AUC of melphalan concentration in the infusate and an increased postoperative serum creatine phosphokinase concentration are factors predictive of acute regional toxicity. Drug dose adjusted for ideal body weight and gender may reduce acute toxicity following ILI. It has been suggested that the use of papaverine prior to the infusion of melphalan might increase its efficacy, but it may also increase toxicity. Large prospective studies are needed to more accurately define the perioperative factors that influence acute regional toxicity after ILI and to establish strategies to optimise clinical outcome.

Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases.

PURPOSE: The aim of this study was to analyze the impact of hepatic arterial infusion (HAI) of oxaliplatin with systemic 5-Fluorouracil and leucovorin on patients with isolated unresectable liver metastases. PATIENTS AND METHODS: A total of 87 patients treated in our hospital with HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin for isolated unresectable colorectal liver metastases from May 1999 to May 2007 were extracted from a prospective database and analyzed. The resectability rate, perioperative findings, postoperative outcomes, and long-term follow-up were evaluated. RESULTS: HAI was delivered after failure of previous systemic chemotherapy in 69 patients (79%). The main criterion for unresectability was massive liver involvement (86% of patients). Most patients had synchronous (85%), bilateral metastases (89%). The median number of HAI courses was 8 (0-25). About 31 patients experienced technical catheter-related problems, which were responsible for withdrawal of HAI in only 7 patients (8%). Finally, a total of 23 patients (26%) were operated on, and resection or radiofrequency ablation was performed in 21 patients (24%). No postoperative mortality was observed and the morbidity rate was 35%. Five-year overall survival was 56% in the surgery group versus none in the nonsurgery group (P < 0.0001). After a median follow-up of 63 months, intrahepatic recurrence occurred in 10 patients among the 23 operated patients. CONCLUSIONS: HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin offers a second chance to remove initially unresectable isolated colorectal liver metastases in 24% of patients, and appears to be more efficient when performed as first-line therapy. Long-term overall survival can be obtained with this approach.

[Case report of infected pseudo-aneurysm after intra-arterial chemotherapy].

A 63-year-old man admitted to emergency center of our hospital with fever and obstructive jaundice. Computed tomography (CT) showed a mass in the head of the pancreas and a dilated bile duct. After performing preoperative biliary drainage, we conducted pancreatico-duodenectomy (PD-II: T3, N1, stage III). As adjuvant chemotherapy, the patient received a hepatic arterial infusion with 5-FU to prevent liver metastasis. A catheter was placed in the right femoral artery and intra-arterial chemotherapy was carried out for one week. After the completion of chemotherapy, swelling and redness of the right inguinal region was observed. CT revealed an infected pseudo-aneurysm of the femoral artery. Despite intravenous antibiotic therapy for 2 days, bleeding and pus discharge at the catheter root were observed. He immediately underwent drainage and primary suture to stop the bleeding. Two weeks after surgery for the infected pseudo-aneurysm, a right external iliac-femoral bypass operation was performed. Five weeks after surgery, he was discharged without further incident. In such cases, it is advisable to drain the infected pseudo-aneurysm following a prompt diagnosis, and perform a secondary bypass operation.

Transarterial chemoembolisation for advanced hepatocellular carcinoma: results from a North American cancer centre.

AIMS: In Asian countries, transarterial chemoembolisation (TACE) has long been used for palliation of unresectable hepatocellular carcinoma (HCC) without strong evidence of improved survival or quality of life. In 2002, a survival benefi of TACE was shown in two randomised controlled trials in Europe and Hong Kong. The effectiveness of interventions fo HCC is influenced by geographical factors related to diverse patient characteristics and protocols. Therefore, the validation of TACE as palliative modality for unresectable HCC requires confirmation in diverse patient populations. The aim of the present study was to assess the effectiveness of TACE for HCC in a North American population. MATERIALS AND METHODS: This was a single centre prospective cohort study. Child-Pugh A cirrhosis or better patients wit unresectable HCC and without radiological evidence of metastatic disease or segmental portal vein thrombosis wer assessed between November 2001 and May 2004. Of 54 patients who satisfied the inclusion criteria, 47 underwent 80 TACE sessions. Chemoembolisation was carried out using selective hepatic artery injection of 75 mg/m(2) doxorubicin and lipiodol followed by an injection of embolic particles when necessary. Repeat treatments were carried out at 2-3 month intervals for recurrent disease. The primary outcome was overall survival; secondary outcomes were morbidity and tumour response. RESULTS: The survival probabilities at 1, 2 and 3 years were 76.6, 55.5 and 50%, respectively. At 6 months after the first intervention, 31% of patients had a partial response and 60% had stable disease by RECIST criteria. Minor adverse events occurred after 39% of TACEs and major adverse events after 20% of sessions, including two treatment-related deaths (4% of patients). One patient had complete cancer remission after undergoing three TACE treatments. Further progression of tumour growth was prevented in 91% of tumours at the 6 month point after the first TACE. At 3 months, serum levels of the tumour marker alpha-feto protein were significantly reduced in patients with elevated levels before TACE. CONCLUSIONS: The survival probabilities at 1 and 2 years after TACE were comparable with results in randomised studies from Europe and Asia. Most patients tolerated TACE well, but clinicians need to be aware that moderately severe sideeffects require close monitoring and prompt intervention.

Transcatheter arterial chemoembolization of hepatocellular carcinoma: a Japanese experience.

Hepatocellular carcinoma is one of the most common causes of cancer death in Japan and in 80% of cases is associated with chronic liver disease caused by hepatitis C virus. Poor hepatic function reserve due to underlying cirrhosis is the primary factor which limits extended surgical resection in many cases. Furthermore, in patients treated by curative resection, high incidence of recurrent tumors or/and newly developed tumor in the residual liver was reported. Therefore, the aim of various therapeutic options such as operation, percutaneous ethanol injection, radiofrequency coagulation therapy and transcatheter arterial chemoembolization should be the local control of hepatocellular carcinoma. Transcatheter hepatic arterial chemoembolization has a main role for the multidisciplinary treatment for hepatocellular carcinoma with this biological behavior.

Estado actual de la estrategia y tratamiento de las metástasis hepáticas del cáncer colo-rectal / Advances in strategy and treatment in hepatic metastasis of colorectal cancer

Antecedentes: El tratamiento de las metástasis hepáticas del cáncer colo-rectal es un tema de permanente revisión. En la actualidad no se demostró todavía la curación real del cáncer colo-rectal con metástasis hepáticas, sin embargo consideramos que la resección del tumor primario acompañada de la extirpación de las metástasis es una modalidad terapéutica eficaz. Capaz de modificar la evolución natural de la enfermedad, mejorando la calidad de vida de los pacientes. Objetivo: Presentar los avances que la cirugía, acompañada con otros métodos y procedimientos alternativos de tratamiento, pueden mejorar la calidad de vida de los pacientes. Material y Método: Entre julio de 1973 y julio de 1998, se realizaron 38 resecciones hepáticas por metástasis de cáncer colo-rectal. Se combinó la cirugía con otras terapias alternativas neoadyuvantes y adyuvantes, como la quimioterapia, la embolización portal y la criocirugía. Resultados: El promedio de supervivencia a 4 años fue del 24 por ciento, y a los 5 años del 20 por ciento. La mortalidad fue del 6 por ciento cuando se efectuaron resecciones hepáticas ampliadas; y también en porcentaje aproximado en las re-resecciones. Con conductas quirúrgicas menos agresivas, la mortalidad fue del 0 por ciento, hecho ocurrido en los últimos 10 pacientes. Conclusiones: La cirugía, combinada con otros métodos alternativos, han mejorado notablemente los resultados. La posibilidad de efectuar resecciones hepáticas económicas ofrece al paciente un mayor índice de supervivencia. En la patología hepática metastásica del cáncer colo-rectal, con la combinación de estos procedimientos se obtuvieron mejores resultados y menos morbimortalidad

Estado actual de la estrategia y tratamiento de las metástasis hepáticas del cáncer colo-rectal / Advances in strategy and treatment in hepatic metastasis of colorectal cancer

Antecedentes: El tratamiento de las metástasis hepáticas del cáncer colo-rectal es un tema de permanente revisión. En la actualidad no se demostró todavía la curación real del cáncer colo-rectal con metástasis hepáticas, sin embargo consideramos que la resección del tumor primario acompañada de la extirpación de las metástasis es una modalidad terapéutica eficaz. Capaz de modificar la evolución natural de la enfermedad, mejorando la calidad de vida de los pacientes. Objetivo: Presentar los avances que la cirugía, acompañada con otros métodos y procedimientos alternativos de tratamiento, pueden mejorar la calidad de vida de los pacientes. Material y Método: Entre julio de 1973 y julio de 1998, se realizaron 38 resecciones hepáticas por metástasis de cáncer colo-rectal. Se combinó la cirugía con otras terapias alternativas neoadyuvantes y adyuvantes, como la quimioterapia, la embolización portal y la criocirugía. Resultados: El promedio de supervivencia a 4 años fue del 24 por ciento, y a los 5 años del 20 por ciento. La mortalidad fue del 6 por ciento cuando se efectuaron resecciones hepáticas ampliadas; y también en porcentaje aproximado en las re-resecciones. Con conductas quirúrgicas menos agresivas, la mortalidad fue del 0 por ciento, hecho ocurrido en los últimos 10 pacientes. Conclusiones: La cirugía, combinada con otros métodos alternativos, han mejorado notablemente los resultados. La posibilidad de efectuar resecciones hepáticas económicas ofrece al paciente un mayor índice de supervivencia. En la patología hepática metastásica del cáncer colo-rectal, con la combinación de estos procedimientos se obtuvieron mejores resultados y menos morbimortalidad (AU)

[Complication due to arterial infusion chemotherapy for liver metastasis from colorectal cancer].

OBJECTIVES: Arterial infusion chemotherapy is considered to be an extremely effective treatment for liver metastasis from colorectal cancer in terms of its tumor reduction and preventing recurrence in residual liver after resection. However, there still remain some unclear points as to the influence on hepatic artery and bile duct when this treatment is used over the long term. We report some conclusions obtained by examining cases of hepatic arterial occlusion (stenosis) and biliary complication who received this treatment. MATERIALS AND METHODS: Thirty-six cases who received this treatment over 3 months were the objects of this study, with the aim of direct effect against metastatic focus (21 cases) and prevention of recurrence in residual liver (15 cases). The ages were from 27 to 81; 22 cases were male and 14 were female. Indwelling routes of catheter were gastroduodenal artery (GDA) in 28 cases and femoral artery (FA) in 8 cases. Intermittent high-dose infusion (WHF: 5-FU 1,000 mg/m2/5 hrs qw) was adopted as the method. RESULTS: Hepatic arterial occlusion or stenosis was observed in 12 cases (GDA: 10; FA: 2). There seemed to be no correlation with the total dosage of 5-FU or the number of administrations. Even when hepatic arterial occlusion or stenosis occurred, no change was observed in liver function, and there no death was caused by this. However, CT showed a low-density area followed by atrophy in the right lobe in one case with right hepatic arterial stenosis, despite normal portal blood flow. Of the 6 cases which developed obstructive jaundice, 4 were due to the increase of metastatic focus or lymph nodes, and 1 case without dilatation of bile duct died from suspected sclerosing cholangitis. In this case, ALP had been increasing since 1 month before the onset of jaundice. Another case which developed biloma accompanied by the increase of serum bilirubin improved by discontinuance of chemotherapy. CONCLUSION: Since arterial infusion chemotherapy for liver metastasis from colorectal cancer causes hepatic arterial occlusion (stenosis) at a high rate, early detection of abnormalities by liver function test and imaging diagnosis which leads to early treatment is important.

[Complication of reservoir hepatic artery infusion chemotherapy and additional treatments].

In 54 patients who underwent hepatic artery infusion chemotherapy for hepatic tumors at our hospital between January 1990 and December 1996, we investigated the complications of this therapy and the therapeutic techniques following its discontinuation. The arterial infusion was discontinued in 36 of the 54 patients; 13 due to death (mean survival period: 15.7 months), and 23 in whom occlusion of the reservoir, etc. made it impossible to use arterial infusion (mean period of use: 13.8 months), and the minimum duration of use was 41 days and maximum duration of use 992 days. The most common complication of the reservoir hepatic artery infusion was reservoir occlusion (14.8%). Another serious complication was reservoir deviation outside the blood vessel in two patients; deviation in to the gastric lumen in one case and intraperitoneal deviation in the other. Four hepatocellular carcinoma patients, in whom it became impossible to use the reservoir due to its occlusion, underwent re-hepatectomy. Three of them survived for more than two years following supplemental local therapy, including subarterial injection, TAE, PEIT, microwave tumor coagulation (MTC). Of four patients with colon cancer metastasizing to the liver, one could undergo re-hepatectomy, one received subarterial injection, and two have survived without relapse. Two of three patients with breast cancer underwent systemic chemotherapy and endocrine therapy successfully, while the third one underwent subarterial injection and TAE, and is still under observation. Hepatic artery infusion should sometimes be discontinued owing to complications caused by various factors. Even if it becomes impossible to use the reservoir, local therapeutic techniques, including re-hepatectomy, TAE, PEIT, MTC, etc., may be performed in some patients. These findings suggest that it is necessary to review the interdisciplinary treatment so as to be appropriate to the primary disease.

Hepatic artery-biliary fistula during infusion chemotherapy.

A 52-year-old man with rectal cancer and liver metastasis underwent tumor resection with hepatic arterial catheterization. During adjuvant chemotherapy, he developed epigastric pain, nausea, and melena. Digital subtraction angiography revealed a hepatic artery-biliary fistula and a pseudoaneurysm at the catheter tip. This rare complication of intra-arterial chemotherapy is reported in detail.

Computed tomography during arterial portography in malignant carcinoid syndrome: a report of two patients.

Computed tomography during arterial portography (CTAP) and delayed high-dose iodine computed tomography (CT) have improved the preoperative localization of hepatic metastases from colon cancer. Nearly all patients presenting with malignant carcinoid syndrome have liver metastases, and removal of tumour bulk is considered the most effective means of management. To determine suitability for hepatic resection, CTAP and delayed high-dose iodine CT were used to evaluate the distribution of hepatic disease in two patients with malignant carcinoid syndrome. In both patients CTAP showed lesions not seen during recent dynamic incremented CT; the location of the lesions precluded resection. CTAP also demonstrated metastases less than 1 cm in diameter in one patient. Facial flushing (both patients) and hypotension (one) occurred during infusion of the contrast agent into the superior mesenteric artery. Because CTAP can demonstrate small hepatic metastases (less than 1 cm in diameter), it is recommended for patients with malignant carcinoid syndrome who are being considered for hepatic resection. The infusion of contrast media through the superior mesenteric artery may induce a carcinoid crisis, and prophylaxis with a somatostatin analogue is suggested.

[Two cases of esophageal varices complication after hepatic arterial infusion chemotherapy (HAI) for metastatic liver tumor].

Mild liver dysfunction is a well-known complication of HAI, but it has been thought to be transient and reversible in most cases. In the case, of metastatic liver disease, in particular, HAI has been performed safely because liver function is normal for the most part. We encountered 2 cases of irreversible severe liver dysfunction and esophageal varices after hepatectomy for metastatic liver tumor from colorectal cancer. They were treated with postoperative adjuvant HAI. Biliary enzyme as alkaline phosphatase elevated, and dilated intrahepatic bile ducts were observed in both patients. Fibrosis of Glissonean sheath, dilatation of intrahepatic bile ducts and intrahepatic biliary stones were observed at autopsy in both patients. One of the patients had obstruction of portal trunk. It must not be forgotten that such complications can occur even in a case with non-cirrhotic liver.

Treatment of symptomatic metastatic cancer to the liver from primary colon and rectal cancer by the intraarterial administration of chemotherapy and radioactive isotopes.

Sixty-five patients were referred for treatment with symptoms resulting from metastatic cancer to the liver from the GI tract. Two groups of patients were analyzed. The first group of 40 patients were subjected to a laparotomy and insertion of a catheter into the hepatic artery and a second group had the catheter inserted percutaneously and a bolus of cancer chemotherapeutic agents injected into the catheter. In both groups, chemotherapy in the form of 5-fluorouracil was supplemented by internal irradiation delivered from the intraarterial administration of Yttrium 90 microspheres. Forty percent of the patients who had an indwelling catheter performed at celiotomy manifested an objective response and in 60% a significant subjective improvement occurred. In the 25 patients whose catheter was inserted percutaneously, the response rate was roughly similar, in that 35% demonstrated an objective response and 65% demonstrated a subjective response.