Hepatic arterial chemotherapy for colorectal liver metastases

The management of hepatic metastasis from colorectal cancer represents a significant clinical problem. For the majority of patients with colorectal liver metastases, chemotherapy will be the mainstay of treatment. Considerable data now exists to support hepatic arterial chemotherapy as being effective over systemic chemotherapy both in terms of quality of life and response rates. Morbidity and mortality rates are reduced when catheters are placed by skilled dedicated surgeons using rigorous protocols.     

Hepatic arterial chemotherapy for colorectal cancer metastatic to the liver

Hepatic metastases of colorectal origin are resistant to radiation and immunotherapy. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients, and surgical resection is feasible in approximately 20% of patients who have a solitary or unilobar lesion. Infusion of cytotoxic agents into the hepatic artery, introduced 2 decades ago, is the most promising form of therapy for unresectable hepatic metastases. Fluorouracil, floxuridine, and mitomycin have been most commonly administered by hepatic arterial infusion. The recent development of a totally implantable pump has allowed prolonged ambulatory infusion of chemotherapeutic agents into the hepatic artery. We review the recent data on the pharmacology, therapeutic outcome, administration techniques, and complications of hepatic arterial chemotherapy. Future trials in this area should use uniform stratification variables and standardized criteria for evaluating response, time to progression, and survival.     

Hepatic arterial infusion alternating with systemic chemotherapy in patients with non-resectable hepatic metastases from colorectal cancer

BACKGROUND AND AIM: Hepatic arterial infusion (HAI) chemotherapy has a number of limitations, including a low rate of complete response and frequent extrahepatic recurrence, in colorectal cancer patients with non-resectable hepatic metastases. METHODS: Twenty-nine colorectal cancer patients with non-resectable hepatic metastases were consecutively enrolled for HAI alternating with systemic chemotherapy (HA + SC group). The protocol comprised six cycles of alternating HAI (5-FU + leucovorin for 14 days, and mitomycin C on the first day) and systemic chemotherapy (5-FU + leucovorin). Colorectal cancer patients with two or more hepatic metastases treated using hepatic resection and systemic chemotherapy (HR + SC group) were selected as a comparative group. RESULTS: Within the HA + SC group, complete response was achieved in eight patients (28%), whereas 13 patients (45%) showed progressive disease. Six of the eight patients with complete response lived for more than 38 months. Extrahepatic recurrences were more frequent in the HR + SC group than the HA + SC group (47 vs 21%, P = 0.024). The two groups did not differ with respect to overall and hepatic progression-free survival (P = 0.947 and 0.444, respectively), displaying median +/- SE values of 38 +/- 7 and 20 +/- 3 months in the HA + SC group, and 39 +/- 9 and 33 +/- 14 months in the HR + SC group, respectively. One patient in each group experienced toxic hepatitis, and sclerosing cholangitis occurred in one patient of the HA + SC group. Other complications were mostly grade 1 or 2. CONCLUSIONS: HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.     

Hepatic arterial infusion chemotherapy of cisplatin for biliary cystadenocarcinoma

Biliary cystadenocarcinoma is a rare tumor which has a better prognosis after complete surgical removal. However, since there is no other effective therapeutic option instead of surgery, the prognosis is very poor if surgical resection is impossible. We report the case of a 78 year-old woman who was treated only by hepatic arterial infusion (HAI) chemotherapy of cisplatin (85 mg) because liver functional reserve was too bad to perform a major hepatectomy. Huge biliary cystadenocarcinoma occupying the right lobe of the liver measuring 12 cm in size before chemotherapy was drastically decreased to 2 cm in size 8 months after chemotherapy. Although she had abdominal pain and anorexia before chemotherapy, she is doing well and has no complaints 9 months after chemotherapy. In conclusion, an effective therapy may be possible using hepatic arterial infusion chemotherapy of cisplatin in patients with biliary cystadenocarcinoma for whom surgical treatment is not suitable.     

Hepatic arterial infusion combined with systemic chemotherapy induced complete response of metachronous liver metastases after resection of pancreatic insulinoma

Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery.     

Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.     

Hepatic arterial infusion of 5-fluorouracil and extrabeam radiotherapy for liver metastases from pancreatic carcinoma

BACKGROUND/AIMS: To examine the efficacy and safety of a combined modality therapy consisting of hepatic arterial infusion of 5-fluorouracil and external-beam radiotherapy in patients with advanced pancreatic carcinoma. METHODOLOGY: Hepatic arterial infusion chemotherapy consisted of 5-FU 1000mg/m2 administrated as a 5-hr continuous infusion once weekly. External-beam radiotherapy (total dose, 50Gy; 2Gy/day) was delivered to the pancreas tumor concurrently for 5-6 weeks. Seventeen patients with no distant metastases except to the liver were enrolled in this study. RESULTS: Patients received a median of 13 cycles of chemotherapy. Sixteen of 17 patients received a total radiotherapy dose of 50Gy. In one patient, treatment was discontinued after 24Gy of radiotherapy and 2 cycles of chemotherapy because of progressive disease. Nausea and vomiting were the most common types of toxicity. Grade 3 or worse toxicity was observed in 2 patients. Four patients developed gastroduodenal ulcers. Of the 16 patients, 7 (41%) showed a partial response, and 9 (53%) showed no change. The median overall survival was 4.5 months and 1-yr overall survival of 11.8% was observed. CONCLUSIONS: The combined therapy is active and well tolerated, but results in a poorer prognosis, in spite of its high initial response rate.     

大肠癌肝转移介入治疗与静脉化疗的对比研究

目的　探讨结直肠癌肝转移的有效治疗方法。方法　肝动脉化疗灌注及栓塞治疗（ ＨＡＩＣＥ）２５ 例,第一次ＨＡＩＣＥ 后４ 周重复一次,以后每间隔３ － ６ 月行一次ＨＡＩＣＥ。静脉化疗（ＶＣ） 采用静脉给药,４ 周为１ 周期,２ 周期后间隔３－ ６ 月化疗一次。结果　ＨＡＩＣＥ 一疗程后上腹疼痛减轻或消失者占８８ ％ ,肝内肿块缩小占６８ ％ ,ＣＥＡ 降低病例占９２ ％ ;ＶＣ 一疗程后肝区疼痛减轻或消失者占１８ ％ ,肝内肿块缩小占８－３ ％ ;两组病例１ 、２ 、３ 年生存率分别为７２ ％ 、５２ ％ 、２４ ％ 和４１－７ ％ 、１６－７ ％ 、０ ％ （ Ｐ＜ ０－０１） 。结论　对于不能手术的结直肠癌肝转移,ＨＡＩＣＥ 在改善临床症状及延长生存期上较ＶＣ更有效,是一个较好的姑息性治疗方法     

Hepatic resections for bilobar liver metastases from colorectal cancer

The present study was performed to assess survival benefits in patients who underwent a hepatic resection for isolated bilobar liver metastases from colorectal cancer. Thirty-eight patients underwent a curative hepatic resection for isolated colorectal liver metastasis. Among them, 11 patients had bilobar liver metastases and 19 had a solitary metastasis. The remaining 8 patients had unilobar multiple lesions. We investigated survival in two groups those with bilobar and those with solitary metastatic tumors. Survival and disease-free survival were 36% and 18% at 5 years, respectively, in the patients with bilobar liver metastases, while these survivals were 43% and 34% in the patients with solitary liver metastasis. In the 38 patients, repeated hepatic resections were performed in 15 patients with recurrent liver disease. The 5-year survival and disease-free survival rates for these patients were 38% and 27%, respectively, after the second hepatic resections. Of the 11 patients with bilobar liver metastases, 5 underwent a repeated hepatic resection, and they all survived for over 42 months. Based on our observations, a hepatic resection was thus found to be effective even in selected patients with either bilobar nodules or recurrence in the remnant liver.     

The impact of hepatic arterial infusion pump chemotherapy on hepatic recurrences and survival in patients with resected colorectal liver metastases

BackgroundThe objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM).MethodsRecurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses.Results2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60–0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57–0.78,p < 0.001).ConclusionAdjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.     

结直肠癌区域动脉灌注化疗的研究进展

术前介入化疗是结直肠癌的重要治疗方法之一,现对结直肠癌术前介入化疗的概念、发展过程、临床意义、生理及分子生物学基础、病理观察和适应证等方面进行综述。     

Hepatic resection for colorectal metastases

PURPOSE: Hepatic resection affords the best hope of survival for patients with colorectal carcinoma metastatic to the liver. However, recurrences are observed in about 60 percent of patients after curative hepatic resection. The purpose of this study was to examine the prognostic factors of patients undergoing curative hepatic resection for colorectal metastases. METHODS: Between April 1984 and September 1997, 168 patients underwent curative hepatic resection for colorectal metastases. The clinicopathologic factors studied for prognostic value were gender, age, primary site, nodal status of primary tumor, time of metastases, preoperative serum level of carcinoembryonic antigen, hepatic tumor size and distribution, number of metastases, type of hepatic resection, resection margin, presence of micrometastases in resected specimen and microscopic fibrous pseudocapsule between the hepatic tumor and surrounding hepatic parenchyma, nodal status of hepatoduodenal ligament, adjuvant regional chemotherapy, and perioperative transfusion. RESULTS: The overall survival was 42 percent at three years and 26 percent at five years, including a 3.5 percent 60-day surgical mortality rate. Thirty-one percent of patients had micrometastases located at a median distance of 3 mm from the metastatic tumor edge. Presence of microscopic fibrous pseudocapsule was observed in 28 percent of patients. Univariate and multivariate analyses showed that significant prognostic factors for survival were nodal status of primary tumor, number of metastases, resection margin, microscopic fibrous pseudocapsule, and adjuvant regional chemotherapy. CONCLUSIONS: We conclude that 1) hepatic resection is effective in select patients with colorectal metastases; 2) adequate resection margin and adjuvant regional chemotherapy can improve outcome; and 3) microscopic fibrous pseudocapsule may offer additional postoperative information as an independent prognostic factor.Presented at the 11th Biennial Scientific Meeting of the Asian Pacific Association for the Study of the Liver, Perth, Western Australia, February 16 to 20, 1998.     

Hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein tumor thrombosis

AIM: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with poor prognosis. The aim of this prospective study was to evaluate the efficacy of hepatic arterial infusion chemotherapy (HAIC) for patients with this disease. METHODS: Eighteen HCC patients with PVTT were treated with HAIC via a subcutaneously implanted injection port. A course of chemotherapy consisted of daily cisplatin (10 mg for one hour) followed by 5-fluorouracil (250 mg for five hours) for five continuous days within a given week. The patients were scheduled to receive four consecutive courses of HAIC. Responders were defined in whom either a complete or partial response was achieved, while non-responders were defined based on stable or progressive disease status. The prognostic factors associated with survival after treatment were analyzed. RESULTS: Six patients exhibited partial response to this form of HAIC (response rate=33%). The 3, 6, 9, 12 and 18-month cumulative survival rates for the 18 patients were 83%, 72%, 50%, 28%, and 7%, respectively. Median survival times for the six responders and 12 non-responders were 15.0 (range, 11-18) and 7.5 (range, 1-13) months, respectively. It was demonstrated by both univariate and multivariate analyses that the therapeutic response and hepatic reserve function were significant prognostic factors. CONCLUSION: HAIC using low-dose cisplatin and 5-fluorouracil may be a useful alternative for the treatment of patients with advanced HCC complicated with PVTT. There may also be survival-related benefits associated with HAIC.