Hepatic arterial infusion chemotherapy with 5-fluorouracil-based regimens in the management of liver metastases of colorectal carcinoma

Background We assessed the efficacy and safety of hepatic arterial infusion chemotherapy, using 5-fluorouracil-based regimens, in the treatment of unresectable liver metastases of colorectal carcinoma. Patients and Methods Thirty patients with liver metastases of colorectal carcinoma were given hepatic arterial infusion chemotherapy using 5-fluorouracil-based regimens, through an implantable port system, inserted into the hepatic artety by percutaneous procedures. Weekly 5-fluorouracil infusions were given to 17 patients, daily 5-fluorouracil infusions were given to 2, the MF (5-fluorouracil-mitomycin) regimen was given to 8, and the FEM (5-fluorouracil-epirubicin-mitomycin) regimen was given to 3. Results The median survival time was 11.6 months, with an overall response rate of 64%. These results were similar to those in previous reports on hepatic arterial infusion chemotherapy using floxuridine. Hematologic and hepatic toxicity was minimal Grade 3 thrombocytopenia occurred in 2 patients (7%), and a grade 2 elevation of alkaline phosphatase, in 1 (4%). Biliary sclerosis was not observed. The major toxicity was nausea and vomiting, grade 2 or 3, most of which was controllable, in 5 patients (18%). The occurrence of hepatic failure resulting in death was significantly (P=0.0015) lower in responsive cases than in nonresponsive cases. Conclusion We consider that 5-fluorouracil-based regimens can be used safely for hepatic arterial infusion chemotherapy with minimal toxicity, and that they are useful in preventing hepatic failure, because of their high response rate.     

Hepatic arterial infusion pump chemotherapy in the management of colorectal liver metastases: expert consensus statement

Despite significant improvements in systemic therapy for patients with colorectal liver metastases (crlms), response rates in the first-line setting are not optimal, and response rates in the second-line setting remain disappointing. Hepatic arterial infusion pump (haip) chemotherapy has been extensively studied in patients with crlms, but it remains infrequently used.We convened an expert panel to discuss the role of haip in the contemporary management of patients with crlm. Using a consensus process, we developed these statements:

• haip chemotherapy should be given in combination with systemic chemotherapy.
• haip chemotherapy should be offered in the context of a multidisciplinary program that includes expertise in hepatobiliary surgery, medical oncology, interventional radiology, nursing, and nuclear medicine.
• haip chemotherapy in combination with systemic therapy should be considered in patients with unresectable crlms who have progressed on first-line systemic treatment. In addition, haip chemotherapy is acceptable as first-line treatment in patients with unresectable colorectal liver metastases.
• haip chemotherapy is not recommended in the setting of extrahepatic disease outside the context of a clinical trial.
• haip chemotherapy in combination with systemic therapy is an option for select patients with resected colorectal liver metastases.

These consensus statements provide a framework that clinicians who treat patients with crlm can use when considering treatment with haip     

Rescue chemotherapy using multidrug chronomodulated hepatic arterial infusion for patients with heavily pretreated metastatic colorectal cancer

BACKGROUND:

Hepatic arterial infusion (HAI) chemotherapy delivers a high concentration of drugs both to liver metastases and to healthy liver with specific, limiting, hepatobiliary toxicities. Relevant detoxification and cellular proliferation pathways are controlled by the molecular circadian clock in normal liver but not in advanced tumors. In this article, the authors report their experience with chronomodulated HAI chemotherapy as rescue therapy in heavily pretreated patients who had metastatic colorectal cancer.

METHODS:

Data from all consecutive patients with colorectal cancer liver metastases who received HAI with chronomodulated, multidrug chemotherapy regimens in the authors' center after failure on standard chemotherapy were reviewed for efficacy and safety.

RESULTS:

Twenty‐nine patients were treated, including 76% with liver metastasis only and 24% with liver and lung metastases. Seventy‐five percent of patients had received ≥3 chemotherapy lines, including intravenous, chronomodulated chemotherapy in 59% of patients. Patients received a median of 4 HAI courses (range, 1‐9 courses). The most frequent grade (according to National Cancer Institute of Canada Common Toxicity Criteria [version 3]) 3 and 4 nonhematologic toxicities were vomiting, diarrhea, abdominal pain, and fatigue. No severe hematologic or hepatic toxicities and no chemical cholangitis were reported. An objective tumor response was observed in 10 patients (34.5%), including 4 patients who subsequently underwent R0 or R1 hepatic resection. The median progression‐free survival and overall survival were 4.5 months (95% confidence limits, 2.4‐6.5 months) and 18 months (95% confidence limits, 5.8‐30.2 months), respectively.

CONCLUSIONS:

HAI chronomodulated chemotherapy had well tolerated activity in selected, heavily pretreated patients, and the authors believe it deserves to be assessed prospectively in clinical trials among patients who have less advanced disease. Cancer 2009. © 2009 American Cancer Society.     

Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis.

BACKGROUND: Response rates to systemic chemotherapy are low after tumor progression on oxaliplatin regimens. Hepatic arterial infusion (HAI) therapy in patients with tumor progression is a viable alternative. PATIENTS AND METHODS: Thirty-nine heavily pre-treated patients (all receiving prior oxaliplatin) with unresectable colorectal hepatic metastases were treated with systemic CPT-11 and concurrent HAI floxuridine (FUDR) and dexamethasone (DEX). RESULTS: Partial responses were seen in 44% of patients. Median time to hepatic progression was 8.6 months, and median time to overall progression was 6.5 months. Median survival from time of initiation of HAI was 20.1 months [95% confidence interval (CI) 16.9-21.4] and from the initiation of treatment of metastatic disease, 32.01 months (95% CI 29.1-34.6). After a median follow-up of 19.1 months, seven patients (18%) proceeded to potentially curative surgery. Grade 3/4 toxic effects included neutropenia (13%), diarrhea (15%), intra-abdominal hemorrhage (2%), and bleeding duodenal ulcer (2%). Elevated liver function tests were seen, including bilirubin concentration >3 mg/dl (7%), alkaline phosphatase 2X baseline (20%), and aspartate aminotransferase >3X baseline (26%). CONCLUSIONS: HAI FUDR/DEX plus systemic CPT-11 achieves a response rate of 44% and a median overall survival of 20 months in heavily pre-treated patients with colorectal hepatic metastases all receiving previous oxaliplatin; 18% of patients proceeded to surgical resection or ablation.     

Hepatic artery infusion chemotherapy for colorectal metastases: a personal experience

A personal experience is reported with hepatic artery infusion (HAI) chemotherapy of 57 patients with metastatic colorectal carcinoma confined to the liver. Fifty-seven percent of the 54 patients who received more than 2 weeks of infusion had objective regressions documented on hepatic scans. The response rate with fluorouracil and mitomycin C (75%) was higher than for fluorouracil alone (52.5%). The median survival of treated patients was 15 months with the longest survivor living 3 years 8 months, and responders had a median survival 3 months longer than nonresponders. Complications included one case of hemolytic uremic syndrome after HAI with mitomycin C. Survival after HAI was 9 months longer than that of comparable historical controls who received no treatment, but survival after HAI with fluorouracil alone was not superior to that of comparable patients treated with intravenous fluorouracil. HAI produces a high frequency of tumor regression, but superior survival has yet to be demonstrated.     

Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial).

BACKGROUND: The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter. RESULTS: The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months. CONCLUSION: The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.     

肝动脉灌注在结直肠癌肝转移治疗中的应用现状及前景

结直肠癌（colorectal cancer ,CRC ）是中国最常见的恶性肿瘤之一,肝转移是其主要的转移模式及治疗关键。相对于全身化疗,肝动脉灌注（hepatic arterial infusion,HAI）给药方式可使肝脏局部药物浓度升高,而外周血液中药物浓度较低,全身不良反应相对较低。HAI 化疗在肠癌肝转移的转化化疗、肝切除术后辅助化疗以及肠癌根治性切除术后的肝转移预防方面显示出一定的应用前景。本文就HAI 在肠癌肝转移的治疗现状及前景做一综述。     

First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases

This study aimed to compare the efficacy and safety of HAI fluoropyrimidine (FUDR)/capecitabine or single capecitabine as first-line treatment for elderly patients with unresectable colorectal liver metastases (CLMs). Fifty-one elderly patients with liver-only CLMs were eligible for enrollment. Patients were divided into HAI FUDR /capecitabine group and single capecitabine group randomly. The primary endpoint was median survival time (MST), defined as the time from the date of catheter implantation to the date of death or the date of the last follow-up. The secondary endpoint was objective antitumor response and adverse events. The HAI pump was implanted before chemotherapy. All patients received a 3-week cycle of oral capecitabin. In Group A, the RR and DCR were both 95.8%. In Group B, the RR and DCR were 48.1% and 81.5%, respectively. There was significant difference between the RRs of the 2 groups (P < 0.001). But there was no significant difference between the DCRs of the 2 groups (P = 0.053). There was a statistical difference between the MSTs of the 2 groups (18.5 vs.13 months, P = 0.0312). HAI FUDR combined with oral capecitabine as the first-line treatment for elderly patients with CLMs has promising efficacy and safety.     

Disappearing colorectal liver metastases: Strategies for the management of patients achieving a radiographic complete response after systemic chemotherapy

The mainstays of treatment for colorectal liver metastases (CRLMs) are surgery and chemotherapy. Chemotherapeutic benefits of tumor shrinkage and systemic control of micrometastases are in part counterbalanced by chemotoxicity that can modify the liver parenchyma, jeopardizing the detection of CRLM. This review addresses the clinical decision-making process in the context of radiographic and pathologic responses, the preoperative imaging workup, and the approaches to the liver for CRLM, which disappear after systemic chemotherapy.     

高能聚焦超声刀联合化疗治疗不能手术的结直肠癌肝转移的近期疗效

目的:探讨高能聚焦超声刀联合化疗治疗不能手术的结直肠癌肝转移的近期疗效及不良反应。方法:96例结直肠癌肝转移的患者,分为实验组和对照组。实验组48例,给予FOLFOX方案、FOLFIRI方案或单药卡培他滨口服方案,同时给予病灶局部高能聚焦超声刀,对照组的化疗方案与实验组相同。比较两组患者的疗效及不良反应。结果:实验组有效率为45.83%,而对照组治疗有效率为20.83%,差异有统计学意义（P=0.03）,不良反应分为血液学和非血液学不良反应,两组患者的不良反应无统计学差异（P>0.05）。结论:高能聚焦超声刀联合化疗可以提高结直肠癌肝转移治疗的有效率,且不增加患者不良反应。     

结直肠癌肝转移经肝动脉栓塞及持续灌注化疗的临床疗效

背景与目的：结直肠癌肝转移患者经肝动脉介入栓塞或静脉持续滴注化疗药物,治疗效果有所提高,但尚存肿瘤局部化疗药物浓度不够高,化疗药物对肿瘤细胞的杀伤力不够强,晚期结肠直肠癌的治疗效果仍然不够好的缺陷。本文将动脉介入与持续灌注化疗药物两种方法相结合,观察结直肠癌肝转移患者经肝动脉介入栓塞或持续灌注化疗的临床疗效。方法：对26例结直肠癌肝转移患者经肝动脉介入治疗93次,单用肝动脉持续灌注化疗42次,肝动脉介入栓塞联合持续灌注化疗51次。化疗药物选用阿霉素（ADM）、顺铂（DDP）、丝裂霉素（MMC）、醛氢叶酸（CF）和5-氟尿嘧啶（5-FU）。先将ADM30mg/m^2和MMC6mg/m^2加入超液化碘油10-30ml中进行肝动脉灌注栓塞,然后留置导管进行持续动脉滴注。方案为CF200mg/m^2,d1-3,静脉滴注;DDP80mg/m^2d1,如肾功能改变则改用Vp-1660mg/m^2,d1-3,应用电动输液泵动脉滴注;5-FU2500mg/m^2,采用便携式输液泵将5-FU持续动脉滴注72h。结果：近期疗效以实体瘤疗效评价标准评价,CR1例,CR率3.85%;PR14例,PR率53.84%,总有效率为57.69%。本组0.5、1、2、3和5年生存率分别为92.31%、76.92%、38.46%、23.07%和3.85%,肝转移后中位生存期为11.5个月。全组病人出现的不良反应主要有肝功能损害、胃肠道反应和骨髓抑制,经护肝、制酸、止呕、水化和应用升白细胞药物对症治疗后可缓解。结论：经肝动脉持续灌注化疗及栓塞是治疗结直肠癌肝转移瘤的较好方法,能提高治疗效果。     

Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose Mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma

BACKGROUND: In vitro data suggest increased cytotoxicity with Mitomycin C (Mit-C) and Floxuridine (FUDR). Based on these data, we performed a phase II trial of hepatic arterial infusion (HAI) of FUDR and Dexamethasone (Dex) plus high-dose Mit-C for patients with unresectable hepatic metastases from colorectal carcinoma. METHODS: High-dose Mit-C (15 mg/m2) was added via the pump sideport to HAI FUDR and Dex for 14 days of a 28-day cycle. Mit-C was given on days 1 and 29, and FUDR was given indefinitely until disease progression or discontinuation of therapy due to toxicity. RESULTS: Sixty-three patients with unresectable liver metastases were entered. The chemotherapy-na?ve group (n = 26) and those previously treated (n = 37) had similar response and median survival: 73% and 70%, and 23 and 20 months, respectively. The major toxicities were liver bilomas (7.9%), elevation in bilirubin level >3 (22%), and biliary sclerosis (9.5%). Hematologic and gastrointestinal toxicity was less than 2%. CONCLUSION: The addition of high-dose Mit-C to HAI FUDR and Dex produced a high response rate even in previously treated patients. The median survival was 21 months even though half the patients were previously treated with chemotherapy. Biliary toxicity was higher than expected; therefore, alternatives to high dose Mit-C should be investigated when exploring additions to HAI therapy with FUDR and Dex.     

A phase II study of radiofrequency ablation of unresectable metastatic colorectal cancer with hepatic arterial infusion pump chemotherapy

BACKGROUND: Adjuvant hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve disease-free survival for colorectal cancer liver metastases. It is unclear if this improvement can be extrapolated to unresectable liver metastases that undergo RFA. The aim of this study was to evaluate the combination of RFA and HAI chemotherapy for unresectable liver metastases. METHODS: Phase II study was conducted from November 2000 to July 2003 evaluating the use of complete extirpation by RFA, or resection/ablation with adjuvant HAI consisting of FUDR for 6 months. RESULTS: Twenty-one patients had successful resection and/or RFA with HAI pump, which included treatment for 100 liver metastases (22 resected, 78 ablated; mean 4.8 tumors/patient). Four of 21 patients completed the full 6-month course of HAI. Six of these patients had 12 adverse events related to HAIP, most commonly elevated liver enzymes. After a median follow-up of 24 months, the median liver specific disease-free and overall survival rates for the entire group were 17 and 30 months, respectively. CONCLUSIONS: Given the complications and toxicity associated with HAI pump chemotherapy, adjuvant HAI chemotherapy after RFA of liver metastases may not be warranted as a first line treatment option.