Hepatic Arterial Infusion Group Research Articles

Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.

3516 Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p < 0.01) and RAS/BRAF mutation (p < 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p < 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .

Oxaliplatin in metastatic colorectal cancer: Does hepatic arterial infusion reduce sensitive neuropathy compared to the intravenous route?

95 Background: Oxaliplatin, a major drug in metastatic colorectal cancer (MCRC), is responsible for a cumulative and limiting peripheral neuropathy (PN). Hepatic arterial infusion (HAI) chemotherapy, which makes sense in cases of exclusive or predominant liver metastases, increases the intratumor concentration of the administered drug(s) to improve efficacy and limit systemic toxicity. Methods: We compared the frequency and severity of NP in oxaliplatin-naive patients with MCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (CHOICE, OSCAR, and PACHA-01 trials) or by intravenous (IV) route (FFCD 2000-05 trial). The primary endpoint was the occurrence of clinically significant NP (grade 2-4) according to the cumulative dose of oxaliplatin received. The secondary endpoints were the occurence of severe NP (grade 3-4) and time to onset of NP. Results: 342 patients were included (IV oxaliplatin: 300; HAI: 42). 180 patients in the IV group (60%) and 24 patients in the HAI group (57%) developed clinically significant NP, with no significant difference between the 2 groups (p = 0.85). 95 patients in the IV group (32%) and 8 patients in the HAI group (19%) developed severe NP, with no significant difference between the 2 groups (p = 0.082). NP appeared earlier in the HAI group, with more treatment discontinuations for neurotoxicity. Conclusions: The administration of oxaliplatin HAI rather than IV in the treatment of MCRC does not seem to reduce the incidence, precocity and severity of NP.

Hepatic Artery Infusion of Floxuridine in Combination With Systemic Chemotherapy for Pancreatic Cancer Liver Metastasis: A Propensity Score-Matched Analysis in Two Centers.

AimTo evaluate the efficacy of hepatic artery infusion (HAI) of floxuridine (FUDR) in combination with systemic chemotherapy in patients with pancreatic cancer liver metastases (PCLM).Patients and MethodsWe retrospectively collected clinical data of 347 patients with PCLM who underwent first-line chemotherapy at two Chinese centers between 2012 and 2019. Propensity score matching between patients with and without HAI was performed to compensate for differences in baseline characteristics. Objective response rate (ORR) and overall survival (OS) between groups were compared. HAI pump functionality was recorded.ResultsData of 258 patients (62 patients with HAI and 196 patients without HAI) were used for matching. After 1:1 ratio matching, 62 patients per group were included. The intrahepatic ORR was 66.1% in the HAI group and 22.6% in the non-HAI group (P < 0.001), and the extrahepatic ORR was 25.0 versus 28.9% (P = 0.679). The median OS was significantly longer in HAI group (14.0 versus 10.8 months, P = 0.001). Multivariance COX regression showed HAI led to a decrease in hazard ratio for death by 61.8% (HR = 0.382; 95% CI: 0.252–0.578; P< 0.001). Subgroup analysis revealed that patients without EHM, with higher intrahepatic tumor burden and with synchronous liver metastasis benefited more from HAI. Dysfunction of HAI pump occurred in 5.7% of patients during the period of follow-up.ConclusionsIn patients with PCLM, first-line treatment with HAI FUDR plus SCT resulted in higher intrahepatic response and better OS.

Anti-PD-1 antibody SHR-1210 combined with apatinib as adjuvant treatment in patients with hepatocellular carcinoma at high risk of recurrence after radical resection: Preliminary results from a multicenter, randomized, controlled phase II trial.

285 Background: There is no globally recognized standard adjuvant therapy for HCC after radical resection. Herein, we explored to evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib as adjuvant treatment versus hepatic arterial infusion (HAI) in HCC patients with high risk of recurrence after radical resection. Methods: This was an ongoing multicencer, randomized, controlled phase 2 trial. All HCC patients were Child-Pugh Class A, and confirmed as high risk of recurrence such as portal vein tumor thrombus (PVTT) involved in second-order branch or above, microvascular invasion (MVI) and microsatellite leisions. Eligible patients were randomly assigned (1:1) to receive SHR-1210 (200mg, q2w) and apatinib (250mg, q.d.) for 12 cycles, or two times of standard HAI treatments (epirubicin 80-100mg or epirubicin 50mg+oxaliplatin 50mg). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoints included safety and quality of life score (QoL). Results: From Jun 12, 2019 to Sep 15, 2020, 32 Chinese HCC patients (pts) (16pts in SHR-1210-apatinib group and HAI group, respectively) had been recruited. Full analysis (FAS) population contained 29 pts and intention to treat (ITT) population included 32 pts. The hadzard ratio for relapse or death with SHR-1210-apatinib as compared with HAI was 0.48 (95% CI 0.12-1.75; P = 0.2992) and 0.38 (95% CI 0.11-1.20; P = 0.0910) in FAS and ITT population, respectively, at date cutoff. Median RFS was not reached and 10.5 months in SHR-1210-apatinib group and HAI group, respectively. The average QoL score during treatment was 48.8 and 49.2 in SHR-1210-apatinib group and HAI group, respectively. The most common grade 3 or 4 adverse events occurred in SHR-1210-Apatinib were γ-glutamyltransferase (GGT) increase (18.75%), leukopenia (12.50%), neutrophil count decrease, alanine and aspartate aminotransferase increase (12.50%), while in HAI group were lymphocyte count decrease (7.69%), hemoglobin increase (7.69%) and GGT increase (7.69%). Conclusions: In HCC patients with high risk of recurrence after radical resection, SHR-1210 combined with apatinib was tolerable, and might offer a new promising choice superior to HAI for adjuvant therapy in HCC, further study is needed to reach the pre-defined primary endpoint. Clinical trial information: NCT03839550.

Hepatic arterial infusion chemotherapy for colorectal liver metastases revisited

BackgroundRecent reports indicate improved survival in patients undergoing surgical treatment for colorectal liver metastases (CRLM) with hepatic arterial infusion (HAI) pump chemotherapy compared to surgery alone. MethodsPatients who underwent resection and/or ablation of CRLM between 1996 and 2016 were included from a single-institution prospectively maintained database. Proportional hazards regression analysis was performed to determine predictors of overall survival (OS) and 3:1 propensity score analysis (PSA). ResultsOf 349 patients included, 36 had HAI pumps placed (HAI group) and 313 did not (no-HAI group). There was no difference in primary tumor grade (p = 0.24), ECOG status (p = 0.44), tumor number (p = 0.1), tumor size (p = 0.56), margin status (p = 0.76) between the two groups.Median overall survival was 44.7months vs 37.1months for the HAI versus no-HAI group (p = 0.01). Cox proportional hazards regression analysis demonstrated positive margin status (HR:2.47,p < 0.0001), HAI therapy (HR:0.56,p = 0.02), preoperative chemotherapy (HR:0.69,p = 0.02) and tumor diameter (HR:1.07,p = 0.005) as predictors of OS. In 3:1 PSA, 32 HAI subjects were matched with 87 non-HAI subjects balancing all covariates. Median OS was 42.4 months versus 35.6 months for the HAI versus no-HAI group (p = 0.03). ConclusionSurgical treatment of CRLM combined with HAI chemotherapy is associated with improved OS compared to surgery alone. Further study of this treatment approach is indicated.

Adjuvant Hepatic Artery Infusion Chemotherapy is Associated With Improved Survival Regardless of KRAS Mutation Status in Patients With Resected Colorectal Liver Metastases: A Retrospective Analysis of 674 Patients.

To investigate the impact of adjuvant hepatic artery infusion (HAI) in relation to KRAS mutational status in patients with resected colorectal cancer liver metastases (CRLM). Patients with KRAS-mutated CRLM have worse outcomes after resection. Adjuvant HAI chemotherapy improves overall survival after liver resection. Patients with resected CRLM treated at MSKCC with and without adjuvant HAI who had available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospectively maintained institutional database. Correlations between KRAS status, adjuvant HAI, clinical factors, and outcomes were analyzed. Cox proportional hazard model was used to adjust for confounders. Between 1993 and 2012, 674 patients (418 KRAS-WT, 256 MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAI. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAI group; however, there were more patients with resected extrahepatic metastases in the no-HAI group. In KRAS-WT tumors, 5-year survival was 78% for patients treated with HAI versus 57% for patients without HAI [hazard ratio (HR) 0.51, P < 0.001]. In KRAS-MUT tumors, 5-year survival was 59% for patients treated with HAI versus 40% for patients without HAI (HR 0.56, P < 0.001). On multivariate analysis, HAI remained associated with improved OS (HR 0.53, P < 0.002) independent of KRAS status and other clinicopathologic factors. Adjuvant HAI after resection of CRLM is independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant HAI may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM.

Abstract No. 523 Locoregional therapy for liver metastases in uveal melanoma: improvements in progression-free survival and predictors of response

Liver is the most common metastatic site in uveal melanoma, and as such, locoregional therapies play an important role in the management of these patients. The purpose of this study was to determine the relative effectiveness of different locoregional therapies for uveal melanoma liver metastases and to determine predictors of response. A single-institution, IRB-approved retrospective review of patients with uveal melanoma who underwent hepatic arterial infusion (HAI) therapy, chemoembolization, bland embolization, radioembolization, or percutaneous thermal ablation was performed. Progression-free and overall survival analysis was performed, and predictors for treatment response were determined by Cox proportional hazards. 59 patients were included in the study; 18 underwent HAI, while 41 underwent non-HAI tumor-targeted therapy (TTT), including 29 chemoembolization, 4 bland embolization, 7 thermal ablation, and 1 radioembolization patients. Progression-free survival (PFS) was significantly higher in the TTT group versus the HAI group (6 months PFS 85.7% vs 68.8%, P < 0.05). Though there was a trend towards improved overall survival (OS) in the TTT group vs the HAI group, the difference was not significant (median OS 2483 vs 724 days, P = 0.07). There was a non-significant trend toward improved survival with cisplatin versus doxorubicin chemoembolization and bland embolization. Pre-procedure LDH (P = 0.04) and neutrophil-to-lymphocyte ratio (NLR) (P = 0.02) were significant predictors of progression-free survival for patients undergoing TTT (P < 0.05), while tumor volume, tumor focality, prior chemotherapy, and time interval from primary tumor presentation to development of metastasis were not. Non-responders to LDH were noted to have significantly greater pre- and postprocedural NLR. LDH was noted to decrease after treatment but increase at the time of progression. TTT improves progression-free survival relative to HAI in patients with uveal melanoma liver metastases. Additionally, preprocedure NLR is a significant predictor of treatment response to TTT, and LDH may be an early indicator of tumor recurrence in patients who undergo TTT.

Impact of adjuvant hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil with systemic gemcitabine for resectable pancreatic cancer.

360 Background: Despite recent advances in cancer treatment, postoperative recurrence remains an unsolved issue for resectable pancreatic cancer. To prevent hepatic recurrence and prolong postoperative survival, we introduced postoperative adjuvant chemotherapy of high-dose 5-fluorouracil (5-FU) hepatic arterial infusion (HAI) with systemic chemotherapy using gemcitabine in 2006. We retrospectively evaluated the clinical impact of HAI. Methods: A total of 251 patients who underwent pancreatic resection for PC were analyzed. Patients received weekly high-dose 5-FU through the hepatic artery using a port-catheter system (1000 mg/m2 for 5 h) plus concurrent systemic gemcitabine (1000 mg/m2) followed by systemic 3 cycles of gemcitabine or 4 cycles of S-1. Patients were divided into two groups. The patients who completed planned adjuvant chemotherapy of HAI were classified as the completion group (HAI), and the patients who failed to complete HAI or received systemic adjuvant chemotherapy other than HAI were classified as the control group. Results: One hundred thirty-eight patients (55%) completed planned adjuvant chemotherapy of HAI. On the other hand, 28 patients (11%) failed to complete HAI and 85 patients (34%) received systemic adjuvant chemotherapy alone. The reasons for incompletion of HAI were as follows: any recurrence during HAI treatment in 8, poor general condition of patients in 4, hepatic arterial stenosis in 4 and catheter trouble in 3. Initial hepatic metastasis rate was significantly lower in the HAI group than the control group (15.2 vs. 26.3%, p=0.029), and liver metastasis free survival was significantly better in the HAI group than the control group (p=0.001). The HAI group had a better prognosis than the control group (58.1 vs. 26.9M, p &lt; 0.001). Prognostic factor analysis indicated that failure to complete HAI (p &lt; 0.001, HR 1.95), borderline resectable tumor (p = 0.028, HR 1.63), and lymph node metastasis (p = 0.018, HR 1.59) were the independent adverse prognostic factors. Conclusions: Our data demonstrate that HAI can significantly prevent hepatic recurrence and also improve the postoperative prognosis in pancreatic cancer.

Preliminary observation on hepatic arterial infusion under temporary hepatic circulation occlusion in rabbits

To explore the advantages, feasibility and limitations of hepatic arterial infusion under temporary hepatic circulation occlusion. Twelve rabbits were randomly divided into two groups: hepatic artery infusion group (HAI group) and hepatic artery infusion under temporary hepatic circulation occlusion group (HAI-THCO). Microcatheters were separately inserted into the proper hepatic artery and right hepatic vein. For the HAI group, 5-Fu (10 mg/ml and 100 mg/kg) was infused into the common hepatic artery with a high pressure injector for 10 minutes. For the HAI-THCO group, the common hepatic artery and hepatic portal vein were temporarily occluded for 15 minutes using artery clamp when 5-Fu was being infused. For the two groups, at 2, 5, 10, 15, 20 and 30 min after the start of infusion, blood samples of the hepatic flow were collected from the right hepatic vein and of the systemic blood flow from the inferior vena cava, 1 ml at each time point. The blood drug concentration of these blood samples was determined by high performance liquid chromatography (HPLC). Except that at 20 and 30 min after infusion, in the HAI group, the blood drug concentration of hepatic circulation was significantly higher than that of systemic circulation (P < 0.05). But in the HAI-THCO group, the blood drug concentration of hepatic circulation was significantly higher than that of systemic circulation at all the time points (P < 0.05). The hepatic circulation blood drug level of the HAI-THCO group was always significantly higher than that of the HAI group (P < 0.05), but the systemic circulation blood drug concentration of the HAI-THCO group was always lower (P < 0.05). The hepatic circulation maximum concentration (Cmax) of blood drug concentration of the HAI-THCO and HAI groups was (23.057±3.270) µg/ml and (4.408±1.092) µg/ml, respectively, and the Cmax of HAI-THCO group was significantly higher (P < 0.001), being 5.23 times of that of HAI group. The systemic circulation Cmax of the two groups was (1.456±0.217) µg/ml and (2.335±0.669) µg/ml, respectively, and the Cmax of HAI group was 1.60 times higher than that of the HAI-THCO group (P = 0.022). The hepatic circulation AUC of HAI-THCO and HAI groups was (368.927±52.416) µg·min·ml(-1) and (65.630±14.928) µg·min·ml(-1), respectively. The AUC of HAI-THCO group was 5.62 times higher than that of the HAI group (P < 0.001). The systemic circulation AUC of the two groups was (27.193±3.948) µg·min·ml(-1) and (45.301±12.275) µg·min·ml(-1), respectively. The AUC of HAI group was 1.67 times higher than that of the HAI-THCO group (P = 0.014). HAI-THCO is a simple and effective regional hepatic infusion chemotherapy technique. It can be performed through occluding the common hepatic artery and the hepatic portal vein by balloon catheter. HAI-THCO can not only increase the blood drug concentration in the hepatic circulation, but also decrease the blood drug concentration in the systemic circulation, therefore, distinctly lowering the systemic toxicity.

Hepatic arterial infusion chemotherapy with cisplatin before radical local treatment of early hepatocellular carcinoma (JIS score 0/1) improves survival.

It has not yet been determined whether hepatic arterial infusion (HAI) chemotherapy improves survival in patients with early hepatocellular carcinoma (HCC). We evaluated the effectiveness of HAI with high-concentration cisplatin (DDP-H) for the treatment of HCC by comparing outcomes between patients who received HAI with DDP-H before radical local treatment of early-stage HCC [Japan Integrated Staging (JIS) score 0/1] and patients who did not receive HAI chemotherapy. Survival was analyzed in 114 patients with early-stage HCC who underwent radical local treatment. The patients were divided into two groups: a HAI group (n = 79) who received DDP-H infusion into the whole liver via the proper hepatic artery, and a non-HAI group (n = 35) who did not receive HAI chemotherapy. The cumulative survival rates at 1, 3, and 5 years were 77.4%, 69.2%, and 55.3% in the non-HAI group and 97.4%, 87.0%, and 84.4% in the HAI group, respectively. Survival time prolonged significantly in the HAI group compared with the non-HAI group (log-rank test: P = 0.023; generalized Wilcoxon test: P = 0.012) Multivariate analysis using the Cox proportional hazards model identified HAI with DDP-H as the most important factor affecting survival. Whole-liver HAI with DDP-H before radical local treatment can improve the prognosis of patients with early-stage HCC.

The re-birth of hepatic arterial infusion for colorectal liver metastases.

The re-birth of hepatic arterial infusion for colorectal liver metastases.

Adjuvant Chemotherapy After Resection of Colorectal Liver Metastases in Patients at High Risk of Hepatic Recurrence

After curatively intended surgery for colorectal liver metastases, liver recurrences occur in more than 60% of patients, despite the administration of adjuvant systemic chemotherapy. The aim of this study was to assess the benefit of combined adjuvant hepatic arterial infusion (HAI) and intravenous (IV) 5-FU compared with standard modern adjuvant IV chemotherapy in patients at high risk of hepatic recurrence. From January 2000 to December 2009, 98 patients, who had undergone curative resection of at least 4 colorectal liver metastases, were selected from a prospective database. Among them, 44 (45%) had received postoperative HAI combined with systemic 5-FU (HAI group) and 54 (55%) had received "modern" systemic chemotherapy (IV group). The 2 groups were similar in terms of age, sex, the stage of the primary, and the administration of preoperative chemotherapy. The median number of HAI cycles received per patient was 7 [range, 1-12]. Twenty-nine patients (66%) had received at least 6 cycles of HAI oxaliplatin, and 22 patients (50%) had received the full planned treatment. For the remaining 22 patients (50%), HAI chemotherapy had been discontinued because of toxicity (n = 8), HAI catheter dysfunction (n = 6), an early recurrence (n = 6), and patient's refusal (n = 2). After a median follow-up of 60 months (51-81 months), 3-year overall survival was slightly higher in the HAI group (75% vs 62%, P = 0.17). Three-year disease-free survival was significantly longer in patients in the HAI group than those in the IV group (33% vs 5%, P < 0.0001). In the multivariate analysis, adjuvant HAI chemotherapy and an R0 resection margin status were the only independent predictive factors for prolonged disease-free survival. Postoperative HAI oxaliplatin combined with systemic chemotherapy after curatively intended surgery of colorectal liver metastases is feasible and may significantly improve disease-free survival of patients at high risk of hepatic recurrence compared with adjuvant modern systemic chemotherapy alone. These results should be confirmed in a randomized study.

Comparison of blood dynamics of anticancer drugs (cisplatin, mitomycin C, epirubicin) in treatment groups of hepatic arterial infusion, hepatic arterial infusion with lipiodol and transcatheter arterial chemoembolization with lipiodol plus gelatin sponge particles in a swine model

To compare the blood dynamics of anticancer drugs (cisplatin, mitomycin, epirubicin) and the negative effect on normal liver tissue among the following procedures: hepatic arterial infusion (HAI), HAI with lipiodol (Lp-HAI) and transcatheter arterial chemoembolization (TACE) with Lp plus particles (Lp-TACE). Nine swine were divided into three groups: (i) HAI group animals were infused with 5 mg/mL cisplatin, 1 mg/mL mitomycin and 4 mg/mL epirubicin in 0.1 mL/kg contrast medium; (ii) Lp-HAI group animals, with the same doses in 0.1 mL emulsified fluid (0.05 mL/kg, Lp); and (iii) Lp-TACE group animals, with the same doses in 0.1 mL emulsified fluid plus gelatin sponge particles. Outflow ratio (area under plasma concentration curve [AUC(0-60) ] / total infused dose of anticancer drug) and necrosis volume ratio (necrosis volume / total slice volume × 100) were explored. Outflow ratios (AUC(0-60) /mg) of cisplatin, mitomycin and epirubicin, and the necrosis volume ratio (%) of the livers, were 2.30, 6.91, 0.97 and 0, respectively, in the HAI group; 1.71, 5.43, 0.79 and 1.37, respectively, in the Lp-HAI group; and 1.23, 3.37, 0.47 and 20.88, respectively, in the Lp-TACE group. The significantly lowest outflow ratio for each anticancer drug (P = 0.05/3) and the significantly highest necrosis volume ratio (P = 0.05/3) were found in Lp-TACE, followed by Lp-HAI and HAI. Although the necrosis volume ratio of the liver was tolerable, Lp-TACE caused the greatest delay in outflow ratio for each cancer drug and the greatest negative effect to liver in a swine model.

124I-huA33 Antibody PET of Colorectal Cancer

Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI). We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.

Hepatic arterial infusion (HAI) with PEGylated liposomes containing 5-FU improves tumor control of liver metastases in a rat model

To investigate the cytostatic effect of 5-fluorouracil (5-FU) encapsulated in polyethylene glycol (PEG) liposomes with or without degradable starch microspheres (DSM) in a long-term trial using a rat liver tumor model. The cytostatics were applied once either as a hepatic arterial infusion (HAI) or were systemically infused via the tail vein. Seven groups were compared with respect to tumor growth and survival times: 5-FU HAI (group I), 5-FU + DSM HAI (group II), PEG-5-FU HAI (group III), PEG-5-FU + DSM HAI (group IV), NaCl HAI (group V), 5-FU i.v. (group VI), and PEG-5-FU i.v. (group VII). Seven and 14 days after treatment in groups III and IV, only group IV had significantly inhibited tumor growth on day 21 compared to the groups treated intravenously. On day 28, none of the animals from the intravenously treated groups were still alive compared to a significantly longer survival time of 6 and 8 weeks in groups III and IV. Locoregional therapy with 5-fluorouracil encapsulated in PEGylated liposomes may further improve the treatment success with longer-lasting tumor regression and prolonged survival times.

Abstract No. 189: Drug pharmacokinetics after hepatic arterial delivery of doxorubicin loaded superabsorbent polymeric microspheres in an animal model

Abstract No. 189: Drug pharmacokinetics after hepatic arterial delivery of doxorubicin loaded superabsorbent polymeric microspheres in an animal model

Is thymidylate synthase a reliable predictor for response and survival during hepatic arterial infusion for hepatic metastases from colorectal cancer?

Sir, Decreased levels of the target enzyme thymidylate synthase (TS) have been repeatedly associated with superior clinical outcome in gastrointestinal cancers, including stomach cancer. In the study by Goekkurt et al (2006), patients who possessed a TS 5′ genotype associated with low TS mRNA expression levels showed a trend for superior survival time compared with those having TS genotypes associated with high TS mRNA expression. A significant association between clinical outcome to 5-fluorouracil (5FU)-based chemotherapy in colorectal cancer and TS polymorphisms was demonstrated when both TS polymorphisms within the 5′ untranslated (UTR) region were contemporarily analysed (Marcuello et al, 2004). TS gene amplification and overexpression can lead to resistance to TS-targeting chemotherapeutic drugs (5FU and fluorodeoxyuridine (FUDR)) (Copur et al, 1995; Davies et al, 1999; Wu and Dolnick, 2003). Moreover, by hepatic arterial infusion (HAI) it is possible to reach lower TS mRNA and higher ribonucleotide reductase activity than with systemic chemotherapy (SC) (Kubota et al, 2002). HAI therapy could generate higher intracellular levels of 5FU and FUDR metabolite, fluorodeoxyuridylate, locally (Gonen et al, 2003a). Among 135 patients randomly assigned to receive HAI vs systemic bolus 5FU and leucovorin, overall survival was significantly longer for HAI vs systemic treatment (P=0.003), as was time to hepatic progression (P=0.03) (Kemeny et al, 2006). By contrast, time to extrahepatic progression was significantly shorter in the HAI group (P=0.02). In a previous study, Gonen et al (2003b) reported that patients with resectable TS overexpressing (TS+) liver metastases from colorectal cancer have better overall survival (OS) when treated by HAI plus SC rather than by SC alone. On the contrary, patients with TS-negative metastatic colorectal cancer treated with SC plus HAI had similar OS compared with SC alone. More interestingly, in the study by Kemeny et al (2006), liver biopsies in the HAI group, although based on small numbers (40 patients), demonstrated that for patients with TS levels in tumour ⩾4 the median OS was 14 months, while for those with levels less than 4, median OS was 24 months. As previously reported (Alimonti et al, 2003), we think that, regarding patients treated with SC, it could be interesting to ascertain the role of the thymidine phosporylase (TP), the first enzyme involved in the metabolic activation pathway of FU to fluorodeoxyribonucleotides. Conversely, continuous HAI of FUDR generates FUDR monophosphate via uptake and activation by thymidine kinase and, unlike i.v bolus 5FU treatment, levels of TP would not likely be of predictive value. Preoperative biopsies and resection specimens from patients with stage II/III rectal carcinoma receiving neoadjuvant 5FU-based chemoradiotherapy have been recently studied for TS and TP protein expression by immunohistochemistry, and results have been compared with histopathologic tumour regression. A significant association was observed between high TS expression in tumour biopsies as well as resection specimens and nonresponse of the tumour to therapy (P=0.04), but low TP expression in the resection specimens was significantly associated with lack of response (P=0.02) (Jakob et al, 2005). However, it is still controversial whether TP expression in tumour is an independent factor that adds to TS positivity in worsening the prognosis of patients with metastatic colorectal cancer. Interindividual variation in the activity of metabolising enzymes can affect the extent of pyrimidine prodrug activation, acting on the efficacy of chemotherapy treatment (Maring et al, 2005). Patients with low levels of TP could be unable to properly metabolise FU administered by i.v. systemic infusion. A repeat polymorphism within the 5′ UTR, that alters TS expression, has been correlated with response and survival in colorectal cancer patients receiving 5FU in several studies (Iacopetta et al, 2001). Thus, the role of germline polymorphisms (uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), TS, dihydropyrimidine dehydrogenase (DPD), and methylene tetrahydrofolate reductase (MTHFR)), tumour-specific somatic mutations and gene/protein expression levels (OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, TP, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase) must be taken into account in explaining variation in anti-tumour efficacy and toxicity of 5F.

Hepatic Arterial Infusion Versus Systemic Therapy for Hepatic Metastases From Colorectal Cancer: A Randomized Trial of Efficacy, Quality of Life, and Molecular Markers (CALGB 9481)

Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome. In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers. Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade > or = 3 neutropenia (2% and 45%; P < .01), stomatitis (0% and 24%; P < .01), and bilirubin elevation (18.6% and 0; P < .01) in the HAI and systemic treatment groups, respectively. A greater proportion of men versus women receiving HAI experienced biliary toxicity (37% and 15%, respectively; P = .05). For HAI patients with thymidylate synthase levels in tumor less than or > or = 4, the median survival was 24 and 14 months, respectively (P = .17). HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.

Combined regional and systemic chemotherapy by a mini-invasive approach for the treatment of colorectal liver metastases.

From February 1996 to December 1998, 95 patients affected with colorectal liver metastases underwent the positioning of an intraarterial hepatic catheter by a transcutaneous subclavian access, under local anesthesia. All patients were evaluated for catheter implantation complications. Moreover, 61 patients of 95 treated at our center were retrospectively evaluated for results of chemotherapy performed with two different schedules of hepatic artery infusion (HAI) combined with systemic chemotherapy (SC). Eleven patients (group A) were treated with combined SC (5-fluorouracil continuous infusion) and HAI (floxuridine). A subsequent 50 patients underwent HAI (floxuridine, 4 cycles) followed, if a response or stable disease were observed, by combined SC and HAI (group B). Three cases of aneurysm of subclavian artery occurred, which were treated by the positioning of a radiologic arterial stent and the reimplantation of the catheter by a femoral access. Thrombosis of the hepatic artery was registered in four cases. We observed 10.5% occurrence of dislocation of the catheter, which was always moved again in the hepatic artery. In group A, with 45% clinical objective response rate and 10% stable disease rate, median survival time and median time to extrahepatic progression were 9 and 6 months, respectively. In group B, we observed 44% clinical objective responses and 26% stable disease after HAI. Patients without disease progression and therefore submitted to sequential SC and HAI had a median survival time of 21 months and a median time to extrahepatic progression of 16 months. The development of the mini-invasive technique of implantation of an arterial port can avoid laparotomy for HAI. Percutaneous implantation of an arterial port has a low rate of technical complications. HAI followed by combined systemic and regional chemotherapy has good results in terms of survival and time to extrahepatic progression.

Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases

BACKGROUND Greater than 50% of patients who undergo curative resection of liver metastases from colorectal carcinoma develop recurrent disease in the residual liver. Although several studies have attempted to use hepatic arterial infusion (HAI) chemotherapy to prevent recurrence, to the authors' knowledge the efficacy of the treatment has not yet been determined. METHODS Nineteen patients who underwent curative hepatectomy for metastatic colorectal carcinoma randomly were assigned into the HAI group (nine patients) or the control group (ten patients). Patients in the HAI group received continuous intraarterial infusion of 5-fluorouracil (5-FU) (500 mg/day) for 4 days followed by a 3-day rest. The treatment was continued for 6 weeks. RESULTS The median follow-up period was 62.2 months. The recurrence was confirmed in three patients in the HAI group and in eight patients in the control group. Of these, recurrence in the remnant liver was observed in one patient and in six patients, respectively. The median disease free interval after hepatectomy was 62.6 months in the HAI group and 13.8 months in the control group. The 1-year, 2-year, and 3-year disease free survival rates were 77.8%, 77.8%, and 66.7%, respectively, in the HAI group and 50.0%, 30.0%, and 20.0%, respectively, in the control group. Significant prolongation of disease free survival was observed in the HAI group (P = 0.045). No patients in the HAI group reported any adverse effect of ≥ Grade 2 (according to the National Cancer Institute Common Toxicity Criteria). Two patients in the HAI group and five patients in the control group were dead of disease at the time of last follow-up. The 1-year, 3-year, and 5-year cumulative survival rates for the HAI group were 88.9%, 77.8%, and 77.8%, respectively, whereas those of the control group were 100.0%, 50.0%, and 50.0%, respectively (P = 0.2686). CONCLUSIONS This randomized study revealed that short term HAI of 5-FU after curative resection of colorectal hepatic metastases is effective in preventing the recurrence of disease without any serious complications. Cancer 2000;88:1549–56. © 2000 American Cancer Society.