Hepatic Arterial Infusion Of Oxaliplatin Research Articles

Hepatic arterial oxaliplatin plus intravenous 5-fluorouracil and cetuximab for first-line treatment of colorectal liver metastases: A multicenter phase II trial

BackgroundThe efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown. MethodsIn this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR). Results35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%−96%) among evaluable patients (n = 32), and 95% (95% CI 70–100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15–23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1–19). Treatment toxicity was manageable, without toxic death. ConclusionHAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study

BackgroundHepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC. MethodsThis retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 administered on day 1, and 5-fluorouracil 2400 mg/m2 infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m2 and raltitrexed 3 mg/m2 on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile. ResultsORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia. ConclusionThe effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.

Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study – (NCT05103020) – study protocol

BackgroundAlthough 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10–25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis.MethodsThis is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate.DiscussionThis is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate.Trial registrationClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.

Survival benefit of preoperative hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin followed by hepatectomy for hepatocellular carcinoma.

Background: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin, fluorouracil, and leucovorin (FOLFOX) demonstrated promising efficacy against advanced hepatocellular carcinoma (HCC) as an alleviative treatment. We aimed to explore the survival benefit of preoperative FOLFOX-HAIC and establish a predictive nomogram. Methods: This study retrospectively reviewed data from 1251 HCC patients who underwent liver resection. 1027 patients received liver resection alone (LR group), and 224 patients were treated with FOLFOX-HAIC followed by liver resection (HLR group). Propensity score matching (PSM) was conducted between the two groups. The nomogram was established based on the findings of the multivariable Cox regression analysis. Results: After Propensity score matching according to initial tumor characteristics, the 1-, 2-, and 3-year overall survival rates were 85.4, 72.0, and 67.2% in the LR group and 95.2, 84.7, and 75.9% in the HLR group, respectively (p = 0.014). After PSM according to preoperative tumor characteristics, the 1-, 2-, and 3-year OS rates were 87.9, 76.6, and 72.3% in the LR group and 95.4, 84.4, and 75.1% in the HLR group, respectively (p = 0.24). Harrell's C-indexes of the nomogram for OS prediction in patients with preoperative FOLFOX-HAIC were 0.82 (95% CI 0.78-0.86) in the training cohort and 0.87 (95% CI 0.83-0.93) in the validation cohort and the nomogram performed well-fitted calibration curves. Conclusion: Preoperative FOLFOX-HAIC is associated with a longer survival outcome for HCC patients. The novel nomogram efficiently predicted the OS of patients who underwent preoperative FOLFOX-HAIC.

Efficacy and safety of first-line treatments for patients with advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

4094 Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.

Postoperative hepatic arterial chemotherapy after resection of colorectal liver metastases in patients at high risk of hepatic recurrence: A multicenter randomized phase II trial (PRODIGE 43 - PACHA-01).

3515 Background: Hepatic arterial infusion (HAI) of chemotherapy (CTx) has been proposed as a potential treatment to decrease the risk of hepatic recurrence after resection of colorectal liver metastases (CRLM). Randomized controlled trials (RCTs) led to controversial results and meta-analyses are inconclusive. We conducted a comparative phase II RCT to assess the efficacy of adjuvant HAI oxaliplatin with concomitant intravenous (IV) CTx in pts at high risk of hepatic recurrence (≥4 resected CRLM). Methods: Pts who underwent curative-intent surgery of at least 4 CRLM after preoperative IV CTx were randomly assigned (1:1) to receive adjuvant IV fluorouracil/leucovorin (LV5FU2) combined with oxaliplatin (85mg/m2) by HAI (HAI-IV arm) or IV route (IV arm) every 2 weeks, for at least 3 months to achieve a minimal duration of perioperative CTx of 6 months. The primary endpoint was the hepatic recurrence free survival (h-RFS). Secondary endpoints included the feasibility of delivering at least 4 CTx cycles, toxicity (NCI-CTCAE 4.0) including HAI catheter-related complications, RFS, overall survival (OS) and recurrence pattern. 108 randomized pts were required to detect a gain in 18-month h-RFS from 30% to 50% with a one-sided α risk of 10% and 95% power. The primary endpoint was analyzed with a Cox regression model, with adjustment for stratification factors (tumor response to preoperative CTx and number of resected CRLM). The study was prematurely stopped after randomization of 99 pts due to recruitment issues and HAI catheters market withdrawal. Results: Between Jun 2015 and Dec 2020, 99 pts (median age, 62; median number of CRLM, 5) were randomly assigned in HAI-IV arm (50 pts) or IV arm (49 pts). After a median follow-up of 56 months, the intent-to-treat analysis showed a significantly longer h-RFS in the HAI-IV arm compared to the IV arm (median 25 [16-37] vs 12 months [8-21]; HR 0.598 [95%CI 0.379-0.944], p = 0.027). 5-year h-RFS was 32% [19-45] in the HAI-IV arm vs 13% [4-27] in the IV arm, respectively. Median and 5-year OS were 74 months [51-74] and 60% [43-74] in the HAI-IV arm vs 54 months [37-69] and 46% [29-61] in the IV arm (HR 0.551 [0.299-1.015], p = 0.056). The median number of postoperative CTx cycles was 6 in both groups with 86% and 78% of patients having received at least 4 cycles in HAI-IV and IV arms (p = 0.7), respectively. Grade 3-4 toxicity rate was 58% in the HAI-IV arm vs 31% in the IV arm (p = 0.01). Overall, nine pts (18%) experienced HAI-related complications. No toxic death occurred in both arms. Conclusions: Despite a higher but acceptable toxicity, combination of HAI oxaliplatin with IV LV5FU2 significantly improved h-RFS after curative resection of CRLM in high-risk patients. This combined treatment should be considered as a valid option for these patients. Clinical trial information: NCT02494973 .

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 arterial infusion of oxaliplatin plus raltitrexed in unresectable hepatocellular carcinoma with or without portal vein tumour thrombosis.

BackgroundUnresectable hepatocellular carcinoma (HCC) has a poor prognosis. According to the HCC management guidelines in China, the standard treatment of Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC with portal vein tumour thrombosis (PVTT) is chemoembolization. However, some patients with BCLC stage B or C HCC with PVTT respond poorly to chemoembolization. We aimed to compare tumour responses and survival benefits between patients with unresectable HCC with or without PVTT.MethodsWe reviewed 119 consecutive patients with unresectable HCC with PVTT (n = 67) and without PVTT (n = 52) who underwent hepatic arterial infusion of oxaliplatin plus raltitrexed between January 2018 and April 2021. Overall survival, progression-free survival, tumour responses, and adverse events were compared between the groups.ResultsThere were no significant between-group differences in the objective response rates and median progression-free survival. The median overall survival was significantly longer in the group without PVTT than in that with PVTT (17.0 vs 10.4 months, respectively; P = 0.024).ConclusionHepatic arterial infusion of oxaliplatin plus raltitrexed may be efficacious in patients with unresectable HCC with or without PVTT.

Sustained-hepatic arterial infusion of oxaliplatin: pharmacokinetic advantages over hepatic arterial infusion using a preclinical animal tumour model.

Hepatic arterial infusion (HAI) of oxaliplatin allows greater liver tumour drug exposure compared to systemic infusion. However, the therapeutic index of HAI oxaliplatin remains poor. Using Pickering emulsion technology, we developed a platform able to provide sustained releases of oxaliplatin. The goal of this study was to evaluate the pharmacokinetic advantages of sustained-HAI oxaliplatin over HAI using a preclinical animal tumour model. Injections of 0.6mg oxaliplatin in 20min were selectively done in left hepatic arteries of 20 rabbits bearing a VX2 liver tumour in the middle left-lobe, using HAI (n=10) or sustained-HAI (n=10). In each group, half of the rabbits were sacrificed at 24h and half at 72h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and oxaliplatin concentrations in tumour tissues, right- and middle left-liver lobes, spleen and lung. Compared to HAI, sustained-HAI of oxaliplatin resulted in lower plasmatic peak (Cmax: 275±41 vs. 416±133ng/mL, p=0.02) and higher concentration in the tumour at 24h (2118±2107 vs. 210±93ng/g, p=0.008). After HAI, oxaliplatin concentration in tumours was significantly higher than in lung at 24h (p=0.03) but no other difference was found between oxaliplatin concentrations in tumours and in liver lobes, spleen or lung, neither at 24h nor at 72h. On the opposite, sustained-HAI resulted in higher concentrations of oxaliplatin in tumour compared to oxaliplatin concentrations in the middle left lobe (163±86ng/g at 24h, p=0.01, and 90±15ng/g at 72h, p=0.04), right lobe (174±112ng/g at 24h, p=0.01, and 112±35ng/g, p=0.04 at 72h), spleen (142±21ng/g at 24h, p=0.01, and 98±12ng/g at 72h, p=0.04), and lung (85±11ng/g at 24h, p=0.01, and 52±4ng/g at 72h, p=0.03). Sustained-HAI improves the therapeutic index of HAI oxaliplatin and offers a great potential for patients suffering from unresectable colorectal liver metastases or hepatocellular carcinoma.

Hepatic arterial infusion of oxaliplatin plus systemic chemotherapy and targeted therapy for unresectable colorectal liver metastases

BackgroundHepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies. MethodsBetween 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed. ResultsA total of 89 patients (median age 55 years (range, 26–76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0–5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1–28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively. ConclusionAddition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure.

Hepatic arterial infusion of oxaliplatin plus raltitrexed in patients with intermediate and advanced stage hepatocellular carcinoma: A phase II, single-arm, prospective study

PurposeTo investigate the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed in patients with intermediate stage and advanced stage hepatocellular carcinoma (HCC). MethodsIn this phase II, single-arm clinical trial, we enrolled patients aged 18–70 years with intermediate stage and advanced stage HCC, which included patients with HCC at Barcelona Clinic Liver Cancer (BCLC) stage B who experienced transcatheter arterial chemoembolization failure/refractoriness, and those with BCLC stage C with portal vein invasion. We performed HAI with oxaliplatin and raltitrexed. Treatment was repeated every 3 weeks and was discontinued either because of disease progression, unacceptable toxicity levels, or refusal of further treatment. We used Simon's two-stage design. The primary end-point was the objective response rate in accordance with the Response Evaluation Criteria in Solid Tumours. ResultsFifty-one patients were screened between January 5, 2018 and August 7, 2019. Of these, 39 patients (34 men and 5 women; median age, 53 years) were enrolled and included in the intention-to-treat population. Objective response was achieved in 18 (51.4%) of 35 patients in the per-protocol population and in 18 (46.2%) of 39 patients in the intention-to-treat population. Treatment-related grade IV adverse events or deaths were not reported, and the observed grade III adverse events were elevated aspartate aminotransferase levels (5 [12.8%]), elevated alanine aminotransferase levels (1 [2.6%]), leukopenia (1 [2.6%]), thrombocytopaenia (1 [2.6%]) and abdominal infection (1 [2.6%]). ConclusionHAI of oxaliplatin plus raltitrexed showed promising efficacy and acceptable toxicity levels in patients with intermediate and advanced stage HCC, and further evaluation is warranted.

Hepatic arterial infusion of oxaliplatin plus raltitrexed in patients with unresectable hepatocellular carcinoma (HAIROX): A phase II, single-arm, prospective study.

4574 Background: Chemoembolisation and oral sorafenib are the recommended treatment for unresectable hepatocellular carcinoma (HCC); however, some patients respond poorly to these. Hepatic arterial infusion (HAI) chemotherapy may have potential benefit in these patients. We aimed to investigate the efficacy and safety of HAI of oxaliplatin plus raltitrexed in patients with unresectable HCC. Methods: In this phase II, single-arm clinical trial, we enrolled patients aged 18–70 years with unresectable HCC at the Fujian Cancer Hospital (China). We performed HAI with oxaliplatin (100 mg/m2 for 4 hours) and raltitrexed (3 mg/m2 for 1 hour). Treatment was repeated every 3 weeks and was discontinued either because of disease progression, unacceptable toxicity levels, or refusal of further treatment. We used Simon’s two-stage design. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. Results: Fifty-one patients were screened between January 5, 2018 and August 7, 2019. Of these, 39 patients (34 men and 5 women; median age, 53 years) were enrolled and included in the intention-to-treat population. Objective response was achieved in 18 (51.4%) of 35 patients in the per-protocol population and in 18 (46.2%) of 39 patients in the intention-to-treat population. Treatment-related grade 4 adverse events or deaths were not reported, and the observed grade 3 adverse events were elevated aspartate aminotransferase levels (5[12.8%]), elevated alanine aminotransferase levels (1 [2.6%]), leukopenia (1 [2.6%]), thrombocytopenia (1 [2.6%]), and abdominal infection (1 [2.6%]). Conclusions: HAI of oxaliplatin plus raltitrexed showed promising efficacy and acceptable toxicity levels in patients unresectable HCC, and further evaluation is warranted. Clinical trial information: ChiCTR-OOC-17014182 . [Table: see text]

Hepatic arterial infusion oxaliplatin plus oral S-1 chemotherapy to improve prognosis for gastric cancer with multiple liver metastases.

e16508 Background: Gastric cancer with multiple liver metastases (GCLM) is associated with a high disease burden with synchronous or metachronous tumour invasions of other organs. In order to improve patient outcome, this study combined hepatic artery infusion (HAI) oxaliplatin with oral S-1 chemotherapy as a first-line palliative therapy. The aim is to assess efficacy and safety of this combination mode. Methods: We reviewed the records of ten patients with GCLM who received HAI oxaliplatin (70-80 mg/m2 2h d1,15) administered via a port-catheter system and S-1 with oral (35-40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically. Results: Until the 4th cycle response evaluation, the local effective rate and control rate was 60% and 90% respectively, only one patient developed progression. HAI oxaliplatin plus oral S-1 chemotherapy had a better local control against hepatic metastases (median progression-free survival: hepatic, 9.0 months vs. extrahepatic, 6.5 months), which showed potential benefit of the combination regimen in gaining local tumour control, maintaining function and improving life quality. Conclusions: HAI oxaliplatin plus oral S-1 chemotherapy can be regarded as an optimized treatment strategy for GCLM, which is also a crucial way for controlling of extrahepatic lesions without much systemic toxicity.

Hepatic Arterial Infusion Combined with Systemic Chemotherapy for Patients with Extensive Liver Metastases from Gastric Cancer.

PurposeLiver metastases in patients with gastric cancer often indicate poor prognosis. Once liver metastases are extensive, it is difficult to achieve disease control by using systemic chemotherapy alone. The purpose of this study was to evaluate the effect and safety of hepatic arterial infusion (HAI) combined with systemic chemotherapy on extensive liver metastases from gastric cancer.Patients and MethodsBetween 2012 and 2019, 21 patients with extensive liver metastases from gastric cancer (LMGC) were enrolled in our study. Liver metastases were identified as unresectable and a major factor affecting prognosis mainly based on size and number of intrahepatic lesions. All patients received systemic chemotherapy with S-1 and HAI oxaliplatin plus floxuridine (FUDR).ResultsLiver metastases in 16 patients (76.2%) were evaluated as H3. The overall response rate was 76.2% (9.5% complete response). Intrahepatic and extrahepatic median progression-free survival times were 9.5 and 5.2 months, respectively. Median survival time (MST) was 12.3 months. All patients did not have the toxicity of grade 4. Grade 3 toxic effects included bone marrow suppression (14.3%) and diarrhea (9.5%). The other treatment-related toxicities were mild and reversible.ConclusionHAI combined with systemic chemotherapy for extensive LMGC seems to be safe and effective, which achieves a high-local response and may contribute to long survival time for patients.

Hepatic Arterial Infusion Oxaliplatin Plus Oral S-1 Chemotherapy in Gastric Cancer with Unresectable Liver Metastases: A Case Series and Literature Review.

ObjectiveThe use of hepatic artery infusion (HAI) as a regional therapy against liver metastasis has rarely been reported in gastric cancer. This study aimed to evaluate the efficacy and safety of HAI oxaliplatin plus oral S-1 chemotherapy in first-line palliative therapy for gastric cancer with multiple liver metastases (GCLM).MethodsWe reviewed the records of five patients with GCLM who received HAI oxaliplatin (70–80 mg/m2 2 hrs d1,15) administered via a port-catheter system and S-1 with oral (35–40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically.ResultsUntil the 4th cycle response evaluation, the local effective rate and control rate were 40% and 80%, respectively; only one patient developed progression. HAI chemotherapy had a better local control against liver metastases (median progression-free survival: hepatic, 8.8 months vs. extrahepatic, 6.2 months), accompanied by less systemic toxicity, decreased tumour markers and symptomatic relief.ConclusionHAI oxaliplatin plus oral S-1 chemotherapy can be considered as a new choice of first-line treatment for GCLM, which is also a good approach for controlling extrahepatic lesions with less adverse events.

Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy \u2013 a randomized phase II study -- SULTAN UCGI 30/PRODIGE 53 (NCT03164655)- study protocol

BackgroundApproximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10–15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low (< 10%). Hepatic arterial infusion (HAI) oxaliplatin may represent a salvage therapy in patients with CRLM unresectable after one or more sys-CT regimens with ORRs and CRRs up to 60 and 30%, respectively. This study is designed to evaluate the efficacy of an intensification strategy based on HAI oxaliplatin combined with sys-CT as a salvage treatment in patients with CRLM unresectable after at least 2 months of first-line induction sys-CT.Objectives and endpoints of the phase II studyOur main objective is to investigate the efficacy, in term of CRR (R0-R1), of treatment intensification in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after at least 2 months of induction sys-CT. Patients will receive either HAI oxaliplatin plus systemic FOLFIRI plus targeted therapy (i.e. anti-EGFR antibody or bevacizumab) or conventional sys-CT plus targeted therapy (i.e. anti-EGFR or antiangiogenic antibody). Secondary objectives are to compare: progression-free survival, overall survival, objective response rate, depth of response, feasibility of delivering HAI oxaliplatin including HAI catheter-related complications, and toxicity (NCI-CTCAE v4.0).MethodsThis study is a multicenter, randomized, comparative phase II trial (power, 80%; two-sided alpha-risk, 5%). Patients will be randomly assigned in a 1:1 ratio to receive HAI oxaliplatin combined with systemic FOLFIRI plus targeted therapy (experimental arm) or the best sys-CT plus targeted therapy on the basis of their first-line prior sys-CT history and current guidelines (control arm). One hundred forty patients are required to account for non-evaluable patients.Trial registrationClinicalTrials.gov, (NCT03164655). Trial registration date: 11th May 2017.

Hepatic Arterial Infusion of Oxaliplatin Plus Raltitrexed in Patients with Intermediate- and Advanced-Stage Hepatocellular Carcinoma (HAIROX): A Phase II, Single-Arm, Prospective Study

Background: Hepatic arterial infusion of oxaliplatin plus fluorouracil could improve the outcomes of patients with advanced hepatocellular carcinoma. Fluorouracil is inconvenient for arterial infusion because it requires prolonged infusion. Conversely, raltitrexed, another antimetabolic drug, could be used in short infusions. We aimed to investigate the efficacy and safety of hepatic arterial infusion of oxaliplatin plus raltitrexed in patients with intermediate- and advanced-stage hepatocellular carcinoma. Patients and methods: We enrolled patients aged 18-70 years with intermediate-stage hepatocellular carcinoma with chemoembolisation failure/refractoriness and advanced-stage hepatocellular carcinoma with portal vein invasion. We performed hepatic arterial infusion with oxaliplatin (100 mg/m2 infusion for 4 hours) and raltitrexed (3 mg/m2 for 1 hour). Treatment was repeated every 3 weeks and was discontinued either because disease progression did not allow further treatment, toxicity levels were unacceptable, or the patient refused further treatment. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. Results: Fifty-one patients were screened between 5 January, 2018 and 7 August, 2019. Of these, 39 patients were enrolled and included in the intention-to-treat population. Objective response was achieved in 18 (51.4%) of 35 patients in the per-protocol population and in 18 (46.2%) of 39 patients in the intention-to-treat population. There were no reports of treatment-related grade 4 adverse events or deaths, and the observed grade 3 adverse events were elevated aspartate aminotransferase levels (5[12.8%]), elevated alanine aminotransferase levels (1 [2.6%]), leukopenia (1 [2.6%]), thrombocytopenia (1 [2.6%]), and abdominal infection (1 [2.6%]). Conclusion: Hepatic arterial infusion of oxaliplatin plus raltitrexed showed promising efficacy and acceptable toxicity levels in patients with intermediate- and advanced-stage hepatocellular carcinoma, and a multi-centre, phase III trial is expected. Clinical Trial Registration: This study is registered with www.chictr.org.cn, number ChiCTR-OOC-17014182. Funding Statement: This work was supported by the Guiding Project of Science and Technology Planning Project in Fujian Province, China (grant number 2019Y0060). Declaration of Interests: The authors have declared no conflicts of interest. Ethical Approval Statement: The trial was approved by the Ethics Committee of Fujian Cancer Hospital and was performed according to the Declaration of Helsinki. All patients involved in the trial provided written informed consent.

Treatment With Hepatic Arterial Infusion of Oxaliplatin in Combination With Systemic FOLFIRI Chemotherapy and Bevacuzimab in Patients With Liver-only Colorectal Liver Metastases (CRLM): Conversion to Complete Resection in Patients With Initially Inoperable Liver-only CRLM.

Treatment With Hepatic Arterial Infusion of Oxaliplatin in Combination With Systemic FOLFIRI Chemotherapy and Bevacuzimab in Patients With Liver-only Colorectal Liver Metastases (CRLM): Conversion to Complete Resection in Patients With Initially Inoperable Liver-only CRLM. - Full Text View.

PRODIGE 53-UCGI 30 (SULTAN): A randomized phase II study comparing treatment intensification with hepatic arterial infusion chemotherapy plus systemic chemotherapy to systemic chemotherapy alone in patients with liver-only colorectal metastases considered still non resectable after at least two months of systemic induction chemotherapy.

TPS3619 Background: In the first-line setting, current combination chemotherapy (CT) achieve high objective response rates (ORR) ranging from 40% to 80% and leads to complete resection rate (CRR) of colorectal cancer liver metastasis (CRCLM) in 25% to 50% of patients with initially non-resectable CRLM. However, when patients with CRLM are still not amenable to resection after induction CT, ORRs (~5-30%) and CRRs ( &lt; 10%) obtained with second-line systemic CT are much lower. Combining hepatic arterial infusion (HAI) and systemic (SYS) CT for unresectable CRLM lead to high ORR and the potential of cure in the second-line and further setting. Methods: This multicenter randomized phase II trial conducted in 20 centers in France plans to include 140 patients with CRLM still not amenable to a curative intent-treatment after at least two months of first-line induction SYS CT whatever the tumor response. Patients are randomized (1:1) between intensified biweekly regimen combining HAI oxaliplatin (100 mg/m²) and SYS FOLFIRI (leucovorin 400 mg/m², irinotecan 180 mg/m², and 5-FU 2.4 g/m²over 48 h) plus cetuximab 500 mg/m² or bevacizumab 5 mg/kg (according to RAS status and prior response/tolerance to SYS induction CT) or SYS CT alone according to current guidelines. The primary endpoint is to evaluate and compare the curative-intent (R0-R1) resection (and/or ablation) rate (CRR) of CRLM in both arms. A gain of 20% in CRR is expected (30% in the experimental arm vs. 10% in the control arm; α 5% [two-sided]; β 20%). Stratification factors at randomization are prior adjuvant or SYS induction oxaliplatin-based CT, tumor response to SYS induction CT, and center. Secondary endpoints include progression-free (overall, hepatic and extrahepatic) and overall survival, ORR, relative change in the sum of longest diameters of RECIST target lesions (DoR) and feasibility/tolerability. Since study start, 3 patients have been enrolled to date (planned accrual period: 3 years). Clinical trial information: NCT03164655.

Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin in Hepatocellular Cancer with Extrahepatic Spread

PurposeTo compare treatment with hepatic arterial infusion of chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) with both extrahepatic spread (EHS) and intrahepatic tumor and patients with intrahepatic tumor only. Materials and MethodsThis single-center retrospective study comprised 116 patients with advanced HCC with both intrahepatic tumor and EHS (EHS group; n = 50) or with intrahepatic tumor only (non-EHS group; n = 66) treated with HAIC including oxaliplatin, fluorouracil, and leucovorin between June 2014 and July 2016. Overall survival (OS) and radiologic responses to treatment were determined and compared between the 2 groups. ResultsBoth the objective response rate and the clinical benefit rate were higher in the non-EHS group than in the EHS group (37.9% vs 16% objective response rate, P = .010; 81.8% vs 62% clinical benefit rate, P = .017). Median OS was not statistically different between the 2 groups (14.8 months vs 9.8 months, P = .068). Subgroup analysis of OS found that patients with lung metastases survived for a shorter time (OS 7 months) than patients with other metastatic sites (P = .003) and patients free of metastases (P = .001). ConclusionsHAIC is a potential treatment option for advanced HCC with limited extrahepatic metastases in a population with hepatitis B virus infection.