FOLFOX-HAIC as Conversion Treatment for Initially Unresectable Colorectal Liver Metastasis

Official title

Conversion Treatment With Hepatic Arterial Infusion of Oxaliplatin, Leucovorin and Fluorouracil Plus Intravenous Bevacizumab or Cetuximab for Initially Unresectable Colorectal Liver Metastasis: A Prospective Study

Overview

Try FOLFOX-HAIC combining bevacizumab or cetuximab for initially unresectable colorectal liver metastasis patients to increase the conversion to resection rate to improve long-term survival outcomes

Detailed description

Colorectal cancer (CRC) was a common malignancy. Approximately 50% CRC patients would develop either synchronous or metachronous liver metastasis, which served as the leading cause of death in CRC, during the course of their diseases. Complete resection of all liver metastases is a major contributor to long-term survival with a median OS of 35 months, while it is just 20-24 months in modern chemotherapy. However,80%-90% colorectal liver metastasis (CRLM) patients present with initially unresectable diseases and the median OS in untreated patients is only 7.5 months. Liver transplantation achieves a 5-year OS rate of 56% compared to the rate of 9% for systemic chemotherapy, organ shortage and high cost limit its popularization. Conversion treatment refers to applying local and/or systemic treatment for IU-CRLM to eliminate technical or biologic unresectable factors to gain potential resectable states and is associated with a 5-year OS rate of 30%-61% in successful patients, which is non-inferior to those who are initially resectable. However, the conversion to resection rates (CTRRs) with negative margin vary from 1.7% to 66% depending on treatment regimens. So, promoting the conversion ability is the only way to improve long-term survival.

The systemic conversion treatment includes systemic chemotherapy and target agents. It shows high adverse event (AE) rates in practice and the CTRRs varies from 1.7% to 49%, which is unsatisfactory. The locoregional conversion treatment, such as hepatic arterial infusion chemotherapy (HAIC), transarterial chemoembolization (TACE), transarterial radioembolization (TARE) and so on, is only suitable for liver-only metastases. For the reason of CRLM deriving predominant blood supply from hepatic artery while liver parenchyma mainly from portal vein, transarterial interventional therapy may not only improve the CTRRs but also reduce AE rates. It's a pity that the CTRRs in TACE or TARE only range from 7% to 10%. HAIC achieves 17.8%-66% CTRRs depending on different drug regimens. Target agents indeed increases the CTTRs in systemic chemotherapy, but bevacizumab doesn't increases it in FUDR-HAIC and brings unexpectedly biliary toxicity. However, in unresectable hepatocellular carcinoma (uHCC), FOLFOX-HAIC combining with Sintilimab® and bevacizumab achieved a CTRR of 48.2% and no biliary toxicity event occurred. Another study, oxaliplatin-HAIC with systemic chemotherapy plus cetuximab achieved an impressive CTTR of 66% but was only suitable for patients without mutational RAS. Maybe a new regimen, oxaliplatin-based complete arterial infusion regimen combining with bevacizumab or cetuximab for IU-CRLM could achieve a milestone outcome, but no literature had reported it.

In this study, we establish a prospective and consecutive IU-CRLM patient cohort treated with FOLFOX-HAIC combining with bevacizumab or cetuximab to evaluate the CTRR, tumor response, safety and long-term oncological outcomes.

Interventions

• Combination product FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil [5FU])
  The procedures of FOLFOX-HAIC were as follows: 1) a 5 French sheath was inserted into the femoral artery by Seldinger technique, then a 3.5 French catheter entered the coeliac trunk and superior mesenteric artery to assess the feeding arteries of tumors and identify any extra-collateral vessels which may cause drug leakage. These vessels would be embolized with gelatin sponge particles or metallic coils if necessary. A 2.7 French microcatheter was selectively inserted into the left/right/proper
• Procedure hepatic arterial infusion chemotherapy (HAIC)
  The procedures of FOLFOX-HAIC were as follows: 1) a 5 French sheath was inserted into the femoral artery by Seldinger technique, then a 3.5 French catheter entered the coeliac trunk and superior mesenteric artery to assess the feeding arteries of tumors and identify any extra-collateral vessels which may cause drug leakage. These vessels would be embolized with gelatin sponge particles or metallic coils if necessary. A 2.7 French microcatheter was selectively inserted into the left/right/proper
• Drug Bevacizumab
  We would inject bevacizumab at the dose of 7.5mg/kg once every 3 weeks if the primary tumors located from right-side to splenic flexure colon or the genotype of RAS or RAF was mutational.
• Drug Cetuximab (Erbitux)
  We would inject cetuximab at an initial dose of 400mg/m2 and maintained a dose of 250mg/m2 once every week if we didn't choose bevacizumab.
• Procedure liver resection
  If patients reached potential resectable state, we would perform liver resection.

Primary outcome measures

• conversion to resection rate [Time frame: 180 days]

Secondary outcome measures (2)

• drug treatment safety assessment [Time frame: Baseline up to study termination, assessed up to 12 months.]
• objective response rate [Time frame: From the time of enrollment until disease progression, death, or the end of the study, assessed up to 12 months.]

Eligibility criteria

Inclusion criteria

• age 18-75 years
• no history of other malignant diseases
• refuse or progress in prior systemic treatment
• diagnosed as CRLM confirmed by pathology, in spite of whether the primary tumor had been resected
• at least one lesion in the liver could be measured
• left ventricular ejection ≥45%, forced expiratory volume in one second/forced vital capacity≥60% and Eastern Cooperative Oncology Group (ECOG) score of 0-1
• Child-Pugh class A
• adequate organ function, i.e.: white blood cell (WBC) ≥3.0×109/L, neutrophils ≥1.5×109/L, platelet (PLT) ≥75×109/L, total bilirubin ≤30μmol/L, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤200U/L, creatinine ≤150μmol/L

Exclusion criteria

• extra-hepatic metastasis verified by medical imaging
• unable to tolerate chemotherapy, anesthesia or surgery
• allergy or previous intolerable to any agent of oxaliplatin, leucovorin, 5-Fu, bevacizumab or cetuximab
• tumor spread in abdomen
• cerebral infarction, cerebral hemorrhage, gastrointestinal hemorrhage/perforation within 6 months, coagulation disorders and gastrointestinal ulcer
• primary tumor may not be completely resected
• prior treatment of CRLM with resection, ablation or radiation
• incomplete clinical or follow-up data

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan

Publications

• Liao W, Cheng Q, Chen L, Zhang B, Ding Z, Mu K, Xu A, Song J, Dong W, Zhang M, Chen J, Huang Z, Chen X, Zhu P, Zhang B. Conversion treatment with hepatic arterial infusion of oxaliplatin, leucovorin and fluorouracil plus intravenous bevacizumab or cetuximab for initially unresectable colorectal liver metastasis: A prospective study. Cancer Treat Res Commun. 2026;47:101153. doi: 10.1016/j.ctarc.202 PMID 41775173

Identifiers

NCT: NCT06988852 · CHALLENGE-A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗