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

NCT ID: NCT06988852

Last Updated: 2025-05-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-01
• Study Completion Date: 2030-12-31

Brief Summary

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.

Conditions

Colorectal Liver Metastasis (CRLM)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment group

Patients in the treatment group would undergo FOLFOX-HAIC combining Bevacizumab or Cetuximab

Group Type: EXPERIMENTAL

FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil [5FU])

Intervention Type: COMBINATION_PRODUCT

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 hepatic artery then patients were transferred to inpatient ward to start chemotherapy drug infusion. The FOLFOX regimen involving oxaliplatin (130mg/m2, day 1, 0-2h), leucovorin (400 mg/m2, day 1, 2-3h), 5-Fu (400mg/m2, day 1, bolus at 3h, then 2400 mg/m2, day 1-3, 3-49h), was administered via the microcatheter. The microcatheter and sheath were removed after HAIC finished. We didn't implanted port catheter system and repeated percutaneous femoral artery puncture and catheterization once every 3

hepatic arterial infusion chemotherapy (HAIC)

Intervention Type: PROCEDURE

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 hepatic artery then patients were transferred to inpatient ward to start chemotherapy drug infusion.

Bevacizumab

Intervention Type: DRUG

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.

Cetuximab (Erbitux)

Intervention Type: DRUG

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.

liver resection

Intervention Type: PROCEDURE

If patients reached potential resectable state, we would perform liver resection.

Interventions

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 hepatic artery then patients were transferred to inpatient ward to start chemotherapy drug infusion. The FOLFOX regimen involving oxaliplatin (130mg/m2, day 1, 0-2h), leucovorin (400 mg/m2, day 1, 2-3h), 5-Fu (400mg/m2, day 1, bolus at 3h, then 2400 mg/m2, day 1-3, 3-49h), was administered via the microcatheter. The microcatheter and sheath were removed after HAIC finished. We didn't implanted port catheter system and repeated percutaneous femoral artery puncture and catheterization once every 3

Intervention Type: COMBINATION_PRODUCT

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 hepatic artery then patients were transferred to inpatient ward to start chemotherapy drug infusion.

Intervention Type: PROCEDURE

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.

Intervention Type: 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.

Intervention Type: DRUG

liver resection

If patients reached potential resectable state, we would perform liver resection.

Intervention Type: PROCEDURE

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tongji Hospital

OTHER

Sponsor Role: lead

Responsible Party

Chen Xiaoping

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, China

Site Status: RECRUITING

Countries

China

Central Contacts

Zhang Bi Xiang

Role: CONTACT

bixiangzhang@hust.edu.cn

862783663400

Facility Contacts

Liao Wei

Role: primary

1009739952@qq.com

8615527803087

Other Identifiers

CHALLENGE-A1

Identifier Type: -

Identifier Source: org_study_id