Induction Treatment for Initially Unresectable Colorectal Liver Metastases: Combined Hepatic Arterial Infusion Pump Therapy With Systemic Therapy

Официальное название

Hepatic Arterial Infusion PUMP Chemotherapy Combined With Systemic Therapy Versus Systemic Therapy Alone as Induction Therapy for Initially Unresectable Colorectal Liver Metastases: a Randomised Controlled Trial

Обзор

The goal of this randomized clinical trial is to investigate induction treatment with Hepatic Arterial Infusion Pump therapy combined with systemic therapy (HAIP-SYST) in chemotherapy-naive patients with unresectable colorectal liver metastases without extrahepatic disease. The main question it aims to answer is if combined HAIP-SYST improves survival compared to induction treatment with systemic therapy alone. Patients in the control arm will receive systemic therapy according to standard of care. Study procedures experimental arm * Surgery for pump placement and resection of the primary tumor * Pre- and postoperative imaging (CT-anghiography, 99mTc-MAA scintigraphy) * Induction treatment with hepatic arterial infusion pump therapy with Floxuridine combined with systemic therapy Study procedures both arms * Evaluation of resectability status by a National Liver Panel with surgeons and radiologists * Questionnaires for Quality of Life

Вмешательства

• Препарат Intra arterial infusion Floxuridine (FUDR) combined with systemic therapy
  Floxuridine is administered via the hepatic arterial infusion pump directly to the hepatic artery with a continous flowrate for a period of 2 weeks. Intra arterial infusion of FUDR is combined with systemic therapy (FOLFOX/FOLFIRI) intravenously. Administration of FUDR via the chemopump is every 4 weeks and systemic therapy is administered every 2 weeks.
• Устройство Hepatic arterial infusion pump (HAIP)
  The HAIP (pump) is implanted during surgery combined with resection of the primary tumor before start of induction treatment with Floxuridine and concomitant systemic therapy
• Препарат Systemic therapy (standard of care)
  Patient included in the control arm will receive systemic therapy according to standard clinical practice. Induction therapy regimens include: CAPOX (3 weekly) or FOLFOX/FOLFIRI/FOLFOXIRI (2weekly) with optional addition of Bevacizumab (2 weekly)

Первичные конечные точки

• Overall survival [Срок оценки: Up to five years after randomization]

Вторичные конечные точки (11)

• Progression-free survival [Срок оценки: Up to five years after randomization]
• Hepatic progression-free survival [Срок оценки: Up to five years after randomization]
• Conversion to resection rate [Срок оценки: if CRLM convert to resectable, often at 3-6 months after start induction treatment]
• Complete local treatment rate [Срок оценки: if CRLM convert to resectable, often at 3-6 months after start induction treatment]
• Objective response rate (ORR) [Срок оценки: During protocol treatment, up to 6 months of induction treatment]
• Disease control rate (DCR) [Срок оценки: During protocol treatment, up to 6 months of induction treatment]
• Pathological response rate [Срок оценки: Pathological assessment of conversion surgery after induction treatment]
• Surgical complication rate [Срок оценки: at 30 days an 90 days postoperatively]
• Adverse events and toxicity of HAIP-SYST and systemic therapy [Срок оценки: During protocol treatment]
• Quality of Life (QoL) [Срок оценки: Up to five years after randomization]
• Cost-effectiveness [Срок оценки: Up to five years after randomization]

Критерии участия

Критерии включения

• Age ≥ 18 years.
• Histologically confirmed colorectal adenocarcinoma.
• Unresectable synchronous CRLM according to a National Liver Panel (CT-scan obtained ≤ 4 weeks prior to registration).
• No extrahepatic metastases. Patients with small (≤ 10 mm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.
• No previous systemic therapy for colorectal cancer.
• Positioning of a catheter for HAIP chemotherapy is technically feasible based on imaging. The default site for the catheter insertion is the gastroduodenal artery (GDA). Accessory or aberrant hepatic arteries are no contra-indication for catheter implantation. The GDA should have at least one branch to the liver. Accessory or aberrant hepatic arteries should be ligated to allow for cross perfusion to the entire liver through intrahepatic shunts. Patients with celiac trunk stenosis are not eligible. Patients with both a replaced right and replaced left hepatic artery are not eligible.
• ECOG performance status 0 or 1.
• Life expectancy of at least 12 weeks.
• Known mutation status of RAS and BRAFV600E.
• Primary tumour in situ and resectable without neoadjuvant therapy.
• Patient is eligible for surgery.
• Patient is eligible for doublet chemotherapy.
• Laboratory requirements: i.e. adequate bone marrow, liver and renal function (obtained within 15 days prior to registration).

• Hb ≥ 5.5 mmol/L
• absolute neutrophil count (ANC) ≥1.5 x 109/L
• platelets ≥100 x 109/L
• total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• ASAT/AST ≤ 5 x ULN
• ALAT/ALT ≤ 5 x ULN
• alkaline phosphatase ≤ 5 x ULN
• Serum creatinine ≤ 1.5 x upper limit of normal or a MDRD (eGFR) ≥ 45 ml/min;
• Prothrombin time or INR < 1.5 x ULN, unless coumarin derivates are used. All patients using coumarin derivates will be treated with LMWH or DOAC instead.
• Before registration, written informed consent must be given and signed according to ICH/GCP, and national/local regulations.

Критерии исключения

• Prior hepatic radiation, resection, or ablation.
• Any malignancy, comorbidity or condition that interferes with the planned study treatment or the prognosis of CRLM, determined by the treating physician.
• History of prior malignancy except for the following: (a) malignancy treated with curative intent and with no evidence of active disease present within 3 years prior to inclusion, (b) curatively treated malignancies felt to be at low risk for recurrence by treating physician and MDT, (c) adequately controlled nonmelanomatous skin cancer, (d) adequately treated carcinoma in situ without current evidence of disease.
• Obstructive primary tumour requiring emergency surgery, primary tumour necessitating a multivisceral resection/abdominoperineal resection or a rectal tumour requiring preoperative short-course radiotherapy or chemoradiotherapy for local tumour control.
• MMR deficiency.
• DPD-deficiency.
• Pregnant or lactating women.
• Serious concomitant systemic disorders that would compromise the safety of the patient or his/her ability to complete the study, at the discretion of the investigator.
• Organ allografts requiring immunosuppressive therapy.
• Serious non-healing wound, ulcer, or bone fracture.
• Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids).
• Known serious infections (uncontrolled or requiring treatment).
• History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for HAIP-SYST or standard systemic therapy.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• Underlying liver disease including liver fibrosis and cirrhosis

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Нидерланды · 1 центр

• Antoni van Leeuwenhoek-Netherland Cancer Institute — Amsterdam

Публикации

• Ter Kuile EM, Kok N, Westerink B, Swijnenburg RJ, Daletzakis A, Jacobs B, Retel VP, van Golen LW, Snaebjornsson P, Klompenhouwer EG, Koerkamp BG, Buffart TE, Punt C, Verhoef C, Bolhuis K, Kuhlmann K; Dutch PUMP-IT study group. Hepatic arterial infusion pump chemotherapy combined with systemic therapy versus systemic therapy alone as induction treatment for initially unresectable colorectal liver m PMID 42143303

Идентификаторы

NCT: NCT06857773 · M23PIT · 2023-506194-35-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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