Hepatic Arterial Infusion Pump Chemotherapy Combined With Systemic Chemotherapy (PUMP-IT)

The PUMP-IT study is designed to prove the feasibility of HAIP chemotherapy with concomitant standard systemic chemotherapy (FOLFOX and FOLFIRI) in the Netherlands. This study will include patients with both unresectable CRLM and resectable CRLM with an indication for upfront systemic therapy (further referred to as potentially resectable CRLM), without extrahepatic metastases. The study will be performed in two tertiary referral centers in the Netherlands.

RATIONALE - Colorectal cancer (CRC) is the third most common cancer with an annual incidence of 14.000 patients in the Netherlands. Of all patients with metastases, 32% have isolated colorectal liver metastases (CRLM). Local treatment of CRLM, i.e. resection, ablation and/or stereotactic radiotherapy, is the only potentially curative option. Unfortunately over 75% of these patients have CRLM which are (initially) not suitable for such local treatment.

Current treatment of unresectable CRLM includes subsequent lines of systemic (chemo)therapy aiming to convert the CRLM from an unresectable to a resectable or local treatable state in order to prolong survival. Conversion rates of modern first line systemic chemotherapeutic regimens, as described in multiple retrospective studies with highly selected patients, are observed in 10-76% of patients, resulting in a 5-year survival of 33-43% after conversion. Patients with progressive disease on first line therapy are offered second line systemic therapy. Conversion during second line systemic therapy is rare and described in only 7-13.5% of patients. These patients have a poor prognosis with a median OS of approximately 10-15 months. However, overall survival (OS) of patients undergoing local treatment after conversion on second line systemic therapy is comparable to what is observed after conversion on first line systemic therapy.

Hepatic arterial infusion pump (HAIP) can deliver high-dose regional chemotherapy to the CRLM using their unique arterial blood supply. Floxuridine is used for HAIP chemotherapy because of the advantages of having a half-life of ten minutes, a 95% first-pass effect and allowing high intrahepatic dosing resulting in increased hepatic exposure by a factor 400, with minimal systemic exposure (e.g. complications). These specific properties of HAIP chemotherapy make it possible to combine high-dose local HAIP therapy with standard of care systemic therapy.

Several single center studies from Memorial Sloan Kettering Cancer Center (MSKCC) (New York, USA) have shown high response rates with HAIP chemotherapy in combination with systemic therapy for unresectable CRLM. Conversion to resection of the initially unresectable CRLM have been observed in up to 57% of chemo-naïve patients and in 20%-38% of patients with prior systemic therapy treated with the combination of HAIP and systemic therapy. Irrespective of conversion, the combined therapy resulted in a median OS of 50.8-76.6 months and a 5-year OS of 51.9% for chemo-naïve patients. The median and 5-year OS was 27.7-35 months and 27.9%, respectively, for patients who have been treated with systemic therapy before.

Although these results are impressive, they come from a single center and have not yet been confirmed elsewhere. Most important reasons were the technically challenging surgical procedure of HAIP implantation and the need for stringent monitoring and specific management of HAIP chemotherapy requiring a highly skilled multidisciplinary treatment team.

A study investigating combined treatment is required to prove feasibility in a multicenter setting outside MSKCC before a multicenter randomized phase III trial can be initiated in the Netherlands.

STUDY DESIGN - All eligible patients who signed informed consent (registration) and meet all inclusion criteria (inclusion) will undergo surgical HAIP implantation. HAIP function is evaluated with a perfusion test during surgery and postoperatively before starting drug treatment. Start of combined HAIP chemotherapy and systemic chemotherapy is aimed within 6 weeks postoperatively. Clinical and laboratory evaluations and chemotherapy administration are scheduled every two weeks. Response evaluations will be conducted with CT thorax/abdomen and CEA measurement every 2 HAIP cycles (every 4 systemic chemotherapy cycles) during combined therapy.

The combined therapy cycles are continued until disease progression, severe toxicity, CRLM conversion to surgical local treatment or patients withdrawal. After HAIP chemotherapy discontinuation, treatment and/or follow-up are according to standard clinical practice.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years.
* ECOG performance status 0 or 1.
* Life expectancy of at least 12 weeks.
* Histologically confirmed CRC.
* Indication for first or second line systemic therapy, confirmed in a multidisciplinary meeting.
* Potentially resectable (i.e. unresectable and upfront resectable CRLM with indication for neoadjuvant systemic therapy), confirmed in a multidisciplinary meeting and radio-logically on (PET) CT thorax/abdomen and/or MRI obtained ≤ 4 weeks prior to regis-tration.
* Positioning of a catheter for HAIP chemotherapy is technically feasible confirmed in the multidisciplinary liver meeting 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.
* Indication and eligibility for abdominal surgery confirmed in a multidisciplinary meeting, e.g. primary tumour resection, stoma revision/reversal and diagnostic surgery.
* In case of primary tumour in situ: tumour should be (potentially) resectable, confirmed in a multidisciplinary meeting.
* Adequate bone marrow, liver and renal function as assessed by the following labora-tory requirements to be conducted within 15 days prior to inclusion.

  * Hb ≥ 5.5 mmol/L
  * Absolute neutrophil count (ANC) ≥1.5 \* 109/L
  * Platelets ≥100 \* 109/L
  * Total bilirubin \< 1.5 mg/dL
  * ASAT ≤ 5 \* times the upper limit of normal (ULN)
  * ALAT ≤ 5 \* ULN
  * Alkaline phosphatase ≤ 5 \* ULN
  * (estimated) glomerular filtration rate (eGFR) \> 45 ml/min.
* Before patient registration, written informed consent must be given and signed according to ICH-GCP, and national/local regulations.

Exclusion Criteria:

* Extrahepatic metastases. Confirmed with CT thorax/abdomen obtained ≤ 4 weeks prior to registration. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.
* Prior hepatic radiation, resection (other than biopsy), or ablation.
* Concurrent malignancies that interfere with the planned study treatment or the prognosis of CRLM.
* Participation in other clinical trials interfering with the study treatment as judged by the treating physician.
* Dihydropyrimidine dehydrogenasedeficiency (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 equiv-alent excluding inhaled steroids).
* Serious infections (uncontrolled or requiring treatment).
* History of psychiatric disability judged by the investigator to potentially hamper compliance with the study protocol and follow-up schedule.
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.