Hepatic arterial infusion PUMP chemotherapy combined with systemIc chemoTherapy for potentially resectable colorectal liver metastases

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 absence of
marketing authorization for FUDR in Europe, 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.

This study has been transitioned to CTIS with ID 2024-515525-28-00 check the CTIS register for the current data.

The aim of this study is to prove feasibility of HAIP chemotherapy
(floxuridine) in combination with standard systemic chemotherapy consisting of
FOLFOX or FOLFIRI.

Multicenter, open label, interventional, feasibility study

Surgical implantation of HAIP followed by administration of intra-arterial
floxuridine (HAIP chemotherapy) to the liver with concomitant standard
systemic FOLFOX (5-FU, leucovorin and oxaliplatin) or FOLFIRI (5-FU, leucovorin
and irinotecan).

High response and conversion rates to locally treatable metastases have been
demonstrated in MSKCC. Irrespective of conversion, survival data suggest
increase of median survival of patients treated with the combined treatment.
These data are single center experience and have not been confirmed elsewhere.

HAIP (chemotherapy) will be added to the standard of care systemic treatment.
Prior to HAIP implantation a CT angiography will be performed to conclude
sufficient vascular anatomy of the liver when this cannot be concluded from
prior imaging. The HAIP willbe implanted surgi-cally and the gallbladder will
be removed during this procedure. Surgical complications related to HAIP
implantation are uncommon (<10%), and include hepatic artery thrombosis, HAIP
pocket infection, and arterial haemorrhage at the site of arterial catheter
insertion. Prior to the first administration of HAIP chemotherapy, a
technetium-99m-labeled macro-aggregated al-bumin nuclear medicine scan
(99mTc-MAA scintigraphy) with or without a CT angiography will be performed to
confirm bilobar hepatic perfusion and to rule out extrahepatic perfusion. The
effective dose of the 99mTc-MAA scintigraphy and the CT angiography are 3-4 mSv
and 15 mSv respectively. A diagnostic CT of the abdomen is approximately 15
mSv.

Patients will proceed with HAIP chemotherapy combined with standard systemic
chemotherapy. Administration of HAIP chemotherapy will be scheduled on the same
day as systemic chemotherapy administration. HAIP chemotherapy toxicities
include ulcer disease and biliary sclerosis, which can both be largely avoided
by imaging prior to treatment, monitoring of liver tests and early FUDR dose
adjustments. Systemic side effects of HAIP chemotherapy are rare (<1%) and
therefore suitable for combination with systemic treatment.

Systemic chemotherapy can be continued after HAIP chemotherapy discontinuation.
After HAIP chemotherapy discontinuation the pump can be surgically removed with
a simple procedure if desired by the patient however, the attached catheter
into the hepatic artery will re-main in situ. Follow-up after HAIP chemotherapy
is similar to standard of care. After conversion surgery, standard follow-up
protocol for postoperative patients after liver surgery will be followed,
independent of the numbers of cycles of FUDR.

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