Adjuvant hepatic arterial infusion pump chemotherapy after repeat hepatectomy for patients with recurrent colorectal liver metastases without a history of extrahepatic disease - a phase II study

Background
Colorectal liver metastasis
Colorectal cancer (CRC) is the third most common cancer in the Netherlands.
About 50% of patients develop colorectal liver metastasis (CRLM) throughout the
course of the disease. Resection and/or ablation of the CRLM is the only
curative treatment. Unfortunately, approximately 70% of patients develop
recurrence, half of which is still confined within the liver. Repeat
hepatectomy has emerged as a viable therapy for recurrent CRLM showing
comparable survival and morbidity as resection for index CRLM. Consequently,
the number of patients undergoing repeat resections for recurrent CRLM is
increasing over the years. This patient group has withstood the test of time
for developing extrahepatic recurrences. Currently, no effective adjuvant
treatment options are available for this patient population. Even after repeat
hepatectomy for recurrent CRLM, half of the recurrences after resection of
recurrent CRLM occur in the liver. Therefore optimal disease control within the
liver may lead to improved disease-free survival and overall survival.

Hepatic arterial infusion pump chemotherapy
Mechanism of action
Hepatic arterial infusion pump (HAIP) chemotherapy for liver tumors is a
treatment that has been developed at Memorial Sloan Kettering Cancer Center
(MSKCC, New York, USA). It is currently not available in the European Union,
because floxuridine is not registered in the EU. The biological rationale for
intra-arterial chemotherapy is that the hepatic artery rather than the portal
vein is responsible for most of the blood supply to liver tumors. Moreover, up
to 95% of drugs such as floxuridine (FUDR) is extracted by the liver during the
first-pass, allowing an up to 400-fold increase in hepatic exposure with
minimal systemic exposure. Intra-arterial chemotherapy is delivered in the
hepatic artery via a surgically implantable pump with a catheter in the
gastroduodenal artery. The pump is filled percutaneously and the liver is
continuously perfused with the infusion solution for two weeks, which is
repeated after a two-week rest period.

Treatment with hepatic arterial infusion pump (HAIP) chemotherapy allows high
dosage chemotherapy to be directed into the liver without the chemotherapy
reaching other organs. The drug used, floxuridine (a 5-FU analogue), has a 95%
first pass effect in the liver. In addition CRLM derive most of their blood
supply from the hepatic artery, rather than the portal vein. By administering
high dose floxuridine in the liver, microscopic liver metastasis that are
invisible during imaging are also tackled, thus preventing growth of these
micrometastases at a later stage.

Floxuridine is best delivered with a subcutaneous pump that can deliver high
dose floxuridine continuously for two weeks and is accessible through the skin.

In a recent retrospective study of 2368 patients treated in MSKCC, patients
receiving adjuvant HAIP chemotherapy after resection of index CRLM had an
Overall Survival (OS) benefit of 2 years compared with those that did not
receive HAIP chemotherapy. Preliminary results of a retrospective study
including 323 patients treated in MSKCC and the Erasmus MC show that patients
that have received adjuvant HAIP chemotherapy after resection of recurrent CRLM
had an hepatic disease frees survival (hDFS) of 50 months compared with 18
months in patients that received resection only (p=0.003). This translated to
an overall survival (OS) of 89 and 57 months with and without adjuvant HAIP
chemotherapy respectively (p=0.01). Due to the retrospective nature of the
studies, the results could be subjected to bias. However, such promising
results deserve further research with a prospective study design.

Primary Objective:
The first objective of this study is to evaluate efficacy of adjuvant HAIP
chemotherapy after repeat hepatectomy for recurrent CRLM in the Erasmus MC.

Secondary Objective(s):
The second objective is to determine treatment related adverse events (grade
III and higher).

This is a single center prospective phase II study.

Resection of CLM, pump placement and adjuvant HAIP chemotherapy.

Included patients have a HAI pump surgically implanted placed at the time of
resection of CLM. The study intervention comes in addition to the standard of
care. Prior to the first administration of HAIP chemotherapy a
technetium-99-labeled macroaggregated albumin nuclear medicine scan is
performed to confirm bilobar hepatic perfusion and rule out extrahepatic
perfusion. Patients will proceed with 6 cycles of chemotherapy. Follow-up after
treatment is identical to the standard of care. Surgical complications related
to HAIP pump placement are uncommon (<10%), but include hepatic artery
thrombosis, pump pocket infection, pump dysfunction, pump dislocation, and
arterial haemorrhage at the site of arterial catheter insertion.

The radiation dose of the Tch99 MAA scan is 3-4 mSv.

HAIP chemotherapy will require two hospital visits for each cycle, with a
maximum total of 12 visits. HAIP chemotherapy toxicities include ulcer disease
and biliary sclerosis, which can both be largely avoided by imaging prior to
treatment and monitoring of liver tests and dosages adjustments, if needed.
Systemic side effects with HAIP chemotherapy of floxuridine are rare (<1%).