Adjuvant hepatic arterial infusion pump chemotherapy after resection of colorectal liver metastases - a feasibility study

Colorectal liver metastases
Colorectal cancer is the third most common cancer with an annual incidence of
14,000 patients in the Netherlands. More than half of these patients will
eventually develop colorectal liver metastases (CLM), of whom 25% have
resectable disease at first presentation.

The efficacy of resection of CLM has never been evaluated in a randomized
controlled trial (RCT). However, 10-year overall survival (OS) of 20% to 30%
has been reported after resection of CLM, which is equivalent to cure. As
compared to resection, systemic chemotherapy alone rarely results in 10-year
OS. Complete resection of CLM, if feasible, is therefore the standard of care.
Most patients (up to 80%) develop recurrent disease after curative intent
resection of CLM, which in about 50% of patients is confined to the liver. A
large phase 3 trial investigating perioperative systemic chemotherapy for
patients with resectable CLM found overlapping survival curves after a median
follow-up of 8.5 years: 5-year OS was 51% with perioperative chemotherapy
versus 48% with surgery alone (p=0.34). This was an unexpected outcome, because
systemic chemotherapy is effective in the adjuvant setting for stage III
colorectal cancer and in the palliative setting for unresectable stage IV
disease. Consequently, better adjuvant treatment is needed.

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.(5, 6)
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 chemotherapy for two weeks, which is
repeated after a two-week rest period.

Evidence for adjuvant HAIP chemotherapy
Four randomized controlled trials (RCT) have evaluated adjuvant HAI
chemotherapy.(9-13) In the first RCT at Memorial Sloan Kettering Cancer Center
(MSKCC), patients received adjuvant systemic 5-fluorouracil (5-FU) and HAIP
chemotherapy or systemic 5-FU alone. The primary outcome of 2-year survival was
85% with HAIP versus 69% (p=0.02). After a median follow-up of 8.5 years, the
median OS was 68 months with HAIP versus 59 months (p=0.10). Median PFS was 31
months with HAIP versus 17 months (p=0.02). Hepatic progression-free survival
(PFS) at 2-years was 85% with HAIP versus 50% (p=0.001).

The second RCT was a multi-site study that found a 4-year recurrence rate of
25% in patients treated with adjuvant HAIP chemotherapy versus 46% without HAIP
chemotherapy (p=0.04). A third multi-site RCT used intra-arterial 5-FU instead
of floxuridine. The study was closed prematurely when no difference was found
at interim analysis. 5-FU has a much smaller first pass effect, resulting in
lower tumor exposure and more systemic toxicity. Moreover, an external (rather
than implanted) pump was used and many patients had pump failure; 26% never
received HAIP chemotherapy in the intervention arm.

Studies from France used intra-arterial oxaliplatin with a percutaneously
placed catheter connected to a mediport. This approach has not been evaluated
in an RCT. The disadvantage is the much lower first pass effect in the liver of
oxaliplatin resulting in lower concentration in the liver tumors and higher
systemic exposure and toxicity. Moreover, the mediport doesn*t allow for
continuous long-term perfusion.

The NCCN guideline recommends adjuvant HAIP chemotherapy for CLM as an option
in experienced centers (Category 2B). Adjuvant HAIP chemotherapy for CLM has
not been widely adopted outside MSKCC. Another phase 3 RCT is required to
compare adjuvant HAIP chemotherapy for CLM with surgery alone.

A recent retrospective analysis evaluated 2368 consecutive patients undergoing
complete resection of CLM with and without adjuvant HAIP chemotherapy at MSKCC
between 1992 and 2012. The median OS with HAIP chemotherapy was 67 months
versus 44 months without HAIP chemotherapy (p<0.001). After adjusting in
multivariable analysis for seven independent prognostic factors including
adjuvant modern systemic chemotherapy, the hazard ratio (HR) of HAIP
chemotherapy was 0.70 (95% CI: 0.60-0.80, p<0.001).(16) The median OS in the
group without HAIP chemotherapy was similar to the 45 months found in a series
of 2715 patients from the UK where no HAIP chemotherapy was used. Subgroup
analyses of patients with a low CRS found a median OS with HAIP chemotherapy of
89 months versus 53 months without HAIP chemotherapy (p<0.001).


Safety and feasibility
HAIP chemotherapy is a complex treatment with a large involved
multidisciplinary team. In Erasmus MC this treatment has not been used before.
Both subcutaneous placement of the pump and the administration of HAIP
chemotherapy itself are complex procedures. Adverse events have been well
characterized in the setting of MSKCC.(19) A safety and feasibility study in
Erasmus MC should determine whether HAIP chemotherapy can be delivered with
adverse events similar to the experienced center (MSKCC). *Safe* means that
adverse events of both surgical placement of the pump and administration of
HAIP chemotherapy are justifiable compared to the expected benefit in overall
survival. *Feasible* means that our multidisciplinary team can administer HAIP
chemotherapy to the majority of eligible patients.

Imaging to assess adequate perfusion of pump
Prior to the first administration of intra-arterial chemotherapy, bilobar
hepatic perfusion and lack of extrahepatic perfusion are confirmed by
post-operative technetium-99-labeled macroaggregated albumin (MAA) nuclear
medicine scanning. MAA is administered through the IP2000V bolus port. Within 1
hour after MAA injection, a SPECT/CT scan is performed. The total radiation
dose of the Tch99 MAA scan is approximately 3-4 mSv. This has been the default
method of imaging in MSKCC.

Concerns with MAA administration are the difficulties in logistics, the low
resolution of SPECT imaging, the absences of anatomical information of vascular
structures and the possible mismatch between MAA deposition in the liver and
distribution of floxuridine during treatment.

Alternatively, CT with contrast injection through the bolus port of an
indwelling hepatic catheter provides high resolution information on the anatomy
of the post-operative vascular status of the hepatic artery and braches, and
the uptake of contrast agent in the liver parenchyma and possible new liver
metastases (a pre-treatment CT can therefore be omitted). Using this technique,
the distribution of contrast agent is depicted during a specific phase, i.e. a
single point in time, without providing information on the dynamic distribution
of contrast agent in the liver parenchyma. Previous experience of hepatic
perfusion imaging using dual source CT is solely based on the intravenous
administration of contrast agents with high flow rates of 4 to 8 ml per second.
In this study, contrast agent is administered through the dedicated bolus port
of the IP2000V pump while acquiring images using dual source perfusion CT at a
temporal resolution of 1.5 second. Because of the position of the tip of the
catheter in the hepatic artery, low flow rates and low contrast dosage of
respectively 0.2 - 0.4 ml per second and 5 - 10 ml dosage are feasible. These
low numbers result in a negligible effect on renal function. The radiation dose
is comparable to a diagnostic scan of the abdomen.

Primary Objective:
The first objective of this study is to evaluate the safety and feasibility of
adjuvant HAIP chemotherapy after resection of CLM in 2 centres in the
Netherlands.

Secondary Objective(s):
The second objective is to determine whether CT angiography can replace a
nuclear medicine scan to rule out extrahepatic perfusion of the pump.

This is a multicenter feasibility study to identify potential hurdles of the
treatment with HAIP chemotherapy in the Netherlands. Participating center are
the Erasmus MC Cancer Institute and Antoni van Leeuwenhoek ziekenhuis.

The expected duration of study will be 6 months. Results of the feasibility
study will be reported 6 months after start of the study.

Resection of CLM, pump placement and adjuvant HAIP chemotherapy.

The intervention comes in addition to the standard of care. A pump will be
surgically implanted at the time of curative-intent liver resection. Prior to
the first administration of HAIP chemotherapy a technetium-99-labeled
macroaggregated albumin nuclear medicine scan and a CT angiography are
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, and arterial haemorrhage at the site of
arterial catheter insertion. The radiation dose of the Tch99 MAA scan is 3-4
mSv. The radiation dose of the CT angiography is 15 mSv, which is comparable to
a diagnostic CT of the abdomen. A total of 5-10 ml contrast agent will be
infused which with a negligible effect on renal function. 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%). The expected
benefit in median OS found in propensity score analysis of more than 2000
patients was 36 months (89 with versus 53 months without HAIP chemotherapy).
*