Can Chemotherapy Directly in the Artery to the Liver Reduce Recurrence of Bile Duct Cancer? – PUMP-4 Study

2023-05-24 02:15:23

Background and problem statement
Bile duct cancer in the liver is a rare cancer with an incidence of 1-2 in 100,000. It is the second most common form of liver cancer. Liver surgery is the only curative treatment.(1,2) Even after this surgery, survival is poor; after 5 years, only 30% are still alive.(3,4,6-10) After surgery, the disease recurs in two-thirds of patients, mostly (in 80%) in the liver.(4,7, 11-14) When it comes back, healing is rarely possible.(12,15)

These patients require additional treatment to prevent the disease from returning after surgery. Such an “adjuvant” treatment is currently not available in the Netherlands. Several studies with chemotherapy as a tablet or via an infusion have found no convincing improvement in survival or quality of life.
The aim of this study is to investigate whether additional chemotherapy directly in the artery to the liver with the chemopump can reduce the recurrence of disease and improve survival.

Proposed solution
The treatment with chemotherapy delivered directly into the artery to the liver is called Hepatic Arterial Infusion Pump (HAIP) chemotherapy. HAIP chemotherapy was developed at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York. In the Netherlands, the treatment is only available in a study context for patients with metastases of colorectal cancer in the liver (PUMP-1, PUMP-3 and PUMP-IT trials) and inoperable bile duct cancer in the liver (PUMP-2). Tumors in the liver are supplied with blood via arteries, while the liver itself is mainly supplied via the portal vein.(16,17) Via the “chemopump” (see Appendix 1, Figure 1), patients receive chemotherapy (floxuridine) directly into the hepatic artery administered. Floxuridine is largely absorbed in the liver, which means that the local effect of the chemotherapy is very high. (18) The side effects are limited, because the chemotherapy hardly reaches the rest of the body. As a result, the quality of life is better than with the usual chemotherapy with a tablet or infusion.

Floxuridine is not yet registered in the European Union (EU) and is therefore only available in a study context. In the autumn of 2017, the Erasmus MC Cancer Institute, with the support of the KWF, was the first hospital in the EU to start using HAIP chemotherapy in a study context. In the first study, patients with operable metastases of colorectal cancer in the liver are treated with the chemopump for 6 months after surgery. The aim of this study is to provide definitive evidence that the chemopump reduces disease recurrence and improves survival. The multidisciplinary treatment team of all hospitals involved was extensively trained before the start of the treatment. During working visits to the MSKCC, the team gained all the expertise necessary for the current study. In addition, the MSKCC treatment team is still involved to advise if necessary. This collaboration is unique in Europe and guarantees optimum quality of care. An online platform has been developed for patients and professionals www.chemopomp.nl with practical information about the treatment. The first results of the feasibility study show that the treatment is feasible and can be performed safely in the Netherlands.(19) More than 200 patients in the Netherlands have now been treated with the chemopump.

The effectiveness of HAIP chemotherapy has been investigated in three studies in patients with bile duct cancer in the liver whose disease is too extensive for surgery. The bile duct cancer became a lot smaller in the majority of patients. As a result, the survival after 3 years was still 40%, while the survival with only intravenous chemotherapy after 3 years was only 2%. These results are promising for the current study proposal for patients whose tumor can be removed after surgery. We expect that HAIP chemotherapy will also work for them to prevent bile duct cancer from returning to the liver. However, this has never been investigated.

Study design
The aim of the current phase II study is to investigate whether additional HAIP chemotherapy reduces recurrence of liver disease and improves survival in patients with operable bile duct cancer of the liver. We also look at quality of life. A total of 40 patients will receive the treatment. After the study, we compare the results with patients who have had surgery for bile duct cancer in the liver in the past 10 years without additional HAIP chemotherapy.
All patients participating in the study will have a chemopump placed during the operation to remove the bile duct cancer. About four weeks after the operation, the HAIP chemotherapy starts. A course of chemotherapy takes four weeks; two weeks of pump chemotherapy followed by two weeks of rest. Patients receive a maximum of six courses. Then, in principle, the subcutaneous pump is removed. This is an outpatient surgery where the patient can go home the same day. Tumor markers are tested in the blood every three months and a CT scan is made every six months to evaluate the effect of the treatment for up to two years after surgery. Thereafter, a CT scan is performed every twelve months for up to five years after surgery.

The PUMP-4 study will take place at Erasmus MC, Amsterdam UMC, and UMC Utrecht. These are three expertise centers for patients with bile duct cancer. Moreover, these three centers now have a great deal of experience with HAIP chemotherapy.

Implementation plan
The first step in the implementation is to present the results at (inter)national conferences and in magazines. The national implementation coincides with the implementation of chemopump treatment for patients with metastases of colorectal cancer in the liver. There are now 8 hospitals in the Netherlands where treatment with the chemopump is possible in a study context. We are in talks with 4 other hospitals to start this treatment. Given the required multidisciplinary expertise, we expect that 12 hospitals is an optimal balance for the patient between travel distance and expertise. Incidentally, the treatment of bile duct cancer in the liver is limited in the Netherlands to a smaller number of academic centres.
Parallel to scientific studies, we have set up a consortium with the pharmaceutical industry to register floxuridine in the EU in the next two years.