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Patients undergo DSA-guided implantation of hepatic artery infusion pump. All patients receive the intervention "Hepatic artery infusion of gemcitabine and floxuridine" the next day after pump implantation. The HAI therapy is initiated on day 1, 8: Gemcitabine 1g/m2 for 30 minutes, followed by a blended solution which comprised floxuridine (FUDR) at 0.15 mg/kg/day, dexa-methasone (DXM) at 1 mg/m2/day, low molecular heparin 3200U and saline, lasted for 7 days continuously.Standard treatments of NPC, including radiotherapy and chemotherapy (induction chemotherapy, concurrent chemotherapy and adjuvant chemotherapy) are performed as desired.

Implant the infusion catheter and injection port (Celsite, B. Braun, Chasseneuil, France) under DSA-guiding. The proximal end of the infusion catheter was connected to the injection port and the device was implanted in a subcutaneous pocket in the right inner thigh; the distal end of the infusion catheter guarantee uni-direction infusion to liver.

DSA-guided implantation of hepatic artery infusion pump

Given intra-arterially continuously for 14 days

Given intra-arterially continuously with 5-FUDR

dexamethasone

A retrospective clinical trial to study the safety and effectiveness of hepatic arterial infusion (HAI) in treating patients who have nasopharyngeal carcinoma metastatic to the liver. Hepatic-direction drug administration improves the control power for intra-hapatic lesions.

OBJECTIVES:

I. Determine the safety and toxicity of hepatic arterial infusion with gemcitabine, floxuridine and dexamethasone in combination with standard treatment (radiotherapy and systemic chemotherapy) in patients with nasopharyngeal carcinoma metastases to liver.

II. Determine the objective response of intrahepatic lesions of patients treated with this regimen.

III. Determine the median survival time or overall survival time in patients treated with this regimen.

OUTLINE: This is a single-center retrospective study.

Patients receive DSA-guided implantation of HAI catheter system. HAI is initiated the next day. Gemcitabine intra-arterially for 30 minutes on day 1,8, floxuridine, dexamethasone intra-arterially continuously on days 1-14. Treatment repeats every 3 weeks in the absence of serious technical catheter-related problems, progression of intrahepatic lesions or unacceptable toxicity. Standard treatment of NPC, including radiotherapy and chemotherapy (induction chemotherapy, concurrent chemotherapy and adjuvant chemotherapy) was performed as desired.

Patients are followed every 2 HAI cycles or when necessary.

Hepatic Artery Infusion Pump for NPC Liver Metastases

Hepatic Artery Infusion Gemcitabine and Floxuridine in Patients With Nasopharyngeal Carcinoma Liver Metastases

Assess the Disease control rate (DCR) of intrahepatic lesions by enhanced spiral-CT scan according to RECIST criteria.

From the date of HAI catheter implantation to the date of death from any cause or to completion of trial, whichever comes first, up to 84 months.

To determine the safety and tolerability of HAI for NPC liver metastases by establishing the rates of toxicity

Xiangya Hospital of Central South University

Colorectal Neoplasms

Cholangiocarcinoma

Bile Duct Neoplasms

Adenocarcinoma

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Biliary Tract Neoplasms

Bile Duct Diseases

Biliary Tract Diseases

Bile Duct Cancer

Intrahepatic Cholangiocarcinoma

Irinotecan

Oxaliplatin

Panitumumab

Patients with unresectable colorectal liver metastases will undergo hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter. Patients will then receive hepatic artery infusion floxuridine as well as disease-appropriate systemic chemotherapy (FOLFOX, FOLRIRI, or oxaliplatin/irinotecan, or panitumumab if KRAS/NRAS wild type)

Patients with unresectable intrahepatic cholangiocarcinoma will undergo hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter. Patients will then receive hepatic artery infusion floxuridine as well as disease-appropriate systemic chemotherapy (gemcitabine/oxaliplatin or gemcitabine alone)

Patients will undergo surgical hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter.

Hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter.

Patients will receive infusion of floxuridine (FUDR) and dexamethasone via hepatic artery infusion through the implanted pump

Hepatic artery infusion pump floxuridine and dexamethasone

Patients will receive disease-appropriate systemic chemotherapy for colorectal liver metastases (FOLFOX, FOLFIRI, or irinotecan/oxaliplatin, or panitumumab if KRAS/NRAS wild type)

Systemic chemotherapy for colorectal liver metastases

Patients will receive disease-appropriate systemic chemotherapy for intrahepatic cholangiocarcinoma (gemcitabine/oxaliplatin or gemcitabine alone)

Systemic chemotherapy for intrahepatic cholangiocarcinoma

Michael J Cavnar, MD

Due to discontinuation of the Codman C3000 pump, an alternate device is necessary to continue serving patients in need of hepatic arterial infusion chemotherapy. This study aims to test the safety of hepatic artery infusion pump placement, a standard surgical procedure, and intraarterial chemotherapy initiation with the standard medication floxuridine (FUDR), using the Medtronic Synchromed II pump combined with the Codman arterial catheter in patients with unresectable (not removable by surgery) liver metastases from colorectal cancer and unresectable intrahepatic cholangiocarcinoma. This study will determine if complication and pump loss rates will be similar to previously published rates for the Codman system.

Patients with unresectable colorectal liver metastases (arm 1) and unresectable intrahepatic cholangiocarcinoma (arm 2), will undergo hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter. All patients will receive hepatic artery infusion floxuridine, and then individual arms will receive disease-specific systemic chemotherapy.

Codman Catheter/Synchromed Pump Hepatic Artery Chemotherapy for Unresectable Colorectal Metastases/Intrahepatic Cholangiocarcinoma

Feasibility Pilot of Hepatic Arterial Infusion Chemotherapy in a Rural Catchment Area, Using the Codman Vascular Catheter With the Synchromed II Pump, for Patients With Unresectable Colorectal Cancer Liver Metastases or Unresectable Intrahepatic Cholangiocarcinoma

The percent of patients who complete the 1st cycle of hepatic artery chemotherapy will be tabulated. This is a conglomerate safety endpoint which is a surrogate for any complication that prevents delivery of hepatic artery chemotherapy via the device combination.

Tabulation of CTCAE serious adverse events attributed to pump implantation

Quantify the percent of patients with inability to meet primary outcome due to catheter disconnects.

Quantify the percent of patients with inability to meet primary outcome due to inability to access pump.

Percentage of patients who need secondary intervention (IR embolization, revision of pump or tubing) to achieve primary pump function.

Patients are screen using a psychosocial assessment tool for high risk of hepatic artery pump loss/failure, percent declined will be tabulated.

Percent of patients that experience pump loss/failure due to inability to attend scheduled followup appointments will be tabulated.

The number of staff contacts (phone calls) to assure patients keep their followup visits will be tabulated.

The percentage of patients who remain on pump chemotherapy at 3 months will be tabulated.

RECIST v1.1 will be used to assess overall response rate at 6 months.

The percent of patients who are downstaged and undergo surgery will be tabulated.

The percentage of patients who remain on pump chemotherapy at 6months will be tabulated.

Assistant Professor

Patients with unresectable colorectal liver metastases will undergo hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter. Patients will then receive hepatic artery infusion floxuridine as well as disease-appropriate systemic chemotherapy (FOLFOX, FOLRIRI, or oxaliplatin/irinotecan, or panitumumab if KRAS/NRAS wild type)

Hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter.: Patients will undergo surgical hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter.

Hepatic artery infusion pump floxuridine and dexamethasone: Patients will receive infusion of floxuridine (FUDR) and dexamethasone via hepatic artery infusion through the implanted pump

Systemic chemotherapy for colorectal liver metastases: Patients will receive disease-appropriate systemic chemotherapy for colorectal liver metastases (FOLFOX, FOLFIRI, or irinotecan/oxaliplatin, or panitumumab if KRAS/NRAS wild type)

Colorectal Liver Metastases

Patients with unresectable intrahepatic cholangiocarcinoma will undergo hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter. Patients will then receive hepatic artery infusion floxuridine as well as disease-appropriate systemic chemotherapy (gemcitabine/oxaliplatin or gemcitabine alone)

Hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter.: Patients will undergo surgical hepatic artery infusion pump placement using the Synchromed II pump and the Codman tapered arterial catheter.

Hepatic artery infusion pump floxuridine and dexamethasone: Patients will receive infusion of floxuridine (FUDR) and dexamethasone via hepatic artery infusion through the implanted pump

Systemic chemotherapy for intrahepatic cholangiocarcinoma: Patients will receive disease-appropriate systemic chemotherapy for intrahepatic cholangiocarcinoma (gemcitabine/oxaliplatin or gemcitabine alone)

Total

40-70 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Michael Cavnar

Percent Completion of 1st Cycle of Hepatic Artery Chemotherapy

30-day Postoperative Serious Adverse Events Related to Pump Implantation

30-day Catheter Malfunction Due to Tubing Disconnect

30-day Catheter Malfunction Due to Inability to Access Pump

Percent of Patients That Require Secondary Intervention in Order to Obtain Primary Pump Function.

Percent of Screened Patients That Are Declined Due to High Risk of Failure as Determined by the Psychosocial Assessment Tool.

Percent Pump Loss Due to Inability to Attend Scheduled Followup Appointments.

Number of Interventions (Phone Calls) to Assure Patients Attend Followup Appointments.

Percent of Patients Who Remain on Hepatic Artery Infusion Pump Chemotherapy at 3 Months.

At the 6 month time point for this outcome there were only 14 evaluable participants for response rate due to attrition, death, or sub-RECIST threshold disease.

Overall Response Rate at 6 Months

Percent of Patients Who Are Downstaged and Undergo Surgery

Percent of Patients Who Remain on Hepatic Artery Infusion Pump Chemotherapy at 6 Months.

Overall Study

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Carcinoma, Ductal

Carcinoma, Pancreatic Ductal

Liver Neoplasms

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Liver Diseases

Pancreatic Cancer

Once enrolled, patients will undergo surgical placement of the HAI pump. This can be accomplished using minimally invasive or open techniques with an anticipated hospital stay of approximately 3-5 days. Prior to discharge from the hospital or at the first postoperative visit the pump is filled with FUDR according to the following equation: 0.12 mg/kg/d (using ideal body weight). This fill initiates day 1 of a 4-week cycle. The chemotherapy is infused by the pump continuously over 14 days. On day 15 (+/-4 days), the remaining chemotherapy is removed from the pump which is refilled with heparinized saline (30,000 units). This remains for an additional 2 weeks until the pump is refilled with FUDR at the start of the next cycle. Treatment is continued for a maximum of 6 cycles or as limited by toxicity. This regimen has been utilized with an acceptable safety profile in the setting of colorectal liver metastases.

Together the FUDR and the HAI pump are experimental because they are being used to treat hepatic liver metastases of Pancreatic adenocarcinoma. They have not yet been FDA approved for this indication, although they are both approved for other indications. The intervention is surgical placement of an HAI pump with subsequent delivery of FUDR via the pump in 28-day cycles. FUDR will be delivered via the HAI pump for 6 months, in 28 day cycles: 2 weeks of therapy, followed by 2 weeks of heparinized saline.

Floxuridine (FUDR)

Together the FUDR and the HAI pump are experimental because they are being used to treat hepatic liver metastases of Pancreatic adenocarcinoma. They have not yet been FDA approved for this indication, although they are both approved for other indications. The intervention is surgical placement of an HAI pump with subsequent delivery of FUDR via the pump in 28-day cycles. The primary tumor will be resected or ablated with irreversible electroporation at the time of HAI pump placement. FUDR will be delivered via the HAI pump for 6 months, in 28 day cycles: 2 weeks of therapy, followed by 2 weeks of heparinized saline.

Hepatic Artery Infusion Pump

Together the FUDR and the HAI pump are experimental because they are being used to treat hepatic liver metastases of Pancreatic adenocarcinoma. They have not yet been FDA approved for this indication, although they are both approved for other indications. FUDR will be delivered via the HAI pump for 6 months, in 28 day cycles: 2 weeks of therapy, followed by 2 weeks of heparinized saline.

Heparinized Saline

G. Paul Wright, MD

Esther Peariso, MSN, RN

Murwarid M Assifi, MD

Esther L Peariso, BSN

This is a single arm, phase II study without blinding. The purpose is to determine the impact of hepatic artery infusion Floxuridine (FUDR) on liver metastases from pancreatic adenocarcinoma. Patients at Spectrum Health will receive standard of care chemotherapy. They will also receive chemotherapy via surgically placed hepatic artery infusion (HAI) pump.

This study hypothesizes that the combination of Floxuridine (FUDR), a type of chemotherapy, delivered via a hepatic artery infusion (HAI) pump, with standard of care systemic chemotherapy will lead to improved survival in the treatment of pancreatic cancer liver metastases. Patients will receive 6 cycles of FUDR and will be followed for two years.

Hepatic Artery Infusional Floxuridine to Treat Pancreatic Cancer Liver Metastases

A Phase II Trial of Hepatic Artery Infusional Floxuridine With Systemic Chemotherapy in the Treatment of Pancreatic Cancer Liver Metastases

The length of time from the start of trial therapy to the time when target liver lesions show progression or new lesions appear. (Determined by RECIST criteria: ≥20% growth in target lesions and/or appearance of new lesions).

The length of time from diagnosis to death, measured as the proportion of patients surviving at specific time points (6, 12 and 18 months from diagnosis).

The length of time from diagnosis to disease progression at any anatomical site (as determined by RECIST criteria) or death.

Determined by RECIST criteria on imaging studies done every 3 months

As measured by the EORTC Quality of Life Questionnaire Core 30 instrument

Spectrum Health Hospitals

Surgical Oncology and Hepatopancreaticobiliary Surgeon

Micronutrients

Leucovorin

Fluorouracil

Patients with potentially resectable colorectal liver metastases will undergo hepatic artery infusion pump placement. Subsequent hepatic artery infusion of floxuridine via the HAIP as well as standard of care Dutch systemic chemotherapy (FOLFOX or FOLRIRI) will be administered in a combined chemotherapy schedule.

Administration of intra-arterial floxuridine via the HAIP (HAIP chemotherapy) to the liver with concomitant Dutch standard of care systemic FOLFOX (5-FU, leucovorin and oxaliplatin) or FOLFIRI (5-FU, leucovorin and irinotecan).

Surgical implantation of hepatic artery infusion pump (HAIP) followed by administration of the combined chemotherapy (HAIP and systemic).

Tricumed IP2000V infusion pump

Myrtle F Krul, MD

Roos Steenhuis, MSc

Koert FD Kuhlmann, MD, PhD

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.

Patients with potentially resectable (i.e. unresectable or upfront resectable with an indication for upfront systemic therapy) will receive hepatic artery infusion pump chemotherapy, consisting of floxuridine (FUDR), combined with standard of care systemic therapy (FOLFOX or FOLFIRI).

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

Hepatic Arterial Infusion PUMP Chemotherapy Combined With systemIc chemoTherapy for Potentially Resectable Colorectal Liver Metastases: The PUMP-IT Study.

The quality of life will be examined with validated questionnaires (EORTC QLQ-C30 \& EQ-5D-3L).

The percentage of patients that complete two cycles of combined chemotherapy (HAIP chemotherapy and systemic therapy) after being scheduled for surgical implantation.

Surgical complications will be defined according to Clavien-Dindo surgical complications score. Complications of Clavien-Dindo grade 3 or higher are recorded for the first 90 days after surgery. Postoperative complications include those related to the HAIP implantation. Postoperative mortality is defined as any death during hospitalization or within 90 days from surgery.

Toxicity grade 3 or higher will be recorded from the time of study inclusion according to the CTCAE criteria.

Treatment related serious adverse events (SAE) and adverse events (AE) of grade 3 or higher will be collected continuously from the time of study inclusion until the end of combined chemotherapy. AE are followed up until the event is either resolved or adequately explained, even after the patient has completed his/her study treatment. Nature and duration of any hospitalization, treatment of any AE, and nature and duration of any outpatient care will be recorded.

Response rates of CRLM will be measured according to RECIST criteria

PFS will be defined from inclusion date until disease progression.

OS will be defined from inclusion date until death.

Conversion rate is defined as the percentage of patients in whom CRLM convert from an unresectable to a resectable state and undergo surgical treatment with curative intent. Possibility of local treatment is at the discretion of the multidisciplinary liver panel.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Hepatic Artery Infusion Pump for NPC Liver Metastases	NCT03876574	Nasopharyngeal ... Neoplasm Metast... Liver	DSA-guided impl... Gemcitabine Floxuridine dexamethasone	-	Xiangya Hospital of Central South University
Codman Catheter/Synchromed Pump Hepatic Artery Chemotherapy for Unresectable Colorectal Metastases/Intrahepatic Cholangiocarcinoma	NCT04276090	Bile Duct Neopl... Colorectal Neop...	Hepatic artery ... Hepatic artery ... Systemic chemot... Systemic chemot...	18 Years -	University of Kentucky
Hepatic Artery Infusional Floxuridine to Treat Pancreatic Cancer Liver Metastases	NCT03856658	Pancreatic Aden... Liver Metastase...	Floxuridine (FU... Hepatic Artery ... Heparinized Sal...	18 Years - 75 Years	Spectrum Health Hospitals
Hepatic Artery Infusional Floxuridine to Treat Pancreatic Cancer Liver Metastases	NCT03856658	Pancreatic Aden... Liver Metastase...	Floxuridine (FU... Hepatic Artery ... Heparinized Sal...	18 Years - 75 Years	Spectrum Health Hospitals
Hepatic Arterial Infusion Pump Chemotherapy Combined With Systemic Chemotherapy (PUMP-IT)	NCT04552093	Colorectal Neop...	Floxuridine Tricumed IP2000...	18 Years - 115 Years	The Netherlands Cancer Institute
Codman Catheter/Synchromed Pump Hepatic Artery Chemotherapy for Unresectable Colorectal Metastases/Intrahepatic Cholangiocarcinoma	NCT04276090	Bile Duct Neopl... Colorectal Neop...	Hepatic artery ... Hepatic artery ... Systemic chemot... Systemic chemot...	18 Years -	University of Kentucky

Spots Global Cancer Trial Database for hepatic artery infusion pump