Hepatic arterial infusion chemotherapy with gemcitabine and 5-fluorouracil or oral S-1 improves the prognosis of patients with postoperative liver metastases from pancreatic cancer

Abstract

Hepatic metastasis is a common cause of treatment failure following resection of pancreatic cancer. In this study, we report our results of hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) plus 5-fluorouracil (5-FU) or oral S-1 treatment for postoperative liver metastases from pancreatic cancer. Seven patients with postoperative liver metastases from pancreatic cancer received HAI with GEM plus 5-FU or oral S-1 between October, 2008 and September, 2010 at Kanazawa University Hospital (Kanazawa, Japan). Three out of the 7 cases exhibited a partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and stable disease (SD) was achieved in 3 out of the 7 cases (response rate, 85.7%). A decrease in serum tumor marker CA 19-9 levels was observed after 10 HAI treatment cycles in 5 out of the 7 cases. The median time to treatment failure was 8 months (range, 0–17 months). Adverse events included grade 3 leukocytopenia in 1 case and anemia in all 7 cases, although 5 out of the 7 patients were anemic prior to HAI therapy. Grade 2 thrombocytopenia was also observed in 2 cases. Non-hematological events, such as nausea, diarrhea, liver injury or neuropathy and life-threatening toxicities were not reported; however, 6 patients (85.7%) developed catheter-related complications and the HAI catheter and subcutaneous implantable port system had to be removed. These findings demonstrated that HAI may deliver high doses of chemotherapeutic agents directly into the tumor vessels, producing increased regional levels with greater efficacy and a lower incidence/severity of systemic side effects. In conclusion, HAI chemotherapy is a safe and effective treatment for liver metastases from pancreatic cancer.

Saturable Hepatic Extraction of Gemcitabine Involves Biphasic Uptake Mediated by Nucleoside Transporters Equilibrative Nucleoside Transporter 1 and 2

“…These results indicate that the low‐affinity site is the main contributor to GEM uptake at this concentration. These results are consistent with the fact that severe adverse events, especially events related to bone‐marrow suppression, were not observed in our phase I clinical study of HAI (dose: 800 mg/SLV) . Indeed, it may be possible to increase the dose of GEM in HAI to achieve a greater therapeutic effect without adverse effects.…”

“…We have confirmed the effectiveness and safety of GEM HAI in a previous phase I clinical study, [18][19][20][21] but nevertheless, dose selection remains a critical issue, because saturation of hepatic extraction in HAI would lead to increased systemic exposure, resulting in potentially severe toxicity. Therefore, in this study, we examined the saturability of hepatic extraction of GEM at clinically relevant concentrations in normal hepatocytes to provide a rational basis for dose selection from the viewpoint of adverse events.…”

“…At this concentration, the high-affinity site would be completely saturated, whereas the low-affinity site would be only partially. On the contrary, we estimated that the local GEM plasma concentration in liver would be about 360 :M when 800 mg/SLV (standard liver volume; around 960 mg/body) was infused in HAI for 30 min in a normal person (SLV: 1.2 L) 18,20,21 in the case of hepatic artery perfusion at 300 mL/min. 35 Therefore, in this situation too, the high-affinity site would be completely saturated, and the low-affinity site would be partially saturated, although the systemic concentration would be lower in GEM HAI treatment compared with i.v.…”

“…These results are consistent with the fact that severe adverse events, especially events related to bone-marrow suppression, were not observed in our phase I clinical study of HAI (dose: 800 mg/SLV). [19][20][21] Indeed, it may be possible to increase the dose of GEM in HAI to achieve a greater therapeutic effect without adverse effects. For example, administration of GEM by HAI at the dose used for i.v.…”

“…We have also reported that administration of 400 mg GEM/body for 30 min by HAI did not lead to severe adverse events in patients with postoperative liver metastases from pancreatic cancer, 19 and we confirmed the effectiveness and safety of GEM HAI. [18][19][20][21] The response rate according to the response evaluation criteria in solid tumors was 80%-100%, and severe adverse events, especially leukocytopenia and thrombocytopenia, were not encountered.…”