Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver

Abstract

BACKGROUND Liver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases. PATIENTS AND METHODS Patients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible. A standard “3+3” phase I study design was used to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Three cohorts were evaluated: HAI of irinotecan with systemic intravenous (IV) (a) bevacizumab, (b) oxaliplatin and bevacizumab, or (c) bevacizumab and cetuximab. RESULTS From October 2009 through December 2013, 98 patients with various tumor types were enrolled (median age, 62 years, range, 34–85; and median number of prior therapies, 4, range, 1–11). In cohorts A and C, dose escalation continued until the highest dose level—considered the MTD—was reached. In cohort B, dose escalation continued until dose level 3, and dose level 2 was considered the MTD. Rates of grade 3/4 adverse events were as follows: diarrhea, 8%; fatigue, 4%; neutropenia, 4%; thrombocytopenia, 2%; and skin rash, 2%. Seventy-seven patients were evaluable for response. Partial response was noted in 5 (6.5%) patients (neuroendocrine cancer, n=2; CRC, n=2; NSCLC, n=1); and stable disease ≥ 6 months in 17 (22.1%) patients (CRC, n=13; breast, n=1; neuroendocrine, n=1; NSCLC, n=1; pancreatic, n=1). CONCLUSIONS HAI irinotecan in combination with bevacizumab; oxaliplatin plus bevacizumab; or cetuximab plus bevacizumab was safe and may be a treatment option for selected patients with advanced cancer and liver involvement.

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

“…Trials on two different—more regional infusion methods—have been conducted. First, locoregional therapy with irinotecan infusion into the hepatic artery has been evaluated for the treatment of unresectable liver metastases; different irinotecan formulations have been demonstrated to be safe and effective [ 95 , 96 ]. This approach resulted in lower systemic exposure to irinotecan and an increased conversion of irinotecan into SN-38 compared with intravenously administered irinotecan [ 97 ].…”

Cancer and the metastatic substrate

“…These patients took docetaxel and two anti-HER-2 agents, trastuzumab and pertuzumab, along with surgery to resect the metastatic liver part [169]. Another option for treating patients with liver metastasis is to administer a combination of drugs via hepatic arterial infusion (HAI): irinotecan, bevacizumab, and oxaliplatin combined with bevacizumab or cetuximab [170] have been used. In colorectal cancer patients with liver and lung metastases, completely resecting metastases in both organs offers the best survival results.…”

Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit

“…However, the combination of systemic bevacizumab with intra-arterial of floxuridine was observed to bear a higher risk of biliary tract damage [86], without significantly improving outcomes [87]. Notwithstanding, other phase I studies have not reported an increment in toxicity associating intravenous bevacizumab and hepatic artery infusion of other cytotoxic drugs [88][89][90][91]. This therapeutic option deserves therefore further testing.…”