DEBIRI therapy for hepatic metastases in colorectal cancer

The worldwide incidence of colorectal cancer is 400,000, in which 60% of patients will develop liver metastases and usually have a poor prognosis, with survival rates at three years less than 5%, explained Professor Giammaria Fiorentini, General Hospital Giuseppe, Empoli, Florence, Italy, and Dr Camillo Aliberti, Delta Hospital AUSL Ferrara, Ferrara, Italy, at the Biocompatibles/Terumo sponsored satellite symposium at this year’s CIRSE meeting.

In terms of treatment, surgery is feasible in a minority of patients with colorectal cancer. Subsequently, the majority of patients are treated with systemic chemotherapy. The doubling of the median survival reached by modern targeted therapy (11-23 months) has been accompanied by a 340-fold increase in therapy costs so new combined strategies and alternatives are warranted. Radiofrequency ablation (RFA) is used in limited liver substitution and transarterial chemoembolisation (TACE) is used more commonly in diffuse liver metastases.

Irinotecan
Irinotecan is an active drug in first- and second-line treatment of advanced colorectal cancer. In a Phase I-II clinical study, irinotecan was the drug of choice for hepatic artery infusion in the treatment of unresectable and pre-treated liver metastases from colorectal cancer. Fiorentini explained that the advantage of delivering chemotherapy by hepatic arterial infusion is the administration of high-dose of the drug into the target area. The combination of local drug infusion and embolisation of the feeding arteries results in direct treatment of the target tissue and necrosis of the tumour.

"Compressible polyvinyl alcohol hydrogel microspheres (DC Bead™, Biocompatibles, UK) are a new embolic product capable of being loaded with irinotecan before administration in TACE procedures," commented Fiorentini, who cited the successful application of irinotecan Drug-Eluting Beads in animal models (Saenger J, Leible MH, Sieger MR, Berger L. Chemoembolization of rat liver metastases with irinotecan and quantification of tumor cell reduction. J Cancer Res Clin Oncol. 2004 Apr;130(4):203-10).

Clinical study
From March 2006 to September 2007, Fiorentini, Aliberti and colleagues completed a study to assess the clinical performance of Drug-Eluting Beads (DEB) loaded with irinotecan to treat unresectable liver metastases from colorectal cancer.

Thirty-four patients (26 male and eight female), average age 63 (range 42-82) were evaluated for recruitment. They presented progression after two lines (n=20) or three lines (n=14) of chemotherapy. Eleven patients refused TACE preferring palliative care, systemic chemotherapy or alternative medicine, and three patients had disease progression during work-up.

In this study, 20 patients were reported, presenting with multiple, unresectable lesions. Liver substitution according to Pettavel classification was: stage I (up to 25%) = 8/20; stage II (up to 50%) = 7/20; and stage III (more than 50%) = 5/20.

Clinical study design endpoints
Primary endpoints

Secondary endpoints

Dose selection
Irinotecan was loaded into the beads (50mg/mL) and was administered as TACE, every three weeks (one to three treatments). Treatment was stopped in case of progressive disease, toxicity lasting more than five weeks or patient refusal.

Diagnostic angiography was performed and under fluoroscopic guidance, a solution of 2-4mL of 100-300µm and/or 300-500µm DC Bead loaded with irinotecan and mixed with non-ionic contrast medium, was injected into the feeding artery.

Results and toxicology
Fiorentini reported that a total of 46 TACE procedures were performed with 100% technical success. Response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, was 80% (16/20 patients) with reduction of more than 50% of the tumour marker (CEA) observed in 60% (12/20) of patients. A reduction of the lesional contrast enhancement by CT scan was also observed in 80% of patients (16/20).

The reported median duration of survival was 210 days and 15 patients were still alive at time of reporting. Causes of death were three cases of disease progression, one pulmonary embolism, and one cardiac arrest.

Study results

Toxicity, which was graded according to the WHO criteria, included grade 2 nausea in all patients mainly within one and six hours after treatment, grade 2 pain in half of the patients and grade 3 in 5/20 patients usually within six and 12 hours after treatment and grade 2 fever and asthenia was reported in all patients two to14 days after treatment (Figure 1). A transient and moderate increase of liver enzymes was observed after the procedure.

One case of liver abscess and one case of acute pancreatitis which completely recovered were also reported.

Future developments
Further developments and evaluations have been planned to assess and compare irinotecan containing regimen to other new chemoembolisations.

A phase III study comparing DEBIRI (ARM-A) versus FOLFIRI (FOLFIRI: irinotecan 180mg/m2 on day one with LV 100mg/m2 administered as a two-hour infusion before FU 400mg/m2 administered as an intravenous bolus injection, and FU 600mg/m2 as a 22-hour infusion immediately after FU bolus injection on days one and two) intravenously (ARM-B) has been carried out with the primary endpoint to increase two-year survival of 40% with DEBIRI. Thirty-two patients were included, with 14 patients recruited in DEBIRI (ARM-A) and 18 patients in FOLFIRI (ARM-B).

The phase III study survival rate showed that after a mean follow-up of 150 days, with a median survival not reached in both groups, more than 80% of patients survived in the DEBIRI (ARM-A), compared to less than 60% in the FOLFIRI (ARM-B) (Figure 2).

However, after the submission of interim results, on August 7, 2007, the Ethical Committee required more details on why there were:

Despite the first interim analysis of survival favouring DEBIRI (ARM-A) (Figure 2), the study has been suspended at the request of the Ethical Committee who have asked for more details in the variation in response and serious adverse effects (SAEs) between the two arms. Fiorentini and his team therefore confirmed the difficulties in carrying out this kind of study adopting locoregional versus systemic therapy.