Purpose
The liver is often the first metastatic site for various solid tumors; in addition, liver metastases are mostly perfused via the hepatic artery. Based on these considerations, locoregional strategies have been studied for many years in order to improve the usually poor prognosis of these patients.Mitomycin C (MMC) is characterized by a high “first pass” liver extraction rate, when administered via the hepatic artery especially during hypoxic conditions. Thus, MMC could be an ideal drug to be administered by stop-flow intraarterial hepatic locoregional therapy, making possible an increase of local drug concentration, by minimizing the systemic exposure and prolonging the contact between the drug and the tumor. This procedure is based on hypoxic effect due to stop-flow, potentiating the cytotoxic activity of MMC, combined to the hischemic damage obtained by embolization of vascular supply to the tumor. In addition, the placement of a vascular stent inside the hepatic artery, before inflating the balloon-catheter to obtain the stop-flow, could be useful to prevent iatrogenic damages of the arterial wall.
Material and methods
From May 2002 to February 2006, 30 patients (pts) with multifocal and/or large liver metastases (21 from colorectal tumors) were treated with hypoxic stop-flow liver perfusion of MMC. Median age was Main eligibility criteria were:multifocal and/or large unresectable liver metastases without extrahepatic disease, regular portal flow (by US-ColorDoppler), ECOG PS 0-1,absence of ascites and/or jaundice, adequate hematologycal reserve and hepatic/renal function. The procedure consisted in 1)percutaneous subclavian (or femural) approach under ultrasonographic guidance and aortography with evaluation of possible abnormal flowing of the hepatic artery; 2)isolation of the hepatic arterial axis and occlusion of gastroduodenal artery (by Gianturco spirales) along its proximal tract; 3)possible occlusion of the right gastric artery andor cystic artery if medium-large caliber; 4)placement of a self-expandible vascular stent at the rising of common hepatic artery, proximally to gastroduodenal artery; 5)placement of the balloon-catheter, which is inflated to fully occlude the vessel without coming out of the stent; 6)after stop-flow of 10 minutes, in which the hypoxia is stabilized, Mitomycin C, at the dosage ranging between 0.30-0.45 mg/kg, dissolved in 300 ml of normal saline, is perfused by a peristaltic pump in 20 minutes; 7)final embolization with gelatine sponge and deflation of the balloon-catheter; 8)Vascular arterial suture with Angio-seal system. Response assessment was performed by contrast-enhanced CT-scan one month after the procedure, and the morphologycal response was evaluated as follows: 1)Complete response: disappearing or complete necrosis of all visible lesions; 2)Partial response: reduction of metastatic volume or necrosis more than 50%; 3)Stable disease; 4)Progressive disease. In addition, a ultrasonographic Color Doppler examination was performed to check the correct placement of the vascular stent and to detect iatrogenic damages of the hepatic arterial wall. Patients showing at least stable disease were submitted to repeated procedures.
Results
A total of 45 sessions of treatment have been administered ; one patient received 4 treatments, 3 pts received 3 treatments while 2 sessions of therapy were administered to 6 pts. With a median follow-up of 15 months, 21 pts showed partial response/stable disease; in 5 cases progression of disease was observed, while 4 pts were not evaluable. In 23 cases the procedure was administered in heavily pretreated pts, while 7 pts received the treatment with concurrent systemic chemotherapy. The toxicity of treatment was mild; grade 3-4 anaemia occurred in one case (2%), while grade 3-4 thrombocytopenia was observed in 3 sessions (7%). Grade 3-4 hepatic toxicity occurred in 4 treatment sessions (10%), resolving in a few days as well as mild/moderate fever observed in 22 sessions (50%). Nausea, vomiting and abdominal pain were mild, short-lasting and easily managed. Two pts showed thrombotic obstruction of hepatic artery, likely iatrogenic, after the first treatment, so precluding successive procedures.
Conclusion
The treatment is safe and feasible; the placement of a vascular stent is able to protect the arterial wall from iatrogenuc lesions, so allowing repeated procedures in responsive patients. The intraarterial administration of MMC, exploiting its high liver extraction rate, would allow, by stop-flow, to achieve: 1)a theoretically complete liver perfusion (although influenced by posture); 2)the maximal drug concentration and a prolonged drug exposure of neoplastic tissue; 3) a synergistic effect of pharmacologycal activity and the hypoxia, obtained by vascular occlusion. Our preliminary results, despite the heterogeneity of patients’population and the short follow-up, support further investigation on this technique as palliative option in pts with usually poor prognosis; furthermore, the good tolerability of the procedure may allow to perform it in combination with systemic chemotherapy and other locoregional and cytoreductive treatments, such as thermoablative procedures and/or free-flow liver antiblastic perfusions in patients with advanced metastatic liver disease.