in vivo 20: 769-772 (2006)

Stop-flow Perfusion with Mitomycin-C as Locoregional Approach in the Treatment of Large-unresectable Liver Metastases

C. GADALETA1, A. CATINO1 and V. MATTIOLI2

1Interventional Radiology Operative Unit and 2Critical Area Department, Oncology Institute, Bari, Italy

Abstract. Background: New treatments are being investigated hepatic locoregional therapy, making an increase of local in patients with multiple or unresectable liver metastases, usually drug concentration possible, minimizing the systemic characterized by poor prognosis. Based on the predominant exposure and prolonging the contact between the drug and arterial blood supply of hepatic neoplasms, liver transarterial the tumor (4-10). This procedure is based on a hypoxic effect chemoembolization administers cytotoxic drugs in combination due to stop-flow, potentiating the cytotoxic activity of MMC, with the ischemic effect due to vascular occlusion. Mitomycin-C combined to the ischemic damage obtained by embolization (MMC) is characterized by a high liver extraction rate and is of vascular supply to the tumor. In addition, the placement potentiated by a hypoxic environment. Patients and Methods: of a vascular stent inside the hepatic artery, before inflating This technique is performed by inducing a stop-flow of the the balloon-catheter to obtain the stop-flow, could be useful hepatic artery, obtained by the placement of a balloon-catheter in preventing iatrogenic damage to the arterial wall. and followed by the infusion of MMC; in addition, in order to prevent iatrogenic lesions of the vascular wall, caused by the Patients and Methods inflation of the balloon-catheter, a vascular stent is placed at the beginning of the procedure. Results: Thirty-one patients with liver From May 2002 to May 2006, 31 patients with multifocal and/or metastases from various solid tumors were treated, while 47 large liver metastases (21 from colorectal tumors) were treated with hypoxic stop-flow liver perfusion with MMC. Main eligibility sessions of treatment were performed. Toxicity was moderate; criteria were: multifocal and/or large unresectable liver metastases three cases of iatrogenic obstruction of the hepatic artery were without extrahepatic disease, regular portal flow (by US- observed, thus precluding further treatment. Conclusion: The ColorDoppler), ECOG PS 0-1, absence of ascites and/or jaundice, feasibility and the good tolerability of this procedure make it an adequate hematological reserve and hepatic/renal function. interesting option in the therapeutical strategy for patients with advanced metastatic liver disease, as well as in combination with Procedure. The procedure consisted of: i) percutaneous subclavian systemic chemotherapy, ablative and cytoreductive treatments (or femural) approach under ultrasonographic guidance and aortography with evaluation of possible abnormal flow of the and/or free-flow liver perfusions with anticancer drugs. hepatic artery; ii) isolation of the hepatic arterial axis and occlusion of gastroduodenal artery (by Gianturco spirales) along its proximal The liver is often the first metastatic site for various solid tract; iii) possible occlusion of the right gastric artery andor cystic tumors. Based on these considerations, locoregional artery if medium-large caliber; iv) placement of a self-expandible strategies have been studied for many years in order to vascular stent at the rising of common hepatic artery, proximally to improve the usually poor prognosis of these patients (1-3). gastroduodenal artery; v) placement of the balloon-catheter, Mitomycin-C (MMC) is characterized by a high "first pass" inflated to fully occlude the vessel without coming out of the stent; vi) after stop-flow of 10 minutes, in which the hypoxia is stabilized, liver extraction rate when administered via the hepatic artery, MMC, at a dosage of 0.30-0.45 mg/kg, dissolved in 300 ml of especially during hypoxic conditions. Thus, MMC could be an normal saline, was perfused by a peristaltic pump for 20 min; vii) ideal drug for administration by stop-flow intra-arterial final embolization with gelatine sponge and deflation of the balloon-catheter; viii) vascular arterial suture with Angio-seal system (St. Jude Medical).

Correspondence to: Dr. Cosmo Gadaleta, Interventional Radiology Evaluations. Response assessment was performed by contrast- Operative Unit, Oncology Institute Bari-Italy, Via Hahnemann, 10 enhanced CT-scan one month after the procedure, and the - 70126 Bari, Italy. Tel: +39(0)805555674, Fax +39(0)805555677, morphological response was evaluated as follows: i) complete e-mail: [email protected] response, disappearance or complete necrosis of all visible lesions; ii) partial response, reduction of metastatic volume or >50% Key Words: Stop-flow liver perfusion, liver metastases, mitomycin-C. necrosis; iii) stable disease; and iv) progressive disease.

0258-851X/2006 $2.00+.40 769 in vivo 20: 769-772 (2006)

Discussion

The rationale of intra-arterial hepatic "stop-flow" chemotherapy is based on the following concepts: - to prolong the contact of neoplastic tissue with the drug, increasing its efficacy (10); - to increase the drug-concentration by reducing the washing due to blood-flow (10); - to potentiate some drugs by hypoxia (3, 4, 6-8). Finally, the embolization with reabsorbable gelatine sponge prolongs the loco-regional antineoplastic effect, without precluding successive repeated treatments. These considerations, as well as the data previously published by Roversi et al. (4) and others (2, 3, 6, 7, 10-13) have represented the basis of our experience, aiming to evaluate the safety and feasibility of this treatment in patients with advanced metastatic liver disease. The intra-arterial administration of MMC, exploiting its high liver extraction rate, would achieve, by stop-flow: i) a Figure 1. The angiogram, obtained during the perfusion, shows an almost theoretically complete liver perfusion (although influenced complete arterial parenchymal liver perfusion with Mitomycin; Gianturco by posture) (14); ii) the maximal drug concentration and a spirales, placed to permanently occlude the gastroduodenal artery, are prolonged drug exposure of neoplastic tissue; iii) a visible, as well as the ballon-catheter inflated inside the stent placed in the hepatic artery. synergistic effect of hypoxia performed by vascular occlusion and drug activity. In addition, liver metastases are characterized by predominant arterial blood supply (9, 15), even if the portal vein system is also involved in nutrition of In addition, a ultrasonographic Color Doppler examination was small metastases, as well as of the surface of large metastases performed to check the correct placement of the vascular stent and (15). These findings might explain the incomplete activity of to detect iatrogenic damage to the hepatic arterial wall. Patients intra-arterial chemotherapy against liver metastases, and showing at least stable disease were submitted to repeated suggest to integrate portal administration of anticancer drugs procedures. in the locoregional chemotherapy for liver metastases. Our Results preliminary results confirm that the procedure used is safe and feasible, also in patients heavily pre-treated for the A total of 47 sessions of treatment were administered: one hepatic metastatic disease; furthermore, the rate of vascular patient received 4 treatments, 4 received 3 treatments, while damage is negligible, so we think that the placement of a 2 sessions of therapy were administered to 6. With a median vascular stent might be useful in protecting the arterial wall follow-up of 17 months, 21 patients showed partial from iatrogenic lesions, thus, allowing for repeated response/stable disease; in 5 cases progression of disease was procedures in responsive patients. The angiogram showing observed, while 5 patients could not be evaluated. In 24 the hepatic perfusion and the optimal occlusion of hepatic cases, the procedure was administered in heavily pre-treated artery by the balloon-catheter is presented in Figure 1. Based patients, while 7 received the treatment with concurrent on our experience and considering the good results systemic chemotherapy. The toxicity of the treatment was previously obtained by other trials with intra-arterial hepatic mild; grade 3-4 anaemia occurred in one case (2%), while chemotherapy, both on therapeutical response and survival grade 3-4 thrombocytopenia was observed in 3 sessions (2, 11, 13, 16, 17), despite the heterogeneity of the patient (6%). Grade 3-4 hepatic toxicity occurred in 4 treatment population and the short follow-up, we support that further sessions (8.5%), resolving in a few days; mild/moderate fever investigation into this technique as a palliative option in was also observed in 22 sessions (47%). Nausea, vomiting patients with poor prognosis is required. Furthermore, the and abdominal pain were mild, short-lasting and easily good tolerability of the procedure may allow to be managed. Two patients showed thrombotic obstruction of performed in combination with systemic chemotherapy and the hepatic artery after the first treatment, likely iatrogenic, other locoregional and cytoreductive treatments, such as hence precluding successive procedures, whereas in one thermoablative procedures and/or free-flow liver antiblastic patient the hepatic arterial obstruction occurred after 3 perfusions in a multimodal therapeutical strategy for procedures. advanced metastatic liver disease.

770 Gadaleta et al: Stop-flow Perfusion as Locoregional Anticancer Treatment for Unresectable Liver Metastases

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