Treatment Of Unresectable Liver Metastases Research Articles

Interventional therapies of unresectable liver metastases

Liver metastases are the major cause of mortality in patients with gastrointestinal carcinomas and other malignant tumors, carrying a poor prognosis and presenting considerable management. Surgical resection remains the only curative therapy for liver metastases up to now. However, only a small percentage of patients are suitable for curative resection due to many factors: multi-centric tumors, extrahepatic metastases, early vascular invasion, and coexisting advanced liver cirrhosis. In non-surgical cases, regional interventional therapies have led to a major break through in the treatment of unresectable liver metastases, which include transarterial chemoembolization (TACE), radiofrequency ablation (RFA), laser-induced thermotherapy (LITT), cryosurgical ablation (CSA), microwave coagulation therapy (MCT), percutaneous ethanol injection (PEI), and others. As a result of the technical development of locoregional approaches for unresectable liver metastases during recent decades, the range of combined interventional therapies has been continuously enlarged. The current roles of these treatment options for liver metastases are discussed in this review.

The importance of scatter correction for the assessment of lung shunting prior to yttrium-90 radioembolization therapy

Treatment of inoperable hepatocellular carcinoma or secondary metastases by radioembolization using yttrium-90 (90Y) microspheres is a promising method for the treatment of unresectable liver metastases. A pretreatment scintigraphy planar scan using 99mTc-labelled macroaggregated albumin (99mTc-MAA) injected directly into the hepatic artery is carried out to assess the degree of portal shunting of blood between the liver and the lungs. The quantitative results of this scan are used to modulate the activity of therapeutic 90Y microspheres injected into the patient to limit the radiation dose received by the lungs. The presence of scattered events in the MAA lung shunt scan leads to an overestimation of the true shunting ratio, which in turn leads to the administered therapeutic activity being lowered unnecessarily to comply with the protocols of radiation protection. Overall, this may impact the efficacy of treatment. This study analyses the impact of a window-based analytical scatter-correction method on lung shunt analysis using an anthropomorphic torso phantom, and retrospectively analysed three patient case studies. Our results of scatter in the phantom show a marked decrease in the lung shunt percentage. Clinical analysis of patient data shows that the lung shunt percentage can be overestimated by up to 50% in clinical cases, and depending on the lung shunt percentage, the efficacy of treatment by therapeutic dose reduction may be compromised. Our results indicate that scatter correction should be used on 90Y pretreatment 99mTc-MAA scans in order to more accurately assess the lung shunting percentage before therapy.

Chemoperfusion und -embolisation von Lebermetastasen

Presentation of techniques and procedures for regional chemotherapy in the treatment of unresectable liver metastases from different primary tumors as a modality of interdisciplinary therapy management. Such transarterial therapy methods include hepatic arterial infusion (HAI), transarterial chemoembolization (TACE), chemoembolization with cytostatic-loaded microspheres (DEBs), transarterial embolization (TAE) and selective internal radiation therapy (SIRT). Regional chemotherapy procedures in the treatment of liver metastases represent a minimally invasive treatment option that can be successfully combined with surgical resection and/or radiofrequency (RFA), laser-induced thermotherapy (LITT), microwave ablation (MWA). These procedures allow optimization of the local control rate with strictly intrahepatic processes and lead to increased survival rates without any quality of life restriction.

A Phase I Study of Hyperthermic Isolated Hepatic Perfusion with Oxaliplatin in the Treatment of Unresectable Liver Metastases from Colorectal Cancer

Isolated hepatic perfusion (IHP) is a proven approach for regional delivery of chemotherapy in patients with unresectable primary and metastatic tumors of the liver. Most trials of IHP have utilized melphalan as the active drug in the perfusate. We performed a phase I trial to evaluate the efficacy, safety, and maximum tolerated dose (MTD) of oxaliplatin delivered by hyperthermic isolated hepatic perfusion. A phase I dose-escalation trial of hyperthermic IHP with oxaliplatin in patients with unresectable metastatic colorectal cancer scheduled to undergo placement of a hepatic arterial infusion (HAI) pump was carried out. Thirteen patients were enrolled between November 2003 and September 2006. Dose-limiting veno-occlusive disease was observed at 60 mg/m(2). At the MTD of 40 mg/m(2) only minor transient liver dysfunction was observed. Ultrafilterable platinum area under the curve and maximum concentration delivered by IHP increased nonlinearly with dose as did platinum concentrations in liver biopsies obtained at the end of the 60 min IHP. Seventy-seven percent of patients had a >50% decrease in serum carcinoembryonic antigen (CEA) after IHP. The overall response rate to the combined IHP and HAI therapy was 66%. One patient had a durable complete response (>4 years). We conclude that hyperthermic IHP with oxaliplatin was safe and feasible at a dose of 40 mg/m(2). The ability to obtain complete vascular isolation with open IHP was confirmed. The response rate in this small phase I study was encouraging.

Hepatic arterial infusion (HAI) compared to systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma: A systematic review and meta-analysis of randomized controlled trials

14519 Background: The treatment of unresectable liver confined metastatic disease from colorectal cancer is a challenging issue. Although locoregional treatments such as HAI claim the advantage of delivering higher doses of anticancer agents directly into the affected organ, the evidence for benefit in terms of overall survival (OS) is conflicting. We aimed to quantitatively summarize the results so far described in randomized trials comparing HAI to systemic chemotherapy. Methods: To date, ten randomized controlled trials (RCT) have been published, for a total of 1,277 patients enrolled. Seven RCT (n=1,098) enrolling at least 50 patients per arm (the minimum sample size required to achieve a type II error lower than 20%) were considered for OS meta-analysis, which was based on the inverse of variance method. For tumor response rates, hazard ratios (HR) and their 95% confidence intervals (CI) were obtained from raw data; for OS, HR and CI were obtained from reported Cox model survival analyses or were calculated from Kaplan-Meier survival curves according to the Parmar method. Results: HAI regimens were based on floxuridine (FUDR) in nine out of ten RCT, while in one case 5-fluorouracil (5FU) + leucovorin (LV) were used. Systemic chemotherapy consisted of FUDR, 5FU, 5FU + LV, or a miscellany of 5FU and best supportive care in three, one, four and two studies, respectively. Tumor response and median OS were better in the HAI arm in eight and three RCT, respectively. At meta-analysis, median tumor response rate was 38.84% and 17.30% for HAI and systemic chemotherapy, respectively (HR: 2.24, CI: 1.80- 2.81; P < 0.0001); on average, median OS was 16.04 and 12.64 months, respectively (HR: 0.83, CI: 0.58–1.19; P value 0.30). Conclusions: Although HAI regimens are followed by significantly higher tumor response rates, no OS advantage can be demonstrated for this locoregional treatment as compared to systemic chemotherapy. Since HAI has been so far compared to systemic chemotherapy regimens not containing modern and more effective antineoplastic agents (e.g. oxaliplatin, irinotecan), these findings do not support the clinical or investigational use of FUDR-based HAI. No significant financial relationships to disclose.

CASH (Chemotherapy-Associated Steatohepatitis) Costs

CASH (Chemotherapy-Associated Steatohepatitis) Costs

90Y microsphere treatment of unresectable liver metastases: changes in 18F-FDG uptake and tumour size on PET/CT

The intra-arterial administration of 90Y microspheres is a new palliative treatment option for unresectable liver metastases. The aim of this study was to quantitatively assess changes in FDG uptake and tumour size following 90Y microsphere treatment (SIR-Spheres) using 18F-fluorodeoxyglucose (FDG) PET/CT imaging. Five patients with unresectable liver metastases who had failed multiple prior chemotherapy regimens received seven 90Y microsphere treatments to a single liver lobe. All patients underwent a baseline PET/CT scan prior to treatment, as well as up to four follow-up PET/CT scans. The tumour area of 30 liver metastases was measured on CT and the FDG uptake was semiquantitatively assessed by calculation of standardised uptake values (SUVs). A total of 18 FDG-PET/CT scans were performed. The SUVs in the 30 treated liver metastases decreased from 6.5+/-2.3 at baseline to 4.2+/-1.8 after the first follow-up PET/CT scan (p=0.001). In contrast, the SUVs of untreated metastases increased slightly from 7.2+/-2.3 to 8.0+/-0.8. There was no difference in FDG uptake in treated versus untreated normal liver tissue. Using a previously defined threshold of 20% decrease in SUV from baseline to determine response, 20 out of 30 liver metastases were considered to have responded at the first follow-up PET/CT scan approximately 1 month after treatment. In these metastases, the SUV decreased by 47+/-12%, compared with a slight increase by 5.9+/-19% in ten non-responding metastases (p=0.0001). The changes in tumour size did not correlate with changes in FDG uptake. On the first follow-up PET/CT scan, the tumour area on CT increased by 3.1+/-57% in treated metastases compared with 23.3+/-32% in untreated metastases. A wide range of post-treatment changes of target lesions was observed on CT, including an increase in the size of hypodense lesions, necrotic features and complete resolution of CT abnormalities. The metabolic information obtained from FDG-PET/CT seems to provide a more accurate and earlier assessment of therapy response following 90Y microsphere treatment than does the anatomical CT information.

Surgical treatment of liver metastases by radiofrequency ablation, resection, or in combination

Aims. Radiofrequency ablation (RFA) has a role in the treatment of unresectable liver metastases either percutaneously or in open surgery. The aim of this study was to determine the feasibility and value using RFA, resection or in combination to cure liver metastases of colorectal or other origin. Methods. Fifty-two consecutive patients were operated on with the intention to treat their liver metastases using both techniques of RFA and resection in the same curative intent. A CT scan was performed 2 months postoperatively and then every 4 months. Results. Fifty patients with 137 metastases could be treated: 55 lesions were resected and 82 were ablated. Curative treatment of 13 patients could only be achieved by using RFA combined with resection. Morbidity was 16% and local treatment proved insufficient in three cases. Estimated 1-year survival probabilities were, respectively, 0.85 in the colorectal group and 0.80 in the non-colorectal group. Conclusions. RFA increased resectability of liver metastases and reduced the morbidity. Respective indications of both techniques were complementary and depend on the size and the topography of the lesion to be treated.

Effect of Intra-Arterial Cisplatin on Multiple Liver Metastases from Rectal Cancer Associated with Ulcerative Colitis

We report a patient with synchronous multiple liver metastases from rectal cancer associated with ulcerative colitis. Because the liver tumors were unresectable, we performed total proctocolectomy and hepatic intra-arterial cisplatin infusion with systemic oral administration of fluorouracil. A complete response was obtained. The patient is alive without sign of recurrence 5 years postoperatively. Hepatic intra-arterial administration of cisplatin should be considered in the treatment of unresectable liver metastases from colorectal cancer.

Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases

Liver metastases concern half of patients with colorectal cancer, and are frequently unresectable, jeopardizing patient outcome. Owing to increased efficacy, chemotherapy can render initially inoperable patients amenable to potentially curative resection. The 34% 5-year and 20% 10-year survival of patients resected following neoadjuvant chronomodulated chemotherapy with 5-fluorouracil, folinic acid and oxaliplatin is similar to that of patients whose disease was operable at diagnosis. Recently, a group of 16 patients were treated with irinotecan and became resectable after treatment. Their survival (56% at 3 years) matches that of patients treated with other forms of chemotherapy. The poor prognosis of patients with non-resectable hepatic metastases might now be improved by the combination of chemotherapy and surgery.

Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma.

This retrospective study was conducted to assess the safety, efficacy, and long-term results of neoadjuvant chemotherapy and cryotherapy as additional means for eradicating liver metastases from colorectal carcinoma when curative treatment was not possible by resection alone. Between January 1996 and December 1997, 131 patients with unresectable liver metastases were referred to our department and received chemotherapy. After 3-6 months of chemotherapy, curative surgery of liver metastases was considered possible in 57 patients, either by resection alone in 33 patients (25%) or cryotherapy associated with resection in 24 patients (18%). Characteristics and survival of patients in the cryotherapy plus resection group were compared with those of the 33 patients in the resection group. All patients in the resection group had partial response to neoadjuvant chemotherapy. In the cryotherapy plus resection group, neoadjuvant chemotherapy resulted in 13 partial responses, 9 stable diseases, and 2 disease progressions. The rate of postoperative complications in the entire series was 14%. No major difference was seen between the two groups. After a median follow-up of 48 months, the median survival time was 39 months. The survival rates at 1, 3, and 4 years were similar in both groups: 94, 58, and 37% in the resection group and 92, 50, and 36% in the cryotherapy plus resection group, respectively. The combination of neoadjuvant chemotherapy, cryotherapy, and liver resection constitutes a promising treatment strategy for patients with extremely advanced metastatic liver involvement. Patients having more than four liver metastases from a colorectal carcinoma or patients with a poor liver reserve due to previous resection should be screened carefully to determine whether they could be candidates for this procedure.

Pharmacokinetics of intraarterial mitomycin C in hypoxic hepatic infusion with embolization in the treatment of liver metastases

1. The pharmacokinetics of mitomycin C (MMC) was evaluated during hypoxic hepatic infusion (HHMI) with arterial embolization for the treatment of unresectable liver metastases. 2. Ten patients with hepatic metastases from colorectal cancer were considered. Antiblastic infusion with MMC (20 mg/m 2 at 30 ml/min) was initiated after 10 min of hepatic arterial occlusion. Peripheral venous blood samples were collected at different time intervals. MMC was assayed by high-pressure liquid chromatography (HPLC), and pharmacokinetic parameters were determined using an open, two-compartment model and linear kinetics. 3. C max of MMC during HHMI was 708±336.6 ng/ml, and t max was 9.3±1.1 min. The plasma concentration–time curve showed a t 1/2α ranging from 1.5 to 9 min, followed by a t 1/2β ranging from 31 to 93 min. The Cl tot was 35.5 l/h/m 2 with an area under the plasma concentration–time curve (AUC) ranging from 251 to 850 μg h/l. The same AUC parameter standardized for the amount of MMC was 15.5 mg −1. The HHMI model that we used revealed a significant increase in Cl tot and a reduction in AUC when compared to the locoregional intraarterial and peripheral intravenous models ( p<.001). 4. The reduction in AUC following HHMI explains the limited systemic toxicity in treated patients, with a greater total tumor exposure to the drug and improved drug activation.

Naked DNA injection for liver metastases treatment in rats

The cytosine deaminase (CD) gene converts the nontoxic prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU). We previously showed that injection of CD-bearing cancer cells followed by 5-FC treatment can act as an autologous tumor vaccine in a syngenic liver metastasis model in rats. In the present work, we analyzed the antitumor efficiency of a direct intratumoral injection of a CD-expressing plasmid. In rats bearing microscopic or macroscopic metastases in right and left liver lobes, an injection of a CD-expressing plasmid was performed in the left lobe tumor, followed by 5-FC treatment of the animals. A significant regression of the DNA-injected tumor was observed in 5-FC–treated rats, both in microscopic ( P = .007) or advanced ( P < .0001) tumor models. Moreover, this treatment also induced a potent distant bystander effect on untreated controlateral liver tumors and extrahepatic metastases, resulting in an increased survival compared with control animals in both tumor models ( P < .05). In conclusion, these data suggest that direct intratumoral injection of a CD-expressing plasmid, associated to 5-FC administration, can constitute a powerful and innocuous alternative treatment for unresectable liver metastases from colon carcinoma. (H EPATOLOGY 2002;35:1144-1152.)

Isolation perfusion of the liver.

Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melphaIan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver. In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, such as colorectal carcinoma, ocular melanoma, and neuroendocrine tumors. Current studies demonstrate that combining hepatic arterial infusion with floxuridine after IHP for patients with colorectal cancer metastases is associated with significant and durable response rates. Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases.

Hepatic arterial infusion chemotherapy with 5-fluorouracil-based regimens in the management of liver metastases of colorectal carcinoma

Background We assessed the efficacy and safety of hepatic arterial infusion chemotherapy, using 5-fluorouracil-based regimens, in the treatment of unresectable liver metastases of colorectal carcinoma.

Irinotecan as second-line treatment for unresectable liver metastases of colon cancer

A 53-year-old woman had shown repeated, partial responses to chemotherapy for large, multiple liver metastases of sigmoid colon cancer. After a partial response to 5-fluorouracil plus leucovorin therapy, an 89.7% reduction of the 5-fluorouracil-resistant metastatic tumor was achieved by giving CPT-11 (irinotecan) at a dose of 100 mg/body per week. We suggest that CPT-11 should be recommended as an effective second-line treatment for unresectable liver metastases of colon cancer, after 5-fluorouracil-based chemotherapy.

A case report of celiac axis compression and implications in regional chemotherapy for liver metastasis

Regional chemotherapy through a catheter placed in the hepatic artery is routinely used for treatment of unresectable liver metastasis from colon carcinoma. With some frequency, anatomical variations of the hepatic artery, including compression of the celiac axis, are found, and must be recognized preoperatively for appropriate management and placement of the catheter. We report a case of a colon cancer patient with multiple liver metastases and compression of the celiac axis, who received decompression of the celiac axis and catheterization of the hepatic artery.

Intraoperative single-dose radiotherapy. Observations on staging and interstitial treatment of unresectable liver metastases.

Fourteen patients with a history of colonic cancer were evaluated for metastatic disease and were thought to have unresectable disease confined to the liver. Exploratory surgery revealed that two patients had extensive extrahepatic disease, and the procedure was terminated. In 12 patients, closed-end needles (diameter, 2.1 mm) were introduced into each nodule and connected to a 370-MBq (10-Ci) afterloading iridium source. Radiation doses were dependent on nodule size, providing minimum doses of 20 Gy (2000 rad) to the lesion's periphery with rapid radiation falloff avoiding toxic effects to adjacent normal tissue. The maximum number of nodules treated in one patient was 11. The largest nodule treated measured 9 x 6.5 x 6 cm. Cholecystectomy in four patients allowed precise implantation and obviated biliary fistula. Preoperative computed tomography underestimated the number of hepatic metastases in all cases but one, and treatment-induced computed tomographic alterations further limited its utility. Radiation treatment was well tolerated, and the median hospitalization was eight days. Of ten patients whose preoperative carcinoembryonic antigen values exceeded 10 ng/dL, the values in six patients decreased postoperatively.