Treatment Of Unresectable Liver Metastases Research Articles

Мультидисциплинарный подход к лечению нерезектабельного метастатического поражения печени при люминальном раке молочной железы

Breast cancer (BC) remains the main oncological pathology in the female population. Liver metastases in such cases mean an extremely unfavorable prognosis of the course of the disease. The key predictor of clinical outcome of metastatic BC is the molecular biological subtype of the tumor. The main goals of treatment of metastatic BC are to increase life expectancy, alleviate tumor-related symptoms, and maintain or improve patients' quality of life. Transarterial chemoembolization (TACE) enables new ways of liver metastases control. This article presents a case of application of TACE in combination with hormone therapy and selective inhibitors of CDK4/6 in a patient with unresectable liver metastases seeded by hormone-receptor positive (ER+/PR‒) breast carcinoma with an unknown Her2 status (2+). The approach allowed achieving regression of the oncological process in the liver to the point of unclear CT visualizations of metastatic foci, and proper disease control in the course of 28 months.

Pleomorphic liposarcoma of the extremity with solitary huge liver metastasis at initial diagnosis treated with conversion surgery combined with adjuvant chemotherapy: a case report

BackgroundPleomorphic liposarcoma is the rarest subtype of liposarcoma. Pleomorphic liposarcomas are generally unresponsive to chemotherapy and radiotherapy. Moreover, metastasis in the liver, as the first and sole site, from a primary extremity soft tissue sarcoma, including pleomorphic liposarcoma, is extremely rare. Information regarding the appropriate management of these lesions is limited.Case presentationA 50-year-old Japanese woman presented with a mass in the left thigh. Imaging examination revealed a soft tissue sarcoma on the left posterior thigh. The tumor was histologically diagnosed as pleomorphic liposarcoma. Computed tomography examination for assessment of metastases incidentally detected a huge liver mass. Wide excision of sarcoma was performed prior to chemotherapy. Right trisectionectomy was necessary to achieve hepatic clearance; however, the future liver remnant volume was insufficient. Therefore, we decided to administer anthracycline-based chemotheraphy to shrink the tumor. After seven courses of adriamycin-based chemotherapy, the liver tumor size was reduced from 211 mm × 106 mm × 180 mm to 105 mm × 66 mm × 90 mm. Finally, a right hemihepatectomy was performed. The patient was continuously monitored and was metastasis or local recurrence free within 5 months after liver surgery.ConclusionChemotherapy is effective in some cases for the treatment of unresectable liver metastases of pleomorphic liposarcoma, and complete resection is possible with conversion surgery. If the patient’s general condition permits, anthracycline-based chemotherapy can be used for the treatment of stage 4 pleomorphic liposarcoma.

Percutaneous electrochemotherapy in primary and secondary liver malignancies - local tumor control and impact on overall survival.

BackgroundLocal nonsurgical tumor ablation currently represents a further option for the treatment of patients with liver tumors or metastases. Electrochemotherapy (ECT) is a welcome addition to the portfolio of local therapies. A retrospective analysis of patients with liver tumors or metastases treated with ECT is reported. Attention is given to the safety and efficacy of the treatment over time.Patients and methodsEighteen consecutive patients were recruited with measurable liver tumors of different histopatologic origins, mainly colorectal cancer, breast cancer, and hepatocellular cancer. They were treated with percutaneous ECT following the standard operating procedures (SOP) for ECT under general anaesthesia and muscle relaxation. Treatment planning was performed based on MRI preoperative images. The follow-up assessment included contrast-enhanced MR within at least 1–3 months after treatment and then after 5, 7, 9, 12, and 18 months until progression of the disease or death.ResultsOnly mild or moderate side effects were observed after ECT. The objective response rate was 85.7% (complete response 61.9%, partial 23.8%), the mean progression-free survival (PFS) was 9.0 ± 8.2 months, and the overall survival (OS) was 11.3 ± 8.6 months. ECT performed best (PFS and OS) in lesions within 3 and 6 cm diameters (p = 0.0242, p = 0.0297). The effectiveness of ECT was independent of the localization of the lesions: distant, close or adjacent to vital structures. Progression-free survival and overall survival were independent of the primary histology considered.ConclusionsElectrochemotherapy provides an effective valuable option for the treatment of unresectable liver metastases not amenable to other ablative techniques.

Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer.

Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM. Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable. M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.

Isolated chemohyperthermal perfusion of the liver with melphalan in the treatment of unresectable liver metastases with uveal melanoma

Uveal melanoma belongs to rare malignant neoplasms, and the biological peculiarity of this tumor determines the high rate of distant metastasis, which reaches 60 %. Most frequently, uveal melanoma metastases are localized in the liver and have an isolated character. At the same time, despite the achievements of modern drug therapy, the treatment results of this category of patients remain unsatisfactory. Among the regional methods of treatment of metastatic uveal melanoma, surgical treatment is considered to be the most effective. Median survival rate in the group of radically operated patients (R0) is 27 months. At present, in the vast majority of cases, surgical treatment is impossible because of multiple bilobar metastasis and advanced cancer process. Median life expectancy of patients with liver metastases is only 9 months. A promising method of regional treatment of inoperable metastatic uveal melanoma is isolated liver chemoperfusion. Multidisciplinary team of Radiology Scientific Research Center and Kostroma Oncologic Dispensary for the first time in Russia presents a clinical case of a patient with isolated inoperable uveal melanoma liver metastases using an innovative method - isolated high-dose chemo hyperthermic liver perfusion with melphalan. The article describes in detail the method of the procedure, estimates immediate (partial response in 1 month after the procedure) and long-term results of the method (stabilization of the condition against the background of immunotherapy in 9 months after surgery). Based on the presented clinical observation, isolated liver chemoperfusion with melphalan for this category of patients is reasonable. However, despite the encouraging immediate results, clinical experience needs to be accumulated in order to be further evaluated in clinical trials.

Phase Ib Study of TAS-102 Plus Radiation Therapy for the Treatment of the Liver in Patients With Hepatic Metastases From Colorectal Cancer

SBRT for liver metastases has emerged as a viable option for treatment of unresectable liver metastases. Among patients with colorectal cancer, however, recent phase II data demonstrated a 1-year local control of 60%, suggesting room for improvement and need for novel strategies to enhance radiosensitivity. TAS 102, an orally administered combination of trifluridine and tipiracil hydrochloride, is an FDA approved regimen for refractor metastatic colorectal cancer. In this study, we evaluated TAS-102 as a radiosensitizer with the goal of improving the efficacy of radiation therapy. In this current abstract, we report the results of the Phase IB study.Patients were enrolled on an investigator-initiated, industry sponsored, prospective, single arm study (NCT03223779). Key eligibility included: histologically confirmed diagnosis of colorectal cancer with 1-4 liver metastases which are deemed unresectable, at least 1 lesion measuring ≥ 1 cm, ECOG PS 0-1, age 18+, and life expectancy > 3 months. Prior treatment including TACE, RFA, and chemotherapy or targeted agents was allowed after a 3-week washout. Prior liver directed RT, including SIRT, was not permitted. Pts were treated with liver RT in 5-6 fractions, delivered 2-4 fractions per week, with RT dose determined by Veff (30-50 Gy in 5 fractions, or 31.8-54 Gy in 6 fractions). TAS 102 dosing occurs on days 1-5 and 8-12. Patients were treated on a 3+3 dose escalation study design, with a starting dose of 20 mg/m2. Dose Limiting Toxicity (DLT) was defined as therapy-related diarrhea, neutropenia, nausea/vomiting, elevation of LFT's, skin toxicity, pain or thrombocytopenia deemed grade ≥ 3. The primary endpoint of the phase Ib component is to determine the maximum tolerated dose (MTD) of TAS-102 when given with SBRT to patients with hepatic metastases from colorectal cancer.From October 2017 to December 2020, 12 patients were enrolled. Median age was 63.5 (range: 32-88), and 7 pts were male (58%). Median RT dose was 50 Gy. On dose level 1 (20 mg/m2 BID), 3 patients were enrolled, none of whom experienced a dose limiting toxicity (DLT). Three patients were enrolled on dose level 2 (25 mg/m2 BID). Two patients completed treatment per protocol, however, the third patient was treated at a reduced dose, on dose level 1, due to elevated bilirubin on C1D1 prior to treatment start and safety concerns. Per protocol design, a fourth patient was enrolled on dose level 2 without toxicity. The third cohort (30 mg/m2 BID) has enrolled 5 patients; 3 have completed treatment as planned, and 2 stopped drug early due to diarrhea (n = 1) and thrombocytopenia (n = 1), both unrelated to study treatment. Of 12 patients, 2 have completed active follow-up, 3 are active in follow-up, and 7 have died. Per protocol design, one more patient is to be enrolled in dose level 3 prior to opening the Phase II portion.In our phase IB study, the MTD dose of TAS-102 with concurrent liver RT is expected to be 30 mg/m2. A phase II study is subsequently planned.

Complications Following Irinotecan-Loaded Microsphere Chemoembolization of Colorectal Metastatic Liver Lesions Associated with Hepatic-Artery Branch Temporary Stasis.

Chemoembolization with irinotecan-loaded microspheres has proven effective in the treatment of unresectable liver metastases in the course of colorectal cancer (CRC). Most researchers recommend slowly administering the embolizate at the level of the lobar arteries, without obtaining visible stasis. However, there are reports of a relationship between postoperative embolizate retention in metastatic lesions and the response to treatment. To retain residual embolizate throughout the entire neoplastic lesion requires a temporary flow stop (stasis) within all supply vessels, which may cause temporary stasis in subsegmental or even segmental vessels. Objective: To assess the risk of complications and post-embolization syndrome severity following chemoembolization of CRC metastatic liver lesions with microspheres loaded with Irinotecan, with regard to hepatic-artery branch level of temporary stasis. Patients and methods: The study included 52 patients (29 female, 23 male) with liver metastases from CRC, who underwent 202 chemoembolization treatments (mean: 3.88 per patient) with microspheres loaded with 100 mg irinotecan. Postembolization syndrome (PES) severity and complication occurrence were assessed with regard to the hepatic-artery branch level of temporary stasis. Adverse events were assessed according to Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events. Results: Median survival from the start of chemoembolization was 13 months. From 202 chemoembolization sessions, 15 (7.4%) significant complications were found. The study found a significant relationship between the branch level of temporary stasis and the presence of complications (p < 0.001), with the highest number of complications observed with temporary stasis in segmental vessels. PES was diagnosed after 103 (51%) chemoembolization treatments. A significant association was found between PES severity and the branch level of temporary stasis (p < 0.001). Conclusions: The branch level of temporary stasis affected the severity of post-embolization syndrome. A significant association was found between the branch level of temporary stasis obtained in chemoembolization procedures and the presence of complications. The apparent lack of change in numbers of complications when stasis was applied at tumor supply vessels or subsegmental arteries may indicate the safe use of temporary stasis in some cases where colorectal cancer metastases are treated. Further research is needed to determine the most effective chemoembolization technique.

Side Effect/Complication Risk Related to Injection Branch Level of Chemoembolization in Treatment of Metastatic Liver Lesions from Colorectal Cancer.

Purpose: Transarterial chemoembolization with drug eluting beads (DEB-TACE) loaded with irinotecan despite having proven efficacy in the treatment of unresectable liver metastases in the course of colorectal cancer (CRC) does not have an established consistent method. In particular, there are discrepancies in the branch level at which microspheres are administered. Lobar embolization supplies microspheres to all vessels supplying a metastatic lesion but exposes the entire liver parenchyma to negative effects from microsphere irinotecan. Superselective chemoembolization compromises healthy liver parenchyma less but may omit small vessels supplying metastatic lesions. Objective: Assessment of the risk of complications and the severity of postembolization syndromes with CRC metastatic liver lesion chemoembolization with irinotecan-loaded microspheres, according to branch level of chemoembolization. Patients and methods: The analysis included 49 patients (27 female/22 male) with liver metastases in the course of CRC, who underwent 192 chemoembolization treatments (mean 3.62 per patient) with microspheres loaded with 100 mg irinotecan. The procedures were performed according to an adopted schema: alternating the right and left lobe of the liver at 3-week intervals. The severity of postembolization syndrome (PES) and the presence of complications were assessed according to the branch level of chemoembolization; microspheres were administered at the branch level of lobar, segmental, or subsegmental arteries. Assessment of adverse events was performed according to the standards of the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events, Version 5.0. Results: The median survival of all patients from the start of chemoembolization was 13 months. With 192 chemoembolization sessions, 14 (7.3%) serious complications were found. The study showed no significant relationship between the branch level of embolizate administration and the presence of complications (p = 0.2307). Postembolization syndrome was diagnosed after 102 chemoembolization treatments, i.e., 53.1% of treatments. A significant correlation was found between the severity of the postembolization syndrome and the branch level of embolization treatment (p = 0.00303). The mean PES severity increased from subsegmental through segmental to lobar administration. Conclusion: Chemoembolization using Irinotecan-loaded microspheres was relatively well tolerated by patients and gave a low risk of significant complications, which did not change with the branch level of microsphere administration. However, an association was found between the branch level of chemoembolization and the severity of postembolization syndrome. Further research is needed to determine the most effective DEB-TACE chemoembolization technique.

A retrospective cohort study of low-dose intensity-modulated radiotherapy for unresectable liver metastases.

ObjectiveTo evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) for the treatment of unresectable liver metastases.MethodsTwenty-five patients with unresectable liver metastases treated with IMRT were enrolled from January 2003 to September 2016. The median longest diameter of the lesions was 3.3 cm (range, 1.6–16.7 cm). The fraction dose ranged from 2 to 5.2 Gy, with a median total dose of 50 Gy (range, 30–60 Gy).ResultsThe median follow-up was 9.2 months (range, 2.1–48.8 months). The overall survival rates at 1 and 2 years were 46.4% and 27.4%, respectively. The 1-year local control rate was 69.8%. The 1-year progression-free survival rate was 26.3%. One patient had grade 4 liver dysfunction. One case of grade 4 leukopenia and one case of grade 3 leukopenia occurred, and one case of grade 3 leukopenia and thrombocytopenia was observed.ConclusionIMRT may be a promising and safe treatment for unresectable liver metastases and can be used as a treatment option.

Abstract No. 686 Retrospective comparison of radiofrequency ablation and microwave ablation for the treatment of colorectal liver metastases

Microwave (MWA) and radiofrequency (RFA) ablation are commonly used for the treatment of unresectable liver metastases from colorectal cancer (CRC). MWA has a few theoretical advantages over RFA (less heat sink, larger ablation zones, faster). However, limited data exists on this field. Our aim was to retrospectively analyse the safety and efficacy of MWA and RFA in the treatment of CRC liver metastases. Patients with unresectable CRC liver metastasis who were treated with RFA or MWA between March 2006 and December 2016 were included. Medical records and imaging studies were reviewed retrospectively for demographic data, to assess for local tumour recurrence and overall survival and to evaluate ablation-related adverse events. 456 ablations were performed in 193 patients (123 men) with a median age of 66 (range 32-91). The majority of patients had a history of surgery of the primary tumour (n=170, 88,1%) and systemic chemotherapy (n=183, 94,8%). 68 patients had a history of liver surgery (35,2%). RFA was used in 343 patients (75,2%), MWA in 113 (24,8%). Median number of procedures per patient was 2 (range 1-10). Median lesion size was 17mm (range 3-80mm). Mean follow-up per lesion was 2.0 years in the RFA group and 1.3 years in the MWA group. Local tumour recurrence rate was 45% for RFA and 28% for MWA, with a hazard ratio of 0.6 in favour of MWA (95%CI 0.4-0.9). Two and five year overall survival rates from time of diagnosis were 88% and 35% for RFA and 89% and 66% for MWA, respectively. Complications were reported in 43 of 456 ablations (9,4%); in 8,2% of RF ablations (n=28) and 13,3% of MW ablations (n=15). Complications classified as CTCAE grade 3 or higher were: haemothorax requiring surgery (n=1 for RFA), biloma (n=2 for RFA and MWA), biliary stricture (n=2 for RFA, n=1 for MWA), liver failure (n=2 for RFA), liver abscess (n=1 for RFA), pneumonia (n=2 for RFA) and pulmonary embolism (n=1 for RFA). Segmental portal vein occlusion was only seen with MWA (n=2). One patient died due to multi-organ failure post RFA. MWA could achieve better local tumour control compared with RFA in the treatment of CRC liver metastasis, with a slightly higher complication rate.

Percutaneous radiofrequency versus microwave ablation for the treatment of colorectal liver metastases.

401 Background: Microwave (MWA) and radiofrequency (RFA) ablation are commonly used for the treatment of unresectable liver metastases from colorectal cancer (CRC). MWA has a few theoretical advantages over RFA (active heating, less affected by heat sink effect, larger ablation zones, faster) however limited data exists on this field. Our aim was to analyse the safety and efficacy of MWA and RFA in the treatment of CRC liver metastases. Methods: All patients with unresectable CRC liver metastasis who were treated with RFA or MWA in a single center between March 2006 and December 2016 were included. Medical records and imaging studies were reviewed retrospectively for demographic data, to assess for local tumour recurrence and overall survival and to evaluate ablation-related adverse events. Results: 456 ablations were performed in 193 patients (123 men) with a median age of 66 (range 32-91). The majority of patients had a history of surgery of the primary tumour (n=170, 88,1%) and systemic chemotherapy (n=183, 94,8%). 68 patients had a history of liver surgery (35,2%). RFA was used in 343 procedures (75,2%) and MWA in 113 (24,8%). Median number of procedures per patient was 2 (range 1-10). Median lesion size was 17mm (range 3-80mm). Mean follow-up per lesion was 2.0 years in the RFA group and 1.3 years in the MWA group. Local tumour recurrence rate was 45% for RFA and 28% for MWA, with a hazard ratio of 0.6 in favour of MWA (95% CI 0.4-0.9). Two and five year overall survival rates from diagnosis of liver metastasis were 88% and 35% for RFA and 89% and 66% for MWA, respectively. Complications were reported in 43 of 456 procedures (9,4%); In 8,2% of RFAs (n=28) and 13,3% of MWAs (n=15). Complications classified as CTCAE grade 3 or higher were: haemothorax requiring surgery (n=1 for RFA), biloma (n=2 for RFA &amp; MWA), biliary stricture (n=2 for RFA and n=1 MWA), liver failure (n=2 for RFA), liver abscess (n=1 RFA), pneumonia (n=2 for RFA) and pulmonary embolism (n=1 RFA). Segmental portal vein occlusion was only seen with MWA (n=2; 1,8%). One patient died due to multi-organ failure post RFA. Conclusions: MWA could achieve better local tumour control compared with RFA in the treatment of CRC liver metastasis, with slightly higher complication rate.

Single-institution experience of radioembolization with yttrium-90 microspheres for unresectable metastatic neuroendocrine liver tumors.

The aim of this study was to assess the effectiveness of yttrium-90 (90 Y) microspheres for the treatment of unresectable metastatic liver neuroendocrine tumors (NET). From February 2006 to September 2015, 36 patients (19 male and 17 female, age 63.6±9.4years) who underwent 90 Y therapy for unresectable liver metastases of NET were included and analyzed retrospectively. All patients received a variety of treatments before 90 Y therapy. The radiological response, symptoms improvement of carcinoid syndrome, tumor marker changes, complications, side effects/toxicity, survival, and factors related to survival were evaluated and analyzed. Of the 36 patients, the mean delivered dose of 90 Y was 1.8±0.7GBq with a total of 40 treatments. Overall disease control rate was 88.9% (32/36) at 3months following therapy. In 16 patients with carcinoid syndrome, 15 (93.8%) patients had symptomatic improvement. Tumor marker response (5-hydroxyindoleacetic acid [n=7] and chromogranin A [n=13]) at 3months after treatment were as follows: none (n=0, 4), partial (n=6, 7), and complete (n=1, 2). Radiation-induced gastrointestinal ulcers (n=2, 5.6%) were identified. Side effects included fatigue (n=31, 86.1%), anorexia (n=26, 72.2%), nausea (n=15, 41.7%), vomiting (n=14, 38.9%), abdominal pain (n=10, 27.8%), and fever (n=8, 22.2%). The mean follow-up was 27.0±16.4months, with a median survival of 41.0months. Child-Pugh classification (P=0.008) and lymph node metastases (P=0.045) had statistically significant influence on overall survival. Yttrium-90 radioembolization can be effective in the treatment of unresectable liver metastases of NET who failed to respond to other treatments.

Quelle place pour la radioembolisation Yttrium 90 dans le traitement des métastases hépatiques du cancer colorectal ?

In the treatment of unresectable liver metastases of colorectal cancer, radioembolization with SIR-Spheres confirms its place in the treatment of refractory disease with a gain in terms of response, progression-free survival, and also overall survival. In combination with first-line systemic standard chemotherapy (FOLFOX6m±bevacizumab), the results of SIRFLOX study show an improvement in hepatic control (objective response rate and liver progression-free survival) without gain in progression-free survival at any site.

Chemoembolization with drug eluting beads preloaded with irinotecan (DEBIRI) vs doxorubicin (DEBDOX) as a second line treatment for liver metastases from cholangiocarcinoma: a preliminary study.

The aim of our preliminary study was to compare the efficacy of drug-eluting beads preloaded with irinotecan (DEBIRI) vs drug-eluting beads preloaded with doxorubicin (DEBDOX) as second-line treatment of unresectable liver metastases from cholangiocarcinoma (CCA). In 2013, 10 patients affected by multiple liver metastases from CCA, resistant to the first-line chemotherapy regimen, were enrolled: 5 patients were submitted to lobar/segmental transarterial chemoembolization (TACE) with DEBIRI (100-mg irinotecan/1 vial) and 5 patients with DEBDOX (50-mg doxorubicin/1 vial), performed every 3 weeks. Patients treated with DEBIRI received antipain premedication consisting of 30-mg of morphine and 3-4 ml of intra-arterial lidocaine. Complications and efficacy were assessed (response evaluation criteria in solid tumour 1.1). A total of 32 TACE were performed (mean: 3.2 TACE/patient), all well tolerated, with only 1 case of asymptomatic cholecystitis spontaneously recovered. Response rates of patients treated with DEBDOX and DEBIRI were: 4/5 progressive disease and 1/5 partial response vs 2/5 partial response, 2/5 stable disease and 1/5 progressive disease, respectively, with the appearance of variable necrosis percentage. Progression-free survival from the first procedure and progressive disease were 12.67 weeks for DEBIRI and 15.78 weeks for DEBDOX, respectively. Overall survival from time of primary diagnosis was 176 weeks for DEBIRI and 125 weeks for DEBDOX, respectively. In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment for hepatic metastases from CCA. Antipain drug administration and the use of the microcatheter led to a good treatment tolerability and a low complication rate. Advances in knowledge: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment of hepatic metastases from CCA; further studies involving a larger cohort of patients are needed.

A comparative study between Embosphere(®) and conventional transcatheter arterial chemoembolization for treatment of unresectable liver metastasis from GIST.

Transcatheter arterial chemoembolization (TACE) is a standard treatment for hepatocellular carcinoma (HCC) and/or some unresectable liver metastasis tumors. Hypervascular liver metastatic lesions such as metastasis from gastrointestinal stromal tumor (GIST) are an indication for transcatheter arterial embolization (TAE). The purpose of this study was to evaluate the efficacy and safety of Embosphere(®)-TAE (Embo-TAE) in comparison with conventional TACE (cTACE) for the treatment of liver metastasis from GIST. A total of 45 patients who underwent TACE between Aug 2008 and Feb 2013 were enrolled. Patients with GIST who underwent TAE with Embosphere(®) (n=19) were compared with controls who received cTACE (n=26). The primary end points were treatment response and treatment-related adverse events. The secondary end points were progression-free survival (PFS) and overall survival (OS). The treatment response of Embo-TAE group was significantly higher than that of the cTACE group (P<0.001). The PFS was significantly better in the Embosphere(®)-group than in the cTACE group (56.6 and 42.1 weeks, respectively; P=0.003). However, there was no statistically significant difference in liver toxicity between the two groups (P>0.05). The median OS in the Embo-TAE group was longer than that in the cTACE group (74.0 weeks, 95% CI: 68.2-79.8 vs. 61.7 weeks, 95% CI: 56.2-67.2 weeks) (unadjusted P=0.045). The use of Embo-TAE significantly reduced the risk of death in patients with GIST with liver metastases according to the Cox proportional hazards regression model [hazard ratio (HR): 0.149; 95% CI: 0.064-0.475]. TAE with Embosphere(®) showed better treatment response and delayed tumor progression compared with cTACE. There was no significant difference in treatment-related hepatic toxicities. Embo-TAE thus appears to be a feasible and promising approach in the treatment of liver metastasis from GIST.

Hepatic Arterial Infusion with Irinotecan, Oxaliplatin, and Floxuridine plus Systemic Chemotherapy as First-Line Treatment of Unresectable Liver Metastases from Colorectal Cancer

Background: The aim of this study was to evaluate the therapeutic efficacy and safety of hepatic arterial infusion (HAI) with irinotecan, oxaliplatin, and floxuridine as a firstline treatment in patients with unresectable liver metastases of colorectal cancer (CRC). Patients and Methods: Individual patients were treated with irinotecan (120 mg/m²), oxaliplatin (100 mg/m²), and floxuridine (500 mg/m²) via tumorsupplying arteries. Intravenous leucovorin (200 mg/day) and floxuridine (300 mg/m²/day) were given on days 1–3 after the procedure. The therapeutic courses were repeated every 4–8 weeks. Tumor responses, overall survival, and the time to tumor progression were observed. Results: 204 cumulative cycles of chemotherapy were performed for 31 patients (median 7.0). 19 patients achieved a partial response; in 10 patients the disease stabilized, and in 2 patients the disease progressed, producing an overall response rate of 61.3%. The median survival time was 24.8 months, and the median time to tumor progression was 10.1 months. Frequencies of grade 3–4 neutropenia, diarrhea, elevation of serum bilirubin, elevation of serum transaminases, and vomiting were 6.5, 9.7, 3.2, 19.4, and 90.3%, respectively. Conclusion: This triplecombination chemotherapy as firstline treatment through HAI was well tolerated and effective in patients with unresectable liver metastases of CRC.

First human study in treatment of unresectable liver metastases from colorectal cancer with irinotecan-loaded beads (DEBIRI)

The objective of this pilot clinical study was to assess the safety, technical feasibility, pharmacokinetic (PK) profile and tumour response of DC Bead™ with irinotecan (DEBIRI™) delivered by intra-arterial embolisation for the treatment of metastatic colorectal cancer. Eleven patients with unresectable liver metastases from CRC, tumour burden <30% of liver volume, adequate haematological, liver and renal function, performance status of <2 were included in this study. Patients received up to 4 sessions of TACE with DEBIRI at 3-week intervals. Feasibility of the procedure, safety and tumour response were assessed after each cycle. PK was measured after the first cycle. Patients were followed up to 24 weeks. Only mild to moderate adverse events were observed. DEBIRI is a technically feasibile procedure; no technical complications were observed. Average Cmax for irinotecan and SN-38 was 194 ng/ml and 16.7 ng/ml, respectively, with average t½ of 4.6 h and 12.4 h following administration of DEBIRI. Best overall response during the study showed disease control in 9 patients (2 patients with partial response and 7 with stable disease, overall response rate of 18%). Our study shows that transarterial chemoembolisation with irinotecan-loaded DC beads (DEBIRI) is safe, technically feasible and effective with a good PK profile.

Selecting the best targeted agent in first‐line treatment of unresectable liver metastases from colorectal cancer: does the bench have the answers?

For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micrometastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent (anti-EGFR or anti-VEGF) to reach these goals. Therefore, a priori molecular identification of patients that could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the currently approved targeted therapies for metastatic colorectal cancer) is of critical importance. In this setting, the KRAS mutation status was the first identified predictive marker of response to anti-EGFR therapy. Since it has been demonstrated that tumors with KRAS mutation do not respond to anti-EGFR therapy, KRAS status must be determined prior to treatment. Thus, for KRAS wild-type patients, the choices that remain are either anti-VEGF or anti-EGFR. In this review, we present the most updated data from translational research programs dealing with the identification of biomarkers for response to targeted therapies.

Irinotecan Drug-Eluting Beads in the Treatment of Chemo-Naive Unresectable Colorectal Liver Metastasis with Concomitant Systemic Fluorouracil and Oxaliplatin: Results of Pharmacokinetics and Phase I Trial

PurposeThe primary objective of this study is to evaluate the safety, tolerance, and pharmacokinetic profile of liver-directed therapy with drug-eluting beads irinotecan (DEBIRI) in combination with systemic modified FOLFOX in the treatment of unresectable liver metastases in chemotherapy-naive patients with colorectal cancer. DesignDEBIRI, loaded with 100 mg irinotecan (100–300μm beads), was administered via hepatic artery during the off week of FOLFOX therapy. Primary endpoints were safety, tolerance, systemic dose-limiting toxicities, and pharmacokinetics of systemic irinotecan and its active metabolite SN-38 at each infusion at 1-, 4-, and 24-h post-DEBIRI. Secondary endpoints were response rate and survival. ResultsThe ten patients have undergone at least 12 cycles of FOLFOX in combination with at least two DEBIRI bead treatments during the patients’ off week. Pharmacokinetic data has demonstrated minimal detectable levels of irinotecan (18.6, 21, and 18.6 ng/ml) and SN-38 (1.06, 1.47, and 1.55 ng/ml) after the first, second, and third DEBIRI treatments, respectively. Currently, there has been only one severe device-related adverse event, a grade 3 hypertensive episode that required 1 day of observation in the hospital. The initial 9- and 12-month response rates have been 100 % (2 CR, 8 PR). Four (40 %) patients were successfully downstaged to resection and/or ablation with a median overall survival of 15.2 months. ConclusionConcomitant DEBIRI and FOLFOX±bevacizumab is safe, with a minimal adverse event rate, no dose-limiting toxicities, and enhanced overall response rate.

Stereotactic Radiotherapy: An Emerging Treatment for Unresectable Liver Metastases from Colorectal Cancer

Stereotactic Radiotherapy: An Emerging Treatment for Unresectable Liver Metastases from Colorectal Cancer