Unresectable Hepatic Metastases Research Articles

In brief: Melphalan (Hepzato) for uveal melanoma.

The alkylating agent melphalan (Hepzato – Delcath) has been approved by the FDA for treatment of uveal melanoma in adults with unresectable hepatic metastases that affects <50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.

Abstract No. 247 Transarterial radioembolization (TARE) versus transarterial chemoembolization (TACE) for the treatment of low-grade neuroendocrine tumors

For patients with unresectable hepatic metastases caused by low-grade neuroendocrine tumors (carcinoid), liver-directed arterial therapies have the potential to provide disease control and/or symptom palliation with a low risk of complications. Although carcinoid has long been regarded as a radioresistant tumor type, more recent studies have shown radiation to be effective in significantly decreasing carcinoid tumor burden and controlling carcinoid syndrome. The goal of this study was to use the TriNetX platform to determine if Y-90 trans-arterial radioembolization (TARE) treatment of carcinoid tumors is noninferior to trans-arterial chemoembolization (TACE).

Selective internal radiation therapy for hepatic metastases of uveal melanoma: a systematic review.

Uveal melanoma (UM) commonly metastasizes to the liver. Treatment usually consists of liver-directed therapies, such as selective internal radiation therapy (SIRT). This review aimed to assess the effectiveness and safety of SIRT for hepatic metastases from UM. The study protocol is available at OSF (https://osf.io/vhyct/). EMBASE and MEDLINE were searched until July 2020, using terms related to SIRT and hepatic metastases from UM. Studies reporting outcomes of SIRT in patients with UM and at least one hepatic metastasis were included. Data on overall survival (OS), hepatic progression free survival (hPFS) or tumor response were collected. The Newcastle-Ottawa Scale (NOS) was used to assess risk of bias. 11 studies were included, reporting outcomes for 268 patients with hepatic metastases from UM. Most studies (n = 9, 81.8%) were retrospective. Disease control was achieved in 170 patients (67.5%) and the median OS from time of SIRT was 12.3 months. Median hPFS was 5.4 months. Low-grade side-effects were common but serious complications were infrequent. There were two treatment-related deaths. The median NOS score was 6 (moderate risk of bias). SIRT appears to be a safe and effective treatment for patients with unresectable hepatic metastases from UM. The certainty of our results is unclear due to predominantly retrospective data with moderate risk of bias. Further prospective studies are required to explore the role of SIRT in UM. SIRT appears to be a safe treatment for patients with unresectable hepatic metastases from UM. Further prospective work is required.

Laparoscopic Gastrojejunostomy for the Treatment of SIRT-Induced Duodenal Ulcer Complicated by Gastric Outlet Obstruction

AbstractSelective internal radiation therapy (SIRT) is an emerging therapeutic modality in patients with unresectable hepatocellular carcinoma or liver metastases. However, complications can occur due to migration of radiation microspheres such as gastrointestinal ulcer, cholecystitis, bleeding, pancreatitis, and many others. A 50-year-old woman with stage IV breast cancer who underwent radioembolization for unresectable hepatic metastasis 6 months ago presented to our hospital with 1 month history of nausea, vomiting, with food intolerance, and weight loss. Esophagogastroduodenoscopy showed large deep duodenal bulbar ulcer along with antral ulcerations and edematous gastropathy. Biopsies revealed typical black, duodenal yttrium-90 sphere, documenting radiation injury. After she was discharged on proton pump inhibitor, the patient came back 1 month later for exacerbation of symptoms; computed tomography scan of the abdomen showed gastric outlet obstruction. Although there is no consensus in treating radiation-induced ulcers, physicians should be aware of this complication in patient who underwent SIRT presenting for abdominal pain.

Role of Surgical Approach to Synchronous Colorectal Liver Metastases: A Retrospective Analysis.

PurposeThis study is a retrospective analysis of exploring the efficiency of surgical management on patients with synchronous colorectal liver metastasis (SCLM).Patients and MethodsNine hundred fifty-three consecutive patients with SCLM from Weifang People’s Hospital of Shandong Province between January 2006 and December 2015 were reviewed. The values of different factors were analyzed, such as different surgical indications of liver metastases, simultaneous or staged resection of primary colorectal cancer and liver metastases, and primary tumor resection (PTR) of asymptomatic patients with unresectable liver metastases.ResultsMedian survival time (47.3 months) and 5-year survival rate (31%) for patients with resected liver metastases were significantly superior to that of with nonoperative treatment (17.2 months, 4%, P<0.001); enlarging the standard of liver metastases resection can improve the resection rates (31.0% vs 13.6%, P<0.001); for patients with resectable liver metastases, the in-hospital cost for simultaneous resection group was lower than that in the staged resection group (36,698 vs 45,134 RMB, P<0.001); for patients of the asymptomatic primary tumor with unresectable liver metastases, PTR was associated with improved median survival (18.0 vs 15.0 months, P=0.006).ConclusionFor patients with SCLM, liver resection is considered the best treatment; expanding indications of liver resection can improve the resection rates. Simultaneous resection of the primary tumor and liver metastases were indicated in patients with resectable SCLM; PTR was recommended for asymptomatic patients with unresectable hepatic metastases.

Current Status of Biologics in Perioperative Treatment for Resectable or Borderline Resectable Liver Metastases

This review provides an overview of the current role of biologics, anti-vascular endothelial growth factor (VEGF) inhibitors and anti-epidermal growth factor receptor (EGFR) inhibitors, in the perioperative treatment of colorectal liver metastases as well as a discussion of their future trends. Over the past decade, a number of clinical trials have suggested that the use of biologics with cytotoxic agents may increase median overall survival in certain subsets of patients with colorectal liver metastases. The benefit of these agents is limited to borderline resectable and unresectable hepatic metastases and is not seen in upfront resectable disease. In the RAS wild-type population, the difference in efficacy of VEGF and EGFR inhibitors in combination with chemotherapy is minimal. These agents perform differently depending on primary tumor location; bevacizumab has greater efficacy in right-sided tumors, whereas cetuximab has greater efficacy in left-sided tumors. While biologics benefit patients in the neoadjuvant setting, studies have not shown similar results in the adjuvant setting. Given the variability of patient presentations as well as the risk of treatment-related toxicity, the addition of biologics requires careful consideration of patient’s medical fitness, surgical risk, and tumor profile.

Liver transplantation in the treatment of unresectable hepatic metastasis from neuroendocrine tumors.

Neuroendocrine tumors (NET) are rare neoplasms with generally indolent growth behavior. The liver is the most common site of NET metastasis. The NET metastatic spread to the liver are usually multiple tumors involving bilateral hemilivers. For patients with isolated NET metastasis to the liver, a complete extirpation (R0) resection of both the primary NET and liver metastasis provide the best chance of tumor recurrence-free patient survival. Orthotopic liver transplantation (OLT) presents a viable treatment option for patients with unresectable liver metastasis from NET. Post-OLT outcomes for the patients of NET with liver metastasis (5-year overall survival rate 47-71%) are comparable to those for other indications. However, the high rate of recurrence after OLT (31-57%) remains a clinical obstacle. As such, it is imperative to consider each patient individually and identify prognostic factors that would impact post-OLT outcomes. This article focuses on the role of OLT in the definitive treatment of metastatic liver NET, review patient selection criteria predictive of survival outcomes and post-OLT outcomes for patients.

Phase Ib trial of gemcitabine with yttrium-90 in patients with hepatic metastasis of pancreatobiliary origin.

Gemcitabine, a chemotherapy for hepatic metastasis with pancreatic cancer (PC) or intrahepatic cholangiocarcinoma (ICC) origin, may radiosensitize the targeted tumor cells for yttrium-90 radioembolization (90Y-RE). This clinical trial was designed to investigate the effects of a combination of 90Y-RE and gemcitabine in hepatic metastasis of PC or ICC origin. Fourteen patients who had histopathologic diagnosis of unresectable hepatic metastasis of PC or ICC origin were enrolled into the open-label phase Ib clinical trial. Induction dose of gemcitabine on day 1 was followed by 90Y-RE on day 2 with predetermined doses of gemcitabine to follow till week 12. Maximal tolerated dose (MTD) of gemcitabine in combination with 90Y-RE, associated toxicities and hepatic progression free survival (HPFS) were assessed. The tumor response rate was evaluated using both RECIST and PERCIST criteria. Eight patients met the study criteria; three with PC and five with ICC. The mean age of the patients was 69.4 years. Seven out of 8 patients tolerated predetermined gemcitabine regime (dose level 1 at 400 mg/m2 and dose level 2 at 600 mg/m2). All of the patients developed grade 1 toxicities. Three patients (37.5%) had grade 2 hepatobiliary toxicity and one patient (12.5%) had grade 3 hepatobiliary toxicity, who was hospitalized for a short-term. The median HPFS was 8.7 months for all patients. The objective response rate was 62%. A combination of 90Y-RE and gemcitabine at 600 mg/m2 is a safe and potential treatment option for hepatic metastasis of pancreaticobiliary origin.

Clinical characteristics and treatments outcomes of patients with metastatic uveal melanoma (UM) in a Brazilian population: A retrospective unicentric study.

e21018 Background: Uveal melanoma is the most common primary ocular tumor in adults and accounts for 5% of all melanoma diagnoses in the United States. Approximately fifty percent of patients with uveal melanoma develop metastatic disease. The most frequent site of metastasis from UM is the liver (89 to 95% of the cases) and liver failure is the leading cause of death. To date, no systemic therapy has shown benefits in terms of overall survival (OS) in UM. Methods: We retrospectively analyzed clinical characteristics and aspects of response to systemic and local therapy of a cohort of 58 patients with UM who were treated in our institution from January of 2000 to December of 2017. Survival curves were calculated by Kaplan-Meier method and log-rank test. Results: Median age was 55y. 64% of the patients were female and 48,3% of them were caucasian. With a median follow-up time of 23 months, the median OS was 28,4 months. The median time between primary treatment and systemic relapse was 3.7 years. In 90% of the cases the liver was the unique site of progression. 12% patients had liver metastasectomy as local treatment, with OS of 102,3 months vs. 24,5 months ( p= 0,04) for no local treatment. 12% of the patients with liver methastasis perfomed regional treatment with intra-arterial chemotherapy (IAC) and 17% with chemoembolization (CE). The progression free survival (PFS) for regional treatment was 2.9 months (0,9-27 m); 4,25 months (0,9-27 m) for IAC and 2,9 months (0,9-27 m) for CE. There was no significant benefit in OS for locorregional treatment. As first line treatment, 29% of patients had chemotherapy, 10% had ipilimumab and 3,4% had anti-PD1. The median PFS for first line treatment was 2,49 months; 2 months for chemotherapy, 3,8 months for ipilimumab and 14 months for anti-PD1. The median PFS for second line treatment was 2,8 months and for third line was 2,3 months. There was no consistent clinical impact in OS for systemic treatment. Conclusions: The current systemic treatments available for cutaneous melanoma have limited efficacy in UM, so far none have yet proven a survival benefit. Locorregional therapies are relevant for patients with unresectable hepatic metastases. Resection of liver lesions in highly selected cases has the potential to improve patient outcomes, but the survival advantage may partially reflect patient selection.

Significant clinical response of advanced colorectal cancer to combination therapy involving capecitabine and adoptive cell transfer therapy: a case report

Significant clinical response was obtained in a patient with stage IV colorectal cancer (CRC) following combination therapy involving capecitabine and adoptive cell transfer therapy. She had laparoscopic lower anterior resection and left liver metastatic carcinoma resecting in 20th, February, 2017. Capecitabine was used to further treatment for an unresectable hepatic metastasis. The serum level of carcinoembryonic antigen (CEA) was increased significantly after dropped temporarily. Since then, the patient took the adoptive cell transfer therapy at the same time. αβT cells and NK cells were injected intravenously into the patient. After the first transfusion with αβT cells, the tumor biomarker, CEA, dropped obviously from 14.7 to 6.1 ng/mL. And it came to 1.9 ng/mL after four times treatment, which was back into normal range (<5 ng/mL). Flow cytometry (FCM) was used to reveal the detailed immunological status of this patient before and after adoptive cell transfer therapy. With 19-month follow-up, neither recurrence or complication was founded. Combination therapy involving adoptive immunotherapy and capecitabine may be the potential method for advanced CRC with less complication.

Embolotherapy for Neuroendocrine Tumors

AbstractThe most frequent solid organ involved in metastatic neuroendocrine tumors (NET) is the liver. Hepatic metastases occur during the lifetime of 46% to 93% of patients with NETs. Intra-arterial embolotherapies are palliative and should be used for patients with unresectable disease not amenable to resection or ablation. The most widely accepted indications for liver embololization for NET metastases are progression of unresectable hepatic metastases threatening liver function and palliation of hormone-related symptoms uncontrolled by somatostatin analogues. This article will discuss patient selection and administration of all embolotherapies currently used for palliation of neuroendocrine liver metastases.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Combined Effects of Yttrium-90 Transarterial Radioembolization around Immunotherapy for Hepatic Metastases from Uveal Melanoma: A Preliminary Retrospective Case Series

PurposeTo evaluate the safety and efficacy of yttrium-90 (90Y) transarterial radioembolization (TARE) around immunotherapy in patients with unresectable hepatic metastases from uveal melanoma (UM). Materials and MethodsFrom March 2013 to December 2017, 11 patients with unresectable hepatic metastases from UM were treated with TARE around immunotherapy. Two patients received TARE as a first-line treatment followed by immunotherapy. Nine patients received immunotherapy before TARE, and 6 of these patients received additional immunotherapy after TARE. Retrospective review of the clinical data was performed to assess hepatic progression-free survival (hPFS), overall survival (OS), treatment response, and toxicities. The median follow-up period from TARE was 10.5 months (range 1–35.5 months). ResultsThe median OS from diagnosis of hepatic metastases was 35.5 months (95% confidence interval [CI] 10.0–55.0 months). The median hPFS and OS from the start of TARE were 15.0 months (95% CI 5.9–24.1 months) and 17.0 months (95% CI 1.8–32.2 months), respectively. Complete response was observed in 1 patient (9.1%), partial response in 2 (18.2%), stable disease in 4 (36.4%), and progressive disease in 4 (36.4%). Ten patients had grade 1 or 2 clinical toxicities, and 1 had grade 3 with a peptic ulcer. Six patients had grade 1 or 2 biochemical toxicities and 1 had grade 3, which was related to tumor progression. ConclusionsThe present results suggest that TARE around immunotherapy is safe and effective. The combined treatment may improve hPFS and OS in patients with hepatic metastases from UM.

Treatment effect of conversion therapy and its correlation with VEGF expression in unresectable rectal cancer with liver metastasis.

To investigate the therapeutic effect of conversion therapy and its correlation with vascular endothelial growth factor (VEGF) expression in unresectable rectal cancer with liver metastasis. A total of 116 cases of unresectable rectal cancer patients with liver metastasis were randomly divided into control and observation group, 58 cases in each group, all of these patients were treated by conversion therapy, patients in control were treated by FOLFOXIRI treatment program, and in observation group were treated by FOLFOXIRI program treatment and bevacizumab. Efficacy and adverse reactions were compared between the two groups, the levels of VEGF in portal vein and the expression of VEGF in cancer tissue were compared, after 5 years of follow-up, the prognosis of the two groups were observed. Objective efficiency and conversion rate of observation was significantly higher than the control group, survival rate of postoperative observation was significantly higher than that of control group (P>0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). The positive rate of VEGF in portal vein blood and the expression of VEGF in the observation was significantly lower than that in the control group (P<0.05). The 5-year survival rate of VEGF high expression was significantly lower than that of VEGF low expression group (P<0.05). FOLFOXIRI combined with bevacizumab in patients with unresectable hepatic metastasis of rectal cancer can provide higher conversion rate and hepatectomy opportunities, and reduce VEGF expression in patients with unresectable rectal cancer, which is closely related to VEGF expression, therefore it is beneficial to better local control and to improve long-term survival.

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors.

Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan-Meier estimation. 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n=11; colorectal carcinoma n=2; pancreatic adenocarcinoma n=2; periampular carcinoma n=2; breast and endometrial cancer each n=1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema. Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumours: A single-centre experience after 54 treatments.

e15625 Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT Delivery System; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumours while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyse the safety and efficacy of the second generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Methods: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Results: A total of 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors (ocular melanoma [OM] n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1) and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumours had durable disease stabilisation (40%). Median OS, PFS and hPFS were 261, 117 and 135 days, respectively. Tumour volume negatively correlated with OS. Complications and toxicites included thrombopenia, cardiovascular events, ulcerous bleeding and edema. Conclusions: Second generation CS-PHP seems to be effective and tolerable. Patient selection based on tumour volume end entity is of importance. Particularly patients with OM and hepatobiliary tumours represent promising candidates for CS-PHP.

Liver Transplant for Nonhepatocellular Carcinoma Malignancy.

Liver transplant is now an acceptable and effective treatment for specific nonhepatocellular malignancies. Worldwide, hilar cholangiocarcinoma accounts for 3% of all primary gastrointestinal malignancies and for 10% of primary hepatobiliary malignancies. For patients who have early-stage, unresectable cholangiocarcinoma, liver transplant preceded by neoadjuvant radiotherapy can result in tumor-free margins, accomplish a radical resection, and treat the underlying primary sclerosing cholangitis when present. Hepatic epithelioid hemangioendothelioma is a rare tumor of vascular origin with a variable malignant potential. Excellent results have been reported with liver transplant for patients with unresectable hepatic epithelioid hemangioendothelioma, with 1-year and 10-year survival rates of 96% and 72%. Hepatoblastoma is the most common primary hepatic malignancy in children. The long-term survival rate after transplant ranges from 66% to 77% in patients with unresectable tumors and good response to chemotherapy. Metastatic liver disease is not an indication for liver transplant, with the exception of cases in which the primary tumor is a neuroendocrine tumor. Indication for liver transplant for hepatic metastasis from neuroendocrine tumors is mainly for patients with unresectable tumors and for palliation of medically uncontrollable symptoms. Posttransplant survival in those patients with low tumor activity index is excellent, despite recurrence of the tumor. Some recent data on liver transplant for unresectable hepatic metastases from colorectal cancer have reported limited survival benefits compared with previous reports. However, due to the high rate of tumor recurrence in a very short time after liver transplant, especially in the era of organ shortage, this indication has not been favored by the transplant community. The indications for liver transplant for nonhepatocellular carcinoma malignancy and its limitations have evolved dramatically over the past decades and will continue to be redefined through future research and investigations.

Abstract No. 501 - Y90 radioembolization with Occlusafe catheter infusion system in patients with unresectable hepatic metastasis

Abstract No. 501 - Y90 radioembolization with Occlusafe catheter infusion system in patients with unresectable hepatic metastasis

Chemosaturation with Percutaneous Hepatic Perfusion in Unresectable Hepatic Metastases

In patients with hepatic metastases from solid-organ malignancies, surgical resection may be a potentially curative option, but it is not possible in most cases. Chemosaturation with percutaneous hepatic perfusion was developed for the management of unresectable metastases to the liver. Relevant medical literature was summarized with regard to the outcomes and limitations of chemosaturation with percutaneous hepatic perfusion. Six articles were identified that contained data on 91 individuals who received chemosaturation with percutaneous hepatic perfusion. More than 60% of these study patients were diagnosed with ocular melanoma. The overall response rate was 48% and the rate of disease control was 90%. Chemosaturation with percutaneous hepatic perfusion improved the rates of overall and hepatic progression-free survival (PFS). The data are limited but suggest that the rate of PFS was improved in study patients with isolated melanoma hepatic metastases who received chemosaturation with percutaneous hepatic perfusion compared with those assigned to standard care. Our results suggest that chemosaturation with percutaneous hepatic perfusion produces favorable tumor response rates in select individuals with unresectable hepatic metastases from multiple primary cancers, particularly ocular and cutaneous melanomas. Data from a single randomized clinical trial have also shown that chemosaturation with percutaneous hepatic perfusion can affect hepatic PFS in certain patients.

Chemosaturation Percutaneous Hepatic Perfusion: A Systematic Review.

The Hepatic CHEMOSAT® Delivery System is an innovative medical device for the treatment of patients with unresectable primary liver tumors or unresectable hepatic metastases from solid organ malignancies. This system is used to perform chemosaturation percutaneous hepatic perfusion (CS-PHP), a procedure in which a high dose of the chemotherapeutic agent melphalan is delivered directly to the liver while limiting systemic exposure. In a clinical trial program, CS-PHP with melphalan significantly improved hepatic progression-free survival in patients with unresectable hepatic metastases from ocular or cutaneous melanoma. Clinically meaningful hepatic responses were also observed in patients with hepatocellular carcinoma or neuroendocrine tumors. Furthermore, the results of published studies and case reports demonstrated that CS-PHP with melphalan resulted in favorable tumor response rates in a range of tumor histologies (ocular or cutaneous melanoma, colorectal cancer, and hepatobiliary tumors). Analyses of the safety profile of CS-PHP revealed that the most common adverse effects were hematologic events (thrombocytopenia, anemia, and neutropenia), which were clinically manageable. Taken together, these findings indicate that CS-PHP is a promising locoregional therapy for patients with primary and secondary liver tumors and has a acceptable safety profile. Funding: Delcath Systems Inc., New York, NY, USA.