Therapy For Liver Metastases Research Articles

Identifying liver metastasis-related hub genes in breast cancer and characterizing SPARCL1 as a potential prognostic biomarker.

The liver is the third most common metastatic site for advanced breast cancer (BC), and liver metastases predict poor prognoses. However, the characteristic biomarkers of BC liver metastases and the biological role of secreted protein acidic and rich in cysteine-like 1 (SPARCL1) in BC remain unclear. The present study aimed to identify potential biomarkers for liver metastasis of BC and to investigate the effect of SPARCL1 on BC. The publicly available GSE124648 dataset was used to identify differentially expressed genes (DEGs) between BC and liver metastases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to annotate these DEGs and understand the biological functions in which they are involved. A protein-protein interaction (PPI) network was constructed to identify metastasis-related hub genes and further validated in a second independent dataset (GSE58708). Clinicopathological correlation of hub gene expression in patients with BC was determined. Gene set enrichment analysis (GSEA) was performed to explore DEG-related signaling pathways. SPARCL1 expression in BC tissues and cell lines was verified by RT-qPCR. Further in vitro experiments were performed to investigate the biological functions of SPARCL1 in BC cells. We identified 332 liver metastasis-related DEGs from GSE124648 and 30 hub genes, including SPARCL1, from the PPI network. GO and KEGG enrichment analyses of liver-metastasis-related DEGs revealed several enriched terms associated with the extracellular matrix and pathways in cancer. Clinicopathological correlation analysis of SPARCL1 revealed that its expression in BC was associated with age, TNM stage, estrogen receptor status, progesterone receptor status, histological type, molecular type, and living status of patients. GSEA results suggested that low SPARCL1 expression in BC was related to the cell cycle, DNA replication, oxidative phosphorylation, and homologous recombination. Lower expression levels of SPARCL1 were detected in BC tissues compared to adjacent tissues. The in vitro experiments showed that SPARCL1 knockdown significantly increased the proliferation and migration of BC cells, whereas the proliferation and migration were suppressed after elevating the expression of SPARCL1. We identified SPARCL1 as a tumor suppressor in BC, which shows potential as a target for BC and liver metastasis therapy and diagnosis.

Enforced dual-specificity tyrosine-regulated kinase 2 expression by adenovirus-mediated gene transfer inhibits tumor growth and metastasis of colorectal cancer.

Colorectal cancer is one of the most common gastrointestinal tumors with good outcomes; however, with distant metastasis, the outcomes are poor. Novel treatment methods are urgently needed. Our in vitro studies indicate that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) functions as a tumor suppressor in colorectal cancer by regulating cell survival, proliferation, and apoptosis induction. In addition, DYRK2 expression is decreased in tumor tissues compared to nontumor tissues in colorectal cancer, indicating a correlation with clinical prognosis. In this context, we devised a novel therapeutic strategy to overexpress DYRK2 in tumors by adenovirus‐mediated gene transfer. The present study shows that overexpression of DYRK2 in colon cancer cell lines by adenovirus inhibits cell proliferation and induces apoptosis in vitro. Furthermore, in mouse subcutaneous xenograft and liver metastasis models, enforced expression of DYRK2 by direct or intravenous injection of adenovirus to the tumor significantly inhibits tumor growth. Taken together, these findings show that adenovirus‐based overexpression of DYRK2 could be a novel gene therapy for liver metastasis of colorectal cancer.

Small Interfering RNA in Colorectal Cancer Liver Metastasis Therapy.

Colorectal cancer (CRC) is associated with numerous genetic disorders and cellular abnormalities, and liver metastasis is a common health concern in patients with CRC. Exploring newer and more efficient therapies to block liver metastasis is pivotal for prolonging patient survival. Therefore, small interfering RNAs (siRNAs) are expected to be remarkable tools capable of regulating gene expression by participating in a process called RNA interference (RNAi). RNAi is a biological process among eukaryotes wherein specific messenger RNA (mRNA) molecules are destroyed and gene expression is inhibited. This technology is a promising therapeutic agent in the treatment of CRC liver metastasis (CRLM). Nevertheless, crucial problems in siRNA therapeutics, including inherent poor serum stability and nonspecific uptake into biological systems, must be recognized. For this reason, delivery systems are being developed in an attempt to solve these problems. Here, we discuss the utility of siRNA therapy for the treatment of CRCLM by targeting the major metastasis-related signaling pathways. siRNA therapy has the potential to be one of the most effective methods for CRLM treatment in the future.

Clinical Effectiveness of Hypofractionated Proton Beam Therapy for Liver Metastasis From Breast Cancer.

BackgroundFew studies of proton beam therapy (PBT) for patients with liver metastasis from breast cancer (LMBC) are available to date. The aim of the present study was to evaluate the clinical effectiveness of PBT for patients with LMBC.Material and MethodsSeventeen patients with LMBC treated with PBT were included in this study. The median prescribed dose of PBT was 66 GyE (range, 60–80) in 10 fractions, 5 times a week. In patients with LMBC receiving PBT, freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) rates were assessed.ResultsThe median follow-up time was 34.2 months (range, 11.5–56.1). The median FFLP time was not yet reached, and the 3-year FFLP rates were 94.1% (95% confidence interval [CI], 82.9–105.3). The median times of PFS and OS were 7.9 months (95% CI, 5.3–10.5) and 39.3 months (95% CI, 33.2–51.9), respectively, and the 3-year PFS and OS rates were 19.6% (95% CI, -1.8–41.0) and 71.7% (95% CI, 46.8–96.6), respectively. Grade 3 or higher adverse events were not observed.ConclusionPBT for patients with LMBC showed promising FFLP and OS with safe toxicity profiles. These findings suggest that PBT can be considered a local treatment option in patients with LMBC.

155: Outcomes of Stereotactic Ablative Radiation Therapy for Liver Metastases from Colorectal Carcinoma

155: Outcomes of Stereotactic Ablative Radiation Therapy for Liver Metastases from Colorectal Carcinoma

Artificial Intelligence-Based Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Quantitative Evaluation of the Efficacy of Targeted Therapy for Liver Metastasis from Colon Cancer and Nursing

The purpose of this study was to quantitatively evaluate the targeted treatment and nursing effect of patients with liver metastasis of colon cancer by enhanced magnetic resonance imaging. First, Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) images were restored. 35 patients with liver metastases from colon cancer were selected as research subjects and treated by bevacizumab, and high-quality nursing methods were used to improve the psychophysiology of the patients. Enhanced CT examination and DCE-MRI scan were performed before and after the treatment. After the image was processed by the artificial intelligence algorithm, apparent diffusion coefficient (ADC), measurement transmission constant (Ktrans), reflux constant (Kep), extravascular extracellular volume fraction (Ve), and other data on the image were recorded. Two months after the treatment, 35 patients were divided into effective and ineffective groups. It was found that, after treatment, the Kep value and Ktrans value of the effective group were significantly reduced, showing statistically significant differences, and the P value was less than 0.05, and the Kep value and Ktrans value of the ineffective group showed no significant changes. The Ve value of the two groups gradually decreased with the progress of the treatment. In the effective group, the Ve values before the treatment, on the third day after the treatment, and on the seventh day after treatment were (0.235 ± 0.134), (0.338 ± 0.116), and (0.457 ± 0.097), respectively. Compared with the Ve values of the ineffective group, there was a statistical difference, F = 3.592, P = 0.0245 ; the ADC value was negatively correlated with the Ktrans and Kep values, and the results were statistically significant. It was concluded that the above indicators are effective in evaluating the efficacy of the targeted therapy of liver metastasis from colon cancer, and DCE-MRI is of great significance in predicting the efficacy of targeted therapy of liver metastasis from colon cancer.

Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases.

Simple SummaryUveal melanoma is a cancer that develops from melanocytes in the eye. This disease is extremely rare and has a strong predilection for liver metastasis, which has a poor long-term prognosis with overall survival of 6 months and 1 year mortality of 80%. Immunotherapy and checkpoint inhibitors have revolutionized treatment for cutaneous melanoma but have largely been proven to be ineffective in uveal melanoma. The poor response associated with systemic chemotherapy and immunotherapy approaches coupled with the fact that most metastatic disease is isolated to the liver suggests a persistent need for regional treatment approaches. Of regional therapies, hepatic perfusion continued to be associated with the best survival outcomes of up to 27 months. Additional therapies that target the unique biology of uveal melanoma are desperately needed. Until these treatments are developed and proven, isolated hepatic perfusion remains a viable treatment option.Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.

H101 treatment of hepatic metastasis of colorectal cancer with recombinant human adenovirus 5 injection: A phase I clinical trial-TROJAN 021.

3605 Background: Recombinant human adenovirus serotype 5 injection (H101), obtained through genetic engineering to delete the E1B domain and part of the E3 domain and then selectively replicated in tumor cells, has been approved in 2005 for the local treatment of nasopharyngeal carcinoma and head and neck cancers. This trial aimed to evaluate the safety and the preliminary treatment efficacy of H101 combined with standard treatments in patients with liver metastases from colorectal cancer. Methods: In this phase 1, dose-escalation trial (ChiCTR1900027922), 17-75 years old colorectal cancer patients with unresectable liver metastases that failed to first-line therapy were included at The Tenth People's Hospital Affiliated to Tongji University between 2018.9 and 2020.12. All patients received H101 combined with standard therapy (bevacizumab + mFOLFOX6/FOLFIRI). Ultrasound-guided injection of H101 into the liver metastases was performed for all patients, with one of the following doses: 5×1011 vp/injection for the low, 1×1012 vp/injection for the moderate, 2×1012 vp/injection for the moderate-high, and 3×1012 vp/injection for the high dose groups. Intravenous infusion of bevacizumab (5 mg/kg) and administration of standard-dose mFOLFOX6 or FOLFIRI within 48 h after the intratumor injection was performed. The primary endpoint of the trial was the maximum tolerated dose (MTD). The secondary endpoints included safety, tumor responses, and tumor marker CEA. The adverse events (AEs) were monitored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) and evaluated within 1 week after injection. Imaging examinations were performed for all patients to evaluate the tumor responses, according to the irRECIST. Results: Finally, 8 patients were included; the numbers of patients in the 4 groups were 1, 3, 3, and 1, respectively. MTD was not observed in this study. No grade >4 AEs were observed. The major AE included fatigue (5/8), fever (4/8), shiver (3/8), abdominal pain (3/8), and night sweat (3/8). The tumor responses included partial response in one patient (moderate dose group), stable disease in 6 patients (1, 1, 3, and 1 in the low, moderate, moderate-high, and high dose groups, respectively), and progressive disease in 1 patient (moderate group). No dose-effect response was found. The tumor marker CEA was reduced in 6 of the 8 patients, including 1 (1/1), 3 (3/3), 2 (2/3), and 0 patients in the low, moderate, moderate-high, and high-dose groups, respectively. Conclusions: The safety of H101 combined with standard therapy for liver metastases from colorectal cancer is acceptable, which also shows certain preliminary efficacy. The phase 2 trial is now ongoing. Clinical trial information: ChiCTR1900027922. [Table: see text]

The role of selective internal radiation therapy for liver metastases from pancreatic adenocarcinoma after progression on prior chemotherapy.

e16272 Background: Selective internal radiation therapy (SIRT) has established benefit for liver metastases in colorectal cancer. Very little data exists on the use of SIRT for liver dominant metastatic pancreatic cancer. A 2015 phase II trial by Gibbs et al suggested that SIRT at diagnosis may be beneficial in liver metastases in pancreatic cancer, particularly in those who have had a previous primary resection. Methods: In this single-institute retrospective audit we identified eleven patients who had liver predominant metastatic adenocarcinoma of the pancreas who received SIRT at any stage of their treatment. Data was analysed from our electronic patient databases. Results: 11 patients with adenocarcinoma of the pancreas, who had SIRT following progression on chemotherapy were identified. 3 had a primary surgical resection. All patients had received a minimum of one line of chemotherapy and had ECOG performance status of 2 or less. The median time from diagnosis to SIRT was 13 months (range 5-24 months). Patients received Yttrium-90 microspheres with a median activity of 2.1GBq with all eleven receiving concurrent infusional 5-FU 225mg/m2/day for 7 days prior and 14 days after. The median survival after SIRT therapy was 6 months (range 2-19 months). The median overall survival from diagnosis was 20 months (range 12-31 months). SIRT appeared safe and well-tolerated with no associated 30 day all-cause mortality. One patient developed radiation induced asymptomatic portal hypertension and liver cirrhosis. Conclusions: This is the first report of the use of SIRT with radiosensitising concurrent infusional 5FU for metastatic pancreatic cancer after failure of prior chemotherapy. We conclude that SIRT with concurrent infusional 5FU offers an additional treatment option for patients with liver dominant metastatic pancreatic cancer, who maintain a good PS who have progressed on prior lines of chemotherapy. This can provide a durable treatment response and requires further exploration.

Stereotactic body radiation therapy for liver metastasis from colorectal cancer: size matters.

We analysed our initial experience with SBRT in liver metastasis from colorectal cancer at our institution. Between January/2014 and December/2017, 22 patients with 31 LMCCR were treated. Local control (LC) was assessed using the Kaplan-Meier and log-rank tests. We analysed potential prognostic factors for LC: sex, PTV size, number of LM and the radiation scheme. Median age: 69years. Prior chemotherapy or local liver treatments: 81.8% and 63.6% of patients, respectively. SBRT consisted of 3 × 20Gy (42.9%) and 3 × 15Gy (31.4%). There were 88.5% responses (57.1% CR and 31.4% PR). Median follow-up was 30months. LC per lesion at 12 and 24months was 85.3% and 61.8%, respectively. Tumour volumes > 30cc correlated with worsened 2-year-control rates (90% vs 34.5%) (p = 0.005). There was only a patient with CTC-grade 3 toxicity. LiverSBRTis a safe and effective treatment that achieves high local control rates. We found a significant correlation between larger LMCRC and worse local control.

Clinical and genomic factors associated with outcome following ablative radiotherapy for oligometastatic and oligoprogressive liver tumors.

515 Background: There is increasing use of ablative radiotherapy (RT) for oligometastatic and/or oligoprogressive cancer, but the population who may benefit from this more aggressive treatment remains poorly defined. We aimed to identify factors associated with improved outcomes following ablative RT for oligometastatic/oligoprogressive liver tumors. Methods: We retrospectively analyzed 106 patients who had tumor genomic profiling and received a 5, 6, or 15-fraction course of ablative RT for liver metastases from 2008-2019. The interval off systemic therapy post-RT was calculated for patients who did not continue treatment through RT. Overall survival (OS) was estimated using the Kaplan-Meier method. The association between clinical and genomic variables and OS were assessed using uni- and multivariable Cox regression. Results: Median follow-up was 12.6 months. Median age was 61.3 years and 57% were male. The most common primary site was colorectum (42%), followed by pancreas (25%) and non-small cell lung cancer (10%). 42% had colorectal adenocarcinoma, 46% had other adenocarcinoma, and 12% had other histology. A BRAF/RAS family mutation (KRAS, NRAS, and/or BRAF) was present in 41%, 69% had > 1 metastasis, and 38% had extra-hepatic disease. Median biological effective dose (α/β = 10) (BED) was 92 Gy. The RT field encompassed all liver metastases in 91%, and 11% received radiosensitizing chemotherapy. Median time off systemic agents was 5 months. Patients with 1 vs > 1 metastasis had a longer interval off systemic therapy (9 vs 4 months, p = 0.026). Median OS was 12.6 months. The table shows the multivariable Cox model for OS. Conclusions: Presence of a BRAF/RAS family mutation, extra-hepatic metastases, exclusion of liver metastases from RT fields, lower BED, and concurrent radiosensitizing chemotherapy were associated with worse OS. This may inform patient selection and RT delivery for aggressive local therapy for liver metastases. [Table: see text]

Local coagulation / ablation therapies for liver metastases – Microwave

Local coagulation / ablation therapies for liver metastases – Microwave

Current status of local ablation therapy for liver metastasis -Radiofrequency ablation therapy-

Microwave and radiofrequency ablation are very effective local treatment for patients with liver metastasis. In the worldwide, it has been widely used alone or in combination with other treatments such as hepatectomy and chemotherapy for patients with various conditions. However, there is no evidence of ablation therapy for patient with liver metastasis. This time, we researched the current status and usefulness of local ablation therapy for metastatic liver cancer from the past literature, and discuss future issues.

Single-cell transcriptome analysis reveals tumor immune microenvironment heterogenicity and granulocytes enrichment in colorectal cancer liver metastases.

Colorectal cancer (CRC) is among the top 3 leading causes of cancer-related deaths, and tumor malignant progression and metastases contribute to the high mortality of advanced CRC. Immune components in the tumor microenvironment can modulate tumor progression and are attractive therapeutic targets. Recently, intra-tumor mutational diversification of colorectal cancer cells at the single cell level was conducted. However, single cell transcriptome analysis of the microenvironment composition and characteristics in CRC liver metastases has yet to be performed. In this study, samples of liver metastasis cancer tissue and adjacent tissue from CRC patients were examined by single cell RNA sequencing. A total of 12 clusters corresponding to 6 cell types, including cancer cells, T cells, myeloid cells, endothelial cells, fibroblasts and B cells, were identified. Expression clustering of 445 cell cluster deregulated genes (CCDGs) identified 6 gene modules and functional enrichment was conducted to analyse the pathways in cancer cell and T cell populations. Next, the clinical significance of the expression of 93 cell cluster specifically deregulated genes (CCSDGs) in tumor-infiltrating immune cells and the correlation of the expression of these genes with patients' survival rates were investigated with the TCGA dataset. Then, the mechanisms for increased proportion of granulocytes in the cancer sample were explored, and abnormal ferroptosis-mediated granulocyte cell death was proposed. Finally, the Wnt signalling pathway was found to be activated and promote granulocytes migration. This single cell RNA sequencing study may shed light on the tumor microenvironment composition and pave the way for CRC liver metastasis therapy.

Long-term survival following multidisciplinary therapy for liver metastasis from pancreatic cancer

Long-term survival following multidisciplinary therapy for liver metastasis from pancreatic cancer

Non-mono-exponential diffusion models for assessing early response of liver metastases to chemotherapy in colorectal Cancer

BackgroundPreoperative chemotherapy is becoming standard therapy for liver metastasis from colorectal cancer, so early assessment of treatment response is crucial to make a reasonable therapeutic regimen and avoid overtreatment, especially for patients with severe side effects. The role of three non-mono-exponential diffusion models, such as the kurtosis model, the stretched exponential model and the statistical model, were explored in this study to early assess the response to chemotherapy in patients with liver metastasis from colorectal cancer.MethodsThirty-three patients diagnosed as colorectal liver metastasis were evaluated in this study. Diffusion-weighted images with b values (0, 200, 500, 1000, 1500, 2000 s/mm2) were acquired at 3.0 T. The parameters (ADCk, K, DDC,α, Dsand σ) were derived from three non-mono-exponential models (the kurtosis, stretched exponential and statistical models) as well as their corresponding percentage changes before and after chemotherapy. The difference in above parameters between the response and non-response groups were analyzed with independent-samples T-test (normality) and Mann–Whitney U-test (non-normality). Meanwhile, receiver operating characteristic curve (ROC) analyses were performed to assess the response to chemotherapy.ResultsSignificantly lower values of K (the kurtosis coefficient derived from the kurtosis model) and σ (the width of diffusion coefficient distribution in the statistical model) (P < 0.05) were observed in the respond group before treatment, as well as higher ΔK and Δσ values (P < 0.05) after the first cycle of chemotherapy were also found compared with the non-respond group. ROC analyses showed the K value acquired before treatment had the highest diagnostic performance (0.746) in distinguishing responders from non-responders. Furthermore, the high sensitivity (100%) and accuracy (76.3%) from the K value before treatment was found in assessing the response of colorectal liver metastasis to chemotherapy.ConclusionsThe non-mono-exponential diffusion models may be able to predict early response to chemotherapy in patients with colorectal liver metastasis.

Stereotactic Body Radiation Therapy for Liver Metastases

In this review, the current state of stereotactic body radiation therapy (SBRT) is presented as a local therapy for patients with oligometastatic, oligoprogressive and oligorecurrent liver metastases - focusing on recent publications from German-speaking countries. In addition to precise imaging, modern SBRT techniques also use gating and tracking techniques that have made local therapy of liver metastases more effective. In combination with optimisation of central tumour dose, local control rates of up to 90% have been achieved with minimal side effects in less than 1% of patients and 5-year survival rates of more than 30% in selected (inoperable) patient populations. In future, hybrid ultrasound or MRI irradiation systems can overcome fiducial marker implantation. Due to the current outcome data, SBRT is a valuable addition to the therapeutic armamentarium for patients with liver metastases and is a true alternative to minimally invasive ablative procedures or can be used in combination with other local or systemic treatments in an interdisciplinary context.

Mixed response to osimertinib and the beneficial effects of additional local therapy.

BackgroundAlthough non‐small cell lung cancers (NSCLCs) harboring EGFR mutations initially respond well to EGFR‐tyrosine kinase inhibitors (TKIs), they typically progress after approximately one year. The EGFR T790M mutation is the most common resistance mechanism. NSCLCs with T790M respond well to osimertinib; however, the heterogeneity of NSCLCs may limit the efficacy. Some patients exhibit a mixed response (MR), in which some lesions shrink and others progress, but little is known of the incidence and characteristics of such a response. We sought to determine the frequency and clinical course in MR patients.MethodsWe retrospectively reviewed the records of patients who had received osimertinib for NSCLC with EGFR T790M.ResultsBetween April and December 2016, 48 patients were administered osimertinib. Seven patients (15%) exhibited one of two MR types: (i) progressive lesions that did not include the re‐biopsy site (5 patients), and (ii) progressive lesions that included the re‐biopsy site (2 patients). The most frequent progressive sites were liver and lung metastases (4 patients). Three patients continued osimertinib following an MR, one of whom had received local therapy for liver metastasis and achieved disease control on osimertinib for an additional four months.ConclusionAn MR was detected in 15% of NSCLC patients with T790M. This finding suggests that several different resistance mechanisms are active within a single patient who develops resistance to EGFR‐TKIs. Osimertinib is basically effective for tumors that acquire resistance to EGFR‐TKIs as a result of T790M mutation. Therefore, additional local therapy may be beneficial for patients who develop an MR to osimertinib.

Computed tomography or contrast-enhanced ultrasonography for follow-up of liver metastases after Cyberknife therapy?: A prospective pilot study.

Contrast-enhanced ultrasonography (CEUS) allows the study of vascularization of secondary liver lesions. The Cyberknife (Accuray, Inc, Sunnyvale, CA) is a therapeutic method that allows a tumor target to be subjected to a high radiant dose gradient. This prospective pilot study aimed to demonstrate the concordance of CEUS versus contrast-enhanced computed tomography (CECT) in determining the stability or disease progression of secondary liver lesions after treatment with the Cyberknife. Twenty-four patients were consecutively enrolled, and 3 different operators evaluated the CEUS images and the intermodality concordance with CECT. All patients received CEUS at 1 and 2 months after the Cyberknife therapy. The intermodality agreement was evaluated by the Cohen κ coefficient and a multivariate analysis according to the method of Janson and Olsson (Educ Psychol Meas 2001; 61:277-289). Forty secondary liver lesions were detected and treated. Forty-one CECT and 51 CEUS examinations were performed without any adverse events in the 24 patients. The intermodality agreement rates, calculated for the operators as Cohen κ values, were κ = 1.00, 0.881, and 0.767, respectively. The multivariate analysis of intermodality agreement showed an almost perfect value (ι = 0.841). This pilot study found excellent diagnostic correspondence between CEUS and CECT in the evaluation of local disease stability or progression after Cyberknife therapy in liver metastases. These findings suggest that CEUS could play an important role in the surveillance of these patients because of its high accuracy and reproducibility, thus reducing the need for CECT.

Additional hepatic 166Ho-radioembolization in patients with neuroendocrine tumours treated with 177Lu-DOTATATE; a single center, interventional, non-randomized, non-comparative, open label, phase II study (HEPAR PLUS trial)

BackgroundNeuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE.MethodsThe HEPAR PLUS trial (“HolmiumEmbolizationParticles forArterialRadiotherapyPlus177Lu-DOTATATE inSalvage NET patients”) is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30–48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry.DiscussionThis is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects.Trial registrationClinicaltrials.gov NCT02067988, 13 February 2014. Protocol version: 6, 30 november 2016.