• Diffusion-weighted MRI
• apparent diffusion coefficient
• colorectal carcinoma
• radioembolization

• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Liver Neoplasms/therapy
• Liver Neoplasms/secondary
• Liver Neoplasms/pathology
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/diagnostic imaging
• Male
• Female
• Prognosis
• Aged
• Middle Aged
• Yttrium Radioisotopes/therapeutic use
• Tumor Burden
• Embolization, Therapeutic/methods
• Aged, 80 and over
• Adult
• ROC Curve
• Retrospective Studies
• Treatment Outcome

• Humans
• Yttrium Radioisotopes/administration & dosage
• Liver Neoplasms/secondary
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Embolization, Therapeutic
• Female
• Male
• Aged
• Middle Aged
• Treatment Outcome
• Tumor Microenvironment
• Prospective Studies
• Radiopharmaceuticals/administration & dosage
• Time Factors
• Microsatellite Instability
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Forkhead Transcription Factors/metabolism
• Biopsy
• Antigens, Differentiation, Myelomonocytic/metabolism
• Tumor-Associated Macrophages/immunology
• Tumor-Associated Macrophages/metabolism
• CD68 Molecule

• dosimetry
• eye90
• holmium
• radioembolization
• selective internal radiation therapy

• HCC
• MCP-1
• biomarker
• diagnosis
• prognosis

• 13GW0473A Federal Ministry of Education and Research (BMBF) via the STIMULATE Research Campus

• hepatocellular carcinoma
• portal hypertension
• transarterial radioembolization

• 90Y-dosimetry
• TARE
• hepatocellular carcinoma
• radioembolization
• retrospective analysis

• Dosimetry
• Hepatocellular carcinoma
• Radioembolization
• Yttrium-90

• Humans
• Carcinoma, Hepatocellular/pathology
• Yttrium Radioisotopes/therapeutic use
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/drug therapy
• Microspheres
• Radiopharmaceuticals/therapeutic use
• Embolization, Therapeutic/methods
• Glass

Purpose

The study aimed to evaluate the adverse event (AE) and hepatotoxicity profile, including radioembolization induced liver disease (REILD), following repeat radioembolization (RE) to the same or overlapping vascular territories in patients with hepatocellular carcinoma (HCC) and limited functional hepatic reserve/cirrhosis.

Methods

Nine patients (seven male and two female; median age, 66 years) with cirrhosis and HCC who underwent repeat RE (cycle 1 and cycle 2) between January 2012 and August 2019 were included. Patient demographics, clinical and treatment history, and pertinent laboratory values were recorded at baseline and post-treatment time points over a period of four months. Post-RE AE/hepatotoxicity was assessed, organized by type and frequency, and graded by severity according to the National Cancer Institute common terminology criteria for adverse events, version 5.0 (CTCAE v5.0). To assess rudimentary comparisons for post-RE hepatotoxicity vs. factors of interest, Spearman's rank correlation/rho was calculated, and all relevant plots were constructed. Kaplan-Meier analysis was performed along with associated median survival time. All statistical analyses were performed with Stata v16.1.

Results

Following cycle 1, 22 objective AE were identified according to CTCAE v.5 (17 grade I, four grade II, and one grade III), with grade I, II, and III AE experienced by 78%, 33%, and 11% of patients, respectively. Following cycle 2, 19 objective AE were identified according to CTCAE v.5 (11 grade I, seven grade II, and one grade III), with grade I, II, and III AE experienced by 89%, 56%, and 11% of patients, respectively. A single patient developed REILD after cycle 1, which progressed to fatal REILD following cycle 2. Following cycle 2, an additional patient advanced from less severe hepatotoxicity to REILD. Following cycle 2, positive correlations between the higher model for end-stage liver disease (MELD; rho=0.70) and Child-Pugh (rho=0.74) scores and degree of post-RE hepatotoxicity/REILD appear to emerge. Post-repeat RE median overall survival was 12.5 months.

Conclusion

Post-RE hepatotoxicity following repeat RE to the same or overlapping vascular territories in patients with limited functional hepatic reserve/cirrhosis is a common occurrence with variable severity ranging from transient laboratory derangement to fatal REILD. Lack of a consensus REILD definition and grading scale results in non-uniform reporting of incidence as well as clinical and laboratory features of the disease process. Strides aimed at improving clinical characterization, forming a more complete diagnostic definition, and establishing a uniform grading system with respect to REILD are of particular importance and would ultimately improve repeat RE patient selection and risk management. 

This study aims to better characterize potential responders of Y-90-radioembolization at baseline through analysis of clinical variables and contrast enhanced (CE) MRI tumor volumetry in order to adjust therapeutic regimens early on and to improve treatment outcomes.

Fifty-eight HCC patients who underwent Y-90-radioembolization at our center between 10/2008 and 02/2017 were retrospectively included. Pre- and post-treatment target lesion volumes were measured as total tumor volume (TTV) and enhancing tumor volume (ETV). Survival analysis was performed with Cox regression models to evaluate 65% ETV reduction as surrogate endpoint for treatment efficacy. Univariable and multivariable logistic regression analyses were used to evaluate the combination of baseline clinical variables and tumor volumetry as predictors of ≥ 65% ETV reduction.

Mean patients’ age was 66 (SD 8.7) years, and 12 were female (21%). Sixty-seven percent of patients suffered from liver cirrhosis. Median survival was 11 months. A threshold of ≥ 65% in ETV reduction allowed for a significant (p = 0.04) separation of the survival curves with a median survival of 11 months in non-responders and 17 months in responders. Administered activity per tumor volume did predict neither survival nor ETV reduction. A baseline ETV/TTV ratio greater than 50% was the most important predictor of arterial devascularization (odds ratio 6.3) in a statistically significant (p = 0.001) multivariable logistic regression model. The effect size was strong with a Cohen’s f of 0.89.

We present a novel approach to identify promising candidates for Y-90 radioembolization at pre-treatment baseline MRI using tumor volumetry and clinical baseline variables.

• A decrease of 65% enhancing tumor volume (ETV) on follow-up imaging 2–3 months after Y-90 radioembolization of HCC enables the early prediction of significantly improved median overall survival (11 months vs. 17 months, p = 0.04).

• Said decrease in vascularization is predictable at baseline: an ETV greater than 50% is the most important variable in a multivariable logistic regression model that predicts responders at a high level of significance (p = 0.001) with an area under the curve of 87%.

The online version contains supplementary material available at 10.1007/s00330-022-08585-x.

• Carcinoma, hepatocellular
• Survival analysis
• Treatment outcome
• Tumor burden
• Yttrium radioisotopes

• Barcelona Clinic Liver Cancer
• chemoembolization
• hepatocellular carcinoma
• interventional radiology
• radioembolization

• anti-PD1
• immunotherapy
• selective internal radiation therapy
• uveal melanoma

Radioembolization has failed to prove survival benefit in randomized trials, and, depending on various factors including tumor biology, response rates may vary considerably. Studies showed positive correlations between survival and absorbed tumor dose. Therefore, increasing currently prescribed tumor doses may be favorable for improving patient outcomes. The dominant limiting factor for increasing RE dose prescriptions is the relatively low tolerance of liver parenchyma to radiation with the possible consequence of a radiation-induced liver disease. Advances in RILD prevention may help increasing tolerable radiation doses to improve patient outcomes. Our study aimed to evaluate the impact of post-therapeutic RILD-prophylaxis in a cohort of intensely pretreated liver metastatic breast cancer patients. The results of this study as well as pathophysiological considerations warrant further investigations of RILD prophylaxis to increase dose prescriptions in radioembolization.

Background: Radioembolization (RE) with yttrium-90 (⁹⁰Y) resin microspheres yields heterogeneous response rates in with primary or secondary liver cancer. Radiation-induced liver disease (RILD) is a potentially life-threatening complication with higher prevalence in cirrhotics or patients exposed to previous chemotherapies. Advances in RILD prevention may help increasing tolerable radiation doses to improve patient outcomes. This study aimed to evaluate the impact of post-therapeutic RILD-prophylaxis in a cohort of intensely pretreated liver metastatic breast cancer patients; Methods: Ninety-three patients with liver metastases of breast cancer received RE between 2007 and 2016. All Patients received RILD prophylaxis for 8 weeks post-RE. From January 2014, RILD prophylaxis was changed from ursodeoxycholic acid (UDCA) and prednisolone (standard prophylaxis [SP]; n = 59) to pentoxifylline (PTX), UDCA and low-dose low molecular weight heparin (LMWH) (modified prophylaxis (MP); n = 34). The primary endpoint was toxicity including symptoms of RILD; Results: Dose exposure of normal liver parenchyma was higher in the modified vs. standard prophylaxis group (47.2 Gy (17.8–86.8) vs. 40.2 Gy (12.5–83.5), p = 0.017). All grade RILD events (mild: bilirubin ≥ 21 µmol/L (but <30 μmol/L); severe: (bilirubin ≥ 30 µmol/L and ascites)) were observed more frequently in the SP group than in the MP group, albeit without significance (7/59 vs. 1/34; p = 0.140). Severe RILD occurred in the SP group only (n = 2; p > 0.1). ALBI grade increased in 16.7% patients in the MP and in 27.1% patients in the SP group, respectively (group difference not significant); Conclusions: At established dose levels, mild or severe RILD events proved rare in our cohort. RILD prophylaxis with PTX, UDCA and LMWH appears to have an independent positive impact on OS in patients with metastatic breast cancer and may reduce the frequency and severity of RILD. Results of this study as well as pathophysiological considerations warrant further investigations of RILD prophylaxis presumably targeting combinations of anticoagulation (MP) and antiinflammation (SP) to increase dose prescriptions in radioembolization.

• RILD
• prophylaxis
• radiation induced liver disease
• radioembolization

Hepatocellular carcinoma (HCC) is difficult to diagnose at an early stage, and its prognosis is generally poor. Sorafenib is the primary treatment for unresectable advanced HCC and targets multiple receptor tyrosine kinases. However, sorafenib only extends the average survival time by 3 months. This observation indicates that sorafenib may need to be combined with other treatments to further improve outcomes. We previously showed that combination of sorafenib with radiotherapy (RT) enhances tumor inhibition in subcutaneous HCC mouse models compared with monotherapy. The present study demonstrated that combining sorafenib and RT could suppress tumor growth in an orthotopic HCC model by regulating apoptosis and NF-κB-related pathways. Moreover, decreased numbers of visible liver tumors and a smaller percentage of spleen metastases were found in the combination group. A transient drop in body weight was initially observed after RT, but progressive recovery of body weight occurred. The current study showed that the combination of sorafenib and RT could be a safe strategy for HCC treatment.

• hepatocellular carcinoma
• orthotopic mouse model
• radiotherapy
• sorafenib

• 90Y-microspheres
• FDG
• Neuroendocrine tumors
• PET
• SPECT
• radioembolization.

• Hepatocellular carcinoma
• Liver cancer
• Radioembolization
• Yttrium-90

• Radioembolization
• Yttrium-90
• liver toxicity

• HCC
• hepatocellular carcinoma
• liver
• locoregional therapy
• radioembolization

• 90Y
• colorectal cancer
• irinotecan-loaded drug-eluting beads
• liver metastases
• microspheres
• radioembolization

• Hepatocellular carcinoma
• Liver metastases
• Locoregional ablation
• Patient selection
• SIRT

• Radioembolization
• biologics
• hepatopulmonary shunt
• liver tumor
• partial liver resection
• radiological liver interventions

• Colorectal cancer
• Liver metastases
• Prognostic score
• Salvage patients
• Y90 radioembolization

• Adult
• Aged
• CA-19-9 Antigen/blood
• Carcinoembryonic Antigen/blood
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Drug Resistance, Neoplasm
• Embolization, Therapeutic/methods
• Female
• Humans
• Kaplan-Meier Estimate
• Karnofsky Performance Status
• Liver/pathology
• Liver Neoplasms/secondary
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Multivariate Analysis
• Neoplasm Metastasis
• Outcome Assessment, Health Care/methods
• Outcome Assessment, Health Care/statistics & numerical data
• Prognosis
• Proportional Hazards Models
• Yttrium Radioisotopes/therapeutic use

• C-arm CT
• Dosimetry
• Glass microspheres
• Resin microspheres
• SIRT
• TARE
• Volumetry

Unresectable primary and secondary liver malignancies present a major problem in the treatment of solid tumors. Transarterial radioembolization (TARE) is an increasingly used technique for treating various types of malignant liver tumors. This approach is appealing, as the mechanism of action is independent from other loco-regional treatments and potentially complementary to systemic therapies. There are two commercially available products in use for TARE: ⁹⁰Y-resin and ⁹⁰Y-glass microspheres. Currently available data indicates TARE so be safe and effective in hepatocellular carcinoma (HCC) and metastatic liver disease. In HCC the results compare well with chemoembolization, while the role of TARE in combination with kinase inhibitors has yet to be established. Current data on TARE in metastatic liver disease is promising, but there is a strong need for prospective randomized trials comparing TARE and modern chemotherapeutic regimen to support the growing role of TARE in metastatic liver disease.

• Hepatocellular carcinoma
• Selective internal radiation therapy
• Radioembolization
• Liver
• Neoplasm
• Metastasis

Radioembolization (RE) is an emerging treatment strategy for patients with primary hepatic malignancies and metastatic liver disease. Though RE is primarily performed in the palliative setting, a shift toward the curative setting is seen. Currently, hepatic resection and in selected cases liver transplantation are the only curative options for patients with a hepatic malignancy. Unfortunately, at diagnosis most patients are not eligible for liver surgery due to the imbalance between the necessary liver resection and the remaining liver remnant. However, in borderline resectable cases, tumor volume reduction and/or increasing the future liver remnant can lead to a resectable situation. The combination of selective tumor treatment, the induction of hypertrophy of untreated liver segments, and its favourable toxicity profile make RE an appealing strategy for downstaging. The present review discusses the possibilities for RE in the preoperative setting as a downstaging tool or as a bridge to liver transplantation.

• Bridge to transplant
• Downstaging
• Future liver remnant
• Radioembolization

• Future liver remnant
• In-situ-split
• Liver hypertrophy induction
• Portal vein embolization
• Yttrium-90-radioembolization

Patients with hepatic metastases who are candidates for Y90-radioembolization (Y90-RE) usually have advanced tumor stages with involvement of both liver lobes. Per current guidelines, these patients have usually undergone several cycles of potentially hepatotoxic systemic chemotherapy before Y90-RE is at all considered, requiring split (lobar) treatment sessions to reduce hepatic toxicity. Assessing response to Y90-RE early, that is, already after the first lobar session, would be helpful to avoid an ineffective and potentially hepatotoxic second lobar treatment. We investigated the accuracy with which diffusion- weighted magnetic resonance imaging (DWI-MRI) and positron emission tomography/computed tomography (PET/CT) can provide this information.

An institutional review board–approved prospective intraindividual comparison trial on 35 patients who underwent fluorodeoxyglucose PET/CT and DWI-MRI within 6 weeks before and 6 weeks after Y90-RE to treat secondary-progressive liver metastases from solid cancers (20 colorectal, 13 breast, 2 other) was performed. An increase of minimal apparent diffusion coefficient (ADCmin) or decrease of maximum standard uptake value (SUVmax) by at least 30% was regarded as positive response. Long-term clinical and imaging follow-up was used to distinguish true- from false-response classifications.

On the basis of long-term follow-up, 23 (66%) of 35 patients responded to the Y90 treatment. No significant changes of metastases size or contrast enhancement were observable on pretreatment versus posttreatment CT or magnetic resonance images.However, overall SUVmax decreased from 8.0 ± 3.9 to 5.5 ± 2.2 (P < 0.0001), and ADCmin increased from 0.53 ± 0.13 × 10⁻³ mm²/s to 0.77 ± 0.26 × 10⁻³ mm²/s (P < 0.0001). Pretherapeutic versus posttherapeutic changes of ADCmin and SUVmax correlated moderately (r = −0.53). In 4 of the 35 patients (11%), metastases were fluorodeoxyglucose-negative such that no response assessment was possible by PET. In 25 (71%) of the 35 patients, response classification by PET and DWI-MRI was concordant; in 6 (17%) of the 35, it was discordant. In 5 of the 6 patients with discordant classifications, follow-up confirmed diagnoses made by DWI. The positive predictive value to predict response was 22 (96%) of 23 for MRI and 15 (88%) of 17 for PET. The negative predictive value to predict absence was 11 (92%) of 12 for MRI and 10 (56%) of 18 for PET. Sensitivity for detecting response was significantly higher for MRI (96%; 22/23) than for PET (65%; 15/23) (P < 0.02).

Diffusion-weighted magnetic resonance imaging appears superior to PET/CT for early response assessment in patients with hepatic metastases of common solid tumors. It may be used in between lobar treatment sessions to guide further management of patients who undergo Y90-RE for hepatic metastases.

We sought to report outcomes and toxicity in patients with hepatocellular carcinoma (HCC) who received resin yttrium-90 selective internal radiation therapy (⁹⁰Y-SIRT) and to identify factors associated with declining liver function.

Patients treated with ⁹⁰Y-SIRT were retrospectively evaluated. Radiographic response was assessed using RECIST 1.1. Median liver progression-free survival (LPFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Bivariate analysis was used to examine associations between change in Child-Pugh (CP) score/class and patient characteristics and treatment parameters.

Twenty-seven patients with unresectable HCC underwent SIRT, 52% were CP Class A, 48% were Class B, 11% were BCLC stage B, and 89% were stage C. Forty-four percent of patients had portal vein thrombus at baseline. One-third of patients received bilobar treatment. Median activity was 32.1 mCi (range 9.18–43.25) and median-­absorbed dose to the liver was 39.6 Gy (range 13.54–67.70). Median LPFS and OS were 2.5 and 11.7 months, respectively. Three-month disease control rate was 63 and 52% in the target lesions and whole liver, respectively. New onset or worsened from baseline clinical toxicities were confined to Grade 1–2 events. However, new or worsened Grade 3–4 laboratory toxicities occurred in 38% of patients at 3 months and 43% of patients at 6 months following SIRT (six had lymphocytopenia, three had hypoalbuminemia, and two had transaminasemia). After 3 months, six patients had worsened in CP score and five had worsened in class from baseline. After 6 months, four patients had worsened in CP score and one had worsened in class from baseline. Pretreatment bilirubinemia was associated with a 2+ increase in CP score within 3 months (P = 0.001) and 6 months (P = 0.039) of ⁹⁰Y-SIRT. Pretreatment transaminasemia and bilirubinemia were associated with increased CP class within 3 months of SIRT (P = 0.021 and 0.009, respectively).

⁹⁰Y-SIRT was well-tolerated in patients with unresectable HCC, with no Grade 3–4 clinical toxicities. However, Grade 3–4 laboratory toxicities and worsened CP scores were more frequent. HCC patients with pretreatment bilirubinemia or transaminasemia may be at higher risk of experiencing a decline in liver function following ⁹⁰Y-SIRT.

• SIRT
• hepatocellular carcinoma
• toxicity
• yttrium-90

• 90Y-radioembolization
• FDG-PET
• breast cancer
• liver metastases
• total lesion glycolysis

• Predictive dosimetry
• Prognosis
• Selective internal radiation therapy

Metastatic spread of the primary is still defined as the systemic stage of disease in treatment guidelines for various solid tumors. This definition is the rationale for systemic therapy. Interestingly and despite the concept of systemic involvement, surgical resection as a local treatment has proven to yield long-term outcomes in a subset of patients with limited metastatic disease, supporting the concept of oligometastatic disease. Radiofrequency ablation has yielded favorable outcomes in patients with hepatocellular carcinoma and colorectal metastases, and some studies indicate its prognostic potential in combined treatments with systemic therapies. However, some significant technical limitations apply, such as size limitation, heat sink effects, and unpredictable heat distribution to adjacent risk structures. Interventional and non-invasive radiotherapeutic techniques may overcome these limitations, expanding the options for oligometastatic patients and cytoreductive concepts. Current data suggest very high local control rates even in large tumors at any given location in the human body. The article focusses on the characteristics and possibilities of stereotactic body radiation therapy, interstitial high-dose-rate brachytherapy, and Yttrium-90 radioembolization. In this article, we discuss the differences of the technical preferences as well as their impact on indications. Current data is presented and discussed with a focus on application in oligometastatic or cytoreductive concepts in different tumor biologies.

• Interstitial brachytherapy
• Minimally invasive interventions
• RFA
• Radiofrequency ablation
• SBRT
• SIRT
• Selective internal radiation therapy
• Stereotactic body radiation therapy
• iBT

• HCC
• liver
• metastasis
• neoplasm
• radioembolization

• endothelial injury
• inflammation
• liver hypertrophy
• liver regeneration
• liver tumours
• radioembolization-induced liver disease

• Drug eluting beads
• Radioembolization
• Transarterial chemoembolization
• Yttrium-90

Background. When associated with isolated four or fewer liver foci, metastatic colorectal cancer is amenable to surgical resection. Alternative therapeutic methods for isolated liver metastases include radioembolization with yttrium 90 (Y90) and transarterial chemoembolization (TACE). We present here a case of a patient with two sites of liver metastatic disease from colorectal cancer who underwent Y90 radioembolization combined with aflibercept and FOLFIRI. Case Report. A 56-year-old female with history of bilateral breast cancer and metastatic colon cancer with prior hemicolectomy and 4 previous chemotherapy regimens developed liver metastasis. She was started on aflibercept and FOLFIRI and concurrently underwent two treatments of radioembolization with Y90, initially targeting the largest right lobe tumor, and then a subsequent treatment targeting the smaller left lobe tumor with retreatment of the right lobe tumor. Her liver metastases exhibited partial response on imaging utilizing the modified RECIST criteria. Interestingly, the patient CEA levels decreased after the procedure. Discussion. This is the first reported case of a patient managed with radioembolization with Y90 combined with aflibercept, an anti-VEGF treatment, and FOLFIRI. An ongoing randomized clinical trial aims to define the role of combined targeted therapy and chemotherapy with radioembolization with Y90.

• HCC
• SIRT
• hepatocellular carcinoma
• radioembolization
• safety
• sorafenib
• survival
• tolerability

We report a case of safe and successful yttrium-90 resin microsphere radioembolization in a patient with a long history of multiple recurrent colon cancer hepatic metastases progressing after hepatic resections, hepatic arterial chemotherapy, and multiple regimens of systemic chemotherapy. One month prior to radioembolization, a biliary stent was placed above the level of the ampulla to relieve tumor-related biliary obstruction and normalize bilirubin levels.