Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

The Post-SIR-Spheres Surgery Study (P4S): Retrospective Analysis of Safety Following Hepatic Resection or Transplantation in Patients Previously Treated with Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres.

BACKGROUND: Reports show that selective internal radiation therapy (SIRT) may downsize inoperable liver tumors to resection or transplantation, or enable a bridge-to-transplant. A small-cohort study found that long-term survival in patients undergoing resection following SIRT appears possible but no robust studies on postsurgical safety outcomes exist. The Post-SIR-Spheres Surgery Study was an international, multicenter, retrospective study to assess safety outcomes of liver resection or transplantation following SIRT with yttrium-90 (Y-90) resin microspheres (SIR-Spheres®; Sirtex). METHODS: Data were captured retrospectively at participating SIRT centers, with Y-90 resin microspheres, surgery (resection or transplantation), and follow-up for all eligible patients. Primary endpoints were perioperative and 90-day postoperative morbidity and mortality. Standard statistical methods were used. RESULTS: The study included 100 patients [hepatocellular carcinoma: 49; metastatic colorectal cancer (mCRC): 30; cholangiocarcinoma, metastatic neuroendocrine tumor, other: 7 each]; 36% of patients had one or more lines of chemotherapy pre-SIRT. Sixty-three percent of patients had comorbidities, including hypertension (44%), diabetes (26%), and cardiopathy (16%). Post-SIRT, 71 patients were resected and 29 received a liver transplant. Grade 3+ peri/postoperative complications and any grade of liver failure were experienced by 24 and 7% of patients, respectively. Four patients died <90 days postsurgery; all were trisectionectomies (mCRC: 3; cholangiocarcinoma: 1) and typically had one or more previous chemotherapy lines and presurgical comorbidities. CONCLUSIONS: In 100 patients undergoing liver surgery after receiving SIRT, mortality and complication rates appeared acceptable given the risk profile of the recruited patients.

Is yttrium-90 radioembolization a viable treatment option for unresectable, chemorefractory colorectal cancer liver metastases? A large single-center experience of 302 patients.

INTRODUCTION: We report the largest series to date on the safety and efficacy of yttrium-90 (90Y) radioembolization for the treatment of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM). METHODS: A total of 302 patients underwent resin-based 90Y radioembolization for unresectable, chemorefractory CRCLM between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the response criteria in solid tumors criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method, and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Median follow-up in the complete cohort was 7.2 months (range 0.2-72.8), and the median survival after 90Y radioembolization was 10.5 months with a 24-month survival of 21%. On imaging follow-up of 293 patients who were followed up beyond 2 months, complete response to treatment was observed in 2 patients (1%), partial response in 111 (38%), stable disease in 96 (33%), and progressive disease in 84 (29%). Four factors were independently associated with a poorer prognosis: extensive tumor volume, number of previous lines of chemotherapy, poor radiological response to treatment, and low preoperative hemoglobin. One hundred fifteen (38%) developed clinical toxicity after treatment; most complications were minor (grade I/II) and resolved without active intervention. CONCLUSIONS: 90Y radioembolization is a safe and effective treatment for unresectable, chemorefractory CRCLM.

Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference.

OBJECTIVES: Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management. METHODS: Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system. RESULTS: Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered. CONCLUSIONS: Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.

Yttrium-90 radioembolization for unresectable, chemoresistant breast cancer liver metastases: a large single-center experience of 40 patients.

INTRODUCTION: There are a paucity of data on the treatment of unresectable, chemoresistant breast cancer liver metastases (BRCLM) with yttrium-90 (Y90) radioembolization. METHODS: Forty patients underwent resin-based Y90 radioembolization for unresectable, chemoresistant BRCLM between 2006 and 2012 in a single institution. All patients were followed up with imaging studies at regular intervals as clinically indicated until death. Radiologic response was evaluated with the Response Criteria in Solid Tumors criteria. Clinical toxicities were prospectively recorded as per the National Cancer Institute Common Toxicity Criteria. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Follow-up was complete in all patients. The median follow-up was 11.2 (range 0.6-30.5) months and the median survival after Y90 radioembolization was 13.6 months, with a 24-month survival of 39 %. On imaging follow-up of 38 patients who survived beyond 1 month of treatment, a complete response (CR) to treatment was observed in two patients (5 %), partial response (PR) in 10 patients (26 %), stable disease (SD) in 15 patients (39 %), and progressive disease (PD) in 11 patients (29 %). Two factors were associated with an improved survival on multivariate analysis: CR/PR to treatment (vs. SD vs. PD; p < 0.001) and chemotherapy after radioembolization (vs. no chemotherapy; p = 0.004). Sixteen patients (40 %) developed clinical toxicity after treatment; all complications were minor grade I/II and resolved without active intervention. CONCLUSION: This study provides supportive evidence of the safety and efficacy on Y90 radioembolization for the treatment of unresectable, chemoresistant BRCLM. Further prospective investigation is required to assess the suitability of this treatment in this population.

Botulinum toxin A in functional popliteal entrapment syndrome: a new approach to a difficult diagnosis.

Functional Popliteal Entrapment Syndrome (FPES) is caused by compression of neurovascular structures in the popliteal fossa by hypertrophic muscles, provoking severe leg pain with exercise. Treatment is limited to myotomy of hypertrophic musculature. 8 FPES patients underwent imaging and exercise studies, before receiving botulinum toxin A injections (BTX-A) into the gastrocnemius and plantaris muscles. 81.3 % of patients reported clinical improvement on follow-up, and pathological ankle-brachial indices were normalized. BTX-A injection may present a new, safe, effective and non-invasive approach to FPES.

Polymerisation of cyanoacrylates: The effect of sclero-embolic and contrast agents.

OBJECTIVES: The objective is to investigate the interaction of sclero-embolic and contrast agents with the polymerisation of medical grade n-butyl-cyanoacrylates. METHODS: An in vitro spectrophotometric absorbance method was developed to detect changes in light transmission to measure n-BCA polymerisation. The initiation and the rate-of-polymerisation of mixtures of n-BCA with sclero-embolic and contrast agents were investigated. RESULTS: Initiation of polymerisation: VENABLOCK™ and HISTOACRYL® were the fastest agents to polymerise, while VENASEAL™ was the slowest. Rate of polymerisation: Hypertonic saline inhibited the polymerisation of all n-BCAs, while hypertonic glucose prolonged the polymerisation rate. ETHANOL and detergent sclerosants had no effect. Contrast agents OMNIPAQUE™ and ULTRAVIST® initiated and prolonged the polymerisation of n-BCA, but in contrast, LIPIODOL® failed to initiate the process. CONCLUSIONS: The commercially available medical cyanoacrylates differ in their polymerisation rates. These polymerisation rates are further affected when these products are used in conjunction with other compounds, such as sclero-embolic and contrast agents.

Radioembolisation of liver metastases.

This review aims to present contemporary data for SIRT in the treatment of secondary hepatic malignancies including colorectal, neuroendocrine, breast and uveal melanoma.

Radioembolization versus standard care of hepatic metastases: comparative retrospective cohort study of survival outcomes and adverse events in salvage patients.

PURPOSE: To retrospectively evaluate the safety and survival of patients with chemotherapy-refractory liver metastases treated with yttrium-90 ((90)Y) resin microspheres, and to compare survival in this patient group versus survival after standard/supportive care to assess whether radioembolization contributes to survival gains in the salvage setting. MATERIALS AND METHODS: While 339 patients with chemotherapy-refractory liver metastases underwent (90)Y microspheres radioembolization at a single institution between 2006 and 2011, 51 patients were referred back to their treating physician for conservative treatment or best supportive care. Adverse events were assessed at the time of treatment and at 1 and 3 months after treatment. Overall survival (OS) was calculated by the Kaplan-Meier method for the radioembolization cohort (as a whole and according to two subcohorts: patients with colorectal primary cancer and patients with all other primary cancers, eg, breast or neuroendocrine) and the standard-care cohort. RESULTS: The median OS after (90)Y radioembolization (339 patients) was 12.0 months, versus 6.3 months for the standard-care cohort (51 patients; P < .001). The median OS times for the two subcohorts were 11.9 months and 12.7 months, respectively. At the 3-month follow-up, the incidence of more serious adverse events was low, with 11 cases (3%) of ulceration, 10 cases (2.9%) of radiation-induced liver disease, and six complications (1.8%) involving the gallbladder (eg, cholecystitis). CONCLUSIONS: The present study suggests that radioembolization shows promise as an effective and safe treatment for patients with chemotherapy-refractory hepatic metastases and improves overall survival in a select population of patients in a salvage setting compared with best supportive care alone.

LIPIODOL reduces the lytic activity of detergent sclerosants in vitro.

OBJECTIVES: Contrast agents are used widely in the interventional setting and in particularly in the management of vascular anomalies and have also been used in combination with sclero-embolic agents. There is limited information on the interaction of contrast agents with sclerosant agents when used as mixtures. The aim of this study was to determine the effect of mixing radiological contrast agents with detergent sclerosants and measuring the effect on change in lytic activity of detergent sclerosants in vitro and by proxy the change in potency. METHODS: Red blood cell lysis was assessed following the incubation of two commonly used contrast agents, LIPIODOL® and ULTRAVIST®, mixed with detergent sclerosants, FIBROVEIN®, sodium tetradecyl sulfate (STS), and AETHOXYSKLEROL®, polidocanol (POL). RESULTS: The density of both contrast agents was higher than STS and POL and neither of the detergent sclerosants were miscible in LIPIODOL. LIPIODOL on its own caused cell lysis (1.01%, p < 0.05) whereas ULTRAVIST did not. Fifty per cent cell lysis for sclerosant and LIPIODOL mix occurred at concentrations of: 0.041% (2.4 times greater than the control, p < 0.05) and 0.08% (3.6 times greater than the control, p = 0.06) for STS and POL, respectively. CONCLUSIONS: LIPIODOL, when mixed with sclerosant detergents (ratio 1:1) causes a reduction in the lytic activity of sclerosants and this effect was statistically significant and most prominent in lower sclerosant concentration mixtures.

Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: a critical appraisal of 48 cases.

BACKGROUND: Yttrium-90 (90Y) radioembolization is a promising treatment option for unresectable neuroendocrine tumor liver metastases (NETLM). This study is the first to evaluate the prognostic variables that influenced radiologic response and survival in patients with unresectable NETLM who were treated with 90Y radioembolization. As a secondary outcome, the impact of this treatment on serologic toxicity was assessed. METHODS: Forty-eight patients underwent resin-based 90Y radioembolization for unresectable NETLM at a single institution between December 2003 and May 2009. Patients were assessed radiologically and serologically at 1 month and then at 3 month intervals after treatment. Prognostic variables that affected response and survival were determined. The impact of this treatment on serologic toxicity over a 6-month period was assessed. DISCUSSION: No patient was lost to follow-up. The median follow-up for the patients who were alive was 41 months. The median survival was 35 months (range: 5-63). On imaging follow-up, 7 patients (15%) had a complete response and 19 patients (40%) had a partial response to treatment. Eleven patients (23%) had stable disease and 11 patients (23%) had progressive disease. Five prognostic factors were associated with an improved survival: complete/partial response (P=0.003), low hepatic tumor burden (P=0.022), female gender (P=0.022), well-differentiated tumor (P=0.001), and absence of extra-hepatic metastasis (P<0.001). Three factors were associated with a complete/partial response: female gender (P=0.040), well-differentiated tumor (P<0.001) and low hepatic tumor burden (P=0.041). There was a significant increase in the level of alkaline phosphatase over the 6-month period (P<0.001). CONCLUSIONS: 90Y radioembolization is a promising treatment option for unresectable NETLM. Patients with low hepatic tumor burden, well-differentiated tumor, female gender, and no extrahepatic disease benefit most from treatment.

A serious complication of selected internal radiation therapy: case report and literature review.

The use of selective internal radiation therapy (SIRT) with SIR-Spheres(R) (Sirtex, Sydney, Australia) is increasingly recognized as a potential therapeutic modality of primary and secondary malignant liver tumors. A number of treatment-related complications have been described despite technical expertise and detailed pretreatment investigations to assess suitability. We describe a case of gastric ulceration from nontargeted deposition of SIR-spheres(R) in the gastric mucosa with life-threatening consequences. This case highlights the need for careful screening and appropriate patient selection, and the need to recognize ulceration from SIRT as a potential complication of treatment. The characteristic endoscopic, radiologic, and histopathologic findings are illustrated and recommendations are reviewed with regard to the current literature.

Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option.

BACKGROUND: There are no treatment options for unresectable intrahepatic cholangiocarcinoma (ICC) with proven efficacy. The objective of this study was to present data on the safety and efficacy of a novel treatment option, yttrium-90 ((90)Y) radioembolization for unresectable ICC. METHODS: Twenty-five patients underwent resin-based (90)Y radioembolization for unresectable ICC between January 2004 and May 2009. Patients were assessed at 1 month and then at 3-month intervals after treatment. Radiologic response was evaluated with the Response Criteria in Solid Tumors (RECIST) criteria. Clinical and biochemical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified. RESULTS: No patient was lost to follow-up. The median follow-up was 8.1 (range, 0.4-56) months and the median survival after (90)Y radioembolization was 9.3 months. Two patients died within 1 month of treatment; the median follow-up for the remaining 23 was 8.9 (range, 1.5-56) months. Two factors were associated with an improved survival: peripheral tumor type (vs. infiltrative, P = .004) and Eastern Cooperative Oncology Group performance status of 0 (vs. 1 and 2, P < .001). On imaging follow-up of 23 patients, a partial response to treatment was observed in 6 patients (24%), stable disease in 11 patients (48%), and progressive disease in 5 patients (20%). The most common clinical toxicities were fatigue (64%) and self-limiting abdominal pain (40%). Two patients (8%) each developed grade III bilirubin and albumin toxicity. One patient (4%) developed grade III alkaline phosphatase toxicity. CONCLUSIONS: (90)Y radioembolization may be a relatively safe and efficacious treatment for unresectable ICC. In the absence of other effective therapeutic options, this treatment warrants further investigation.

Survival outcomes of a salvage patient population after radioembolization of hepatic metastases with yttrium-90 microspheres.

PURPOSE: To determine in a retrospective study the potential benefit on survival outcomes of radioembolization using yttrium-90 ((90)Y) resin microspheres in a cohort of patients presenting with chemotherapy-refractory liver metastases, primarily from colorectal cancer (CRC). MATERIALS AND METHODS: Over 3 years, 249 patients were referred to the authors' center to determine suitability for radioembolization as treatment for hepatic metastases. All patients were defined as salvage, having failed first-line and second-line chemotherapies. These patients were divided into group 1 (CRC) and group 2 (all other cancers, eg, breast, neuroendocrine) and assessed for overall survival (OS) as a whole and according to group. RESULTS: Using (90)Y resin microspheres, 208 patients were treated, undergoing 223 radioembolization treatments. The median OS was 8.3 months for the whole cohort, 7.9 months for group 1, and 8.7 months for group 2. At the 3-month follow-up, there was an overall adverse event rate of 9%. At the end of the data collection period, 62 patients were still alive. CONCLUSIONS: Radioembolization shows promise as an effective and safe treatment for patients with chemotherapy-refractory hepatic metastases providing an extension to survival in the salvage setting.

Radioembolization with yttrium-90 microspheres for pancreatic cancer liver metastases: results from a pilot study.

BACKGROUND: Patients with liver metastases from pancreatic adenocarcinomas have a dismal prognosis. Surgical resection remains the only curative option but is appropriate for only a minority of patients as a treatment option. This is the first study to examine the safety and efficacy of radioembolization with yttirum-90 microspheres for these patients. PATIENTS AND METHODS: All patients with histologically proven pancreatic carcinoma liver metastases referred to a single institution from 2006-2009 were included in the study. After radioembolization, follow-up abdominal computed tomography scans were performed to assess response according to the Response Criteria in Solid Tumors guidelines. RESULTS: Seven patients were identified from our prospectively collected data base. Of the five patients with available computed tomography follow-up, 2 patients achieved a partial response and 1 patient had stable disease. One patient with partial response survived for nearly 15 months after radioembolization therapy. No patient experienced major post-radioembolization complications. CONCLUSIONS: Radioembolization with yttrium-90 microspheres may have a useful role in treating patients with pancreatic carcinoma liver metastases in a multimodality setting. Results of the current study warrant further investigation of this novel treatment.

Radioembolization for hepatocellular carcinoma: current role and future directions - the medical oncologist's perspective.

The incidence and impact of hepatocelluar carcinoma (HCC) continues to increase worldwide. While radical therapies such as resection, radiofrequency ablation or transplantation are potentially curative for patients with early-stage HCC, the majority of patients in routine practice present with more advanced tumors, where treatment goals are palliation and extending survival. With multiple new and promising treatment options emerging for these patients, the challenge for the medical oncologist is how best to integrate these therapies into routine clinical practice. Here we review the most recent data on the efficacy and safety of yttrium-90 radioembolization in HCC, the considerations involved in patient selection, and the optimal assessment and management of patients receiving treatment. We also examine the potential impact of several ongoing clinical trials.

Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review.

BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (ICC) portends a poor prognosis despite standard systemic treatments which confer minimal survival benefits and significant adverse effects. This study aimed to assess clinical outcomes, complications and prognostic factors of TAE therapies using chemotherapeutic agents or radiation. METHODS: A literature search and article acquisition was conducted on PubMed (MEDLINE), OVID (MEDLINE) and EBSCOhost (EMBASE). Original articles published after January 2000 on trans-arterial therapies for unresectable ICC were selected using strict eligibility criteria. Radiological response, overall survival, progression-free survival, safety profile, and prognostic factors for overall survival were assessed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesized by narrative review and quantitative analysis. RESULTS: Twenty articles were included (n=929 patients). Thirty three percent of patients presented with extrahepatic metastases. After treatment, the average rate of complete and partial radiological response was 10% and 22.2%, respectively. Overall median survival time was 12.4 months with a median 30-day mortality and 1-year survival rate of 0.6% and 53%, respectively. Acute treatment toxicity (within 30 days) was reported in 34.9% of patients, of which 64.3% were mild to moderate in severity. The most common clinical toxicities were abdominal pain, nausea and vomiting, and fatigue. Multiplicity, localization and vascularity of the tumor may predict worse overall survival. CONCLUSIONS: Trans-arterial therapies are safe and effective treatment options which should be considered routinely for unresectable ICC. Consistent and standardized methodology and data collection is required to facilitate a meta-analysis. Randomized controlled trials will be valuable in the future.