Angiogenesis in 90Y-Radioembolization of Colorectal Liver Metastases.

In order to evaluate the role of angiogenesis in 90Y-radioembolization for colorectal cancer liver metastasis an overview was provided of angiogenic growth factors and their function, the angiogenic mechanisms in colorectal cancer, the role of hypoxia, and the advances in antiangiogenic therapy. Last, the use of circulating angiogenic growth factors in 90Y-radioembolization was reviewed. Two literature searches were conducted. A search query in PubMed on angiogenesis in colorectal cancer, and a systematic search in PubMed (Medline), Embase, and the Cochrane Library (October 2018) with synonyms for "radioembolization" and "angiogenic growth factor." The first search yielded 3 relevant publications on the role of angiogenic growth factors in colorectal cancer, hypoxia, and antiangiogenic therapy. The second search yielded two prospective studies on circulating angiogenic factors and their relationship with response and survival after 90Y-radioembolization for colorectal cancer liver metastases. Rises in circulating angiogenic growth factors after radioembolization were seen in both studies. High baseline values of Ang-2 and IL-8 correlated with shorter survival and post 90Y-radiembolization rises in Ang-2 and HGF correlated with early progression. Various angiogenic growth factors play a role in the development and progression of colorectal cancer. Several factors show correlation with poor outcomes after 90Y-radioembolization and might be used for patient selection in the future, however, validation in larger comparative studies is required.

Anatomic versus Metabolic Tumor Response Assessment after Radioembolization Treatment.

PURPOSE: To assess applicability of metabolic tumor response assessment on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) after radioembolization (RE) in patients with colorectal liver metastases (CRLM) by comparison with one-dimensional size-based response assessment on MR imaging. MATERIALS AND METHODS: This prospective cohort study comprised 38 patients with CRLM undergoing RE. MR imaging and 18F-FDG PET/CT imaging were performed at baseline, 1 month (n = 38), and 3 months (n = 21). Longest tumor diameter (LTD) reduction on MR imaging at these time points was compared with reduction in total lesion glycolysis (TLG) on 18F-FDG PET/CT. Hepatic response was compared between RECIST and total liver TLG and correlated with overall survival (OS). RESULTS: TLG and LTD were positively correlated in 106 analyzed metastases (38 patients) at 1 month and 58 metastases (22 patients) at 3 months. Agreement was poor, with LTD underestimating TLG response. A significant association with prolonged OS was found in total liver TLG at 1 month (HR 0.64, P < .01) and 3 months (HR 0.43, P < .01). For LTD, a significant association with OS was found at 3 months (HR 0.10, P < .01). Important differences in liver response classification were found, with total liver TLG identifying more patients and situations where there appeared to be treatment benefit compared with RECIST. CONCLUSIONS: TLG response assessment on 18F-FDG PET/CT appears to be more sensitive and accurate, especially at early follow-up, than size-based response assessment on MR imaging in patients with CRLM treated by RE. Semiautomated liver response assessment with total liver TLG is objective, reproducible, rapid, and prognostic.

Insights into the Dose-Response Relationship of Radioembolization with Resin 90Y-Microspheres: A Prospective Cohort Study in Patients with Colorectal Cancer Liver Metastases.

UNLABELLED: Randomized controlled trials are investigating the benefit of hepatic radioembolization added to systemic therapy in the first- and second-line treatment of patients with colorectal liver metastases (CRLM). Remarkably, administered activity may still be suboptimal, because a dose-response relationship has not been defined. The purpose of this study was to characterize the relationship between tumor-absorbed dose and response after (90)Y radioembolization treatment for CRLM. METHODS: Thirty patients with unresectable chemorefractory CRLM were treated with resin (90)Y-microspheres in a prospective phase II clinical trial. Tumor-absorbed dose was quantified on (90)Y PET. Metabolic tumor activity, defined as tumor lesion glycolysis (TLG*) on (18)F-FDG PET, was measured at baseline and 1 mo after treatment. The relationship between tumor-absorbed dose and posttreatment metabolic activity was assessed per metastasis with a linear mixed-effects regression model. RESULTS: Treated metastases (n = 133) were identified. The mean tumor-absorbed dose was 51 ± 28 Gy (range, 7-174 Gy). A 50% reduction in TLG* was achieved in 46% of metastases and in 11 of 30 (37%) patients for the sum of metastases. The latter was associated with a prolonged median overall survival (11.6 vs. 6.6 mo, P = 0.02). A strong and statistically significant dose-response relationship was found (P < 0.001). The dose effect depended on baseline TLG* (P < 0.01). The effective tumor-absorbed dose was conservatively estimated at a minimum of 40-60 Gy. CONCLUSION: A strong dose-response relationship exists for the treatment of CRLM with resin microsphere (90)Y radioembolization. Treatment efficacy is, however, still limited, because the currently used pretreatment activity calculation methods curb potentially achievable tumor-absorbed dose values. A more personalized approach to radioembolization is required before concluding on its clinical potential.

Screening and referral to identify children at risk for FASD: Search for new methods 2006-2013.

As part of the Canadian Association of Paediatric Health Centres Taskforce on FASD Screening commitment to further pilot, validate and evaluate the multiple components of the Canadian FASD Screening Tool Kit, it was deemed necessary that recent developments and/or improvements in FASD screening were identified and considered. In 2008 a literature review of methods for screening for FASD was published until 2006 and identified five tools which met pre-set criteria. A review of all new papers was published from the period January 2006 until July 1, 2013. Out of 1392 papers, two new screening methods met the inclusion criteria: Clarren et al's new norms for palpebral fissure length by age in Canada; and Breiner et al's extension of the Neurobehavioral Screening Test (NST) to age 4 years. Further work is needed to validate these methods in other settings. 

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review.

PURPOSE: Treatment efficacy of intra-arterial radioembolization for liver tumors depends on the selective targeting of tumorous tissue. Recent investigations have demonstrated that tumors may receive inadequate doses of radioactivity after radioembolization, due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-II) is reported to increase the T/N blood flow ratio. The purpose of this systematic review was to provide a comprehensive overview of the effect of hepatic arterial AT-II on T/N blood flow ratio in patients with hepatic malignancies, and determine its clinical value for radioembolization. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A structured search was performed in the PubMed, EMBASE and Cochrane databases. Only studies that presented data on T/N ratios before and after infusion of AT-II into the hepatic artery, in human patients with hepatic malignancies, were selected. Median T/N ratios before, during and after AT-II infusion, and the median T/N ratio improvement factor were extracted from the selected articles. All data on systemic blood pressure measurements and clinical symptoms were also extracted. RESULTS: The search identified 524 titles of which 5 studies, including a total of 71 patients were considered relevant. Median T/N ratios before infusion of AT-II ranged from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A transitory increase of systemic blood pressure was observed during AT-II infusion. CONCLUSIONS: Infusion of AT-II into the hepatic artery leads to an increase of the tumor to non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are warranted to assess safety aspects, optimal administration strategy and impact on treatment efficacy during radioembolization.

Radioembolization for treatment of salvage patients with colorectal cancer liver metastases: a systematic review.

UNLABELLED: Currently, there is no consensus on the use of (90)Y radioembolization for salvage patients with colorectal cancer liver metastases. The purpose of this study was to provide a comprehensive overview of the available data on tumor response and survival after (90)Y radioembolization for this group of patients. METHODS: A systematic literature search was conducted in PubMed (Medline), Excerpta Medica (EMBASE), and the Cochrane Library (September 2012) with synonyms for "radioembolization" and "colorectal cancer liver metastases." Results were described separately for patient cohorts treated with (90)Y radioembolization as monotherapy and with (90)Y radioembolization in combination with chemotherapy. RESULTS: The search yielded 13 relevant articles for systematic review on (90)Y radioembolization as monotherapy and 13 relevant articles on (90)Y radioembolization combined with chemotherapy. Disease control rates (i.e., complete response, partial response, and stable disease) ranged from 29% to 90% for (90)Y radioembolization as monotherapy and from 59% to 100% for (90)Y radioembolization combined with chemotherapy. Heterogeneity in the data prohibited pooling of response rates. Survival proportions at 12 mo ranged from 37% to 59% for (90)Y radioembolization as monotherapy and from 43% to 74% for (90)Y radioembolization combined with chemotherapy. CONCLUSION: In the studies included in this systematic review, approximately 50% of salvage patients with colorectal cancer liver metastases survive more than 12 mo after treatment with (90)Y radioembolization, either as monotherapy or in combination with chemotherapy. Heterogeneity between studies has unfortunately prohibited pooling of data. Future research will discern the precise role of (90)Y radioembolization in general clinical practice in comparison with chemotherapy.

Clinical and laboratory toxicity after intra-arterial radioembolization with (90)y-microspheres for unresectable liver metastases.

OBJECTIVE: To investigate clinical and laboratory toxicity in patients with unresectable liver metastases, treated with yttrium-90 radioembolization ((90)Y-RE). METHODS: Patients with liver metastases treated with (90)Y-RE, between February 1(st) 2009 and March 31(st) 2012, were included in this study. Clinical toxicity assessment was based on the reporting in patient's charts. Laboratory investigations at baseline and during a four-month follow-up were used to assess laboratory toxicity according to the Common Terminology Criteria for Adverse Events version 4.02. The occurrence of grade 3-4 laboratory toxicity was stratified according to treatment strategy (whole liver treatment in one session versus sequential sessions). Response assessment was performed at the level of target lesions, whole liver and overall response in accordance with RECIST 1.1 at 3- and 6 months post-treatment. Median time to progression (TTP) and overall survival were calculated by Kaplan-Meier analysis. RESULTS: A total of 59 patients, with liver metastases from colorectal cancer (n = 30), neuroendocrine tumors (NET) (n = 6) and other primary tumors (n = 23) were included. Clinical toxicity after (90)Y-RE treatment was confined to grade 1-2 events, predominantly post-embolization symptoms. No grade 3-4 clinical toxicity was observed, whereas laboratory toxicity grade 3-4 was observed in 38% of patients. Whole liver treatment in one session was not associated with increased laboratory toxicity. Three-months disease control rates for target lesions, whole liver and overall response were 35%, 21% and 19% respectively. Median TTP was 6.2 months for target lesions, 3.3 months for the whole liver and 3.0 months for overall response. Median overall survival was 8.9 months. CONCLUSION: The risk of severe complications or grade 3-4 clinical toxicity in patients with liver metastases of various primary tumors undergoing (90)Y-RE is low. In contrast, laboratory toxicity grade 3-4 can be expected to occur in more than one-third of patients without any clinical signs of radiation induced liver disease.

Intra-arterial radioembolization of breast cancer liver metastases: a structured review.

Radioembolization using yttrium-90 microspheres (9°Y-RE) is an emerging treatment option for breast cancer liver metastases (BCLM) patients if other locoregional and systemic treatment options fail. The purpose of this study was to provide a systematic overview of the current literature concerning 9°Y-RE for BCLM patients. A systematic search for relevant articles was performed in MEDLINE, EMBASE, and The Cochrane Library (January 2012) by combining an extensive list of synonyms for the determinants 'radioembolization', 'yttrium-90' and 'microsphere' with synonyms for the domain 'liver'. Data on tumor response, survival and toxicity were extracted and collected from all relevant articles. The search yielded 4078 studies, of which six were finally included for analysis, concerning a total of 198 patients. Tumor response was scored in five studies using either RECIST (n=3) or WHO criteria (n=2). Overall disease control rates (complete response, partial response and stable disease) at 2-4 months post treatment ranged from 78% to 96%. Median survival, available in four studies, ranged from 10.8 to 20.9 months. In total, gastric ulceration was reported in ten patients (5%) and treatment related mortality in three patients (2%). The results from the analyzed studies consistently show that 9°Y-RE is a safe and effective treatment option for BCLM patients. Comparative studies, especially combining 9°Y-RE with systemic therapy are strongly encouraged.

The maternal drinking history guide: development of a national educational tool.

BACKGROUND: The National Taskforce for the development of screening tools for FASD has identified maternal drinking as a critical area that should be screened. We describe the steps of development and implementation of a knowledge translation program for health care providers. The slide presentation is attached in English and French to allow its maximal use. METHODS: In 2010, the National Taskforce for the development of screening tools for FASD identified maternal drinking as a critical area that should be screened. The systematic review and associated recommendations have been published and were included in the toolkit developed by the Canadian Association of Paediatric Health Centres with funding support from the Public Health Agency of Canada. Effective inquiry of maternal drinking can be conducted at three levels: Primary level, as part of practice-based screening; Level 2 use of structured questionnaires; and Level 3 laboratory-based screening. CONCLUSION: It was acknowledged that most physicians do not ask women of reproductive age questions regarding their drinking habits, and the Taskforce was seriously concerned that even an effective guide may not change practice at the primary level. To that end, the Taskforce developed a three phase Knowledge Translation plan, to ensure that the educational program developed will be optimally effective for Canadian healthcare providers.

Added value of FDG-PET imaging in the diagnostic workup for yttrium-90 radioembolisation in patients with colorectal cancer liver metastases.

OBJECTIVE: Yttrium-90 radioembolisation (Y90-RE) is recommended for unresectable, chemorefractory liver-dominant disease; however, the incidence of extrahepatic disease (EHD) is high. FDG-PET may have additional value to CT in demonstrating EHD. Our aim was to evaluate the added diagnostic value of FDG-PET to abdominal CT and study the influence of FDG-PET findings on treatment decisions. METHODS: All consecutive patients with colorectal cancer liver metastases (CRCLM) referred for Y90-RE were included. Patients who underwent both CT and FDG-PET in the diagnostic workup were selected. Imaging reports were scrutinised for documented sites of EHD, and changes of management due to FDG-PET findings were determined. RESULTS: A total of 42 patients were included. Findings on CT and FDG-PET matched in 20 patients (no EHD, n = 15; identical EHD, n = 5). In 4 patients, lesions detected on CT were not FDG-avid, and in 18 patients, FDG-PET showed more lesions than CT (P < 0.05). In 7/42 patients (17 %) a change of management was made based on the additional FDG-PET findings, i.e. exclusion from Y90-RE treatment (n = 6) and change in treatment plan (whole liver rather than segmental treatment, n = 1). CONCLUSIONS: In patients with CRCLM referred for Y90-RE, FDG-PET showed significantly more EHD and led to a considerable change of management.

Development of Canadian screening tools for fetal alcohol spectrum disorder.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is the most common cause of neurobehavioural handicap in North America. Screening for FASD may facilitate diagnosis and hence management of these children. We present a variety of screening tools for the identification of children at risk for FASD. METHODS: We critically reviewed and evaluated published and practiced methods for their potential of screening suspected cases, their epidemiological characteristics (sensitivity, specificity, positive and negative predictive values) [Phase I], as well as their feasibility [Phase II]. RESULTS: The following five tools were selected for the FASD screening toolkit: screening fatty acid ethyl esters in neonatal meconium, the modified Child Behaviour Checklist, Medicine Wheel tool, Asante Centre Probation Officer Tool, and maternal history of drinking and drug use. CONCLUSIONS: The toolkit for FASD screening aims at screening different populations, from the newborns to youth and at-risk mothers. It is anticipated that the toolkit will facilitate diagnosis of FASD.