Yttrium-90 Resin Microspheres Research Articles

Preliminary Findings on Overall Survival from a Recent Single-Center Cohort of Patients Treated with Yttrium-90 Resin Microspheres for Unresectable HCC

Median overall survival (OS) after selective internal radiation therapy with Y-90 resin microspheres (Y-90 SIRT) for unresectable hepatocellular carcinoma (HCC) has ranged from 4 to 41 months in prospective and retrospective studies. In a previous study of patients treated at our center from 2004 to 2013, OS was 13.1 months (Mantry et al. 2017). We are retrospectively examining a more recent cohort of patients to determine whether outcomes have improved from those we reported earlier and to further examine factors that predict response. Demographics, disease etiology and presentation, Y-90 treatment parameters, response, and OS were abstracted from the charts of patients with unresectable HCC treated with Y-90 SIRT at our facility from April 2013 through March 2017 (n = 150). OS (from the first Y-90 SIRT treatment to death or last follow-up) was assessed with the Kaplan-Meier method. To date, we have analyzed data from 63 patients with HCC who underwent 89 SIRT procedures. Most were male (78%) and white (71%). Hepatitis C was the most common etiology (49%). Mean MELD score was 6.6 (SD 4.9). Most patients (41/63, 65%) had a single Y-90 SIRT treatment, 19 (30%) had 2 treatments, and 3 (5%) had >2 treatments. Best RECIST response was available for 45 patients and was complete response in 10 (22%), partial in 16 (36%), stable disease in 12 (27%), and progression in 7 (16%). Median OS was 19.3 months (95% CI 12.4, 26.1). The presence of ascites was associated with shorter OS (9.6 vs. 26.1 months, P < .001), and white race was associated with shorter OS (16.3 months) than nonwhite race (median not reached, P = .007). Median OS was also not reached for patients (n = 6) with subsequent liver transplant. Survival in this analyzed subset of patients (19.3 months) was longer than in our previously reported cohort (13.1 months), possibly due to improved technique (especially the use of single-lobe and segmental SIRT) and patient selection over time. Future analyses will investigate OS in the full cohort and compare factors predicting survival between our current and previous cohorts and in the 2 cohorts combined.

A Rare Case of Delayed Gastric Ulcerations Several Months After Y-90 Radioembolization for Hepatic Carcinoid Tumor

Radioembolization using Yttrium-90 (Y-90) resin microspheres infused through the hepatic arteries is a common treatment modality for primary and secondary hepatic tumors. We present a case of delayed symptoms and endoscopic evidence of gastric ulcerations due to radioembolic microspheres months after Y-90 therapy. A 71 year old male presented with epigastric pain and intractable nausea with history of metastatic carcinoid tumor involving the liver. He underwent radioembolization of a unresectable liver lesion with two treatments of SIR-Spheres Yttrium-90 resin microspheres approximately 6 months previously. Endoscopic evaluation revealed several non-bleeding, cratered gastric ulcerations within the lesser curvature of the stomach and gastric antrum measuring up to 15 mm. MRI Abdomen with contrast showed stable liver lesions with no other changes and serum gastrin level was unremarkable. CD34 immunohistochemistry staining of gastric biopsies demonstrated focally ulcerated gastric mucosa, foveolar epithelial hyperplasia and decreased capillary networking. Additionally, H&E stain showed scattered basophilic globules within the gastric mucosa consistent with radioembolic Y-90 microspheres. Gastric ulceration is an uncommon, but well-described complication of locoregional treatment of hepatic tumors with radioembolization treatment such as Y-90. Typically, this occurs due to reflux of microspheres into the gastroduodenal artery from the hepatic artery at the time of non-target embolization. Damage to the mucosal and submucosal surfaces is thought to be caused by direct radiation exposure from microspheres as well as occlusion of the arterial supply to gastric tissues. Although there is no consensus on the most efficacious treatment strategy, endoscopic management of hemorrhage combined with institution of PPIs and avoidance of NSAIDs is generally enough to provide full recovery. In patients with a prior history of Y-90 treatment who present with endoscopic evidence of gastric ulcerations, non-target embolization resulting in arterial reflux of microspheres into the gastric mucosa should be considered as a possible etiology.2686_A Figure 1. Endoscopic image of large cratered ulcer2686_B Figure 2. CD34 stain, used in vascular-associated tissue, showing decrease capillary network with presence of Y-90 microspheres2686_C Figure 3. H&E, 10X stain showing foveolar and smooth muscle hyperplasia with Y-90 microspheres in gastric mucosa

Correlation of radiation dose and activity with clinical outcomes in metastatic colorectal cancer after selective internal radiation therapy using yttrium-90 resin microspheres.

Yttrium-90 (Y)-resin microspheres are prescribed using activity. We evaluated overall survival (OS) and radiographic tumor response after selective internal radiation therapy (SIRT) with resin microspheres in patients with liver metastases from colorectal cancer. We retrospectively reviewed 60 metastatic colorectal cancer patients treated at our institution with SIRT using Y-resin microspheres. Each patient underwent pre-SIRT MRI or computed tomography imaging of the liver with intravenous contrast. Patients underwent post-treatment imaging at 2-3-month intervals with response assessed according to unidimensional Response Evaluation Criteria in Solid Tumors (RECIST) criteria as well as published three-dimensional volumetric criteria. We then related the prescribed activity established by the body surface area method and the corresponding prescribed dose to radiographic treatment response and OS. The median follow-up after the first SIRT treatment was 8.9 months. The mean prescribed activity and the prescribed dose were 26.6 mCi and 52.8 Gy, respectively. OS was not significantly associated with either prescribed activity or prescribed dose. Prescribed dose was also not related to response. However, a significant relationship was found between a higher prescribed activity and an improved radiographic response by RECIST (P=0.04) at the second follow-up. The prescribed activity of Y-resin microspheres may be correlated with radiographic response by RECIST criteria at 4-6 months post-treatment. For a more accurate prediction of response, a valid dose calculation model based on post-Y PET dosimetry is likely needed given the heterogeneous dose delivery seen in SIRT.

Tumor Targeting and Three-Dimensional Voxel-Based Dosimetry to Predict Tumor Response, Toxicity, and Survival after Yttrium-90 Resin Microsphere Radioembolization in Hepatocellular Carcinoma

PurposeTo identify predictive factors of tumor response, progression-free survival (PFS), overall survival (OS), and toxicity using three-dimensional (3D) voxel-based dosimetry in patients with intermediate and advanced stage hepatocellular carcinoma (HCC) treated by yttrium-90 (90Y) resin microspheres radioembolization (RE). Materials and MethodsFrom February 2012 to December 2015, 45 90Y resin microspheres RE procedures were performed for HCC (Barcelona Clinic Liver Cancer stage B/C; n = 15/30). Area under the dose-volume histograms (AUDVHs) were calculated from 3D voxel-based dosimetry to measure 90Y dose deposition. Factors associated with tumor control (ie, complete/partial response or stable disease on Modified Response Evaluation Criteria in Solid Tumors) at 6 months were investigated. PFS and OS analyses were performed (Kaplan-Meier). Toxicity was assessed by occurrence of radioembolization-induced liver disease (REILD). ResultsTumor control rate was 40.5% (17/42). Complete tumor targeting (odds ratio = 36.97; 95% confidence interval, 1.83–747; P < .001) and AUDVHtumor (odds ratio = 1.027; 95% confidence interval, 1.002–1.071; P = .033) independently predicted tumor control. AUDVHtumor ≥ 61 Gy predicted tumor control with 76.5% sensitivity and 75% specificity. PFS and OS in patients with incomplete tumor targeting were significantly shorter than in patients with complete tumor targeting (median PFS, 2.7 months [range, 0.8–4.6 months] vs 7.9 months [range, 2.1–39.5 months], P < .001; median OS, 4.5 months [range, 1.4–23 months] vs 19.2 months [range, 2.1–46.9 months], P < .001). Patients with incomplete tumor targeting and AUDVHtumor < 61 Gy, incomplete tumor targeting and AUDVHtumor > 61 Gy, complete tumor targeting and AUDVHtumor < 61 Gy, and AUDVHtumor > 61 Gy had median PFS of 2.7, 1.8, 6.3, and 12.1 months (P < .001). REILD (n = 4; 9.5%) was associated with higher dose delivered to normal liver (P = .04). ConclusionsComplete tumor targeting and 90Y dose to tumor are independent factors associated with tumor control and clinical outcomes.

P-097 - SIRT therapy with Yttrium-90 resin microspheres in patients with liver cirrhosis Child Pugh B7-9 and unresectable nonmetastatic hepatocellular cancer

P-097 - SIRT therapy with Yttrium-90 resin microspheres in patients with liver cirrhosis Child Pugh B7-9 and unresectable nonmetastatic hepatocellular cancer

PS-018 - Role of 99mTc-Macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response of patients with locally advanced and inoperable hepatocellular carcinoma (HCC) treated by selective intra-arterial radiation therapy (SIRT) with yttrium-90 resin microspheres, a cohort from SARAH study

PS-018 - Role of 99mTc-Macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response of patients with locally advanced and inoperable hepatocellular carcinoma (HCC) treated by selective intra-arterial radiation therapy (SIRT) with yttrium-90 resin microspheres, a cohort from SARAH study

Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies

PurposeRadioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation.MethodsThis was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records.ResultsMost radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1–45.9) versus 30.9 months (19.6–46.8); p = 0.243); stage B: 18.4 months (11.2–19.4) versus 22.8 months (10.9–34.2); p = 0.815; and stage C: 8.8 months (7.1–10.8) versus 10.8 months (7.7–12.6); p = 0.976.ConclusionsRadioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.

Quality of life in patients with liver metastases from colorectal cancer treated with first-line selective internal radiotherapy (SIRT): EQ-5D, EORTC QLQ-C30 and LMC21 results from the FOXFIRE study

Background: Little is known about quality of life (QoL) in colorectal cancer patients with liver metastases treated with selective internal radiotherapy (SIRT) using Yttrium-90 resin microspheres combined with FOLFOX (standard chemotherapy) compared to FOLFOX alone. We report QoL results from a multicentre randomized trial: FOXFIRE.

Abstract P1-14-06: Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016

Abstract Background: SIRT is a globally licensed technique of Radio-Embolization (RE) of hepatic tumors via intra-arterial infusion of β-particle emitting Yttrium-90 (Y-90) radio-labelled microspheres. It increases response rates and hepatic time to progression in metastatic colorectal cancer when used in combination with 5FU/Oxaliplatin (FOLFOX) chemotherapy with acceptable toxicity profile. FOLFOX gives a radio-sensitizing effect and also controls disease outside the liver. Breast cancer liver metastases (BCLM) patients often have extra-hepatic disease and respond to multiple lines of systemic therapy and SIRT is infrequently used. Methods and patients Between 2010 and 2016 we treated 25 BCLM patients with Y-90 SIRT. Receptor status: 20 ER+ve/HER-2 -ve, 3 ER-ve/HER-2 +ve, 2 triple -ve. Eleven patients had liver only disease with 14 also having known extra-hepatic disease. Average number of previous lines of therapy in metastatic setting: chemotherapy = 2.4; endocrine = 1. Sixty-four % patients had prior Capecitabine (n=16); 12% platinum (n=3, all Carboplatin). Twenty patients received chemotherapy with SIRT: 17 had modified FOLFOX6 (Oxaliplatin/bolus 5FU day1, infusional 5FU day 1-3 (46 hrs); 3 patients had Modified de Gramont style 5FU alone. Five patients had no chemotherapy. Sir-spheres were inserted on day 2 of FOLFOX with the 5FU infusion pump continuing to day 3. Further 2-weekly FOLFOX chemo cycles were at clinician's discretion: average number delivered 3.8. Four patients had the liver treated in two halves, approximately 6 weeks apart. One patient received SIRT only to half the liver. Patients were imaged with PET-CT/CT before and 2-3 months after SIRT. Retrospective case note review was performed and data correlated to evaluate tumor response (RR); hepatic and extra hepatic progression free survival (HPFS and EHPFS) and overall survival (OS). Accurate toxicity data was not recorded. Results Hepatic CT response rates: PR 56% (n=14), SD 28% (n=7) and PD 16% (n=4). Hepatic PET response rates: CR 32% (n=8), PR 40% (n=10), SD 12% (n=3), PD 16%(n=4). (Overall PET liver disease control rate = 84%). Eight patients (32%) had extra-hepatic PD at first assessment. Of them, 4 had PR, 2 SD and 2 PD in the liver at that assessment. Two HER-2 +ve patients had brain metastases as first sign of PD within 75 days, an area not previously screened. Of 16 pre-treated with Capecitabine, liver CT response rates: 62.5% PR, 18.75% SD (n=10,3). Post SIRT/FOLFOX, average number of therapy lines: 2 for chemo and 0.75 for endocrine, with 8 patients still alive at time of censoring. Median OS: 766 HPFS: 210 days (CI 140-286). Median EHPFS in patients with extra-hepatic disease: 152 days (CI 96-636). Conclusions SIRT with FOLFOX in previously treated BCLM patients produces high response rates, excellent tumor control and time to progression in the liver with good overall survival. It does not seem to decrease the ability to give further lines of chemotherapy and can be considered as an option for breast cancer patients with liver metastases. Citation Format: Wilson G, Mullamitha S, Bentley D, Bell J, Mullan D, Carter L, Chittalia A, Howell S, Laasch H-U, Westwood T, Jeans S, Tipping J, Ryder D, Farquharson F, Arumugam P, Sheen A, Rajashanker B, Armstrong A, Misra V, Manoharan P, Lawrance J. Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-06.

Yttrium-90 resin microspheres and their use in the treatment of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a severe and rapidly progressive hepatic tumor. Surgery is often impracticable due to locally advanced presentation. On the other hand, chemotherapy has demonstrated only limited effectiveness. For these reasons, liver-directed therapies have been successfully applied for treating ICC. In particular, radioembolization with Yttrium-90 (90Y)-labeled spheres has been reported to be a promising therapeutic approach for this neoplasia. Two commercial forms of 90Y-labeled spheres are available: glass (TheraSphere®) and resin (SIR-Spheres®) microspheres. The aim of the present paper is to review the existing literature on the use of the resin microspheres for the treatment of unresectable and chemorefractory ICC, focusing on the methodology, clinical applications and side effects.

The effect of selective internal radiation therapy with yttrium-90 resin microspheres on lung carbon monoxide diffusion capacity

BackgroundSelective internal radiation therapy (SIRT) with embolization of branches of the hepatic artery is a valuable therapeutic tool for patients with hepatic malignancies; however, it is also associated with lung injury risk due to shunting. Diffusion capacity of the lungs for carbon monoxide (DLCO) is a clinically significant lung function test, and worsening in DLCO is suggested to reflect a limited gas exchange reserve caused by the potential toxicity of chemoradiotherapy or it may be a marker of related lung injury. This study aimed to examine the changes in DLCO during SIRT with resin microspheres in newly treated and retreated patients. Forty consecutive patients who received SIRT for a variety of malignant conditions were included. All subjects were treated with Yttrium-90 labelled resin microspheres. DLCO tests were performed after the procedures. In addition, patients were specifically followed for radiation pneumonitis.ResultsThe mean DLCO did not significantly change after the first (82.8 ± 19.4 vs. 83.1 ± 20.9, p = 0.921) and the second treatments (87.4 ± 19.7 vs. 88.6 ± 23.2, p = 0.256). Proportion of patients with impaired DLCO at baseline was not altered significantly after the first (37.5 vs. 45.0%, p = 0.581) and the second treatments (27.3 vs. 27.3%, p = 1.000). Also, percent change in DLCO values did not correlate with radiation dose, lung shunt fraction, or lung exposure dose (p > 0.05 for all comparisons). None of the patients developed radiation pneumonitis.ConclusionsOur results suggest that no significant change in DLCO in association with SIRT occurs, both after the first or the second treatment sessions. Further larger studies possibly with different protocols are warranted to better delineate DLCO changes after SIRT in a larger spectrum of patients.

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial

Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. Sirtex Medical Inc.

Selective internal radiation therapy using yttrium-90 resin microspheres in patients with unresectable hepatocellular carcinoma: a retrospective study.

Selective internal radiation therapy (SIRT) with yttrium-90 resin (Y-90 resin) microspheres has been used as a locoregional therapy for patients with unresectable hepatocellular carcinoma (HCC). We examined patient and disease characteristics that might affect survival after Y-90 resin, as well as treatment tolerability. Data from patients with unresectable HCC treated with Y-90 resin at a single institution were reviewed retrospectively. Survival was assessed with Kaplan-Meier curves and log-rank tests. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) criteria. Adverse events (AEs) were noted, and laboratory values were graded with CTCAE v3.0. Data from 111 patients were analyzed. AEs occurred in 23 patients at 1 week after treatment and in 46 at 3 months. At 6 months, 13 patients had a complete response and 13 had a partial response. Factors associated with longer overall survival (OS) included early-stage disease [27.8 months for patients with Barcelona-Clinic Liver Cancer (BCLC) A vs. 9.2 months for BCLC C]; treatment with other locoregional therapies (69.0 vs. 11.4 months); and lack of bilobar disease (23.5 vs. 9.4 months), portal vein thrombosis (16.2 vs. 8.6 months), ascites (16.6 vs. 10.3 months), and treatment with sorafenib (17.2 vs. 10.3 months). In six patients, Y-90 resin was used as a bridge to liver transplantation, which greatly improved survival (69.0 vs. 12.1 months). Several characteristics may prove useful for selecting patients likely to respond well to Y-90 resin. These results should be confirmed in prospective studies.

Is a Technetium-99m Macroaggregated Albumin Scan Essential in the Workup for Selective Internal Radiation Therapy with Yttrium-90? An Analysis of 532 Patients

PurposeTo determine if baseline patient, tumor, and pretreatment evaluation characteristics could help identify patients who require technetium-99m (99mTc) macroaggregated albumin (99mTc MAA) imaging before selective internal radiation therapy (SIRT). Materials and MethodsIn this retrospective analysis, 532 consecutive patients with primary (n = 248) or metastatic (n = 284) liver tumors were evaluated between 2006 and 2015. Variables were compared between patients in whom 99mTc MAA imaging results contraindicated/modified SIRT administration with yttrium-90 (90Y) resin microspheres and those who were treated as initially planned. The 99mTc MAA findings that contraindicated/modified SIRT were a lung shunt fraction (LSF) > 20%, gastrointestinal 99mTc MAA uptake, or a mismatch between 99mTc MAA uptake and intrahepatic tumor distribution. ResultsLSF > 20% and gastrointestinal MAA uptake were observed in 7.5% and 3.9% of patients, respectively, and 11% presented a mismatch. Presence of a single lesion (odds ratio [OR] = 2.4) and vascular invasion (OR = 5.5) predicted LSF > 20%, and GI MAA uptake was predicted by the presence of liver metastases (OR = 3.7) and 99mTc MAA injection through the common/proper hepatic artery (OR = 4.7). Vascular invasion (OR = 4.1) was the only predictor of LSF > 20% and/or GI MAA uptake (sensitivity = 49.2%, specificity = 80.3%, negative predictive value = 92.4%). Previous antiangiogenic treatment (OR = 2.4) and presence of a single lesion (OR = 2.6) predicted mismatch. ConclusionsImaging with 99mTc MAA is essential in SIRT workup because baseline characteristics may not adequately predict 99mTc MAA results. Nevertheless, the absence of vascular invasion potentially identifies a group of patients at low risk of SIRT contraindication/modification in whom performing SIRT in a single session (ie, pretreatment evaluation and SIRT on the same day) should be explored.

Tumor Dose Response in Yttrium-90 Resin Microsphere Embolization for Neuroendocrine Liver Metastases: A Tumor-Specific Analysis with Dose Estimation Using SPECT-CT

PurposeTo evaluate dose-response relationship in yttrium-90 (90Y) resin microsphere radioembolization for neuroendocrine tumor (NET) liver metastases using a tumor-specific dose estimation based on technetium-99m–labeled macroaggregated albumin (99mTc MAA) single photon emission computed tomography (SPECT)-CT. Materials and MethodsFifty-five tumors (mean size 3.9 cm) in 15 patients (10 women; mean age 57 y) were evaluated. Tumor-specific absorbed dose was estimated using a partition model. Initial (median 2.3 months) follow-up data were available for all tumors; last (median 7.6 months) follow-up data were available for 45 tumors. Tumor response was evaluated using Modified Response Evaluation Criteria in Solid Tumors (mRECIST) on follow-up CT. Tumors with complete or partial response were considered responders. Mean tumor absorbed dose was 231.4 Gy ± 184.3, and mean nontumor liver absorbed dose was 39.0 Gy ± 18.0. ResultsThirty-six (65.5%) and 30 (66.7%) tumors showed response at initial and last follow-up, respectively. Mean absorbed doses in responders and nonresponders at initial and last follow-up were 285.8 Gy ± 191.1 and 128.1 Gy ± 117.1 (P = .0004) and 314.3 Gy ± 195.8 and 115.7 Gy ± 117.4 (P = .0001). Cutoff value of ≥ 191.3 Gy for tumor-specific absorbed dose predicted tumor response with 93% specificity, whereas < 72.8 Gy predicted nonresponse with 100% specificity at last follow-up. Estimated mean absorbed tumor dose per patient was significantly higher in responders versus nonresponders over the follow-up period (224.5 Gy ± 90.3 vs 70.0 Gy ± 28.0; P = .007). ConclusionsTumor-specific absorbed dose, estimated with a partition model, was significantly associated with tumor response in NET liver metastases. An estimated dose ≥ 191.3 Gy predicted treatment response with high sensitivity and specificity.

592P - Quality of life in patients with liver metastases from colorectal cancer treated with first-line selective internal radiotherapy (SIRT): Results from the FOXFIRE prospective randomized studies

Background: Quality of life (QoL) in patients with colorectal cancer and liver metastases treated with selective internal radiotherapy (SIRT) using Yttrium-90 resin microspheres combined with FOLFOX (standard chemotherapy) has not been compared to FOLFOX alone. We report QoL results from a prospectively pooled analysis of 3 multicentre randomized trials: FOXFIRE, FOXFIRE-Global and SIRFLOX. Methods: Patients were randomized to FOLFOX or FOLFOX+SIRT in 14 countries. Second-line therapy was permitted upon disease progression. EORTC QLQ-C30 and EuroQoL EQ-5D (3 level) questionnaires were given to all patients at baseline, 2-3, 6 and 12 months from starting treatment and yearly thereafter, and at disease progression. We compared QoL scores between arms at each timepoint, calculating mean differences adjusted for baseline scores, using a 5% significance level. No missing data imputation was performed. Results: 1103 patients were randomised overall. Questionnaire response rates ranged from 92% (1010/1103) at baseline to 33% (163/493) at 24 months. Patients randomised to SIRT showed significantly (p < 0.05) worse scores on 3 of 6 QLQ-C30 functioning scales and 3 of 9 symptom scales (fatigue, nausea and vomiting, appetite loss) at 4-8 weeks after treatment (2-3 months from baseline). SIRT patients had significantly better functioning scores on 3 of 6 scales at disease progression, and significantly less dyspnoea or constipation. Almost no other QLQ-C30 scales showed significant differences at 6, 12 or 24 months. The EQ-5D showed a statistically significant decrement of 0.02 in patients in the SIRT group 2-3 months from baseline, but no differences at other timepoints. Conclusions: This analysis has shown that QoL is slightly impaired in functioning and symptom domains 4-8 weeks after treatment with SIRT+FOLFOX compared with FOLFOX alone, but slightly better when measured at disease progression. These differences were consistent between the QLQ-C30 and EQ-5D instruments. The differences detected were not large enough to be considered clinically significant. Clinical trial identification: FOXFIRE ISRCTN83867919; SIRFLOX NCT00724503; FOXFIRE-Global NCT01721954 Legal entity responsible for the study: University of Oxford Funding: Bobby Moore Fund of Cancer Research UK; Sirtex Medical Ltd Disclosure: I. Chau: Advisory Board: Sanofi Oncology, Eli Lilly, Bristol-Myers Squibb, MSD, Bayer, Roche, Five Prime Therapeutics. Research funding: Janssen-Cilag, Sanofi Oncology, Merck Serono, Novartis. Honorarium: Taiho, Pfizer, Amgen, Eli Lilly, Gilead Science. S. Love: Grants from: Cancer Research UK, Sirtex Medical and non-financial support from Sirtex Medical. J. Moschandreas: Grants from Cancer Research UK, Sirtex Medical and non-financial support from Sirtex Medical. P. Virdee: Grants from Cancer Research UK, Sirtex Medical and non-financial support from Sirtex Medical. P. Tait: Medical advisor and medical proctor for Sirtex medical. H. Wasan: Grants, personal fees, non-financial support and other uncompensated work from Sirtex Medical. G. Van Hazel: Compensation for participation in advisory committees from Sirtex. P. Gibbs: Personal fees from Sirtex. R. Sharma: Research funding, honoraria and consultancy fees from Sirtex Medical. All other authors have declared no conflicts of interest.

First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials

SummaryBackgroundData suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival.MethodsFOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global).FindingsBetween Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group.InterpretationAddition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.FundingBobby Moore Fund of Cancer Research UK, Sirtex Medical.

Treatment options for unresectable HCC with a focus on SIRT with Yttrium-90 resin microspheres.

To identify relevant publications, the PubMed database was queried using one or more of the following search terms alone or in combination with Boolean operators: epidemiology, hepatocellular, hepatocellular cancer, hepatocellular carcinoma, unresectable, radioembolisation, selective internal radiation therapy, SIR-Spheres, yttrium 90, TACE, and sorafenib. The results were sorted or filtered by "Author", "Publication dates" or "Article types" to identify articles relevant to each section of the review. To ensure that information on ongoing clinical trials involving Y-90 resin was included, we conducted a search on "ClinicalTrials.gov", by combining the search terms "HCC" OR "hepatocellular carcinoma" with "Y 90" OR "yttrium 90" OR "radioembo", and screened for studies that involved treatment with Y-90 resin microspheres.

Recommendations for radioembolisation after liver surgery using yttrium-90 resin microspheres based on a survey of an international expert panel

IntroductionGuidelines on how to adjust activity in patients with a history of liver surgery who are undergoing yttrium-90 radioembolisation (90Y-RE) are lacking. The aim was to study the variability in activity prescription in these patients, between centres with extensive experience using resin microspheres 90Y-RE, and to draw recommendations on activity prescription based on an expert consensus.MethodsThe variability in activity prescription between centres was investigated by a survey of international experts in the field of 90Y-RE. Six representative post-surgical patients (i.e. comparable activity prescription, different outcome) were selected. Information on patients’ disease characteristics and data needed for activity calculation was presented to the expert panel. Reported was the used method for activity prescription and whether, how and why activity reduction was found indicated.ResultsTen experts took part in the survey. Recommendations on activity reduction were highly variable between the expert panel. The median intra-patient range was 44 Gy (range 18–55 Gy). Reductions in prescribed activity were recommended in 68% of the cases. In consensus, a maximum DTarget of 50 Gy was recommended.ConclusionWith a current lack of guidelines, large variability in activity prescription in post-surgical patients undergoing 90Y-RE exists. In consensus, DTarget ≤50 Gy is recommended.Key points• BSA method does not account for a decreased remnant liver volume after surgery.• In post-surgical patients, a volume-based activity determination method is recommended.• In post-surgical patients, a mean DTargetof ≤ 50Gy should be aimed for.

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.

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). 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. 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. In 100 patients undergoing liver surgery after receiving SIRT, mortality and complication rates appeared acceptable given the risk profile of the recruited patients.