Hepatopulmonary Shunting: A Prognostic Indicator of Survival in Patients with Metastatic Colorectal Adenocarcinoma Treated with 90Y Radioembolization.

Purpose To determine if high lung shunt fraction (LSF) is an independent prognostic indicator of poor survival in patients who undergo yttrium 90 radioembolization for unresectable liver-dominant metastatic colorectal cancer. Materials and Methods Retrospective data were analyzed from 606 patients (62% men; mean age, 62 years) who underwent radioembolization to treat liver metastases from colorectal adenocarcinoma between July 2002 and December 2011 at 11 U.S. centers. Institutional review board exemptions were granted prior to the collection of data at each site. Overall survival was estimated by using Kaplan-Meier survival and univariate Cox proportional hazards models to examine the effect of LSF on survival and to compare this to other potential prognostic indicators. Multivariate analysis was also performed to determine whether LSF is an independent risk factor for poor survival. Results LSF higher than 10% was predictive of significantly decreased survival (median, 6.9 months vs 10.0 months; hazard ratio, 1.60; P < .001) and demonstrated a mild but significant correlation to serum carcinoembryonic antigen levels and tumor-to-liver volume ratio (Pearson correlation coefficients, 0.105 and 0.113, respectively; P < .05). A progressive decrease in survival was observed as LSF increased from less than 5% to more than 20% (P < .05). LSF did not correlate with the presence of extrahepatic metastases or prior administration of bevacizumab. Conclusion Increased LSF is an independent prognostic indicator of worse survival in patients undergoing radioembolization for liver-dominant metastatic colorectal adenocarcinoma. High LSF correlates poorly to other potential markers of tumor size, such as tumor-to-liver volume ratio or serum carcinoembryonic antigen level, and does not correlate to the presence of extrahepatic metastases. © RSNA, 2016 Online supplemental material is available for this article.

SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer.

PURPOSE: SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS: Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION: The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study.

BACKGROUND: In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-SpheresR; Sirtex Medical Limited, North Sydney, Australia). METHODS/DESIGN: SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy+/-SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naive patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of >=3 months and a WHO performance status of 0-1. Patients will be randomised to receive either mFOLFOX6 or SIRT+mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1-3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting >=450 patients will be sufficient for 80% power and 95% confidence. DISCUSSION: The SIRFLOX trial will establish the potential role of SIRT+standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases. TRIAL REGISTRATION: SIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008.

Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis.

PURPOSE: Intraarterial delivery of yttrium-90 ((90)Y)-bound microspheres (ie, radioembolization) is a promising treatment for hepatocellular carcinoma (HCC). An early concern was the "embolic" nature of the microspheres, and their potential to reduce hepatic arterial blood flow in patients with compromised portal blood flow secondary to portal vein thrombosis/occlusion (PVT). In this situation, the risk of liver failure could be enhanced, particularly in patients with cirrhosis who have increased hepatic arterial blood flow. This retrospective analysis was undertaken to assess the safety and clinical benefits of radioembolization with (90)Y resin microspheres in HCC with branch or main PVT. MATERIALS AND METHODS: A total of 25 patients presenting with unresectable HCC and compromised portal flow received segmental, lobar, or whole-liver infusion of (90)Y resin microspheres. For the analysis of tumor response, changes in target lesions, appearance of new lesions, and changes in portal vein thrombus were studied. Controlled disease was defined by absence of progression in all these components. RESULTS: Globally, controlled disease was achieved in 66.7% of patients at 2 months and 50% of patients at 6 months. No significant changes were observed in liver-related toxicities according to Common Toxicity Criteria (version 3.0) at 1 and 2 months after treatment. Median survival time was 10 months (95% CI, 6.6-13.3 months). CONCLUSIONS: Radioembolization of unresectable HCC and branch or main PVT with (90)Y resin microspheres was associated with minimal toxicity and a favorable median survival time. Further prospective studies are warranted to validate the findings in this clinically challenging patient population.

Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival.

PURPOSE: To prospectively evaluate the safety, efficacy, and survival of patients with chemorefractory liver metastases who have been treated with yttrium 90 ((90)Y) glass microspheres. MATERIALS AND METHODS: Institutional review boards from two institutions approved the HIPAA-compliant study; all patients provided informed consent. One hundred thirty-seven patients underwent 225 administrations of (90)Y microspheres by using intraarterial infusion. Primary sites (origins) included colon, breast, neuroendocrine, pancreas, lung, cholangiocarcinoma, melanoma, renal, esophageal, ovary, adenocarcinoma of unknown primary, lymphoma, gastric, duodenal, bladder, angiosarcoma, squamous cell carcinoma, thyroid, adrenal, and parotid. Patients underwent evaluation of baseline and follow-up liver function and tumor markers and computed tomographic or magnetic resonance imaging. Patients were observed for survival from first treatment. Median survival (in days) and corresponding 95% confidence intervals were computed by using the Kaplan-Meier method. The log-rank statistic was used for statistical significance testing of survival distributions between various subgroups of patients. RESULTS: There were 66 men and 71 women. All patients were treated on an outpatient basis. Median age was 61 years. The mean number of treatments was 1.6. The median activity and dose infused were 1.83 GBq and 112.8 Gy, respectively. Clinical toxicities included fatigue (56%), vague abdominal pain (26%), and nausea (23%). At follow-up imaging, according to World Health Organization criteria, there was a 42.8% response rate (2.1% complete response, 40.7% partial response). There was a biologic tumor response (any decrease in tumor size) of 87%. Overall median survival was 300 days. One-year survival was 47.8%, and 2-year survival was 30.9%. Median survival was 457 days for patients with colorectal tumors, 776 days for those with neuroendocrine tumors, and 207 days for those with noncolorectal, nonneuroendocrine tumors. CONCLUSION: (90)Y hepatic treatments are well tolerated with acceptable toxicities; tumor response and median survival are promising.

Radioembolization with yttrium-90 microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies: part 3: comprehensive literature review and future direction.

Treatment options for primary and secondary liver tumors that cannot be resected or ablated are based on transarterial techniques. Although the majority of these are based on bland and chemoembolization techniques, yttrium-90 microspheres represent an alternate transarterial option. Although the amount of literature on (90)Y does not rival that of bland or chemoembolization, there nevertheless are ample data that support its use for primary and metastatic liver tumors. A comprehensive review of the entire available literature dating from the early 1960s is presented, as is a discussion of the possibilities for future research with use of radioembolization as a platform.

Radioembolization with 90yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 2: special topics.

Yttrium-90 microspheres are increasingly being used as a treatment modality for primary and secondary liver tumors. As these therapies continue to be accepted, it is natural that their application in more complex clinical scenarios will become more common. This article is meant to introduce these controversies and to generate interest and dialogue by the interventional oncology community. This discussion is based on more than 900 (90)Y radioembolization procedures performed over a 5-year period.

Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and methodologic considerations.

Microsphere and particle technology represent the next-generation agents that have formed the basis of interventional oncology, an evolving subspecialty of interventional radiology. One of these platforms, yttrium-90 microspheres, is rapidly being adopted in the medical community as an adjunctive therapeutic tool in the management of primary and secondary liver malignancies. Given the complexity of the treatment algorithm of patients who may be candidates for this therapy and the need for clinical guidance, a comprehensive review of the methodologic and technical considerations was undertaken. This experience is based on more than 900 (90)Y infusions performed over a 5-year period.

Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival.

PURPOSE: To present safety and efficacy results obtained in treatment of a cohort of patients with unresectable hepatocellular carcinoma (HCC) with use of 90Y microspheres (TheraSphere). PATIENTS AND METHODS: Forty-three consecutive patients with HCC were treated with 90Y microspheres over a 4-year period. Patients were treated by liver segment or lobe on one or more occasions based on tumor distribution, liver function, and vascular flow dynamics. Patients were followed for adverse events, objective tumor response, and survival. Patients were stratified into three risk groups according to method of treatment and risk stratification (group 0, segmental; group 1, lobar low-risk; group 2, lobar high-risk) and Okuda and Child-Pugh scoring systems. RESULTS: Based on follow-up data from 43 treated patients, 20 patients (47%) had an objective tumor response based on percent reduction in tumor size and 34 patients (79%) had a tumor response when percent reduction and/or tumor necrosis were used as a composite measure of tumor response. There was no statistical difference among the three risk groups with respect to tumor response. Survival times from date of diagnosis were different among the risk groups (P < .0001). Median survival times were 46.5 months, 16.9 months, and 11.1 months for groups 0, 1, and 2, respectively. Median survival times of 24.4 months and 12.5 months by Okuda scores of I and II, respectively, were achieved (mean, 25.8 months vs 13.1). Patients had median survival times of 20.5 months and 13.8 months according to Child class A and class B/C disease, respectively (mean, 22.7 months vs 13.6 months). Patients classified as having diffuse disease exhibited decreased survival and reduced tumor response. There were no life-threatening adverse events related to treatment. CONCLUSIONS: Use of 90Y microspheres (TheraSpheres) provides a safe and effective method of treatment for a broad spectrum of patients presenting with unresectable HCC. Further investigation is warranted.

90Y microsphere (TheraSphere) treatment for unresectable colorectal cancer metastases of the liver: response to treatment at targeted doses of 135-150 Gy as measured by [18F]fluorodeoxyglucose positron emission tomography and computed tomographic imaging.

PURPOSE: The purpose of this phase II study was to determine the safety and efficacy of TheraSphere treatment (90Y microspheres) in patients with liver-dominant colorectal metastases in whom standard therapies had failed or were judged to be inappropriate. MATERIALS AND METHODS: Twenty-seven patients with unresectable hepatic colorectal metastases were treated at a targeted absorbed dose of 135-150 Gy. Safety and toxicity were assessed according to the National Cancer Institute's Common Toxicity Criteria, version 3.0. Response was assessed with use of computed tomography (CT) and was correlated with response on [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Survival from first treatment was estimated with use of the Kaplan-Meier method. RESULTS: Tumor response measured by FDG PET imaging exceeded that measured by CT imaging for the first (88% vs 35%) and second (73% vs 36%) treated lobes. Tumor replacement of 25% or less (vs >25%) was associated with a statistically significant increase in median survival (339 days vs 162 days; P = .002). Treatment-related toxicities included mild fatigue (n = 13; 48%), nausea (n = 4; 15%), and vague abdominal pain (n = 5; 19%). There was one case of radiation-induced gastritis from inadvertent deposition of microspheres to the gastrointestinal tract (n = 1; 4%). Three patients (11%) experienced ascites/pleural effusion after treatment with TheraSphere as a consequence of liver failure in advanced-stage metastatic disease. With the exception of these three patients whose sequelae were not considered to be related to treatment, all observed toxicities were transient and resolved without medical intervention. CONCLUSION: TheraSphere administration appears to provide stabilization of liver disease with minimal toxicity in patients in whom standard systemic chemotherapy regimens have failed.

Angiographic considerations in patients undergoing liver-directed therapy.

The rapid evolution and increasing complexity of liver-directed therapies has forced the medical community to further advance its understanding of hepatic arterial anatomy. The anatomy of the mesenteric system, and particularly the hepatic arterial bed, has been demonstrated to have a high degree of variation. This is important when considering presurgical planning, catheterization, and transarterial hepatic therapies. Although anatomic variants have been well described, the characterization and understanding of regional hepatic perfusion is also required to optimize endovascular therapy and intervention. Although this is true for patients undergoing bland embolization or chemoembolization, drug delivery, and hepatic infusional pump therapy, it is particularly true for intraarterial brachytherapy. The purpose of this review is to provide historical perspective in angiographic aspects of liver-directed therapy, as well as a discussion of normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors. Methods of optimizing the safety and efficacy of liver-directed therapies with use of percutaneous techniques will be discussed. This review is based on the experience gained in treating more than 500 patients with transarterial liver-directed therapies. Although the principles described in this article apply to all liver-directed therapies such as chemoembolization and administration of drug-coated microspheres, they apply particularly to intraarterial brachytherapy.

Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis.

PURPOSE: To present the findings of a risk-stratification survival analysis with use of data collected on a heterogeneous group of patients with hepatocellular carcinoma (HCC) treated with TheraSphere. MATERIALS AND METHODS: Baseline, treatment, and follow-up data were collected and analyzed from 121 TheraSphere-treated patients. Survival analyses were performed to identify those variables most strongly associated with 3-month mortality. The presence of any of the identified risk variables resulted in the assignment of a patient to the high-risk category. RESULTS: Five liver reserve and two non-liver reserve variables were identified and used to stratify patients into low- or high-risk groups. Sixteen of the 33 patients assigned to the high-risk group (49%) did not survive the first 3 months after treatment, compared with six of the 88 patients assigned to the low-risk group (7%; Fisher exact test, P < .0001). Median survival for the low- and high-risk groups were 466 days and 108 days, respectively (hazard ratio, 6.0; P < .0001). Eleven of 12 patients who experienced a treatment-related major complication ending in death were included in the high-risk group. No single variable explained the major complication relationship to treatment. CONCLUSION: Patients with HCC who are being considered for treatment with TheraSpheres should be evaluated for the presence of the risk variables described herein. The absence of these variables is predictive of improved survival (median of 466 days) compared with patients at high risk (median of 108 days).

Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities.

PURPOSE: Intraarterial injection of yttrium 90 microspheres (TheraSpheres) is used in the treatment of hepatocellular carcinoma (HCC). This article presents an analysis of the incidence of liver toxicities (liver-related events) and pretreatment factors associated with liver toxicities after TheraSphere treatment. PATIENTS AND METHODS: Eighty-eight TheraSphere-treated patients with low 90-day mortality risk were selected for analysis, with liver toxicities coded with use of standard oncology criteria. Descriptive and inferential statistical methods were applied to estimate the incidence of liver toxicities and to evaluate the influence of liver radiation dose and various pretreatment factors on the risk of their occurrence. RESULTS: Sixty-eight liver toxicities occurred in 37 of the 88 patients (42%). Thirty-two patients (36%) experienced 50 liver toxicities after the first treatment and nine of 23 patients (39%) who received a second treatment experienced 18 liver toxicities. Pretreatment total bilirubin and liver radiation dose were found to be associated with the risk of at least one liver toxicity and with the time to first occurrence of a liver toxicity after first treatment. Pretreatment total bilirubin also was associated with liver toxicities after the second treatment. Most of the toxicities resolved; however, those that did not resolve were attributed to tumor progression or advancing cirrhosis. CONCLUSIONS: The risk of liver toxicities in patients with unresectable HCC treated with TheraSpheres increases with increasing pretreatment total bilirubin level and liver radiation dose to a maximum of 150 Gy for a single administration. The toxicities attributed to treatment resolved over time, and none of the patients studied had confirmed radiation-induced liver disease. Consequently, doses as high as 150 Gy on a single administration and as high as 268 Gy on repeated administrations were well tolerated.

Yttrium-90 microspheres for the treatment of hepatocellular carcinoma.

Unresectable hepatocellular carcinoma is extremely difficult to treat. TheraSphere consists of yttrium-90 (a pure beta emitter) microspheres, which are injected into the hepatic arteries. This article reviews the safety and survival of patients with hepatocellular carcinoma who were treated with yttrium-90 microspheres. Eighty patients were selected from a database of 108 yttrium-90 microsphere-treated patients and were staged by using Child-Pugh, Okuda, and Cancer of the Liver Italian Program scoring systems. Patients were treated with local, regional, and whole-liver approaches. Survival from first treatment was analyzed with Kaplan-Meier and Cox regression methods. Adverse events and complications of treatment were coded by using the Southwest Oncology Group toxicity scoring system. Patients received liver doses ranging from 47 to 270 Gy. Thirty-two patients (40%) received more than 1 treatment. Survival correlated with pretreatment Cancer of the Liver Italian Program scores ( P = .002), as well as with the individual Cancer of the Liver Italian Program components, Child-Pugh class, alpha-fetoprotein levels, and percentage of tumor replacement. Patients classified as Okuda stage I (n = 54) and II (n = 26) had median survival durations and 1-year survival rates of 628 days and 63%, and 384 days and 51%, respectively ( P = .02). One patient died of liver failure judged as possibly related to treatment. Thus, in selected patients with hepatocellular carcinoma, yttrium-90 microsphere treatment is safe and well tolerated. On the basis of these results, a randomized controlled trial is warranted comparing yttrium-90 microsphere treatment with transarterial chemoembolization by using the Cancer of the Liver Italian Program system for prospective stratified randomization.

Use of Yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis.

PURPOSE: Intra-arterial injection of Yttrium-90 glass microspheres ((90)Y- microS; TheraSphere, MDS Nordion, Ottawa, Canada) is indicated for treatment of unresectable hepatocellular carcinoma (HCC) in the presence of acceptable liver function. This study presents hepatic toxicity results after unilobar and bilobar intra-arterial administration of (90)Y- microS in patients with unresectable HCC who had known portal vein thrombosis (PVT) without evidence of cavernous transformation. MATERIALS AND METHODS: Fifteen patients with unresectable HCC and PVT of one or both first order and related segmental portal venous branches received a total of 29 infusions of (90)Y- microS for treatment of HCC. All patients had pretreatment evaluation including: computed tomography (CT) imaging, alpha-fetoprotein (AFP) levels, liver function tests, technetium-99m macroaggregated albumin ((99)Tc-MAA) scan for evaluation of lung and visceral shunting, and angiography with visualization into the portal venous phase. (90)Y- micro S dose was based on lobar hepatic volume with adjustment for lung shunt activity. Liver toxicity was assessed by serum total bilirubin graded for severity according to the NIH NCI Clinical Toxicity Criteria (CTC version 2.0). Other adverse events were reported according to the standards established by the Society of Interventional Radiology. RESULTS: There were no procedural complications with delivery of (90)Y- microS, and treatment was well tolerated by all patients. Increased post-treatment bilirubin levels were observed across all treatments in five patients, four of whom had CT or AFP evidence of intrahepatic disease progression. After initial treatment, two patients developed bilirubin toxicity (grades 1 and 2); one patient demonstrated an increment in bilirubin toxicity grade (grade 1 to grade 3) and one patient had an improvement in grade after initial treatment. There were no new treatment-related toxicities in nine patients after a second treatment. CONCLUSIONS: (90)Y- microS treatment was well tolerated and appears to be safe to use in patients with compromised portal venous flow in one or both first order and related segmental portal venous branches and no evidence of cavernous transformation. In patients who did not exhibit disease progression, there appeared to be no clinically significant change in bilirubin.

Yttrium-90 microspheres: radiation therapy for unresectable liver cancer.

Hepatocellular carcinoma (HCC) constitutes a difficult health challenge because of its poor prognosis and limited treatment options. Most available therapies are used only for palliation. The use of yttrium-90 microspheres is a new intraarterial therapy consisting of beta-irradiating microspheres measuring 20-30 micro m in diameter that can be delivered directly to the tumors. (90)Y microspheres, which carry the radiation, are selectively taken up by the tumors, thus preserving normal liver. In several studies to date, (90)Y microspheres have proved to have a low toxicity profile and have generally been well tolerated by patients. Other than transient elevation in liver enzyme levels and mild fatigue and fever, no substantial treatment-related toxicities have been observed. Gastrointestinal toxicities occur in a limited number of cases and are preventable with proper knowledge of visceral arterial anatomy. The effect on survival is also promising, with median survival rates of 23 months (95% confidence interval = 14, 44) and 11 months (95% confidence interval = 6, 26) for patients with Okuda stage I and stage II disease, respectively. On the basis of these data, intraarterial delivery of (90)Y microspheres offers a new alternative in the treatment of unresectable HCC.