Intra-arterial Peptide Receptor Radionuclide Therapy for the Treatment of Hepatic Neuroendocrine Tumor Metastases: Hope or Hype?

Peptide receptor radionuclide therapy (PRRT) confers significant progression-free survival advantage for patients with small bowel grade 1 and 2 well-differentiated neuroendocrine tumors (WD NET). PRRT may also be clinically beneficial for patients with NET of pancreatic, bronchial, and other sites of origin; patients with paragangliomas; as well as for patients with well-differentiated grade 3 NET. Direct intra-arterial (IA) administration of PRRT into the hepatic artery for patients with NET liver metastases may result in higher radiopharmaceutical dose and longer dwell time in the liver tumors while relatively sparing non-tumor liver tissue and other organs such as the kidneys and bone marrow when compared with intravenous (IV) administration. This review summarizes currently available data on IA and IV PRRT dose distribution, reports safety and efficacy of IA PRRT, and proposes future research questions.

Cost-effectiveness analysis of interventional liver-directed therapies for downstaging of HCC before liver transplant.

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are the 2 most used modalities for patients with HCC while awaiting liver transplant. The purpose of this study is to perform a cost-effectiveness analysis comparing TACE and TARE for downstaging (DS) patients with HCC. A cost-effectiveness analysis was performed comparing TACE and TARE in DS HCC over a 5-year time horizon from a payer's perspective. The clinical course, including those who achieved successful DS leading to liver transplant and those who failed DS with possible disease progression, was obtained from the United Network for Organ Sharing. Costs and effectiveness were measured in US dollars and quality-adjusted life years (QALYs). Probabilistic and deterministic sensitivity analyses were performed. TARE achieved a higher effectiveness of 2.51 QALY (TACE: 2.29 QALY) at a higher cost of $172,162 (TACE: $159,706), with the incremental cost-effectiveness ratio of $55,964/QALY, making TARE the more cost-effective strategy. The difference in outcome was equivalent to 104 days (nearly 3.5 months) in compensated cirrhosis state. Probabilistic sensitivity analyses showed that TARE was more cost-effective in 91.69% of 10,000 Monte Carlo simulations. TARE was more effective if greater than 48.2% of patients who received TACE or TARE were successfully downstaged (base case: 74.6% from the pooled analysis of multiple published cohorts). TARE became more cost-effective when the cost of TACE exceeded $4,831 (base case: $12,722) or when the cost of TARE was lower than $43,542 (base case: $30,609). Subgroup analyses identified TARE to be the more cost-effective strategy if the TARE cohort required 1 fewer locoregional therapy than the TACE cohort. TARE is the more cost-effective DS strategy for patients with HCC exceeding Milan criteria compared to TACE.

ACR Appropriateness Criteria® Dialysis Fistula Malfunction.

The creation and maintenance of a dialysis access is vital for the reduction of morbidity, mortality, and cost of treatment for end stage renal disease patients. One's longevity on dialysis is directly dependent upon the quality of dialysis. This quality hinges on the integrity and reliability of the access to the patient's vascular system. All methods of dialysis access will eventually result in dialysis dysfunction and failure. Arteriovenous access dysfunction includes 3 distinct classes of events, namely thrombotic flow-related complications or dysfunction, nonthrombotic flow-related complications or dysfunction, and infectious complications. The restoration of any form of arteriovenous access dysfunction may be supported by diagnostic imaging, clinical consultation, percutaneous interventional procedures, surgical management, or a combination of these methods. This document provides a rigorous evaluation of how variants of each form of dysfunction may be appraised and approached systematically. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Lower Extremity Chronic Venous Disease.

Lower extremity venous insufficiency is a chronic medical condition resulting from primary valvular incompetence or, less commonly, prior deep venous thrombosis or extrinsic venous obstruction. Lower extremity chronic venous disease has a high prevalence with a related socioeconomic burden. In the United States, over 11 million males and 22 million females 40 to 80 years of age have varicose veins, with over 2 million adults having advanced chronic venous disease. The high cost to the health care system is related to the recurrent nature of venous ulcerative disease, with total treatment costs estimated >$2.5 billion per year in the United States, with at least 20,556 individuals with newly diagnosed venous ulcers yearly. Various diagnostic and treatment strategies are in place for lower extremity chronic venous disease and are discussed in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Liver-Directed Therapy for Neuroendocrine Tumor Metastases in the Era of Peptide Receptor Radionuclide Therapy.

OPINION STATEMENT: The treatment of neuroendocrine neoplasm (NEN) liver metastases involves a multidisciplinary approach that includes liver-directed therapies (LDT) and systemic treatments, such as peptide receptor radionuclide therapy (PRRT). LDT has demonstrated efficacy in rapidly reducing tumor bulk, improving symptoms, and delaying disease progression. Interventional radiologists should be consulted prior to switching therapy for patients with progressive or symptomatic neuroendocrine tumor liver metastases. Long-term follow-up data on the safety of Yttrium-90 radioembolization before and after PRRT remain limited. Therefore, a more conservative approach may be to preferentially employ transarterial embolization (TAE) or transarterial chemoembolization (TACE) for patients' somatostatin receptor-avid disease who may be future candidates for PRRT. Notable exceptions where radioembolization may be a preferred treatment strategy may be patients with history of biliary tract instrumentation, asymmetric unilobar disease distribution, and rapidly progressive diffuse liver involvement. Selection of local treatment modality, sequencing, and combination of LDT with systemic therapy require further investigation.

Per-patient Negative Predictive Value of the CT and MRI Liver Imaging Reporting and Data System Version 2018 Treatment Response Algorithm for Hepatocellular Carcinoma.

Background The Liver Imaging Reporting and Data System version 2018 (LI-RADS) treatment response algorithm (TRA) is a high-specificity, lower-sensitivity grading system to diagnose hepatocellular carcinoma (HCC) and recurrence after local-regional therapy. However, the emphasis on specificity can result in disease understaging, potentially leading to poorer posttransplant outcomes. Purpose To determine the negative predictive value (NPV) of pretransplant CT and MRI assessment for viable HCC on a per-patient basis using the LI-RADS TRA, considering explant pathology as the reference standard. Materials and Methods Patient records from 218 consecutive adult patients from a single institution with HCC who underwent liver transplant from January 2011 to November 2017 were retrospectively reviewed. Two readers blinded to the original report reviewed immediate (within 90 days) pretransplant imaging and characterized observations according to the LI-RADS TRA. Based on this, patients with LR-4, LR-5, or LR-TR (treatment response) viable tumors were designated as viable tumor; patients with solely LR-3 or LR-TR equivocal tumors were designated as equivocal; and patients with only LR-TR nonviable lesions were designated as no viable disease. Patients were designated as within or outside the Milan criteria. These per-patient designations were compared with the presence of viable disease at explant pathology. Fisher exact test was used to compare the differences between CT and MRI. Weighted κ values were used to calculate interreader reliability. Results Final study sample consisted of 206 patients (median age, 61 years [IQR, 57-65 years]; 157 male patients and 49 female patients). Per-patient LI-RADS TRA assessment of pretransplant imaging had an NPV of 32% (95% CI: 27, 38) and 26% (95% CI: 20, 33) (readers 1 and 2, respectively) for predicting viable disease. Seventy-five percent (reader 1) and 77% (reader 2) of patients deemed equivocal had residual tumors at explant pathology. Weighted interreader reliability was substantial (κ = 0.62). Conclusion Patient-based stratification of viable, equivocal, and nonviable disease at pretransplant CT or MRI, based on LI-RADS TRA, demonstrated low negative predictive value in excluding HCC at explant pathology. © RSNA, 2023 See also the editorial by Tamir and Tau in this issue.

Ethiodized oil as an imaging biomarker after conventional transarterial chemoembolization.

Conventional transarterial chemoembolization (cTACE) utilizing ethiodized oil as a chemotherapy carrier has become a standard treatment for intermediate-stage hepatocellular carcinoma (HCC) and has been adopted as a bridging and downstaging therapy for liver transplantation. Water-in-oil emulsion made up of ethiodized oil and chemotherapy solution is retained in tumor vasculature resulting in high tissue drug concentration and low systemic chemotherapy doses. The density and distribution pattern of ethiodized oil within the tumor on post-treatment imaging are predictive of the extent of tumor necrosis and duration of response to treatment. This review describes the multiple roles of ethiodized oil, particularly in its role as a biomarker of tumor response to cTACE. CLINICAL RELEVANCE: With the increasing complexity of locoregional therapy options, including the use of combination therapies, treatment response assessment has become challenging; Ethiodized oil deposition patterns can serve as an imaging biomarker for the prediction of treatment response, and perhaps predict post-treatment prognosis. KEY POINTS: • Treatment response assessment after locoregional therapy to hepatocellular carcinoma is fraught with multiple challenges given the varied post-treatment imaging appearance. • Ethiodized oil is unique in that its' radiopacity can serve as an imaging biomarker to help predict treatment response. • The pattern of deposition of ethiodozed oil has served as a mechanism to detect portions of tumor that are undertreated and can serve as an adjunct to enhancement in order to improve management in patients treated with intraarterial embolization with ethiodized oil.

Contemporary applications of Y90 for the treatment of hepatocellular carcinoma.

Transarterial radioembolization (TARE) with yttrium-90 (90Y) microspheres has been widely adopted for the treatment of HCC. Recent advances in yttrium-90 (90Y) dosimetry have led to durable local responses. Radiation segmentectomy has become a viable alternative to thermal ablation for early-stage HCC (Barcelona Clinic Liver Cancer 0 and A) and has been commonly used as a bridge to transplant. TARE is also commonly used for downstaging to transplant using traditional lobar dosimetry and radiation segmentectomy techniques. Radiation lobectomy has a dual role in local tumor control and induction of contralateral liver lobe hypertrophy as a bridge to resection for patients with an inadequate future liver remnant. TARE continues to provide disease control for patients with limited vascular invasion and may be an alternative to systemic therapy for patients with localized advanced disease. The potential synergy between TARE and immunotherapy has been recognized, and prospective studies evaluating this combination are needed for patients with Barcelona Clinic Liver Cancer B and C HCC.

ACR Appropriateness Criteria® Central Venous Access Device and Site Selection.

The use of central venous access devices is ubiquitous in both inpatient and outpatient settings, whether for critical care, oncology, hemodialysis, parenteral nutrition, or diagnostic purposes. Radiology has a well-established role in the placement of these devices due to demonstrated benefits of radiologic placement in multiple clinical settings. A wide variety of devices are available for central venous access and optimal device selection is a common clinical challenge. Central venous access devices may be nontunneled, tunneled, or implantable. They may be centrally or peripherally inserted by way of veins in the neck, extremities, or elsewhere. Each device and access site presents specific risks that should be considered in each clinical scenario to minimize the risk of harm. The risk of infection and mechanical injury should be minimized in all patients. In hemodialysis patients, preservation of future access is an additional important consideration. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Cost-Effectiveness Analysis of Interventional Liver-Directed Therapies for a Single, Small Hepatocellular Carcinoma in Liver Transplant Candidates.

PURPOSE: To assess the cost effectiveness of 3 main locoregional therapies (LRTs) (transarterial chemoembolization [TACE], transarterial radioembolization [TARE], and percutaneous ablation) as bridging therapy. MATERIALS AND METHODS: A cost-effectiveness analysis was performed comparing the 3 LRTs for patients with a single hepatocellular carcinoma (HCC) with a diameter of 3 cm or less over a 5-year time horizon from a payer's perspective. The clinical courses, including transplantation, decompensation resulting in delisting, and the need for a second LRT, were based on data from the United Network for Organ Sharing (2016-2019). Costs and effectiveness were measured in U.S. dollars and quality-adjusted life-years, respectively. Probabilistic and deterministic sensitivity analyses were performed. RESULTS: A total of 2,594, 1,576, and 903 patients underwent TACE, ablation, and TARE, respectively. Ablation was the dominant strategy, with the lowest expected cost and highest effectiveness. The probabilistic sensitivity analysis demonstrated that ablation was the most cost-effective strategy in 93.9% of simulations. A subgroup analysis was performed for different wait times, with ablation remaining the most cost-effective strategy. The sensitivity analysis showed that ablation was most effective if the risk of waitlist dropout was less than 2.00% and the rate of transplantation was more than 15.1% quarterly. TARE was most effective if the risk of dropout was less than 1.19% and the rate of transplantation was more than 24.0%. TACE was most effective if the risk of dropout was less than 1.01% and the rate of transplantation was more than 45.7%. Ablation remained the most cost-effective modality until its procedural cost was more than $34,843. CONCLUSIONS: Ablation is the most cost-effective bridging strategy for patients with a single, small (≤3 cm) HCC prior to liver transplantation. The conclusion remained robust in multiple sensitivity analyses.

Socioeconomic and Survival Analysis of Radioembolization in Patients with Intrahepatic Cholangiocarcinoma: A Propensity Score-Adjusted Study.

PURPOSE: To determine whether transarterial radioembolization (TARE) is associated with longer survival of patients with intrahepatic cholangiocarcinoma (ICC) and whether access to TARE is influenced by socioeconomic factors. MATERIALS AND METHODS: Retrospective review of patients with ICC in the National Cancer Database from 2004 to 2018 was performed with Cox regression analysis to identify predictors of survival. Overall survival (OS) was estimated using the Kaplan-Meier method. Socioeconomic factors were compared between 2 groups using the Wilcoxon rank-sum test and χ2 test. Propensity score-matched cohorts were created between patients with ICC who did and did not undergo TARE. RESULTS: The number of patients receiving TARE for ICC increased over time from 1 in 2004 to 210 in 2018. Patients in the TARE group were more likely to be White (87.9% vs 84.3%; P = .012) and less likely to be Hispanic/Latino (7.7% vs 11.0%; P = .009). Fewer patients who underwent TARE were uninsured (0.9% vs 2.8%; P = .012). Older age, male sex, non-White race, higher tumor grade size, and stage, earlier year of diagnosis, lack of treatment with surgery or systemic therapy, and presence of lymphatic or vascular invasion exhibited significant associations with decreased survival (P < .05 for all). Patients who underwent TARE had longer survival in both unadjusted and adjusted cohorts, with an OS of 17.5 months (vs 7.2 months in the non-TARE group) after propensity matching. CONCLUSIONS: Patients with ICC who had undergone TARE experienced significantly longer survival than that experienced by those who had not after adjusting for measurable confounders. Significant socioeconomic disparities in access to TARE remain.

Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.

BACKGROUND: Extrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. METHODS: Sequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE. RESULTS: A total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%). CONCLUSIONS: The combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

ACR Appropriateness Criteria® Radiologic Management of Mesenteric Ischemia: 2022 Update.

Mesenteric ischemia is a serious medical condition characterized by insufficient vascular supply to the small bowel. In the acute setting, endovascular interventions, including embolectomy, transcatheter thrombolysis, and angioplasty with or without stent placement, are recommended as initial therapeutic options. For nonocclusive mesenteric ischemia, transarterial infusion of vasodilators, such as papaverine or prostaglandin E1, is the recommended initial treatment. In the chronic setting, endovascular means of revascularization, including angioplasty and stent placement, are generally recommend, with surgical options, such as bypass or endarterectomy, considered alternative options. Although the diagnosis of median arcuate ligament syndrome remains controversial, diagnostic angiography can be helpful in rendering a diagnosis, with the preferred treatment option being a surgical release. Systemic anticoagulation is recommended as initial therapy for venous mesenteric ischemia with acceptable rates of recanalization. If anticoagulation fails, transcatheter thrombolytic infusion can be considered with possible adjunctive placement of a transjugular intrahepatic portosystemic shunt to augment antegrade flow. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Molecular and Radiological Features of Microsatellite Stable Colorectal Cancer Cases With Dramatic Responses to Immunotherapy.

BACKGROUND/AIM: The majority of colorectal cancer (CRC) cases, which are microsatellite stable (MSS) and do not harbor mismatch repair deficiency/microsatellite instability, are resistant to immunotherapy. Identification of patients with exceptional responses in MSS CRC and predictive biomarkers is an unmet need that needs to be addressed. CASE REPORT: We report three cases of MSS CRC with durable clinical benefit from immunotherapy with anti-PD-1 checkpoint inhibitors. Two cases bear a POLE P286R mutation, which has been associated with lack of immunotherapy response in MSS CRC. Two cases bear alterations in Ataxia-Telangiectasia Mutated (ATM) which may contribute to observed responses, including interaction with a co-administered intratumoral stimulator of interferon genes (STING) pathway agonist in one patient. CONCLUSION: Novel DNA damage repair alterations, including mutations in ATM, can provide insight into additional mechanisms by which genomic alterations can sensitize MSS CRC to diverse immunotherapies.

Outcomes after high-dose radiation in the management of neuroendocrine neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. MATERIALS AND METHODS: We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/ß = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. RESULTS: 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. CONCLUSIONS: These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.

Non-operative management of biliary complications after Liver Transplantation in pediatric patients: A 30-year experience.

BACKGROUND: To evaluate the efficacy of percutaneous and endoscopic therapeutic interventions for biliary strictures and leaks following LT in children. METHODS: Retrospective analysis of 49 consecutive pediatric liver transplant recipients (27 girls, 22 boys, mean age at transplant 3.9 years) treated at our institution from 1989 to 2019 for biliary leak and/or biliary stricture was performed. Minimally invasive approach was considered clinically successful if it resulted in patency of the narrowed biliary segment and/or correction of the biliary leak. RESULTS: Forty-two patients had a stricture at the biliary anastomosis; seven had a biliary leak. After an average 13.8 years of follow-up, long-term clinical success with minimally invasive treatment (no surgery or re-transplant) was achieved for 24 children (57%) with biliary stricture and 4 (57%) with biliary leaks. Eight patients required re-transplant; however, only one was due to failure of both percutaneous and surgical management. For biliary strictures, failure of non-surgical management was associated with younger age at stricture diagnosis (p < .02). CONCLUSIONS: Percutaneous and endoscopic management of biliary strictures and leaks after LT in children is associated with a durable result in >50% of children.

ACR Appropriateness Criteria® Radiologic Management of Lower Gastrointestinal Tract Bleeding: 2021 Update.

Diverticulosis remains the commonest cause for acute lower gastrointestinal tract bleeding (GIB). Conservative management is initially sufficient for most patients, followed by elective diagnostic tests. However, if acute lower GIB persists, it can be investigated with colonoscopy, CT angiography (CTA), or red blood cell (RBC) scan. Colonoscopy can identify the site and cause of bleeding and provide effective treatment. CTA is a noninvasive diagnostic tool that is better tolerated by patients, can identify actively bleeding site or a potential bleeding lesion in vast majority of patients. RBC scan can identify intermittent bleeding, and with single-photon emission computed tomography, can more accurately localize it to a small segment of bowel. If patients are hemodynamically unstable, CTA and transcatheter arteriography/embolization can be performed. Colonoscopy can also be considered in these patients if rapid bowel preparation is feasible. Transcatheter arteriography has a low rate of major complications; however, targeted transcatheter embolization is only feasible if extravasation is seen, which is more likely in hemodynamically unstable patients. If bleeding site has been previously localized but the intervention by colonoscopy and transcatheter embolization have failed to achieve hemostasis, surgery may be required. Among patients with obscure (nonlocalized) recurrent bleeding, capsule endoscopy and CT enterography can be considered to identify culprit mucosal lesion(s). The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma.

BACKGROUND: Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II. METHODS: This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria. RESULTS: Twenty-seven patients (mean [range] age of 66.4 [37-79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m2 I.V. and 20 mg/m2 I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3-5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7-78.9) achieved complete response (CR), and 84% (95% CI=63.9-95.5) had complete and partial response per mRECIST for target lesions. DISCUSSION: TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.