Adventitial Drug Delivery of Dexamethasone to Improve Primary Patency in the Treatment of Superficial Femoral and Popliteal Artery Disease: 12-Month Results From the DANCE Clinical Trial 

Clinical Question:
Does adventitial delivery of dexamethasone as an adjuvant to standard endovascular revascularization improve outcomes in femoropopliteal peripheral artery disease?

Take-away Point:
Adventitial delivery of dexamethasone may be an effective and safe therapy to prevent restenosis of femoropopliteal popliteal artery disease.

Reference:
Razavi, M. K., Donohoe, D., D’Agostino, R. B., Jaff, M. R., & Adams, G. (2018). Adventitial Drug Delivery of Dexamethasone to Improve Primary Patency in the Treatment of Superficial Femoral and Popliteal Artery Disease. JACC: Cardiovascular Interventions, 11(10), 921-931. doi:10.1016/j.jcin.2017.12.015

Click here for abstract

Study Design: Prospective, multicenter, single-arm, open-label study

Funding Source: Mercator MedSystems, Inc.

Setting: Multicenter, 27 US sites

Summary 

The DANCE study enrolled 262 patients for a total of 283 limbs across 27 sites for the evaluation of adventitial delivery of dexamethasone as an adjunct to standard endovascular treatment of femoropopliteal PAD. The patient population consisted of more high-risk patients - increased calcification, popliteal artery involvement, complex TASCII B-D lesions and Rutherford category 4 disease – compared to those in the trials used to generate performance goals. Patients were categorized into two cohorts: atherectomy (ATX) and angioplasty (PTA). Adventitial access was achieved using the Bullfrog device in which a compliant balloon adapts to the vessel wall and a microneedle punctures into the perivascular tissue. An 80% dexamethasone to 20% contrast 3.2 mg/mL solution was used with an intended ratio of 1.6 mg drug per 1-cm of lesion length.

The overall 12-month primary patency in DANCE was 74.6% (95% CI 68.7-79.7%); 74.8% (66.6-81.5%) in the ATX cohort and 74.3% (65.6-81.5%) in the PTA cohort. This was noninferior to the 72.3% contemporary performance goal (met-analysis of pooled DCB studies) and superior to the 52.5% historical performance goal for both primary patency and intention to treat. ABI/TBI improved from baseline of 0.77 ± 0.24 to 12-month follow-up 0.94 ± 0.25 (p < 0.001). There were more stents placed in the DANCE trial than compared to pooled DCB studies however primary patency rates did not vary significantly in limbs with or without stents. There were no 30-day device or drug related severe adverse events. Of note, there was no concurrent control group that did not receive dexamethasone therapy.



Figure 5. The Kaplan-Meier estimates from (A) DANCE-ATX and (B) DANCE_PTA) are shown, with 12- and 130month data highlighted. ATX = atherectomy; CD-TLD = clinically driven targe lesion revascularization; DANCE = Dexamethasone to the Adventitia to Enhance Clinical Efficacy After Femoropopliteal Revascularization; PTA = percutaneous transluminal angioplasty.

Commentary

Dexamethasone is known to down-regulate cells linked to inflammatory re-stenosis. The delivery of dexamethasone is not a new concept, previously studied with systemic dosing and coronary drug-eluting stents, however those studies showed mixed results. Moreover, the concentration delivered in this study is more than 30 times the dosage concentration delivered from prior coronary stents.

Adventitial delivery offers many attractive qualities for drug delivery. The adventitia functions to regulate all cell trafficking into and out of the intimal cells; it is primed for the treatment of intimal disease such as restenosis. Tesfamarian states that “the adventitia appears to be an attractive therapeutic target to effectively inhibit inflammatory mediators,” in Vascular Pharmacology. This delivery system has the potential to modify the way drug delivery is performed for endovascular procedures, perhaps not just dexamethasone but alternative agents in the future.

Post Author:
Nicole A. Keefe, MD
Resident Physician
Department of Radiology and Medical Imaging
University of Virginia
@NikkiKeefe

Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer

Clinical Question: Does the combined used of microwave ablation and anti-CTLA-4 antibody tremelimumab improve outcomes among patients with refractory biliary tract cancer?

Take-away Points: A 50% disease response rate was observed among patients with refractory biliary tract cancer treated with the checkpoint inhibitor tremelimumab and microwave ablation. Non-dose-limiting adverse events were common.

Reference: Xie C, et al. Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer. Hepatology. Epub ahead of print 22 December 2018.

Click here for abstract

Study design: Prospective open-label single-arm cohort study

Funding source: National Institutes of Health/National Cancer Institute, AstraZeneca

Setting: Single Institution

Summary

Without surgical intervention, survival with first-line chemotherapy for biliary tract cancer (BTC) is less than one year. No standard second-line regimen exists, and outcomes among patients with treatment-refractory disease are poor. Recently, immunotherapy has shown promise for treatment of hepatocellular carcinoma (HCC), a close histologic relative of BTC. While response rates remain low, preliminary studies have suggested a positive effect of adjuvant treatments such as ablation or radiation therapy, possibly through immune stimulation. In the present investigation, researchers at the National Institutes of Health evaluated outcomes for 20 patients treated with the anti-CTLA4 checkpoint inhibitor tremelimumab combined with subtotal microwave ablation for refractory BTC. Primary outcome measures included progression-free survival (PFS) and overall survival (OS). An analysis of multiple immune response parameters was also performed. Results showed median PFS and OS values (3.4 months and 6.0 months, respectively) comparable to published data using cytotoxic chemotherapy. Overall response and disease control rates were 12.5% and 50.0%, respectively, with two patients achieving partial response and six (37.5%) with stable disease. One or more adverse events were observed in all patients (25.0% grade 4). Immune assays showed a significant increase in a subset of CD8+ cytotoxic T lymphocytes and decreased T cell clonality following initiation of therapy in a pattern different from that previously observed in HCC patients.



Figure: Progression-free survival (A) and overall survival (B) among patients with refractory biliary tract cancer treated with tremelimumab and microwave ablation.

Commentary

The revolution of cancer immunotherapy currently underway has revived interest in the potential immunomodulatory effects of local treatment modalities such as image-guided thermal ablation (IGTA). Spontaneous regressions of distant disease following IGTA—so called “abscopal effects”—have been known to occur since at least the early 2000s, though the phenomenon has proven infrequent and stubbornly unpredictable in routine clinical practice. As with abscopal effects observed following radiation therapy, the mechanism of action has been long been assumed immunologic in nature, and multiple studies have been conducted in an attempt to clarify the manner in which IGTA treatments augment tumoral antigenicity, such as increased levels of circulating pro-inflammatory cytokines and heat shock proteins. With the advent of checkpoint inhibitors and related agents, this paradigm has since shifted toward the investigation of IGTA as a potential immune-stimulatory adjuvant with the goal of optimizing treatment effects among patients receiving systemic immunotherapies. In the present investigation, researcher describe the feasibility of such an approach among patients with refractory biliary tract cancers undergoing treatment with CTLA4 inhibitor tremelimumab. Though clinical response rates were low, combination therapy with subtotal microwave ablation was found to yield significant modulation of T cell subspecies within the tumor microenvironment, and treatment-related adverse events were acceptable. Trials such as these offering compelling proof-of-principle evidence that medicine’s two “IOs”—immuno-oncology and interventional oncology—may together yield sufficiently powerful synergies to significantly impact patient outcomes, particularly for cancers that have proven themselves recalcitrant to conventional cytotoxic chemotherapy treatment regimens.

Post Author:
Aaron W.P. Maxwell, M.D.
Radiology Resident, PGY-5
Department of Diagnostic Imaging
The Warren Alpert Medical School at Brown University
@DoctorAWPM

In Vitro Evaluation of the Polymerization Properties of N-Butyl Cyanoacrylate/Iodized Oil Mixtures for Lymphatic Interventions 

Clinical question
What are the properties of N-Butyl cyanoacrylate (NBCA)-iodized oil mixtures which affect polymerization in an in vitro model?

Take-away point
Polymerization time of NBCA/iodized oil in lymphatic fluid is prolonged by increasing iodized oil and triglyceride (TG) concentrations.

Reference
Kuetting, Daniel, et al. In Vitro Evaluation of the Polymerization Properties of N-Butyl Cyanoacrylate/Iodized Oil Mixtures for Lymphatic Interventions. Journal of Vascular and Interventional Radiology. January, 2019. Volume 30, Issue 1, 110–117.

Click here for abstract

Study design: Translational

Funding source: Self-funded or unfunded

Setting: Single institution

Summary

The polymerization characteristics of NBCA/iodized oil mixtures have been studied extensively in the vascular system and, therefore, use of glue in the vascular system is reliable and predictable. However, factors influencing NBCA/iodized oil polymerization within the lymphatic system, which differs from the vascular system in both flow and fluid composition, is not as well studied.

In order to elucidate factors affecting polymerization of NBCA/iodized oil in the lymphatic system, the authors of this study looked at varying ratios of NBCA/iodized oil in lymphatic fluid samples which differed by triglyceride content. NBCA/iodized oil mixture ratios from 1:0 to 1:7 were evaluated in 8 different lymphatic fluid samples which, apart from triglyceride content, did not differ significantly in total protein, leukocytes, sodium, potassium, calcium, or chloride levels. Fluid samples were designated as low TGs (< 50 mg/dL), n=3;
Medium TGs (100–400 mg/dL), n=3; High TGs (> 700 mg/dL), n=2. They performed a “static analysis” of polymerization time by dropping different NBCA/oil mixtures in the various lymphatic samples and evaluating time to polymerization and total polymerization time using a high-speed camera. “Dynamic analysis” of polymerization time was performed by injection of different NBCA/oil mixtures into a dynamic flow model transfusion tube containing microcoils with a constant lymph flow rate. The total polymerization time was found to be dependent on the ratio of iodized oil and the concentration of TGs. In dynamic experiments, this difference in polymerization time was found to be less pronounced but in high TG samples, polymerization took significantly longer (between 43 s at a 1:1 ratio and 467 s at a 1:7 ratio). Occlusion with a 1:7 mixture was achieved in only 1 attempt and failed in the other 4 experiments.

Commentary

Using a clever dynamic flow model, the authors were able to determine that polymerization time of NBCA/iodized oil in the lymphatic system is dependent on both the NBCA/iodized oil ratio in addition to the TG content of lymphatic fluid. This is important because, until now, the behavior of glue was only best understood in the vascular system. The use of glue, however, is important in the treatment of chylous leaks as lymphatic fluid does not have the same clotting ability of blood. Knowledge of glue polymerization characteristics in the lymphatic system is important to avoid complications. Additionally, a priori knowledge of TG content in a patient for whom thoracic duct embolization is planned may warrant initiation of nutritional therapy to mitigate the risk of treatment failure. All in all, this work represents an important step toward better understanding the optimal use of one of our increasingly-utilized embolic agents in the lymphatic system.

Post Author:
Zagum Bhatti, MD
Assistant Professor
Department of Radiology, Interventional Radiology Division
University of Texas Health Science Center at Houston, Houston, TX
@ZagumBhatti

Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial

Clinical question
Does combination therapy of Sorafenib with cTACE increase overall survival for patient with advanced hepatocellular carcinoma?

Take-away point
In this phase III prospective appropriately powered clinical trial, there was no improvement in overall survival by combining TACE with Sorafenib in advanced HCC.

Reference
Park, Joong-Won, et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial. Journal of Hepatology. December, 2018. In Press.

Click here for abstract

Study design: Prospective Randomized Control Trial

Funding source: National Cancer Center, Korea.

Setting: Multihospital – across South Korea.

Summary

This is a prospective phase III randomized controlled clinical trial to evaluate the primary endpoint of overall survival (OS) in advanced HCC patients receiving either sorafenib alone or in combination with cTACE. The study was powered to detect no change. The authors found no improvement in OS with concurrent therapy (median survival 12.8 months) vs monotherapy with sorafenib alone (median survival 10.8 months). There was significant improvement in secondary outcomes, including time to progression, progression free survival, and tumor response rates, in those patients receiving combination therapy. The authors also noted in post-hoc analysis that patients who were only able to receive one cTACE session did especially worse (decreased OS), attributed to the significant increase in adverse events seen with combination therapy. Contrary to this, there was a suggestion of improved survival in those patients who underwent at least two cTACE sessions.

Commentary

This is a well-designed prospective study that sheds light on the use of multimodality therapy in advanced HCC. It should be noted that this study was performed in Korea, where hepatitis B virus (75%) was the dominant etiology with 68% of patients having cirrhosis. In addition, advanced HCC was defined by the modified Union for International Cancer Control (mUICC) staging system, that, while similar to BCLC, is slightly different in its definition of advanced HCC. The majority of the included patients had also undergone prior interventions for HCC, including 72% having previously undergone TACE.

The authors note the limitations of this study including the pre-supposed survival times not matching the observed survival times, potentially affecting the power of the study. They also note that while subject to bias, there was some observed improvement in survival for combination therapy in patients who were able to tolerate multiple sessions of cTACE. This may warrant additional evaluation, as patients who tolerate the side effect profile and can undergo multiple locoregional therapies may see some benefit from this dual therapy approach.

Post Author:
Daniel P. Sheeran, MD
Assistant Professor
Department of Radiology and Medical Imaging
Division of Vascular and Interventional Radiology
University of Virginia

Angioplasty Versus Stenting for Infrapopliteal Arterial Lesions in Chronic Limb-Threatening Ischaemia (Review)

Clinical question
Is there a benefit to percutaneous transluminal angioplasty (PTA) with stent placement versus PTA alone in the infrapopliteal arterial system in patients with Chronic Limb Threatening Ischemia (CLTI).

Take-away point
Based on review of available suitable studies, there is not enough evidence to suggest that stent placement in addition to PTA is superior to PTA alone the infrapopliteal arterial system provides added patency, and reduction in complications, mortality or amputation in patients with CLTI.

Reference
Hsu CCT et al. Angioplasty Versus Stenting for Infrapopliteal Arterial Lesions In Chronic Limb-Threatening Ischaemia (Review). Cochrane Database of Systematic Reviews 2018, Issue 12. Art No.: CD009195

Click here for abstract

Study design: Meta-analysis (other)

Funding source: Self-funded or unfunded

Setting: Various (meta-analysis)

Summary

Comprehensive review was performed of studies and trials that examined PTA versus PTA with stent placement in the infrapopliteal arteries (anterior tibial, peroneal and posterior tibial arteries, and the tibioperoneal trunk in patients classified with CLTI. After sorting through approximately 14k results, after multifactorial analysis to filter down to randomized or quasi-randomized trials, a total of seven studies were included. These included a variety of stent types (structure/drug presence/permanence) and CLTI stage. The timeframe of the selected studies ranged from 2006-2016. Exclusion criteria included patients that underwent atherectomy.

After analysis of the seven studies, the authors deducted that there was increased technical success rates when stent scaffolding was used. However, they found no significant difference in short term patency, complications, mortality or amputations. A weakness identified in comparing these studies included lack of uniformity of anti-platelet/anti-coagulation regimens.

Commentary

This review attempts to determine if there is sufficient evidence that can help establish superiority of scaffold placement in the infrapopliteal arteries for patients with CLTI. Although patency is considered similar for the two, the 6-month follow-up of most of the included studies is not sufficient enough to draw conclusions. Technical success is considered better with stenting, however availability and experience with tibial stenting would already assume better outcomes. There is considerable variability between the studies, including one study looking at bio absorbable stents (incidentally industry funded), and another that demonstrated a 5-fold increase in size of ulcers that were treated in the stenting cohorts. The lack of uniformity in anti-platelet/anti-coagulation treatment also creates significant bias.

What is clear is that truly randomized studies are needed for this patient population that needs as much patent flow as possible to prevent major amputation and death. This is of particular importance as currently there are self-expanding drug eluting tibial stents that will be shortly available for use, and we all need more understanding as to the appropriateness of stent placement other than as a bailout or clear refractory lesions despite aggressive interventions with differing balloon types and atherectomy.

Post Author:
Kumar Madassery, MD
Assistant Professor, Vascular & Interventional Radiology
Rush University Medical Center
Rush Oak Park Hospital
@kmadass

Effect of Hyperbilirubinemia on Hepatic Hypertrophy after Portal Vein Embolization and Liver Failure after Hepatectomy in Primary Biliary Malignancy

Clinical question
Does hyperbilirubinemia at the time of portal vein embolization (PVE) have an impact on hypertrophy of the future liver remnant (FLR) and the incidence of post-hepatectomy liver failure in primary biliary malignancy?

Take-away point
Hyperbilirubinemia at the time of PVE does not appear to have an effect on FLR hypertrophy. The incidence of grade 3 post-hepatectomy liver failure is not likely to be influenced, either.

Reference
Yim, Jaehyun et al. Effect of Hyperbilirubinemia on Hepatic Hypertrophy after Portal Vein Embolization and Liver Failure after Hepatectomy in Primary Biliary Malignancy. JVIR, Volume 30 , Issue 1 , 31 - 37

Click here for abstract

Study design:
Retrospective case-control study

Funding source:
Self-funded or unfunded

Setting:
Single tertiary referral center

Summary

Percutaneous transhepatic PVE is considered when extended hepatic resection for hepatobiliary malignancy is required but future liver remnant (FLR) volume is too small (recommended FLR 20-40%). High bilirubin levels at the time of PVE have been associated with poor hepatic hypertrophy and surgical outcomes. Treatment is often delayed to decrease serum bilirubin levels, which in turn risks progression of disease leading to unresectability. By convention, total serum bilirubin < 5mg/dl is recommended prior to PVE but this is not well defined in the literature. The authors divided 87 patients with primary biliary malignancy into a hyperbilirubinemia group (>3mg/dl) and a control group. FLR volumes and % FLR change were compared. Liver failure post-hepatectomy (defined as increasing INR and bilirubin levels on or after postop day 5) was also assessed. FLR volume and %FLR were not significantly different between the 2 groups on both univariable analysis and multivariable analysis (i.e. accounting for other potential factors affecting FLR hypertrophy). 75 patients underwent hepatectomy (n=23 right hepatectomy , n=52 right + seg IV). 63 patients experienced post-hepatectomy liver failure. Patients with hyperbilirubinemia had higher rates of hepatic failure after hepatectomy on univariable analysis but not significantly different on multivariable analysis.

Commentary

This retrospective study correlates total hyperbilirubinemia (5.80 ± 2.44 mg/dL) at time of PVE to FLR hypertrophy. The results suggest that PVE can be safely performed with hyperbilirubinemia without concern for inferior FLR hypertrophy outcomes. The study has the common limitations of a retrospective review and low patient numbers. The authors note that several factors affect FLR hypertrophy and many of these were accounted for in the multivariable analysis. This lends credence to the results of the study. A few factors were unaccounted for (e.g. fatty liver change) however the authors recognize this as a potential weakness. The percentage of liver failure following hepatic resection in this study is unusually high and substantially higher than comparative studies (49% vs 1.2-32%). This is attributed to a large number of patients in this study not achieving an FLR > 20% after PVE and prior to hepatectomy. FLR remnants < 20% following PVE suggest either a substandard PVE technique resulting in lower hypertrophy percentages or un-accounted confounding factors. Additionally, no explanation was provided by the authors for the amplified resection rates in patients without standard adequate FLRs, which in most literature requires at least 20% FLR. There is good merit in this study in that many practitioners performing PVE are likely using an anecdotal bilirubin of < 5mg/dl as a cutoff for PVE, which is based upon surgical literature. Future directions of study could include a subgroup analysis to identify a bilirubin inflection point where hepatic hypertrophy noticeably decreases. Further studies in this area will providence evidence based bilirubin criteria for improved outcomes following PVE and surgical resection.

Post author
Trevor Downing, M.D.
Assistant Professor
Department of Interventional Radiology
Wake Forest University, Baptist Medical Center
Winston Salem, N.C.

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization

Clinical question: What effect does the UGT1A1 phenotype have on plasma and tumor drug and metabolite concentrations and pharmacokinetics after hepatic chemoembolization with irinotecan-eluting beads (DEBIRI)?

Take-away point: Hepatic lobar DEBIRI results in similar exposure of target tumor and remote normal liver tissue to irinotecan and active metabolite regardless of UGT1A1 mutation status.

Reference: Levy EB, Peer C, Sissung TM, Venkatesan A, Pandalai P, Greten T, et al. Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization. J Vasc Interv Radiol. 2019 Jan;30(1):19–22.

Click here for abstract

Study design: Cohort study (prospective observational study)

Funding sources: Cooperative Research and Development agreement with BTG/Biocompatibles, the Intramural Research Program of the National Institutes of Health and the Center of Interventional Oncology, Grant ZID BC011242-10.

Setting: Single institution pilot study

Summary 

Chemoembolization with irinotecan-eluting beads (DEBIRI) as salvage therapy for colorectal hepatic metastases has shown improved progression-free survival (PFS) and overall survival (OS). However, the concentrations of irinotecan and active metabolites achieved within hepatic metastases after fixed-dose chemoembolization and the role of the UGT1A1 polymorphism on response and toxicity from DEBIRI are unknown.

The investigators performed a prospective study on five patients with inoperable hepatic metastases from 2011 to 2014. In the seven treatments performed, each patient received 2 ml of 100–300-μm DC Bead preloaded with 100 mg irinotecan through a microcatheter positioned in the proximal lobar and/or segmental artery. Demographic data collected included prior treatments, lesion max diameter, and UGT1A1 status. Plasma and liver tissue samples of irinotecan (CPT-11), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G, were sequentially measured to determine the maximum concentration (Cmax) and the time to Cmax (Tmax). Within the cohort, three patients had wild-type (WT) UGT1A1 genotypes while 2 had variants (VARs). The plasma CPT-11 Cmax was significantly higher for WT and the SN-38 Cmax and AUC for WT was significantly lower versus VAR. No differences in tissue pharmacokinetic parameters were observed between VAR and WT patients.

Commentary

DEBRIRI resulted in four times higher exposure delivered to the tumor and 1000–10,000 times less systemic irinotecan and SN-38 compared to systemic administration of irinotecan. Despite these findings, three patients experienced lymphopenia during the study. Additionally, it does not appear as though the UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI. While DEBIRI imparts a survival benefit compared to systemic therapy with folinic acid, fluoroucil, and irinotecan, the adverse event profile appears to mimic that of systemic therapy. Previous studies have demonstrated the non-significant influence of the UGT1A1 gene polymorphism on the rate of irinotecan-associated toxicity in patients receiving irinotecan based chemotherapy .In accordance, this study demonstrated that predicting the incidence of thrombocytopenia based on UGT1A1 status following DEBIRI is not reliable.

Post Author:
Jacob Bundy, MD, MPH
PGY-1
Department of Surgery
University of Michigan Health System
@JBundyRad

Efficacy and Radiation Expoure of Ultra-Low-Dose Chest CT at 100 kVp with Tin Filtration in CT-Guided Percutaneous Core Needle Biopsy for Small Pulmonary Lesions Using a Third-Generation Dual-Source CT Scanner 

Clinical question
What is the efficacy and radiation dose performing a percutaneous core needle biopsy using an ultra-low-dose CT at 100 kVp with tin filtration?

Take-away point
Ultra-low-dose CT utilizing a Tin filtration can decrease patient effective dose by over 92% during percutaneous lung lesion biopsy.

Reference
Li, Chunhai et al. Efficacy and Radiation Exposure of Ultra-Low-Dose Chest CT at 100 kVp with Tin Filtration in CT-Guided Percutaneous Core Needle Biopsy for Small Pulmonary Lesions Using a Third-Generation Dual-Source CT Scanner. Journal of Vascular and Interventional Radiology. January, 2019. 30: 95-102.

Study design: Randomized Control Trial

Funding source: Self-funded or unfunded

Setting: Single Institution

Summary

Percutaneous lung biopsy (PLB) is a minimally invasive procedure to guide subsequent treatment. Radiation dose continues to be a hot topic within radiology with continued research in minimizing patient dose during diagnostic and interventional procedures. Prior studies have demonstrated that low-dose protocols using kVp less than or equal to 100 can significantly lower radiation dose during PLB with comparable technical success to standard CT technique (120 kVp). While decreasing kVp reduces patient dose, the lower photon energy range of the polyenergetic spectrum does not exit the patient. Newer technology in third-generation dual-source CT scanners with tin filtration allow spectral shaping to minimize this dose effect by removing much of the low-energy photons that predominantly lead to patient exposure. While low-dose CT with tin filtration has been studied for diagnostic purposes, to this date, there has been no study to evaluate the purpose for PLB.

Using a third-generation dual source CT scanner (SOMATOM Force; Siemens), 210 patients were randomly assigned to standard low-dose CT (110 kVp, 70 patients) or ultra-low-dose CT with filtration (100 kVp, 140 patients). Biopsies were evaluated for diagnostic accuracy and subjective image quality. Technical success was achieved in 97.1% vs 98.5% (ultra-low-dose vs low-dose CT). Pulmonary hemorrhage, pneumothorax and chest tube placement rates were comparable between the two groups: 50.7%, 21.4% and 13.3% vs 45.7%, 18.5% and 7.6% (ultra-low-dose versus low-dose CT). On a subjective 1-5 scale, diagnostic quality was lower in the ultra-low-dose CT group (3.67 vs 4.32, p=0.33). Mean total dose length product and effective dose were significantly lower in the ultra-low-dose CT group (9.84 mGy-cm vs 110.52 mGy-cm, P < .001 and 0.14 mSv vs 1.78 mSv , p < .001) with an 92.1% average reduction of effective dose. The authors concluded that despite decreased image quality, PLB can be performed with comparable safety and accuracy and with a significant decrease in patient dose.



Fig 3. Ultra-lowe dose CT-guided PCNB of a small pulmonary lesion. (a, b) Diagnostic quality CT images at 120 kVp showed a 1.9 cm lesion (arrow) in the left upper lobe before the lung biopsy. Note also the biopsy pathway should not cross a lung fissure (arrowhead). (c, d) The position of the lesion and the needle tip were clearly seen by ultra-low-dose CT scanning at 100Sn kVp and 70 mAs (total DLP, 9.6 mGy-cm; ED, 0.13 mSv). PCNB was conducted successfully without complications. The lesion was confirmed as adenocarcinoma on both biopsy and surgical resection.

Commentary

CT guided biopsies and drainage are common procedures. This study demonstrates there is comparable safety and accuracy while utilizing an ultra-low-dose CT technique with tin filter for PLB. This result may be reproducible in other parts of the body and with other procedures such as ablation and drainage. However, the lung may be the optimal organ for ultra-low-dose CT given the drastic differentiation between lesion (solid) and back ground tissue (predominantly air). As such, degraded image quality may be a larger hindrance for performance in other locations. Additional investigation, will further determine how widespread this technique should be employed, however any protocol that can significantly lower effective dose should be strongly considered for its benefits compared to risks.

Post Author:
David M Mauro, MD
Assistant Professor
Department of Radiology
Vascular and Interventional Radiology
University of North Carolina
@DavidMauroMD

Outcomes of Patients with Hepatocellular Carcinoma Treated with Conventional Transarterial Chemoembolization Using Guidance Software

Clinical question
Does guidance software during conventional TACE improve outcomes in patients with HCC?

Take-away point
Guidance software during c-TACE for HCC can help identifying tumor feeders promoting procedural technical success.

Reference
Miyayama S, Yamashiro M, Sugimori N, Ikeda R, Okimura K, Sakuragawa N. Outcomes of Patients with Hepatocellular Carcinoma Treated with Conventional Transarterial Chemoembolization Using Guidance Software. J Vasc Interv Radiol. 2019 Jan;30(1):10-18.

Click here for abstract

Study design: Retrospective

Funding source: Self-funded or unfunded

Setting: Single-center

Summary

Japanese investigators presented their results on outcomes of conventional transarterial chemoembolization (c-TACE) using guidance software for hepatocellular carcinoma (HCC). 

102 patients were included for a total of 190 tumors. Maximum diameter and the number of lesions were 7cm and 5, respectively. Patients who had other types of liver-directed therapy such as DEB-TACE and percutaneous ablation were excluded. Technical success was classified by computed tomography performed 1 week after the procedure (A, complete embolization with a safety margin; B, entire tumor embolization without a safety margin; and C, incomplete embolization). Intrahepatic tumor recurrence was classified into 2 categories: local tumor progression (LTP) and intrahepatic distant recurrence (IDR). The incidences of LTP between grade A and B tumors, IDR with/without LTP, and OS with/without LTP were compared. They found that 156 (82.1%) tumors were grade A, 26 (13.7%) were grade B, and 8 (4.2%) were grade C. The 1-, 3-, and 5-year LTP and IDR rates were 31.7%, 49.4%, and 59.4% and 33.9%, 58.2%, and 73.3%, respectively. LTP developed more frequently in grade B tumors than in grade A tumors (P = .0016). IDR developed more frequently in patients with LTP than without LTP (P = .0004). The overall 1-, 3-, and 5-year OS rates were 96.1%,71.1%, and 60%; the 1-,3-,and 5-year OS rates in patients with LTP was 95.7%, 69.8%, and 59.3%, and 96.2%, 71.6%, and 59.4% in patients without LTP (P = .9984). Authors concluded that guidance software during c-TACE promotes the technical success of the procedure with excellent OS in HCC patients.



Figure: Conventional 2D DSA imaging compared to 3D roadmap provided by guidance software.

Commentary

This paper presents an additional tool to ensure proper lesion targeting during c-TACE for HCC patients.

Selective embolization of all vessels feeding the tumor and adjacent parenchyma is a fundamental requirement to ensure proper tumor response. Although local tumor control did not impact OS in this study, there have been other studies showing that complete tumor response, especially after first TACE, is a predictor of favorable outcome. Therefore, appropriate targeting is critical during the procedure. Given the variance of the hepatic arterial vascularization and exuberant tumoral vessel recruitment commonly seen in HCC, conventional 2D images may not display all the feeding vessels. This study demonstrates the application of guidance software, which highlights all the feeding vessels in a 3D fashion, creating an accurate roadmap for catheter navigation and positioning prior to embolization. In the study, a great majority of lesions (82.1%) presented excellent tumor response (complete embolization of the tumor with safety margin) and these patients had less local and distant intrahepatic tumor progression. One of the limitations of this study was the lack of a control group treated without guidance software to better assess the impact of this new technology. Nevertheless, the study shows excellent results by utilizing this new technology, therefore paving the way for larger comparative studies. Technological advancement and innovation are embedded in our specialty and we should always explore new tools to better treat our patients.

Post Author:
Ricardo Yamada, MD
Assistant Professor
Department of Radiology
Division of Vascular and Interventional Radiology
Medical University of South Carolina

Feasibility of Boosted Radioembolization for Hepatocellular Carcinoma Larger than 5 cm 

Clinical question
Are Y90 doses larger than 150 Gy beneficial in the treatment of HCCs measuring more than 5 cm?

Take-away point
Boosted Y90 doses seem to show promising results, with 80% complete response of the target tumor, however 15% of patients suffered symptomatic biliary strictures requiring treatment.

Reference
Kim HC, Kim YJ, Lee JH, Suh KS, Chung JW. Feasibility of Boosted Radioembolization for Hepatocellular Carcinoma Larger than 5 cm. J Vasc Interv Radiol. 2019 Jan;30(1):1-8. doi: 10.1016/j.jvir.2018.07.002. Epub 2018 Oct 4. PubMed PMID: 30293734.

Click here for abstract

Study design
Retrospective review 20 patients

Funding source
Self-funded, unfunded

Setting:
Seoul National University Hospital

This retrospective study evaluated the outcomes of radioembolization with glass microspheres using doses larger than 150 Gy for the treatment of HCCs larger than 5 cm. Other inclusion criteria included nodular tumor, BCLC stage A/B and tumors treated with a single Y90 session. Patients were excluded if the tumor was infiltrative, smaller than 5 cm, BCLC stage C/D, 2 treatment sessions for bilobar HCC, previous treatment for HCC and extra-hepatic metastasis.

Twenty, non-consecutive patients were included, 13 patients had a single tumor, 7 multiple tumors. Average tumor diameter was 7.6 cm (range 5.1-13 cm). Radioembolization was performed in a) segmenta/sub-segmental branches, if the tumor was peripheral, b) in lobar arteries if the tumor was central and small branches arising from the lobar branch fed the tumor and c) dominant tumor feeding artery or caudate artery if the tumor had a dominant artery or the tumor was central and supplied by the caudate artery. The authors sought to treat the target liver volume with doses that ranged from 180-240 Gy, with an intended tumor dose of 300 Gy.

The mean percentage of treated liver volume divided by whole liver volume was 61% (33-79%), mean total radiation activity was 4.96GBq (1.63-9.15GBq), mean target perfused tissue dose 263.5 Gy (156.2-550.6 Gy), median number of vials 4 (2-7 vials). 19.3% of vials were injected into a lobar artery, 45.8 % into a segmental artery and 35% into a sub-segmental artery. Five extra-hepatic feeding arteries were treated (inferior phrenic and right internal mammary artery. Seven patients suffered abdominal/chest pain requiring medication, 3 patients developed biliary strictures that required biliary drainage and antibiotic therapy, 1 patient developed asymptomatic biliary dilation. All 4 patients that presented with biliary stricture underwent treatment of the caudate artery.

Median follow up was 11.6 months (6.3 – 22 months). Complete response (CR) was seen in 60% of patients at 3 months, based on best tumor response, CR was seen in the entire liver and for the primary index tumor in 70% and 80% of patients, respectively. Local progression-free survival and progression free survival rates were 94% and 74% at 1 year respectively. 25% of patients underwent surgical resection, 1 patient had partial response at 1 month on CT and underwent resection 1.6 months after radioembolization, and on pathologic evaluation there was 60% necrosis. 4 patients had CR on a 3 month CT and underwent resection after 3 months showing complete necrosis on pathologic examination.

The authors highlight that the median total activity used in this study, 4.88 GBq, is higher than what has been reported for radiation segmentectomy (0.95-1.59 GBq) and for the previously reported boosted dose (2.9 GBq), with no instances of radiation induced liver disease (RILD). By applying surgical criteria for HCC surgical resection, if 40% of the total liver is not treated with Y90, the risk of RILD can be minimized even if a boosted dose is used for treatment. In this study the mean percentage of untreated liver was 38.9%. Complications in this study included seven patients that suffered chest/abdominal discomfort classified as Grade 2, 3 patients with a biliary stricture requiring antibiotics and drainage, and 1 patient with asymptomatic biliary stricture. The authors reinforce that care should be taken when treating a caudate artery branch, and that further studies are needed to identify the adequate dose to maximize tumor death and minimize biliary damage.

This study is limited by the retrospective nature of the study, the small sample size, the non-consecutive treatment of patients, and the lack of long term follow up.

The authors conclude that boosted dose radioembolization of large HCC shows favorable results, but with a relatively high biliary complication rate.



Figure- A) Hypervascular central HCC measuring 5.2 cm B) MIP image from C arm CT showing the hypervascular tumor being supplied by 3 major branches (marked by the arrows). C) 1 month follow up CT scan shows no viable tumor, D) MRI at 6 months shows no residual tumor enhancement and biliary dilation (arrowhead).

Commentary

Boosted doses of Y90 microspheres appear to show promising results in the treatment of large HCCs. CR for the entire liver and for the primary tumor index was seen in 70% and 80% respectively, with local progression free survival and progression free survival rates at 1 year of 94% and 74% respectively. The authors highlight that from a technical standpoint, boosted doses of Y90 can be safely injected by sub-selecting the segmental and sub-segmental branches feeding the tumor, or by additional treatment of the dominant tumor supplying artery or caudate artery. The doses injected were clearly above previously published doses, with no instances of RILD, however if the caudate artery is treated with high doses there could be a high risk of biliary strictures requiring treatment. Larger studies are required to be able to confirm the results as well as maximization of caudate artery doses to maximize tumor death and minimize biliary damage.

Post Author
Carlos J. Guevara, MD
Assistant Professor
Department of Radiology, Interventional Radiology Division
University of Texas Health Sciences, Houston
@CarlosGuevaraIR