An overview of select clinical research trials in IR
By Chad Burk, MD Summer 2016
Interventional radiology is at a crucial turning point. While innovation and feasibility testing has been and will always be at the foundation of our ﬁeld, the future of interventional radiology is dependent on prospective, randomized clinical trials. Such outcomes research will allow us to demonstrate the efficacy, safety, cost-effectiveness and comparative beneﬁt of the therapies IR offers.
A number of pioneering SIR members have been leading important clinical trials to investigate the possible synergistic effects of radioembolization with standard chemotherapy for nonresectable hepatic metastases, the therapeutic applications of new devices including the Kiva device for vertebral compression fractures and a convertible inferior vena cava ﬁlter, and the possible improved management of acute deep venous thrombosis.
FOLFOX Plus SIR-SPHERES MICROSPHERES Versus FOLFOX Alone in Patients With Liver Mets From Primary Colorectal Cancer (SIRFLOX)
Participants: 500+ patients; 136 sites
Primary investigators: Peter Gibbs; Guy A. van Hazel, MBBS
Launched: August 2006
Estimated completion: January 2017
Status: Ongoing, not recruiting
Systemic chemotherapy has long been ﬁrst-line therapy for unresectable metastatic colorectal cancer to the liver. While other gastrointestinal neoplasms have demonstrated increased response to the synergistic effects of concurrent systemic chemotherapy and radiation therapy, nonconformal and stereotactic radiotherapy of liver lesions has been complicated by technical factors, such as the movement of many hepatic lesions with the respiratory cycle and dose-limiting radiation-induced liver disease that has been associated with mean radiation dose to normal liver parenchyma.
Drs. Gibbs and van Hazel therefore set out to investigate whether selective internal radiation therapy (SIRT) could provide a synergistic added beneﬁt to systemic chemotherapy in the treatment of unresectable metastatic colorectal cancer (mCRC).
The international SIRFLOX multicenter randomized controlled study was designed to primarily determine if there was a difference in progression- free survival in patients with unresectable liver-only or liver- dominant metastatic colorectal cancer when treated with the standard first-line FOLFOX6m (with or without bevacizumab) chemotherapy regimen and those treated with FOLFOX6m (±bev) with ytterium-90 (Y-90) radioembolization.
More than 500 patients have been enrolled at 136 study locations since August 2006. Although the estimated primary completion date is not until January 2017, preliminary data suggest an increase in liver progression-free survival from 12.6 months with FOLFOX alone to 20.5 months when Y-90 is added. Statistically signiﬁcant increases were also observed in hepatic response rates (68.8–78.7 percent) and the rate of complete response (1.9–6.0 percent) when Y-90 SIRT is added to the treatment regimen.
At the SIR 2016 Annual Scientiﬁc Meeting, further data was presented that demonstrated that, while extrahepatic-only sites of ﬁrst progression, primarily lung, more commonly occurred in the SIRT treatment cohort, 47.7 percent compared to 7.9 percent for the systemic chemotherapy-alone regimens, the median time to lung- only progression was delayed in the SIRT cohort measuring 12.5 months as compared to 8.9 months in those treated with FOLFOX.
Furthermore, in patients treated with Y-90, not only was the liver less commonly the site of ﬁrst progression but, when hepatic ﬁrst progression did occur, it less frequently involved existing liver lesions. Not only are these preliminary results very exciting, but SIRFLOX is also the largest randomized trial ever conducted that is combined in interventional radiology procedure with chemotherapy and oncology.
Final data from the SIRFLOX trial, and associated FOXFIRE and FOXFIRE Global studies, including other secondary endpoints such as liver resection rate and overall survival, are expected to be available in 2017.
The Kiva System as a Vertebral Augmentation Treatment (KAST)
Primary investigators: Steven R. Garvin, MD; Sean M. Tutton, MD, FSIR
Launched: July 2010
Published in: Spine, volume 40, number 12, pages 865–875.
Osteoporotic vertebral compression fractures (VCFs) pose a signiﬁcant burden to patients and the US. medical system as a whole because of the resulting morbidity and possibility of complication-related mortality to a signiﬁcant portion of the U.S. population. Minimally invasive vertebroplasty and balloon kyphoplasty are offered to patients with refractory pain, progressive deformity, and functional decline due to VCFs. However, new adjacent level fractures can occur at an incidence up to 50 percent up to two years after balloon kyphoplasty.
“We really have not changed how we have treated vertebral body compression fractures for many years, and the KAST trial is the ﬁrst prospective randomized trial in the space to evaluate a new technology,” explains Dr. Tutton. The Kiva vertebral compression fracture treatment system is a novel unipedicular cannula- delivered, coil-shaped, implantable vertebral body reservoir deployed over a nitinol coil and subsequently injected with polymethylmethacrylate (PMMA) developed by Benvenue Medical (Santa Clara, California) as an alternative to traditional vertebral augmentation.
Starting in July 2010, under the guidance of Dr. Sean Tutton (Medical College of Wisconsin) and Dr. Stephen Garﬁn (University of California, San Diego), the KAST trial begin enrolling patients with one or two vertebral compression fractures of the thoracic or lumbar vertebral spine, conﬁrmed by marrow edema on T2 STIR MR, a functional disability measuring greater than 30 percent on the Oswestry Disability Index, and greater than 70/100 pain at two weeks or 50/100 pain at six weeks of conservative fracture management, to test the new Kiva device. Absence of device-related adverse events, maintenance or improvement in functional disability, and greater than 15 mm in fracture-related pain reduction were evaluated as the primary measures at 12 months post randomization into the balloon kyphoplasty or Kiva implant treatment arms.
Results from the patients enrolled in this international multispecialty multicenter trial were ﬁrst received in August 2014 and have demonstrated noninferiority of the Kiva implant relative to balloon kyphoplasty in VCF pain or functional disability without serious device-related adverse events, concluding the trial before full enrollment.
In addition to demonstrating reduced contrast extravasation in the Kiva implant treatment arm, Dr. Tutton is hopeful that longer-term follow-up and more robust meta-analysis with similarly designed international clinical trials may reveal improvements in posttreatment kyphotic angle and decreased adjacent fracture rates compared to current treatment methods. Preliminary subgroup analysis also suggests that there may be a reduction in readmission and re-intervention in the cohort treated with the Kiva VCF treatment system.
At SIR 2016, the results from a smaller cohort study using the KIVA device in the treatment of pathologic compression fractures secondary to multiple myeloma were presented demonstrating noninferiority to vertebroplasty in postprocedural pain relief. The ﬁndings of the KAST trial have been published in the Spine Journal (volume 40, number 12, pages 865–875).
VenaTech Convertible Vena Cava Filter U.S. Multi- Center Clinical Trial
Participants: 149 patients; 11 sites
Primary investigator: William S. Rilling, MD, FSIR
Launched: December 2011
Estimated completion: September 2015
Inferior vena cava (IVC) ﬁlters play an important role in mitigating the risks of acute pulmonary embolism when patients have failed medical anticoagulation therapy or anticoagulants are contraindicated. However, retrieval of optional IVC ﬁlters following the period of increased risk for venous thromboembolism can be impaired by ﬁlter tilting, migration or embedding into the IVC wall, which may require complex sophisticated invasive techniques for ﬁlter retrieval or may result in nonretrieval of a ﬁlter. Furthermore, retrievable ﬁlters are designed with limited points of contact with the IVC, which may result in ﬁlter stress point fractures or IVC penetration and possible damage to adjacent organs.
The VenaTech convertible ﬁlter (B. Braun Medical, Chasseneuil, France) uses features of durable permanent IVC ﬁlters, such as self-centering stabilizing legs for fewer long-term ﬁlter complications, and incorporates the ability to remove the ﬁlter head, leaving a nonﬁltering IVC stent-like device in place.
Under the guidance of principal investigator, Dr. Rilling (Medical College of Wisconsin; MCW), 149 patients at 11 sites were deemed candidates for IVC ﬁlter placement and underwent VenaTech convertible IVC ﬁlter implantation since December 2011. The preliminary data presented at SIR’s 2015 annual meeting and deemed one of the “Abstracts of the Year” demonstrated a primary outcome measure of IVC ﬁlter conversion rate of 93 percent, which exceeds reported IVC ﬁlter retrieval rates.
The technical complications associated with the 7 percent nonconversion rate involved inability to snare the ﬁlter hook and incomplete conversion to IVC stent conﬁguration despite adjunctive measures. Dr. Rilling emphasizes that although this is an entirely new concept in IVC ﬁltration, ﬁlter conversion is a simple procedure and no adverse events such as inferior vena cava injury or ﬁlter head embolism were related to the conversion procedure.
At SIR 2016, the results of additional follow-up of the enrolled patients demonstrated a low incidence of adverse ﬁndings on CT examination 6 months after IVC ﬁlter conversion. In the cohort, 6 percent of converted ﬁlters demonstrated incomplete opening of the ﬁltering legs, 3 percent demonstrated grade 2 penetration of the IVC, and no instances of intimal hyperplasia, spontaneous conversion, or ﬁlter fracture were seen at 6-month follow-up. “The design of this new convertible ﬁlter utilizes many of the characteristics of a durable long-term tested permanent IVC ﬁlter, which addresses many of the most signiﬁcant ﬂaws associated with retrievable ﬁlters that can lead to complications,” explains Eric J. Hohenwalter, MD, FSIR, of MCW.
Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT)
Participants: 692 patients; 58 sites
Primary investigator: Suresh Vedantham, MD, FSIR; Clieve Kearon, MB, MRCP, FRCP(C), PhD
Launched: November 2009
Estimated completion: May 2016
Status: Active, not recruiting
The clinical controversy of whether catheter-based interventions for new-onset acute deep venous thrombosis should be routinely implemented has persisted, for many years, unanswered. Thanks to Dr. Vedantham, Washington University, St. Louis, Missouri, and his collaborators nationwide, this question is gaining some much-needed scrutiny. For patients who experience acute deep venous thrombosis, there is up to a 50 percent risk for developing postthrombotic syndrome (PTS), a debilitating long-term complication that can include pain, paresthesias and edema, symptoms that are most pronounced after walking or standing for long periods of time.
It has long been suspected that rapid clot lysis could decrease the incidence or completely prevent PTS. However, operative thrombectomy or endovascular thrombolysis only carries a 2B recommendation by the American College of Chest Physicians Evidence-based Practice Guidelines.
The ATTRACT trial has sought to delineate the comparative efficacy of the current standard of care, unfractionated heparin bridge to warfarin with elastic compression stockings, versus pharmacomechanical catheter-directed thrombolysis (PCTD) with intrathrombus delivery of ﬁbrinolytic recombinant tissue plasminogen activator (rt-PA) up to 24 hours at improving long-term DVT patient outcomes with acceptable risk and cost.
Since November 2009, roughly 700 patients aged 16 to 75 at 58 centers in the United States presenting with new-onset symptomatic proximal DVT, deﬁned as less than 2 weeks of symptoms and without previous symptomatic DVT within the index leg within the last 2 years, involving the iliac, common femoral and/or femoral vein have been randomized to receive optimal standard DVT therapy alone or pharmacomechanical catheter-directed thrombolysis utilizing a Trellis-8 or Angiojet device or a multisidehole infusion catheter with rt-PA.
The study seeks to primarily determine the cumulative incidence of PTS, as measured by the Villalata scale, in both the intervention and control cohorts.
Secondarily, they seek to determine relative differences in PTS severity, degree of clot lysis, venous valvular reflux prevalence, cost-effectiveness, major bleeding, symptomatic pulmonary embolism, and death, among other factors, within 10 days and 24 months after randomization between the two groups.
This will be the largest prospective database correlating postthrombotic quality of life to objective measures of chronic venous disease and physiologic measures of venous valve function. Dr. Vedantham hopes that the ATTRACT trial will provide “insights into how to improve the care of patients with acute deep vein thrombosis and what pathways future investigations should take” to prevent PTS. He is optimistic that a positive outcome in the ATTRACT trial will demonstrate the medical need for further investigation and financial investment in new therapies. Final two-year follow-up data for the ATTRACT trial will be collected in December 2016.
As we reﬂect on the idea-cultivating excitement surrounding the scientiﬁc discoveries presented at the SIR annual meeting in Vancouver and the potential modiﬁcations we may try to implement in our own individual practices based on the presented research, it is easy to comprehend how the above clinical trials can have a profound impact on the future of patient care and the ﬁeld. Dr. Vendantham says that “these are the types of studies that will convince others outside our ﬁeld that what we do has value and help us re-evaluate procedures where the value is less evident.” We must continue to develop and cultivate clinical investigators to properly design and perform these types of randomized prospective studies. There is truth in the data. Now all we need to do is generate the data.
Chad Burk, MD, is a member and immediate past communications chair of the SIR Residents, Fellows and Students Section