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Supplement • Volume 5, Issue 12 • July 25, 2014

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma Reports From the Society of Interventional Radiology (SIR) 2014 Annual Scientific Meeting, San Diego

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Plus a Discussion on Interventional Oncology:

The Fourth Pillar of Oncology Editor-in-Chief, James O. Armitage, MD

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The ASCO Post (ISSN 2154-3283), USPS Publication Number 6885, is published semi-monthly, except monthly in January, April, August, and October by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at 888.282.2552, 703.299.0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email norman@harborsidepress.com or fax 631.692.0805. Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologists/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $271; Individual International: $523; Institutional Domestic: $335; Institutional International $587. Contact subscriptions@harborsidepress.com. Correspondence: Address general inquiries to Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

About the Cover Art Chemoembolization treats cancerous tumor 1. Chemotherapy delivered to tumor 2. Embolic agents block blood flow 3. Reduced-sized tumor by chemoembolization (1) A high dose of chemotherapy is delivered directly to the organ while depriving the tumor of its blood supply. (2) By blocking, or embolizing, the arteries feeding the tumor, embolization particles obstruct blood flow to and from the tumor. (3) The embolic agents keep the chemotherapy in the tumor by blocking the flow to other areas of the body. The illustrations are copyrighted to the Society of Interventional Radiology.

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting INTRODUCTION

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Reports From the Society of Interventional Radiology (SIR) 2014 Annual Scientific Meeting, San Diego By Jonathan Batchelor

nterventional therapies for hepatocellular carcinoma landed in interventional radiology’s wheelhouse a little over 20 years ago, with the development of doxorubicin-ethiodized oil emulsion and gelatin sponge particles to chemoembolize unresectable liver tumors.1,2 Median survival rates associated with these early interventional treatments were reported at 14 months, which was a significant gain over the 4.5 to 6 months’ expected survival of untreated patients.1 Subsequently, a wide range of therapeutic interventions have been assessed in patients with unresectable hepatocellular carcinoma, including transarterial embolization (with or without chemotherapy), hormone therapy with antiestrogens and androgens, octreotide, interferon, and systemic chemotherapy. Of these interventions, only chemoembolization has improved survival over symptomatic care.3 Sorafenib (Nexavar), approved by the U.S. Food and Drug Administration in 2007 for the treatment of patients with unresectable hepatocellular carcinoma, showed an improvement in survival of approximately 3 months compared to placebo.4 External-beam radiation therapy was considered a treatment option in patients with unresectable hepatocellular carcinoma, but its role has been limited due to radiation toxicity to adjacent normal liver tissue.5 Stereotactic techniques have mitigated much of this issue, but current research has found median survival for patients treated with stereotactic body radiotherapy is 7.9 months (95% confidence interval = 2.8–15.1 months).6 Over the past 2 decades, much has changed for transarterial chemoembolization. Tools and techniques have become more refined, beads have become smaller, radioembolization has been introduced, and criteria for patient suitability have expanded. It remains the only treatment to have a demonstrated record for significant improvements in overall surJonathan Batchelor is a medical reporter and writer living in Tuscon, Arizona

vival, progression-free survival, and quality of life in patients with unresectable hepatocellular carcinoma. The Society of Interventional Radiology (SIR) 2014 Annual Scientific Meeting held in San Diego earlier this year brought together researchers and clinicians from all over the world. In this supplement to The ASCO Post, readers will find a compilation of reports on data presented at SIR in regard to interventional oncology therapies for unresectable hepatocellular carcinoma. First, however, we present highlights from interviews The ASCO Post conducted with four interventional oncology practitioners on current practices and procedures used in treating patients with unresectable hepatocellular carcinoma. n Disclosure: This supplement is supported by BTG. The ASCO Post reporter and writer, Jonathan Batchelor, has reported no potential conflicts of interest.

References 1. Clouse ME, Stokes KR, Krystal JB, et al: Chemoembolization for hepatocellular carcinoma: Epinephrine followed by a doxorubicin-ethiodized oil emulsion and gelatin sponge powder. J Vasc Interv Radiol 4:717-725, 1993. 2. Stuart K, Stokes K, Jenkins R, et al: Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oil/gelatin powder chemoembolization. Cancer 72:3202-3209, 1993. 3. Burroughs A, Hochhauser D, Meyer T: Systemic treatment and liver transplantation for hepatocellular carcinoma: Two ends of the therapeutic spectrum. Lancet Oncol 5:409–418, 2004. 4. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008. 5. Fuss M, Salter BJ, Herman TS, et al: External beam radiation therapy for hepatocellular carcinoma: Potential of intensity-modulated and image-guided radiation therapy. Gastroenterology 127(5 suppl 1):S206–S217, 2004. 6. Culleton S, Jiang H, Haddad CR, et al: Outcomes following definitive stereotactic body radiotherapy for patients with ChildPugh B or C hepatocellular carcinoma. Radiother Oncol. June 3, 2014 (early release online). The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

The Fourth Pillar of Oncology: Four Topics, Four Perspectives on the Role of Interventional Oncology in Managing Patients With Hepatocellular Carcinoma

nterventional oncology has been called the fourth pillar of oncology—teaming up with medical oncology, surgical oncology, and radiation oncology disciplines in the fight against cancer. Recent data, reported in this supplement, suggest that interventional oncologic treatments for hepatocellular carcinoma can shrink tumors, relieve painful symptoms, improve quality of life, and potentially extend survival in patients who cannot be treated effectively with other approaches. The ASCO Post sat down with four interventional oncology practitioners at the recent Society of Interventional Radiology 2014 Annual Scientific Meeting in San Diego: ■■ Daniel B. Brown, MD, FSIR, Chief of Interventional Oncology, Vanderbilt University Medical Center, Nashville; Chair, SIR 2014 Annual Scientific Meeting ■■ Hyun S. “Kevin” Kim MD, FSIR, Vice Chair, Image Guided Therapy and Interventional Oncology Research; Director, Interventional Oncology Transitional Laboratory; Associate Professor and Chief, Interventional Radiology, University of Pittsburgh Medical Center, Pittsburgh ■■ Ziv J. Haskal, MD, FSIR, FACR, FAHA, Professor of Radiology and Fellowship Director, University of Virginia Health System, Charlottesville; Editor in Chief, Journal of Vascular & Interventional Radiology ■■ Roger Williams, DO, Director of Interventional Ser vices, Emory University Hospital Midtown, Atlanta. Each physician shared his thoughts on the role of interventional oncology in treating hepatocellular carcinoma, patient management and outcomes, what they can offer medical oncologists and their patients, and possible future roles of this subspecialty for liver cancer treatment.

The Role of Interventional Oncology in Hepatocellular Carcinoma Daniel B. Brown, MD, FSIR: There are essentially two roles that interventional oncologists are playing in the treatment of patients with hepatocellular carcinoma. I look at patients in one of two groups: those who are trying to go to transplant and those at their destination therapy, meaning this [interventional therapy] is going to be their primary modality of care. An additional group is composed of patients we can-

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not treat whom we direct toward hospice or palliative care. For the patients seeking transplant, the interventional oncologist aims to slow tumor progression. Patients are able to receive a transplant if the size of the tumor is within certain criteria, either the Milan or University of California, San Francisco (UCSF) criteria (see sidebar on page 6). We either try to keep the tumor within those criteria or reduce the size of the tumor to fit the criteria that would qualify the patient for a transplant. We do this be- Daniel B. Brown, MD, FSIR cause for a patient with nonresectable disease, transplant is that patient’s only chance of being alive in 5 years. For patients who are ineligible for transplant—ie, the tumors are too big, or the patient is too old or has too much medical comorbidity—arterial or ablative therapies are standard of care. If patients are not eligible to get a liver transplant, the tumors probably cannot be resected. In such cases, survival up to 4 years is being reported using chemoembolization with drug-eluting beads. Hyun S. “Kevin” Kim, MD, FSIR: Hepatocellular carcinoma is on the verge of becoming epidemic—especially with the rise of hepatitis C—globally, as well as in the United States. There are treatments available for hepatocellular carcinoma, from transplant surgery to systemic therapies. Unfortunately, more than 80% of patients diagnosed with hepatocellular carcinoma cannot receive what is considered the definitive therapy—surgical resection or transplantation. Interventional oncology plays an integral role in taking care of this group, with multiple treatment modalities that are available to us. These modalities have proven to be quite effective in treating these Hyun S. “Kevin” Kim, MD, FSIR patients.

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting Ziv J. Haskal, MD, FSIR, FACR, FAHA: When I did my fellowship in 1991 to 1992 at the University of California, San Francisco, we performed chemoembolization of hepatocellular carcinoma using a combination of cisplatin, mitomycin, and doxorubicin injected with ethiodol in a lobar or whole liver fashion, mixed with gelfoam or polyvinyl alcohol. Microcatheters were only beginning to appear. Remarkably, aspects of those same early procedures form the basis of today’s much more sophisticated selective and multipronged intervenZiv J. Haskal, MD, FSIR, tional radiologic approaches FACR, FAHA to primary and metastatic liver cancer. Today we can target very precisely, combine ablative tools, choose amongst chemotherapeutic agents and sized embolics, and add or solely use ablation tools. And, finally, systemic therapies have arisen allowing adjunctive therapies. Roger Williams, DO: As interventional radiologists, our most important role is probably bridging patients with inoperable hepatocellular carcinoma to liver transplant. The most definitive treatment for hepatocellular carcinoma is transplantation. Because of the limited availability of donor livers, we have to think in terms of what we can do to keep patients alive and to improve their condition to the point where they can receive a liver transplant. That is why we define the care of those patients as bridging—we take them along to get them to that point. For other patients in whom the lesions are too big for transplantation, we are able to downstage those patients. We can perform locoregional therapy such as bead embolization, using whichever choice of beads/embolic material a physician wants to use, and we reduce the size of those lesions to a size that renders the patient as eligible for transplantation. Roger Williams, DO A third and equally important group of patients comprises the nonsurgical candidates, those who will never receive transplantation. We can help those patients improve their survival by decreasing the tumor burden. Alternatively, we can keep the tumor burden at such a level that the patient’s quality of life either remains the same or may potentially improve.

Patient Management and Outcomes Dr. Brown: In managing patients with hepatocellular carcinoma, my advice is to be careful, and to be honest. I am upfront with patients in clinic, and I tell them what to expect. Once in a while I see patients who may say: “Doc, if you can treat my tumors, why do I need a transplant?” And I tell them that if they do not get a transplant, they are almost certain to develop new tumors elsewhere in their liver, or it may fail on its own. We treat in the artery as far distally as we can to spare as much normal liver tissue as possible. When we perform tumor ablation, we avoid the liver capsule to avoid seeding. The number of treatment options that we have available has increased over the years, and the survival rate is continuing to improve as more physicians get more experience. Interventional radiologists work collaboratively with liver transplant surgeons and medical oncologists. We have a tumor board every Tuesday afternoon that meets

I think that future hepatocellular carcinoma treatment will be even more integrative—in some instances depending on marker types, genotyping, and personalized care—that will combine locoregional therapy like yttrium-90 radioembolization with chemotherapy. — Daniel B. Brown, MD, FSIR

as a group. We decide whether patients should get surgery. We move toward transplant. If a patient is going to be placed on the transplant list, we need to manage that patient by keeping the tumors from growing or by shrinking them. Further, it’s important to recognize that adverse events can happen with interventional therapies, just as with any other therapies. I helped write the Quality Improvement Guidelines for Transhepatic Arterial Chemoembolization, Embolization, and Chemotherapeutic Infusion for Hepatic Malignancy.1 We know going in to a procedure what we will have to manage and what to expect. Even when we do everything right, [adverse events] can occur; however, our overall complication rate is very low. Dr. Kim: Patient management is a very complex and challenging process. Not only do we need to manage the tumor itself, but we need to consider the pathology and The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma biology of the tumor, the patient’s liver status, and the patient’s performance status. By looking not only at the tumor, but also at how well the patient’s liver is functioning and at the patient’s overall condition, we can determine how well therapies will be tolerated. We need to be mindful that a lot of these patients are very ill. Often they

I expect, and I foresee, that patient outcomes and quality of life will be further advanced and enhanced by further investigation, research, and clinical trials of minimally invasive therapies,…so that they can be even more effective, yet with even fewer side effects, allowing our patients even longer survival while maintaining a good quality of life. — Hyun S. “Kevin” Kim MD, FSIR

have two different diseases. Hepatocellular carcinoma often develops, but not always, in patients with liver disease. Managing these patients is very complex and very challenging. These patients need a lot of care from many specialties in a multidisciplinary fashion, and interventional oncologists are trained, and have the experience, to be an integral part of that care. We have been able to help a number of patients achieve positive outcomes, such as prolonging their survival and helping to maintain their quality of life. That is the goal of our therapies. There are always patients whom we cannot treat, which is difficult for our patients and their loved ones, as well as for us, their cancer-care providers. Dr. Haskal: As interventional radiologists our approaches to cancer are, rightly, now integrated into multidisciplinary boards that hope to offer the best, individualized care based upon outcomes. National and international guidelines have been developed, local expertise can be accounted for, and best treatment options can be offered to patients. These are great steps for standardizing care and optimizing outcomes. The interventional oncology approaches are generally two, namely, infusion (and embolization) and/or ablation. Infusions include chemoembolization with oily-based

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solutions or several drug-eluting embolics or radioactive agents (ie, yttrium-90 or holmium). Ablations include radiofrequency, microwave, cryo, and electroporation. All of these therapies have relative advantages, but heads-up comparisons are still lacking. Still, image-guided interventional therapies are the most potent, nonsurgical, nontransplant therapies around the world for patients with unresectable hepatocellular carcinoma. Naturally, these image-guided therapies extend beyond hepatocellular carcinoma, spanning kidney cancer, soft tissue and bony tumors, lung cancer, among other conditions. Dr. Williams: Over time, a lot of research has gone into patient selection for therapy. And the things that we have learned are: We [interventional radiologists] expect healthier patients to have better outcomes with whatever treatment course we perform; in order to treat those healthier patients, we need to have earlier diagnosis and earlier referral; and we need to be part of a multidisciplinary organization—with medical oncologists, surgical oncologists, and our other health-care colleagues— so that we can optimize therapy. Over time, we have realized the utility of embolization. When we first started out we thought we could do embolization to palliate these patients. Now, as everybody is getting more aggressive and realizing that we have better drugs and better tools to treat these patients, we are seeing that we are able to bridge these people to

My mentor always used to tell me that there are four pillars in oncology: medical oncology, surgical oncology, radiation oncology, and interventional oncology. Now and in the future, this four-pronged collaboration will be fighting the cancer battle and continuing in the effort to make cancer a chronic, ‘livable’ disease. — Roger Williams, DO

definitive treatment much better and much more quickly. We are also seeing tighter collaboration with our colleagues in other specialties. In the liver transplant clinic and on the liver transplant board in our hospital, we are told: “These patients are yours—bridge them and keep them within the criteria we need to get a transplant for them.”

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Role of Interventional Oncology in the Management of Unresectable Hepatocellular Carcinoma ■■ Interventional oncology therapies for unresectable hepatocellular carcinoma are utilized to prepare patients for transplant, and to extend survival and maintain quality of life for patients not eligible for transplant.

■■ Earlier diagnosis and earlier referral to interventional

treatment result in better outcomes for unresectable hepatocellular carcinoma patients.

■■ Interventional oncologists are part of a multidisciplinary team in the treatment of unresectable hepatocellular carcinoma.

Dr. Haskal: When meeting patients in my clinic, I take great pains to make clear that, as an interventional radiologist with a dedication to cancer care, I will be responsible for all care related to what I do for and with them. This means decisions, therapy, and follow-up care needs until their care is ended. Equally, I emphasize that this is still ‘matrix’ or ‘team’ care. Our conversation and communications must be

Image-guided interventional therapies are the most potent, nonsurgical, nontransplant therapies around the world for patients with unresectable hepatocellular carcinoma. — Ziv J. Haskal, MD, FSIR, FACR, FAHA

Collaboration With Medical Oncology Dr. Brown: Our group generally follows the Barcelona Clinic Liver Cancer (BCLC) criteria, and when a patient has stage C disease, I want him to see our medical oncologist first. For patients with stage B disease, we will generally treat first (see sidebar on page 6). I think it is important, until evidence is different, to make sure that patients with hepatocellular carcinoma are guided in the most appropriate direction for therapy. The reason I say that is, if you have a patient who has nodular hepatocellular carcinoma and you chemoembolize the tumor, and later a new tumor and portal vein thrombosis develop, then the patient has a second-line option. But if the patient presents with nodular hepatocellular carcinoma and receives sorafenib (Nexavar) first, and then the tumor progresses, that patient may not benefit from any treatment currently available. My goal with these patients is to collaborate with other specialists to extend their window of therapy. The ultimate goal for nontransplant patients is to make this more of a chronic-like disease for as long as we can.

crystal clear, efficient, and timely, so that their primary physicians, medical oncologists, transplant surgeons, and other specialists, are all apprised, aware, and informed. As a specialty, interventional radiology is a full-service referral oncologic specialty. Practicing in any lesser way should be abjured.

Dr. Kim: Interventional oncologists have worked in close collaboration with our medical oncologist colleagues, whether at large or small sites. This collaboration also extends to hepatologists, liver-transplant teams, and surgical oncologists. The key to success with hepatocellular carcinoma patients is providing multidisciplinary care on a long-term basis, and interventional oncologists are part of this integrative care. Our therapies are complementary to systemic therapies that are offered by medical oncologists. Only by a team approach can we deliver the best possible care to these patients.

Future Treatments

Dr. Williams: Hepatocellular carcinoma is a unique pathology; the role that we can play with medical oncologists is providing robust and durable treatments for their patients that would otherwise have no treatment. There is a big difference between living longer with a terrible quality of life and living longer with a better quality of life. In my practice, we also provide palliative service. We know that embolization works well for liver pain due to hepatocellular carcinoma, and we have learned other procedures for mitigating cancer pain. The therapeutic interventions that we can provide demonstrate that our role is beyond just one organ, it is treating the person as a whole in collaboration with a medical oncologist. Dr. Brown: Pretty much all patients with neuroendocrine tumors receive chemotherapy as their first-line treatment, which should be their first-line therapy. Unresectable hepatocellular carcinoma was the primary tumor that interventional oncology got involved with because chemotherapy is not that effective, and there were no other therapies. I think that future hepatocellular carcinoma treatment will be even more integrative—in some instances depending on marker types, genotyping, and personalThe ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Diagnostic, Treatment, and Prognostic Criteria for Patients With Hepatocellular Carcinoma Undergoing Liver Transplantation Milan Criteria The Milan criteria are a set of useful predictors for favorable outcomes in patients with hepatocellular carcinoma undergoing liver transplantation after transarterial chemoembolization. The criteria require that a patient have no lesion larger than 5 cm or fewer than three lesions with diameters ≤ 3 cm, no extrahepatic involvement, and no major vessel involvement.1 University California, San Francisco Criteria The University California, San Francisco (UCSF) criteria are a set of standards used in patients with tumors larger than those restricted under the Milan criteria. The UCSF criteria allow patients fitting the following standards to undergo liver transplantation: a single lesion ≤ 6.5 cm or multiple lesions ≤ 3 cm, the largest tumor diameter if multiple must be ≤ 4.5 cm, and the total diameter if multiple must be ≤ 8 cm. It is believed that the UCSF criteria are better able to predict acceptable posttransplant outcomes than the Milan criteria. The United Network for Organ Sharing has not adopted the UCSF criteria because of the limited availability of organs.2 Barcelona Clinic Liver Cancer Criteria The Barcelona Clinic Liver Cancer (BCLC) criteria combine tumor burden, hepatic function, and performance status with an evidence-based treatment algorithm, aiming to incorporate prognosis estimation and potential treatment advancements in a single unified proposal.3-6 Patients at stage 0 with very early hepatocellular carcinoma are optimal candidates for resection; patients at stage B with intermediate hepatocellular carcinoma may benefit from chemoembolization; patients at stage C with advanced hepatocellular carcinoma may receive new agents in the setting of randomized controlled trials; patients at stage D with end-stage disease receive symptomatic treatment. n References

1. Kim JM, Kwon CH, Joh JW: Patients with unresectable hepatocellular carcinoma beyond Milan criteria: Should we perform transarterial chemoembolization or liver transplantation? Transplant Proc 42:821-824, 2010. 2. Unek T, Karademir S, Naciye C, et al: Comparison of Milan and UCSF criteria for liver transplantation to treat hepatocellular carcinoma. World J Gastroenterol 17:4206-4212, 2011. 3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 362:1907-1917, 2003. 4. Bruix J, Llovet JM: Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 35:519-524, 2002. 5. Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329338, 1999. 6. Llovet JM, Fuster J, Bruix J: The Barcelona approach: Diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplantation 10(2 suppl 1):S115-S120, 2004.

ized care—that will combine locoregional therapy like yttrium-90 radioembolization with chemotherapy. For example, as we treat more tumors of different types, we have begun to treat more colorectal cancer than we used to. There is a study called SIRFLOX (an international study designed to evaluate whether F OLFOX chemotherapy in combination with selective internal radiation therapy is more effective than chemotherapy alone),2 for which the results should be coming out in about 9 months. This trial could radically change the paradigm of how patients with metastatic colorectal cancer are addressed. But today we do not have that data. That is why we now mostly treat patients with colorectal cancer in what I call the salvage setting. They have gone through the first two lines of treatment, and maybe even have received rego-

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rafenib (Stivarga), and then the interventional oncology specialists get called. Our level of evidence to this point has not supported more of a role than that. I think that studies such as SIRFLOX will get done, and the level of appropriateness may change in the future. Dr. Kim: The training in interventional oncology gets better and better, and so does the research—at both the basic science level and the translational and clinical science level. I expect, and I foresee, that patient outcomes and quality of life will be further advanced and enhanced by further investigation, research, and clinical trials of minimally invasive therapies, where these therapies become

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting less and less invasive—perhaps even noninvasive. Further, the therapies will be more targeted to the cancer so that they can be even more effective, yet with even fewer side effects, allowing our patients even longer survival while maintaining a good quality of life. Dr. Haskal: The last decade’s evolution of Journal of Vascular & Interventional Radiology reflects a clear focus upon high level oncology research, both laboratory and clinical. The pipeline of research is tremendous. It encompasses early therapies, international phase I to pivotal trials, comparative assessments, guidelines documents, prospective research, and more. I see exciting therapies in all the areas I mentioned—from improved ablative tools, tailored and targeted embolotherapies, combination therapy trials, and, above all, and clear increase in rigor and quality of efforts. Equally, as our specialty helps mature this research, come analyses of prognostic factors and best forms of palliation for desperate situations. Being able to offer intelligent and compassionate options springs from these efforts. Dr. Williams: My mentor always used to tell me that there are four pillars in oncology: medical oncology,

surgical oncology, radiation oncology, and interventional oncology. Now and in the future, this four-pronged collaboration will be fighting the cancer battle and continuing in the effort to make cancer a chronic, “livable” disease. I feel that the greater the minds that go into fighting this very difficult process, the better the outcomes will be. “Cure” is not something many can even imagine, but making cancer a chronic disease is something that is potentially on the horizon. n Disclosure: Drs. Brown, Kim, and Williams reported no potential conflicts of interest. Dr. Haskal has reported receiving royalties from Cook Medical, serving on an advisory board for WL Gore and Associates, receiving research support from Bard Peripheral Vascular, W.L. Gore and Associates, Merit Medical, and CeloNova and receiving speaker honorarium from Bard Peripheral Vascular and WL Gore and Associates. He is a stockholder of AngioDynamics.

References 1. Brown DB, Nikolic B, Covey AM, et al: Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J Vasc Interv Radiol 23:287-294, 2012. 2. SIRflox. Available at www.sirflox.com. Accessed July 8, 2014.

SIR Names James B. Spies, MD, MPH, FSIR, as President, 2014–2015

ames B. Spies, MD, MPH, FSIR, Chair of the Radiology Department at MedStar Georgetown University Hospital and Professor of Radiology at Georgetown University Medical Center in Washington, D.C., assumed office as the Society of Interventional Radiology’s (SIR) 2014–2015 President during the Society’s 39th Annual Scientific Meeting in San Diego. “Advancing a better understanding of both the limitless potential of interventional radiology and its positive impact on patient care will be a main focus during my term as President,” James B. Spies, MD, said Dr. Spies, who will repMPH, FSIR

resent the Society’s nearly 5,000 doctors, scientists, and allied health professionals dedicated to improving health care through image-guided minimally invasive treatments.

SIR’s 2014–2015 Executive Council Besides Dr. Spies, other members of SIR’s 2014– 2015 Executive Council who took office during the SIR 2014 Annual Scientific Meeting are listed below. President-elect Alan H. Matsumoto, MD, FSIR, University of Virginia Health System, Charlottesville Secretary Charles E. Ray Jr, MD, PhD, FSIR, University of Illinois, Health Sciences Center, Chicago Treasurer M. Victoria Marx, MD, FSIR, LAC and USC Medical Center, Los Angeles Immediate Past President Scott C. Goodwin, MD, FSIR, University of California, Irvine

The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Impact of Bead Size on Response in Patients With Unresectable Hepatocellular Carcinoma Receiving Transarterial Chemoembolization

lmamoon Justaniah, MD, from the Department Radiology at Lahey Clinic in Burlington, Massachusetts, reported results from a study conducted at his institution to assess the influence of bead size on hepatocellular carcinoma response rate after drug-eluting bead transarterial chemoembolization.1 He presented the study at the SIR 2014 Annual Scientific Meeting in San Diego.

Study Details Dr. Justaniah and his team conducted a retrospective analysis of consecutive patients treated with drug-eluting bead transarterial chemoembolization for hepatocellular carcinoma between 2008 and 2013. The patients were separated into three groups. A large-bead group (300– 500 μm and 500–700 μm) consisted of 73 patients, average age 64 ± 9 years, who were treated between 2008 and 2010. A medium-bead group (100–300 μm and 300–500 μm) consisted of 33 patients, average age 64 ± 9 years, who were treated between 2010 and 2011. A Almamoon Justaniah, MD small-bead group (75–150 μm and 100–300 μm) consisted of 36 patients, average age 62 ± 10 years, who were treated between 2012 and 2013. Dr. Justaniah noted that all patients presented with Barcelona Clinic Liver Cancer (BCLC) stage A, B, and C. The patients did not receive other treatment during the observation period. All patients received 100 mg of doxorubicin in two vials of beads under slow infusion (50 mg each), and there were two consecutive treatments prior to imaging followup. Imaging consisted of dynamic contrast-enhanced CT or MRI in 3-month intervals over a 12-month period. Retrospective imaging analysis was performed for all patients using residual arterial enhancement assessment.

Response Results at 3-Month Intervals Dr. Justaniah reported that at 3 months, complete response rates for large-, medium-, and small-bead groups were 25/74 (34%), 24/33 (73%), and 33/36 (92%),

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Transarterial Chemoembolization in Patients With Unresectable Hepatocellular Carcinoma: Impact of Bead Size on Response ■■ Complete response rates for patients treated with

70-150 μm drug-eluting bead transarterial chemo embolization were significantly higher at 3 and 6 months than for patients treated with larger-size beads.

■■ At 9 and 12 months, complete response rates between the two groups were not significant; this was due primarily to disease progression in untreated areas, noted the investigators.

respectively (P < .01); results at 6 months were also significant, the investigators reported. At 9 and 12 months, however, differences in complete response rates for large-, medium-, and small-bead groups were not significant. At 12 months, complete response rates for large-, medium-, and small-bead groups were 22/74 (30%), 19/33 (58%), and 27/36 (75%), respectively (P = not significant). P value was .06 for all groups given the use of the Anova test. “Treatment with smaller drug-eluting beads has a better treatment response [at 3 and 6 months] in hepatocellular carcinoma [than large- and medium-sized beads],” Dr. Justaniah concluded. The investigators reported that the lack of difference in response at 9 and 12 months for the small-bead group was primarily related to disease progression in untreated areas. Dr. Justaniah noted that among the limitations of the study were a stage inhomogeneity between the groups, there was a relatively short follow-up, and there were no data on side effects, length of hospital stay, or survival. n Disclosure: Dr. Justaniah reported no potential conflicts of interest.

Reference 1. Justaniah AI, Iqbal SI, Hakky MM, et al: Influence of bead size on tumor responser rate after drug-eluting bead transcatheter arterial chemoembolization in hepatocellular carcinoma. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 249. Presented March 26, 2014.

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

In Patients With Unresectable Hepatocellular Carcinoma Receiving Transarterial Chemoembolization, Smaller Bead Size May Be Associated With More Liver-Related Complications

ata from a retrospective single-site study presented at the SIR 2014 Annual Scientific Meeting showed that utilization of 70- to 150-μm drug-eluting beads in transarterial chemoembolization for patients with unresectable hepatocellular carcinoma may cause greater liver-related complications than 100- to 300-μm drugeluting beads. “Previous work with 100- to 300-μm drug-eluting bead transarterial chemoembolization found [the smaller bead size] safer and more effective than 300- to 500-μm drugeluting bead transarterial chemoembolization for hepatocellular carcinoma,” said Amy Deipolyi, MD, PhD, from the Department of Radiology at Massachusetts General Hospital in Boston.1 Dr. Deipolyi presented results from a retrospective review of transarterial chemoembolization using 70- to 150-μm drug-eluting beads assessing the safety of the beads compared with transarteAmy Deipolyi, MD, PhD rial chemoembolization with 100- to 300-μm drug-eluting beads at her institution.2

Study Details “We conducted a retrospective review of all patients with unresectable hepatocellular carcinoma who underwent drug-eluting bead transarterial chemoembolization,” said Dr. Deipolyi. The patients were sorted into two groups. One group consisted of patients who received one vial of 70- to 150μm drug-eluting bead transarterial chemoembolization followed by one vial of 100- to 300-μm drug-eluting bead transarterial chemoembolization. Dr. Deipolyi said this protocol was initiated in December 2012. The other group comprised patients who received two vials of 100- to 300-μm drug-eluting bead transarterial chemoembolization—the protocol in place prior to December 2012. A total of 100 mg of doxorubicin was given to each patient (50 mg per vial).

Both groups had a chart review that consisted of demographic and clinical data, the number of vessels treated, laboratory values, hospital stay, and complications within 1 month of treatment.

Key Results In group 1, 34 patients underwent 39 lobar treatments and 5 selective treatments. Group 2 had 38 patients who underwent 42 lobar treatments and 2 selective treatments. Dr. Deipolyi noted that there was no statistical difference in age, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh score, Eastern Cooperative Oncology Group (ECOG) performance status, or preprocedure bilirubin level among the groups. Both groups had a similar number of hospital readmissions within 1 month, including nine patients from group 1 and eight patients from group 2. Dr. Deipolyi reported that group 1 showed a trend toward a longer hospital stay: 1.4 days compared with 1.1 days in group 2. There was also a trend for worse postembolization syndrome requiring readmission or prolonged hospital stay in group 1 (five patients vs one patient in group 2). Dr. Deipolyi’s team also reported a trend toward increased New biliary dilatation

Before TACE

After TACE

Fig 1: A 57-year old male with negative hepatitis C virus, alcoholic cirrhosis, and hepatocellular cancer treated with drug-eluting bead transarterial chemoembolization. Presented to urgent care with severe right upper quadrant abdominal pain; transferred, stented endoscopically. Courtesy of Amy Deipolyi, MD, PhD, Massachusetts General Hospital, Boston.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Transarterial Chemoembolization for Patients With Inoperable Hepatocellular Carcinoma: Effect of Bead Size on Outcomes ■■ Smaller drug-eluting beads (70–150 μm) may cause

worse postembolization syndrome and greater liverrelated complications.

■■ Patients treated with 70–150 μm drug-eluting bead

transarterial chemoembolization should be monitored for possible side-effects of therapy, including liverrelated complications.

bilirubin levels in group 1 post-transarterial chemoembolization, and a decrease in bilirubin levels of 13% in group 2. There were two deaths in group 1 and none in group 2. Dr. Deipolyi noted that 10 patients in group 1 experienced liver-related complications, compared with only 2 patients in group 2 (P < .05). In addition, patients with liver-related complications had significantly greater increases in post-transarterial chemoembolization bilirubin levels (P = .004). “Group 1 patients were more likely to be readmit-

ted or have a prolonged hospital stay for complications related to liver dysfunction,” Dr. Deipolyi said. The investigators concluded that transarterial chemoembolization with smaller 70- to 150-μm drug-eluting beads may cause worse postembolization syndrome and greater liver dysfunction than transarterial chemoembolization with 100- 300-μm drug-eluting beads. Dr. Deipolyi noted that her institution is continuing to collect more data to validate the findings she presented and that research is underway to ascertain if the smaller bead size increases the efficacy of drug-eluting bead transarterial chemoembolization. n Disclosure: Dr. Deipolyi reported no potential conflicts of interest.

References 1. Padia SA, Shivaram G, Bastawrous S, et al: Safety and efficacy of drug-eluting bead chemoembolization for hepatocellular carcinoma: Comparison of small- vs medium-size particles. J Vasc Interv Radiol 24:301-306, 2013. 2. Deipolyi AR, Oklu R, Liu RW, et al: Safety of 70-150 μm drug eluting beads in transarterial chemoembolization for hepatocellular carcinoma. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 246. Presented March 26, 2014.

Drug-Eluting Bead Transarterial Chemoembolization Benefits Survival vs Supportive Care in Patients With Unresectable Hepatocellular Carcinoma

rug-eluting bead transarterial chemoembolization treatment for unresectable hepatocellular carcinoma yields significantly higher median overall survival rates than best supportive care in this patient population, according to a study by Minzhi Xing, MD, and Kevin Kim, MD, from the Division of Interventional Radiology, Department of Radiology at the University of Pittsburgh School of Medicine. Dr. Xing presented their results at the SIR 2014 Annual Scientific Meeting in San Diego. Dr. Kim is senior author of the study. “Advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma includes patients with symptomatic tumors or an invasive tumoral pattern, including vascular invasion or extrahepatic spread,” said Dr. Xing. “These patients typically have limited treatment op-

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tions and a poor prognosis due to the underlying liver disease and a lack of effective treatment options.”1 Although systemic treatment is a recommended option for treating the disease, she noted, the median survival benefit is modest—with sorafenib (Nexavar) demonstrating a benefit of almost 3 months compared with placebo.2 “Prospective studies on drug-eluting bead transarterial chemoembolization in advanced hepatocellular carcinoma have reported a median survival of 13.5 months,” said Dr. Xing. She added that “Child-Pugh class A patients without portal vein thrombosis and metastasis benefitted the most, with a survival time of 18.8 months.”3 Dr. Xing and colleagues compared the overall survival of patients with unresectable hepatocellular carcinoma treated with drug-eluting bead chemoembolization at their tertiary cancer referral center with patients with the

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting same disease who received best supportive care found in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database.

Criteria and Methods “Our inclusion criteria consisted of advanced unresectable hepatocellular carcinoma in both cohorts,” Dr. Xing stated. “We used the most recent SEER database, which was updated in 2013.” The researchers queried 18 registries of that database for patients diagnosed with hepatocellular carcinoma, up to 2010, with outcome and follow-up of a minimum of 3 years. The liver was defined as the primary site and the histology code for hepatocellular carcinoma was used, with none of the patients receiving either radiation or cancer-directed surgery. “We compared patients from the SEER database with patients at our institution who similarly had BCLC stage C advanced unresectable hepatocellular carcinoma, diagnosed in the same time period, and deemed suitable for drug-eluting bead transarterial chemoembolization after evaluation by a multidisciplinary tumor board,” said Dr. Xing.

Drug-eluting bead transarterial chemoembolization yielded significantly higher median survival for patients and provided benefits for long-term survival. — Minzhi Xing, MD

The researchers reviewed the SEER data for demographic and clinical information and compared it with their institution’s database of drug-eluting bead transarterial chemoembolization–treated patients. Median and overall survival rates were estimated and compared between the groups.

largest tumor size, and the number and distribution of tumors (P > .05). The median overall survival from hepatocellular carcinoma diagnosis was 21.8 months (95% confidence interval [CI] = 18.1–25.4) in patients receiving drug-eluting bead transarterial chemoembolization, compared with 4 months (95% CI = 3.9–4.1) in the best supportive care group (P < .001). The median overall survival from the first drug-eluting bead transarterial chemoembolization was 15 months (95% CI = 9.6–20.4). “At 6 months, drug-eluting bead transarterial chemoembolization patients had a survivorship of 75.3% vs 35.5% from SEER, which is about a twofold difference,” Dr. Xing said. “At 2 years out, 35.9% of drug-eluting bead transarterial chemoembolization patients had survived vs 9% of SEER patients. Three-year survival was 20.4% for the drug-eluting bead transarterial chemoembolization recipients, compared with 4.4% of SEER patients.” Dr. Xing observed that at 2 years, the researchers found an approximately fourfold difference in overall survival for patients who were treated with drug-eluting bead transarterial chemoembolization compared with those in the SEER database who received neither radiation nor surgery. At 3 years, they reported a fivefold difference in overall survival. “We found that the SEER population without radiation or cancer-directed surgery had a median survival of 4 months from diagnosis, which is in line with previous literature for patients with advanced, unresectable hepatocellular carcinoma,” Dr. Xing stated. “Comparatively, the overall survival for drug-eluting bead transarterial chemoembolization patients was significantly higher at [approximately] 22 months from diagnosis.” Log-rank test of survival data showed P < .0001, a significant survival benefit of drug-eluting bead transarterial chemoembolization compared with best supportive care.

Key Results

Child-Pugh Score

“Altogether, we found 20,897 patients in the SEER database who fit the criteria of advanced unresectable hepatocellular carcinoma who received neither radiation nor cancer-directed surgery,” Dr. Xing said. “We had 231 patients who had undergone drug-eluting bead transarterial chemoembolization who were diagnosed during the same period. Importantly, no significant difference was found between the groups in terms of age at diagnosis, gender, race, bilobar disease, or presence of portal vein thrombosis, when comparing the populations.” The researchers reported both groups of patients were similar for presence of unilobar or bilobar disease, mean

The Child-Pugh score, a prognostic measure used in patients with chronic liver disease, is determined by five clinical measures, including total bilirubin level; serum albumin level; prothrombin time expressed by international normalized ratio (INR); presence of ascites (none, mild, severe); and presence of hepatic encephalopathy (none; grade I-II; grade III-IV). Each clinical measure is assigned 1 to 3 points, ranging from least severe (1 point) to most severe (3 points). A total score based on the five clinical measures is used to determine ChildPugh class of disease (A, B, or C).

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma Study Limitations Dr. Xing noted that there were several limitations to the study. Because they used Surveillance, Epidemiology, and End Results Registry data, the study did not cover all states or geographic areas within the United States, and it did not provide data on Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh class, or tumor-node-metastases (TNM) staging. Furthermore, the SEER database only stratified pa-

Drug-Eluting Bead Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma vs Best Supportive Care ■■ Drug-eluting bead transarterial chemoembolization yielded significantly higher median survival (~22 months vs 4 months) for patients with unresectable hepatocellular carcinoma than best supportive care.

■■ At 6 months after treatment, patients receiving drugeluting bead transarterial chemoembolization had a survivorship of 75.3% vs 35.5% in the best supportive care population, about a twofold difference.

■■ Drug-eluting bead transarterial chemoembolization in

this patient population provided benefits for longterm survival with a four- to fivefold increase in survival rate at 2 or more years after diagnosis.

tients who did or did not receive radiation or cancerdirected surgery. There was a lack of data about systemic chemotherapy, such as sorafenib (Nexavar), or specific therapeutic regimens that would have been useful as a comparator group for locoregional therapies. “In a comparison of drug-eluting bead transarterial chemoembolization for advanced unresectable hepatocellular carcinoma vs patients who received neither radiation nor cancer-directed surgery, we found that drug-eluting bead transarterial chemoembolization yielded significantly higher median survival for patients and provided benefits for long-term survival—with a four- to fivefold increase in survival rate at 2 or more years after hepatocellular carcinoma diagnosis,” she concluded. n Disclosure: Drs. Xing and Kim reported no potential conflicts of interest.

References 1. Xing M, Prajapti HJ, Kokabi N, et al: Survival trends in unresectable hepatocellular carcinoma and the effect of DEBTACE: SEER vs tertiary cancer center. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 43. Presented March 23, 2014. 2. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008. 3. Prajapati HJ, Dhanasekaran R, El-Rayes BF, et al: Safety and efficacy of doxorubicin drug-eluting bead transarterial chemoembolization in patients with advanced hepatocellular carcinoma. J Vasc Interv Radiol 24:307-315, 2013.

Bland vs Drug-Eluting Beads Show Similar Results for Embolization of Hepatocellular Carcinoma

single-blind controlled investigation found no difference in response or disease control rate at any time point between patients with unresectable hepatocellular carcinoma who had hepatic artery embolization performed with unloaded beads (in which no chemotherapeutic or other agent was added) vs drug-eluting beads that were loaded with doxorubicin, according to Interventional Oncologist Karen Karen Brown, MD, FSIR Brown, MD, FSIR, from the

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Department of Radiology at Memorial Sloan Kettering Cancer Center in New York. “Our primary objective was to determine if there was a difference in response to treatment when the embolic agent used was loaded with doxorubicin,” said Dr. Brown. Secondary objectives were toxicity and safety, disease control rate, local progression-free survival, and overall survival. Results were presented at the SIR 2014 Annual Scientific Meeting.1

Embolization in Unresectable Hepatocellular Carcinoma As background for the study, Dr. Brown cited a 2002 study by Llovet,2 which concluded that chemoemboliza-

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting tion improved survival of stringently selected patients with unresectable hepatocellular carcinoma. She explained that the sequential analysis design allowed for stopping the trial when a survival benefit was demonstrated for any group, and the study was stopped when a survival benefit was demonstrated for chemoembolization. Dr. Brown said, “Some people believe that this study also demonstrated the superiority of chemoembolization compared to bland embolization but, in fact, when the study was stopped, the ‘Z score plot line’ in the bland embolization group remained within the triangular boundaries [comparison of embolization and control]—indicating the need to recruit additional patients to achieve a valid conclusion.” The team’s analysis of the Llovet data also found that there was little difference in the 1- and 2-year survival rates between the chemoembolization and bland embolization arms. The 1-year survival rate for the chemoembolization group was 82% compared to 75% in the bland embolization group; 2-year survival was 63% in the chemoembolization group vs 50% in the bland embolization group. For her group’s study, Dr. Brown utilized two study agents: Bead Block (the bland or unloaded beads) and LC Beads (the drug-eluting beads). Bead Block is a preformed deformable microsphere consisting of a biocompatible, acrylamido polyvinyl alcohol macromer. “The development of LC Bead provided the perfect platform for designing a study that used essentially the same

0.6 0.4 0.0

0.2

Survival Probability

0.8

1.0

Bead Block (ITT) LC Bead (ITT) Bead Block (Treated) LC Bead (Treated)

Months From Randomization

Fig. 1: There was no difference (6.5%) in initial response to treatment by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Courtesy of Karen T. Brown, MD, FSIR, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.

Bland vs Drug-Eluting Beads in Embolization of Hepatocelluar Carcinoma ■■ Hepatic artery embolization performed with

unloaded beads (bland block) vs doxorubicin-eluting beads demonstrated no difference in response or disease control rate at any time point for patients with unresectable hepatocellular carcinoma.

■■ The addition of doxorubicin to the embolic agent

when treating patients with hepatocellular carcinoma, although apparently safe, does not appear to confer a response or survival advantage.

■■ The results of this single-arm trial may call into

question the use of chemotherapy for embolization of hepatocellular carcinoma.

spherical embolic in both arms, the only difference being whether the agent was loaded or unloaded—a sulphonate modification that allows for ionic binding of doxorubicin being the only structural difference,” she e xplained.

Criteria and Materials The inclusion criteria for the study included a confirmed diagnosis of hepatocellular carcinoma in a patient who was not a candidate for resection or ablation. Patients with portal vein and extrahepatic disease were allowed. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 was required, as was Okuda I or II, and Child-Pugh class A or B. Patients could not have any systemic therapy within 4 weeks of registration. “Patients needed to have renal function that allowed for the administration of contrast, a bilirubin level less than 3, be able to clot their blood, and have a white blood cell count greater than 3,000,” Dr. Brown added. Randomization of patients who met the criteria and consented to be part of the trial was stratified into those whose treatment cycle was anticipated to require one embolization vs those requiring two embolizations to complete treatment. “Within 2 to 3 weeks of the first treatment cycle, patients were seen in clinic with laboratory studies and a multiphase computed tomography [CT],” said Dr. Brown. “This was the scan used to determine response to treatment, the primary endpoint.” The patient groups were seen again with laboratory tests and multiphase CT performed at 10 to 12 weeks. Further treatment decisions were made based on that CT scan. “Patients who had not responded to treatment or who had disease progression were taken off the study, whereas The ASCO Post • Volume 5, Issue 12 • Supplement

100

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Bead BeadBlock Block LC LCBead Bead

80 60 0

Response Rate (%)

60 40 20

Response Rate (%)

Bead BeadBlock Block LC LCBead Bead

Weeks

Fig. 2: Modified Response Evaluation Criteria In Solid Tumors (mRECIST) demonstrated response to treatment of 76.1% in the drug-eluting bead group, and a response to treatment of 71.7% in the bland block group (P = .81).Courtesy of Karen T. Brown, MD, FSIR, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.

Fig. 3: The intent-to-treat analysis of 101 patients demonstrated a median survival of 20.8 months in the drug-eluting bead group and 19.6 months in the bland block group, (P = .64). The treated group of 92 patients demonstrated a median survival of 20 months in the drug-eluting bead group and 21.4 months in the bland block group (P = .14). Courtesy of Karen T. Brown, MD, FSIR, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.

those who had significant residual disease or new lesions were retreated. Patients who had a complete or near-complete response, meanwhile, entered into a surveillance pathway with repeat laboratory tests and imaging every 3 months until death or progression,” Dr. Brown added. The bland block cohort comprised 51 patients (14 women, 37 men, with a mean age of 68.3 years), while the drug-eluting bead cohort comprised 50 patients (9 women, 41 men, with a mean age of 65.5 years). Barcelona Clinic Liver Cancer (BCLC) stage was assessed as A in 10 patients (20%), B in 22 (43%), and C in 19 (37%) of the bland block cohort. The drug-eluting bead cohort comprised 12 stage A patients (24%), 23 stage B (46%), and 15 (30%) stage C. In addition, Dr. Brown reported that 80% of patients had underlying liver disease, with over one-third infected with the hepatitis C virus, about one-third with alcoholrelated cirrhosis, and just under 20% with the hepatitis B virus. Target lesion size was similar in the groups. “Both groups were embolized to a stasis endpoint,” Dr. Brown said. “In the [drug-eluting bead] group, 150 mg of doxorubicin was loaded onto either 4 mL or 6 mL of drug-eluting bead, depending on an assessment of tumor volume and vascularity, and an attempt was made to deliver the entire dose proportionately into vessels supplying the tumor. If there was persistent ante-

grade flow after the drug-eluting bead had been used, the target vessels were embolized to stasis using additional unloaded embolic agents.” The researchers hypothesized that there would be no difference at 2 to 3 weeks in the proportion of responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. “The study was designed to have approximately 80% power to detect a difference of 28%,” Dr. Brown stated.

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Key Results “Of the 101 patients enrolled in the study, 6 patients were never treated, 2 died after treatment, and 1 developed renal dysfunction precluding follow-up scans; 92 subjects were thus evaluable for response,” Dr. Brown reported. Postembolization syndrome (pain, nausea, vomiting, fever, or hypertension) was the same in both groups at 85%. There were also no significant differences in serious adverse event occurrence among the groups, with each having one 30-day mortality. The researchers reported there was no difference in initial response to treatment, disease control rate, or local tumor progression-free survival by either RECIST or modified RECIST (mRECIST) criteria (Figs. 1–3). There was no difference detected at the 3-, 6-, 9-, or 12-month intervals. “And, by either intent-to-treat analy-

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting sis or analysis of only the treated evaluable patients, there was no difference in overall survival at a median followup of 34 months,” Dr. Brown said. The intent-to-treat analysis (101 patients) found the drug-eluting bead group with a median survival of 20.8 months, compared with 19.6 months for the bland block group (P = .64). The treated analysis (92 patients) reported the drug-eluting bead group had a median survival of 20 months, compared with 21.4 months for the bland block group (P = .14). “In summary, the addition of doxorubicin to the embolic agent when treating patients with hepatocellular carcinoma, although apparently safe, does not appear to confer a response or survival advantage,” concluded Dr. Brown. “We believe the results of this trial call into question the use of chemotherapy for embolization of hepatocellular carcinoma.”

In response to an audience question about bead size, she stated the team used 100- to 300-µm beads for bland embolization. n

Disclosure: Dr. Brown reported no potential conflicts of interest. The study was supported by a grant from the National Cancer Institute. LC Beads used in the study were provided by Biocompatibles UK.

References 1. Brown KT, Gonen M, Do K, et al: Randomized phase II study of hepatic arterial embolization of hepatocellular carcinoma with microspheres alone vs doxorubicin loaded microspheres. 2014 Society of Interventional Radiology Annual Scientific Meeting. Abstract 40. Presented March 23, 2014. 2. Llovet JM, Real MI, Montana X, et al: Arterial embolisation or chemoembolisation vs symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomized controlled trial. Lancet 359:1734-1739, 2002.

Chemoembolization Safe in Unresectable Hepatocellular Carcinoma Patients With Transjugular Intrahepatic Portosystemic Shunt

atients with unresectable hepatocellular carcinoma who also have a transjugular intrahepatic portosystemic shunt can receive doxorubicin-eluting bead chemoembolization safely and effectively, according to Michael Jordan Ray, MD, from the Department of Diagnostic Radiology at Baylor University Medical Center in Dallas. Transjugular intrahepatic portosystemic shunt placement, a procedure that creates a new connection between the portal and hepatic vein in order to relieve portal vein hypertension, is often used in patients presenting with severe liver cirrhosis. Dr. Ray and colleagues retrospectively evaluated the clinical outcomes of doxoruMichael Jordan Ray, MD bicin-eluting beads chemoembolization in patients with transjugular intrahepatic portosystemic shunt to determine if the embolization of hepatic arterial supply in this cohort may predispose an increased risk of complications due to the loss of dual vascular supply. He presented their findings at the SIR 2014 Annual Scientific Meeting in San Diego.1

Criteria and Materials “We conducted a retrospective review of patients with a functioning transjugular intrahepatic portosystemic shunt who underwent chemoembolization for unresectable hepatocellular carcinoma at our institution from 2010 to 2013,” Dr. Ray noted. The team analyzed data about the patients’ liver disease, transjugular intrahepatic portosystemic shunt, tumor characteristic, doxorubicin-eluting beads chemoembolization, procedure complication, and modified response evaluation criteria in solid tumors (mRECIST). Posttreatment toxicity within 90 days was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. A total of 14 patients with transjugular intrahepatic portosystemic shunt met the study criteria for inclusion: 12 men and 2 women, with a mean age of 58.4 years (range, 46–76 years). Dr. Ray reported that the indications for transjugular intrahepatic portosystemic shunt creation in the patient cohort were refractory ascites in three, variceal bleeding in six, lower gastrointestinal bleeding in one, and unknown in the remaining four p atients. Cirrhosis etiology presented as hepatitis C in nine patients, cryptogenic in two, alcohol in two, and primary The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma sclerosing cholangitis in one. Tumor size ranged from 1.2 to 8.7 cm with a mean diameter of 3.1 cm. Seven patients had focal disease, and the remaining seven had multifocal disease. Barcelona Clinic Liver Cancer (BCLC) stage was assessed as stage A in four patients (28.5%), stage B in one patient (7%), and stage C in nine patients (64%). Eastern Cooperative Oncology Group (ECOG) performance status was rated as 0 in six patients, 1 in five patients, and 2 in three patients. All patients were treated with one vial of 100- to 300‑μm beads loaded with 50 to 75 mg of doxorubicin. “The endpoint of chemoembolization was delivery of the entire prescribed dose or the presence of reduced antegrade blood flow in the target vessel and tumor devascularization on completion arteriography,” Dr. Ray said.

Key Results There were 22 sessions of doxorubicin-eluting bead chemoembolization performed in the patient cohort. A majority (64%, nine patients) had one session, three pa-

Doxorubicin-eluting bead chemoembolization in patients with transjugular intrahepatic portosystemic shunt appears safe and effective for treatment of unresectable hepatocellular carcinoma,…with the majority of patients [in our study population] showing stable to favorable tumor response, serving as a helpful bridge to curable liver transplantation. — Michael Jordan Ray, MD

tients had two sessions, one patient had three sessions, and one patient had four sessions. The mean time of follow-up was 191 days (range, 18–449 days) after initial doxorubicin-eluting beads chemoembolization. No deaths were reported during follow-up. Dr. Ray reported that postprocedure, 11 (78.5%) of the patients were observed overnight, two (14%) had a 24-hour admission, one (7%) was admitted for a nonrelated procedure, and subsequently one (7%) required readmission a week after doxorubicin-eluting bead che-

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Doxorubicin-Bead Embolization in Unresectable Hepatocellular Carcinoma Patients With Transjugular Intrahepatic Portosystemic Shunt ■■ Doxorubicin-eluting beads chemoembolization in

unresectable hepatocellular carcinoma patients with a transjugular intrahepatic portosystemic shunt appears safe and effective.

■■ The majority of patients in this study showed stable to favorable tumor response.

moembolization therapy because of encephalopathy and high levels on liver function tests. Imaging follow-up was obtained in 10 of 14 patients, and complete response was found in two (20%), partial response in six (60%), stable disease in one (10%), and progressive disease in one (10%). “ECOG performance status remained stable in 13 patients and progressed in one patient from 0 to 1,” Dr. Ray said. Five patients experienced CTCAE bilirubin toxicity: grade 1 toxicity was found in three patients (21%), grade 2 in one (7%), and grade 3 in one (7%). Ascites subjectively increased in three patients (none to small in two and small to large in one). Encephalopathy progressed in two patients with baseline hepatic encephalopathy (mild to severe in one and none to mild in one). In addition, one patient suffered iatrogenic arterial dissection. Five of 14 patients (35%) subsequently underwent liver transplantation. “Doxorubicin-eluting bead chemoembolization in patients with transjugular intrahepatic portosystemic shunt appears safe and effective for treatment of patients with unresectable hepatocellular carcinoma,” concluded Dr. Ray. “In our population, the procedure was tolerated well with the majority of patients showing stable to favorable tumor response, serving as a helpful bridge to curable liver transplantation.” n Disclosure: Dr. Ray reported no potential conflicts of interest.

Reference 1. Zarghouni M, Ray M, Cura M: Doxorubicin-eluting beads chemoembolization for unresectable hepatocellular carcinoma in patients with functioning transjugular intrahepatic portosystemic shunt. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 149. Presented March 25, 2014.

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Transarterial Chemoembolization Should Be Considered in Elderly Patients With Unresectable Hepatocellular Carcinoma

ransarterial chemoembolization should be considered a reasonable locoregional therapeutic option in patients 65 or older with unresectable hepatocellular carcinoma, according to Niraj Bhalakia, MD, from the Department of Radiology at Thomas Jefferson University Hospital, Philadelphia. “In general, the therapeutic benefit and toxicities of many cancer treatments remain unknown in elderly patients, as they are often underrepresented in clinical trials,” said Dr. Bhalakia. He added, “Many elderly patients thus may not be receiving the optimal cancer treatment, as it is often withheld from them because of the fear of potential toxicities and perceived survivNiraj Bhalakia, MD al advantage.” Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide, and incidence rates are increasing in the United States. Of particular concern, age-adjusted hepatocellular carcinoma incidence rates tripled between 1975 and 2005, rising from 1.6 per 100,000 to 4.9 per 100,000.1 “The risk of developing hepatocellular carcinoma is known to be age-dependent,” stated Dr. Bhalakia. “Thus, there will be an increasing number of elderly patients diagnosed with hepatocellular carcinoma in the coming years because of the longevity increase in the population.”

cinoma patients in the Medicare population who received therapy experienced substantial advantage over their peers who received no treatment or palliative treatment, less than 30% of patients in this population diagnosed with unresectable hepatocellular carcinoma received therapy, even when they had favorable biologic characteristics.

Criteria and Materials The researchers reviewed the records of all patients who had a transarterial chemoembolization procedure for unresectable hepatocellular carcinoma at Thomas Jefferson between January 2001 and July 2011. The patients were separated into two groups on the basis of age: those younger than 65 years of age and those 65 years and older. The following demographics and baseline parameters were compared: Child-Pugh scores, TNM (Tumor, Node, Metastases) stage, hepatitis B or C positivity, tumor number and size, number of transarterial chemoembolization sessions, and transarterial chemoembolization regimen (doxorubicin/ethiodol [Lipiodol]; cisplatin/doxorubicin/mitomycin three-drug therapy/ethiodol; or drug-eluting beads).

Transarterial chemoembolization should be considered a reasonable locoregional therapeutic option in elderly patients with hepatocellular carcinoma. — Niraj Bhalakia, MD

Retrospective Review Dr. Bhalakia and colleagues retrospectively reviewed all patients who underwent transarterial chemoembolization at their institution for the treatment of unresectable hepatocellular carcinoma over the past decade. They then evaluated whether outcomes of transarterial chemoembolization were inferior in patients 65 and older. He presented the findings at the SIR 2014 Annual Scientific Meeting.2 Colette Shaw, MD, and Daniel B. Brown, MD, also contribued to this project. Dr. Bhalakia and colleagues found that despite the increasing frequency of hepatocellular carcinoma in the aging population, and despite evidence showing that h epatocellular car-

Patients were excluded from the study if they were transplant recipients or had prior liver resection. Also excluded were patients who had received a transarterial chemoembolization regimen other than doxorubicin/ ethiodol, cisplatin/doxorubicin/mitomycin three-drug therapy/ethiodol, or drug-eluting beads. If pre- or posttreatment imaging was not available, a patient had a Child-Pugh score of C, or a patient had received prior treatments such as radiofrequency or microwave ablation, the patient was excluded. Dr. Bhalakia said that the researchers evaluated tumor response and overall disease control, evaluating target The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Transarterial Chemoembolization In Elderly Patients With Unresectable Hepatocellular Carcinoma ■■ Transarterial chemoembolization may be considered

a reasonable locoregional therapeutic option in patients 65 or older with unresectable hepatocellular carcinoma.

■■ Tumor response was observed in 64% of patients under 65 and in 57% of those 65 and over who underwent transarterial chemoembolization.

■■ Disease control was achieved in 69% of patients under 65 and in 74% of those 65 and over who underwent transarterial chemoembolization.

and no-target lesion response, and the presence of new lesions. Imaging outcomes were based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST), and allowed for patients to be categorized as complete or partial response, stable disease, and progressive disease. Adverse events were identified by reviewing the patients’ electronic medical records and grading, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 criteria. A value of P ≤ .002 was deemed to be statistically significant, derived by Bonferroni correction. “The Bonferroni correction is a method used to counteract the problem of multiple comparisons,” explained Dr. Bhalakia. “It is a method to control familywise error rate, which is the probability of making one or more false discoveries, or type 1 errors, among all the hypotheses when performing a multiple-hypothesis test. It is derived by finding an alpha value for the entire set of comparisons and dividing by the number of comparisons.”

Key Results A total of 179 treatments were performed in 97 patients, 42 of whom were older than 65 in an age range

of 43 to 84 years. The mean number of treatments was 1.6 in those 65 or younger and 2.1 in those over 65 (P = .03). According to the researchers, the groups had similar Child-Pugh status, tumor, node, metastasis stage, hepatitis B, hepatitis C, tumor number, tumor size, and drug type (P = .44). They reported that tumor response was observed in 64% of patients under 65 and in 57% of those 65 and over. Disease control was achieved in 69% of patients under 65 and in 74% of those 65 and over. The mean time to progression was 245 days for patients under 65 and 130.5 days for those 65 and over. “With regard to adverse events as defined by CTCAE criteria, four patients in the under 65 group had a grade 3 event, while five patients in the 65 and over group had a grade 3 event,” noted Dr. Bhalakia. “None of the patients in our study population had a grade 4 or 5 event, and there was no statistically significant difference between the groups in terms of major adverse events.” Major events included abscess, hematoma, fever, sepsis, and hypertension, he said. “During a similar follow-up period, the efficacy of transarterial chemoembolization for the treatment of hepatocellular carcinoma in elderly patients is comparable to that in a younger population,” Dr. Bhalakaia concluded. “Transarterial chemoembolization should be considered a reasonable locoregional therapeutic option in elderly patients with hepatocellular carcinoma.” n Disclosure: Dr. Bhalakia reported no potential conflicts of interest.

References

1. Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27:1485-1491, 2009. 2. Bhalakia N, Shaw CM, Brown DB: The efficacy of TACE in elderly patients with hepatocellular carcinoma. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 39. Presented March 23, 2014.

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Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Phase II Study Finds Yttrium-90 Radioembolization Safe, Efficacious in Patients With Infiltrative Hepatocellular Carcinoma and Portal Vein Thrombosis

ttrium-90 radioembolization is a safe and efficacious therapy for patients with infiltrative hepatocellular carcinoma and portal vein thrombosis, according to research presented by Nima Kokabi, MD, from the Department of Interventional Radiology and Image Guided Medicine, Emory University School of Medicine, in Atlanta, Georgia. Dr. Kokabi and colleagues conducted a prospective, single-arm, single-center study that recruited patients with unresectable infiltrative hepatocellular carcinoma with portal vein thrombosis to conduct a multidisciplinary evaluation of the safety and efficacy of glass-bead yttrium-90 radioembolization. He presented their results at the SIR 2014 Nima Kokabi, MD Annual Scientific Meeting.1 “As a phase II study, the objective of the investigation was to evaluate the safety and efficacy of glassbased microsphere yttrium-90 therapy for infiltrative unresectable hepatocellular carcinoma and portal vein thrombosis in our cohort of patients,” said Dr. Kokabi. Safety was evaluated by monitoring organ-related toxicity, related mortality, number of emergency department visits, and hospitalization. Efficacy was evaluated by overall survival, time to progression, and objective imaging tumor response.

Criteria and Materials Patients with unresectable (Barcelona Liver Cancer Stage C) infiltrative (T2 hyperintense geographic lesion, arterial enhancement, and early washout) hepatocellular carcinoma with portal vein thrombosis (enhancing filling defect in the portal venous system) were recruited at the facility. Inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, ChildPugh class A/B, a life expectancy greater than 3 months, lung shunt fraction ≤ 20%, bilirubin level < 2 mg/dL, serum albumin > 2.5 g/dL, and less than 75% tumor involvement of the liver.

A total of 30 patients were enrolled, with a mean age of 62 years (range, 35–82 years). The median tumor size was 9.2 cm (range, 4.9–19 cm). Dr. Kokabi said that 19 of the patients had received prior hepatocellular carcinoma–directed therapy. He added “Of those, 14 received from one to four courses of transarterial chemoembolization or drug-eluting bead transarterial chemoembolization,” he said. “Seventeen patients were on sorafenib (Nexavar) at one point prior to yttrium-90 therapy. However, only six patients were taking sorafenib at the time of yttrium-90 therapy; the remaining patients stopped taking it due to side effects.”

Study Design The study was designed to assume that the radioembolization therapy would prolong survival by 50% over best supportive care. Dr. Kokabi said this is approximately 4 months for Barcelona Liver Cancer Stage C patients. The yttrium-90 therapy protocol was performed on an outpatient basis. It included angiography performed to define the arterial blood supply, and identify and embolize accessory vessels from the hepatic artery that supply extrahepatic structures prior to the procedure. In addition, technetium-99m macroaggregated albumin single-photon emission computed tomography/ computed tomography scan was performed for postprocedural assessment of arteriovenous shunting to the

Yttrium-90 Radioembolization in Infiltrative Hepatocellular Carcinoma With Portal Vein Thrombosis ■■ Yttrium-90 radioembolization is a safe and efficacious therapy option for patients with infiltrative hepatocellular carcinoma and portal vein thrombosis.

■■ Adequate liver performance status at initiation of therapy is a positive prognostic factor.

■■ Median overall survival from the first yttrium-90 therapy was 13 months.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma lungs. A preplanned dose of 120 Gy was delivered to the treated liver lobe as well as a single therapeutic lung dose of ≤ 30 Gy. After the yttrium-90 beads were administered, a Bremsstrahlung single-photon emission computed tomography/computed tomography scan was conducted to confirm the safe distribution of yttrium-90 microspheres and aid in the prediction of possible gastrointestinal side effects. “Safety was assessed using full clinical and laboratory workup at 1 week and monthly thereafter for 6 months,” said Dr. Kokabi. “Related organ toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. We also monitored related mortality, emergency department visits, and hospitalization.” Overall survival and time to progression were measured from the first yttrium-90 therapy. Objective tumor response was evaluated with dynamic contrast-enhanced magnetic resonance imaging using Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) criteria at 1 and 3 months and then monthly until death. The overall survival and time to progression were measured by Kaplan-Meier estimation from the day of the first yttrium-90 treatment. Prognostic factors were analyzed using univariate analysis via log-rank and multivariate analysis via the Cox regression model. Significance levels were set at .05 for all tests.

Key Results “The most common complications were postembolization syndrome experienced by approximately two-thirds of the patients,” said Dr. Kokabi. “The most serious organ toxicities were grade 3 bilirubin toxicity in 10% of the patients and grade 2 transaminitis in 6% of the patients.” He reported that there was not treatment-related mortality, radiation pneumonitis, or gastrointestinal ulcerations in the study group. Five (17%) of the patients were hospitalized due to hepatobiliary complications, which were all transient with a mean hospital stay of approximately 5 days. No significant difference between the baseline Child-Pugh classification and ECOG performance status were observed (P > .05).

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At 1 month, 86% of the patients demonstrated objective response according to mRECIST criteria, while 43% had response in the same time period based on EASL criteria. The median overall survival from the first yttrium-90 therapy was 13 months (95% confidence interval [CI] = 4.4–22 months). The median time to progression was 9 months (95% CI = 6.2–13.1 months). The researchers determined grade ≥ 2 liver toxicity to be predictor of poor outcome— median overall survival of 3.6 months vs 13 months for grade ≥ 2 and others, respectively (P = .004). Child-Pugh class B, international normalized ratio (INR) ≥ 1.5, and grade ≥ 2 hepatobiliary toxicities were found to be poor prognostic factors by log-rank and univariate analysis (P < .05). Child-Pugh class A patients had a median overall survival of 13 months vs 3.3 months for Child-Pugh class B (P = .012). “The significant positive prognostic factors of survival by univariate analysis in our study included the lack of ascites, INR < 1.2, ECOG performance status 0, ChildPugh class A, lung-shunt fraction < 10%, no drug-related toxicity, and objective tumor response at 1 month,” said Dr. Kokabi. An ECOG performance status of 1 or above, ChildPugh class B, grade 2 or more toxicity, and lack of objective tumor response were negative prognostic factors by multivariate analysis, according to the researchers. “The results of our current phase II trial demonstrate that yttrium-90 radioembolization therapy is a safe and efficacious treatment in patients with unresectable infiltrative hepatocellular carcinoma and portal vein thrombosis with positive prognostic factors predominantly related to well-compensated liver function and adequate performance status at baseline,” Dr. Kokabi said. n Disclosure: Dr. Kokabi reported no potential conflicts of interest.

Reference 1. Kokabi N, Camacho JC, Xing M, et al: Prospective openlabel single center study of safety and efficacy of glass-based Y90 radioembolization for infiltrative HCC with PVT. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 189. Presented March 25, 2014.

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Yttrium-90 Radioembolization Improves Outcomes in Patients With Genotype 4 Hepatitis C and Hepatocellular Carcinoma, Study Finds

atients with unresectable hepatocellular carcinoma with portal vein tumor thrombosis and genotype 4 hepatitis C showed encouraging survival data after undergoing yttrium-90 radioembolization treatment, according to Mohamed H.K. Abdelmaksoud, MD, from the Department of Interventional Radiology at Stanford University in Palo Alto and the Department of Interventional Radiology at the Theodor Bilharz Research Institute in Cairo. “Hepatocellular carcinoma is one of the most common cancers worldwide, with about 700,000 deaths annually,” said Dr. Abdelmaksoud. “In Egypt, it accounts for about 13% of all cancers—the majority due to hepatitis C virus. At the time of Mohamed H.K. diagnosis, about 10% to 40% of Abdelmaksoud, MD patients with hepatocellular carcinoma have portal vein tumor thrombus, and at the time of death, the incidence is 44%, Dr. Abdelmaksoud noted. Egypt has one of the highest rates of liver cancer worldwide, as well as a high prevalence (14.7% of the population) of infection with the hepatitis C virus. There are more than nine genotypes of the virus, with genotype 4 being the most common (90%) in Egypt and the Middle East.

Radioembolization Safety and Efficacy Dr. Abdelmaksoud and colleagues retrospectively evaluated the safety and efficacy of radioembolization as a treatment option in patients with genotype 4 hepatitis

Radioembolization and Genotype 4 Hepatitis C Hepatocellular Carcinoma ■■ Yttrium-90 radioembolization treatment benefitted

patients with genotype 4 hepatitis C and hepatocellular carcinoma complicated by portal vein tumor thrombosis.

■■ Fatigue was noted by 55% of patients and was the main clinical toxicity.

C and hepatocellular carcinoma with portal vein tumor thrombosis. He presented their findings at the SIR 2014 Annual Scientific Meeting.1 The study cohort consisted of 31 patients (30 men, 1 woman) with a mean age of 59 (range, 41–78 years). Eastern Cooperative Oncology Group (ECOG) performance status was rated as 0 in 12 patients (39%), 1 in 14 patients (45%), and 2 in 5 patients (16%). The Child-Pugh score for cirrhosis mortality was A

Yttrium-90 treatment for patients with genotype 4 hepatitis C and hepatocellular carcinoma complicated by portal vein tumor thrombosis demonstrates a high rate of radiological response, a high rate of portal vein tumor thrombosis regression, and encouraging survival statistics. — Mohamed H. K. Abdelmaksoud, MD

in 26 patients (84%) and B in 5 patients (16%). Portal vein tumor thrombosis involved the segmental branch in 10 patients (32%), lobar branch in 16 (52%), and main branch in 5 (16%). The patients underwent 36 yttrium-90 radioembolization treatment procedures (19.3% single session, whole liver; 6.5% two sessions, whole liver; and 74.2% single session, lobar or segmental). The median dose of yttrium-90 infused was 1.92 gigabecquerel (GBq); 14 patients (40%) started sorafenib therapy 1 week after radioembolization. Clinical and biochemical toxicities were examined. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria. Survival statistics were also calculated.

Key Results The researchers reported overall response and portal vein tumor thrombosis response rates by RECIST of 59% and 63.6% and by mRECIST of 77.3% and 63.6%, respectively. Mean and median overall survival rates The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma Pre-yttrium-90 radioembolization

3-month follow-up

Fig. 1: Near-complete resolution of portal vein thrombosis in a 55-year-old male is seen pre-yttrium-90 radioembolization at 3-months’ follow-up. Courtesy of Mohamed H.K. Abdelmaksoud, MD, Stanford University, Palo Alto.

were 13.7 months and 8.3 months, respectively. The mean overall survival stratified by the location of portal vein tumor thrombosis was reported as 14.4, 10.9, and 17.9 months for patients with segmental, lobar, and main portal vein tumor thrombosis (P = .407). Using univariate analysis, the researchers stated that Eastern Cooperative Oncology Group performance status (P = .01, hazard ratio [HR] = 4.0), Child-Pugh score (P = .032, HR = 4.6), serum bilirubin (P = .024, HR = 8.5), and alpha-fetoprotein (P = .024, HR = .19) correlated with survival. “Yttrium-90 treatment for patients with genotype 4 hepatitis C and hepatocellular carcinoma complicated by portal vein tumor thrombosis demonstrates a high rate of radiological response, a high rate of portal vein

tumor thrombosis regression, and encouraging survival statistics,” Dr. Abdelmaksoud said. The main clinical toxicity was fatigue, which was noted in 55% of patients. One patient experienced grade 3 bilirubin toxicity. There were no instances of gastroduodenal ulcers. n Disclosure: Dr. Abdelmaksoud reported serving as a Proctor for Sirtex Medical Inc.

Reference 1. Abdelmaksoud M, Abdelmaksoud A, Mostafa M, et al: Y-90 radioembolization of hepatocellular carcinoma with portal vein tumor thrombus associated with hepatitis C genotype 4. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 229. Presented March 26, 2014.

Simulation Shows Yttrium-90 Radioembolization Is Most Cost-Effective in Patients With Barcelona Clinic Liver Cancer Stage C Unresectable Hepatocellular Carcinoma

ttrium-90 radioembolization treatment is most cost-effective for hepatocellular cancer patients who present with Barcelona Clinic Liver Cancer stage C, according to data presented by Nassir Rostambeigi, MD, from the Department of Radiology at the University of Minnesota in Minneapolis. “The overall per patient cost of hepatocellular car-

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cinoma is approximately $33,000 per year,” said Dr. Rostambeigi. “As the incidence of hepatocellular carcinoma continues to rise, so do the costs. We know that yttrium-90 radioembolization is effective in downstaging hepatocellular carcinoma, but is there a survival benefit from radioembolization over conventional transarterial chemoembolization?”

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting To properly power a trial to answer that question one would need more than 1,000 subjects, said Dr. Rostambeigi. He and colleagues created a simulation for the cost-effectiveness of radioembolization and conventional transarterial chemoembolization in the treatment of hepatocellular carcinoma. They then used the model’s findings to compare the financial burden of radioembolization and conventional transarterial chemoembolization in the treatment of unresectable hepatocellular carcinoma. Dr. Rostambeigi presented their findings at the SIR 2014 Annual Scientific Meeting.1

Criteria and Methods “We first did a systematic review of literature [from 2003– 2013] to get the survival costs and complications for each of these procedures,” Dr. Rostambeigi said. “We then did a simulation study to obtain our costeffectiveness analysis.” The researchers excluded Nassir Rostambeigi, MD studies that had no clinical outcomes by Barcelona Clinic Liver Cancer stages and those that had transarterial ethanol ablation performed. Furthermore, studies that included patients who took sorafenib (Nexavar), patients with portal vein thrombosis, or patients with liver cancer that was a metastatic result of other cancers were excluded. “We wanted to have a target population that could potentially receive either [conventional] transarterial chemoembolization or yttrium-90 radioembolization,” said Dr. Rostambeigi. Out of 44 studies surveyed, 11 met the inclusion criteria. The cost of each procedure was determined by the researchers on the basis of current procedure terminology (CPT) code Medicare reimbursements. The codes used for an yttrium-90 radioembolization procedure were: 36247, 37204, 75774, 75894, 78205, 79445, 77470, 78205, and 74170 for a cost of $12,038. Yttrium-90 costs (code C2616) were calculated for two procedures (for two liver lobes) at $15,716 per embolization. The codes used for a transarterial chemoembolization procedure were: 36247, 37204, 75726, 75774, 75894, 96367, 96368, 96411, 96413, 96417, 96420, 96521, and 96523 for a cost of $14,070. Angiography for two liver lobes (code 75726) was calculated at $4,052, plus the cost of a 23-hour overnight hospitalization stay without complications priced at $2,743. In addition, they assumed a technetium-99 microaggregated albumin scan would be ordered at a cost of $1,000. The scientists then created three patient subgroups

Cost-Effectiveness of Yttrium-90 Radioembolization Treatment ■■ Yttrium-90 radioembolization treatment is most

cost-effective for hepatocellular cancer patients who present with Barcelona Clinic Liver Cancer stage C.

■■ In this model, patients with Barcelona Clinic Liver

Cancer stage A may be treated more cost-effectively with transarterial chemoembolization opposed to yttrium-90 radioembolization.

■■ The cost-effective choice of whether to use transarterial

chemoembolization or radioembolization on Barcelona Clinic Liver Cancer stage B patients depends on factors such as portal vein thrombosis or patient intolerance of chemoembolization, in this model.

that were defined on the basis of Barcelona Clinic Liver Cancer stage A, B, or C and Child-Pugh classifications to represent the most frequently encountered patient groups. “We designed the model such that each of these groups had 250 patients,” said Dr. Rostambeigi. According to the researchers, the set of probabilities for events (recurrence, mortality, or being waitlisted for

In Barcelona Clinic Liver Cancer stage C patients, [radioembolization] is a cost-effective way to treat this group. — Nassir Rostambeigi, MD

liver transplant) that could happen after each procedure were determined based on the published literature. The team then determined survivals on the basis of the literature and assumed that each episode of recurrence would increase mortality by 10% for the month following recurrence. In addition to improved rates of overall survival, procedure, and complication costs and incremental costs of radioembolization over conventional transarterial chemoembolization were the primary outcomes.

Key Results The researchers reported that total costs approached $17,000 for transarterial chemoembolization and $49,000 for radioembolization. The 5-year survival rate for the Barcelona Clinic Liver Cancer stage A transarterial chemoembolization group was 40% (range, 34%-46%)—37 months—compared with 19% (range, 14%–24%)—32 months—in the same The ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

BCLC-A, B, or C (each with 250 patients)

RE: 50% chance of repeat every 6 or 10 months, max 2 or 3 treatments

Survival (wait-list/transplant, recurrence rate at 40%, 60%, or 80%)

Mortality

TACE: Repeat every 6 or 10 months, max 6 treatments

Survival (wait-list/transplant, recurrence rate at 60%)

Mortality

Fig. 1: The Decision Tree—A total of 250 patients were considered in each subgroup of Barcelona Clinic Liver Cancer stage A, B, or C. This decision tree was repeated for 5,000 iterations until the time of death or up to 3 or 5 years in separate models. At each iteration, radioembolization had less chance to be repeated to comply with real-life practice than conventional transarterial chemoembolization, which could be staged and repeated more frequently. RE = radioembolization; TACE = conventional transarterial chemoembolization; BCLC = Barcelona Clinic Liver Cancer. Courtesy of Nassir Rostambeigi, MD, University of Minnesota, Minneapolis.

stage radioembolization group (P = .001). Incremental costs were not associated with any survival benefit, according to the researchers. However, when they examined the Barcelona Clinic Liver Cancer stage C group, the researchers found a median survival of 12 months for the transarterial chemoembolization group compared with 19 months for the radioembolization group. This included an incremental cost-effectiveness ratio of $360 for radioembolization over transarterial chemoembolization. “Radioembolization does not appear to be cost-effective for Barcelona Clinic Liver Cancer stage A patients in this model,” said Dr. Rostambeigi. “However, this is a cost-effective way to treat Barcelona Clinic Liver Cancer stage C patients.”

In the borderline Barcelona Clinic Liver Cancer stage B patients, secondary considerations become important when considering radioembolization, he said. “If the first embolization is not tolerated, or there is a portal vein stenosis, consider radioembolization,” said Dr. Rostambeigi. Disclosure: Dr. Rostambeigi reported no potential conflicts of interest.

Reference 1. Rostambeigi N, Dekarske A, Austin E, et al: Simulation study on cost-effectiveness of radioembolization compared with transarterial chemoembolization for hepatocellular carcinoma. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 224. Presented March 26, 2014.

Radiation Shielding Necessary for Physicians Delivering Yttrium-90 Radioembolization Treatment

lthough radiation dose to health-care professionals delivering yttrium-90 radioembolization treatment is 1.4% that of fluoroscopy exposure, radiation shielding is necessary, according to Jong Yun Won, MD, from the Research Institute of Radiological Science, Yonsei University College of Medicine in Seoul, South Korea.

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Yttrium-90 is a pure beta-emitting radionuclide with high energy that is used in radioembolization treatment for hepatocellular carcinoma. It has a 64-hour half-life and mean 2.5-mm penetration depth in human tissue. “Radioembolization is becoming one of the standard treatment modalities for hepatocellular carcinoma,” not-

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting ed Dr. Won at the SIR 2014 Annual Scientific Meeting, where he presented his study.1 Patients can be released from confinement postprocedure if their emitted dose rate at 1 meter is less than 25 microsieverts (μSv) per hour, according to guidelines set by the U.S. Nuclear Regulatory Commission. In addition, under the same guidelines, patients treated with less than 5 gigabecquerels (GBq) of y ttrium-90 can be released without contact restriction. However, according to Dr. Won, there are no data or reports of yttrium-90 exposure dose to the health-care professionals delivering the radioembolization treatment. His team sought to measure the radiation exposure dose during and after the radioembolization and to validate the safety of the procedure.

Criteria and Methods “We measure the radiation dose during and after the infusion of yttrium-90 in 10 patients with hepatocellular carcinoma,” Dr. Won said. Injection of the yttrium-90 was done over the course of 10 minutes with a dose from 2 to 3 GBq (mean, 2.7 GBq). A survey meter (FH-40, Thermo Scientific) was placed 50 cm from the radionuclide source, 1.5 meters Jong Yun Won, MD

Although radiation exposure was acceptable, considering a long infusion time of yttrium-90, radiation shielding is necessary to avoid radiation exposure. — Jong Yun Won, MD

Radiation Protection During Yttrium-90 Radioembolization ■■ Patient isolation is not necessary after yttrium-90 radioembolization.

■■ Radiation shielding is necessary for the physician administering yttrium-90 infusion.

■■ Radiation dose exposure to the administering physician is within the safe exposure range.

treatment, and 1 meter from the patient after the completion of the infusion.

Key Results According to Dr. Won, radiation dose before the infusion was approximately 0.2 μSv per hour. After starting the infusion, it rose to 6 μSv per hour. Mean radiation exposure was 5.83 μSv per hour at 30 seconds after injection of yttrium-90, 6.13 μSv per hour at 1 minute, 4.5 μSv per hour at 3 minutes, and 2.1 μSv per hour at 5 minutes. Postprocedure, the patient emitted approximately 2 μSv per hour. “These were all very much lower than the radiation dose from fluoroscopy,” noted Dr. Won. The researchers reported that radiation exposure to the physician during the yttrium-90 infusion was about 1.4% that of fluoroscopy, the dose was maximal 1 to 3 minutes after starting the infusion, and the radiation from the patient after treatment was approximately 8% of the maximum safety dose permitted under radiation dose guidelines to the physician. “Although radiation exposure was acceptable, considering a long infusion time of yttrium-90, radiation shielding is necessary to avoid radiation exposure,” Dr. Won concluded. n Disclosure: Dr. Won reported no potential conflicts of interest.

off the floor and 1 meter from the patient, which is where Dr. Won usually positions himself during the procedure. Radiation dose measurement was taken at this position before yttrium-90 infusion, during fluoroscopy (anterior-posterior view) for comparison, at 30 seconds and 1, 3, and 5 minutes after the initiation of yttrium-90

Reference 1. Lee S, Won J, Kim I, et al: Measurement of radiation exposure dose during yttrium-90 radioembolization of hepatocellular carcinoma. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 190. Presented March 25, 2014.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Yttrium-90 Radioembolization Between First- and Second-Line Chemotherapy May Improve Progression-Free Survival in Patients With Liver-Dominant Metastatic Colorectal Cancer

reliminary data from a phase II trial indicate that yttrium-90 radioembolization, administered be tween first- and second-line chemotherapy for liverdominant metastatic colorectal cancer, may improve progression-free survival, according to Kazim Narsinh, MD, from the Department of Radiology at the University of California, San Diego. “We know that yttrium-90 improves objective response rate during front-line treatment of liver-dominant metastatic colorectal cancer,” said Dr. Narsinh. “We also know that yttrium-90 radioembolization has shown benefit lately as a salvage therapy in patients with chemorefractory liver-dominant metastatKazim Narsinh, MD ic colorectal cancer.” Dr. Narsinh and colleagues hypothesized that insertion of resin-based yttrium-90 radioembolization after failure of first-line chemotherapy may improve response rates as well as progression-free and overall survival associated with second-line chemotherapy. Their rationale was that radiation may increase chemosensitivity of liver tumors. The benchmark in their single-arm study was a comparison to published outcomes in similar cohorts of patients. Dr. Narsinh presented the findings at the SIR 2014 Annual Scientific Meeting. Steven C. Rose, MD, Assistant Professor, Department of Radiology, University of California, San Diego, was the study’s lead author.1

Criteria and Materials The researchers reported that patients with liverdominant metastatic colorectal adenocarcinoma were offered enrollment into the phase II trial after failure of first-line oxaliplatin-based chemotherapy between January 2010 and June 2011. Ten patients were enrolled, with a mean age at recruitment of 61.3 ± 11.7 years. Eight patients had died by October 2013. Bevacizumab (Avastin) treatment had

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been given prior to yttrium-90 radioembolization in eight patients. The primary endpoint was progressionfree survival, Dr. Narsinh said. Patients were required to be off their first-line chemotherapy for 4 weeks or more, and in the case of bevacizumab, for 6 or more weeks. A baseline was established in three phases: computed tomography (CT) imaging, positron-emission tomography (PET) imaging, and laboratory tests. If there was a single-lobe metastasis, a single yttrium-90 treatment was administered; bilobar involvement required a second yttrium-90 infusion at 4 weeks. Second-line irinotecan-based chemotherapy was initiated 4 weeks after a patient’s last yttrium-90 therapy. Progression-free survival was assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) from CT and PET imaging conducted within 12 weeks. This was then corroborated to rates of biochemical recurrence assessed by serum carcinoembryonic antigen levels.

Historical Control Data The researchers assessed survival analysis using aplan-Meier curves and Cox proportional hazard K models, and comparisons were made to historical control data of 111 patients receiving similar second-line irinotecan-based chemotherapy after failure of first-line oxaliplatin-based chemotherapy. 2,3 “For patients receiving a FOLFIRI-like regimen (leucovorin, fluorouracil [5-FU], irinotecan) after progression on FOLFOX (leucovorin, 5-FU, oxaliplatin), the benchmark [in the literature] was a response rate ranging from 4% to 20%, with median progression-free survival of 2.5 to 7.1 months,” said Dr. Narsinh.

Key Results “We have 7 patients [of 10] who had a partial response or complete response, which gives us a response rate of about 70%,” said Dr. Narsinh. “Progression-free survival was also quite good compared to historical controls.” The researchers found that median time to progres-

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Yttrium-90 Radioembolization in Liver-Dominant Metastatic Colorectal Cancer ■■ Yttrium-90 radioembolization, administered between first- and second-line chemotherapy for liverdominant metastatic colorectal cancer, may improve progression-free survival.

■■ Median time to progression in this regimen was

10.2 months, compared with 2.5 to 7.1 months in historical controls.

sion after study recruitment was 10.2 months, and median overall survival was 17.6 months. “We have preliminary data from a small cohort of patients that suggests yttrium-90 resin microsphere embolization sandwiched between first-line oxaliplatin-based chemotherapy and second-line irinotecanbased chemotherapy improves response rate and progression-free survival compared to the historical control populations treated with systemic chemotherapy in the absence of radioembolization,” said Dr. Narsinh. “We think further patient recruitment is warranted,” he continued. He noted that limitations of the

study included that it involved a small cohort from a single institution. In response to an audience question, Dr. Narsinh reported that he and his colleagues noted no significant damage to liver vessels in their patient population as a result of first-line chemotherapy. n Disclosure: Dr. Narsinh reported no potential conflicts of interest. One of his coauthors serves as a Proctor and is a minor stockholder in Sirtex Medical.

References 1. Narsinh K, Newton I, Kikolski S, et al: Phase II study of yttrium-90 resin microspheres in treatment of colorectal adenocarcinoma metastatic to the liver after failure of first-line oxaliplatin-based chemotherapy: Preliminary results of the InSIRT trial. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 221. Presented March 26, 2014. 2. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR Study. J Clin Oncol 22:229-237, 2004. 3. Bidard FC, Tournigand C, Andre T, et al: Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study. Ann Oncol 20:1042-1047, 2009.

Three-Dimensional Magnetic Resonance Imaging May Deliver Better Colorectal Cancer Liver Metastases Assessment Response

hree-dimensional (3D) magnetic resonance imaging (MRI) has the potential to refine the predictive value of tumor response assessment in patients with colorectal cancer metastases to the liver, reported Julius Chapiro, MD. Dr. Chapiro is with the Russell H. Morgan Department of Radiology and Radiological Sciences, Section of Interventional Radiology at The Johns Hopkins Hospital in Baltimore. “If we look at the 5-year survival in patients with metastases to the liver, the rates are really poor—35% in the United States and 43% in Europe,” said Dr. Chapiro. Julius Chapiro, MD “Approximately 70% of the

colorectal cancer patients are diagnosed with liver metastases, which ultimately becomes the dominant disease and the main cause of death. We know that new systemic chemotherapies have come a long way and can improve overall survival. However, chemoresistance is a major problem, and locoregional therapies can be used as salvage therapy.” The key to achieving favorable outcomes is accurately assessing tumor response to intra-arterial therapeutic intervention. However, relying solely on anatomic tumor size measurement guidelines, such as Response Evaluation Criteria in Solid Tumors (RECIST), can be inaccurate, said Dr. Chapiro. Dr. Chapiro believes that current 3D imaging technology can deliver a more accurate assessment of tumor response than conventional one-dimenThe ASCO Post • Volume 5, Issue 12 • Supplement

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma sional (1D) and two-dimensional (2D) anatomic assessment criteria. He and his colleagues, including MingDe Lin, PhD and Jean-Francois Geschwind, MD, have developed an enhancement-based quantitative European Association for the Study of the Liver (EASL) MRI guideline for tumor assessment. Dr. Chapiro presented their findings at the SIR 2014 Annual Scientific Meeting.1

Criteria and Materials “We designed our study to evaluate 3D quantitatively assessed MRI response of colorectal metastasis after y ttrium-90 radioembolization and transarterial chemoembolization as a predictor of survival,” Dr. Chapiro stated. “We also compared 1D, 2D, and 3D assessment techniques and compared enhancement-based and diffusion-based measurements.” The team began their investigation with a total of 49 patients. Patients without follow-up MRI were excluded as well as those who were treated with non–intra-arterial, liver-targeted therapies. The study cohort included 29 patients that were analyzed using 3D and non-3D techniques. All patients had unresectable colorectal cancer metastases to the liver and were treated with intra-arterial salvage therapy using conventional transarterial chemoembolization or yttrium-90 radioembolization. All patients underwent pre- and postprocedural contrast-enhanced MRI within 1 month of treatment. The baseline and follow-up MRI scans were used for processing. The semiautomatic 3D segmentation processing took between 20 and 80 seconds per patient, according to Dr. Chapiro. This included image subtraction, transposition on an apparent diffusion coefficient (ADC) map, selection of extratumoral region of interest, and calculation of enhancing tumor volumes on pre- and post–intra-arterial tumor imaging. “Because this technique simply mimics a radiological reading while quantifying what we see, we call the techniques simply quantitative EASL and ADC,” Dr. Chapiro said.

The Role of 3D MRI in Colorectal Cancer Liver Metastases Assessment Response ■■ Conventional anatomic imaging tumor assessment criteria may be inaccurate.

■■ The authors suggest that all RECIST-based studies should be viewed with caution.

■■ A 3D tumor assessment technique for MRI is fast and

may provide critical therapeutic response information.

The researchers, based on this methodology, then stratified all patients as responders or nonresponders according to 3D as well as non-3D techniques. They then performed Kaplan-Meier analysis of patient survival after the first session of intra-arterial therapy.

Key Results According to Dr. Chapiro, the patient cohort was a typical salvage therapy cohort, with a majority of patients receiving more than two lines of systemic chemotherapy—60% received more than five lines. There was an almost even split among the patients treated with yttrium-90 (16 patients) and conventional transarterial chemoembolization (14 patients). The median overall survival for the entire group was 7.5 months with no significant differences between conventional transarterial chemoembolization (7.3 months) and radioembolization (6.1 months) in the unmatched cohort (P ≥ .05). When the researchers reviewed the anatomic criteria before and after therapy, RECIST did not show significant changes. However, the volume RECIST technique demonstrated a statistically significant increase after therapy (P = .02). The functional criteria showed a significant decrease in tumor volume. The modified RECIST (P < .001) and quantitative EASL (P < .001) both demonstrated a decrease of enhancement and the quantified apparent diffusion coefficient (P = .02) demonstrated an increase of diffusion-restricted volume. (Left to right) Julius Chapiro, MD, Leading Scientist; MingDe Lin, PhD, Leading Engineer, Philips Biomedical Engineer, based at Johns Hopkins Hospital; Jean-Francois Geschwind, MD, Principal Investigator; Director, Vascular and Interventional Radiology; Director, Interventional Radiology Center, Johns Hopkins Hospital; Professor of Radiology, Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore.

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Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Survival according to quantitative EASL

Responder

100

Nonresponder

% Survival

P = .038

10 Time in months

Survival according to quantitative ACD

Responder

100

Nonresponder

% Survival

P = > .05

10 Time in months

Fig. 1: (A) The 3D quantitative analysis of a contrast-enhanced MRI in a patient with liver metastasis from colorectal cancer, prior to locoregional therapy with transarterial chemoembolization. (B) The stratification of patient survival according to postprocedural tumor response analysis using the enhancement-based 3D technique (quantitative EASL). (C) The analysis of the same tumor using diffusion-based, 3D quantitative imaging (quantitative ADC). (D) No stratification between responders and nonresponders was achieved using the diffusion-based technique. Courtesy of Julius Chapiro, MD, The Johns Hopkins Hospital, Baltimore.

When stratified according to quantitative EASL, responders showed an overall survival of 11.5 months and nonresponders showed a significantly lower overall survival of 7.0 months (P = .03). “Enhancement-based [quantitative] EASL is the only imaging marker that predicts patient survival,” Dr. Chapiro concluded (Fig. 1). “Anatomic parameters did not provide any stratification between responders and nonresponders. In addition, functional non-3D markers

were not predictive of survival.” n

Disclosure: Dr. Chapiro reported no potential conflicts of interest.

Reference 1. Chapiro J, Duran R, Lin M, et al: Quantitative 3D volumetric assessment of tumor response after intraarterial therapy of colorectal cancer metastases to the liver: A new surrogate marker for survival. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 241. Presented March 26, 2014.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Yttrium-90 Radioembolization Safe in Women With Metastatic Breast Cancer and Liver-Dominant Disease

adioembolization with yttrium-90 is safe in patients with metastatic breast cancer with liver-dominant disease late in their treatment course, and the treatment demonstrates consistent radiologic antitumoral response, according to data presented at the SIR 2014 Annual Scientific Meeting in San Diego by Andrew Gordon, a medical student at Northwestern University Feinberg School of Medicine in Chicago and a second-year PhD candidate in the Department of Biomedical Engineering, Northwestern University in Evanston, Illinois.1 Robert Lewandowski, MD, FSIR, Andrew Gordon Associate Professor of Radiology at Northwestern University Feinberg School of Medicine in Chicago, was the study’s lead author. “Breast cancer is the most commonly diagnosed cancer in women worldwide,” said Mr. Gordon. “And the liver is a common site of metastases that ultimately worsens the patient’s prognosis. Progression of hepatic disease represents a major treatment challenge. It impacts eligibility for systemic chemotherapy, it causes abdominal pain, and it causes overall hepatic dysfunction.”

Mr. Gordon and colleagues conducted a review of a prospectively collected database of patients treated with bilobar, lobar, or segmental yttrium-90 radioembolization protocols. The primary outcomes of their research were clinical and biochemical toxicities and imaging response by Re-

The liver is a common site of metastases [from breast cancer] that ultimately worsens the patient’s prognosis. Progression of hepatic disease represents a major treatment challenge. It impacts eligibility for systemic chemotherapy, it causes abdominal pain, and it causes overall hepatic dysfunction. — Andrew Gordon

sponse Evaluation Criteria in Solid Tumors (RECIST). Survival was a secondary outcome. According to Dr. Lewandowski, this is the largest study of its kind to date.

Fig. 1A: Patient 1, image 1—A 76-year-old woman with (A) multiple liver lesions in both lobes treated with selective right hepatic arterial catheterization and infusion of yttrium-90 followed by treatment of the left lobe 35 days later. Treatment delivered localized radiation at 131 Gy and 122 Gy to the right and left lobe tumors targeted with yttrium-90, respectively. (B) CT demonstrates treatment changes at 1 month and (C) 2 months’ imaging post–right-lobe treatment and 1 month post– left-lobe treatment confirming globally decreased hepatic disease burden. This patient had stable bone metastases without extrahepatic disease progression for 111 days after the first yttrium-90 treatment. Courtesy of Andrew Gordon, Northwestern University Feinberg School of Medicine, Chicago.

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Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting Criteria and Materials

Yttrium-90 Radioembolization for Patients With Metastatic Breast Cancer With Liver-Dominant Disease

“This was a single-arm retrospective study of patients treated intra-arterially with a dose of 120 Gy,” said Mr. Gordon. “Patients were included if they had image- or biopsy-proven liver metastases that were progressive on the standard of care, systemic chemotherapy.” There were 75 women who met the study criteria. According to the researchers, the median age was 53.7 (range, 26.7–82.4) years. The patients had predominantly multifocal (n = 64, 85.3%) bilobar (n = 61, 81.3%) disease with < 25% tumor burden (n = 44, 58.7%). There were 17 women whose metastatic dis-

■■ Yttrium-90 radioembolization treatment is a safe and effective therapy for chemorefractory metastatic breast cancer patients with liver-dominant disease.

■■ Disease was stabilized in 98.5% of the women treated in this study. Liver tumor reduction was seen in 82.4% of the women who underwent yttrium-90 radioembolization.

■■ Although not a cure, yttrium-90 radioembolization can shrink liver tumors, relieve painful symptoms, improve the quality of life, and potentially extend survival.

ease was confined to the liver; the other 58 patients had extrahepatic involvement. “Extrahepatic metastases were most commonly found in the bone, lung, and brain and were found in 77% of these cases,” said Mr. Gordon.

Key Results

Fig. 1B: Patient 1 (76-year-old woman), Conebeam CT (coronal view) demonstrating selective visceral catheterization and angiography of hypervascular multifocal tumors perfused by the right hepatic artery. Large as well as small nodules recruited arterial perfusion and conebeam CT confirmed both catheter placement and preferential tumor perfusion over the normal hepatic tissues. Courtesy of Andrew Gordon, Northwestern University Feinberg School of Medicine, Chicago.

The researchers reported clinical grade 3 toxicities of fatigue, abdominal pain, nausea, and fever, posttreatment. The rate of any grade 3 clinical toxicity was 7.6%, with nausea/vomiting in 1.5%. Biochemical grade 3 toxicities included elevated alanine transaminase (+4.4%) and aspartate transaminase (+8.8%), decreased albumin (–4.2%), and increased total serum bilirubin (+5.9%) levels. Mr. Gordon said that imaging follow-up was available in 69 of 73 living patients (93.2%), and 276 scans were

Fig. 2: Patient 2, image 1—(A) An 82-year-old woman with a solitary tumor in the right lobe measuring 4.5 x 3.3 cm. (B) CT image obtained 5 months later demonstrated a reduction in bidimensional size to 1.3 x 1.3 cm after two right lobar treatments at 93 Gy subsequently followed by 119 Gy. This patient had isolated liver metastases and remained free of extrahepatic disease 666 days after the first yttrium-90 treatment. Courtesy of Andrew Gordon, Northwestern University Feinberg School of Medicine, Chicago.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Fig. 3: Patient 3, image 1—A 55-year-old woman with (A) multiple tumors on magnetic resonance imaging (MRI) treated with selective right hepatic arterial catheterization and infusion of yttrium-90 followed by treatment of the left lobe 46 days later. Sequential bilobar treatment delivered 118 Gy and 146 Gy to the right and left lobe tumors targeted with yttrium-90, respectively. MRI demonstrated posttreatment changes at (B) 4 months’ and (C) 7 months’ imaging post–right-lobe treatment and at (B) 3 months and (C) 6 months post–left-lobe treatment confirming globally decreased multifocal bilobar disease burden. Courtesy of Andrew Gordon, Northwestern University Feinberg School of Medicine, Chicago.

Fig. 4: Patient 4, image 1—(A) Pretreatment positron-emission tomography (PET) scan shows prominent FDG uptake in metastatic left lobe lesions targeted with yttrium-90 (arrow). (B) Post-treatment PET shows decreased metabolic tumor activity attributable to a partial response to treatment. Courtesy of Andrew Gordon, Northwestern University Feinberg School of Medicine, Chicago.

Fig. 5: Patient 5, image 1—A 54-year-old woman with metastatic breast cancer that has progressed on multiple systemic therapies. The patient was treated on a clinical trial that combines systemic therapy (capecitabine) with radioembolization. The right hepatic lobe received 170 Gy as part of this phase 1 dose-escalating study. (A) Pre-treatment CT scan shows a large posterior right hepatic lobe tumor (arrow). (B) Post-treatment CT shows decreased size of the tumor and less enhancement, consistent with a favorable response (arrow). There is compensatory hypertrophy of the untreated left hepatic lobe (asterisk). Courtesy of Andrew Gordon, Northwestern University Feinberg School of Medicine, Chicago.

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Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting reviewed with partial response (24 patients, 35.3%) and stable disease (43 patients, 63.2%) with progression in 1 patient (1.5%) by rECIST (see Figs. 1 through 5). Positron-emission tomography imaging was available in 25 patients. The researchers noted complete response in 3 patients (12%), partial response or stable disease in 18 patients (72%), and progressive disease in 4 patients (16%). Median survival for patients with < 25% vs ≥ 25% tumor burden was found to be 9.3 and 3.9 months, respectively (P < .0001). Unilobar vs bilobar disease conferred a median survival of 6.7 months, compared with 6.4 months, respectively (P = not significant). Extrahepatic disease, multifocal disease, and performance status were not found to be significant predictors of

survival on univariate analyses, according to the researchers. “Response by index lesions indicated disease control in 98.5% of the patients,” Mr. Gordon said of postradioembolization follow-up. “By long-axis measurements, 82.4% of patients had an overall, objective decrease in their tumor size.” n Disclosure: Dr. Lewandowski has served as an advisor to BTG. Mr. Gordon reported no potential conflicts of interest.

Reference 1. Gordon AC, Ryu R, Sato KT, et al: Yttrium-90 radioembolization for hepatic breast cancer metastasis: A contemporary analysis of safety, response, and survival. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 192. Presented March 25, 2014.

Expert Point of View

n a related press conference at the SIR 2014 Annual Scientific Meeting in San Diego, Robert Lewandowski, MD, FSIR, Associate Professor of Radiology at Northwestern University Feinberg School of Medicine, and one of the study authors, offered his thoughts on the study.1 “Although this is not a cure, yttrium-90 radioembolization can shrink liver tumors, relieve painful symptoms, improve the quality of life, and potentially extend survival,” said Robert Lewandowski,MD, FSIR Dr. Lewandowski, who is Chair of SIR’s Interventional Oncology Service Line. “While patient selection is important, the therapy is not limited by tumor size, shape, location, or number—and it can ease the severity of disease in patients who cannot be treated effectively with other approaches.” Dr. Lewandowski cited proven work with yttrium-90 radioembolization in treating patients with unresectable liver cancer and metastatic colon cancer as cause for expanding the therapy to other metastatic indications.

“We are looking to gain maximal tumor control while minimizing toxicity and preserving quality of life,” he said. “Yttrium-90 warrants further study of its efficacy in provid-

Yttrium-90 warrants further study of its efficacy in providing supportive care to relieve patients of debilitating symptoms and control the progression of their disease. — Robert Lewandowski, MD, FSIR

ing supportive care to relieve patients of debilitating symptoms and control the progression of their disease.” n Disclosure: Dr. Lewandowski has served as an advisor to BTG.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Yttrium-90 Radioembolization Shows Better Overall Survival vs Supportive Care in Patients With Unresectable Intrahepatic Cholangiocarcinoma

retrospective population-based study demonstrated that patients with chemorefractory unresectable intrahepatic cholangiocarcinoma treated with yttrium-90 radioembolization had significantly greater median overall survival and favorable long-term survival rates compared with best supportive care, according to Minzhi Xing, MD, and Kevin Kim, MD, from the Division of Interventional Radiology, Department of Radiology at the University of Pittsburgh School of Medicine. “Intrahepatic cholangiocarcinoma is rare, with approximately 3,000 cases diagnosed every year in the United States,” said Dr. Xing. “Age-adjusted incidence has increased rapidly, from 0.32 per 100,000 in 1975– 1979 to 0.85 per 100,000 in 1995–1999.” She noted that complete surgical resection or liver transplantation are the only curative approaches; however, most patients present with advanced disease and relapse despite surgery. In addition, traditional systemic chemotherapies have shown poor outcomes in advanced cases of intrahepatic cholangiocarcinoma. “Gemcitabine, with or without other chemotherapeutic agents, has been found to provide uncertain benefit in patients with advanced biliary tract cancers,” Dr. Xing said. “Conventional transarterial chemoembolization has been used in several small, uncontrolled trials of intrahepatic cholangiocarcinoma, with median survival ranging widely from 9 to 21 months.” She added that yttrium-90 radioembolization is an emerging treatment for unresectable liver tumors. Several small, uncontrolled studies have proven the safety and efficacy of the treatment for unresectable intrahepatic cholangiocarcinoma. Dr. Xing and colleagues compared the overall survival of patients with chemorefractory unresectable intrahepatic cholangiocarcinoma treated with yttrium-90 radioembolization at their tertiary cancer referral center with patients with the same disease who received best supportive care in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. She presented their results at the SIR 2014 Annual Scientific Meeting in San Diego.1

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Criteria and Materials “Our inclusion criteria consisted of chemorefractory intrahepatic cholangiocarcinoma in both cohorts,” Dr. Xing stated. “We use the most recent SEER database, which was updated in 2013.” The researchers queried 18 registries of that database for patients diagnosed with chemorefractory intrahepatic cholangiocarcinoma, up to 2010, with outcome and follow-up of a minimum of 3 years. The intrahepatic bile duct was defined as the primary site and the histology code used for cholangiocarcinoma. No patients received either radiation or cancer-directed surgery. “We then compared these patients from the SEER database with patients at our institution who had advanced chemorefractory intrahepatic cholangiocarcinoma, diagnosed in the same time period, and deemed suitable for yttrium-90 radioembolization after evaluation by a multidisciplinary tumor board,” said Dr. Xing.

For advanced unresectable intrahepatic cholangiocarcinoma, … yttrium-90 yielded significantly higher median survival for patients, and provided benefits for long-term survival. — Minzhi Xing, MD

The researchers reviewed the SEER data for demographic and clinical information and compared it with their institution’s database of yttrium-90 treated patients. Overall survival and survival rates were estimated and compared between the groups.

Key Results “Altogether, we found 2,757 patients on the SEER database who fit the criteria of advanced intrahepatic cholangiocarcinoma who received neither radiation nor cancerdirected surgery,” Dr. Xing said. “We had 24 patients who

Reports From the Society of Interventional Radiology 2014 Annual Scientific Meeting

Yttrium-90 vs Best Supportive Care for Unresectable Intrahepatic Cholangiocarcinoma ■■ Yttrium-90 yielded significantly higher median

survival (~21 vs 3 months) for unresectable intrahepatic cholangiocarcinoma patients than best supportive care.

■■ At 6 months after treatment, yttrium-90 patients had

a survivorship of 91.7% vs 29.9% in the best supportive care population, about a threefold difference.

■■ Radioembolization in this patient population provided benefits for long-term survival – with a six- to sevenfold increase in survival rate at 2 or more years after diagnosis.

had undergone yttrium-90 therapy who were diagnosed during the same period. Importantly, no significant difference was found between the groups in terms of age at diagnosis, gender, race, bilobar disease, or presence of portal vein thrombosis, when comparing the populations.” The researchers reported the median overall survival from intrahepatic cholangiocarcinoma diagnosis for the yttrium-90 radioembolization patients was 20.8 months (95% confidence interval [CI] = 11.2–30.5), while the best supportive care group was 3.0 months ( 95% CI = 2.7–3.3) for P < .001. The median overall survival from the first yttrium-90 infusion was 11.5 months (95% CI = 4.8–18.2). “At 6 months, yttrium-90 patients had a survivorship of 91.7% vs 29.9% from SEER, which is about a threefold difference,” Dr. Xing stated. “At 1 year, yttrium-90 survival was 66.7%, compared with 17.3% in the SEER population. And, at 2 years from intrahepatic cholangiocarcinoma diagnosis, 41.9% of yttrium-90 patients had survived, vs 6% of SEER patients. Three-year survival was 16.7% with the yttrium-90 patients, as compared with 2.5% of SEER patients.”

Log-rank test of survival data showed P < .0001, a significant survival benefit of radioembolization compared with best supportive care.

Study Limitations Dr. Xing noted that there were several limitations to the study. Because they used SEER data, it did not cover all states or geographic areas within the United States. It also did not provide data on Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh class, or tumor-node-metastases (TNM) staging, which are a crucial part of the comprehensive assessment of intrahepatic cholangiocarcinoma patients for therapy. In addition, the SEER database only stratified patients who did or did not receive radiation or cancer-directed surgery. There was a lack of data about systemic chemotherapy, such as Gemcitabine, or specific therapeutic regimens that would have been very useful as a comparator group for locoregional therapies, Dr. Xing stated. “In a comparison of yttrium-90 for advanced unresectable intrahepatic cholangiocarcinoma vs patients who receive neither radiation nor cancer-directed surgery we found that yttrium-90 yielded significantly higher median survival for patients, and provided benefits for long-term survival—with a six- to sevenfold increase in survival rate at 2 or more years after intrahepatic cholangiocarcinoma diagnosis,” she concluded. n

Disclosure: Drs. Xing and Kim reported no potential conflicts of interest.

Reference 1. Xing M, Kokabi N, Camacho JC, et al: Survival trends in chemorefractory unresectable intrahepatic cholangiocarcinoma and the effect of resin-based yttrium-90 radioembolization: Surveillance, Epidemiology and End Results database vs. tertiary cancer center. Society of Interventional Radiology 2014 Annual Scientific Meeting. Abstract 223. Presented March 26, 2014.

See page 36 for information on radioembolization and issues in reimbursement.

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Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma

Radioembolization and Issues in Reimbursement

dward Kim, MD, Director of Interventional Oncology and Assistant Professor of Radiology and Surgery in the Division of Vascular and Interventional Radiology at the Mount Sinai Medical Center in New York, headed a symposium held in conjunction with the SIR 2014 Annual Scientific Meeting. The symposium “TheraSphere Reimbursement in HCC: Facts vs Fiction” was sponsored by BTG. The U.S. Food and Drug Administration has approved yttrium-90 radioembolization for patients with unresectable hepatocellular carcinoma under a Humanitarian Device Exemption. It is eligible for Medicare reimbursement as well as reimbursement by a majority of commercial health insurance plans, and state-government sponsored programs such as Medicaid and Tri-Care for military personnel. Dr. Kim shared his experience with obtaining insurance coverage for the interventional procedure. According to Dr. Kim, Medicare has no national coverage determination for yttrium-90 microspheres. Coverage is determined at the local level by Medicare Administrative Contractors. In addition, predetermination is not offered and payment is made Edward Kim, MD after the claim has been submitted. On a state level, there are no published coverage policies. Tri-Care requires predetermination and referral from a Veterans Administration primary care physician. Also, there are three regions—East, Central, and West—in TriCare, and rules are different at each region. Approximately 95%-98% of private health insurance plans have positive coverage policies for yttrium-90 radioembolization, said Dr. Kim. These plans also require a predetermination and may require a clinical review for medical necessity. Following the symposium, Daniel B. Brown, MD, FSIR, Chief of Interventional Oncology, Vanderbilt University Medical Center, Nashville; Chair, SIR 2014 Annual Scientific Meeting, noted that radioembolization reimbursement can be difficult to attain from insurance companies. Without precertification specifically, it can be difficult to treat patients without subjecting them to large payments, Dr. Brown noted. “The biggest challenge I have is getting precertification from insurance companies. This delays access to care for patients unless they are fortunate enough to be able to pay sizable sums out of pocket. This continues to happen despite data showing the benefits of arterial interventions to patients,” said Dr. Brown.

Reimbursement Assistance Manufacturers of yttrium-90 radioembolization products offer reimbursement assistance to physicians and their patients. Further information is available at: Daniel B. Brown, MD, FSIR BTG (TheraSphere): Through TheraSphere Reimbursement Services, BTG provides patients and health-care providers a full range of reimbursement services including billing and coding support, material to support precertification for those health plans that require it, and patient assistance. George Atkins, Reimbursement Specialist: George.atkins@btgplc.com SIRTeX (SIR-Spheres): SIRTeX maintains a reimbursement link on its United States region website. Visit http://www.sirtex.com/us/clinicians/reimbursement/ or email: info-us@sirtex.com. Disclosure: Dr. Kim is on the speakers’ bureau for BTG. Dr. Brown reported no potential conflicts of interest.

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