Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs This promotional literature was developed in conjunction with and sponsored by Onyx Pharmaceuticals, Inc., an Amgen subsidiary, and Bayer Pharmaceuticals, Inc., based on interviews with Ayse Aytaman, MD; Michael Beheshti, MD; Douglas Heuman, MD; David Kaplan, MD; David Ross, MD; and Tamar Taddei, MD 1
Table of Contents Thousands of Veterans at Risk For Liver Cancer Development... 3 Evolving Treatment Options Offer Hope, Longer Lives for VA s HCC Patients... 6 Multidisciplinary Teams Improve Treatment Of Hepatocellular Carcinoma... 8 HCC Surveillance Increases 50% with VA s Clinical Reminders for Primary Care... 10 This advertisement was written and edited in conjunction with Bayer and Onyx by Brenda L. Mooney, Editorial Director, U.S. Medicine and contributing writer Annette M. Boyle. Copy editing by Eden Jackson Landow. Art & Production by CranCentral Graphics.
Thousands of Veterans at Risk For Liver Cancer Development Early Diagnosis at VA Saves Lives RICHMOND, VA The VA now has 10 times more patients diagnosed with hepatocellular carcinoma (HCC) than it did a decade ago, and physicians on the front lines of treatment predict the death toll will rise sharply. Unless we do something dramatic, 10,000 Vietnam veterans will die of liver cancer in the next five years, said Douglas Heuman, MD, chief of hepatology and medical director of liver transplantation at the Hunter Holmes McGuire VA Medical Center and professor of medicine at Virginia Commonwealth University, both in Richmond. It s the most rapidly increasing cause of cancer death in the country, driven by the burgeoning hepatitis C virus epidemic. Vietnam veterans have the greatest risk of developing hepatocellular carcinoma because they have the highest rates of hepatitis C virus (HCV) infection. Advanced liver disease, especially cirrhosis, associated with HCV is the No. 1 risk factor for liver cancer in the United States. The VA is very much aware of the importance of eradicating HCV in hopes of breaking the back of this epidemic, Heuman said. The VA follows the Centers for Disease Control and Prevention s recommendation for screening everyone born between 1945 and 1965 once for HCV. The majority of veterans born during the time period served in Vietnam. In 2002, the VA had 146,290 veterans in care who had HCV. Of those, approximately 270 patients had newly diagnosed HCC, and about 500 had ever been diagnosed with HCC, said David Ross, MD, PhD, director of the HIV, HCV and public health pathogens programs for the VA. By 2013, the VA had nearly 20% more veterans with HCV (174,302), but six times as many with recent diagnoses (1,600) and 10 times as many who had ever been diagnosed with HCC (4,900). While the latest wave of treatments for HCV cost much more than the interferon and ribavirin combination regimen previously Unless we do something dramatic, 10,000 Vietnam veterans will die of liver cancer in the next five years. Douglas Heuman, MD recommended, they also achieve sustained viral response at far higher rates and with greatly reduced side effects. The newest treatments are frightfully expensive, but we only need to treat patients once. All these therapies are batting over 90% in noncirrhotic patients in curing HCV, Ross noted. The VA s infectious disease group has actively taken the position that financial resource limitations will not keep us from treating people who need treatment. Implications for Survival Keeping patients with HCV from developing HCC has huge implications for survival. About 4% of patients with HCV who have developed cirrhosis are diagnosed with HCC each year. While curable when caught early, liver cancer overall is a very bad actor. The five-year survival rate is just 14% across all stages, though in its earliest stage, that may be closer to 30% to 40%, Heuman told U.S. Medicine. That s the challenge: Liver disease is rarely caught in its early stages. Eighty percent or more of liver cancer diagnosed in the U.S. is not curable because it is diagnosed too late, said Tamar Taddei, MD, director of the liver cancer teams and tumor boards at the VA Connecticut Healthcare system and Smilow Cancer Hospital at Yale-New Haven Hospital. Most people do not develop symptoms until their liver is 80% shot. Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs 3
Increasing Primary Care Awareness To identify HCC early, or to prevent it, primary care providers in the VA need to know what to look for. Because liver disease is often silent until it s too advanced, raising awareness among primary care providers is critical, Taddei told U.S. Medicine. If you find liver cancer, you re probably looking for it. The goal is to get providers to look sooner, starting with screening for HCV. Now that we have drugs that can effectively treat HCV in most patients, we need to screen all baby boomers and those who have been treated in the past but had a relapse, she noted, adding that veterans with HCV should be referred to specialists for treatment. Treating patients with HCV before they develop cirrhosis almost completely protects them from HCC, according to Heuman. If they already have cirrhosis and you eradicate HCV, it looks as though the risk improves immediately, perhaps by 75%, but you need to keep an eye on them, he added. Other factors also can increase a veteran s risk for developing advanced liver disease that might progress to HCC and should be considered in screening. Within the VA, the causes for advance liver disease include alcohol use (30%), alcohol and HCV (25%), HCV alone (19%), fatty liver disease (16%) and hepatitis B virus (8%), according to Ross. While hepatitis B infection (HBV) occurs in lower rates in the U.S. than in other regions of the world, veterans have twice the rate of past infection with HBV compared to the general population. VA researchers are working to determine Age-adjusted Liver Cancer Mortality Rates Per per 100,000 by State, 2006 2010 Source: American Journal of Gastroenterology. Apr 2014; 109(4): 542 553 the number of veterans in care who have chronic HBV infections. Ross noted that all FDA-approved treatments for chronic hepatitis B infection are available through the VA National Formulary, and the Office of Public Health is preparing to distribute general guidelines for VA practitioners on diagnosis, treatment and prevention of HBV. Nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (NAFLD/NASH) occur primarily in obese patients who develop fat around the liver that can sometimes cause liver fibrosis and liver cancer. As obesity rates have risen, fatty liver disease has become a greater risk factor in HCC and is likely to be a problem even after we eradicate HCV, according to Heuman. Eighty percent or more of liver cancer diagnosed in the U.S. is not curable because it is diagnosed too late. Most people do not develop symptoms until their liver is 80% shot. Tamar Taddei, MD When to Screen Because patients who have cirrhosis have the greatest risk of developing HCC and because early detection increases the likelihood that a patient will be eligible for a curative treatment, several professional societies, including the American Association for the Study of Liver Disease, endorse screening for cirrhosis. The Preventative Task Force of the American Society for Oncology does not. A pair of recent articles in the Annals of Internal Medicine, both written by VA researchers and program 4 Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs
managers, highlighted the sometimes bitter debate about screening. 1, 2 On one hand, researchers from the Evidence-based Synthesis Program at the Portland VAMC conducted a meta-analysis of published literature to better understand the incremental benefits and harms of routine HCC screening in patients with chronic liver disease compared to clinical or incidental diagnosis and found that the overall strength of evidence for screening was very low. They concluded that screening tests can identify early-stage HCC, but whether systematic screening leads to a survival advantage over clinical diagnosis is uncertain. Ross, together with David Atkins, MD, MPH, director of the health services research and development, office of research and development at the VA and Michael Kelley, MD, VA s national program director for oncology, conceded in an accompanying commentary that the current evidence for screening has significant limitations. Consequently, they agree that current screening should not be expanded and new screening programs should not be initiated. A six-month interval is more biologically sensible due to expectations of average tumor doubling times of about 100 days, the limited sensitivity of ultrasound for nodules less than 1 cm and a goal of detecting tumors less than 5 cm. Age-adjusted SEER 18 HCC incidence and U.S. liver cancer mortality rates by age group and year; 2000 2010 David Kaplan, MD However, they conclude that existing screening programs should continue as the benefits of detecting preclinical HCC through screening outweigh the potential harm in high-risk patients with HCV and cirrhosis, as patients identified with preclinical tumors are more likely to be eligible for curative treatment by resection or transplantation. They recommend conducting more and higher quality research to determine the true efficacy of screening, particularly in the VA setting. Ross told U.S. Medicine that the VA s 2009 guidelines are under review for potential updates, but the current AASLD and VA guidelines recommend an ultrasound every six to 12 months for patients with cirrhosis. A six-month interval is more biologically sensible due to expectations of average tumor doubling times of about 100 days, the limited sensitivity of ultrasound for nodules less than 1 cm and a goal of detecting tumors less than 5 cm, said David Kaplan, MD, director of hepatology at the Philadelphia VMAC and assistant professor of medicine at the University of Pennsylvania. Many hepatologists also look at alpha fetoprotein level as a tumor marker for liver cancer. Patients with chronic hepatitis B infections at high risk of HCC, primarily individuals of African or Asian descent, should be screened as well, Kaplan said. 1 Kansagara D, Papak J, Pasha AS, O Neil M, Freeman M, Relevo R, Quiñones A, Motu apuaka M, Jou JH. Screening for hepatocellular carcinoma in chronic liver disease: a systematic review. Ann Intern Med. 2014 Aug 19;161(4):261-9. Source: American Journal of Gastroenterology. Apr 2014; 109(4): 542 553 2 Atkins D, Ross D, Kelley M. Acting in the Face of Uncertainty. Ann Intern Med. 2014 Aug 19;161(4):300-301. Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs 5
Evolving Treatment Options Offer Hope, Longer Lives for VA s HCC Patients LITTLE ROCK, AR Two decades ago, patients diagnosed with liver cancer were generally told to get their affairs in order, as little could be done to help them. Now, surgery and ablation can cure hepatocellular carcinoma (HCC), while a variety of radiologic therapies can extend life, sometimes by several years. In 1992, my very first liver cancer patient had been seen at a reputable university hospital in the Midwest and told she had six months to live, said Michael Beheshti, MD, chief of diagnostic and therapeutic imaging at the Central Arkansas Veterans Healthcare System and associate professor of interventional radiology at the University of Arkansas for Medical Sciences in Little Rock, AR. After treatment with chemoembolization and isolated hepatic perfusion, the patient lived another three years, and she and her husband enjoyed those years immensely, he recounted. Still, Beheshti fought for more than a decade to have patients referred to him because of lack of evidence that locoregional treatments, such as that received by that first patient, were effective. Not until late 2003 did two prospective, randomized trials come out that proved that chemoembolization improved survival in patients with HCC. Today, the interventional radiologist is front and center in the evaluation, management and treatment of patients with HCC, Beheshti told U.S. Medicine. Because of the complexity of establishing the best treatment and special issues inherent in managing liver cancer, interventional radiologists often work in a multidisciplinary team that includes oncologists, surgeons, hepatologists and others. Generally, the number and size of the tumors determine the treatments available to the individual patient. Curative Options The problem with liver cancer is that it occurs in a sick organ. You can t just cut out 5 centimeter margins like you can with breast or other cancers. You need to leave as much as possible so that the patient doesn t go into liver failure. Ayse Aytaman, MD Treatment with curative intent, including resection, transplantation and ablation, critically depends on identification of early-stage HCC, said David Kaplan, MD, director of hepatology at the Philadelphia VAMC and assistant professor of medicine at the University of Pennsylvania. HCC predominantly kills by precipitating liver failure. Preserving non-tumor hepatic mass is therefore of the utmost importance. The earlier a diagnosis, the more hepatic function that can be preserved. About two-thirds of early-stage cases are potentially curable with local treatments such as thermal ablation or resection, according to Douglas Heuman, MD, chief of hepatology and medical director of liver transplantation at the Hunter Holmes McGuire VAMC and professor of medicine at Virginia Commonwealth University, both in Richmond. The most limited treatment is radiofrequency or microwave ablation that burns out the tumor and a margin of surrounding tissue, he told U.S. Medicine. Resecting or removing the part of the liver with the malignancy also can offer a cure and is generally preferred for patients who can tolerate it and have tumors of less than 5 centimeters. The problem with liver cancer is that it occurs in a sick organ, said Ayse Aytaman, MD, chief of gastroenterology and 6 Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs
hepatology at the VA New York Harbor Health Care System in Brooklyn and director of the VISN-3 liver cancer team. You can t just cut out 5 centimeter margins like you can with breast or other cancers. You need to leave as much as possible so that the patient doesn t go into liver failure. Transplantation cures HCC, too, but is available only to relatively few patients. The advantage of transplantation is that it cures cirrhosis as well as cancer, said Heuman. The drawback is that every year there are about 6,000 livers available in the U.S. for 20,000 patients dying of HCC and another 30,000 with cirrhosis. As a result, HCC patients may wait a year or more for a new liver. Many veterans who initially qualify for transplantation will never receive a new liver because their disease progresses to the point they are no longer eligible for a transplant or they die waiting. Typically, [veterans with HCC] believe they are going to die within a year or two. Celebrating the third, and then fourth and now even the fifth anniversary of the beginning of treatment is a great joy. Strict Guidelines Veterans and other patients must meet strict guidelines to qualify for one of the rare organs. Transplantation is limited to patients with a single tumor of less than 5 centimeters or up to three tumors, all less than 3 centimeters. Transplant teams also consider a number of other risk factors that may limit the success of a liver transplant including age over 55 years; comorbidities such as cardiovascular, pulmonary or renal disease; obesity; poorly controlled diabetes; metastases or other primary malignancies beyond the liver; infections; cachexia; addictions and other mental health issues; and social supports. In some instances, two of these potentially curative treatments may be combined. Patients whose tumors exceed the size limitations for transplantation may have ablation or resection first to reduce the size or number of tumors. If successful, they may then go on the waiting list for a transplant. Other patients may meet the transplantation requirements but have ablation or resection with hope for a cure or to remain within the transplantation criteria while they wait for a new liver. Extending Life Patients ineligible for one of the curative options may benefit from interventional radiation therapies that can extend their lives by a number of months or even several years. The most common interventional radiation procedures today release targeted chemotherapeutic agents or radiation into the tumor. Some also block blood supply to the tumor with tiny glass or resin beads for a double whammy. In recent years, transarterial bead embolization (TABE) has largely replaced the traditional lipiodol-based chemoembolization (transarterial chemoembolization or TACE), though Michael Beheshti, MD quality evidence of its superiority is scarce, according to Kaplan. Yttrium-90 microsphere radioembolization (transarterial radiotherapy or TARE) also has gained traction. TARE delivers yttrium-90 (Y90), which emits very high energy beta particles, directly into a tumor but kills little surrounding tissue because of its narrow area of effect (less than 2.5 millimeters). Because it uses much smaller beads than TABE, TARE does not block arterioles. TARE is most appropriate as an alternative to TABE or TACE in patients with central portal venous thrombosis, but its use has been extended significantly in the absence of randomized clinical trial data despite its significant cost differential, Kaplan said. Recent advances have made embolization of all types much easier for patients to tolerate. Beheshti s first patient and many others treated through the 1990s who received chemoembolization suffered significant adverse effects. Most of my patients were admitted to the hospital for three days for pain control and control of other very unpleasant side effects. Today, my patients are almost exclusively treated on an outpatient status both for radioembolization and chemoembolization, he noted. New and revived therapies also are attracting interest for use in HCC. Stereotactic body radiotherapy (SBRT) and proton therapy are being tested, along with alternative ablative techniques that overcome some of the limitations of traditional heat-based ablation. Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs 7
Multidisciplinary Teams Improve Treatment of Hepatocellular Carcinoma NEW YORK In the past three years, the VA has focused on early detection and evaluation of hepatocellular carcinoma (HCC) to enable curative treatment in a larger number of veterans. That s a tall order and not one any hepatologist or oncologist would want to tackle alone, even at the facility level. But a team can and has taken on the challenge with remarkable results. At some facilities, the Veterans Integrated Service Network (VISN) 3 HCC team has decreased the time from initial detection of a liver lesion to treatment by 70%, said David Ross, MD, PhD, director of HIV, HCV and public health pathogens programs at the VA. In 2010, Ayse Aytaman, MD, chief of gastroenterology and hepatology at the VA New York Harbor Health Care System in Brooklyn and director of the VISN 3 liver cancer team, along with her colleagues Kristel Hunt, MD, a gastroenterologist at the James J. Peters VAMC in the Bronx, and Patrick Malloy, MD, chief of radiology and associate chief of staff at the New York Harbor VA in Manhattan, set out to create a facility-wide liver cancer team and tumor board. Since then, the trio has taken what they ve learned plus contributions from Tamar Taddei, MD, director of the hepatocellular carcinoma initiative at the VA Connecticut Healthcare System in West Haven, and others and established a VISN-wide cancer team and tumor board that is expanding across the country. Ross said the VISN 3 HCC team incorporates the key components of excellent case management for HCC: Use of clinical reminders to increase surveillance for HCC in high-risk patients; Deployment of an innovative cancer tracking system developed by Taddei at the West Haven VA that allows automated scheduling and tracking of patients undergoing work-up of suspicious lesions; Standardization of liver imaging protocols and radiology interpretation standards; Creation of VISN-wide tumor boards that meet weekly to discuss patients and make definitive treatment recommendations; and Establishment of VISN-wide networks to link patients to available specialized treatment resources without delay. Multidisciplinary teams are essential in liver cancer. It s not the typical cancer model where an oncologist runs the team, because there are so many ways to approach HCC. Tamar Taddei, MD The results speak to the effectiveness of the program: The average number of days from diagnosis to treatment dropped from 90 days to 30 days or less in every facility, and VISN 3 now offers treatment to 100% of patients. When we started, just 10% to 15% of HCC patients were offered some treatment nationally in the VA, Aytaman recounted. The New York team has achieved such outstanding results by connecting everyone involved in treating HCC and establishing a multidisciplinary weekly tumor board that works together to evaluate patients and agree on treatment very shortly after diagnosis. Multidisciplinary teams are essential in liver cancer. It s not the typical cancer model where an oncologist runs the team, because there are so many ways to approach HCC. Instead, hepatologists usually lead the team, but everybody who has a hand in deciding on the appropriate care for a patient is at the table, said Taddei. The team may include primary care, hepatology, interventional radiology, oncology, palliative care, oncologic surgery, radiation oncology, psychology, transplant surgery, radiology and social work specialists. The hepatologist says whether the patient has enough liver function to tolerate treatment; an oncological surgeon and transplant surgeon can assess a candidate for curative 8 Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs
resection or transplant. It s often too late for surgery, so an oncologist contributes to the discussion and palliative care needs to be introduced early on, too. Even a tumor registrar has a role, Taddei told U.S. Medicine. By bringing all parties together to evaluate a patient early in the process, Aytaman and her colleagues significantly streamlined the process for patients and made cutting edge HCC care available to all patients across the VISN. While we had a group that included interventional radiology, oncology, gastroenterology and palliative care that worked well together at NY Harbor three years ago, I was constantly reminded how lucky we were that our patients had all those treatment options available. We had some patients driving three hours one way just to get a consultation, said Aytaman. She envisioned standardized care across six facilities with five university affiliations. Standardizing imaging proved a critical step in standardizing care. HCC is the only cancer that you can diagnose by imaging only, without biopsy. If you re going to start treatment without a biopsy, though, imaging better be very high quality, with a very strict protocol covering all aspects, including a reading template, Aytaman told U.S. Medicine. All facilities in VISN 3 also added MRI capability so those scans can be done in local clinics rather than only in Brooklyn. In addition, the group also created templates for tumor board notes, tumor board submissions and a liver transplant order set. Before the VISN-wide tumor board started meeting, a patient found to have a liver lesion could have required eight visits, some to distant medical centers, for scans, biopsy, consults and surgery referrals before starting treatment. Now, every lesion goes into the tumor tracker, a tracking nurse brings new ones to the attention of the tumor board, a cancer coordinator orders appropriate imaging and the completed images go to the tumor board for the next weekly meeting. The board uses a telehealth system available throughout the VISN so every member can stay in his or her local facility but still participate. The board makes a recommendation and schedules an appointment for the patient the next day, also via a local telehealth system, and the patient is routed immediately to proper treatment, whether surgery, interventional radiation or palliation. Now, we can see the patient, evaluate the case, make recommendations and answer questions for the family without making anyone travel, except for procedures, Aytaman said. Members of the VISN 3 HCC (Hepatocellular Cancer) Team: (l-r) Sabina Kirtich, NP; Kristel Hunt, MD; Marina Pilic, NP; Patrick Malloy, MD; Sharon Morgan, NP; Ayse Aytaman, MD; and Alice Beal, MD Photo from NY Harbor VAMC To facilitate communication among all 112 members of the VISN 3 HCC team, the team has its own shared network space, SharePoint tools and website as well as a weekly working teleconference and weekly administrative teleconference and regular educational meetings. The VISN 3 tumor board already works closely with VISNs 1 (New England) and 6 (Mid-Atlantic) on a regional basis. Last year, a grant designed to facilitate nationwide spread enabled the team to expand to VISN 4 (Pittsburgh/ Philadelphia) and 12 (Great Lakes). Workshops on all aspects of VISN-wide tumor board operation from telehealth equipment to templates to team dynamics and a national summit have helped those two new areas to launch their own tumor boards, participate in joint tumor boards and use the new tools. By joining forces with VISNs 1, 6, 4 and 12, we ve created the backbone for a national team that will allow us to bring cutting-edge expertise to every corner of the nation and improve care for all our veterans, Aytaman said. Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs 9
HCC Surveillance Increases 50% with VA s Clinical Reminders for Primary Care SEATTLE Because patients with hepatocellular carcinoma (HCC) have the most options when diagnosed early in their disease progression, the VA recommends screening for liver cancer every six to 12 months in veterans with cirrhosis. Screening levels remain low, particularly among patients with compensated livers those who could most benefit from early disease detection. That could change soon, though, if an unusually effective clinical reminder system rolls out across the country. Researchers at eight VA facilities in the Pacific Northwest tested a clinical reminder for hepatocellular carcinoma (HCC) from January 1, 2011 until June 30, 2012 and found it increased surveillance by 51% at the intervention site. Clinical reminders typically result in modest improvements in adherence to processes of care with a median absolute improvement of only 4.2%, the researchers noted in their study, which appeared in a recent issue of Clinical Gastroenterology and Hepatology 1 An analysis of the findings demonstrated that a clinical reminder led to significantly more utilization of abdominal imaging for HCC surveillance in patients with cirrhosis, first author Lauren Beste, MD, of the Puget Sound, WA, VAMC and co-author David Ross, MD, PhD, director of the VA s HIV, hepatitis and public health pathogens programs, told U.S. Medicine in an email. The facility that introduced the reminder had a baseline HCC surveillance rate of 18.2%, while the other seven facilities averaged 16.1%, similar to the overall U.S. rate of surveillance. After introducing the reminder, the intervention site had a surveillance rate of 27.6%, while the rate at the control locations remained statistically unchanged. The researchers noted that primary care providers (PCPs) Researchers at eight VA facilities in the Pacific Northwest tested a clinical reminder for hepatocellular carcinoma (HCC) from January 1, 2011 until June 30, 2012 and found it increased surveillance by 51% at the intervention site. less frequently order the imaging recommended for surveillance of cirrhotic patients and that future care for patients with cirrhosis likely will be performed increasingly by PCPs, given a projected shortage of hepatologists. To address this challenge, the intervention reminded providers at the point of care that surveillance was due for patients who had a prior diagnosis of cirrhosis, had not had abdominal imaging in the previous six months and had not been diagnosed with liver cancer. While the reminder can be used by providers from any clinic, including gastroenterology and hepatology clinics, it was specifically designed for primary care providers in order to promote HCC surveillance among cirrhosis patients who are not necessarily followed in a specialty clinic, Beste and Ross said. Based on initial testing with one group of physicians, the reminder was designed to minimize PCP workload, permit flexible resolution and not disrupt the physician s workflow. The provider could automatically generate a liver ultrasound order from the reminder or could indicate why one was not appropriate for the patient at the time. Reasons included screening recently conducted outside the VA, short life expectancy, improper diagnosis, existing HCC and other options. Developed as a quality improvement project by the Office of Public Health, the reminder remains in use in the Puget Sound. Given the substantial improvement in surveillance seen in the study, which is easily exportable to other VA facilities, OPH will support efforts to disseminate the clinical reminder, according to Ross and Beste. 1 Beste LA, Ioannou GN, Yang Y, Chang MF, Ross D, Dominitz JA. Improved Surveillance for Hepatocellular Carcinoma With a Primary Care-Oriented Clinical Reminder. Clin Gastroenterol Hepatol. 2014 May 6. pii: S1542-3565(14)00668-5. 10 Advances in Hepatocellular Carcinoma Treatment at Veterans Affairs
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981 USA 249 E. Grand Avenue, South San Francisco, CA 94080 USA BAYER, the Bayer Cross, and NEXAVAR are registered trademarks of Bayer. NEXAVAR is co-promoted in the USA by Bayer HealthCare Pharmaceuticals Inc. and Onyx Pharmaceuticals, Inc., an Amgen subsidiary. 2015 Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ PP-810-US-1589 4/15 Printed in USA 2015, Marathon Medical Communications, Inc. 39 York Street, Lambertville, NJ 08530 U.S. Medicine (ISSN 0191-6246)