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American Thoracic Society
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Possible link between sleep-disordered breathing and cardiovascular disease revealed

Doctors have long known that snoring is hazardous to health for a number of reasons. In addition to restless nights and increased daytime sleepiness, sleep-disordered breathing (SDB) has a series of associated health problems, including increased risk of cardiovascular disease (CVD). While it is not always clear what the association between SDB and a given health problem is, new research exposes that at least one factor may help to explain the increased risk of cardiovascular problems that affects even people with mild to moderate SDB. Researcher Reena Mehra, M.D., M.S., assistant professor of medicine at the Case Western Reserve School of Medicine in Cleveland, Ohio, and colleagues set out to investigate the morning and evening levels of three pro-thrombotic markers, plasminogen activator inhibitor-1 (PAI-1), fibrinogen and D-dimer, relative to the severity of SDB as defined by the apnea/hypopnea index (AHI) in 537 subjects. The study appears online ahead of the print edition of the American Journal of Respiratory and Critical Care Medicine on the American Thoracic Society's Web site. After controlling for variables including body mass index (BMI), age, sex and co-morbidities, they found that for every 5-unit increase in AHI under 15, there was a corresponding significant increase of about 10 percent in PAI-1. Similarly, for every 5-unit increase in AHI under 15, fibrinogen significantly increased on average by about 8.4 mg/dL. There was no significant increase in D-dimer in relation to AHI, however. "These data suggest that individuals with even modest levels of SDB (which describes a large proportion of the adult population) may have an enhanced pro-thrombotic biochemical profile, increasing their CVD risk," said Dr. Mehra. Increased morning PAI-1 remained significantly associated with SDB severity in those with mild to moderate SDB even after taking into account evening PAI-1, suggesting that morning may be a reflection of overnight SDB-related physiologic stress, and indicating that PAI-1 may be a good biomarker for assessing SDB stress. These diurnal findings were not noted with fibrinogen. Interestingly, there was no association between either PAI-1 or fibrinogen at AHI above 15, which is generally the clinical cut-off between moderate and more sever SDB. "These data suggest that even at levels of SDB considered to be mild, there is an enhanced thrombotic state. Further research is needed to identify whether treatment of milder degree of SDB results in improvements in markers of thrombosis, a known contributor to cardiovascular disease," said Dr. Mehra. "In summary, these data suggest that, at low to modest levels of SDB, incremental increases in AHI are associated with increases in levels of two pro-thrombotic biomarkers associated with CVD. Future directions include exploring whether treatment of even mild to moderate levels of SDB improves biomarkers of thrombosis, and performing further work to understand the specific pathways and pathobiology of SDB-related increased risk of thrombosis." John Heffner, M.D., past president of the American Thoracic Society, commented, "This study joins so many others that paint a consistent picture of sleep as a fundamentally important physiologic process for health that can negatively impact multiple organ systems when disordered breathing occurs. This study provides an important insight into how sleep disruptions can trigger prothrombotic processes that may eventually lead to cardiovascular diseases and perhaps other conditions like strokes. Other investigators will now pursue the interaction of SDB with prothrombic states." This research was funded by the National Heart Lung Blood Institute.

Jun 14, 2010
Health

HPV-positive tumor status indicates better survival in patients with oropharyngeal cancer

HOUSTON - Oropharyngeal cancer patients whose tumors in the upper part of the throat test positively for the human papillomavirus (HPV) have better overall survival than patients with HPV-negative disease, researchers from The University of Texas MD Anderson Cancer Center report in a study published in the New England Journal of Medicine. The study - the largest and most definitive to date completed in a joint effort with the Radiation Therapy Oncology Group (RTOG) - shows that tumor HPV status is a strong and independent prognostic factor for survival for these patients. Follow-up data from the study were presented today at the 44th annual meeting of the American Society of Clinical Oncology (Abstract #5510). "This is the strongest prognostic factor we have ever identified for head and neck cancer patients," said K. Kian Ang, M.D., Ph.D., professor in MD Anderson's Department of Radiation Oncology and lead author on the paper. "Its value is stronger than other prognostic factors we have used such as the size of the tumor or presence of tumor in lymph nodes. Knowing that the tumor is associated with HPV is telling the patient that the prognosis is excellent with currently available treatments." The Phase III clinical trial established by the RTOG examined overall survival and progression-free survival in 323 patients with stage III-IV oropharyngeal cancer treated with a combination of radiation therapy and chemotherapy. Of these patients, 206 had HPV-positive tumors and 117 were HPV-negative. The three-year overall survival rate for patients with HPV-positive tumors was 82.4 percent compared to 57.1 percent with HPV-negative cancer. Progression-free survival rates were 73.7 percent and 43.4 percent, respectively. When researchers adjusted for other significant determinants of survival, including patient age, race, tumor and nodal stage and tobacco use, patients with HPV-positive cancer had a 58 percent reduction in risk of death relative to patients with HPV-negative tumors. The study noted tobacco use substantially increased risk of death. Results will allow physicians to stratify patients enrolled in clinical trials into low, intermediate or high-risk of death based on HPV status, tobacco use and cancer stage. This information can then be used to better determine which patients are candidates for more intensive investigational therapies. Oropharyngeal cancer develops in the part of the throat just behind the mouth. The American Cancer Society estimates that 28,500 people in the United States are diagnosed with cancer of the oral cavity and oropharynx each year. While the incidence of head and neck cancer has been declining during the past 30 years, the rate of HPV-positive oropharyngeal cancer is rapidly rising. Today, nearly 70 percent of oropharynx cancer cases are HPV-positive. Ang credits the strength of the study to its size and the importance of collaboration among investigators. "Even large cancer centers like MD Anderson cannot do these types of studies alone. Working with our collaborators including, Maura Gillison, M.D., Ph.D., professor of medicine, epidemiology and otolaryngology at The Ohio State University, an experienced investigator on the role of HPV in head and neck cancer and co-author on the study, we were able to build on what smaller studies have suggested and produce numbers large enough to examine HPV status together with other prognostic factors." Head and neck tumors are routinely tested for HPV at MD Anderson and other large institutions. While it remains unclear why patients with HPV-positive tumors have better outcomes than those with HPV-negative tumors, researchers speculate it may be due to biologic and immunologic properties that render HPV-positive cancers inherently less malignant or better able to respond to treatment. Ang notes future studies are warranted to determine how the HPV vaccine, made available to the public in 2006, affects the incidence of HPV-related head and neck cancers. In addition to Ang and Gillison, other authors on the study include: Randal Weber, M.D., Department of Head and Neck Surgery, David Rosenthal, M.D., Department of Radiation Oncology, Charles Lu, M.D., Department of Thoracic/Head and Neck Medical Oncology, all from MD Anderson; Jonathan Harris, M.S., RTOG Statistical Center; Richard Wheeler, M.D., Huntsman Cancer Institute; Phuc Nguyen-Tan, M.D., entra Hospitaler de L'Universite de Montreal; William Westra, M.D., The Johns Hopkins University; Christine Chung, M.D., Vanderbilt University School of Medicine; Richard Jordan, D.D.S., Ph.D., The University of California at San Francisco; Rita Axelrod, M.D., Thomason Jefferson University Hospital; Craig Silverman, M.D., University of Louisville, Kevin Redmond, M.D., University of Cincinnati College of Medicine. The RTOG is a multi-institutional international clinical cooperative group funded primarily by National Cancer Institute grants CA21661 and CA37422. RTOG comprises 300 major research institutions in the United States, Canada and internationally. About MD Anderson The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2010, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

Jun 7, 2010
Health

Vandetanib shows clinical benefit when combined with docetaxel for lung cancer

HOUSTON - When combined with standard chemotherapy, an international Phase III trial has shown that the oral targeted therapy vandetanib improves progression-free survival for patients with advanced non-small cell lung cancer, according to research from The University of Texas MD Anderson Cancer Center. The findings, published in the Lancet Oncology, mark the first clinical benefit of a small molecule targeted agent and standard chemotherapy in combination for lung cancer. The study was first presented at the 2009 Annual Meeting of the American Society of Clinical Oncology. "This study shows that an oral tyrosine kinase inhibitor can be combined with chemotherapy safely and effectively to provide systematic benefit to patients with this life-threatening disease," said Roy Herbst, M.D., Ph.D., professor and chief of the section of MD Anderson's Department of Thoracic/Head and Neck Medical Oncology and the study's corresponding author. "Still, we need to build on this research and turn our focus toward better identifying molecular markers involved, with the ultimate goal of personalizing our patient's care." The therapy is unique in that it's a dual inhibitor and targets the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). It is the first single agent in lung cancer to target both receptors, said Herbst, the study's international principal investigator. "Both receptors are active in lung cancer. EGFR targets the tumor cell and VEGF targets the blood vessels, so, with vandetanib, we're really targeting the entire tumor environment at the same time," explained Herbst. "As a dual inhibitor, it also may provide cost-savings to patients in that they can now potentially take one therapy instead of two." According to the American Cancer Society, lung cancer accounts for the most cancer-related deaths. In 2009, approximately 219,440 were diagnosed and 159,390 died from the disease. The ZODIAC, (Zactima in cOmbination with Docetaxel In non-smAll cell lung Cancer) study enrolled 1,391 patients with non-small cell lung cancer from 198 centers between May 2006 and April 2008; all had received chemotherapy previously. Participants were randomized to receive either docetaxel and placebo, or docetaxel and vandetanib. The median follow-up was 12.8 months and the study's primary endpoint was progression-free survival. Patients in the combination arm had a 21 percent reduction in disease progression, compared to those who received docetaxel alone (hazard ratio, .79), and their median progression-free survival was 17.3 weeks. In contrast, the median progression-free survival in the control arm was 14 weeks. While it trended positive, however, there was no statistical difference in overall survival in the two groups. There was a statistically significant improvement in the time to worsening of symptoms (hazard ratio, .77). "Obviously, our ultimate goal is to always improve survival for our patients, however the improved time to progression with less of a number of significant effects is important," said Herbst. "This is certainly a drug, where, if we could identify molecular parameters that predict response, we could some day take a group that's receiving docetaxel and vandetanib and see them do even better. We're not there yet, but hopefully this study will serve as the foundation for the merger of personalization and discovery with the now-proven safety and efficacy." In terms of side effects, patients who received vandetanib experienced more diarrhea, rash and neutropenia. However, they experienced less of the significant side effects - nausea, vomiting, and anemia - than those who received docetaxel alone. The lack of significant side effects is quite striking, said Herbst, because other agents that target VEGF are associated with increased toxicity, including pulmonary bleeding. In addition to Herbst, other authors on the study include: Yan Sun, Cancer Hospital, Bejing, China; Sönke Korfee, West German Tumor Center, University Duisburg-Essen; Paul Germonpré, Antwerp University Hospital, Belgium; Nagahio Saijo, National Cancer Center Hospital East, Chiba, Japan; Caichun Zhou, Tongji University, Shanghai, China; Jie Wang, Beijing Institute for Cancer Research, Beijing, China; Bruce Johnson, Dana-Farber Cancer Institute; and Peter Langmuir, Hiroomi Tada, Sarah Kennedy, all with AstraZeneca. Herbst has been a consultant for and has received research support from AstraZeneca. About MD Anderson The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

Jun 4, 2010