Medical Magazine

Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can be conceptualized as membrane-bound receptor kinases (HGF/c-Met, human epidermal growth factor receptor and insulin growth factor receptor pathways), intracellular signaling kinases (Src, PI3k/Akt/mTOR, and mitogen-activated protein kinase pathways), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, HIF, endothelium, integrins). Several technologies are available to target these abnormalities. Of these, monoclonal antibodies and small-molecule inhibitors have been the more successful, and often complementary, approaches so far in clinical settings. The success of this target-based cancer drug development approach is discussed with examples of recently approved agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. This review also highlights the pipeline of rationally designed drugs in clinical development that have the potential to impact clinical care in the near future. CA Cancer J Clin 2009;59:111-137.

Wen W. Ma　MD1　Alex A. Adjei　MD　PhD2 *
[1]Assistant Professor, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY;[2]Senior Vice President, Clinical Research, Chair, Department of Medicine, Katherine Anne Gioia Chair in Cancer Medicine, Roswell Park Cancer Institute, Buffalo, NY

In the adult population, thyroid nodules are common and are increasingly detected by ultrasound examination or other scanning techniques. Depending on their size and ultrasonographic features, these nodules may require further investigation, including tissue diagnosis. Fine-needle aspiration (FNA) has become the predominant method to obtain tissue for microscopic analysis. In October 2007, the National Cancer Institute sponsored a conference to review the state of the science for the use of FNA in the management of thyroid nodules. This conference reviewed indications for thyroid FNA and pre-FNA requirements, training and credentialing, techniques for thyroid FNA, diagnostic terminology and morphologic criteria, utilization of ancillary studies, and post-FNA testing and treatment options. The results of those discussions have been published in both print and electronic versions. The aim of the current article was to discuss indications for FNA, diagnostic terminology, and post-FNA options, issues that are important to physicians who are managing patients with thyroid nodules. CA Cancer J Clin 2009;59:99-110.

Lester J. Layfield　MD1 *　Edmund S. Cibas　MD2　Hossein Gharib　MD3　Susan J. Mandel　MD　MPH4
[1]Professor and Head, Anatomic Pathology, University of Utah School of Medicine, University of Utah Hospital and Clinics, Salt Lake City, UT;[2]Associate Professor of Pathology, Harvard Medical School Director of the Division of Cytopathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA;[3]Professor of Medicine, Department of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN;[4]Professor of Medicine, Associate Chief of the Division of Endocrinology, Diabetes and Metabolism, Hospital of the University of Pennsylvania, Philadelphia, PA

The skin often mirrors changes in the organism it envelops. Many neoplastic diseases that affect internal organs display cutaneous manifestations, which may be the presenting signs and symptoms of the underlying malignancy. These may reflect direct involvement of the skin by the tumor (ie, tumor metastasis) or indirect involvement, in which changes in the skin occur in the absence of malignant cells. This review focuses on the latter conditions, which are often referred to as paraneoplastic dermatoses. Included in the discussion are the cutaneous manifestations of inherited syndromes that are associated with an increased risk of internal malignancy, cutaneous changes in patients with hormone-secreting tumors, and the wide spectrum of proliferative and inflammatory dermatoses that have been associated with internal cancer. CA Cancer J Clin 2009;59:73-98.

Bruce H. Thiers　MD1 *　Rachel E. Sahn　BA2　Jeffrey P. Callen　MD3
[1]Professor of Dermatology and Chair, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC;[2]College of Medicine, Medical University of South Carolina, Charleston, SC;[3]Professor of Medicine and Chief, Division of Dermatology, University of Louisville School of Medicine, Louisville, KY

The authors systematically reviewed the association between provider case volume and mortality in 101 publications involving greater than 1 million patients with esophageal, gastric, hepatic, pancreatic, colon, or rectal cancer, of whom more than 70,000 died. The majority of studies addressed the relation between hospital surgical case volume and short-term perioperative mortality. Few studies addressed surgeon case volume or evaluated long-term survival outcomes. Common methodologic limitations were failure to control for potential confounders, post hoc categorization of provider volume, and unit of analysis errors. A significant volume effect was evident for the majority of gastrointestinal cancers; with each doubling of hospital case volume, the odds of perioperative death decreased by 0.1 to 0.23. The authors calculated that between 10 and 50 patients per year, depending on cancer type, needed to be moved from a “low-volume” hospital to a “high-volume” hospital to prevent 1 additional volume-associated perioperative death. Despite this, approximately one-third of all analyses did not find a significant volume effect on mortality. The heterogeneity of results from individual studies calls into question the validity of case volume as a proxy for care quality, and leads the authors to conclude that more direct quality measures and the validity of their use to inform policy should also be explored. CA Cancer J Clin 2009;59:192–211. © 2009 American Cancer Society.

Russell L. Gruen, MBBS, PhD1　Veronica Pitt, PhD2　Sally Green, PhD3　Anne Parkhill, MBIT, GradDipLib4　Donald Campbell, MMedSci (ClinEpi), MD　Damien Jolley, MSc (Epidemiol), MSc (Stats), DipEd, AStat
[1]Associate Professor of Surgery, University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia;[2]Health Technology Assessment Evaluator, Monash Institute of Health Services Research, Melbourne, Victoria, Australia;[3]Professorial Fellow, Monash Institute of Health Services Research, Melbourne, Victoria, Australia;[4]Information Specialist, Monash Institute of Health Services Research, Melbourne, Victoria, Australia;Professor of Medicine, Monash Medical Center, Melbourne, Victoria, Australia;Associate Professor and Senior Biostatistician, Centre for Research Excellence in Patient Safety, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

According to the 2008 World Health Organization classification system for hematologic malignancies, the myeloproliferative neoplasms (MPN) include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, mastocytosis, chronic eosinophilic leukemia-not otherwise specified, chronic neutrophilic leukemia, and “MPN, unclassifiable.” All of these clinicopathologic entities are characterized by stem cell-derived clonal myeloproliferation, and their phenotypic diversity is ascribed to the occurrence of distinct oncogenic events. In the last 4 years, new JAK2 and MPL mutations have been added to previously described ABL and KITmutations as molecular markers of disease in MPN. These discoveries have markedly simplified the approach to clinical diagnosis and have also provided molecular targets for the development of small-molecule drugs. In the current article, the authors provide a clinically oriented overview of MPNs in terms of their molecular pathogenesis, classification, diagnosis, and management. CA Cancer J Clin 2009;59:171–191. © 2009 American Cancer Society, Inc.

Alessandro M. Vannucchi, MD1　Paola Guglielmelli, MD2　Ayalew Tefferi, MD3
[1]Associate Professor of Hematology, Department of Hematology, University of Florence, Florence, Italy;[2]Research Fellow at the Department of Hematology, University of Florence, Florence, Italy;[3]Professor of Medicine and Hematology, Mayo Clinic College of Medicine, Rochester, NY

Because local therapies directed toward a specific tumor mass are known to be effective for treating early-stage cancers, it should be no surprise that there has been considerable historical experience using local therapies for metastatic disease. In more recent years, increasing interest in the use of local therapy for metastases likely has arisen from improvements in systemic therapy. In the absence of effective systemic therapies, such local treatments were often considered futile given both the difficulty in eliminating all sites of identifiable metastatic disease as well as realities regarding the rapid natural history of uncontrolled tumor dissemination. However, with a higher likelihood of patients surviving longer after effective systemic therapy, even if not cured, the goal of the eradication of residual metastases via potent local therapies can be rationalized. However, this rationalization should be evidence-based so as to avoid harming patients for no established benefit. Although surgical metastectomy remains the most common and first-line standard among local therapies, nonsurgical alternatives, including thermal ablation and stereotactic body radiotherapy, have become increasingly popular because they are generally less invasive than surgery and have demonstrated considerable promise in eradicating macroscopic tumor. Rather than eliminating the need for local therapies, improvements in systemic therapies appear to be increasing the prudent utilization of modern local therapies in patients presenting with more advanced cancer. CA Cancer J Clin 2009;59:145–170. © 2009 American Cancer Society, Inc.

Robert D. Timmerman, MD1　Costas S. Bizekis, MD2　Harvey I. Pass, MD3　Yuman Fong, MD4　Damian E. Dupuy, MD5　Laura A. Dawson, MD6　David Lu, MD7
[1]Professor of Radiation Oncology, Professor of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX;[2]Attending Surgeon, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, NY;[3]Director and Attending Surgeon, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, NY;[4]Vice Chair, Technology Development, Chief, Gastric and Mixed Tumor Service, Murray F. Brennan Chair in Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY;[5]Professor, Brown Medical School, Director of Ultrasound, Department of Diagnostic Imaging, Rhode Island Hospital, Providence, RI;[6]Associate Professor, Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada;[7]Professor, Department of Radiology, Director, Hepatic Tumor Ablation Program, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA

The primary goals of oncologic therapy are the compassionate care of cancer patients, eradication of disease, and palliation of symptoms. Advances in various targeted therapies such as highly conformal and image-guided radiotherapy techniques, sentinel lymph node dissection, and molecularly targeted agents hold the promise of allowing those goals to be reached with fewer treatment-related complications. Unfortunately, certain side effects remain problematic due to the inability to completely avoid injuring normal tissues. Lymphedema, a chronic condition that occurs as a result of the body’s inability to drain lymph fluid from the tissues, is a common treatment-related side effect experienced by cancer patients. In this review, many of the important aspects of lymphedema with which clinicians who treat cancer patients should be familiar are outlined, including the anatomy, pathophysiology, diagnosis, and management of this condition. The authors also identify some of the resources available both to cancer patients with lymphedema and to the clinicians who treat them. It is hoped that this review will convey the importance of the early identification and management of this incurable disorder because this is essential to minimizing its complications. CA Cancer J Clin 2009;59:8-24.

Brian D. Lawenda　MD1 *　Tammy E. Mondry　DPT　MSRS　CLT-LANA2　Peter A. S. Johnstone　MD3

Given the recent significant increase in the use of oral therapies in cancer management, an understanding of patients’ adherence to and persistence with oral therapy is crucial. Nonadherence and early cessation may be substantial barriers to the delivery of valuable therapies, and may impair health. Potential obstacles to adherence and persistence include personal characteristics, treatment features, and system factors. Techniques for measuring adherence and persistence include self-report, pill counts, microelectronic monitoring systems (MEMS), prescription database analysis, and the assessment of serum or urine drug levels. This review article describes available data regarding adherence and persistence among patients with cancer, as well as studies of interventions to improve adherence. All reports of studies of adherence with oral cancer therapy that the authors could find on PubMed or in the reference sections of these PubMed-located articles were included. Adherence and persistence rates ranged from 16% to 100% with different therapies and different methods of measurement. Studies that included educational, behavioral, and multidimensional interventions to improve adherence were also described. CA Cancer J Clin 2009;59:56-66.

Kathryn Ruddy　MD1 *　Erica Mayer　MD　MPH2　Ann Partridge　MD　MPH3

Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five-stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside. CA Cancer J Clin 2009;59:42-55.

R. Stephanie Huang　PhD1 2　Mark J. Ratain　MD2 3 *

Each year, the American Cancer Society (ACS) publishes a report summarizing its recommendations for early cancer detection, data and trends in cancer screening rates, and select issues related to cancer screening. In 2008, the ACS, the American Gastroenterological Association, the American College of Gastroenterology, the Society for Gastrointestinal Endoscopy, and the American College of Radiology issued a joint update of guidelines for colorectal cancer screening in average-risk adults. In this issue, the current ACS guidelines and recent issues are summarized, updates of testing guidelines for early prostate cancer detection and colorectal cancer screening by the United States Preventive Services Task Force are discussed, and the most recent data from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System and the National Health Interview Survey pertaining to participation rates in cancer screening are described. CA Cancer J Clin 2009;59:27-41.

Robert A. Smith　PhD1 *　Vilma Cokkinides　PhD2　Otis W. Brawley　MD3