Medicine Health RHODEI SLAND VOL. 85 NO. 1 JANUARY 2002

Cancer Update A CME Issue UNDER THE JOINT
VOLUME 85, NO. 1 JANUARY, 2002 EDITORIAL SPONSORSHIP OF: Medicine Health Brown University School of Medicine Donald Marsh, MD, Dean of Medicine HODE SLAND & Biological Sciences R I Rhode Island Department of Health PUBLICATION OF THE RHODE ISLAND MEDICAL SOCIETY Patricia Nolan, MD, MPH, Director Rhode Island Quality Partners Edward Westrick, MD, PhD, Chief Medical Officer Rhode Island Chapter, American College of COMMENTARIES Physicians-American Society of Internal Medicine Fred J. Schiffman, MD, FACP, Governor 2 Demented Politicians Rhode Island Medical Society Joseph H. Friedman, MD Yul D. Ejnes, MD, President 3 Some Comments On a Possible Ancestor EDITORIAL STAFF Stanley M. Aronson, MD, MPH Joseph H. Friedman, MD Editor-in-Chief Joan M. Retsinas, PhD CONTRIBUTIONS Managing Editor CANCER UPDATE: A CME ISSUE Hugo Taussig, MD Guest Editor: Paul Calabresi, MD, MACP Betty E. Aronson, MD Book Review Editors 4 Cancer in the New Millennium Stanley M. Aronson, MD, MPH Paul Calabresi, MD, MACP Editor Emeritus 7 Update in Non-Small Cell Lung Cancer EDITORIAL BOARD Betty E. Aronson, MD Todd Moore, MD, and Neal Ready, MD, PhD Stanley M. Aronson, MD 10 Breast Cancer Update Edward M. Beiser, PhD, JD Mary Anne Fenton, MD Jay S. Buechner, PhD John J. Cronan, MD 14 Screening for Colorectal Cancer in Rhode Island James P. Crowley, MD Arvin S. Glicksman, MD John P. Fulton, PhD Peter A. Hollmann, MD 17 Childhood Cancer: Past Successes, Future Directions Anthony Mega, MD William S. Ferguson, MD, and Edwin N. Forman, MD Marguerite A. Neill, MD Frank J. Schaberg, Jr., MD 23 Brain Tumors Fred J. Schiffman, MD Lloyd M. Alderson, MD, DSc Lawrence W. Vernaglia, JD, MPH Newell E. Warde, PhD 28 CME Information William J. Waters, Jr., PhD OFFICERS COLUMNS Yul D. Ejnes, MD 30 Rhode Island Quality Partners President Tilak K. Verma, MD PREVENTION AND TREATMENT RECOMMENDATIONS FOR COMMUNITY Vice President ACQUIRED PNEUMONIA David B. Ettensohn, MD Deidre Spellisey Gifford, MD, MPH President-Elect Fredric V. Christian, MD 32 Health By Numbers Secretary RHODE ISLAND HISPANICS HAVE MAINSTREAM CANCER RATES Peter A. Hollmann, MD John P. Fulton, PhD, and Jay S. Buechner, PhD Treasurer Michael B. Macko, MD 34 Public Health Briefing Immediate Past President THE RHODE ISLAND CANCER COUNCIL Arvin S. Glicksman, MD, and Paul Calabresi, MD, MACP DISTRICT & COUNTY PRESIDENTS Pamela A. Harrop, MD 37 Judicial Diagnosis Bristol County Medical Society WHAT NOW?! THE OIG WORRIES ABOUT PHYSICIAN BILLING, REFLECTED Robert A. Salk, DO N THE ORK LAN Kent County Medical Society I 2002 W P Jayanthi Parameswaran, MD Lawrence W. Vernaglia, JD, MPH Newport County Medical Society 38 Vital Statistics Stephen T. Conway, MD Pawtucket Medical Association Edited by Roberta Chevoya Patrick J. Sweeney, MD, PhD, MPH 39 A Physician’s Lexicon Providence Medical Association NAUSEA AND VOMITING R. Scott Hanson, MD Washington County Medical Society Stanley M. Aronson, MD, MPH Naeem M. Siddiqi, MD 41 Rhode Island Medical Journal Heritage Woonsocket District Medical Society 42 2001 Index

Cover: “Some Freesias,” a hand colored etching by Penny Feder. Penny Feder’s artwork can be seen at her website, www.pennyfeder.com and at the JRS Gallery Medicine and Health\Rhode Island (USPS 464-820), a monthly publication, is owned and published by the Rhode Island Medical Society, 106 Francis Street, Providence, RI 02903, Phone: 401-331-3207. Single copies $5.00, individual subscriptions $50.00 per year, and $100 on Wickenden St. in Providence. per year for institutional subscriptions. Published articles represent opinions of the authors and do not necessarily reflect the official policy of the Rhode Island Medical Society, unless clearly specified. Advertisements do not imply sponsorship or endorsement by the Rhode Island Medical Society. Periodicals postage paid at Providence, Rhode Island. ISSN 1086-5462. POSTMASTER: Send address changes to Medicine and Health\Rhode Island, 106 Francis Street, Providence, RI 02903. Classified Information: RI Medical Journal Marketing Department, 175 Mathewson Street, Providence, RI 02903, phone: (401) 331-4637, fax: (401) 331-3594
COMMENTARIES
Demented Politicians

newspaper recently reported that ies, of course, with the politician (the one draw the line in declaring a Presi- Aa U.S. senator described his friend, analogy of the physician “thought dent unfit for office? another U.S. Senator, Strom leader” who lectures for a corporate We all applaud Senator Thurmond, almost 100 years old, as sponsor for a fee should be kept in Thurmond’s determination and dedi- “not keen.” I am not completely con- mind here). However, regardless of cation, but even Cal Ripken, Jr., the fident what this means although I’m who wields the power, the fact remains new “iron man” of baseball had to re- pretty sure. I’m also pretty sure that that the buck stops with the voter. tire when his skills weakened with age. Thurmond’s press aide’s response, Legislation backed by a senator, or ini- I think that questions of competence “That’s nonsense. He swims a full lap tiated by a senator, bears that that devolve into medical issues require in the swimming pool each day,” was a politician’s imprimatur and therefore a medical evaluation. Do we know troubling response. I don’t know how his responsibility, regardless of who whether our older leaders have annual old the aide is, or whether he too swims actually wrote it. To exercise this de- medical examinations and if so, do they a lap or two in the pool daily, but I gree of responsibility, the final arbiter include neurobehavioral assessments? wonder if the two of them are “not of a single vote, the voter must be I, for one, would feel reassured to know keen”. “compos mentis.” that Senator Thurmond is cognitively I have wondered about Senator After Woodrow Wilson suffered a intact and that he makes his own deci- Thurmond for some time. William debilitating stroke, his wife took over sions when he votes and signs his name Safire, the New York Times columnist, much of the function of the president. onto legislation. recently vilified a Democratic-run This was a perversion of our constitu- As people live longer and work committee for scheduling lengthy talks, tion. Mrs. Wilson was never voted into longer we need to grapple with the is- that they knew Thurmond would not an office. Even Hillary Clinton was sues of medical competency for elected be able to stay awake for. given powers designated by the presi- officials, just as we have them for air- “Not keen.” Excessive daytime dent as if she were a private citizen and line pilots and some other professions. somnolence. Age 98. Are these early did not simply assume them. It seems Doctors too need to consider this, warnings of my own “ageism?” Al- to me that it is a very straightforward rather than depending on “after the though people don’t get smarter with requirement for those who serve our fact” reporting of incompetence, be- age, many do become wiser. While nation to be held to some standards of cause more of us practice in our old mathematicians peak early, the capac- accountability and capability. While age. Recredentialing requirements help ity to pursue intellectual challenges re- those who serve elected officials are address this issue and the Joint Com- quiring wisdom, knowledge and responsible and hopefully loyal to the mission on the Accreditation of Hos- sensitivity seems to ripen with age, as person they serve, there should be a pitals has recently required bylaw is often seen in fine literature, music higher loyalty to the office that the changes in hospitals to help weed out composition and philosophy. How- elected official fills. When the official incompetent physicians. We need a ever, with age comes frailty and too fre- is corrupt and accepts bribes, the staff similar procedure to deal with public quently, dementia. is obligated to report this. They are officials. Is Strom Thurmond demented? Is equally obligated to report medical in- it possible that an important political firmity, which precludes adequate dis- – Joseph H. Friedman, MD figure, who still votes in the Senate, charge of the office’s responsibility. The may not know what he is voting for? question of Ronald Reagan’s capabil- Of course one might answer that it ity may be considered here as a “gray doesn’t matter, that most politicians are zone.” He was elderly when in office guided by their advisors and “han- and was known to fall asleep during dlers.” Senators have large staffs pre- cabinet conferences that he chaired. sumably full of experts on various He also developed Alzheimer’s disease issues, depending on the senator’s in- that might have been clinically detect- terests and the interests of his constitu- able while in office. Perhaps he may ents and financial supporters. How have exhibited mild cognitive impair- much a politician is independent rather ment (MCI) only without language than a puppet of his financial-base var- or personality changes. Where would 2 Medicine and Health / Rhode Island Some Comments On a Possible Ancestor

Lutheran minister from Dusseldorf, Joachim Neumann by disappeared, for unknown reasons, some 30,000 years ago, their Aname, achieved some modest fame in the late 17th Century last stand being in Spain. as an author of sacred hymns. It had been his custom to take Paleontologists agree on this: Modern man [Cro-Magnon solitary walks in a neighboring valley to help assemble the proper man or Homo sapiens ] and Homo neanderthalensis co-existed in words and melodies for his liturgical poetry. He frequently signed Europe for many thousands of years. Earlier scenarios, many text- his completed hymns with the name Neander, the Greek equiva- books and certainly the film industry portrayed the primitive lent of his German name [Neumann, in German, meaning new Neanderthals as incapable of competing with the innovative, tool- man.] And years after his death, his parishioners honored his making, language-speaking, agronomically-skilled Homo sapiens memory by naming this modest valley Neanderthal [thal, in Ger- migrating north out of Africa. And, finally, some 30,000 years man, meaning valley.] ago, the last of the beleaguered Neanderthals died in some forgot- The fame of the valley extended no further than its neigh- ten Iberian cave, leaving the European continent to the new hu- boring villages until 1856, when Neanderthal quarry workers man arrivals. encountered some human bones in a hillside cave. A local school But science is never satisfied with well-rounded stories. It teacher, Johan Fuhlrott, recognized them as essentially human wasn’t long before newer and more meticulous studies of Nean- although they exhibited some unusual anatomic features suggest- derthal dwellings turned up evidence that suggested a somewhat ing that they were derived from a different species. In the next different scenario. Diggings in Spain, for example, suggested that few years bones with similar aberrant characteristics were uncov- the art of transportable fire, thought to be an exclusive skill of ered in central and southern Europe as well as the Middle East; Homo sapiens, was also practiced by the Neandertals. Further- so many, in fact, that by 1864 they were designated as a separate more, these protohumans were capable of foraging for edible plants, hominid species [Homo neanderthalensis]. of creating stone tools including spearheads and of decorating The Neanderthal man [now spelled Neandertal], as the rep- pendant jewelry made of wood or bone. resentative of this newly defined species was commonly called, And there was accumulating evidence that the two groups excited the attention of a wide audience who viewed him either of hominids had co-habited for thousands of years. Then, in as paleontological confirmation of Darwin’s newly declared theory 1996, exploration of sites in Moravia uncovered the fossil re- of evolution [The Origin of the Species was published in 1859]; mains of a child, dating back some 50,000 years, with the com- or, alternatively, as a palpable threat to the accepted concept of bined anatomic characteristics indisputably those of Homo sapiens creation which held that man was divinely created on the sixth and Homo neanderthalensis. Some paleontologists eagerly grasped day, as related in Genesis; and that man was biologically and theo- this finding to signify that the two hominid groups, at least in logically distinguishable from, and held dominion over, the mass certain sites, had shared certain cultural customs; and not only of dumb creatures which had earlier been brought into being. did they live together but they also interbred. Thus, if these Furthermore, declared the creationists, there was nothing in the inferences hinting at interbreeding are accurate, it would appear Holy Scriptures to suggest that man, created in the perfect image that the fate of the Neanderthals was not irreversible extinction of God, could have evolved from any other species, hominid or but rather assimilation into the more adaptable, more sophisti- otherwise. To accept biological evolution, they declared, was there- cated and numerically superior modern man. fore equivalent to accepting imperfections in God. But then other scientists recently managed to extract some If indeed there had existed another human-like species in residual DNA from the bones of Neandertal fossil bones. And the past, it was commonly held, its members must have been careful analyses of the chemical sequences within these DNA little more than lumbering, cultureless beasts with anatomical samples demonstrated no similarities with the DNA of Homo features vaguely human, but who were at best brutish cave dwell- sapiens. Remarked one anthropologist: “Limired interbreeding ers incapable of any of the social, creative or communicative at- may have occurred between Neanderthals and modern humans, tributes of humans; and therefore they were not truly “human”; but that appears less likely with these new genetic data.” The nor could they be ancestors of humans. DNA evidence, admittedly based on only a small handful of Paleontologists gradually formed an image of this creature. samples, thus favored the theory that Homo sapiens took origin He was, they speculated, quite robust, with a barrel-chest and in East Africa some 100 millennia ago and then populated the short limbs. His head was large, its top somewhat flattened in world, completely replacing all other hominid species, includ- contrast to modern man’s dome-shaped skull. His nose was large, ing the Neandertals. cheekbones inapparent, brows over each eye very prominent, fore- Those scientists who advocate a multiregional origin of mod- head narrow and sloping, and chin small without indentation. ern man still believe, however, that some Neandertal hereditary There were very wide muscle-attachment grooves on the limb material has persisted as part of the genetic constitution of con- bones suggesting that Neandertal man was quite muscular. [These temporary man. dramatic muscle attachment grooves had prompted Fuhlroot to It is curious that an obscure region of western Germany surmise that the Neandertal bones were not from contemporary called Neandertal [a hybrid Greco-German word meaning new man.] man’s valley], named to honor the daily strolls of an obscure The composite profile of the Neandertal man was compat- composer of hymns named Neumann, should also be the site of ible with what would be expected of hominids struggling to sur- important fossil evidence casting some doubt upon the genetic vive in the harsh environment of the Euorpean ice age. and theological uniqueness of the new man called Homo sapiens. Paleontologists concluded that this race of hominids flourished as a separate species beginning about 200,000 years ago; and then – Stanley M. Aronson, MD, MPH 3 Vol. 85 No. 1 January 2002 Cancer in the New Millennium Paul Calabresi, MD, MACP

n December, 1971, our nation de- additional 20%, could be prevented or of new cancer patients are older than Iclared war on cancer. Thirty years saved, if all the knowledge we have to- 65 years and the median age for can- later, at the beginning of a new mil- day were applied to all of the people. cer in the United States is now 70 years. lennium, is an appropriate time to re- For the other 20%, we need more re- It is estimated that, at current rates, the evaluate our progress, assess our current search. rise in cancer will be such that one in status, and chart a rational course for The cancer burden, however, is two Americans will experience the dis- the future. In the 1960s, approxi- increasing in America. This is due, in ease in their lifetime and it will surpass mately 30% of patients with cancer part, to more effective prevention and heart disease as the leading cause of survived. Today more than 60% are treatment of heart disease, infections, death in just a few years. cured. Of the remaining 40% of can- and strokes, as well as to an increase in The National Cancer Legislation cer cases, approximately half, or an aging of our population. Sixty percent Advisory Committee was created in order to address this mounting TABLE I threat and to chart a strategy that Members of the National Cancer Legislation Advisory Committee would ultimately eradicate can- cer as a major public health prob- Vincent T. DeVita, Jr., MD Ronald B. Herberman, MD lem. A group of 21 concerned NCLAC Co-Chair Director, University of Pittsburgh cancer scientists and survivors, Director, Yale Comprehensive CancerInstitute and President, patient advocates and health pro- Cancer Center American Association of Cancer viders, non-profit leaders and Institutes John R. Seffrin, PhD business executives (Table I) met NCLAC Co-Chair Paula Kim for 2 years to develop a compre- Chief Executive Officer, Chairman of the Board & Co-Founder, hensive report entitled: “Con- American Cancer Society Pancreatic Cancer Action Network (PANCAN) quering Cancer: A National Battle Plan to Eradicate Cancer Anna D. Barker, PhD Amy S. Langer 1 President/CEO, BIO-NOVA, Inc. Executive Director, National Alliance of Breast in Our Lifetime” (Table II). Cancer Organizations (NABCO) Building on the success of the Helene G. Brown National Cancer Act of 19712 Associate Director, Community Research, Deborah Mayer, RN, MSN and previous reports,3,4,5,6,7 the Jonsson Comprehensive Cancer Center, UCLA Chief Medical Officer, Cancer Source.Com recommendations included in this Joan S. Brugge, PhD Susan Kenyon Parsons, MD document provide the President Professor of Cell Biology, Assistant Professor in Pediatrics, and the Congress of the United Harvard Medical School Dana-Farber Cancer Institute States with a roadmap for achiev- ing this vital goal. [See Note.] Paul Calabresi, MD Janet Rowley, MD In Rhode Island, what can Professor of Medicine, Brown University Blum-Riese Professor, Department of Medicine, University of Chicago we do, at the local and regional Robert W. Day, MD level, to reduce mortality and suf- President and Director Emeritus, Ellen V. Sigal, PhD fering from cancer? Outlined Fred Hutchinson Cancer Research Center Chair, Friends of Cancer Research below are 4 broad approaches that would enhance our participation Carl F. Dixon, Esq. George Vande Woude, PhD President and Chief Executive Officer, Director, Van Andel Institute in this renewed national effort to Kidney Cancer Association conquer cancer: Armin D. Weinberg, PhD Albert B. Einstein, Jr., MD Co-Founder, Intercultural Cancer Council and * Familiarize ourselves with the Executive Director, Swedish Cancer Institute Director, Chronic Disease Prevention & goals and recommendations pro- Control Research Center, Baylor College of John H. Glick, MD Medicine vided in this report and partici- Director, University of Pennsylvania Cancer pate in implementing those that Center and the Abramson Family Cancer Fran C. Wheeler, PhD apply to our individual activities, Research Institute Director, Office of Public Health Practice, institutions and organizations. A University of South Carolina School of summary of these actions is listed M. Alfred Haynes, MD Public Health Chair, Institute of Medicine Study on in Table II; some apply primarily Unequal Burden of Cancer at the Federal level, while others can be implemented in the State. 4 Medicine and Health / Rhode Island * Unite the many resources in our based cancer action plans, in col- the country. community to re-establish a Can- laboration with all relevant experts * Improve access to and delivery of cer Center with translational re- in the region (Table II, Goals 9, 10, quality cancer care to all of our pa- search capabilities that would move 11, 12). The Rhode Island Cancer tients. Although these goals are ad- new drugs and technologies for- Council, established in May 1999 dressed in public health terms in ward into clinical trials, and ulti- and described in more detail in this the Conquering Cancer report mately develop new methods and issue of the Journal,8 already pro- (Table II, Chapters 3 and 4), spe- products to prevent and cure can- vides the basic mechanisms and cific recommendations (Table II; cer (Table II, Goal 4). initial resources for implementing Goals 8, 11 and 12) can only be * Provide an organization for coor- these programs. In this respect, we implemented if every physician and dinating and implementing State- are ahead of most other states in health care professional assumes a personal obligation to become TABLE II more informed, knowledgeable, and qualified to provide quality Conquering Cancer: cancer care. A National Plan to Eradicate Cancer in Our Lifetime Accordingly, it is important for all Chapter One: Discovery Research and Training physicians to be fully aware of the new Goal. 1 Fund the National Cancer Institute (NCI) Bypass Budget in advances in this field and state of the this and future years and provide additional supplemental art approaches to prevention, early de- funding for critical research that is not adequately covered in tection, diagnosis, and treatment. For the Bypass Budget. this special issue of the Journal, review Goal 2 Increase the pool of talented and well-trained biomedical articles dealing with 3 of the most com- researchers. mon neoplasms were selected: carci- Goal 3 Increase National Institute for Environmental Health Science noma of the lung, carcinoma of the and NCI funding for cancer research that examines the interaction of genes and the environment. breast and colorectal tumors. Dr. Todd Moore and Dr. Neal Ready have pre- Chapter Two: Translating Scientific Discoveries into New Cancer sented a thorough update of the status Medicines and Technologies of non-small cell carcinomas of the Goal 4 Enhance our cancer research centers (and other cancer- lung, which comprise 80 to 85% of focused efforts) to build a multidisciplinary network of ìtranslational centersî to move new drugs and technologies lung cancers in the United States and forward into clinical trials, and ultimately develop new are responsible for the largest number methods and products to prevent and cure cancer. of cancer deaths in both men and Goal 5 Streamline and accelerate the Food and Drug women. Dr. Mary Anne Fenton has Administrationís approval system for cancer drugs, biologics, provided a detailed review of our re- devices and technologies. cent advances in the treatment of car- Goal 6 Empower federal agencies to build public-private partnerships cinoma of the breast, stressing the across the entire continuum of cancer research to ultimately benefits of a multidisciplinary ap- develop new cancer treatments, preventives and technologies. proach to therapy and including a dis- Chapter Three: Improving access to Quality Cancer Care cussion of long-term management for Goal 7 Provide adequate health insurance coverage for all Ameri- the many survivors of this most com- cans concerned about or diagnosed with cancer. mon neoplasm of women in America. Goal 8 Significantly increase the pool of health care professionals Reflecting the fact that chemotherapy trained to conquer cancer. and radiation therapy have contributed Goal 9 Launch a National Cancer Screening Initiative to increase little to the treatment of colorectal can- substantially the early detection of cancer. cers, Dr. Arvin Glicksman has inci- Chapter Four: Delivering Quality Cancer Prevention and Care sively outlined a strategy that could through a Coordinated Health Care System prevent most of the deaths from the Goal 10 Implement comprehensive state-based cancer action plans, second most frequent cause of cancer in collaboration with all relevant experts in the region. lethality in Rhode Island, for both men Goal 11 Develop, communicate and use universal guidelines and and women. practice standards to provide quality cancer care to all In addition, papers in 2 important cancer patients, and monitor progress through improved and contrasting oncologic specialty ar- quality care surveillance systems. eas have been included: Pediatric On- Goal 12 Implement a National Cancer Prevention Initiative that cology and Neuro-Oncology. Dr. focuses on eliminating tobacco use, increasing physical William Ferguson and Dr. Edwin activity, and improving nutrition. Forman have offered us a rewarding 5 Vol. 85 No. 1 January 2002 description of an important field, tu- 1. National Cancer Legislation Advisory nual Report of the President’s Cancer mors of childhood, which illustrates Committee, DeVita VT, Seffrin JR, Panel. The National Cancer Program: and characterizes the best progress we Co-chairs. Conquering Cancer: A Assessing the Past, Charting the Future, National Battle Plan to Eradicate Can- 1999. have made against cancer during the cer in our Lifetime. 59 pages, Wash- 6. Glicksman A, Calabresi P. The Rhode past 30 years. Dr. Lloyd Alderson, on ington, DC, 2001. Island Cancer Council. Med & Health/ the other hand, has had the unenvi- 2. National Cancer Act of 1971, J NCI RI 2002;85:34-6. able task of analyzing objectively one 1987; 78:5. of the most difficult and challenging 3. Hewitt M, Simone JV. (eds.) Ensuring Paul Calabresi, MD, MACP, is Pro- areas of oncology: tumors of the cen- Quality Cancer Care. National Can- fessor of Medicine and Chairman Emeri- cer Policy Board, Institute of Medicine tral nervous system. tus, Brown Medical School. and National Research Council, 256 I am deeply grateful to these out- pages, 1999. standing Rhode Island oncologists for 4. Calabresi P, Bettinghaus E, Coleman CORRESPONDENCE: their comprehensive and informative CN, et al. Cancer at a Crossroads: A Paul Calabresi, MD, MACP contributions to this special issue of the Report to Congress for the Nation. Rhode Island Hospital Journal, dedicated to a most important Cancer 1995; 76:135-48. 593 Eddy St. and timely topic. 5. The MARCH-Coming Together to Providence, RI 02903 Conquer Cancer. Report From The phone: (401) 444-8977 March Research Task Force, Sigal, EV, Note: It should be noted that, notwithstand- Barker, AD. Co-chairs. 37 pages, fax: (401) 444-8483 ing the current international problems e-mail: [email protected] with terrorism, the White House has Washington, D.C., 1998. already expressed great interest in this 6. Freeman H, Visco F, Calabresi P. An- report and Senators Dianne Feinstein nual Report of the President’s Cancer (D-CA) and Sam Brownback (R-KS) Panel. Cancer Care Issues in the United have held hearings on the subject with States: Quality of Care, Quality of Life. a plan to introduce appropriate legisla- 1998. tion in 2002. 7. Freeman H, Visco F, Calabresi P. An-

REFERENCES

6 Medicine and Health / Rhode Island Update in Non-Small Cell Lung Cancer Todd Moore, MD, and Neal Ready, MD, PhD ung cancer is a common and viru- only 15% of patients, have 5-year sur- diastinal lymph nodes, but the sensitiv- Llent disease with an estimated vival which approaches 70% with sur- ity and specificity of CT for detecting 164,000 new cases and 156,900 deaths gical resection. Detection of early stage metastatic carcinoma is low (50-60%). annually in the US.1 The magnitude of cancers in the asymptomatic at-risk Mediastinoscopy is therefore a critical the burden of lung cancer is exempli- population would thus be expected to investigation in patients with enlarged fied by the fact that the number of improve survival. However, random- mediastinal lymph nodes by CT to deaths annually from lung cancer ap- ized controlled trials conducted in the avoid denying patients a potentially proximates the total number of deaths 1980s showed no improvement in lung curative resection. While the precise from the second through fifth leading cancer mortality with chest x-ray and definition of “inoperable” disease is de- causes of cancer mortality combined sputum cytology screening in male bated, mediastinoscopy is also useful for (colorectal, breast, prostate and pancre- smokers4-6 and no national advisory identifying patients with contralateral or atic cancers). Non-small cell carcinomas group currently recommends screening extensive ipsilateral lymph node spread (adenocarcinoma, squamous cell and for lung cancer. Recent results with the who do not benefit from surgical resec- large cell carcinomas) account for 80- use of low-dose computed tomography tion. 85% of lung cancers and have been tra- (CT) screening have called this pessi- Recent studies using PET ditionally considered collectively for mistic view into question and spurred (positron emission tomography) scan- purposes of treatment. As our experi- renewed interest in screening efforts. ning suggest that PET is more accurate ence with molecular-targeted therapy The initial report of the Early Lung than CT in the detection of involved grows, future therapy may be directed at Cancer Action Project (ELCAP), which mediastinal nodes. PET scanning uti- specific molecular abnormalities associ- is investigating annual low-dose CT lizes tracers such as F-18 FDG ated with the different subtypes of non- screening, found 27 cancers (23 of (fluorodeoxyglucose) which allow tu- small cell lung carcinoma. This review which were stage I) in 1000 volunteers. mor identification by its increased will cover screening, staging and treat- Chest radiography detected only 7 of anaerobic metabolism of glucose rela- ment of non-small cell lung carcinoma. the 27 cancers found by low-dose CT.7 tive to normal tissues. Sensitivity and Smoking is the cause of most lung The NCI has recently launched a 3000 specificity of PET scanning for medias- cancers and has been estimated to ac- person randomized trial of screening tinal node involvement by carcinoma count for 80% of lung cancer deaths.2 low-dose CT and chest radiography have been approximately 80% and 80- The accepted link with smoking which will address the feasibility of do- 90%, respectively, in reported series. coupled with educational activity and ing a larger study. The negative predictive value of PET recent legislative efforts (smoke-free ar- (86-93%) may be sufficient to forego eas and restrictions on tobacco adver- Five-year survival is mediastinosopy prior to attempted re- tisements) have been temporally approximately 60-70% section, but given the reported positive associated with an overall decrease in the predictive value of PET for mediastinal incidence of lung cancer since the late for stage I and 40-50% disease of between 80-90%, mediasti- 1980s.1 The potential for secondary noscopy remains a crucial procedure to prevention strategies is obvious given for stage II cancers avoid denying patients a potentially that smoking is a largely preventable following complete curative resection.8 Staging by medias- behavior. Counseling and tinoscopy for potentially resectable lung pharmacotherpy have been shown to be surgical resection. cancer remains the standard of care un- effective treatments for tobacco depen- less large clinical trials validate the use dence and a recently published clinical  of PET scan staging alone. PET scan- practice guideline summarizes these in- ning may also have utility in assessing terventions.3 Following a diagnosis of non-small disease status after definitive Several salient factors in non-small cell lung cancer, staging is undertaken chemoradiation, a situation where re- cell lung cancer suggest a potentially to assess the extent of disease prior to sidual fibrosis often makes interpreta- important role for screening programs. definitive therapy. CT scanning of the tion of response or detection of Clinical symptoms occur late in the chest and upper abdomen is routinely recurrence by CT difficult.9 natural history of lung cancer and, at performed to exclude metastases to the The primary prognostic factors for present, over half of patients present lung, liver or adrenal glands and to as- patients with early stage disease are the with metastatic (40%) or unresectable sess invasion of the chest wall, vertebrae presence of lymph node spread and the locally advanced disease (15%). Patients or mediastinal structures. CT scanning size of the primary tumor. Stage I can- with pathologic stage I disease, currently can also identify enlarged (> 1 cm) me- cers have no lymph node involvement 7 Vol. 85 No. 1 January 2002 and stage II cancers have involvement node involvement, respectively.12 Post- als of combined modality therapy in this of intrapulmonary or ipsilateral hilar operative adjuvant therapies have not setting have produced promising results. lymph nodes. Surgical resection is the shown benefit for resected stage IIIA A phase II trial of weekly paclitaxel, treatment of choice for these patients. cancers. Postoperative radiotherapy carboplatin and concurrent radiation Five-year survival is approximately 60- has been reported to decrease local re- reported a 75% response rate with 38% 70% for stage I and 40-50% for stage currence in some studies but does not survival at 2 years.15 An ongoing ran- II cancers following complete surgical improve survival. Similarly, postopera- domized trial is looking at the addition resection. Despite the fact that many tive adjuvant chemotherapy has not pro- of induction chemotherapy to this patients will relapse following surgery, duced meaningful improvements in chemoradiotherapy regimen. there is no proven role for adjuvant ra- survival. A meta-analysis of eight Progress in the treatment of meta- diotherapy or chemotherapy. Postop- cisplatin-based chemotherapy trials re- static non-small cell lung cancer has erative radiotherapy does not improve ported a 13% reduction in the risk of been incremental and modest. Trials survival in this group of patients, and death with chemotherapy, which sug- from the 1980ís showed that cisplatin- in fact a published meta-analysis has gests an absolute benefit of 5% at five based chemotherapy improved survival suggested a detrimental effect on sur- years.13 The most recent Intergroup trial by a matter of weeks when compared vival in patients with resected early stage of postoperative adjuvant to best supportive care.13 More recent cancers.10 Adjuvant chemotherapy tri- chemoradiotherapy has also been re- trials using doublets of cisplatin, als have similarly failed to show signifi- ported to show no survival advantage carboplatin, paclitaxel (Taxol), docetaxel cant survival improvements in this following complete surgical resection.14 (Taxotere), navelbine, and gemcitabine setting. Despite these disappointing Given these data, the routine use of (Gemzar) have produced average sur- results, the poor survival rates and the postoperative adjuvant therapy is not vival improvements of several months. understanding that survival is deter- justified. Phase II trials of preoperative One-year survival rates of up to 50% mined by systemic recurrence justify chemotherapy and radiation followed have been reported in some aggressive ongoing attempts at improving systemic by surgical resection in selected, good phase II cooperative group trials of com- adjuvant therapy. Administration of performance status patients have pro- bination chemotherapy. These encour- chemotherapy prior to surgical resection duced promising results. Two phase III aging response rates have not always (neoadjuvant chemotherapy) is an at- trials of neoadjuvant chemotherapy have been confirmed in randomized trials, tractive approach in this setting where reported survival benefits in potentially however. A recent Intergroup trial of delivery of adequate systemic therapy resectable IIIA disease, but both trials over 1000 patients comparing four cur- postoperatively is often difficult. A re- were small and, although promising, rent generation chemotherapy regimens cent study of neoadjuvant chemo- have not become accepted as standard showed disappointing response rates of therapy in early stage disease reported a treatments. Progress in this difficult area 15-20% and median survivals of about response rate of 56% with 86% of pa- will only be made through enrollment 8 months for patients with good per- tients able to undergo complete resec- of patients into prospective randomized formance status.16 No chemotherapy tion without excessive toxicity.11 trials. regimen has been shown to be clearly Randomized trials of neoadjuvant che- superior in the initial treatment of meta- motherapy in this setting are planned Postoperative adjuvant static disease. Interestingly, however, to determine whether survival can be therapies have not shown single agent docetaxel has shown im- improved for these patients. proved one-year survival and enhanced Stage IIIA non-small cell lung can- benefit for resected stage quality of life as second line therapy cer is composed primarily of patients when compared to supportive care.17 with involvement of ipsilateral medias- IIIA cancers. There is no demonstrated survival ben- tinal or subcarinal (N2) lymph nodes.  efit for chemotherapy in patients with The optimal management of these pa- poor performance status and the deci- tients is controversial and the large A combination of chemotherapy sion to recommend therapy for these amount of clinical data is often diffi- and radiation therapy is the standard patients is often difficult. Novel thera- cult to interpret. Patients with N2 dis- treatment for most patients with peutic agents will be needed to make ease are recognized to be a unresectable locally advanced significant progress in the treatment of heterogeneous group with a wide varia- (unresectable stage IIIA and stage IIIB) metastatic non-small cell lung cancer. tion in prognosis based upon the extent non-small cell lung cancer. Stage IIIB Hope for improved outcomes for of mediastinal node involvement. A re- includes patients with N3 disease (con- patients with advanced non-small cell cent French study reported 5-year sur- tralateral mediastinal node involvement) lung cancer comes from advances in vival rates with surgery of 34% for or T4 lesions. Historically the progno- molecular biology, immunology and patients with involvement at only one sis for these patients has been dismal pharmacology. Anti-cancer therapies node level, but only 11% and 3% for with 5-year survival of less than 5% with kill tumor cells by initiating an intrac- those with multiple levels of involve- surgical resection and less than 10% ellular process of programmed self-de- ment or preoperatively determined N2 with primary radiotherapy. Recent tri- struction called apoptosis. 8 Medicine and Health / Rhode Island Chemotherapeutic agents and radiation sults of the initial (prevalence) radiologic cell lung cancer. Proc Am Soc Clin Oncol initiate apoptosis by damaging DNA or and cytologic screening in the Mayo 1999;18:465a(#1973). directly interfering with basic cellular Clinic Study. Am Rev Respir Dis 15. Choy H, Akerley W, Safran H, et al. 1984;130:561-5. Multiinstitutional phase II trial of components such as microtubules. Re- 5. Frost JK, Ball WC, Levin ML, et al. paclitaxel, carboplatin, and concurrent cent preclinical research has demon- Early lung cancer detection:: Rresults of radiation therapy for locally advanced strated that small biologic molecules or the initial (prevalence) radiologic and non-small cell lung cancer. J Clin Oncol monoclonal antibodies that interfere cytologic screening in the Johns Hopkins 1998;16:3316-22. with growth factor receptor signaling Study. Am Rev Respir Dis 1984;130:549- 16. Schiller J, Harrington D, Sandler A, et pathways can also initiate apoptosis. 54. al. A randomized trial of four chemo- Typically a growth factor binds to a re- 6. Flehinger BJ, Melamed MR, Zaman therapy regimens in advanced non-small MB, et al. Early lung cancer detection: cell lung cancer (NSCLC). Proc Am Soc ceptor on the cell surface which acti- Results of the initial (prevalence) radio- Clin Oncol 2000;19:1a(#2). vates a signaling cascade that ultimately logic and cytologic screening in the Me- 17. Shepherd F, Dancey J, Ramlau R, et al. leads to gene expression for proteins that morial Sloan-Kettering Study. Am Rev Prospective randomized trial of docetaxel stimulate tumor cell growth and inhibit Respir Dis 1984;130:555-60. versus best supportive care in patients apoptosis. By designing monoclonal 7. Henschke CI, McCauley DI, Yankelevitz with non-small cell lung cancer previ- antibodies against the growth factor re- DF, Naidich DP, et al. Early Lung Can- ously treated with platinum-based che- ceptors or small molecules that inhibit cer Action Project: overall design and motherapy. J Clin Oncol findings from baseline screening. Lan- 2000;18:2095-103. components of the signaling cascade, cet 1999;354:99-105. cell proliferation can be inhibited and 8. Goldsmith SJ, Kostakoglu L. Nuclear Todd Moore, MD, is an oncologist programmed cell death initiated. An medicine imaging of lung cancer. Radiol in pivate practice. Previously he was a example of effective antibody therapy Clin North Am 2000;38:511-24. Senior Fellow in Oncology/Hematology, is the clinical activity of Herceptin in 9. MacManus MP, Hicks RJ, Wada M, et the Department of Medicine, Brown breast cancer that over-expresses the al. Early F-18 FDG-PET response to Medical School. HER-2 growth factor receptor. Small radical chemoradiotherapy correlates strongly with survival in unresectable Neal Ready, MD, PhD, is Assistant molecules such as zd-1839 that inter- non-small cell lung cancer. Proc Am Soc Professor, Department of Medicine, Brown fere with the function of the epidermal Clin Oncol 2000;19:483a. Medical School. growth factor receptor have shown great 10. PORT Meta-Analysis Trialists Group. promise and are currently being tested Post-operative radiotherapy in non-small CORRESPONDENCE: in numerous trials in lung cancer and cell lung cancer: Systematic review and Todd Moore, MD other solid tumors. It is of particular meta-analyses of individual patient data Medical Oncology Group importance that cytotoxic chemothera- from nine randomised controlled trials. Lancet 1998;352:257-63. 1110 Broad Ave., Suite 500 peutic agents and these new ìmolecular- 11. Pisters KM, Ginsberg RJ, Giroux DJ, et Gulfport, MS 39502-1210 targetedî therapies are often synergistic al. Induction chemotherapy before sur- phone: (228) 864-3000 in causing tumor cell apoptosis. Many gery for early-stage lung cancer: A novel fax: (228) 864-8053 oncologists believe that our best chance approach. J Thor Cardiovasc Surg e-mail: [email protected] to improve therapy for cancer patients 2000;119:429-37. will be by combining traditional che- 12. Andre F, Grunenwald D, motherapy with one or more novel Pignon J, et al. Survival of patients with resected N2 therapeutic agents directed at new mo- non-small cell lung cancer: lecular targets. Clinical investigators at Evidence for a subclassifica- the Brown University Oncology Group tion and implications. J (BrUOG) and the Rhode Island teach- Clin Oncol 2000;18:2981- ing hospitals have been active in both 9. participating in and designing these 13. Non-Small Cell Lung Can- important clinical trials. cer Collaborative Group. Chemotherapy in non- small cell lung cancer: A REFERENCES meta-analysis using updated 1. Greenlee RT, Murray T, Bolden S, data on individual patients Wingo P. Cancer statistics 2000. CA from 52 randomized clini- Cancer J Clin 2000;50:7-33. cal trials. BMJ 2. Loeb LA, Ernster VL, Warner KE, et al. 1995;311:899-909. Smoking and lung cancer: An overview. 14. Keller S, Adak S, Wagner H, Cancer Res 1984;44:5940. et al. Prospective random- 3. A clinical practice guideline for treating ized trial of postoperative tobacco use and dependence. JAMA adjuvant therapy in patients 2000;283:3244-54. with completely resected 4. Fontana RS, Sanderson DR, Taylor WF, stages II and IIIA non-small et al. Early lung cancer detection: Re- 9 Vol. 85 No. 1 January 2002 Breast
Cancer Update Mary Anne Fenton, MD reast cancer is the most common radiation therapy has been completed to tinel lymph node staging include preg- Bnon-cutaneous malignancy in optimize cosmetic results.. Neoadjuvant nancy, previous radiation to the axilla, or women and the second leading cause of chemotherapy may downstage large pri- clinically palpable lymph nodes. In sum- cancer mortality in the United States. mary tumors to allow for better cosmetic mary, SLND appears to have significant Breast cancer mortality has fallen over the results, though this approach has yet to less morbidity in patients who require axil- past four years due to early detection and demonstrate an impact on overall sur- lary staging but long-term follow-up data 3 gains in adjuvant therapy, yet it is pro- vival. is necessary to determine incidence of axil- jected that there will be 184,200 new A standard component of surgical lary recurrence and impact on overall sur- cases of breast cancer this year, and treatment of invasive breast cancer has vival. 41,200 breast cancer deaths.1 In this re- included level one and two axillary lymph node dissection (ALND) for axillary stag- DJUVANT HERAPY view I will discuss recent advances in A T ing and local control. Complications of The patient’s medical oncologist will breast cancer treatment including the ALND may include postoperative pain estimate the patient’s risk of systemic re- multidiciplinary approach to invasive and numbness, lymphedema and limita- currence based on established prognostic breast cancer which have resulted in a tion of arm movement. Sentinel lymph factors including histologic type, tumor size, decrease in morbidity and mortality, fol- node dissection (SLND) has been stud- pathologic grade, presence of lymphatic and lowed by a discussion of long term health ied in breast cancer patients to provide vascular invasion, axillary lymph node sta- maintanence for the 2 million breast can- prognostic information on axillary lymph tus and hormone receptor status. In addi- cer survivors in the United States. node status and avoid the morbidity of a tion, the patient’s age, menopausal status Surgical therapy of breast cancer in- full ALND in patients with a negative sen- and general health will influence recom- cludes resection of the primary tumor and tinel node. This technique involves iden- mendations for systemic adjuvant therapy. axillary staging. Options for resection of a tifying the draining lymph node with The impact of HER2 receptor over expres- patient’s breast tumor include modified injection of blue dye or isotope into the sion as a prognostic factor and a predictive radical mastectomy (MRM) and partial tumor bed. In a multicenter validation factor for response to chemotherapy and mastectomy followed by radiation therapy. study with preceding period of surgical hormone therapy is currently under pro- For the appropriate patient, there is no training sessions, one or more sentinel spective evaluation following retrospective difference in overall survival for breast con- lymph nodes were identified in 93% of studies that suggest that HER2 serving treatment though there is a slightly patients. The accuracy of sentinel nodes overexpression is a marker of poor outcome. increased rate of local recurrence, with 8- defined as the percentage of cases in which The goal of adjuvant therapy is to cure year incidence of recurrence in the ipsilat- the pathologic status of the sentinel nodes micrometastatic disease. The benefits of ad- eral breast of 10% after partial mastectomy reflected the status of a ALND was 97% juvant chemotherapy and hormone therapy versus up to 8% local recurrence for and the false negative rate, defined as the in reducing the risk of systemic recurrence MRM.2 Patients who are not candidates failure to identify metastatic disease and death from metastatic breast cancer was for partial mastectomy include those who present in the axilla was 11%.4 Compli- validated with the 1995 overview analysis are unable to receive 6 weeks of breast ra- cations of sentinel lymph node staging by the Early Breast Cancer Trialists’ Col- diation. Examples of such patients include include a 5% incidence of local seromas. laborative Group (EBCTCG). This those who live a great distance to a radia- Serial sectioning and immunohistochemi- metanalysis included all randomized clini- tion facility, patients with medical or psy- cal evaluation of sentinel lymph nodes de- cal trials of adjuvant therapies, which began chiatric conditions which would prevent crease the false negative rate but increase before 1990, with early breast cancer defined participation in 6 weeks of daily radiation, the detection of micrometastatic disease as surgically resectable tumors.5,6 patients with connective tissue disorders, which would not have been noted with The EBCTCG findings for adjuvant patients who have had prior radiation to standard H and E staining. The clinical tamoxifen demonstrated statistically sig- the same region, and pregnant patients. significance of micrometastatic disease de- nificant benefit for disease free and over- In addition, partial mastectomy is not rec- tected by immunohistochemistry alone is all survival for all patients with estrogen ommended for patients who would have unclear. The American College of Sur- receptor (ER) positive tumors. Five years a poor cosmetic result from tumor resec- geons (ACS) and the National Surgical Ad- of tamoxifen provides a significant ben- tion due to a large primary tumor and juvant Breast and Bowel Project (NSABP) efit as compared to two years of tamoxifen patients with multicentric cancer in the have initiated clinical trials to assess the therapy with a proportional risk reduction breast. Most patients who undergo a impact of SLND on local control, systemic of recurrence of 47% and reduction in MRM are candidates for immediate re- recurrence and survival. Individual surgeons death of 26% for patients in all age groups, construction, although patients requiring participating must demonstrate their pro- regardless of lymph node status and meno- postoperative radiation including patients ficiency with the sentinel lymph node iden- pausal status. Node positive patients had at high risk for local recurrence may be tification, and validate their accuracy with an absolute benefit in overall survival of advised to delay reconstruction until after standard ALND. Contraindications to sen- 10.9% and node negative of 5.6%. In 10 Medicine and Health / Rhode Island addition, tamoxifen provides a 47% re- tamoxifen as adjuvant therapy. Patients In summary, the decision to recom- duction in contralateral breast cancer for are encouraged to discuss concerns with mend adjuvant treatment to a particular patients with estrogen positive tumors. their physicians. In Rhode Island, post- patient is based on overall prognosis and Tamoxifen therapy results in a slight in- menopausal patients completing 5 years evaluation of predictive factors for response crease in the incidence of endometrial can- of adjuvant tamoxifen are candidates to to hormone and chemotherapy. This is a cer and thromboembolic events. In the participate in a CALGB trial of an process of shared decision making, with dis- EBCCTG overview, actual excess deaths aromatase inhibitor vs. placebo after cussion between the medical oncologist and from endometrial cancer in patients re- completion of 5 years of adjuvant patient as to the benefits and toxicity of ceiving tamoxifen was 2 deaths per 1000 tamoxifen. [Call 1-877-788-6667 for adjuvant chemotherapy and hormone patients. An increase in pulmonary em- details.] treatment. Ongoing areas of investigation bolus was also noted, with no increase in Benefits of polychemotherapy in the of adjuvant treatment include role of ova- mortality. In addition, the benefit for com- EBCCTG metanalysis were statistically sig- rian ablation in premenopausal women, bination chemotherapy and tamoxifen nificant for all age groups below 70 years benefit of aromatase inhibitors in ER posi- was additive.6 of age, with the proportional benefit greater tive patients, variations of drug dose and Tamoxifen, a selective estrogen re- for younger women. In women below the schedule for standard chemotherapy regi- ceptor modulator (SERM), is the cur- age of 50, proportional risk reduction of mens, and the addition of novel therapies rent standard adjuvant hormone therapy breast cancer relapse was 35% and death to the adjuvant setting, including the for patients with estrogen receptor posi- was 27%, and in women over the age of bisphosphonates and trastuzumab, a hu- tive tumors. Aromatase inhibitors, which 50, the proportional risk reduction in risk manized monoclonal antibody directed prevent the conversion of androgens to of relapse was 20% and mortality 11%. In against the HER2 protein. estrogens, are an effective therapy for terms of actual risk reduction, postmenopausal women with advanced polychemotherapy reduced recurrence in MANAGEMENT OF METASTATIC breast cancer. At the December 2001 San node positive patients by 15% and mor- DISEASE Antonio Breast Cancer Symposium, pre- tality by 12% and node negative recurrence Ever increasing options for metastatic liminary results of a clinical trial explor- by 10% and mortality by 5.7%.5 The disease include new hormone strategies, ing the role of the aromatase inhibitor EBCCTG overview also noted a statisti- new chemotherapy agents, less toxic anastrozole (trade name Arimidex) in the cally significant advantage in overall sur- weekly regimens, and immune and bio- adjuvant setting were presented. The trial, vival with anthracycline containing logic based therapies. ER positive pre- entitled Arimidex, Tamoxifen, Alone or regimens, although the standard 4 cycles menopausal patients are candidates for in Combination (ATAC), randomized of adriamycin and cytoxan (AC) appear tamoxifen or ovarian ablation with sur- patients who were candidates for adju- equivalent to 6 cycles of cytoxan, methotr- gery, radiation, or GNRH agonists. Post- vant hormone therapy to 5 years of exate and 5-flourouracil.7 Side effects of menopausal patients with estrogen anastrozole, tamoxifen, or the combina- chemotherapy include alopecia, mucositis, positive tumors are candidates for tion. At a median duration of 3 years, nausea and vomiting, and tamoxifen or aromatase inhibitors, which patients receiving anastrozole had a sig- myelosuppression, and risk of cardiac tox- reduce peripheral conversion of adrenal nificant reduction in disease-free survival icity from anthracycline containing regi- androgens to estrogens. Chemotherapy compared to tamoxifen alone or the com- mens is less than 1%. Chemotherapy is also options now include taxanes, gemcytabine bination. In addition, the incidence of associated with a slight increased risk of sec- and capecitabine, an oral medication, contralateral breast cancer was reduced ondary leukemia (<1.5%). which does not include alopecia as a side significantly in patients receiving Ongoing areas of investigation include effect. anastrozole compared to those random- dose escalation of standard regimens and Biologic agents including angiogen- ized to tamoxifen. Longer follow-up is addition of newer agents such as the taxanes esis inhibitors and signal transduction in- required to determine the effect of each to standard adjuvant chemotherapy pro- hibitors have shown promise in the therapy on disease-free survival, overall grams. Two randomized clinical trials as- treatment of a variety of cancers in early survival, and to determine the risk ben- sessed the addition of paclitaxel to standard clinical trials, and currently phase 1 and 2 efit of aromatase inhibitors on bone min- AC chemotherapy for node positive pa- trials with such agents are underway in eral density, endometrial cancer, tients. The Cancer and Leukemia Group breast cancer. Targeted immune therapy incidence of new breast primaries and B (CALGB) and NSABP have completed has now become standard treatment in cognitive function. The ATAC trial is the accrual of this regimen, data released at the patients with overexpression of the HER2 single largest adjuvant trial ever con- NIH consensus conference in November protein with trastuzumab (Herceptin), a ducted in women with early breast can- 2000, after limited follow-up, do not show humanized monoclonal antibody. HER2 cer, and enrolled 9,366 postmenopausal a statistical improvement in survival with is a transmembrane tyrosine kinase growth women from 21 countries. Patient en- the addition of a taxane. Data currently factor receptor, and overexpression is seen rollment in clinical trials and completion available from randomized trials of dose in 20-30% of breast cancers. Phase II tri- of trials such as ATAC are crucial to an- escalation of standard regimens or dose in- als of Hereceptin as a single agent dem- swer outstanding questions in breast can- tense regimens with stem cell support do onstrate a response rate of 26% with a cer treatment and prevention. The media not demonstrate a significant survival ad- median duration of 9.1 months, and in portrayal of the ATAC preliminary re- vantage for high dose versus conventional combination with chemotherapy includ- sults has raised anxiety for patients on dose chemotherapy. ing pacletaxel and navelbine demonstrate 11 Vol. 85 No. 1 January 2002 an additive response rate of 38 to 75%. Breast cancer risk reduction strate- Tamoxifen reduced only the incidence of Issues of cardiac toxicity in combination gies include chemoprevention, prophylac- estrogen-receptor positive cancers, and with anthracyclines need to be clarified, tic surgery, and lifestyle changes. Proposed there has been, as yet, no demonstrated but overall Herceptin has minimal side lifestyle changes currently the subject of effect on survival. Side effects of tamoxifen effects including chills and fever and the investigation includes reduction in fat in- may include hot flashes, vaginal discharge, rare incidence of anaphylaxis. take, increase in exercise, weight loss and and a 1% incidence per year of vascular Bisphosphonates can provide a sub- reduction in alcohol intake.8 Surgical ap- events including deep vein thrombosis, stantial benefit in patients with bone me- proaches include bilateral mastectomies pulmonary embolus, and stroke. There is tastasis. Pamidronate, given as a monthly and/or oophorectomy. Prophylactic mas- also an increase in the incidence of en- IV infusion, decreases the incidence of tectomies reduced the risk of breast can- dometrial cancer. Both the vascular events skeletal complications and hypercalcemia. cer incidence and mortality by 90% in a and endometrial cancer are seen prima- retrospective cohort study.9 Prophylactic rily in older patients, along with a small PREVENTION: RISK STRATIFICATION mastectomies, which can result in breast increase in cataracts. Women on AND REDUCTION numbness and absence of nipple sensa- tamoxifen should have a review of their Several tools are currently available tion, do not remove all breast tissue, and gynecologic history, annual pelvic exams to primary care physicians to assess a are irreversible, should be reserved only and evaluation of abnormal vaginal dis- patient’s individual risk of breast cancer. for very high risk women after appropri- charge or bleeding. Routine vaginal ultra- Discussion of individual risk can help re- ate counseling. In a study BRCA1 muta- sound or endometrial biopsies are not duce unwarranted fears in some patients tion carriers, bilateral oophorectomy was recommended. In contrast, two European who overestimate their risk and also iden- associated with a 47% reduction in the trials failed to find any breast cancer re- tify high risk-patients who can be referred calculated risk of breast cancer and also in duction with tamoxifen, this was prob- for further counseling or testing and re- the incidence of ovarian cancer.10 The ably due to differences in trial design and view of strategies for risk -reduction.8 The utility of prophylactic oophorectomy in populations.12,13 The impact of tamoxifen most commonly used risk-prediction women with increased risk of breast can- on high-risk women with risk based on model is the Gail model, which predicts a cer from factors other than germ line family history is unknown at this time. woman’s five year and lifetime risk of de- mutations is unclear. The results of NSABP P1 led the Food veloping breast cancer based on age at me- and Drug Administration (FDA) to ap- narche, age at first live birth, number of Ever increasing options prove tamoxifen for the reduction of breast breast biopsies and the number of first de- cancer risk in women with increased risk gree family members with breast cancer. for metastatic disease of the disease. No impact on survival has The Gail model is useful though it may include new hormone been shown in any prevention trial. overestimate risk for young women be- Tamoxifen is one of a class of com- low the age of routine mammographic strategies, new pounds referred to as selective estrogen- screening and underestimate risk in pa- receptor modulators (SERM), with tients who carry a breast cancer suscepti- chemotherapy agents, less partial agonist antagonist properties on the bility gene. To calculate an individual estrogen receptor. Other SERMs may have patient’s risk based on the modified Gail toxic weekly regimens, a more favorable safety profile. Raloxifen model, access the National Cancer Insti- and immune and is a SERM approved for use in preven- tute at http/cancernet.nci.nih.gov/ tion and treatment of osteoporosis in post- h_detect.html. A more appropriate model biologic based therapies. menopausal women. In the Multiple for patients who may carry a genetic sus- Outcomes Raloxifen Evaluation ceptibility to breast cancer is the Claus  (MORE) trial, Raloxifen was found to model, which incorporates both first and reduce the annual odds of receptor posi- second degree relatives including paternal Chemoprevention has emerged as a tive breast cancer by 65%.14 Patients on relatives, although it does not incorporate viable alternative for risk reduction. In raloxifen do experience symptoms of es- other risk factors. The Claus model should patients with breast cancer, adjuvant treat- trogen deficiency similar to tamoxifen in- be considered for patients with a family ment with tamoxifen for five years reduced cluding hot flashes, and is also associated history of early onset breast cancer, breast the risk of contralateral breast cancer by with a small increase in vascular events. and ovarian cancers, and women of 47%, regardless of the receptor status of Raloxifen appears to have little effect on Ashkenazi Jewish ancestry, who are at risk the initial tumor.6 This observation led the the risk of endometrial cancer based on for carrying the two major breast-cancer- NSABP to conduct the Breast Cancer animal models and limited clinical follow- susceptibility genes which have been iden- Prevention Trial, NSABP P1, a random- up. Clinical data are insufficient to sup- tified, BRCA1 and BRCA2. These ized placebo-controlled trial of women port the use of raloxifen for breast cancer patients are best served with referral to a with a calculated 5 year risk of breast can- risk reduction or treatment. high risk assessment clinic with facilities cer based on the modified Gail model of The Study of Tamoxifen and for assessment of cancer risk and special- >1.66%, which is equivalent to the 5 year Raloxifen (STAR) trial is a randomized ized genetic counseling regarding the pros risk of a 60 year old women. Tamoxifen placebo control trial conducted by the and cons of genetic testing and discussion reduced the annual odds of invasive and National Surgical Breast and Bowel of risk reduction strategies. noninvasive breast cancer by 50%.11 Project (NSABP), in conjunction with the 12 Medicine and Health / Rhode Island National Cancer Institute. The goal of this ture, pressure, heat or trauma to the in- known modest systemic absorption of es- study is to compare the effectiveness of volved limb. The incidence and extent of trogen. Due to this systemic absorption, tamoxifen and raloxifen in reducing the lymphedema will be lower in women fol- the safety of topical estrogens is unknown. incidence of breast cancer in postmeno- lowing sentinel lymph node staging. In Recently, the FDA approved a sylastic pausal women age 35 or older who are at patients who develop significant lymphe- device impregnated with estrogen, which increased risk for the disease. Eligible dema, symptoms may be improved with appears to have less systemic absorption women must be postmenopausal, at least arm elevation, use of a compression stock- than topical estrogens. age 35, and have a 5 year risk of develop- ing, or massage by a physical therapist cer- ing breast cancer of >1.7%. Risks of the tified in lymphedema management. FUTURE DIRECTIONS treatment include a slight increase in risk Chemotherapy frequently induces There has been a significant decrease of deep vein thrombosis, pulmonary em- premature menopause. Menopause is ac- in breast cancer mortality based on ad- bolus and endometrial cancer. Ineligible companied by symptoms of hot flashes vances in adjuvant therapy. The current women include women with a previous and urogenital atrophy and results in loss goals for patients with early stage disease diagnosis of ductal carcinoma in situ or of bone density secondary to estrogen are to minimize disease recurrence as well invasive breast cancer, a history of uncon- deprivation. Patients should have evalua- as minimize toxicity of treatment. In ad- trolled diabetes or hypertension, prior tion of bone density within 6 to 12 dition, significant advances have been deep vein thrombosis, pulmonary embo- months of completion of adjuvant made in therapeutic options for patients lus atrial fibrillation, TIA or stroke. Fol- therapy, and treatment to prevent further with metastatic disease with a particular low-up includes annual physical exams, bone loss should be considered in patients emphasis on quality of life as well as over- mammograms, pap smears and pelvic with bone mineral density well below the all survival. We should continue to encour- exams. Postmenopausal women interested mean bone density for their age. Thera- age patients to participate in well designed in participating in the STAR trial may call pies for osteoporosis include clinical trials to further our goals of breast the Breast Cancer Prevention Group of bisphosphonates and calcitonin. cancer prevention and cure. Rhode Island Office of Clinical Research Raloxifen, a selective estrogen receptor (1-877-788-6667), or the National Can- modulator (SERM) is approved for treat- REFERENCES cer Institute’s (NCI) Cancer Information ment of osteoporosis in postmenopausal 1. Greenlee RT, et al. Cancer Statistics, Service at 1-800-4-CANCER (1-800- women, but its impact on disease recur- 2000. CA A Cancer J for Clinicians 422-6237). rence in breast cancer survivors is un- 2000;50:7-33. known. 2. Fisher B, et al. Eight-year results of a ran- BREAST CANCER SURVIVORS Many therapies have been touted to domized clinical trial comparing total For the more than 2 million breast reduce vasomotor symptoms such as hot mastectomy and lumpectomy with or cancer survivors in the United States, flashes dues to menopause or tamoxifen. without irradiation in the treatment of breast cancer. NEJM 1989;320:822-8. health concerns include risks of local and Randomized clinical trials have demon- 3. Fisher B, et al. Effect of preoperative systemic recurrence, short and long term strated modest benefits from selective chemotherapy on the outcome of consequences of treatment, and risks of seritonin uptake inhibitors such as women with operable breast cancer. J other malignancies.15 In monitoring pa- fluoxetine (Prozac®) and verlefaxine Clin Oncol 1998;16:2672-2685. tients for disease recurrence, there is no (Effexor®) and transderm clonidine. 4. Krag D, et al. The sentinel node in breast evidence to support intense screening with Megestrol acetate has significant benefit cancer, A multicenter validation study. radiologic exams such as bone scans, CT but the safety in breast cancer survivors is NEJM 1998;339:941-6. scans or even chest x-ray or laboratory tests unknown. Soy tablets have shown no 5. Early Breast Cancer Trialists’ Collabora- including tumor markers as compared to improvement compared to placebo and tive Group: Polychemotherapy for early physical exam, mammogram and evalua- the safety of soy phytoestrogens after breast breast cancer: An overview of the random- ized trials. Lancet 1998;352;930-42. tion of symptoms. The American Soci- cancer is unknown. Breast cancer survi- 6. Early Breast Cancer Trialists’ Collabora- ety of Clinical Oncology (ASCO) vors should discuss any herbal therapies tive Group: Tamoxifen for early breast guidelines for breast cancer follow-up, with their physicians, as some herbal rem- cancer: An overview of the randomized derived from evidence-based clinical tri- edies provide symptomatic relief due to trials. Lancet 1998; 351; 1451-67. als, recommend review of systems and phytoestrogen content. The safety and 7. Fisher B, et al. Two months of doxoru- physical exam including close evaluation benefits of hormone replacement therapy bicin-cyclophosphamide with and with- for evidence of local recurrence every 3-6 in breast cancer survivors is currently un- out interval reindution therapy months for three years, then every 6-12 der investigation. compared with 6 months of cyclophos- months for 2 years, then annually. Rou- Postmenopausal women also may phamide, methotrexate, and fluorouracil tine laboratory or radiologic studies may develop atrophy of urogential epithelium in Positive-Node Breast Cancer Patients detect clinically asymptomatic disease but from estrogen deprivation, with symp- with Tamoxifen-Nonresponsive Tumors: Results from the National Surgical Ad- do not clearly alter overall survival. toms of urinary frequency, dyspareunia juvant Breast and Bowel Project B-15. J A major complication from ALND and vaginal dryness. Vaginal lubricants or Clin Oncol 1990;8:1483-96. is the development of lymphedema. To moisturizers may provide some relief of 8. Chilebowski RT. Reducing the risk of limit the morbidity of lymphedema pre- mild symptoms. For patients with more breast cancer. NEJM 2000;343:191-8. ventative strategies to reduce compression significant symptoms, topical estrogens 9. Hartmann LC, Schaid DJ, Woods JE, or infections, include avoiding venipunc- provide a more significant benefit with a et al. Efficacy of bilateral prophylactic 13 Vol. 85 No. 1 January 2002 Screening for Colorectal
Cancer in Rhode Island Arvin S. Glicksman, MD Colorectal cancer is the second lications11,12,13 concerning colonoscopy and more endoscopists recommending most frequent cause of cancer deaths have forced reconsideration of the rec- colonoscopy somewhat more fre- in Rhode Island, killing more men and ommendations, which were written in quently. (Figure 1) For high-risk popu- women than either breast or prostate 1996 through 2000. A recent study lations, there was very little cancer. Although the incidence in found that Sigmoidoscopy and Fecal disagreement. Almost uniformly, both Rhode Island is slightly higher than the Occult Blood Test (FOBT), well ac- the primary care physicians and the national average, the death rate from cepted for screening of standard risk specialists recommended colonoscopy colorectal cancer ran between 10 and individuals and even for high-risk in- as the procedure of choice. Almost the 20% higher than the national average dividuals by some14,15 failed to detect same uniformity of opinion was found for the years 1994 to 1998.1 Screening lesions in approximately one quarter of for the frequency with which these tests on a regular basis, however, can lead to those tested.16,17 In addition no group should be performed. (Table 1) the discovery - and removal - of pre- enthusiastically supports double con- We asked each group to evaluate cancerous polyps. trast barium enema,18,19 even with spi- the most important and least impor- In 1999, over 60% of the popula- ral CT. tant barriers to colonoscopy and flex- tion over the age of 50 in Rhode Is- The State Health Department ible sigmoidoscopy (Table 2). land never had any colorectal cancer asked the RI Cancer Council to review Adequate resources was the most im- screenings. Screening was less frequent and possibly revise the recommenda- portant barrier for the primary care in men than women. Over 80% of tions in the State Cancer Plan10 for physicians to perform flexible sigmoi- uninsured individuals have never been colorectal screening. We surveyed the doscopy; having sufficient time was screened.2 In response, the Rhode Is- sixty-two endoscopists who perform next in importance. One-third con- land Legislature passed a Joint Resolu- colonoscopy and/or sigmoidoscopy sidered third-party payers an important tion in the 2001 session recommending and 250 primary care physicians who barrier; only one-quarter ranked pa- that the State Health Department in may perform sigmoidoscopy but will tient acceptance a barrier. For collaboration with The Rhode Island be referring patients for colorectal colonoscopy, the endoscopists ranked Cancer Council and other organiza- screening as well. Sixty-nine percent third-party payers as the most impor- tions raise awareness of colorectal of those endoscopists and approxi- tant barrier; resources second, followed screening and the importance of early mately 50% of those primary care phy- by patient acceptance and availability detection.3 sicians responded. of time. Primary care physicians who There is no shortage of recom- This survey defined high-risk in- do not perform colonoscopy divided mendations for colorectal screening of dividuals as those with a family history evenly on the four barriers to perform- the population - this may be part of of colorectal cancer in a first degree ing colonoscopy. Since the Centers for the problem. The American relative (mother, father, sister, brother). Medicare and Medicaid Services Gastroenterological Association, the Grandparents, uncles, and aunts raise (CMS) (formerly the Health Care Fi- American Society of Clinical Oncol- a suspicion of a somewhat higher risk. nance Administration, HCFA) an- ogy, The American Society of Colon Family history of colorectal polyps and nounced that they will pay for and Rectal Surgery, the American Can- hereditary colorectal syndromes with colonoscopy screening in July 2001, cer Society, the Centers for Disease a high incident of colorectal cancer the perception of the importance of Control, the United States Preventive were considered high risk. Individuals third party carrier barrier may change. Task Force, the Rhode Island Depart- with a personal history of inflamma- Under the new guidelines, colorectal ment of Health have all addressed tory bowel disease, ulcerative colitis, or cancer screening will start at age 50. screening.4-10 A review of these recom- Crohn’s disease were also considered Coverage will include annual FOBT mendations shows considerable con- high risk, as well as a personal history and flexible sigmoidoscopy every 4 sistency in the recommendations for of colorectal adenomas or colorectal years for standard risk individuals. For standard risk and for high risk people, cancer. Standard risk were people over high-risk individuals colonoscopy ev- but the number of available screening the age of 50 with no known risk fac- ery 2 years will be covered, but will be tests and the frequency with which they tors. covered once every 10 years for stan- are to be performed can be confusing, There was strong agreement be- dard risk. There will be co-payments not only to the specialists in endoscopy tween primary care physicians and spe- required; no coinsurance or part B and to the primary care physicians who cialists on the tests that they would deductible for FOBT; 20% co-pay- must recommend the procedures, but recommend for standard risk popula- ment after part B deductible for flex- especially to the patients. Furthermore, tion, with more primary care physi- ible sigmoidoscopy and colonoscopy. the situation is not static. Recent pub- cians recommending sigmoidoscopy Based on survey responses, for 14 Medicine and Health / Rhode Island high risk individuals the endoscopists venting cancer in the population in ists trained to perform colonoscopy and and the primary care physicians recom- general. It will, in the long run, save increase the facilities where this can be mend the initiation of screening at least lives and be cost effective in terms of performed. Only with the cooperation at age 50 or 10 years before a first- or utilization of medical resources. We of the medical community, the hospi- second-degree relative developed must raise public awareness of the im- tals, and third-party payers can we ac- colorectal cancer. The procedure of portance of colorectal screening and complish our mission to lower the choice would be colonoscopy repeated encourage primary care physicians to mortality from colorectal cancer. every 3 to 5 years, or more frequently prevail upon patients to have the nec- if polyps are found. For standard-risk essary examination. Hopefully, the REFERENCES patients, primary care physicians fa- number of Rhode Islanders being 1. Howe HL, Wingo PA, Thun MJ, et vored colonoscopy over flexible sigmoi- screened will increase over the current al. Annual report to the nation on the doscopy but did not exclude fecal poor participation. status of cancer (1973 through 1998), featuring cancers with recent increas- occult blood and flexible sigmoidos- On the other hand, we must be ing trends. J Natl Cancer Inst copy as a reasonable screening proce- concerned that we do not create a de- 2001;93:824-42. dure. Seventy-seven percent of the mand for a procedure which may not 2. Hackey RB, Hesser JE. Health risks primary care physicians would recom- be easily available in the State. We will among Rhode Island adults in 1999. mend colonoscopy for standard-risk need to increase the number of special- RI Department of Health Office of patients over the age of 50 every 5 to Health Statistics. December 2000. 10 years. Approximately 40% of the endoscopists considered flexible sig- moidoscopy and annual fecal occult blood an appropriate recommenda- tion; however, 93% of these specialists favored colonoscopy as the screening test of choice with the test repeated every 7 to 10 years for standard risk patients. In Rhode Island these recommen- dations could exceed our current ca- pacity. Sixty-two specialists perform colonoscopy. Currently, they can per- form between 25,000 and 30,000 colonoscopies per year. (Table 3) If colonoscopy was the recommendation for screening for standard-risk people once at the age of 50 and repeated 7 to 10 years later after a negative exami- nation and for high-risk individuals, colonoscopy starting at least age 50 or earlier and repeated every 3 to 5 years, or more frequent depending upon findings, we would require between 55,000 and 60,000 colonoscopies per year to meet the needs of the people of Rhode Island, twice the current capac- ity. Actually, if only the high-risk population were to be screened as rec- ommended starting at the age of 50, current capacity would already be ex- ceeded. Herein lies the problem. Increased colorectal screening is badly needed if we are to find the early cancers that can be cured and pre-cancerous lesions be- fore they become a threat. This can change the outcome of colorectal can- cer, curing most of the patients and pre- 15 Vol. 85 No. 1 January 2002 September 1998:21. 11. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. NEJM 2000; 343:162-8. 12. Imperiale TF, Wagner DR, Lin CY, et al. Risk of advanced proximal neo- plasms in asymptomatic adults accord- ing to the distal colorectal findings. NEJM 2000; 343:169-74. 13. Podolsky DK. Going the distance ñ the case for true colorectal-cancer screen- ing. NEJM 2000; 343:207-8. 14. Mandel JS, Church TR, Bond JH, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. NEJM 2000; 343:1603-7. 15. Woolf SH. The best screening test for colorectal cancer a personal choice. NEJM 2000; 343:1641-3. 16. Lieberman DA, Weiss DG. One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. NEJM 2001; 345:555-60. 17. Detsky AS. Screening for colon can- cer - can we afford colonoscopy? NEJM 2001; 345:607-8. 18. Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. NEJM 2001; 342:1766-72. 19. Fletcher RH. The end of barium en- emas? NEJM 2000;342:1823-4.

Arvin S. Glicksman, MD, is Execu- tive Director, Rhode Island Cancer Council, Inc.

CORRESPONDENCE: Arvin S. Glicksman, MD The Rhode Island Cancer Council 249 Roosevelt Ave. Pawtucket, RI 02850 phone: (401) 728-4800 6. Preventive Services Task Force. Guide fax: (401) 728-4816 3. Rhode Island General Assembly. Joint to clinical preventive services: Report of resolution requesting the Rhode Island the U.S. Preventive Services Task Force. Department of Health to promote 2nd ed. Baltimore: Williams & annual check ups and screening for pro Wilkins, 1996. state and colorectal cancer. January 7. Colorectal cancer screening. Technical session 2001. review1. Rockville, Md.:Agency for 4. Byers T, Levin B, Rothenberger D, et Health Care Policy and Research, 1998. al. American Cancer Society guide- 8. NCCN colorectal cancer screening lines for screening and surveillance for practice guidelines: National compre- early detection of colorectal polyps and hensive Cancer Network. Oncol cancer: Update 1997. CA Cancer J Clin (Huntingt) 1999;13:152-79. 1997;47: 154-60. 9. Randall WB. Colon cancer screening. 5. Winawer SJ, Fletcher RH, Miller L, Gastroenterol (in press). et al. Colorectal cancer screening: 10. Cancer Control Rhode Island. Stra- clinical guidelines and rationale. tegic plan for 1998-2005. Adopted Gastroenterol 1997;112:594-642 16 Medicine and Health / Rhode Island Childhood Cancer: Past
Successes, Future Directions William S. Ferguson, MD, and Edwin N. Forman, MD

The 20th century has had its share ACUTE LEUKEMIA teristic of T-lymphocytes, and 1-3% of horrific man-created events. One Acute leukemia is the most com- will be mature B-lymphocytes. might even fantasize God looking at mon malignancy in children, account- Additional prognostic informa- humanity and asking; “What reasons ing for roughly one-third of all tion is provided by patient character- can be given to justify your continued childhood cancers. Once universally istics such as age, degree of wbc existence?” One response might be the fatal, there has been steady progress elevation at diagnosis, and gender; curing of children afflicted with can- since the late 1950s both in under- these have subsequently proven useful cer, which we believe ranks among the standing the basic biology of leukemia in modifying the intensity of treat- great achievements of the second half and in its treatment, and it is now one ment. More recently, a variety of cy- of the past century. Prior to this pe- of the most survivable of neoplasms. togenetic changes have also proven of riod, almost all such children died; now Acute lymphoblastic leukemia prognostic significance and may soon we expect to cure about three out of (ALL) comprises about 80-85% of be the target of new modalities of treat- four children diagnosed with cancer childhood leukemia. Acute myeloid ment. (Figure 1).1 leukemia (AML) accounts for most of B-precursor ALL: Newly-diag- This statistic is a remarkable testi- the remainder; chronic myelogenous nosed ALL is responsive to many che- monial to the success that can be achieved leukemia is rare, and chronic lympho- motherapy agents. Although through the close cooperation of sur- cytic leukemia unheard of in children. complete—albeit transient—remis- geons, oncologists, radiation therapists, Although ALL and AML can usu- sions can be attained with single agent and pathologists. Because childhood can- ally be distinguished by their different therapy, prolonged remissions became cers typically grow rapidly and metasta- histologic appearances, the identifica- common only with the use of multi- size early, surgery alone - even with the tion of surface markers characteristic agent chemotherapy. Today, induction addition of local radiotherapy - is typi- of different lymphocyte lineages has therapy for B-precursor ALL includes cally not curative for pediatric solid tu- proved to be a powerful tool in sub- glucocorticoids (prednisone or dexa- mors, and of course is ineffective against classifying ALL for prognostic and methasone), vincristine, and L-Aspara- the leukemias that comprise about one- therapeutic purposes. The majority ginase; in high risk/poor prognosis cases, third of childhood malignancies. There- (~85%) of cases of childhood ALL have an anthracycline such as doxorubicin or fore, it has only been since the advent of markers of early B-lymphocyte differ- daunorubicin is added. Maintenance effective adjuvant chemotherapy that entiation, but not the surface immu- therapy generally builds upon a back- more than a small proportion of children noglobulins characteristic of bone of antimetabolites, including mer- could be cured of cancer. mature B-lymphocytes; these are now captopurine and methotrexate.3 Since cancer in children is an un- generally called “B-precursor” ALL. In the early eras of ALL treatment, common disease (approximately 12/ About 15% will have markers charac- the central nervous system (CNS) was 100,000 children/year), even large institutions have insufficient num- bers of patients to advance manage- ment rapidly. It has been through the advent of the cooperative cancer groups and the widespread use of na- tionally organized clinical trials that our knowledge of how best to treat cancer has progressed. In contrast to adults, the majority of children afflicted with cancer in the United States are now registered on research trials, and data strongly support the contention that these children, with access to the most state-of-art treat- ment, have outcomes superior to children who are not registered on national protocols.2

17 Vol. 85 No. 1 January 2002 a common site of recurrence, presum- and Europe. diagnosis) or with relapse confined to ably because the blood-brain barrier T-cell leukemia: T-lymphocyte the CNS or testicle.6 Perhaps 50% or prevents systemic therapy from consis- differentiation was identified as an ad- more of patients with “late” relapse can tently achieving cytotoxic levels in the verse biologic factor during the 1970s. attain long-term survival with either CNS. Prevention of CNS relapse was T-cell ALL occurs more often in teen- chemotherapy or bone marrow trans- first achieved with irradiation of the age males, who commonly present with plantation; while a fully histocompat- neuraxis. Although effective, CNS ra- very high peripheral wbc counts and ible sibling generally confers the best diation is fraught with long-term com- mediastinal enlargement, which at chance of cure, only a minority of pa- plications, including learning times can be massive and rapidly life- tients will have an appropriate donor. disabilities, impaired growth, endo- threatening because of airway obstruc- The relative merits of intensive chemo- crine dysfunction, and secondary brain tion and tumor lysis syndrome. therapy vs. marrow transplantation tumors. An alternative is direct instil- Treatments effective in B-precursor from unrelated or partially-matched lation of chemotherapy into the CNS. ALL have tended to be less likely to donors is hotly debated. Despite the need for repeated lumbar cure T-cell ALL. Aggressive multi- In contrast, the survival of “early” punctures, the long-term toxicity of agent chemotherapy resulted in only relapse patients with chemotherapy intrathecal chemotherapy seems to be modest improvement until the addi- alone is dismal (<10%). Bone marrow considerably less than radiation. For tion of intensive L-Asparaginase transplantation is the preferred option this reason radiation is now reserved therapy, which has significantly im- in this situation, although survival re- for patients with overt CNS leukemia proved survival (~75% cure). Patients mains lower than for patients who are at diagnosis, plus selected subgroups of with T-cell leukemia continue to be at transplanted following a late relapse. high-risk patients. relatively high risk of CNS relapse even Survival has been further im- with intrathecal chemotherapy, and so NON-HODGKIN’S LYMPHOMA proved by the addition of a period of usually receive additional prophylactic Non-Hodgkin’s lymphomas relatively intense chemotherapy imme- CNS radiation. (NHL) in children are almost always diately following induction therapy. B-cell leukemia: Defined by the high-grade, undifferentiated malignan- For patients with favorable biologic presence of surface immunoglobulins, cies. Early studies revealed that these characteristics - for example, children B-cell ALL is an explosive disease, of- tumors are virtually always dissemi- >1 years but <10 years of age with a ten presenting with significant aden- nated at diagnosis, even if this is not relatively low white blood count (wbc) opathy and a rapidly rising wbc count. clinically demonstrable. Thus, use of - intensification of antimetabolite It responds poorly to conventional ste- systemic chemotherapy and protocols therapy with the administration of roid- and antimetabolite-based regi- similar conceptually to those used for high-dose intravenous methotrexate mens. However, B-cell ALL is leukemia have proven extremely ben- (rescued with citrovorum factor) can biochemically and genetically similar eficial. The rapid proliferation, which result in relatively high rates of cure to the undifferentiated non-Hodgkin’s is a hallmark of these lymphomas, is (>80%).4 For patients with especially lymphomas (Burkitt’s lymphoma). also their Achilles’ heel, making them favorable cytogenetic changes, long- D.P. Burkitt first demonstrated among relatively sensitive to chemotherapy. term survival may exceed 90%. The children in Africa that this lymphoma Indeed, the survival of patients with challenge for current cooperative trials was quite sensitive to cyclophospha- bulky or disseminated NHL is gener- is to identify whether modest addi- mide. Treatment now includes not ally 65-75%,7 and for patients with tional intensification of therapy in only cyclophosphamide, but clinically localized lymphomas the cure some of these patients can improve anthracyclines, high-dose methotrexate rate exceeds 90%. survival without excessive additional and cytosine arabinoside, and vincris- The vast majority of childhood morbidity. tine; although intense, treatment pro- NHL fall into three categories: For higher risk patients (e.g., high tocols generally last only about 6 Undifferentiated lymphoma, presenting wbc, unfavorable cytogenet- months and have resulted in cure rates which is further subdivided into ics, or teenagers), an intensive multi- of >70%. Burkitt’s and non-Burkitt’s lymphoma agent consolidation phase - which Relapsed leukemia: Relapsed ALL on the basis of morphology. The typi- includes anthracyclines, cytosine ara- often remain chemotherapy-respon- cal presentation in the United States is binoside, and alkylating agents such as sive, but traditionally second (and sub- with massive intra-abdominal disease. cyclophosphamide - clearly improves sequent) remissions were of Undifferentiated lymphomas exhibit survival despite the additional drug- increasingly shorter duration, and surface makers of mature B-lympho- related toxicity.5 Overall survival for long-term survival was elusive. Bone cytes, are biologically similar to B-cell this group is ~65%. The optimal com- marrow transplantation and more in- leukemia, and respond to the same bination and timing of intensification tensive chemotherapy now offer some short, intensive chemotherapy regi- therapy for high-risk patients is the chance of cure for relapsed ALL, par- mens as B-cell ALL. object of considerable study among the ticularly in patients who relapse rela- Lymphoblastic lymphomas are cooperative groups in the United States tively late (e.g., >18 months after initial comprised of T-lymphocytes and are 18 Medicine and Health / Rhode Island similar in behavior to T-cell leukemia, term effects as well as significant long- tastases occur early in the course of the including the propensity to present term toxicity, including (depending disease, so historically few children with cervical adenopathy and/or an upon the drug combination) marrow were cured by surgery alone. The liver enlarged mediastinum. Treatment is suppression, damage to lung and heart, and lung are the most common sites similar to that for T-cell ALL, includ- sterility, and secondary leukemia. The of metastatic spread. ing the intensive use of L-Asparaginase. rate of second malignancies for adults Wilms’ tumor was the first solid Large cell lymphomas have vari- treated with combined radiation and tumor for which the adjuvant use of able surface markers, which may reflect chemotherapy is exceptionally high. chemotherapy was shown to enhance an underlying biologic heterogeneity. survival. While surgery remains a They tend to grow somewhat more The spectacular success in mainstay of treatment, combinations slowly than either undifferentiated or of vincristine, actinomycin-D and lymphoblastic lymphomas. Treatment treating childhood doxorubicin - along with radiation for for high-stage disease includes pulses patients with extra-renal spread of dis- of multi-agent chemotherapy (typically malignancies must be ease—has resulted in survivals of >90% prednisone, vincristine, cyclophospha- weighed against the for patients with localized disease, and mide, doxorubicin, and methotrexate). even patients with distant metastases Although NHL most often pre- considerable short- and have a cure rate of ~80%.10 sents with massive disseminated dis- long-term side effects of With the development of success- ease, several clinical trials in the 1980s ful treatment regimens, it became evi- and 1990s convincingly showed a cure treatment ... dent that the presence of anaplasia in rate of >90% for children with clini- the tumor predicted poorer outcomes. cally localized undifferentiated and  Further study has shown that a single large cell lymphomas using only a 6- focus of anaplastic change requires week course of chemotherapy alone, The pediatric approach to slightly more aggressive use of radia- without the addition of radiation Hodgkin’s Disease has striven to mini- tion and chemotherapy but still has an therapy.8 Children with clinically lo- mize long-term toxicity by pardoxically excellent cure rate. Diffuse anaplasia calized lymphoblastic lymphoma are combining moderate amounts of che- confers a significantly worse progno- treated with the same regimen followed motherapy and radiotherapy.9 The ra- sis, although the addition of cyclophos- by 6 months of therapy with mercap- tionale has been that modest amounts phamide has improved survival to topurine and methotrexate; although of chemotherapy can eradicate micro- ~50%.11 Current studies are testing ~25% of lymphoblastic lymphomas scopic disease, thus often eliminating new drug combinations for these pa- treated with this regimen will recur, the need for staging laparotomy and tients in an effort to improve their out- most patients can subsequently be sal- allowing more limited fields and doses come. vaged with more intensive therapy. of radiation. Conversely, targeting National studies over the last de- bulk disease with radiation has allowed cade have focused on trying to mini- HODGKIN’S DISEASE lower cumulative doses of chemo- mize therapy (and thus long-term Hodgkin’s Disease comprises therapy. Several successive pediatric toxicity) while maintaining a high cure about half of all lymphomas in chil- trials have shown that this approach rate for the majority of children with dren. Radiation therapy has been suc- can eradicate disease in the majority of favorable histology tumors. Indeed, cessfully used for many years against patients (80-90+% depending upon patients with favorable histology tu- localized or regional disease, and with stage), and the expectation of less long- mors confined to the kidney can now the advent of effective chemotherapy term effects so far appears to be justi- be successfully treated with as little as regimens in the 1970s even patients fied, although clearly longer follow-up 16 weeks of vincristine and actinomy- with disseminated disease had a reason- of these patients will be necessary. For cin-D, without radiation, and even able chance of cure. However, these patients who relapse following com- patients with more advanced tumor treatments were not without significant bined therapy, intensive chemotherapy receive relatively moderate courses of toxicity, especially in children. Effec- followed by stem cell support (also therapy.10 For these patients, the cur- tive use of radiation mandates accurate called autologous bone marrow trans- rent National Wilms’ Tumor Study is staging (usually including staging lap- plantation) offers a chance of long-term focusing on identifying new biologic arotomy and splenectomy, with the survival. factors that predict relapse, thus allow- resulting life-long risk of infection) and ing new or more intensive therapies to requires doses of radiation that could WILMS’ TUMOR be targeted to high-risk patients. result in organ damage (lung, heart, Wilms’ tumor is by far the most Many patients who relapse after thyroid), growth arrest, and second common malignant renal tumor in treatment for Wilms’ tumor remain malignancies. Patients who receive pro- children. Rare in infancy, it is prima- responsive to chemotherapy, particu- longed chemotherapy for disseminated rily seen in children 1-5 years of age. larly those who received relatively lim- disease experience both severe short- Like many embryonal tumors, me- ited treatment initially. Initial reports 19 Vol. 85 No. 1 January 2002 echolamines in an effort to detect and treat tumors while they were still re- sponsive to surgery and chemotherapy. In reality, screening resulted in a marked increase in the number of tumors de- tected at birth, but no change in the incidence of tumors diagnosed later in life.15 Based on our cur- rent understanding, the aggressive tumors devel- oping after infancy prob- ably were not present at suggest that intensive chemotherapy of neuroblastoma.12 (Table 1) The first birth; indeed, many if not most neo- followed by radiation and/or autolo- is comprised of localized tumors, gen- natal neuroblastomas are probably des- gous bone marrow transplant may sal- erally arising in infants, which are hy- tined to spontaneously differentiate vage many of these children. perdiploid and lack mycN into benign tissue - a hypothesis that amplifications. These tumors have an is supported by recent reports from NEUROBLASTOMA excellent outcome with surgery along Japan showing that the majority of Neuroblastoma has perhaps the (and perhaps without surgery - see be- neonates with neuroblastoma do well most variable clinical spectrum and low). with no intervention whatsoever. natural history of any childhood tu- To the second group belong tu- mor. At one end of the spectrum are mors with regional nodal spread, usu- RHABDOMYOSARCOMA localized tumors in infants with little ally in children older than 1 year of age, Arising from striated muscle, or no propensity to metastasize. At the with diploid DNA content but with- rhabdomyosarcoma is the most com- other extreme are the disseminated and out mycN amplification. These tu- mon soft tissue sarcoma in children. rapidly growing tumors of older chil- mors usually respond well to It can arise from any muscle in the dren, which are often quite resistant to chemotherapy (typically combinations body; its distribution does not parallel treatment. of cisplatin or carboplatin, doxorubi- muscle mass, with the orbit and geni- As for other pediatric tumors, cin, etoposide, and cyclophosphamide tourinary tract being relatively com- there has been parallel progress both or ifosfamide), and in some instances mon sites. in out understanding of the basic biol- may be curable with surgery alone.13 Unlike many other soft tissue sar- ogy of these tumors, as well as their Finally, there are tumors that comas, rhabdomyosarcoma is quite practical treatment. Central to both present as disseminated disease, with sensitive to chemotherapy as well as of these is the growing understanding mycN amplification. The outcome for radiation. Outcome is strongly influ- of the biologic features that predict re- children with these tumors has been enced by how completely the primary sponsiveness to therapy and outcome. poor with conventional chemotherapy, tumor can be surgically removed, but It has long been evident that localized although a recent clinical trial con- is also dependent on the site from tumors can usually (>90%) be cured ducted by the Children’s Cancer Group which the tumor arises. This site-de- with surgical resection alone. It has also suggested that multi-agent chemo- pendent variation in prognosis is only been known that infants have a prog- therapy (including intensified chemo- partially due to differences in the fre- nosis superior to older children, even therapy with stem cell support) quency of unfavorable (alveolar) and with regional or distant spread of dis- followed by the differentiating agent favorable (embryonal) histologies ob- ease. Over the last 20 years, other bio- cis-retinoic acid can result in survival served at different sites, and indeed is logic features have been found to be of ~50% of children.14 so marked that tumors arising in cer- strong predictors of outcome, espe- The biologic diversity of neuro- tain very favorable locations (such as cially amplification of the mycN blastoma helps to explain the results the orbit) are typically not subjected oncogene (which predicts a poorer out- of newborn screening programs for to attempts at complete resection that come) and hyperdiploid DNA content neuroblastoma conducted in Japan and might lead to disfigurement or func- (a predictor of good outcome among Quebec. Based on the assumption that tional losses. infants, albeit not older children). relatively unaggressive neuroblastomas Using this data, rhabdomyosarco- On the basis of extended scientific in infants progress into more malignant mas are now classified both by stage study, Brodeur and colleague have sug- tumors in older children, these pro- (which is based on site, size, and pres- gested that there are really 3 subtypes grams screened for elevated urine cat- ence or absence of metastases) and sur- 20 Medicine and Health / Rhode Island gical group (based on degree of resec- a year, which implies the almost-uni- teratoma). Immature teratomas are tion), and the intensity of treatment is versal presence of micrometastatic dis- graded according to their varying con- adjusted accordingly. The “gold stan- ease. Lung is the most common site tent of immature neuroepithelium. dard” treatment is a combination of of spread, with bone being second most The malignant germ cell tumors have vincristine, actinomycin-D, and cyclo- common; Ewing’s sarcoma/PNET can varying histologic appearances, appar- phosphamide with the addition of ra- also spread to bone marrow. ently representing differentiation of diation for residual local disease. Dose Ewing’s sarcoma is moderately re- pluripotent germ cells along different intensification of chemotherapy (espe- sponsive to both chemotherapy and pathways, and include yolk sac tumors cially of cyclophosphamide) appears to radiation. Current adjuvant protocols (= endodermal sinus tumors), have improved survival over the last 2 use a combination of vincristine, doxo- germinomas (= dysgerminoma) and decades, especially for children with rubicin, cyclophosphamide, etoposide, seminomas, embryonal carcinomas, gross residual disease following initial and ifosfamide; control of the primary and choriocarcinomas. In addition to resection.16 tumor is accomplished by surgical re- tumors with a single malignant histol- The outcome for children with section and/or radiation. Patients ogy, tumors may contain multiple his- metastatic disease remains poor (sur- without metastatic disease currently tologic types (mixed germ cell tumors) vival of <25%), although within this have long-term survival rates of ~70%, and teratomas may also have malignant group younger children with embryo- with tumors arising in the extremities elements. nal histology tumors fare better. Tu- having a better survival than other Although benign teratomas may mors with alveolar histology in general sites.17 Osteosarcoma is considerably grow to prodigious size, they are suc- remain more resistant to therapy than less sensitive to chemotherapy, and is cessfully treated with surgery alone. those with embryonal histology, al- also relatively resistant to radiation. The earlier literature suggested that though recent data suggest that the new Nonetheless, adjuvant regimens based immature teratomas had a risk of re- drug Topotecan may be especially ef- on doxorubicin and cisplatin, usually currence that increased with increas- fective against alveolar rhabdomyosar- accompanied by high-dose methotrex- ing grade of immaturity. However, coma. ate and sometimes other drugs, has more recent data suggest that the pres- increased survival to ~65% for patients ence of immature elements alone does OSTEOSARCOMA AND EWING’S without overt metastases.18,19 Survival not predict recurrence, and so the ear- SARCOMA is also strongly dependent upon the lier results probably were skewed by the Bone tumors overall comprise ability to completely remove the pri- undetected presence of malignant ele- only a small proportion of childhood mary tumor, since in most instances ments, a problem ameliorated by more malignancies. However, since both radiation cannot be used to control complete pathologic examination of osteosarcoma and (to a lesser extent) disease remaining after surgery. Im- resected tumors and the ability to de- Ewing’s sarcoma have peak incidences pressively, improvements in surgical tect low levels of tumor markers in both in adolescence, and the more common technique - combined with the fact that tissue and blood (alpha-fetoprotein, pediatric tumors peak during the pre- most osteosarcomas arise in the ex- usually associated with yolk sac ele- school years, bone tumors are actually tremities - now allow the majority of ments, and (β-HCG, usually associated the second most common cancer seen patients to avoid amputation and un- with embryonal carcinoma). during the second decade of life. dergo so-called “limb salvage” proce- Like other childhood cancers, the Although both tumors can arise dures. malignant germ cell tumors tend to from any bone, osteosarcomas prefer- Overt metastases at the time of spread early in their development and entially develop in the metasphyses, diagnosis presage a considerably worse so, with the exception of localized tes- especially of the distal femur, proximal outcome. Despite aggressive chemo- ticular tumors in young boys, are not tibia, and proximal humerus. In con- therapy and treatment of metastatic usually curable with surgery alone. trast, about half of Ewing’s sarcomas lesions with surgery and/or radiation, Response to chemotherapy remained will develop in the bones of the axial overall survival for patients with meta- mediocre until the development of skeleton (especially pelvis) and even static bone tumors is <25%. For both platinum-based regimens. The most when present in long bones are often osteosarcoma and Ewing’s sarcoma, common combination used in the seen in the diaphysis. Both Ewing’s patients with metastases confined to United States is bleomycin, cisplatin, sarcoma and the closely related primi- the lung appear to have a somewhat and etoposide; carboplatin is also used tive neuroectodermal tumor (PNET) better prognosis than those with extra- in some regimens and for recurrent can arise in soft tissue. pulmonary disease. disease, although it appears to be some- Visible metastases are present at what less effective than cisplatin. diagnosis only in a small percentage of GERM CELL TUMORS The malignant germ cell tumors patients (<15%). However, surgery Germ cell tumors include a bewil- are so sensitive to this combination that alone is rarely curative even in the ab- dering array of entities. The most com- four cycles are curative for >90% of sence of detectable metastatic disease; mon germ cell tumors are teratomas, pediatric patients with gonadal prima- 80-90% of patients will relapse within most of which are benign (= mature ries (even those with metastatic disease) 21 Vol. 85 No. 1 January 2002 and ~75% of patients with extra-go- perience discrimination in jobs, insur- 12. Brodeur GM, Marris JM, Yamachiro DJ, nadal disease.20 Because of this exquis- ance, and education as a result of their et al. Biology and genetics of human ite sensitivity to chemotherapy, patients medical history. Indeed, as more pa- neuroblastoma. J Pediatr Hematol/Oncol 1997;19:93-101. who are judged to be at modest risk of tients survive their original disease, it 13. Kushner BH, Cheung N-KV, LaQuaglia recurrence (e.g., teratomas with a small becomes vitally important to deal with MP, et al. Survival from locally invasive percentage of malignant elements) are their long-term medical, emotional, or widespread neuroblastoma without now often observed without adjuvant and social needs. cytotoxic therapy. J Clin Oncol treatment, since the ability to salvage 1996;14:373-81. those who do relapse is excellent, and REFERENCES 14. Matthay KK, Villblanca JG, Seeger RC, the toxicity of the chemotherapy— 1. Landis SH, Murray T, Bolden S, Wingo et al. Treatment of high-risk neuroblas- toma with intensive chemotherapy, ra- both acute and late—can be signifi- PA. Cancer Statistics 1999. Ca-A Can- diotherapy, autologous bone marrow cant. Future research will probably cer J for Clinicians 1999;48:8-31. 2. Murphy S. The national impact of clini- transplantation, and 13-cis-retinoic acid. focus on further decreasing the dura- cal cooperative trials for pediatric can- NEJM 1999;341:1165-73. tion and intensity of treatment for low- cer. Med Ped Oncol 1995;24:279-80. 15. Woods WG, Tuchman M, Robison LL, risk patients. 3. Pui C-H, Evans WE. Acute lymphoblas- et al. A population-based study on the tic leukemia. NEJM 1998;339:605-15. usefulness of screening for neuroblas- toma. Lancet 1996;348:1682-7. CONCLUSION 4. Harris MB, Shuster JJ, Pullen DJ, 16. Pappo AS, Shapiro DN, Crist WM, The spectacular success in treat- Borowitz MJ, et al. Consolidation Maurer HM. Biology and therapy of ing childhood malignancies must be therapy with antimetabolite-based therapy in standard-risk acute lympho- pediatric rhabdomyosarcoma. J Clin weighed against the considerable short- blastic leukemia of childhood: A Pediat- Oncol 1995l134:2123-39. and long-term side effects of treatment ric Oncology Group Study. J. Clin Oncol 17. Grier HE. The Ewing family of tumors. (growth impairment, organ damage, 1998;16:2840-7. Ped Clin North Amer 1997;44:991-1004. sterility, and second malignancies). 5. Nachman J, Sather HN, Gaynon PS, et 18. Link MP, Goorin AM, Miser AW, et al. These can be tempered, in part, by our al. Augmented Berlin-Franfurt-Munster The effect of adjuvant chemotherapy on relapse-free survival in patients with os- ability to target more intensive thera- therapy abrogated the adverse prognos- teosarcoma of the extremity. NEJM pies for patients at higher risk of re- tic significance of slow early response to induction therapy for children and ado- 1986;314:1600-6. lapse, a consequence of our burgeoning lescents with acute lymphoblastic leuke- 19. Meyers PA, Gorlick R, Heller G, et al. knowledge of prognostic indicators. mia and unfavorable presenting features: Intensification of preoperative chemo- Improved supportive care and new A report of the Children’s Cancer Group. therapy for osteogenic sarcoma: Results ways of protecting normal tissue from J Clin Oncol 1997;15:2222-30. of the Memorial Sloan-Kettering (T12) chemotherapy- and radiation-induced 6. Rivera GK, Hudsen MM, Liu Q, et al. protocol. J Clin Oncol 1998;16:2452-8. 20. Giller R, Cushing B, Lauer S, et al. damage are also beginning to make an Effectiveness of intensified rotational Comparison of high dose or standard impact on long-term toxicity. Further- combination chemotherapy for late he- matologic relapse of childhood acute dose cisplatin with etoposide and more, our increasing knowledge of the lymphoblastic leukemia. Blood bleomycin (HDPEB vs PEB) in children underlying biology of cancer holds the 1996;88:831-87. with stage III and IV malignant germ promise that we can develop new mo- 7. Sandlun JT, Downing JR, Crist WM. cells tumors (MGCT) at gonadal pri- dalities of treatment that may, at least Non-Hodgkin’s lymphomas in child- mary sites: a pediatric intergroup trial. in part, avoid some of the potential life- hood. NEJM 1996; 334:1238-48. Proc Amer Soc Clin Oncol 1998;17:525a. long consequences of traditional che- 8. Link MP, Shuster JJ, Donaldson SS, et motherapy and radiation. al. Treatment of children and young William S. Ferguson, MD, is Di- adults with early-stage non-Hodgkin’s A recent national summit on rector of Clinical Oncology, Department lymphoma. NEJM 1997; 337:1259-66. childhood cancer, which one of us of Pediatrics, Rhode Island Hospital and 9. Hunger SP, Link MP, Donaldson SS. Brown Medical School. (ENF) was privileged to attend, iden- ABVD/MOPP and low-dose involved- Edwin N. Forman, MD, is Direc- tified goals for the 21st century. While field radiotherapy in pediatric Hodgkin’s research continues on improving the Disease: The Stanford Experience. J Clin tor, Pediatric Hematology-Oncology, medical treatment of childhood can- Oncol 1994; 12:2160-6. Department of Pediatrics, Rhode Island cer, awareness of other important is- 10. Green DM, Breslow NE, Beckwith JB, Hospital and Brown Medical School. et al. Comparison between single-dose sues affecting these patients must not and divided-dose administration of be lost. Access to appropriate, high- CORRESPONDENCE: Dactinomycin and doxorubicin for pa- William S. Ferguson, MD quality medical care remains far from tients with Wilms’ tumor: A report from Rhode Island Hospital universal. Furthermore, our care must the National Wilms’ Tumor Study take into account not just rates of sur- Group. J Clin Oncol 1998;16:237-45. 593 Eddy St. vival, but also the quality of life for our 11. Green DM, Beckwith JB, Breslow NE, Providence, RI 02903 patients and their families, both dur- et al. Treatment of children with stages phone: (401) 444-5171 II to IV anaplastic Wilms’ tumor: A re- ing and after treatment. Beyond the fax: (401) 444-8845 port from the National Wilms’ Tumor e-mail: [email protected] medical consequences of their treat- Study Group. J Clin Oncol ment, many children continue to ex- 1994;12:2126-31. 22 Medicine and Health / Rhode Island Brain
Tumors Lloyd M. Alderson, MD, DSc Few diseases elicit the sense of hope- egories of neuroepithelial tumors that are (medulloblastoma, neuroblastoma, ret- lessness and despair as cancer of the brain. all defined by histologic criteria.1 A inoblastoma) are characterized by a high The most common primary brain tumor, modified version of this list is presented density of rapidly growing cells. These glioblastoma, is often refractory to treat- in Table 1. tumors are not graded, and prognosis ment and fatal within a year of diagno- Many occur primarily in children depends on the extent of tumor spread. sis. However, not all of the neoplasms (i.e., embryonal tumors, pineal tumors, Tumors of the nerves and nerve that involve the central nervous system germ cell tumors, choroid plexus tu- sheath (schwannomas, neurofibromas) (CNS) carry such a grim prognosis. In mors); most are rare. Gliomas are by far are usually slow growing and carry a fa- the following, I will discuss the classifi- the most common in adults and can ex- vorable prognosis if they can be excised.. cation and epidemiology of primary hibit features of astrocytes, oligodendro- When two or more of these are found in brain tumors, the treatment and prog- cytes, or both (mixed glioma).2 The the same patient or family, the issue of nosis of the most common tumors and WHO schema uses a three-tiered system an inherited disorder, such as neurofibro- end with a discussion of CNS metastases. where the grade of the tumor reflects the matosis type 1 or 2, is raised. Unfortu- I hope to leave the primary care physi- extent to which the tumor cells are mor- nately, neurofibromas can degenerate cian with a general sense of how to ap- phologically abnormal (anaplasia), their into malignant sarcomas, particularly in proach a patient with a brain tumor. apparent rate of growth, and the pres- patients with NF1. The presenting signs and symptoms ence of necrosis. Low-grade tumors may Meningiomas are also classified in a of patients with brain tumors reflect the appear to contain a high density of al- three-tier system: typical, atypical, and somatotopic organization of the CNS most normal appearing cells and a growth malignant. Unlike gliomas, the vast and the fact that specific regions of the rate of less than 2%. Anaplastic gliomas majority of meningiomas is of the low- brain are indispensable for specific func- exhibit more atypical cells with pleomor- est grade. Atypical meningiomas have a tions. Symptoms, such as focal weak- phic nuclei, growth rates in the 5-10% relatively increased degree of cellularity ness or numbness, identify the location range but no evidence of necrosis. Glio- and prevalence of mitotic figures. Ma- of the tumor as contralateral cerebral mas with high growth rates (>20%) and lignant meningiomas are defined by in- hemisphere, brainstem, or spinal cord de- necrosis are classified as glioblastoma vasion of adjacent brain. A malignant pending on the distribution of the loss. multiforme. A grading scale first de- tumor of the pituitary (pituitary carci- Homonymous visual defects always re- scribed by Daumas-Duport and Szikla noma) is also, fortunately, rare. Most flect an intracranial process, usually in uses similar criteria to classify glioma tumors of the pituitary are adenomas the occipital lobe. Speech and language patients into one of four grades where characterized by the expression and se- symptoms suggest a lesion in the domi- grades II, III, and IV corresponding to cretion of hormones. nant hemisphere (the left in 90% of pa- low-grade glioma, anaplastic glioma, and Of the remaining tumors, most are tients). The time course of the illness is glioblastoma respectively (Grade I re- very rare and primarily affect children. also an important indicator of the dis- served for pilocytic astrocytoma).3 The The exceptions are CNS lymphomas and ease process. Unlike stroke, which pre- tumor grade is the most reliable predic- metastases. Primary CNS lymphoma is sents suddenly, symptoms of a brain tor of prognosis. Even if the lesion can- a form of extranodal non-Hodgkinís tumor often progress over weeks or not be safely excised, a needle biopsy is lymphoma and is classified according to months. The exception is a seizure, often indicated. We are moving toward the International Working Formulation which can be either focal or generalized a classification system that relies more on (National Cancer Institute 1982). Most and is the presenting symptom of a tu- genetics than cellular morphology, but lymphomas that involve the brain are of mor in one-third of patients. Seizures whether it will prove a better predictor B-cell lineage, and diffuse large cell or represent cortical dysfunction, and focal of response to therapy and prognosis re- immunoblastic are the most common seizures suggest involvement of the con- mains to be proven. subtypes. In CNS metastases of systemic tralateral cerebral cortex. Other symp- Similar approaches are used to clas- malignancies, such as breast or lung, the toms that are common but not localizing sify other neuroepithelial tumors. Ana- lesion will have the same histologic ap- include headache (40% of patients), plasia and growth rate differentiate pearance as the primary. In 15% of pa- papilledema, and mental status changes, between malignant and less aggressive tients with metastases, the primary is all of which can result from increased in- tumors of the pineal, choroid plexus, and unknown but can sometimes be dis- tracranial pressure. ependyma. When tumors contain neu- cerned with immunohistochemical stains rons (gangliogliomas, gangliocytomas), of the biopsied brain lesion CLASSIFICATION this suggests a less aggressive behavior, but The World Health Organization it is sometimes difficult to identify EPIDEMIOLOGY (WHO) classification of brain tumors, whether neurons are part of the tumor The chance of developing a malig- published in 1979, includes 9 major cat- or just trapped by an invading glioma. nant brain tumor in this country is small egories of brain tumors and nine subcat- The primitive neuroectodermal tumors (5.8/100,000 person years) but is high 23 Vol. 85 No. 1 January 2002 Table 1 Tumors of Neuroepithelial Tissue Variant Astrocytic tumors Olfactory neuroepithelioma Astrocytoma Ganglioglioma Variants Dysembryoplastic neuroepithelial tumor Fibrillary Desmoplastic infantile ganglioglioma Protoplasmic Medulloblastoma Gemistocytic Medulloepithelioma Anaplastic astrocytoma Glioblastoma multiforme Pineal tumors Variants Germ cell tumors Giant cell glioblastoma multiforme Germinoma Gliosarcoma Embryonal carcinoma Astroblastoma Yolk sac tumor (Endodermal sinus tumor) Gliomatosis cerebri Choriocarcinoma Pilocytic astrocytoma Teratoma Pleomorphic xanthoastrocytoma Mixed germ cell tumors Subependymal giant cell astrocytoma Pineocytoma Pineoblastoma Oligodendroglial tumors Mixed/transitional pineal tumors Oligodendroglioma Anaplastic oligodendroglioma Tumors of the Meninges Meningioma Ependymal tumors Variants Ependymoma Meningothelial Variants Fibrous Cellular Transitional (mixed) Papillary Psammomatous Clear cell Angiomatous Anaplastic ependymoma Microcystic Ependymoblastoma Secretory Myxopapillary ependymoma Clear cell Subependymoma Chordoid Atypical meningioma Mixed gliomas Papillary meningioma Anaplastic meningioma Choroid plexus tumors Hemangiopericytoma Choroid plexus papilloma Hemangioblastoma Choroid plexus carcinoma Primary melanocytic lesions Neuronal and mixed neuronal-glial tumors Diffuse melanosis Gangliocytoma Melanocytoma Dysplastic gangliocytoma of cerebellum Malignant melanoma (Lhermitte-Duclos) Variant Central neurocytoma Meningeal melanomatosis Neuroblastoma Lymphomas Variant (Esthesioneuroblastoma) Ganglioneuroblastoma Olfactory neuroblastoma

enough so that most primary care physi- alone, the highest incidence occurs at 60 roughly half that of New England. In cians will encounter a patient every few years of age. CBTRUS data demon- our own study of the incidence of glio- years. The majority of these patients with strates the incidence declines in older mas in Rhode Island, we found relatively a single brain lesion will have a glioma, people (>75 years). However, several in- high rates overall (7.6/100,000 p-y com- and unfortunately, the most common vestigators, including ourselves, have re- pared to 5.1 from CBTRUS) and for histologic grade is glioblastoma. Data ported the incidence of glioma is rising glioblastoma alone (4.6 vs. 2.5 from on the incidence of brain tumors in sev- rapidly in patients over 75. The male to CBTRUS). Specific rates for menin- eral regions of the US have been collected female ratio for all brain tumors is ap- gioma and other less common tumors by the Central Brain Tumor Registry proximately 1.0. However, if you look have not been reported. of the United States (CBTRUS) and at meningioma alone, the M:F is 0.5 and Surveillance, Epidemiology, and End for malignant glioma, 1.6. In Rhode Is- LOW-GRADE GLIOMA Results (SEER) consortia. Like many land the M:F is 2.0 for all gliomas. The Gliomas are grouped into three his- cancers, the incidence of brain cancer incidence of brain cancer also varies in tologic categories - low grade, anaplas- rises with age, peaking at approximately different regions of the country. The in- tic, and glioblastoma. The histologic 65-70 years (Figure 1). For glioblastoma cidence of brain tumors in Hawaii is grade has important therapeutic and 24 Medicine and Health / Rhode Island prognostic implications. Table 2 lists astrocytoma, the indications for surgery Focal radiation (radiosurgery or gamma some of the clinical and morphologic are slightly different. In this disease, a knife) has been used in some patients features that distinguish low-grade glio- complete resection may constitute a cure, with low-grade glioma, but there is cur- mas from the higher-grade tumors. and a more aggressive surgical approach rently no long-term follow-up data re- Although low-grade glioma carries may be indicated. porting a clear benefit. with it a better prognosis, the majority Chemotherapy is in general not part of patients with low-grade tumors will It is important to of the initial management of patients with progress to glioblastoma and will suc- low-grade glioma. The exception to this cumb to their disease. Low-grade glio- remember that the is patients with an oligodendroglial tumor mas are slow growing lesions that often surgeon can never “get it who are either older or whose tumor has do not enhance with gadolinium. His- a relatively high mitotic index. These pa- tologically they are classified as either as- all out”, and the tumor tients may benefit from PCV trocytoma, oligodendroglioma, or mixed will progress at some (procarbazine, CCNU, and vincristine) oligoastrocytoma. A history of symp- chemotherapy. The benefit of this ap- toms can extend back many months or point even after a gross proach is that it delays the use of RT, which years, and a patient may enjoy several total resection. can result in long-term cognitive impair- years of stable disease before the tumor ment, particularly in the elderly patient. progresses. Factors which predict a longer  Chemotherapy, however, is not without progression-free survival include a low risk, and chemo-induced leukemia occurs mitotic index (as measured by Ki-67 or Whether to recommend external in approximately 1-2% of patients treated mib-1 immunostaining), younger age of beam radiation therapy is often the next with PCV who survive 5 years. patient, and a lesion that is supratento- decision. Until recently, data from ran- Although the prognosis for patients rial and amenable to resection. domized studies has not been available. with low-grade tumors is much better How we as physicians can alter the Preliminary data from a large random- than anaplastic glioma and GBM, it is course of this disease is the next question. ized European study suggests that radia- still a fatal disease for most patients. The Surgical resection is always the first con- tion therapy does not prolong overall median survival for patients with astro- cern. Retrospective studies suggest pa- survival in patients with low-grade cytoma is 5-7 years and for oligodendro- tients who have had a gross total resection glioma. However, there was an increase glioma, 7-10 years. have a longer progression-free survival in PFS for treated patients. This benefit than those who do not.4 We, therefore, may be offset by a higher incidence of ANAPLASTIC GLIOMA recommend surgery for patients with tu- cognitive impairment in the treated Anaplastic glioma is an intermedi- mors that can be safely removed. It is im- group. Survival is not the only factor ate grade tumor which has a higher mi- portant to remember that the surgeon can when considering RT. Patients with large totic index than low-grade gliomas but never “get it all out”, and the tumor will tumors that are symptomatic often ben- lacks the necrosis seen in glioblastoma. progress at some point even after a gross efit functionally from RT. RT may also It commonly affects patients in the 35- total resection. Therefore, a disabling re- reduce seizure frequency in patients who 50 age range, and patients often present section in a patient with astrocytoma or are refractory to anticonvulsant drugs. with a history of symptoms that goes oligodendroglioma is not helpful. A sub- We, therefore, recommend RT for pa- back several weeks. A complete surgical total resection is indicated in patients tients with large symptomatic residual resection of the lesion is again the best where the mass effect of the tumor is caus- disease, but for most patients, we with- first step, but a heroic disabling proce- ing disability that can be addressed with hold therapy until there is radiographic dure is not beneficial. The majority of decompression. In patients with pilocytic or clinical evidence of tumor progression. patients with anaplastic tumors will re- ceive both radiation therapy Table 2 and chemotherapy at some Grades of Gliomas point. In anaplastic astrocy- tomas, patients should re- Low-Grade Glioma Anaplastic Glioma Glioblastoma ceive RT soon after surgery. In a large randomized study Symptoms years months weeks published 15 years ago, ad- Duration juvant PCV chemotherapy Age at Diagnosis 5-30 30-50 > 50 was shown to be of some 7 MRI Enhancement Ð +/Ð + + benefit. Subsequent studies have not confirmed a survival Pathology Hypercellular Anaplastic Necrosis Endothelial Cell Proliferation advantage to adjuvant PCV. Temozolomide is an oral che- Mitotic index < 2% 5-10% > 10% motherapeutic drug that is (Ki-67) approved for the treatment of Treatment observe RT RT and chemotherapy recurrent anaplastic gliomas. Survival 5-10 years 3-4 years 12 months The chance of a response (ei- 25 Vol. 85 No. 1 January 2002 ther complete, partial, or stable disease) changes which are also seen in low-grade meningiomas are asymptomatic. On is high (40-50%), and it is very well tol- and anaplastic tumors. MRI they appear as a dural-based, ho- erated. It is currently being evaluated as The first step in treatment is best mogeneously enhancing mass. The in- adjuvant to radiation and concomitant surgical resection. Patients who are cidence of the disease increases with age, with radiation therapy in patients with younger, have a normal examination and and meningiomas are more common in anaplastic astrocytoma. The postsurgi- have had a gross total resection have the women. Meningiomas frequently ex- cal approach is somewhat different in best prognosis. Postoperative RT clearly press estrogen and progesterone recep- patients with anaplastic oligodendroglio- benefits these patients and is the stan- tors, and the risk of tumor progression mas and mixed anaplastic gliomas. There dard of care.5 In a large randomized study may increase with pregnancy or estrogen is an approximately 70% chance these conducted in the 1970s, patients with replacement. Because they grow slowly, patients will respond to PCV chemo- GBM who received RT had a median these tumors can achieve a remarkable therapy. We, therefore, recommend PCV survival, roughly twice that of those who size before they are discovered. A com- (6 cycles if tolerated) prior to RT in most did not.6 In patients with a small vol- mon scenario is that an elderly patient is patients. There is now a chromosomal ume of residual disease (less than 3 cm noted to have behavioral changes and marker (loss of heterozygosity at 1p and in diameter), a focal radiation boost has cognitive decline, potentially attributable 19q) that can predict with 95% sensitiv- also been shown to prolong survival. The to dementia, and imaging reveals a 4-5 ity whether a patient will respond to PCV benefit of chemotherapy is more contro- cm subfrontal mass. chemotherapy. Patients that lack this versial. BCNU is an intravenous che- In patients with typical meningioma, marker have only a 30% chance of re- motherapy that penetrates the brain, but surgical resection alone can be curative, sponding, and their prognosis is much most studies suggest that only 20-25% and the chance of recurrence at 10 years worse. This and other genetic markers of patients will benefit. BCNU can also following gross total resection is less than may soon play an important role in how be delivered directly to the brain in a bio- 20%. In patients with subtotal resection, we decide which therapies to use. degradable wafer (Gliadel) at the time of the chance of recurrence is much higher The prognosis for patients with ana- surgery. This approach has resulted in a (60% at 5 years), and RT or preferably plastic astrocytoma is approximately 3 modest improvement in survival when focal radiation (gamma knife or radiosur- years (median survival), and again ana- used at either tumor recurrence or at the gery) is indicated. Patients with atypical plastic oligodendrogliomas do better, initial surgery. Temozolomide is now the meningioma or malignant meningioma particularly if the tumor has the chro- most commonly used FDA approved should be treated with radiation even if a mosomal abnormalities described above. drug for patients with recurrent GBM. gross total resection is achieved. Chemo- Aggressive chemotherapy (with bone Response rates are higher than BCNU therapy for recurrent tumors has been at- marrow transplant) has not significantly (30-40%), and it is better tolerated. tempted but with little success. Interferon prolonged survival. There are currently a wide variety of clini- alpha and hydroxyurea have been used in cal trials of new agents for patients with slowly growing tumors; response rates are GLIOBLASTOMA MULTIFORME recurrent or recently diagnosed GBM. I less than 20%. For tamoxifen (anti-es- This is both the most common and strongly encourage clinicians to get these trogen) and mifepristone (anti-progestin), most aggressive of the gliomas and un- patients involved in at least one of them. the data are more promising (PR + SD fortunately the least likely to respond to The median survival for patients with 30%), but larger studies in progress are therapy. The average age at presentation GBM who have received RT is slightly likely to show lower response rates. Ag- is 62 years, and males are at higher risk less than a year. The chance of survival at gressive chemotherapy with ifosfamide than females (M:F 1.5-2). The term 2 years is 5-10%, and the chance of sur- and adriamycin in rapidly growing tumors multiforme refers to the gross appearance vival at 5 years is less than 2%. Long- has been tried but again with little suc- of the tumor. There are often areas of term survivors are often younger patients cess. necrosis, areas of hemorrhage, and areas who have had complete resection and re- of fleshy tumor, all in the same lesion. ceived both radiation therapy and some PNET AND OTHER TUMORS At a clinical and a molecular level, there form of chemotherapy. The fact that sur- Medulloblastoma, pinealoblastoma, is a dichotomy in how a GBM develops. vival rates for patients with GBM have and other primitive neuroectodermal tu- In younger patients with GBM, a long not changed in 30 years is discouraging mors are rare and primarily affect children. history of seizures can sometimes be elic- but emphasizes the need for more basic These tumors often appear as a homoge- ited suggesting their tumor developed science and clinical research. neously enhancing mass adjacent to the from a lower grade precursor. In older third or fourth ventricle, and patients typi- patients with GBM, symptoms often MENINGIOMA cally present with nausea, headache, and develop quite suddenly suggesting the Meningioma is a tumor of the fi- double vision. Histologically they appear tumor did not evolve through less aggres- brous connective tissue that forms the as hypercellular lesions with a high nuclear sive precursors. Genetic studies confirm dura. They are classified into three to cytoplasmic ratio. Surgical resection is this dichotomy. Tumors from older pa- grades, typical, atypical, and malignant, again the best first step in management. tients with GBM frequently have ampli- based on their mitotic index and whether Unlike gliomas, these tumors frequently fication of the gene encoding the EGF they invade normal brain. Fortunately, seed the CSF, and patients can develop receptor, whereas GBM in younger pa- the vast majority of these tumors is typi- drop metastases in the spinal cord. In tients often exhibit mutation of p53 and cal meningioma and is slow growing. medulloblastoma, patients are classified as loss of portions of chromosome 19, Autopsy studies have shown that most low risk if they have had a complete sur- 26 Medicine and Health / Rhode Island gical resection and have no evidence of ternist, this is perhaps the most common 2. Giles GG, Gonzales MF. Epidemiology of CSF dissemination. Patients in this group neuro-oncology issue that comes up. brain tumors. In Kaye AH, Lawes ER. (ed) Brain Tumors. Churchill Livingston, who are treated with craniospinal RT have Twenty-five percent of all patients with Edinburgh, London, 1997: 47-67. a 60% chance of 5-year progression-free cancer will develop CNS metastases at 3. Daumas-Duport C, Scheithauer BW, O survival. The addition of chemotherapy some point. This can take the form of ‘Fallon J, Kelly P. Grading of Astrocytomas. may raise this chance to as high as 80% in solid tumors compressing the brain and A simple and reproducible method. Cancer 8 1998;62:2152-65. children. High-risk patients with CSF in- spinal cord or cancer cells infiltrating CSF 4. Sofietti R, Choi A. Giordana MT. Prognostic volvement or metastases usually receive and peripheral nerve. CNS metastases factors in well-differentiated cerebral astrocyto- both RT and chemotherapy but are at from lung cancer are the most common mas in the adult. Neurosurg 1989; 24:686-69. much higher risk of recurrence. primary tumor that metastasizes to the 5. Curran WJ, Scott CB, Horton J. Recursive partitioning analysis in three Radiation Pinealoblastomas and other PNETs are CNS (50%) followed by breast (33%), GI Therapy Oncology Group malignant glioma treated in a similar fashion. tumors (9%), and melanoma (7%). The trials. J Natl Cancer Inst 1993;85:704-710. Tumors that contain neuronal ele- time interval between the primary diag- 6. Walker MD, Alexander E Jr, Hunt WE. Evalu- ments are referred to as gangliogliomas or nosis and CNS metastasis is dependent ation of BCNU and/or Radiotherapy in the gangliocytomas. These lesions develop on the tumor type. For lung cancer, the treatment of anaplastic gliomas: A cooperative clinical trial. J Neurosurg 1978; 49:333-43. from cells that are precursors for both neu- median interval is 4 months and for breast, 7. Levin VA, Silver P, Hannigan J, et al. Superior- rons and glia. Radiographically they ap- 3 years. CNS metastasis is an indicator of ity of post-radiotherapy, adjuvant chemotherapy pear as a nonenhancing cystic mass poor prognosis and portends a survival of with CCNU, procarbazine, and vincristine adjacent to the lateral ventricle. In gen- less than 6 months for most patients. (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol eral, they are more indolent than glial tu- Although treatment is clearly pallia- Biol Physical Examination year; 1990:321-4. mors. When symptomatic, they should tive, most patients do benefit from CNS 8. Krischer J, Ragab A. Kun L, et al. Nitrogen be removed. However, asymptomatic tu- directed therapy. Whole brain radiation mustard, vincristine, procarbazine, and pred- mors can be observed and addressed with therapy is indicated for most patients with nisone as adjuvant chemotherapy in the treat- ment of medulloblastoma: a Pediatric surgery or RT only if they progress. parenchymal brain lesions. If only a single Oncology Group study. J Neurosurg lesion is present and the systemic disease 1991;74:905-909. PRIMARY CNS LYMPHOMA is stable, surgical resection of the lesion 9. Packer R, Sutton L, Elterman R, et al. Out- (PCNSL) should be considered. Similarly, focal ra- come for children with medulloblastoma treated with radiation and cisplatin, CCNU, Primary CNS Lymphoma diation is helpful only in patients with one and vincristine chemotherapy. J Neurosurg 11 (PCNSL) is a form of extranodal non- or two lesions and are otherwise stable. 1994;81:690-698. Hodgkin’s lymphoma that involves the Both of these local approaches do not ad- 10. Rock JP, Cher L, Hochberg FH, Rosenblum brain, eyes, and CSF.10 Immunocompe- dress the significant chance of new lesions ML. Central nervous system lymphomas in tent patients usually present in the 5th or occurring elsewhere in the brain, and pa- AIDS and non-AIDS patients, in McL. Black 12 P, and Loeffler JS. (ed) Cancer of the nervous 6th decade with a homogeneously enhanc- tients should also receive RT. Symptoms system. Blackwell Science, Inc., Cambridge ing lesion located adjacent to the lateral consistent with a spinal cord metastasis MA, 1997: 593-606. or third ventricle. Multiple lesions occur, include back pain, incontinence, sensory 11. Fuller BG, Kaplan ID, Adler J, et al 1992 and the differential diagnosis often in- loss in a dermatomal pattern, or bilateral Stereotactic radiosurgery for brain metastases: the importance of adjuvant whole brain irra- cludes glioma and metastases. The vitre- motor deficits in the absence of mental diation. Int J Radiat Oncol Biol Phys ous and the CSF are frequently involved status changes. These patients need to be 1992;23:413-418. (20% and 33% respectively), but tumors evaluated urgently. The chance for neu- 12. Cairncross JG, Kim JH, Posner JB. Radia- are rarely seen outside the neuraxis. Pa- rologic recovery is dependent on the func- tion therapy for brain metastases. Ann Neurol tients are treated with high-dose intrave- tional status at the time of diagnosis. 1980;7:529-41. nous methotrexate or a combination of Therefore, evaluation with MRI or my- chemotherapy and RT. Unlike malignant elogram and treatment with surgery, RT, Lloyd M. Alderson, MD, DSc, is an glioma, the chance of responding to or both should proceed without delay. Assistant Professor in the Division of therapy is high (70%), but patients fre- Carcinomatous meningitis commonly Neurosurgery, Brown Medical School. quently relapse within 3 years. The risk presents with headache, nausea, and cra- of PCNSL in the general population his- nial neuropathies. The diagnosis is made CORRESPONDENCE: torically has been 1-2 per million person by CSF cytology and meningeal enhance- Lloyd M. Alderson, MD, DSc years, but several lines of evidence indi- ment on gadolinium MRI of the brain or Neurosurgery Foundation cate it is rising. In Rhode Island we see 3- spine. The treatment involves direct in- 55 Claverick St. 5 patients a year. Patients with acquired fusion of chemotherapy (methotrexate or Providence, RI 02903 or congenital immunodeficiency have a cytarabine) into the spinal fluid via a lum- phone: (401) 455-1749 much higher risk of PCNSL (2-6% of bar puncture or preferably an Ommaya fax: (401) 455-1292 AIDS patients, 1-5% of transplant pa- reservoir. e-mail: [email protected] tients). Unless the immune deficiency can be rectified, these patients may have a more REFERENCES malignant course. 1. Kepes JJ. 1990 Review of the WHOís proposed new classification of brain tumors. Proceedings of the XIth International Congress of Neuropa- METASTASES thology, Kyoto, September 2-8, 1990. Japanese For the medical oncologist and in- Society for Neuropathology, Kyoto, Japan. 27 Vol. 85 No. 1 January 2002 CME Background
Information

This CME activity is sponsored by Brown Medical School.

TARGET AUDIENCE This enduring material is designed for physicians licensed in Rhode Island.

CME OBJECTIVES At the conclusion of this course, participants should be able to: * describe diagnosis, staging and treatment of non-small cell lung carcinoma * describe multidisciplinary approach to breast cancer, including the long-term maintenance of breast cancer survivors * describe recommendations for colorectal screening * describe the childhood cancers and their treatments * describe treatment and prognosis of common brain tumors

NEEDS ASSESSMENT Diagnosis and treatment of cancer have made dramatic advances in the past decade. This issue will inform Rhode Island physicians of those advances.

ACCREDITATION STATEMENT Brown Medical School is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians.

CREDIT DESIGNATION Brown Medical School designates this education activity for 2 hours in category 1 credit toward the AMA Physician’s Recognition Award. Credit can be obtained by reading the issue and comleting the following quiz. The estimated time for completion of this activity is 2 hours.

DATE OF ORIGINAL RELEASE This issue was published January 2002. This actvity is eligible for CME credit through December 2002.

FACULTY DISCLOSURE In accordance with the disclosure policy of Brown Medical School as well as standards set forth by the Accreditation Council on Continuing Education (ACCME), authors have been asked to disclose (1) any significant financial or any other relationship with the manufacturers(s) or any commercial products(s) and/or provider(s) of commercial services discussed in any educational presentation and (2) with any commercial supporters of this activity. The intent of this policy is not to prevent an author with a potential conflict of interest from making a presentation. It is merely intended that any potential conflict should be identified openly so that the reader may form his/her own opinion. The following authors have disclosed that they have no commercial relationships to report. Lloyd Alderson, MD, DSci, Paul Calabresi, MD, William Ferguson, MD, Mary Anne Fenton, MD, Edwin Forman, MD, Arvin Glicksman, MD, Todd Moore, MD, Neal Ready, MD, PhD

ACKNOWLEDGEMENT The material contained in this issue is a result of the editorial work by Paul Calabresi, MD, guest editor. The opinions expressed herein are those of the authors and do not necessarily reflect the views of the sponsors, publisher or the planning committee.

TO OBTAIN CREDIT To obtain credit, please submit answer grid and $25 fee to Office of Continuing Medical Education, Brown University. Respondents must receive a score of 70 or higher for credit.

DEADLINE FOR SUBMISSION CME REGISTRATION FORM PRINT OR TYPE For credit to be received, please mail your registration with Name ______$25 fee to Office of Continuing Medical Education, Brown University School of Medicine, Box G-A2, Providence, RI Address ______02912. Submit your answers no later than December 31, 2002. City, State, Zip ______KEEP A COPY FOR YOUR FILES. Phone ( ) ______Retain a copy of your answers and compare them with the correct answers, which will be made available upon request, Fax ( ) ______e-mail ______and receipt of submission requirements. ___Hospital ___Private Practice ___Resident ___Intern ___Other EVALUATION Please evaluate the effectiveness of the CME activity on a scale of 1 to 5 (1 being poor; 5 being excellent) by circling your choice. 1. Overall quality of this CME activity 12345 2. Content 12345 3. Format 12345 4. Faculty 12345 5. Achievement of educational objectives * Describe diagnosis, staging and treatment of non-small cell lung carcinoma 12345 * Describe multidisciplinary approach to breast cancer, including the long-term maintenance of breast cancer survivors 12345 * Describe recommendations for colorectal screening 12345 * Describe the childhood cancers and their treatments 12345 * Describe treatment and prognosis of common brain tumors 12345

Please comment on the impact that this CME activity might have on your practice of medicine. ______Additional comments and/or suggested topics for future CME activities. ______28 Medicine and Health / Rhode Island 10) Which statement is true? Cancer in the New Millenium Questions A) For patients with a genetic susceptibility to breast cancer, the Claus model is more appropriate than the Gail model. 1) The percentage of patients with cancer that can be cured in 2001 is B) Clinical data support the use of raloxifen for breast cancer risk reduction. approximately: C) To monitor patients for disease recurrence, physicians should screen A) 20% with bone scans and CT scans. B) 40% D) A and C are true. C) 60% E) No statement is true. D) 80% E) None of the above 11) Screening for colorectal cancer was performed on less than ______% of the Rhode Island population. 2) The median age for patients with cancer in the United States is: A) 40%) A) 50 years B) 50% B) 55 years C) 60% C) 60 years D) 80% D) 65 years E) Not known E) 70 years 12) Both primary care physicians and endoscopists preferred which study 3) The largest number of cancer deaths in the United States occurs for high-risk individuals? from: A) FOBT and sigmoidoscopy A) Brain tumors B) Flexible sigmoidoscopy B) Prostate cancer C) Colonoscopy C) Lung cancer D) Double-contrast barium enema D) Colorectal cancer E) None of the above E) Breast cancer 13) If the recommendation for standard risk individuals to be screened using colonoscopy once at age 50 and every 10 years thereafter unless 4) During the past 40 years we have made the most progress in the some pathology is found for high-risk individuals every two years were treatment of: to be implemented, current resources could handle the load. A) Tumors in the elderly A) True B) Tumors of childhood B) False C) Colorectal tumors D) Brain tumors 14) An individual’s risk of developing cancer between birth and 20 years of E) Breast tumors age is approximately A) 1 in 500 5) The intervention that would have the most impact on decreasing B) 1 in 1000 mortality from non-small cell lung cancer would be: C) 1 in 5,000 A) Public health programs that decreased the number of teenagers who D) 1 in 10,000 start smoking. E) 1 in 25,000 B) Screening programs using high resolution CT scan of the chest. C) Aggressive surgery for stage I and II lung cancer. 15) In a child with newly diagnosed acute lymphoblastic leukemia, all of D) More extensive use of multi-agent chemotherapy. the following are required/important for therapeutic decisions except E) Use of positron emission scanning to identify surgically curable sub- A) Lumbar puncture clinical disease. B) Chest x-ray C) Testicular biopsy 6) Standard therapy for stage I or II non-small cell lung cancer would be: C) Cytogenetics of leukemic cells A) Surgery followed by post-operative chemotherapy. D) None of the above B) Surgery followed by post-operative radiation. C) Surgery alone. 16) The number of Rhode Island children newly diagnosed with cancer D) Pre-operative chemotherapy followed by surgery. each year is approximately E) Surgery followed by post-operative chemotherapy and radiation. A) 20 B) 40 7) The current standard treatment for unresectable stage III non-small C) 80 cell lung cancer in patients with good performance status is: D) 160 A) Chemotherapy alone. E) 250 B) Radiation alone. C) Sequential chemoradiotherapy (chemotherapy followed by radiation). 17) The most common primary brain tumor is: D) Concurrent chemoradiotherapy (chemotherapy and radiation given A) Glioma at the same time). B) Pituitary adenoma E) Twice per day radiation therapy. C) Meningioma D) CNS lymphoma 8) Which women are not candidates for partial mastectomy? E) Medulloblastoma A) Patients who live too far from a radiation facility to receive 6 weeks of 18) The chance a meningioma recurs within 10 years of complete surgical breast radiation resection is: B) Pregnant patients A) Less than 5% C) Patients with connective tissue disorder B) Less than 20% D) Patients with multicentric cancer in the breast C) 50% E) All of the above D) Greater than 60% E) 80% 9) Which statement is true? A) There is no significant difference in outcome between 5 years of 19) The most common source of brain metastases is: tamoxifen therapy and two years. A) Melanoma B) Chemotherapy is associated with a large increased risk of secondary B) Breast cancer leukemia. C) Lung cancer C) Capecitabine does not include alopecia as a side effect. D) Lymphoma D) Bisphosphonates provide no benefit in patients with bone metasis. E) Prostate cancer E) No statement is true. 29 Vol. 85 No. 1 January 2002 Prevention and Treatment Recommendations for Community Acquired Pneumonia Deidre Spellisey Gifford, MD, MPH

Each year in the United States there are an estimated emphasizing the opportunity for improvement in this area. two to three million cases of community acquired pneu- Empirical antibiotic therapy based on the most likely caus- monia (CAP), resulting in approximately ten million phy- ative organism should begin as soon as the diagnosis of CAP sician visits, 500,000 hospitalizations, and 45,000 deaths.1 is made, and should not be delayed pending results of blood Pneumonia is the sixth most common cause of death in the culture, sputum gram stain, or any other microbiological stud- US, and the overall rate of death due to pneumonia (to- ies. For most patients, this will require that the initial antibi- gether with influenza) is rising. Appropriate and timely otic dose be given in the emergency department rather than antibiotic therapy for CAP has been shown to decrease mor- waiting until the patient is transferred to a medical ward or tality rates. Three recently published guidelines have evalu- intensive care unit. ated the available evidence on the appropriate treatment of CAP.2-4 Below is a summary of some of their treat- ment recommendations. The reader is re- ferred to the specific guidelines for a discussion of the evidence supporting the recommendations, and for additional detail on treating CAP in patients with specific complications.

PREVENTION OF PNEUMOCOCCAL PNEUMONIA All patients 65 years and older who are not allergic to the pneumococcal vaccine and who have not received the vaccine (or re- ceived it more than five years ago, if prior to age 65), should be offered the pneumococ- cal vaccine. If a hospitalized vulnerable eld- erly patient is eligible and not up-to-date with the pneumococcal and influenza vac- cines, then the patient should receive the vac- cines while hospitalized.

PROMPT INITIATION OF THERAPY For patients requiring hospitalization, the importance of prompt initiation of em- pirical antibiotic therapy cannot be over-em- phasized. In an analysis of 14,000 patients hospitalized for pneumonia, initiation of an- tibiotic therapy within eight hours of hospi- tal admission was associated with a 15% reduction in 30 day mortality.5 However, in this national study, nearly one quarter of pa- tients received their first dose of antibiotics more than eight hours after hospital arrival, 30 Medicine and Health / Rhode Island ETIOLOGY AND ANTIBIOTIC SELECTION 5. Meehan, TP, Fine MF, Krumholz HM, et al. Quality of care, In nearly half of cases, the etiologic agent of CAP is process and outcomes in elderly patients with pneumonia. never identified. Epidemiological studies have shown that JAMA 1997;278:2080-4. the causative agents of CAP differ depending on the site of Deidre Spellisey Gifford, MD, MPH, is Clinical Coordi- acquisition, the severity of the infection and the nator at RIQP and Clinical Assistant Professor of Obstetrics/ comorbidities and immune status of the patient.2-4 Table 1 Gynecology, Brown Medical School. summarizes the recommended initial antibiotic therapy for various patient characteristics, based on the guidelines of ORRESPONDENCE the American Thoracic Society.4 Advanced generation C : Deidre Spellisey Gifford, MD, MPH macrolides are recommended for uncomplicated outpatient Phone: (401) 528-3255 CAP, because of H. Influenzae resistance to erythromycin Fax: (401) 528-3210 and the improved side-effect profile of the advanced gen- e-mail: [email protected] eration drugs. Initial recommended therapies for inpatients 6SOW-RI-PNEU-02-01 and outpatients, with and without additional risk factors are described Table 1. The analyses upon which this publication is based were performed un- der Contract Number 500-99-RI02, entitled “Utilization and Quality REFERENCES Control Peer Review Organization for the State of Rhode Island,” spon- 1. Centers for Disease Control and Prevention. Premature sored by the Health Care Financing Administration, Department of deaths, monthly mortality and monthly physician contacts: Health and Human Services. The content of this publication does not United States. MMWR 1997;46:556. necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial prod- 2. Bartlett JF, Dowell SF, Mandell LA, et al. Practice gGuidelines ucts, or organizations imply endorsement by the U.S. Government. for the management of community-acquired pPneumonia The author assumes full responsibility for the accuracy and com- in adults. Guidelines from the Infectious Diseases Society of pleteness of the ideas presented. This article is a direct result of the America. Clin Infect Dis 2000;31:347-82. Health Care Quality Improvement Program initiated by the Health Care 3. Mandell LA, Marrie TJ, Grossman RF, et al. Canadian guide- Financing Administration, which has encouraged identification of quality lines for the initial management of community-acquired improvement projects derived from analysis of patterns of care, and there- pneumonia: An evidence-based update by the Canadian In- fore required no special funding on the part of this Contractor. Ideas fectious Diseases Society and the Canadian Thoracic Soci- and contributions to the author concerning experience in engaging with issues presented are welcomed. ety. Clin Infect Dis 2000;31:383-421. 4. American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2001;163:1730-54.

Information for Contributors, Medicine & Health/Rhode Island

Medicine & Health/Rhode Island is a peer-reviewed pub- ADVANCES IN LABORATORY MEDICINE lication, listed in the Index Medicus. We welcome submis- Authors discuss a new laboratory technique. Maximum sions in the following categories. length: 1200 words.

CONTRIBUTIONS MEDICAL MYTHS Contributions report on an issue of interest to clinicians Authors present an iconoclastic, research-based analysis in Rhode Island: new research, treatment options, collabora- of long-held tenets. Maximum length: 1200 words. tive interventions, review of controversies. Maximum length: 2500 words. Maximum number of references: 15. Tables, For the above articles: Please submit 4 hard copies and an charts and figures should be camera-ready. Photographs electronic version (Microsoft Word or Text) with the author’s should be black and white. Slides are not accepted. name, mailing address, phone, fax, e-mail address, and clinical and/or academic positions to the managing editor, Joan CREATIVE CLINICIAN Retsinas, PhD, 344 Taber Avenue, Providence, RI 02906. Clinicians are invited to describe cases that defy text- phone: 272-0422; fax: 272-4946; e-mail: [email protected] book analysis. Maximum length: 1200 words. Maximum number of references: 6. Photographs, charts and figures IMAGES IN MEDICINE may accompany the case. We encourage submissions from all medical disciplines. Image(s) should capture the essence of how a diagnosis is es- POINT OF VIEW tablished, and include a brief discussion of the disease pro- Readers share their perspective on any issue facing clini- cess. Maximum length: 250 words. The submission should cians (e.g., ethics, health care policy, relationships with pa- include one reference. Please submit the manuscript and one tients). Maximum length: 1200 words. or two cropped 5 by 7 inch prints with the author’s name, degree, institution and e-mail address to: John Pezzullo, MD, ADVANCES IN PHARMACOLOGY Department of Radiology, Rhode Island Hospital, 593 Eddy Authors discuss new treatments. Maximum length: 1200 St., Providence, RI 02903. Please send an electronic version words. of the text to: [email protected]. 31 Vol. 85 No. 1 January 2002 Health by Numbers

Rhode Island Department of Health Patricia A. Nolan, MD, MPH, Director of Health Edited by Jay S. Buechner, PhD  Rhode Island Hispanics Have Mainstream Cancer Rates  John P. Fulton, PhD, and Jay S. Buechner, PhD

The 2000 US Census enumerated more than 85,000 father’s surname from death certificates with cancer as the cause persons in Rhode Island who self-identified as Hispanic, rep- of death for the years 1989-1998 were searched for any of the resenting about 8.5% of the state’s total population and com- 639 names. (Data on father’s surname are not available on prising the state’s largest racial or ethnic minority group. Rhode Island Cancer Registry case reports.) Producing regular health statistics for Hispanics is challenging Synthetic aggregates of Hispanic cancer cases and cancer deaths because ethnicity is difficult to measure in health surveillance were created by adding the additional cases and deaths classified as systems of even the best design. Here we have evaluated the Hispanic on the basis of the surname analysis to those deaths iden- ability of two major surveillance systems, the Rhode Island tified as Hispanic in case reports and on death certificates. These Cancer Registry and the Vital Records death certificate file, to measure cancer morbidity and mortality among resident Hispanics. Methods Because Census Bureau inter-censal estimates of the number of resident Rhode Island Hispanics were inconsistent with counts from the 2000 Census, new inter- censal estimates were constructed for resi- dent Rhode Island Hispanics by year, sex, and age group for the years 1989-1998, using linear interpolation and extrapola- tion from 1990 and 2000 Census counts. Data on resident cancer cases and deaths identified as Hispanic were ex- Figure 1. Number of Diagnosed Cases of Cancer among Hispanic Males, by Year and Source of tracted from Cancer Registry case reports Hispanic Identification, Rhode Island, 1989-1998. and from Vital Records death certificates for the ten years 1989-1998 and aggre- gated by age group, sex, and year of event. Alternative counts of cases and deaths for resident Rhode Island Hispanics were estimated using a validated US Census technique for identifying Hispanics by sur- name.1 For resident males, data on sur- name from cancer case reports and from death certificates with cancer as the cause of death for the years 1989-1998 were searched for any of “639 most frequently occurring heavily Hispanic surnames” identified by the Bureau of the Census. (“Heavily Hispanic” means that 75% or more of the people with a particular sur- name self-identified as Hispanic on the Figure 2. Age-adjusted Cancer Incidence and Mortality Rates per 100,000 Population, Hispanics survey.) For resident females, data on and All Residents, by Sex and Year (Grouped), Rhode Island, 1989-1993 and 1994-1999. 32 Medicine and Health / Rhode Island Discussion This analysis of data on cancer inci- dence and mortality among Hispanic Rhode Island residents supports conclu- sions concerning both patterns of disease and the reliability of the underlying data. The use of an authoritative list of His- panic surnames to augment Hispanic ori- gin information on cancer registry case reports and death certificates approximately doubles the number of cancer cases that are presumably Hispanic in each of the two databases. Thus, these reporting systems are substantially understating the extent of cancer in this population. Figure 3. Anatomic Site of Diagnosed Cases of Cancer among Hispanic Males and among All Based on the rates produced from the Males, Rhode Island, 1994-1998. synthetic aggregates, Hispanic cancer rates estimates were combined with the estimates of the Hispanic popu- are generally similar to statewide cancer rates for all sites. lation of Rhode Island for 1989-1998 to construct age-adjusted The site distribution for cancer incidence among male cancer incidence rates (males only) and age-adjusted cancer mor- Hispanics follows the statewide distribution with two diver- tality rates (males and females). The year 2000 standard U.S. gences worth noting. The observed higher proportions of stom- population was used for age-adjustment. ach and liver cancers may be linked to the dietary patterns and The synthetic aggregates of Hispanic cancer cases were infectious disease patterns (e.g., Hepatitis B) in developing coun- also used to examine the proportion of cancer cases by ana- tries and in immigrants from those countries. The high pro- tomic site, comparing them with similar data for the Rhode portion of leukemias is consistent with a population whose age Island population as a whole. distribution is heavily weighted towards the very young. Healthy People 2010 set a national goal of eliminating Results health disparities, in particular among disadvantaged racial and 2 Over the ten-year period examined, a total of 507 diag- ethnic populations. To support the accomplishment of this nosed cases of cancer were identified among Hispanic males, sweeping goal, public health surveillance data must have accu- identified either from case reports or from the surname analysis. rate and consistent reporting of race and ethnicity. The Rhode Of these, 224 (44.2%) were identified from case reports, and an Island Department of Health has recently revised its policy on additional 283 (55.8%) were identified only by Hispanic sur- the collection of data on race and ethnicity and intends to im- name. By year, aggregation of cases from the two methods more prove the quality of the collected data as the changes in policy 3 than doubled the number of cases originally reported to the are implemented. The findings of this analysis show the clear Cancer Registry as Hispanic in each of the first eight years of need for such quality improvement efforts. observation, and enhanced case counts substantially in 1997 and 1998 as well. (Figure 1) The number of cancer deaths References among Hispanic males and females during this period showed 1. Word DL, Perkins RC. Building a Spanish surname list for the similar enhancements from the surname analysis. 1990s – a new approach to an old problem. Technical Working Figure 2 presents age-adjusted cancer incidence and mor- Paper No. 13. US Census Population Division Working Paper tality rates for resident Rhode Island Hispanic males and age- Series, March 1996. adjusted cancer mortality rates for resident Rhode Island 2. US Department of Health and Human Services. Healthy People 2010: 2nd ed. Understanding and Improving Health and Objec- Hispanic females in 1989-1993 and in 1994-1998, along with tives for Improving Health. (2 vols.) Washington, DC: US Gov- comparable rates for the state as a whole. In all comparisons, ernment Printing Office. November 2000. Hispanics have age-adjusted cancer rates that fall near but be- 3. Buechner J, Brown-Small V. Race, ethnicity, and health: A new low age-adjusted cancer rates for the state as a whole. data policy. Med & Health/RI 2001;84:248-50. The three most frequently occurring cancers by anatomi- cal site during 1994-1998 were the same for Hispanic males John P. Fulton, PhD, is Associate Director, Division of Dis- in Rhode Island as for all males: prostate; lung and bronchus; ease Prevention and Control, Rhode Island Department of Health colon and rectum. (Figure 3) Among other major sites, resi- and Clinical Associate Professor of Community Health, Brown dent Hispanic males were more likely than resident males over- Medical School. all to develop cancers of the stomach and liver and leukemias, Jay Buechner, PhD, is Chief, Office of Health Statistics, Rhode and less likely than resident males overall to develop cancer of Island Department of Health, and Clinical Assistant Professor of lung and bronchus and of the urinary bladder. Patterns for Community Health, Brown Medical School. the period 1989-1993 were similar. 33 Vol. 85 No. 1 January 2002 Rhode Island Department of Health PUBLIC HEALTH BRIEFING Patricia A. Nolan, MD, MPH, Director of Health Edited by John P. Fulton, PhD The Rhode Island Cancer Council Arvin S. Glicksman, MD, and Paul Calabresi, MD

Although Rhode Island’s cancer incidence rate is not recommendation of the NCLAC (Table II, Goal 10).] The above the national average for an aging population in an cooperation and collegiality of the participants in develop- urban industrial state in the Northeast, the number of ing the algorithm for breast care is encouraging and bodes deaths from cancer in Rhode Island exceeds the national well for its incorporation into medical practice in the State. average. Even with the state’s excellent hospitals and edu- Although mammography utilization in Rhode Island is above cational facilities, coupled with a large corps of dedicated the national average, our death rate is 10% above the na- physicians, Rhode Island has a significant cancer problem. tional average. Based on the rule that “all politics is local,” programs to Colorectal cancer is the second leading cause of cancer improve the well being of Rhode Islanders must be local. deaths after lung cancer. Our death rate is 34% higher than The Rhode Island Cancer Council was established to the national average for men and 21% higher for women. encourage cooperative, comprehensive and complementary Although early detection by regular screening can reduce planning among the public, private and volunteer sectors our death rate, fewer than 50% of the population over the of the State by maintaining an integrated information net- age of 50 have ever been screened for colorectal cancer. We work of resources for all to use. The Council became op- recently surveyed two groups: the sixty-two gastroenterolo- erational in May 1999; the Governor, the Senate Majority gists and surgeons who perform colonoscopy, and over 120 Leader, and the Speaker of the House of Representatives primary care physicians. The data point to a good deal of appointed the nine members to the Board, chosen for their uniformity on screening guidelines across the specialists and leadership in oncology and in the community (Table I). the primary care physicians. [See “Colorectal Screening,” [The national plan, “Conquering Cancer,” calls for the this issue.] establishment of comprehensive State-based cancer action The Council has embarked upon a broad public and plans in collaboration with all experts in the region - See professional education program. To reduce cancer deaths “Cancer in the New Millenium,” this issue). in Rhode Island, we must remove barriers to Rhode Island’s In conjunction with the Department of Health, the state-of-the-art cancer programs. The Council maintains Rhode Island Cancer Council has the responsibility to keep an integrated information network of resources. Our the Cancer Plan for the State of Rhode Island current and website, www.ricancercouncil.org, provides cancer-related broadly applicable for all residents. information for Rhode Island, much of which is not avail- As one of our first tasks we re-examined the treatment able anywhere else (Table II). algorithm for breast cancer. A panel of experts addressed Each month the Rhode Island Cancer Council provides the issue of screening and diagnosis. Another panel devel- a health column for an e-magazine, www.findri.com. Short- oped treatment guidelines. A third panel is addressing sup- ened versions of these columns are distributed to the portive care and quality of life. [This responds to the churches, synagogues and mosques in Rhode Island for in- clusion in their monthly bulletins. TABLE I The Rhode Island Cancer Members of The Rhode Island Cancer Council Council maintains a Cancer Fo- (for bioosketches, see www.ricancercouncil.org) rum (message board) on the Internet. In addition, the Paul Calabresi, MD, MACP - Medical Oncologist, Chairman Councial receives inquiries by tele- The Honorable J. Joseph Garrahy - Former Governor of Rhode Island phone. Frequently people ask for Arvin S. Glicksman, MD, FACR - Radiation Oncologist, Executive Director assistance with the cost of medica- Laura Hilderley, RN, MS - Nurse Oncologist tions. We relay information on Louis Luzzi, PhD - Dean, School of Pharmacy, University of Rhode Island the Drug Assistance Program at the Marlene McCarthy - Breast Cancer Activist University of Rhode Island and state programs. When appropri- Charles McDonald, MD - Dermatologist ate we recommend clinical trials, Patricia M. Nolan, MD, MPH - Director, Department of Health referring callers back to their The Honorable George Panichas - Former Member of the State Legislature, Treasurer oncologists to discuss the appro- 34 Medicine and Health / Rhode Island Lymphoma Society and The Rhode Island Breast Cancer TABLE II Coalition. The Council will repeat this program in differ- Cancer Resources in Rhode Island ent parts of the State. (available on www.ricancercouncil.org) Last year the Council renewed the Waterman Dialogue lectureships in conjunction with the American Cancer So- Oncologists: ciety. Dr. Judah Folkman and Dr. James F. Holland spoke Subspecialties Geographic Area on “Cancer Treatment for the 21st Century.” The Council will continue the Waterman Dialogue, bringing experts to Mammography Centers: Rhode Island. The Council has also sponsored lectures by Geographic Area Handicap Accessibility visiting professors on bladder cancer, prostate and other Hours of Operation urological cancers, and breast cancer. Languages Spoken The Rhode Island Cancer Council encourages new re- Support Groups: search programs. Last year the newly-formed Transition Disease Specific Support Grant Program, awarded four grants (each approxi- Geographic Area mately $15,000) to individuals who were in the process of Clinical Trials: applying for funds from national agencies but required sup- Disease Site port to enhance their competitiveness in the national pool. Stage of Disease Three of the four were successful for a total of approximately Principal Investigator $6,000,000 in research funds coming into Rhode Island. Contact Information The fourth grant is under review. This year the Council Smoking Cessation Programs: hopes again to fund four or five promising projects. Geographic Area Last year the Council held a roundtable on “Women’s Issues in Cancer,” bringing together twelve community lead- priateness of their participation. Health insurers in Rhode ers in this field. Copies of this report are available from the Island cover the costs associated with Phase II, III, and IV Council office. clinical trials, as well as the costs of drugs used off-label. The NCLAC report stresses the importance of imple- The Rhode Island Cancer Council has developed free menting a National Cancer Prevention Initiative that elimi- printed “Fact Sheets” on the most prevalent cancers and nates tobacco use, increases physical activity, and improves brochures on screening guidelines. (Table III) nutrition (Table II, Goal 12). The Rhode Island Cancer Following up on Resolution 2000-H-6942 of the Council has been an active participant in the tobacco wars House of Representatives, the Rhode Island Cancer Coun- as a member of the Rhode Island Tobacco Leadership Coa- cil has contacted every city and town in Rhode Island, mak- ing our services available to develop cancer awareness TABLE III programs. To date, Pawtucket, Foster, Warren, Warwick, Cranston, Tiverton, and Cumberland have responded; pro- Cancer Fact Sheets and Resource Brochures gram development is in progress. (available on www.ricancercouncil.org and in The Council has produced thirty-second information printed form) spots, shown on cable television, as well as on the wide screen in the Food Court at the Warwick Mall. The Coun- Cancer Fact Sheets: cil broadcasts radio spots on most of the popular stations. Bladder Cancer Frequently, the Council places cancer-related announce- Breast Cancer ments in local newspapers. Cervical Cancer Initially the Legislature asked the Council to catalogue Chemotherapy all laws and resolutions in Rhode Island relating to the de- Colorectal Cancer Head & Neck Cancer tection and/or treatment of cancer. We have completed Hodgkinís Disease this task. The Secretary of State now has a new category Lung Cancer “cancer.” Ovarian Cancer Last fall the Council sponsored a public information Melanoma forum, “Successful Survivorship After Cancer.” Dr. Julia Prostate Cancer Rowland, Director of the Office of Survivorship at the Stomach (Gastric) Cancer National Cancer Institute, was the keynote speaker. Over Testicular Cancer 150 individuals attended. Another public forum in con- Resource Brochures: junction with the Oncology Nurses Society on Quality of Breast Prostheses Life issues associated with end-of-life was held in spring of Cancer Screening Guidelines 2001, again drawing an audience of over 150. In the fall, a Smoking Cessation Programs public forum on complementary care was held, a joint ef- Support Groups Wigs fort with the Rhode Island Chapter of the Leukemia and 35 Vol. 85 No. 1 January 2002 lition, a group representing essentially all of the organiza- women with positive mammograms. This includes a bi- tions and programs working to reduce tobacco use in the opsy of the suspicious area of the breast and a pathological State. The Coalition will launch a major advertising cam- analysis leading to a diagnosis. If cancer is detected, a net- paign to reduce tobacco use in Rhode Island. work of providers is prevailed upon so that necessary sur- The Rhode Island Cancer Council has undertaken a gery, medical oncology, radiation oncology, and psychosocial study of tobacco use on the campuses of the eleven colleges support are available. This program is not available to and universities in the State. We developed a question- women below the age of 50 under the CDC grant. How- naire based, in large part, on the published Centers for ever, the State Legislature enacted legislation last year that Disease Control and Prevention (CDC) questionnaire, established a comparable program for women between the modified with questions concerning readiness to quit for ages 40 to 49. The State Health Department uses the exist- current smokers. In the first year, this was administered to ing network by extending the age eligibility. The Rhode approximately 100 freshmen at each campus. Students have Island Cancer Council funds this program under the legis- also been offered the opportunity to participate in focus lation as passed. In the first six months of the fiscal year, groups concerning tobacco use. Referrals to smoking ces- 154 women have been screened. Since this program is now sation programs are available. Of particular importance established by law, it will continue to provide services for has been information from Focus Groups held on three women between the ages of 40 and 49 in future years. campuses last year, giving us unusual insights to students’ Since its inception the Council has emphasized pro- attitudes and influences. The questionnaire to the second viding information in a timely and usable way to the pub- group of freshmen have been distributed on the various lic. It has developed programs with the assistance of a broad campuses throughout the State and some of this year’s data array of recognized leaders of oncology, and it has found have already come in for collation. strong support from many civic-minded public leaders with- This population is the fastest growing tobacco users. out whom we could not have moved so rapidly to establish It had been generally accepted that children who did not our programs. We believe that in this environment we can start smoking by the age of 18 would probably never be achieve our goal to diminish the burden of cancer in Rhode addicted to tobacco; however, since the tobacco settlement, Island and improve cancer literacy throughout the State. tobacco companies have targeted their media campaigns The Council can also serve as a model for other community on 18 year-olds. Accordingly, we are seeing a rise in smok- cancer programs as envisioned by the National Cancer Leg- ing among college students. Our program is designed to islation Advisory Committee. understand how students balance the pressures from the tobacco industry and from the various public health anti- Arvin S. Glicksman, MD, is Executive Director, Rhode tobacco campaigns. This program will yield information Island Cancer Council. concerning attitude, about pressures coming from multiple Paul Calabresi, MD, is Chairman, Rhode Island Cancer sources. Importantly, the Behavioral Study Group of The Council. Miriam Hospital/Brown University provides an interven- tion component. CORRESPONDENCE: “Conquering Cancer” urges a National Cancer Screen- Arvin S. Glicksman, MD ing Initiative to increase substantially the early detection of The Rhode Island Cancer Council cancer (Goal 9). The State of Rhode Island has been in- 249 Roosevelt Ave. volved in screening programs for some time and has pub- Pawtucket, RI 02850 lished a “Guide to Cancer Screening.” In addition the phone: (401) 728-4800 Council has initiated a mammography program for early fax: (401) 728-4816 detection of breast cancer. e-mail:[email protected] Annual screening mammograms are provided to all in- sured women in Rhode Island and are covered by Medi- care for women over 65. For women without health insurance, the Depart- ment of Health has received funds from the Centers for Disease Control and Pre- vention to support mammograms for underinsured and uninsured women be- tween the ages of 50 and 64. The pro- gram, working through the Community Health Centers, provides for outreach to the at-risk population. In addition, the program provides medical attention for

36 Medicine and Health / Rhode Island Judicial Diagnosis What Now?! The OIG Worries About Physician Billing, Reflected In the 2002 Work Plan Lawrence W. Vernaglia, JD, MPH

The Bush administration has wavered in its reaction * Billing for Residents’ Services. to the health care enforcement efforts and bureaucracies of A related investigation will focus on whether hospitals the Clinton era. Former Wisconsin Republican Governor are properly using their interns’ and residents’ physician Tommy Thompson, the new Secretary of the Department identification numbers (PIN) when billing Medicare. Resi- of Health and Human Services (HHS), appears torn be- dents may bill Medicare only when they are “moonlight- tween two desires: to loosen-up health care red tape, and ing.” The OIG’s Work Plan defines “moonlighting” as to guard against those who abuse or neglect the elderly ben- “providing medical treatment, other than in the resident’s eficiaries of government health programs. For example, in field of study, in an outpatient clinic or an emergency room.” March 2001, Thompson pledged, “I am fairly certain, with- It is curious that the OIG omitted resident services in a out saying for sure, there will be some modifications to physician’s office as “moonlighting” for reimbursement pur- simplify and to lessen the financial burden” of compliance poses. with the mammoth Clintonian health information privacy regulations. However, two weeks later he allowed the regu- * Physician Evaluation and Management Codes. lations to roll out (in Thompson’s words, “begin the pro- The proper selection of evaluation and management cess of implementing”) on schedule, and without a single (E&M) codes for patient encounters continues to be a bug- edit. Observers await promised interpretive guidelines that bear for a great many physicians. The American Medical will mitigate some of the more onerous requirements. Association (AMA) and the Centers for Medicare and Med- On October 1, 2001, the HHS Office of the Inspec- icaid Services (CMS, formerly HCFA) have sparred over tor General (OIG), under its new boss, Janet Rehnquist, revisions to the E&M coding guidelines for a decade. Cur- daughter of Chief Justice William Rehnquist, released its rently, physicians may use either the 1995 or 1997 coding Work Plan for 2002.1 The Work Plan provides insights guidelines in selecting codes. Consequently, it is extremely into the OIG’s planned research and investigations for the difficult for a physician to choose a particular E&M code coming year. This Work Plan does not depart from past level with any certainty - unless the physician is able to bill policing policies of the physician community, as some had based on the amount of time spent with the patient. De- hoped. This essay will outline some of the OIG’s plans for spite this chaotic coding environment, the OIG plans to review of physician billing, patient care, and business prac- “determine whether physicians correctly coded evaluation tices, as reflected in the 2002 Work Plan, and will offer and management services in physician offices and effectively predictions for the government’s enforcement interests. used documentation guidelines.” They will also evaluate The OIG’s large-scale physician investigations of the whether the carriers are doing enough to hunt down im- 1990s related to billing by teaching physicians, interns and proper E&M coding, a clear signal to the carriers to step-up residents, and all doctors providing evaluation and man- their E&M enforcement efforts. agement services. These investigations generated fear and confusion in the industry, particularly because the under- * Services and Supplies Incident to Physicians’ Services. lying requirements were vague, inconsistently applied, and A similarly confusing billing area relates to physician difficult to translate into clinical practice. The OIG now “incident-to” billing. Under these rules, physicians may bill promises new investigations into these same issues. for the services provided by other professionals, such as nurses, technicians, and therapists, as incident-to their pro- *Physicians at Teaching Hospitals fessional services. Incident-to services must generally be The OIG plans an initiative “to verify compliance with provided by an employee of the physician and under the Medicare rules governing payment for physician services physician’s “direct supervision.” There remains a level of provided in the teaching hospital setting and to ensure that uncertainty as to what “direct supervision” means, and how claims accurately reflect the level of service provided to pa- and when to submit a bill for incident-to services. More- tients.” Fortunately, the requirements for teaching physi- over, there is a proposal to do away with the “employee” cian billing have been made clearer since 1995. requirement that should be in effect by January 1, 2002. Nevertheless, the OIG plans to investigate physician com- 37 Vol. 85 No. 1 January 2002 pliance in this area. doctors by such an entity - then the physician should not The OIG plans to investigate two customary relation- reassign payment rights to the company. ships between physicians: consults and emergency room staffing arrangements. * Advance Beneficiary Notices. The government continues its quest to be sure that * Consultations. Medicare providers and suppliers offer patients advance writ- This study promises to review whether physician con- ten notice (ABNs) prior to a service that may not be medi- sultations are properly billed. Under Medicare policy, con- cally necessary, and agree to submit a “demand bill” to sultations are generally reimbursable if made at the request Medicare if the patient so desires, or else be unable to bill of the patient’s attending physician, the consulting physi- the patient privately. The OIG will look into whether phy- cian reviews and examines the patient’s condition, and the sicians are following the ABN rules, “especially with respect report of the consult is made part of the patient’s perma- to noncovered laboratory service.” nent medical record. [Medicare Carriers Manual § 2020.C.] The OIG did not indicate in the Work Plan what vulner- Finally, three other procedure-specific investigations are abilities exist in the consulting relationship. However, in planned regarding inpatient dialysis services, bone density the past several years, the government has loosened restric- screening, and preventative services such as annual screen- tions on billing for consultations. It will be informative if ing mammography for all women aged 40 and over; screen- the OIG believes that these policy changes have produced ing pap smear and pelvic exams every 3 years; colorectal undesirable results. screening; and bone mass measurements to identify bone mass, detect bone loss, or determine bone quality, all of * Reassignment of Benefits. which were made reimbursable by the Balanced Budget Act The OIG is interested in investigating how physician of 1997. staffing or practice management companies man hospital These proposed investigations are varied, but one fea- emergency rooms. A potential vulnerability is in the reas- ture is clear: the OIG plans to continue reviewing some of signment of Medicare payment from the physician to the the billing rules that are the most complex and confusing to staffing company. If the company does not employ the physicians. Whether these studies result in recommenda- physician - and state law may prohibit the employment of tions to clarify the rules, or prosecutions of more doctors

Rhode Island Department of Health Vital Statistics Patricia A. Nolan, MD, MPH, Director of Health Edited by Roberta A. Chevoya

Underlying Reporting Period Rhode Island Monthly Cause of Death January 12 Months Ending with January 2001 Vital Statistics Report 2001 Number (a) Number (a) Rates (b) YPLL (c) Diseases of the Heart 291 3,063 309.9 4,109.0 ** Provisional Occurrence Data Malignant Neoplasms 214 2,401 242.9 6,495.0 * from the Cerebrovascular Diseases 58 503 50.9 770.0 Injuries (Accident/Suicide/Homicide) 24 364 36.8 6,792.5 ** Division of Vital Records COPD 53 481 48.7 372.5

Reporting Period Vital Events (a) Cause of death statistics were derived from the July 12 Months Ending with underlying cause of death reported by physicians on 2001 July 2001 death certificates. Number Number Rates Live Births 1142 13,428 13.6* (b) Rates per 100,000 estimated population of Deaths 775 10,199 10.3* 988,480 Infant Deaths (4) (98) 7.3# Neonatal deaths (4) (84) 6.3# (c) Years of Potential Life Lost (YPLL) Marriages 929 8,557 8.7* Note: Totals represent vital events which occurred in Rhode Is- Divorces 246 3,266 3.3* land for the reporting periods listed above. Monthly provisional Induced Terminations 451 5,488 408.7# totals should be analyzed with caution because the numbers Spontaneous Fetal Deaths 90 995 74.1# may be small and subject to seasonal variation. Under 20 weeks gestation (81) (919) 68.4# 20+ weeks gestation (9) (76) 5.7# * Rates per 1,000 estimated population # Rates per 1,000 live births ** Excludes two deaths of unknown age. 38 Medicine and Health / Rhode Island for their inability to navigate these regulatory mazes, re- Lawrence W. Vernaglia, JD, MPH, is a Partner in the health mains to be seen. law practice group, Hinckley, Allen & Snyder LLP, and a mem- ber of the editorial board of Medicine & Health/Rhode Island. ACKNOWLEDGEMENT The author would like to thank his partner at CORRESPONDENCE Hinckley, Allen & Snyder, Bruce Goodman, for his review Lawrence W. Vernaglia, JD, MPH of this essay. Hinkley, Allen & Snyder LLP 1500 Fleet Center REFERENCES Providence, RI 02903 1. http://www.hhs.gov/oig/wrkpln/2002/Work_Plan_2002.htm. phone: (401) 274-2000, x4731 fax: (401) 277-9600 e-mail: [email protected]

– A Physician’s Lexicon –

Medical Lexicon: Nausea and Vomiting

“Everything is gratuitous, the garden, this city and my- The Latin, vomere, is related to and originally derived self. When you suddenly realize it, it makes you feel sick from an earlier Greek word, emetos, also defining the act of and everything begins to drift. . . that’s nausea.” vomiting. This Greek word has produced a number of di- Jean Paul Sartre wrote this fragment of autobiographic rect English language offspring of its own, including emesis self-appraisal in 1938, a part of his larger commentary called [the act of vomiting], hematemesis [blood-tinged vomitus], “Nausea.” melanemesis [black-colored vomitus], copremesis [fecal vom- Nausea - and its intimate companion, vomiting - hark- iting] and emetine, the principal alkaloid of ipecac, a strong ens back to an earlier Greek word, nautio, meaning sea- emetic. sickness, and is etymoglocially related to the Latin, nauticus, And then there is Nux Vomica, a prominent member meaning from the sea, and its many English language de- of the 19th Century physician’s pharmacopeia. Nux Vomica rivatives, including nautical, nautilus [a genus of mullusk], [from the Latin, literally meaning the nut that poisons] is navy, navigate, as well as argonaut, aeronaut, cosmonaut extracted from the seed of an East Indian tree containing and astronaut [all of whom, in principle at least, are sub- strychnine. [The vomica, in this case, refers back to the ject to seasickness]. There also was a prominent character poisonous quality of the seed extract since nux vomica gen- in ancient Greek legend called Nausicaa. She was the daugh- erally does not cause vomiting. It was typically prescribed ter of Alcinous, king of the Pheaecians. Her name, liter- in the form of a weak tincture which allegedly stimulated ally, means burner of ships. the cardiac and respiratory systems.] Dictionaries and high school English instructors in- The agent, strychnine, was first isolated from the plant sist that nausea, nauseous and nauseated are not inter- Strychnos ignatii in 1818 by the French chemist, Pelletier. changeable. Nausea defines the clinical state of queeziness Strychnos, in Greek, meant deadly nightshade and may and vertigo; nauseous defines those chemical or physical have been derived from an earlier Greek word, trychno, states which cause nausea; and to be nauseated is to be a meaning a destroying agent. victim of nausea. Vomiting, the inseparable partner of nausea, comes – Stanley M. Aronson, MD, MPH from the Latin, vomere, meaning to throw up or, in an earlier meaning, to ulcerate or poison. A vomitory is any agent which causes vomiting and vomitus is the term to describe that which is vomited. The Latin word, vomer, defines a plowshare, namely, an agricultural tool which throws up the soil. And the bone in the nasal septum is called vomer because of its resemblance to a plow. [Sud- den blows, incidentally, to the facial vomer are known to cause acute nausea and vomiting.]

39 Vol. 85 No. 1 January 2002

THE RHODE ISLAND MEDICAL JOURNAL The Official Organ of the Rhode Island Medical Society Issued Monthly under the direction of the Publications Committee

VOLUME 1 PER YEAR $2.00 NUMBER 1 PROVIDENCE, R.I., JANUAR Y, 1917 SINGLE COPY, 25 CENTS NINETY YEARS AGO TWENTY FIVE YEARS AGO ANUARY ANUARY

[J , 1912] [J , 1977]

Among the obituaries was one for Oliver Henry Paul B. Metcalf, MD, FACS, in “Perspectives on Hos- Arnold, born in Coventry, Rhode Island. Dr. Arnold had pitalization,” called for “an objective, reproducible, widely received his AB from Brown (’65), his MD from Harvard applicable means of measuring quality of care.” In particu- (’67), his AM from Brown (’68). A member of the Ameri- lar he cited the shorfall of ALOS (average length of stay) as can Institute of Homeopathy, he practiced in Providence the overall barometer. The ALOS didn’t include transfers, and Pawtucket. “He was interested in the biological and hospital size, or patient’s status. The ALOS, though, was comparative anatomy departments at Brown University and over-emphasized as one solution to reducing costs. left a large part of his property for their support.” [The W.E. Lockhart, Jr. MD, FACA, who practiced in Al- Arnold Laboratory at Brown was named in his memory.] pine, Texas, near Big Bend National Park, contributed D.L. Richardson, MD, the Superintendent of the City “Treatment of snakebite.” An accompanying editorial urged Hospital at Providence, contributed “Laryngeal Stenosis fol- physicians to recognize the symptoms. lowing Diphtheria.” The condition developed in 1-3% of Gerald E. Meyer, PharmD, Louis P. Jeffrey, MS, George cases. “The common impression that intubation, particu- K. Boyd, MD, Charles D. Mahoney, MD, and Philip N. larly if roughly performed, is responsible for the condition Johnson, PhD, contributed “Theophylline derivatives: A is erroneous. It occurred as frequently before O’Dwyer Current review.” They explained, “With improved under- made intubation practicable, and as frequently now in coun- standing, theophylline preparations can be more judiciously tries where tracheotomy is more general than intubation.” utilized.” At the Providence City Hospital, Dr. Richardson opted to An editorial, “Lifestyle and Health,” highlighted the gave the larynx a rest by tracheotomy and removal of la- shifting role of the patient. “For centuries it has been the ryngeal tube. He described the cases of 3 young children. patient who has been the supplicant, asking the physician Dr. Charles V. Chapin, in “Health of Providence,” re- to heal wounds, restore energies, or even pend off death. ported 255 deaths for October 1911, or 12.95 per 100,000 Now conversely, in the face of escalating health care costs, it (based on an estimated population of 231,848). This was may well be the time for the physician to enlist the help of “the lowest death rate ever recorded for October.” his patients in order to balance our books.” The editorial November’s rate was higher {276 deaths, a rate of 14.46), cited the “self-induced ailments,” like emphysema, cirrho- the same as for November 1908, but lower than average. sis of the liver, peptic ulcer, and hypertension. Diphtheria was more prevalent; scarlet fever, less. FIFTY YEARS AGO [JANUARY, 1952]

Lawrence A. Senseman, MD, contributed, “Who Sees the Psychiatrist?” He found encouraging “this new accceptance of the psychiatrist by his fellow practitioners and their acceptance of the advice and opinion regarding the emotional aspects of the patient’s illness.” To answer the ques- tion of the title, he surveyed 250 of his consecutive new patients. Roughly half (52%) were women, 60% were be- tween 21 years and 50 years of age; 66% had functional prob- lems; 27% had neurological problems. Dr. Senseman routinely gave complete physical exams (“as much a part of the psychiatrist’s armamentarium as it is for the internist...”) An editorial, “Progressive Health Education,” praised the City of Providence for issuing 16-page Health Record booklets to parents of each newborn child. 40 Medicine and Health / Rhode Island Quality is Worth More

ith important purchases, the lowest price isn’t always the W best buy. Quality is more critical in the purchase of a home, car, medical equipment and that all-important purchase: medical malpractice insurance. With the future of your practice and your reputation on-the-line you can’t afford second best.

Take a look at ProMutual Group: • The largest provider of medical malpractice insurance in New England. • Over 25 years experience. • Insures more than 12,000 healthcare professionals. • Financial strength that has earned us an A- (Excellent) rating from A.M. Best, the nation’s leading independent insurance rating organization. • Over $1.3 billion in total assets with $398 million in surplus.* • Outstanding risk management service from the largest staff in New England. • Experienced claim professionals close over 60% of claims without payment and have a 95% trial win-ratio.*

Isn’t it time you got the best protection from one of the largest providers of medical malpractice insurance in New England? Call or visit our web site today. www.promutualgroup.com

101 Arch Street, Boston, Massachusetts 02110 888-776-6888 www.promutualgroup.com * As reported in our 2000 Annual Report. Connecticut • Maine • Massachusetts • New Hampshire • New Jersey • Rhode Island • Vermont Not all products are available in all states.

ProMutual Group Charter Agents:

Sharon Connolly John H. Lathrop James L. Mastors Anthony Paolino, Jr. John Tickner Starkweather & Shepley Lathrop Ins. Agency Mastors & Servant Paolino Ins. Agency Babcock & Helliwell East Providence, RI Westerly, RI East Greenwich, RI Providence, RI Wakefield, RI Phone: 401-435-3600 Phone: 888-596-2530 Phone: 800-335-5701 Phone: 401-421-2588 Phone: 401-782-1800

41 Vol. 85 No. 1 January 2002 Epstein, Alan 354 O’Neill, Robert T. 79 2001 Index Feit, Lloyd R. 161 Panarace, Jeanne 304 Author Index Fernandez, Jocelyn S. 57 Panter, Kip 128 Fine, Michael 83,189 Papudesu, Bhagya 89 Adrien, Arielle 354 Fletcher, James 117 Parik Joel T. 353 Akelman, Edward 117 Friedman, Joseph H. 2,34,74,106,146,186,222, Park, Jennifer 304 Akinsete, Omobosola 355 254,274,286,314,350,386 Parker, Annie Lin 369 Aronson, Stanley M. 2,34,75,107,147,187, Fulton, John P. 100,215,245,277,307,343,376 Patil, Sufala 173 219,223,251,255,269,283, Ganim, Marie 192 Perry, Donald K. 26 287,310,315,346,351,382, Geffroy, Michael 142 Pezzullo, John A. 201 387,414 Gibson, Sharon 403 Phillips, Katharine 292 Austin, Paul W. 401 Gifford, David R. 22 Plevyak, Michael P. 148,165 Bandy, Utpala 24,178 Gifford, Deidre 136 Posteraro, Anthony F. III 19 Barbour, Marilyn M. 55 Gilbert, Eileen [abs] 353 Quirk, Catherine M. 296 Barcohana, Yusef 329 Giuliano, Peter 338 Regan, Laura 292,416 Barry, Patrick C. 344 Gleason, Sarah 309 Retsinas, Joan 30,72,104,144,182,220,252, Bert, Alfred A. 332,336 Gold, Richard L. 415 284,312,348,384,420 Bertrand, Thomas 178 Goldberg, Arnold (letter) 28 Robinson-Bostom, Leslie 232,416 Bevivino, Jack 120 Gordon, Paul C. 44 Rochefort, David A. 365 Blake, Douglas 117,119 Grimm, E. Paul 344 Rogowski, Amy 241 Bledsoe, Thomas A. 279 Hamel, David 304 Rubin, Lewis P. 148,152 Boni, Cathy E. 199 Hamolsky, Milton W. 269 Ryan, Colleen 376 Brown-Small, Vania 248 Harrington, Colin 207 Sadaniantz, Ara 37 Browning, Richard A. 316,317,327 Heckel, Mark C. 353 Saddler, Kirk D. 232 Buczko, George B. 321 Hennessey, James V. 353 Safran, Howard 204 Buechner, Jay S. 67,176,248,341,374,412 Hesser, Jana E. 98,275,376 Saritelli, Robert 15,379 Burchard, Kenneth W. 264 Heru, Alison M. 76 Scheiner, Jac D. 132 Burgess, Frederick W. 323,327 Kahn, Charles 204 Schiffman, Fred 352,354 Buxton, Alfred E. 58 Kesan, Sree H. 267 Sehl, Mary E. 360 Buyse, Marylou 21 Kerr, Philip E. 228,294 Shah, Samir A. 88 Cahill, John D. 16 Kim, Hanna 304 Sharaf, Barry L. 353 Cain, Rachel 138 Kirk, Malcolm M. 58 Shearer, Douglas 50 Caldamone, Anthony A. 155 Koff, John [abs]353 Shemin, Douglas 352 Carr, Stephen R. 148,165 Kohn, Robert 92 Shepardson, Susan 140 Chang, Howard 274 Korr, Kenneth S. 36 Sherman, Charles B. 214,353 Chen, James Y. 415 Kottilil, Shyam 89 Shetty-Alva, Neetha 63 Chevoya, Roberta 20,69,102,143,175,219, Koutkia, Polyxeni 204 Siddiq, Farjaad M. 155 250,282,308,346,378,418 Krupp, Brandon H. 218 Simon, Peter R. 138 Chiarelli, Tanya G. 288 Kurdous, Antioan 299 Singer, David 389 Chougale, Prakash 50 Kurkchubasche, Alret G. 159 Smith J.D. 355 Christian, Fredric V. 70 Lapidus, Candace S. 294 Smith, Stephen R. 256,260 Churnick, Donald 304 Lee, Sung-Hee R. 329 Sollito, Russell 200 Colangelo, Sara 304 Lemay, Virginia 241 Spangenberger, Anthony 128 Coldiron, John C. 356 Leongardt, Dmitriy 354 Spencer, Patricia 338 Combs, Walter S. Jr. 178 Levinson, Paul D. 81 Srinivas, V.S. 50 Cooper, Tara A. 24 Lin, Chyi Her 260 Stein, Nancy 406 Coppola, Joyce 267 Lodhavia, Parag J. 88 Stone, V.E. 355 Crausman, Robert S. 267,355 Luks, François I. 148,169 Sullivan, Robert J. 269 Cross, Jason 209 Mainiero, Martha B. (letter) 28 Sullivan, Patrick M. 108,110,117,388,389,392 Cunanan, Manuel 134 Maslow, Andrew 332,336 Tattini, Chad D. 392 Davis, Kala 355 Maxim, Raymond 65,96,174,302,410 Teno, Joan M. 195 Deary, Nikki Samaras 269 Mayo-Smith, William W. 19 Tinajero, Alvaro M. 212,275 DePalo, Vera 355 McCool, F. Dennis 369 Triebwasser, Andrew 317,406 DeSilva, Debra L. 195 McDonald, Charles J. 224 Trieschmann, Martha 134 DiGiovanna, John J. 228 Menon, Mridula 89 Tuohy, Kathryn 352 Dillon, Johanne E. 195 Michaud, Gregory F. 58 Vaidyan, Philip B. 415 Dollase, Richard 260 Miele, Nicholas J. 353 Vanner, Cynthia L. 178 Donnelly, Edward F. 212,341,412 Moniz, Charlene J. 10 Vernaglia, Lawrence W. 29,142 Donohue, Andrew 207 Morang, Alexandra 256 Viner-Brown, Samara 138 Duff, Brian E. 399 Muglia, Jennie J. 288 Viticonte, Janice 256 Dufresne, Raymond G. Jr. 225,292 Nahvi, Shadi 267 Wacker, Margaret S. 10 Duncan, John A. 395 Nogueira, Jennifer 239 Wedekind, Cynthia A. 209 Earls, Emily A. 199 Noto, Richard B. 132 Weaver, Charles E. 395 Edstrom, Lee E. 114, 117,128 Ng, Cynthia Y. 237 Weinstock, Martin A. 234,237,416 El-Gamal, Hazem M. 225 O’Dowd, Philip 4 Weinzweig, Jeffrey 128 42 Weiss, Arnold-Peter 117 Medicine and Health / Rhode Island Weitberg, Alan 299 Cleft lip deformity 120 network 178 Williams, David O. 50,353 Coldness that does not abate 315 Images in Medicine 19,88,132,173,201, Woodard, Marie L. 79 Complications of anesthesia 341 239,274,338,415 Yunis, Nidal 89 Contemporary evaluation and management Impact of diabetes on coronary angiographic Zhou, Linda 299 of twin-twin transfusion syndrome 165 findings in acute coronary syndrome [abs] 353 Zienowicz, Richard 117,123 Creative Clinician 89,134,204, Improving the oral health of children in Zuwallack, Alicia 55 299,369 Rhode Island 192 Current approaches to evaluation and In memoriam 50 management of patients with ventricular Index 2000 31 Title Index arrhythmias 58 Influenza vaccine delays in 2000: Rhode Island Access to services and assistive technology Cutaneous anthrax 416 response 140 in Rhode Island 304 Delaying the diagnosis of abdominal pain Intracoronary brachytherapy: An evolving Acne vulgaris: Update on therapy 296 with analgesics 63 modality for treatment of restenosis ACP-ASIM abstracts 352 Dermatology: Introduction 224 following percutaneous coronary intervention 51 Adult asthma prevalence in Rhode Island 376 Doctor-to-doctor program 202 Invasive disease attributed to streptococcus Advances in pharmacology 209,241 Doctor’s rescue and a lawyer’s poem 387 pneumoniae,1998-99 24 Age of enlightenment: Current uses of Drug and devices “10 years after” 36 Invasive pneumococcal disease 89 lasers in dermatology 288 Early evaluation and management of Judicial Diagnosis 29,142,200,344 Air: A choice of foul or fair 75 craniofacial dysmorphology 392 La belle indifferene: Medical myth or Airway management in children with Email feedback to preclinical medical useful marker of psychiatric disease 207 craniofacial anomalies 403 students in a problem-based learning Letters to the Editor 28 Aks me no questions 414 discussion group [abs] 355 Looking good, feeling bad, the Marilyn Alpha-thalassemia major:Antenatal Epidemiology, etiology and control of Monroe syndrome 314 diagnosis and management 152 melanoma 234 Managed care contract check-list 29 Alzheimer’s disease brain 274 Epidemiology of work and work-related Management of pediatric head shape Anesthesia for craniofacial surgery 406 disease in Rhode Island, 1876-2001 189 abnormalities: Craniosynostosis and Anesthesiology: Patient care, innovation Ethics, money & negative studies 74 positional posterior plagiocephaly 395 and safety 316 Evolving medicine 146 Medical malpractice implications of Aortic dissection 201 Face Value: Comprehensive care for problems end-of-life care and treatment 344 Approach to measuring and comparing related to the face and calvarium 388 Medical Myths 63,92,207 performance and improvement in hospitals 356 Facial rejuvenation: Art and science of Meperidine: Second-line agent with Artistic shaping of key facial features in cosmetic surgery 110 first-line prescribing practices 10 children and adolescents 389 Febrile traveler 16 Metastatic carcinoma mimicking primary Asthma and flu vaccination 343 Fetal cardiac arrhythmias: Diagnosis and thyroid cancer 204 Atrial fibrillation and anticoagulation 96,410 management 161 Mohs micrographic surgery: Overview 225 Beta-blockers, diabetes and hypoglycemia: Fetal obstructive uropathy: Diagnosis and Move over Lance Armstrong 386 Risky business? 81 management 155 Moyamoya 415 Beta-blockers an important cause of depression: Fetal surgery 169 Nail-biting experience 346 A medical myth without evidence 92 Fetus with an abdominal wall defect 159 New treatments for influenza: Neuraminidase Better than medicine 2 For the wounds that will never heal 223 inhibitors 209 Bilateral cystic ovarian teratomas 19 Free patient education materials 240 Nonsteroidal anti-inflammatory drugs for Body contouring 114 From Machiavelli to mad cow disease: perioperative pain control 327 Body dysmorphic disorder: A clinician’s 20th century ecological changes and the Obstetric anesthesia and analgesi: Options introduction 292 inevitable role of medicine in disease for pain relief during childbirth 329 Boerhaave’s syndrome 88 prevention 379 Occurrence and characteristics of inadvertent Book Review 218 From vitamin to vesanoid®: Systemic lithium intoxication: Cases and review Breast reconstruction: Sorting out the options 123 retinoids for the new millenium 228 of the literature [abs] 352 Bringing Baby Friendly to Rhode Island 79 Ganglioneuroma 239 Office-based anesthesia for plastic surgery 119 Brown Medical School: Class of 2001 256 Garlic: The panacea with bad breath 2 Office-based operatory experience: Overview Burden and the heat of day 187 Generic drug substitution 241 of anesthetic technique, procedures, But are you really sure? Requiring psychiatric Gilles de la Tourette’s syndrome 15 complications 117 proof of patients’informed consent prior Governor Lucius F.D. Garvin, MD - Open neural tube defects among newborns to elective surgery 142 Rhode Island’s champion dreamer 83 in Rhode Island 138 Buy this book! 106 Health by Numbers 24,67,98,138,176,212, Opioid therapy for chronic painful conditions 323 CME Background: Face and Calvarium 408 245,275,304,341,374,412 Overview of HCFA’s acute myocardial CME Background: Fetal medicine 171 Hearing loss in children with craniofacial infarction national project 22 Cancer in Rhode Island: Common anomalies 399 Pain medication and criminal law 200 questions, simple answers 277 Hospital preparedness for acts of bioterrorism: Pharmacotherapy of systolic heart failure: Cancer prevalence estimates, Rhode Island 1998 215 Assessment of emergency preparedness Emphasis on mortality outcomes 55 Case of domestic violence [abs], 354 plans of hospitals in Rhode Island 197 Physician’s Lexicon 219,251,283,310, Case of esophageal Crohn’s disease [abs] 354 Hospitals and the changing work environment: 346,382,414 Cassava and roots of malnutrition 287 Promoting gender equity and fair Physicians newly licensed in Rhode Certified male 382 treatment for medical students 76 Island during 1999-2000 269 Chimney sweeps of yesteryear 107 Identifying bacterial agents of bioterrorism: Plastic surgery: A diverse specialty derived Classic watershed infarct 134 Pivotal role of the laboratory response from science, art and creativity 108 43 Vol. 85 No. 1 January 2002 Point of View 21,70,279,309,379 Rhode Island Quality Partners 22,65, Tobacco use in households with athmatics 275 Positron emission tomography in the 96,136,174,240, Toward an understanding of the cleft palate evaluation of a solitary pulmonary nodule 132 302,339,372,410 anomaly using a congenital model 128 Precepting in a community-based internal Running of many words 283 Treating the many to benefit the few: The medicine teaching practice: Results of a Salpingitis isthmica nodosa 338 modern reach of preventative medications 4 time-motion study 267 Screening for breast cancer in women over Trends and patterns in health insurance Preconceptual folic acid: Opportunity for the age of 70 136 coverage, 1991-2000 67 counseling offers opportunity to help Sedation and analgesia by non-anesthesiologists 317 Trends in asthma hospitalizations in prevent neural tube defects 21 Sedation in critically ill patients: A Review 321 Rhode Island 212 Prevalence of asthma in a rural Guatemalan Senescence, frailty and mortality: Trends in inpatient cholecystectomies, community [abs] 353 Mathematical models of aging 360 1991-2000 176 Prevention and control of influenza 302 Shining city set upon a hill 34 Two-week low iodine diet is necessary for Prevention of pneumococcal disease among SHOCK, SEPSIS, UTI and DRGs: adequate preparation for 131-I adults 174 A mistranslation 65 scannning [abs] 353 Primary and secondary prevention of Silence is golden 286 Ultraviolet radiation and sunscreens 236 coronary artery disease 339 Skin-deep vocabulary 251 Use of low-molecular-weight heparin and Primary angioplasty for acute myocardial Smallest patient: Foundations in fetal glycoprotein IIb/IIIa inhibitors in acute infarction 44 medicine introduction 148 coronary syndromes 37 Problems in the control of melanoma, Social impact of atopic dermatitis 294 Utility of transesophageal echocardiography Rhode Island, 1987-1998 245 Speech, language and hearing management in non-cardiac surgery 332 Progress in the control of oral cancer, of the child with cleft palate 401 Utilization of clinical preventive services Rhode Island, 1987-1998 307 Spells 186 among Rhode Island adults with and Progress in the control of prostate cancer, Stereophonic sounds 310 without insurance coverage, 1999 98 Rhode Island, 1987-1998 100 Straight-horned creature and its crooked Utilization of inpatient rehabilitation services 412 Protecting patients 70 journey 255 Value of a diagnostic punch biopsy 232 Psychogenic purpura 299 Stroke update 372 Vertigo: The turning of many words 219 Public Health Briefing 26,100,140,178,215, Subclavian steal syndrome diagnosed by Vital statistics 20,69,102,143,175,219,250, 248,277,307,343,376,416 MR angiography 173 282,308,346,378,418 Putting on shoes - Acts of humility 350 Teaching professionalism 260 What is reality? 34 Quackery in the incurable 254 TWW for intra-op monitoring and What medications do physicians give Quality of care in the last month of life management of vena caval tumor 336 to HIV/AIDS patients and why? [abs] 355 among Rhode Island nursing home Terminal days of Oscar Wilde 147 Why teach? Treatise in honor of residents 195 Thank God for rich women with mustaches 222 Henry T. Randall, MD, first true Race, ethnicity and health: A new data policy 248 Those adorable little bunny rabbits 351 chairman of surgery, Brown Medical Reaching out for reading in Rhode Island 309 Tobacco control report card: Schoool 264 Reductions in premature mortality, Rhode Island,2000 26 Rhode Island, 1989-1998 374 Respecing patient’s wishes at the end of life: Hospital and physician concerns 279 Respiratory system mechanics in a patient with massive subcutaneous emphysema 369 Rhesus isoimmunization 149 Rhode Island Medical Journal Heritage 30,72,104,144,182,220, 252,284,312,348,384,420 Rhode Island public and mental health parity debate 365

44 Medicine and Health / Rhode Island