R E G I O N A L. What Is A D-dimer? D-dimer - Isn t That One of Those Hematology Tests? So What Does It Do For Me?

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1 R E G I O N A L O N C O L O G Y U P D A T E A Publication of the Evansville Cancer Center Winter 2003 Rick Ballou, M.D., Ph.D. Dr. Ballou is a Medical Oncologist/Hematologist who has been practicing in the Tri-State area since July He received his medical degree from the University of Louisville School of Medicine where he also completed his residency in Internal Medicine. His fellowship in Medical Oncology/Hematology was completed at the James Graham Brown Cancer Center in Louisville, Kentucky. Dr. Ballou is board eligible. In addition to his medical degree, Dr. Ballou has a PhD. in anatomy from the University of Louisville. He has contributed to many scientific publications and is co-author of a book on cancer of the breast. D-dimer - Isn t That One of Those Hematology Tests? So What Does It Do For Me? What Is A D-dimer? Venous thromboembolism is a common disorder associated with significant morbidity and mortality. Deep vein thrombosis (DVT) occurs approximately 650,000 times per year and results in an estimated 200,000 deaths per year. The most dangerous venous thrombosis is obviously the pulmonary embolus (PE) which when this occurs in the elderly population results in a mortality rate as high as 40%. Symptoms of a pulmonary embolus are the classic triad of chest pain, cough, and hemoptysis which are associated with dyspnea, a feeling of undue apprehension, as well as syncopy and diaphoresis. Physical examination is inadequate for establishing the diagnosis of PE, and not all patients with suspected pulmonary emboli exhibit these symptoms in a classic presentation. When a pulmonary embolus is suspected the current standard-of-care is diagnostic tests such as the ventilation-perfusion scan or spiral CT scanning. However, at times, when movement of the patient for these radiographic tests is prohibitive or when the risks estimated for a PE is low then a simple test to help the practitioner make appropriate decisions may be helpful. This is where the metabolic test of the D-dimer may play a role. In the normal clotting process fibrin monomers are formed as the result of thrombin-catalyzed cleavage of soluble fibrinogen available in the plasma. These monomers result in a cross-linking process which then results in fibrin formation and ultimately a thrombus. Once a thrombus is formed, the serum has a major clot lysing enzyme (plasmin) capable of cleaving the fibrin thus resulting in break down of excess or unneeded thrombus. Therefore, with the normal clotting system, plasmin lysis of cross-linked fibrin generates the D- dimer fragment. This fibrin fragment (D-dimer) can now be measured and an elevated level can be found in many clinical conditions including DVT and specifically PE. The specificity of the D-dimer specifically for VTE/PE is low since many other processes can also elevate the level of fibrin breakdown products. Thus, while it cannot diagnose a specific thrombotic event, the D-dimer can be used to rule out an acute thrombolic event such as VTE/PE. This is due to the high sensitivity and the corresponding negative predictive valve. With the appropriate methodology for analysis, the D-dimer level has a sensitivity for DVT/PE of 90% or greater as well as a negative predictive value of 90% or greater by most studies. Thus a negative D-dimer by this methodology in a patient with suspected DVT/PE provides high probability of exclusion of a DVT/PE diagnosis. However, conversely a positive D-dimer does not confirm that DVT/PE is present. A positive D-dimer just indicates a fibrinolytic process is currently occurring and further testing would be indicated. There are several commonly used methods to detect D-dimer levels, all of which use monoclonal antibodies that recognize epitopes of the above discussed D-dimer fragment. ELISA is considered to be the standard test for D-dimer concentrations. In ELISA testing a non-radiolabled antibody, which binds the D-dimer, is coated onto a membrane or microtiter test plate. This antibody binds to the D-dimer fragments in patientʼs test plasma, then a second radiolabled antibody is added and the amount of radiolable bound to the membrane/plate is in direct proportion to the amount of D-dimer present. However, ELISA testing is not practiced in the diagnosis of PE because results are typically not available the same day the test is requested. What makes it even more problematic is that it is not available in most centers and thus becomes a send out lab, therefore the diagnosis is often made before the ELISA test results return. Latex agglutination (LA) assays rely on the use of monoclonal antibodies to the D-dimer fragment where the antibodies are coated onto latex particles. Macroscopic agglutinates are seen when elevated levels of fibrin break down products (i.e. D-dimer) are present in the patientʼs plasma which then binds to the latex particles. The advantage of this testing is that it is rapid and relatively inexpensive. This makes this a preferred test for D-dimer. Unfortunately, original latex testing lacked the sensitivity to be used as a screening assay for VTE/PE and was generally reported only as a positive or negative report for fibrin breakdown products. However, now with newer modifications of this D-dimer assay, the Continue to page 2

2 use of automated analyzers has been shown to be comparable to the conventional ELISA method (98-100) in giving a negative predictive value of PE. Another commonly used methodology is the SimpliRED assay which is a whole blood assay. This method relies on a bispecific antibody that causes visible agglutination of red cells in the presence of D-dimer. It requires one drop of whole blood and results are available in minutes. Most studies show its sensitivities are similar to conventional ELISA and have become more widely used in clinical settings such as large Emergency Rooms. So what does it do for me? Measurement of elevated levels of D-dimer is now practical and a marker of incipient or ongoing thrombotic events. The D-dimer test can, therefore, evaluate patients for clinical disorders such as deep venous thrombosis (DVT), disseminated intravascular coagulation (DIC), arterial thromboembosis (AT), and of course pulmonary embolism (PE). The D-dimer analysis can be a valuable and rapid test and in the appropriate clinical setting highly effective for ruling out a DVT/PE. This type of evaluation is most appropriate for assessment of out-patients since these patients generally have more narrowed differential diagnoses for their symptoms. In addition, out-patients also most times have less co-morbidities that would result in an elevated D-dimer, thus, making the test more valuable and cost effective. The lack of specificity of the D-dimer assay in hospitalized patients, often times with multiple co-morbidities which can result in D-dimer formation, warrants interpreting a positive assay with great caution, and additional testing will be required to confirm DVT/PE. However, if a DVT/PE is suspected and D-dimer testing is negative, then a different diagnosis for the symptoms should be pursued. These tests are now becoming much more widely available at various hospitals and are now rapid enough to be valuable in decision making to form appropriate differential diagnoses. The ELISA, the automated latex agglutination test, and the SimpliRED assay all have a high predictive value for active thrombus lysis and if these tests are negative there is reasonable sensitivity to rule out DVT/PE in the majority of cases where DVT/PE are suspected. Currently, St. Maryʼs Medical Center and Methodist Hospital are using quantitative latex microparticle assay with an 80% negative predictive value. Ronald Ruszkowski, M.D. Dr. Ruszkowski is a Medical Oncologist/ Hematologist who has been practicing in the Tri-State area since He is a graduate from the Marquette School of Medicine (presently the Medical College of Wisconsin) in Milwaukee, Wisconsin. Dr. Ruszkowski completed his residency program at Montefiore Hospital and Medical Center in Bronx, New York and at Yale University School of Medicine in New Haven, Connecticut. He is a Post-Doctoral Fellow in Hematology/Medical Oncology at Yale University of Medicine and a Post-Doctoral Fellow in Hematology at the University of Connecticut School of Medicine in Farmington, Connecticut. Dr. Ruszkowski is a board certified by the American Board of Internal Medicine, the American Board of Internal Medicine - Hematology and the American Board of Medicine - Oncology. Past appointments include Assistant Clinical Professor of Medicine with the University of Louisville in Louisville, Kentucky, Clinical Instructor at Yale University School of Medicine as well as the University of Connecticut Health Center. - Rick Ballou, M.D., Ph.D. Everything You Wanted to Know About von Willebrand Disease... The Evansville Cancer Center announces a new series of articles on hemostasis and thrombosis. The primary mission at the Evansville Cancer Center is the treatment of malignant disease; however, we do see a number of cases of nonmalignant hematologic problems and some of those cases are related to defects in hemostasis and abnormal thrombotic disorders. In future issues we will review hemostatic defects and what was once known as hypercoagulability but now known as thrombophilia. We will start with this article on a very complicated subject - von Willebrand Disease. Since von Willebrand Disease is fairly prevalent in the population, it is likely that practitioners will encounter such cases in the future. The complexity of diagnosis and at times the treatment of the various degrees of severity can complicate the management of these patients. I. INTRODUCTION von Willebrand Disease (vwd) is usually caused by a decreased von Willebrand Factor (vwf), which is essential for the binding of platelets to vascular endothelium. The genetic abnormality in vwd is an autosomal dominant inheritance. One percent of the population is affected. This may seem high; however, because of the mild nature of some cases of vwd, it may be overlooked in many patients due to a lack of symptomatology. Mild cases may come to light, however, when a patient takes aspirin or nonsteroidals before a surgical procedure and somewhat excessive bleeding is noted. The disease was first described by Erik von Willebrand in The connection of vwd with Factor VIII levels had been described in the mid-20th century, but the relationship of vwd to the Factor VIII molecule was not clarified for years to come. It is now known that vwf and Factor VIII are two different molecules bound together, and that vwf has three functions: (1) platelet to vascular subendothelial binding, (2) platelet to platelet binding, and (3) that vwf serves as a carrier for Factor VIII. The molecular biology and genetics of vwd is beyond the scope of this article but it can be said that vwf exists as multimers of varying size in plasma. vwf appears to be produced in vascular endothelial cells and in megakaryo

3 cytes. During insults to the vascular system, the vwf binds to subendothelial collagen and to platelet glycoprotein Ib. It combines to the IIb/IIIa platelet receptor as well. II. CLINICAL FINDINGS Mild vwd abnormalities may go undetected. Those with more severe abnormalities generally have mucocutaneous bleeding, especially in childhood, with epistaxis and gingival bleeding and at the onset of menses, menorrhagia. Diagnosis is sometimes confirmed after dental extraction or a surgical procedure in childhood, such as a tonsillectomy. In families, the severity of bleeding can vary between affected individuals. Bleeding may be affected by a number of factors in a single individual, such as inflammatory processes and infections, the use of birth control pills and HRT, and pregnancy. These factors may complicate diagnosis and treatment of this disorder. III. DIAGNOSIS The diagnosis of vwd can, at times, be straightforward and, at times, difficult. Of utmost importance is clinical suspicion. A personal history of any type of bruising or bleeding in childhood, adolescents with menorrhagia, adult females with menorrhagia, bleeding with previous procedures, or a history of bleeding in the family should alert the practitioner to the possibility of an underlying coagulopathy. Screening tests, such as the activated partial thromboplastin time (aptt), may be abnormal. However, if the practitioner does have a suspicion of vwd, the finding of a normal screening test, such as aptt, should not deter one from proceeding to specific studies. There are three important and essential studies for vwd, including: (1) the vwf antigen (vwf:ag), (2) vwf activity (vwf:rco), and (3) Factor VIII activity (FVIIIc). In the past, the bleeding time, which may be normal in mild vwd, was included. The PFA-100, a test of platelet function, should be employed if at all possible, as the bleeding time should be looked upon as an antiquated historical study which is difficult to interpret because of operator variation. Indeed, at times the bleeding time is inappropriate to use because of abnormalities of the skin on the forearm, especially in older individuals. Once the diagnosis of vwd has been made by the above-mentioned studies, it is essential to classify the types of vwd and this is mainly done by the use of the vwf multimer analysis. It should be pointed out that this is not just for academic interest. The various types of vwd will respond differently to various treatments and there may be relative contraindications to certain treatments. Therefore, proper classification is essential. In testing for vwd, the use of specialty coagulation laboratories is frequently to be desired. Laboratories that are dedicated to performing large amounts of coagulation studies obviously can be depended on for better results. A location with a pathologist who specializes in clotting disorders can be very helpful at times, especially with difficulty in regard to diagnosis. The von Willebrand antigen, previously known as Factor VIII antigen, is usually done by an ELISA method. The use of the term von Willebrand antigen (vwf:ag) is preferred and is standard at the present time. von Willebrand activity is measured by the ristocetin cofactor. Ristocetin, an antibiotic, has been noted to aggregate normal platelets but is only able to do so with the presence of vwf in the plasma. Therefore, a patient with abnormalities of vwf will not be able to support ristocetin aggregation of normal platelets. Factor VIII activity is done basically as a functional assay and, obviously, it would be low in vwd. Thus, in vwd one will have a low vwf antigen (vwf:ag), a low von Willebrand activity (vwf:rco), and a low Factor VIII activity (FVIIIc). Patients with hemophilia will have low FVIIIc, normal vwf:rco, and a normal vwf:ag. vwd is divided into three types: I, II, and III. Type II is subclassified into types IIA, IIB, IIM, and IIN. A very detailed discussion of the types of vwd again is beyond the scope of this article; however, a number of important points need to be discussed. First of all, again, the work up of vwd is never completed until multimer studies are done. Type I is the classic vwd - having a deficiency of all multimers. However, the distribution of vwf multimers is normal. This will be the type of vwd that most practitioners encounter, as it includes about two-thirds of all cases. When multimer studies return, they will be returned as normal, because the distribution will be in the normal range. This does not mean that the patient does not have vwd. That diagnosis depends upon the previously mentioned studies, FVIIIc, vwf:ag, and vwf:rco. Type I vwd can result in a mild to moderately severe bleeding tendency. In type IIA, there is an abnormal distribution of vwf multimers. The high and intermediate molecular weight multimers are absent and this would be demonstrated on the multimer study. This will include about 15% of all cases. The bleeding tendency can be moderately severe. Type IIB is one of the more interesting of the classifications of vwd. There is an abnormality in the area of the von Willebrand molecule for the attachment to the GP Ib region for platelets. This results in an increased binding, which can occur spontaneously in plasma and results in the removal of the largest multimers and platelets, leading to thrombocytopenia. Although all patients may not necessarily have thrombocytopenia, platelet counts may be at lower limits of normal at times. A variation on the ristocetin test previously mentioned, the so-called ristocetin-induced platelet aggregation (RIPA) test, which is usually low in cases of vwd, will show increased aggregation in type IIB. However, these studies should probably be done by a dedicated coagulation laboratory. It is in this type that treatment with desmopressin, which will be discussed further in the article, may be contraindicated; therefore, the determination of the type of vwd gains even more importance. Moderately severe bleeding tendencies may occur in this type. Other unusual type II abnormalities are type IIM and type IIN. Type IIN deserves some mention, although it is infrequent. Patients will have low Factor VIII levels, typical inheritance, and moderate to partly severe symptoms. The vwf:ag, vwf:rco, and RIPA will usually be normal. vwf multimers may be normal or abnormal. In males, this could be misdiagnosed as hemophilia A, as the bleeding is characteristic of bleeding seen with hemophilia, with muscle bleeding or severe bleeding after invasive procedures. The key to diagnosis is the presence of autosomal dominant inheritance rather than sex-linked inheritance. Bleeding in females also would not be typical of hemophilia A. vw collagen-binding capacity (vwf:cb), the key test in

4 vwd IIN, is available but only in limited laboratories in the United States. The abnormality was named IIN as it was described in Normandy, France. The apparent cause is an abnormality of vwf for the binding of Factor VIII. Factor VIII then loses the protective effect of von Willebrand multimers in circulation. In type IIM all multimers are present but there is decreased binding to platelet GP Ib. It is uncommon. Type III is a severe deficiency of vwf and Factor VIII, as well. It may be inherited in homozygous fashion, with the patient receiving both alleles for vwd, or possibly in a doubly heterozygous manner, receiving genes for sex-linked hemophilia and the autosomal dominant vwd. Mucocutaneous bleeding occurs and is associated with muscle and joint bleeding. von Willebrand antigen can be unmeasurable, Factor VIII activity will be below 10%, and vwf multimers may be completely absent. Table: Characteristic Patterns of the Different Types of vwd1 vwf:rco/ Multimers Miltimers Type Inheritance BT FVIIIc vwf:ag vwf:cb RIPA in Plasma in Platelets 1 AD /N N/ N N N 2A AD/(AR) N/ /N /N abnormal abnormal/n 2B AD/AR N/ /N / abnormal N 2M AD /N N/ /N /N N/ N/abnormal 2N AR N N/ N/ N N/(abnormal) N 3 AR nd nd nd nd nd AD = autosomal dominant; AR = autosomal recessive; N = normal; nd = not detectable Types of acquired vwd can occur and may be associated with autoimmune or lymphoproliferative disorders but they are beyond the scope of this discussion. The amount of vwf in patients who suffer from this disorder can vary, as previously mentioned. Hypothyroidism is associated with lower levels of vwf and can worsen a mild case. vwf also changes with the menstrual cycle, and when studies are done in the late luteal phase of the cycle, mild vwd may be missed as both vwf and Factor VIII can rise during that time. The best time to test is during the follicular phase in women who are premenopausal. Clinical impressions based upon the patientís previous histories of bleeding episodes and family histories are important and, if necessary, testing should be repeated as many as three times. Factor VIII and vwf increase in the last two trimesters of pregnancy and diagnosis of many pregnant women with vwd would usually be impossible. Suspected vwd in pregnant women should await laboratory diagnosis six to eight weeks after delivery. Testing that is done during infections and inflammatory states may also result in elevations of vwf. The testing should also be repeated at a more appropriate time. Preferably, testing should be done in the morning especially in suspected mild cases of vwd because just moderate daily work activities can increase vw multimers and cloud the diagnosis. IV. TREATMENT Obviously, patients with vwd should be cautioned against using aspirin and nonsteroidal anti-inflammatory agents and antiplatelet drugs. Treatment of vwd includes the use of desmopressin, known as DDAVP, vwf concentrates, and antifibrinolytic drugs. DDAVP is an artificial compound related to antidiuretic hormone. The substance results in the release of vwf and Factor VIII. This drug can be used in mild to moderate cases of vwd, especially type I, for basically minor surgical procedures and dental procedures as well. It is usually effective in patients with type I, as mentioned, and in some cases of type IIA. It is problematic and said to be relatively contraindicated in patients with type IIB vwd. This type, as mentioned above, has abnormal binding for the GP Ib platelet receptor and results in the clearing of both large multimers and platelets, resulting in thrombocytopenia. Any DDAVP increase in large multimers may be followed by increased clearing of platelets. Although relatively contraindicated, DDAVP may be used in type IIB if DDAVP pretesting is performed to check reactions of platelets and vwf to drug. DDAVP is not helpful in type III vwd due to the very low levels of vwf. All patients who have type I and type IIA vwd, and possibly IIB vwd, should, at the time of their diagnosis, undergo a DDAVP test so that plans can be made for elective or urgent use of this drug. Patients should have von Willebrand activity, von Willebrand antigen, and Factor VIII activity levels drawn. DDAVP should be administered intravenously and the levels should be rechecked 60 minutes after the infusion. Side effects of DDAVP are usually minimal, such as flushing,

5 but hypertension, hypotension, and headache can occur. It should be used with caution in children and a pediatric hematologist should be consulted to carry out these studies if they are thought to be indicated in the pediatric age group. Small children may be affected by hyponatremia due to antidiuretic effects. DDAVP is administered for one to two hours preceding a surgical or dental procedure. The effect can last up to four to six hours, at which time vwf levels may drop. DDAVP can be repeated but tachyphylaxis does occur with repeated dosages, at which time the drug is no longer effective. It is not a good treatment during major surgery, when prolonged physiologic levels of hemostasis need to be achieved. Nasal sprays containing DDAVP have been used. They are frequently helpful in patients who develop menorrhagia, and it can be used in patients in whom bleeding occurs after minor injuries. von Willebrand concentrates are a relatively new development in the treatment of vwd. Up to the recent past, the treatment that was employed was that of cryoprecipitate, which contains high amounts of Factor VIII and vwf. With the development of Factor VIII concentrate, patients with hemophilia were much more conveniently treated. However, these concentrates do not contain any significant amount of vwf and are ineffective in treating patients with vwd. Patients with vwd were previously exposed to possible viral contamination from blood products when cryoprecipitate was employed. Patients with hemophilia, however, have benefited from treatment with heat-treated Factor VIII concentrates and recombinant Factor VIII, which makes these latter products safe, in regard to transmission of viruses. Recently, however, a Factor VIII concentrate, Humate-P, became available in the United States. While it is labeled with the concentration of von Willebrand cofactor, this product contains both Factor VIII and vwf. It is now indicated for the treatment of vwd. It is the product of choice in patients with this disorder. Cryoprecipitate is effective, but each unit of cryoprecipitate exposes the patient to a unit of blood and this product should be avoided. It is also important to remember that other Factor VIII concentrates, whether heat treated or recombinant, should not be employed since they are ineffective in treating vwd, due to low or absent vwf levels. Humate-P is indicated in patients with type I vwd who have failed the DDAVP test or who are undergoing major surgical procedures and require prolonged hemostasis beyond the limits of DDAVP. The same can be said for type II patients and all type III patients with vwd. Be sure to check with pharmacies, before elective procedures, as to the availability of Humate-P. Also, one should confirm results of presurgical treatment with appropriate lab tests prior to specific surgery. Antifibrinolytic drugs such as Amicar can be used in patients undergoing dental procedures. This is given along with DDAVP in the appropriate patient. The mouth has a high degree of antifibrinolytic activity and Amicar can be very helpful extending the time of better hemostasis in patients undergoing dental procedures. In addition, tranexamic acid solution can be used as a topical agent after dental procedures. Pregnancy produces a special scenario in patients with vwd. Because of the increase of vwf in the last two trimesters of pregnancy, patients with type I disease generally do not need treatment during delivery. Patients need to be watched very carefully, however, post-delivery because vwf levels can drop within a very short period of time or during the two weeks following delivery. In patients with type II disease, the correction with increases of von Willebrand multimers can be a variable in pointing out the need for classification of this disorder. DDAVP should be used only after delivery in those who have been previously tested with DDAVP. In patients for whom bleeding does occur, Humate-P should be used. A special mention of vwd in gynecologic practice can be found in the International Journal of Gynecology and Obstetrics, 76: , Recommendations of the ACOG committee are as follows: Adolescents presenting with severe menorrhagia should be screened for vwd...before the initiation of hormonal therapy. Hormonal therapy can obscure diagnosis. Screening is warranted among adult women with significant menorrhagia without another cause, because it is not unusual to encounter adult women with menorrhagia who have a mild form of vwd. Hysterectomy for excessive bleeding should not be performed without consideration of bleeding disorders. Treatment of patients with acquired vwd is a detailed subject, again out of the scope of this article. For those in which the disorder is related to an autoimmune phenomenon, high-dose IVIG may be helpful. Other possible treatments include plasmaphoresis and immunosuppressive medications. This article is obviously limited in scope and if one wishes to read further about this disease, a chapter about vwd by Margaret E. Rick, M.D. in Consultative Hemostasis and Thrombosis, edited by Kitchens, Alving, and Kessler, W. B. Saunders Company, 2002, would be an excellent reference. - Ron Ruszkowski, M.D. 1 Laboratory Diagnosis of Congenital von Willebrand Disease, Budde, U., et al., Seminars in Thrombosis and Hemostasis, 28:173, April Patient Gives His ʻSweetheartsʼ in Medical Oncology A Beautiful Valentine Chocolate Cake & Words of Thanks & Appreciation! Photographed with patient Mr. William Michem are kneeling in front, Beth Moore, standing from left to right, Cyndi Williams, RN, wife Maxine, Cynthia Hodges, RN holding cake Shannon Hyslop, Paige Benson, RN, patient Mr. Mitchum, Renee Crowder, RN and Kim Blakeley, RN

6 PRESORTED STANDARD U.S.POSTAGE PAID Permit No Evansville, IN CONGRATULATIONS... to Jolanta U. Cichon, M.D. Congratulations to Dr. Cichon for recently receiving board certification in Medical Oncology. Dr. Cichon is a Medical Oncologist who began practicing in the Evansville-Princeton communities in October of She completed her medical residency at St. Francis Medical Center in Pittsburgh, Pennsylvania. Dr. Cichon s fellowship in Hematology/ Oncology was completed at the University of Texas Southwestern Medical Center in Dallas, Texas. She is also board certified in Internal Medicine. Dr. Cichon has a special interest in breast cancer. Evansville Cancer Centerʼs On-Site Laboratory The Medical Oncology Department at Evansville Cancer Center is supported by our on-site laboratory. Our lab is COLA (Commission of Office Laboratory Accreditation) accredited, a prominent national healthcare accreditation organization. The Evansville Cancer Center Laboratory has been COLA accredited since This presigious accreditation is awarded every two years and is given only to laboratories that apply rigid standards of quality for their daily operations, demonstrate continued accuracy in the performance of proficiency testing, and pass a rigorous on site laboratory survey. Belinda Self, Chief Medical Tech for the lab states, Our COLA accreditation is a result of our long term commitment to providing the best services possible to our patients. Frederick J. Sigda, M.D. is the Laboratory Director. RADIATION ONCOLOGISTS Al Korba, M.D., FACRO, Aly Razek, M.D., FACRO & Shannon Lamb, M.D. MEDICAL ONCOLOGISTS Rick Ballou, M.D., Ph.D., Ronald Ruszkowski, M.D. & Jolanta U. Cichon, M.D. RADIATION PHYSICISTS Saiyid Masroor Shah, Ph.D. & Arnold Sorensen, B.S. 700 N. Burkhardt Road Evansville, Indiana Evansville Cancer Center 700 N. Burkhardt Road Evansville, Indiana 47715