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Defining the Stages of Aggressive Non-Hodgkin’s Lymphoma

Defining the Stages of Aggressive Non-Hodgkin’s Lymphoma

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conceptually attractive, provided that it can be administered without an increased risk of bleeding. For patients who are receiving fibrinolytic therapy, a combination of clopidogrel and aspirin appears, in fact, to be effective and safe.
From the Cardiology Division, Department of Internal Medicine, Johns Hopkins Medical Institution, Baltimore (R.A.L.), and the University of Texas Southwestern Medical Center, Dallas (L.D.H.). This article was published at www.nejm.org on March 9, 2005.
1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. 2. Campbell CL, Steinhubl SR. Variability in response to aspirin: do we understand the clinical relevance? J Thromb Haemost (in press). 3. Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 2000;101: 2788-94. 4. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombol-

ysis in myocardial infarction (TIMI) 14 trial. Circulation 1999;99: 2720-32. 5. Topol EJ. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001;357:1905-14. 6. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-13. 7. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171-5. 8. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. [Errata, N Engl J Med 2001;345:1506, 1716.] 9. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179-89. 10. Lange RA, Hillis LD. Antiplatelet therapy for ischemic heart disease. N Engl J Med 2004;350:277-80. [Erratum, N Engl J Med 2004; 351:200.]
Copyright © 2005 Massachusetts Medical Society.

Defining the Stages of Aggressive Non-Hodgkin’s Lymphoma — A Work in Progress
James O. Armitage, M.D. It is well known that localized cancers, including aggressive non-Hodgkin’s lymphoma, have a better prognosis than cancers that have spread. When the results of treatment for aggressive non-Hodgkin’s lymphoma are reported, the results for Ann Arbor stage I disease (involvement of a single lymph-node region) are typically reported separately from those for stage III (involvement of lymph nodes on both sides of the diaphragm) and stage IV (stage III plus extranodal involvement). The results of treatment for stage II disease (involvement of two or more lymph nodes on the same side of the diaphragm) may be included in either group. Radiotherapy cures only a minority of cases of apparently localized aggressive non-Hodgkin’s lymphoma. The addition of adjuvant chemotherapy improves the results, and administering chemotherapy before radiotherapy further augments the results. A study has shown that the use of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone is inferior to CHOP plus adjuvant radiotherapy.1 In this issue of the Journal, Reyes et al. report that the very intensive regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) is superior to CHOP plus ad1250
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juvant involved-field radiotherapy for patients less than 61 years of age with apparently localized diffuse large B-cell lymphoma.2 Assuming the ACVBP regimen is superior to CHOP, would the addition of adjuvant radiotherapy further improve results? Would the addition of rituximab (a monoclonal antibody against CD20, which is expressed only on B cells) to both regimens have changed the results? These are important questions, because approximately 20 percent of the patients treated with ACVBP and more than 25 percent of those who were treated with CHOP plus radiotherapy were not cured. One of the most important advances in the treatment of cancer is the concept of “staging.” Determination of the stage of cancer came into general use in the mid-20th century (the American Joint Commission on Cancer was established in 1959) and initially focused on the anatomical stage (the specific sites of tumor involvement). For certain cancers, however, other factors clearly affect the prognosis. Symptoms, the results of specific laboratory tests, and the differentiation of the tumor are among the factors now considered in establishing the stage of certain types of cancer. The anatomical stage is an imperfect surrogate for other prognostic factors.
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The anatomical stage is extremely important to the success of localized treatments, because it can be used to predict the likelihood that the tumor will be encompassed in the resected specimen or radiation field. With systemic therapy, other factors are clearly at play. Assigning a stage to a cancer should accomplish three important goals: determining the optimal choice of therapy, imparting an accurate prognosis to the patient and the family, and accurately stratifying patients for clinical trials and quality assessment. The sixth edition of the AJCC Cancer Staging Manual 3 recognizes that the anatomical stage is not a sufficient predictor of the outcome of aggressive non-Hodgkin’s lymphomas and adopts the International Prognostic Index (IPI).4 The IPI was developed in an attempt to improve the ability to predict the outcome among patients with aggressive nonHodgkin’s lymphomas. The IPI takes into account not only anatomical stage but also age, performance status, lactate dehydrogenase level, and the presence or absence of multiple extranodal sites of disease. When the IPI was applied to patients with aggressive non-Hodgkin’s lymphomas, five-year survival ranged from approximately 40 to approximately 75 percent among patients with Ann Arbor stage II and from approximately 25 to approximately 65 percent among those with stage IV. Although the IPI is a step forward in the prognostic process, it still does not take certain factors into account, including simple clinical observations such as the presence of a very large mass. The effect of bulky masses was not considered in the IPI because of the lack of uniform collection of data on the maximal tumor diameter at the sites participating in the study. However, the presence of a 10-cm mass is a predictor of a poor outcome of treatment, and clinicians often take very bulky sites of disease into account by adding radiotherapy to that site. The development of the World Health Organization’s system of classification for non-Hodgkin’s lymphomas was an important advance in our ability to manage these disorders.5 The system, an outgrowth of the revised European–American lymphoma classification,6 recognizes that non-Hodgkin’s lymphomas are a group of illnesses, each with unique biologic and clinical characteristics. The diseases previously grouped in studies as “aggressive non-Hodgkin’s lymphomas” are predominantly made up of diffuse large B-cell lymphomas (80 to 90 percent) and peripheral T-cell lymphomas (approximately 10 to 15 percent). When these kinds of

lymphomas are treated similarly, the survival rate among patients with most types of peripheral T-cell lymphoma is approximately half that of patients with diffuse large B-cell lymphoma.7 However, patients with anaplastic large T-cell or null-cell lymphoma have a better outcome than patients with diffuse large B-cell lymphoma. The poor outcome among patients with the more common peripheral T-cell lymphomas probably reflects the fact that the current treatment regimens were all developed in trials that enrolled mainly patients with diffuse large B-cell lymphoma. Future trials should study these different diseases separately if at all possible. Although not considered in any prognostic system, the site of origin of non-Hodgkin’s lymphomas probably affects the biologic characteristics of the tumor and the outcome of treatment. Nancy Lee Harris, a pathologist in Boston specializing in the diagnosis of lymphomas, often points out that, although squamous-cell carcinomas originating in different sites of the body are not considered to be the same disease, diffuse large B-cell lymphomas originating in different sites of the body are considered to be the same. It is clear that certain extranodal sites of origin have important clinical implications. For example, testicular diffuse large B-cell lymphoma frequently metastasizes to the central nervous system and has a pattern of delayed relapse not seen with this type of lymphoma originating at other sites.8 Although not yet ready for widespread use, the patterns of gene and protein expression have recently been shown to be powerful predictors of the outcome of treatment for diffuse large B-cell lymphoma. Lymphomas of this type exhibit distinctive gene-expression patterns: one is similar to the pattern of normal germinal-center B cells, and the other resembles the gene-expression pattern of activated circulating B cells.9 Patients whose lymphoma has the germinal-center pattern survive approximately twice as long as patients with a lymphoma of the activated B-cell type, and this difference appears to be independent of previously considered prognostic factors.10 Genes are information-storage devices, and the effect of gene expression is mediated by the proteins they produce. Since the relationship between gene expression and the production of specific proteins is not straightforward, the level of expression of a specific protein, rather than the level of gene expression, might be a better predictor of the overall outcome of treatment and the likelihood of a response to specific therapies.

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Diffuse large B-cell lymphomas that overexpress the bcl2 protein, as shown by immunohistochemical analysis, but do not have the t(14;18) translocation, seem particularly susceptible to rituximab.11,12 As the concept of staging continues to evolve, multiple factors other than the Ann Arbor stage will be important in predicting prognosis and choosing treatment for patients with aggressive non-Hodgkin’s lymphoma. In addition to the factors considered in the IPI, the specific type of non-Hodgkin’s lymphoma, the specific extranodal primary sites, and the patterns of gene and protein expression are likely eventually to be incorporated into staging systems. Correlating these observations with specific treatments might allow the identification of subgroups of patients most likely to benefit from a particular intensive regimen, such as ACVBP, or those for whom a simpler and less toxic treatment would be equally efficacious. For example, ACVBP may not have been the best treatment for all patients in the study by Reyes et al. Physicians who treat patients with lymphomas hope that we will continue to move away from the “one-size-fits-all” approach to the management of aggressive lymphomas.
Dr. Armitage has reported receiving consulting fees from GlaxoSmithKline, Corixa, and Geneotope and lecture fees from Genentech, Corixa, GlaxoSmithKline, and Amgen. From the University of Nebraska Medical Center, Omaha.
1. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone

mediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998;339:21-6. 2. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005;352:1197-205. 3. Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag, 2002. 4. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993;329:987-94. 5. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors. Lyon, France: IARC Press, 2001. 6. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361-92. 7. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 1997;89:390918. 8. Zucca E, Conconi A, Mughal TI, et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 2003;21:20-7. 9. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-11. 10. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse largeB-cell lymphoma. N Engl J Med 2002;346:1937-47. 11. Mounier N, Briere J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 2003;101:4279-84. 12. Wilson HP, Pittaluga S, O’Connor P, et al. Rituximab may overcome Bcl-2-associated chemotherapy resistance in untreated diffuse large B-cell lymphoma. Blood 2001;98:343a. abstract.
Copyright © 2005 Massachusetts Medical Society.

compared with chemotherapy plus radiotherapy for localized inter-

Financing Health Care — Finding the Money Is Hard and Spending It Well Is Even Harder
Richard Kronick, Ph.D. In this issue of the Journal, Mongan and Lee argue persuasively that physicians should lead the way in confronting the unpleasant truth that we cannot achieve universal health care coverage in the United States without tax increases.1 There is a second unpleasant truth that we must confront: if we are going to create a sustainable system of health care financing in which there is a balance between the costs and benefits of care, then the government must become more involved in influencing how the money is spent. And although the difficulties of figuring out desirable ways of raising money are primarily political, there are substantial political and technical difficulties in figuring out desirable ways of spending money. The calls for universal health care in this issue of the Journal, including a proposal for a voucher system by Emanuel and Fuchs,2 raise at least four questions in thinking about publicly financed systems. First, what role, if any, should there be for state governments? Second, what role, if any, should there be for health plans? Third, how should decisions be made about the rate of growth in expenditures? And fourth, what mechanisms of accountability are built into the system to ensure that resources are used well? Unfortunately, there are no obvious right answers to any of these questions. Administration by the federal government has the advantages of increasing the chances of equitable treatment across the country and potentially pro-

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