The new england journal of medicine
conceptually attractive, provided that it can be ad- ysis in myocardial infarction (TIMI) 14 trial. Circulation 1999;99:
ministered 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) Collabo-
rative Group. Randomised trial of intravenous streptokinase, oral
aspirin, both, or neither among 17,187 cases of suspected acute my-
ocardial 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 Depart-
ment (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 facil-
itates the rate and extent of thrombolysis: results of the thrombol-
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 ag-
gressive 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 lym-
phoma. The addition of adjuvant chemotherapy im-
proves the results, and administering chemotherapy
before radiotherapy further augments the results.
A study has shown that the use of cyclophospha-
mide, doxorubicin, vincristine, and prednisone
(CHOP) alone is inferior to CHOP plus adjuvant ra-
diotherapy.1 In this issue of the Journal, Reyes et al.
report that the very intensive regimen of doxorubi-
cin, cyclophosphamide, vindesine, bleomycin, and
prednisone (ACVBP) is superior to CHOP plus ad-
1250 n engl j med 352;12 www.nejm.org
Downloaded from www.nejm.org on December 13, 2009 . Copyright © 2005 Massachusetts Medical Society. All rights reserved.
2720-32.
5. Topol EJ. Reperfusion therapy for acute myocardial infarction
with fibrinolytic therapy or combination reduced fibrinolytic thera-
py and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V ran-
domised 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 tenecte-
plase in combination with enoxaparin, abciximab, or unfractionat-
ed heparin: the ASSENT-3 randomised trial in acute myocardial in-
farction. 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 clopid-
ogrel 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 dis-
ease. N Engl J Med 2004;350:277-80. [Erratum, N Engl J Med 2004;
351:200.]
Copyright © 2005 Massachusetts Medical Society.
juvant involved-field radiotherapy for patients less
than 61 years of age with apparently localized dif-
fuse 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 approxi-
mately 20 percent of the patients treated with ACVBP
and more than 25 percent of those who were treat-
ed with CHOP plus radiotherapy were not cured.
One of the most important advances in the treat-
ment of cancer is the concept of “staging.” Determi-
nation of the stage of cancer came into general use
in the mid-20th century (the American Joint Com-
mission on Cancer was established in 1959) and ini-
tially 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.
march 24, 2005
 editorials
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 accom-
plish three important goals: determining the opti-
mal choice of therapy, imparting an accurate prog-
nosis to the patient and the family, and accurately
stratifying patients for clinical trials and quality as-
sessment.
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 Inter-
national Prognostic Index (IPI).4 The IPI was devel-
oped in an attempt to improve the ability to predict
the outcome among patients with aggressive non-
Hodgkin’s lymphomas. The IPI takes into account
not only anatomical stage but also age, perfor-
mance 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 approxi-
mately 75 percent among patients with Ann Arbor
stage II and from approximately 25 to approxi-
mately 65 percent among those with stage IV. Al-
though the IPI is a step forward in the prognostic
process, it still does not take certain factors into ac-
count, 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 max-
imal 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 cli-
nicians often take very bulky sites of disease into
account by adding radiotherapy to that site.
The development of the World Health Organiza-
tion’s system of classification for non-Hodgkin’s
lymphomas was an important advance in our ability
to manage these disorders.5 The system, an out-
growth of the revised European–American lympho-
ma classification,6 recognizes that non-Hodgkin’s
lymphomas are a group of illnesses, each with
unique biologic and clinical characteristics. The dis-
eases 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 (ap-
proximately 10 to 15 percent). When these kinds of
n engl j med 352;12 www.nejm.org
Downloaded from www.nejm.org on December 13, 2009 . Copyright © 2005 Massachusetts Medical Society. All rights reserved.
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, pa-
tients with anaplastic large T-cell or null-cell lym-
phoma 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 sys-
tem, 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, al-
though 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 consid-
ered to be the same. It is clear that certain extranod-
al sites of origin have important clinical implica-
tions. For example, testicular diffuse large B-cell
lymphoma frequently metastasizes to the central
nervous system and has a pattern of delayed re-
lapse not seen with this type of lymphoma originat-
ing at other sites.8
Although not yet ready for widespread use, the
patterns of gene and protein expression have recent-
ly been shown to be powerful predictors of the out-
come of treatment for diffuse large B-cell lympho-
ma. Lymphomas of this type exhibit distinctive
gene-expression patterns: one is similar to the pat-
tern of normal germinal-center B cells, and the oth-
er resembles the gene-expression pattern of activat-
ed circulating B cells.9 Patients whose lymphoma
has the germinal-center pattern survive approxi-
mately twice as long as patients with a lymphoma
of the activated B-cell type, and this difference ap-
pears to be independent of previously considered
prognostic factors.10 Genes are information-stor-
age devices, and the effect of gene expression is
mediated by the proteins they produce. Since the
relationship between gene expression and the pro-
duction 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.
march 24, 2005 1251
 The new england journal
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-Hodg-
kin’s lymphoma. In addition to the factors consid-
ered 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 sys-
tems. Correlating these observations with specific
treatments might allow the identification of sub-
groups of patients most likely to benefit from a par-
ticular 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
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 un-
pleasant truth that we must confront: if we are going
to create a sustainable system of health care financ-
ing 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 polit-
ical, there are substantial political and technical dif-
ficulties in figuring out desirable ways of spending
money.
1252 n engl j med 352;12 www.nejm.org
Downloaded from www.nejm.org on December 13, 2009 . Copyright © 2005 Massachusetts Medical Society. All rights reserved.
of medicine
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 Fac-
tors Project. A predictive model for aggressive non-Hodgkin’s lym-
phoma. 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 Interna-
tional 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;89:3909-
18.
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 large-
B-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 over-
come Bcl-2-associated chemotherapy resistance in untreated dif-
fuse large B-cell lymphoma. Blood 2001;98:343a. abstract.
Copyright © 2005 Massachusetts Medical Society.
The calls for universal health care in this issue of
the Journal, including a proposal for a voucher sys-
tem by Emanuel and Fuchs,2 raise at least four ques-
tions in thinking about publicly financed systems.
First, what role, if any, should there be for state gov-
ernments? 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 an-
swers to any of these questions.
Administration by the federal government has
the advantages of increasing the chances of equita-
ble treatment across the country and potentially pro-
march 24, 2005