The Working Formulation tested the clinical utility of a consensus
diagnosis based on morphology of patients with lymphoma. The variable
to be tested was histology. Unfortunately, other factors affecting
outcome were not kept constant such that the results are confounded
by many variables including, most notably, stage and treatment.
Patients having stages I and II were included, thereby allowing a
200% variation in survival within some histologic subtypes (Table
1). Additionally, few patients received treatment of curative
potential. These shortfalls of the Working Formulation suggest that a
reappraisal of what constitutes an intermediate-grade histology is in order.
The question of whether any subset of follicular lymphoma is
potentially curable has fueled controversy for at least 15
years.[4-6] The answer is elusive for at least four reasons:
First, criteria used to determine what constitutes a follicular
architecture are variably applied (prominent or vague nodularity,
complete or partial nodularity). Within the Southwest Oncology Group
(SWOG), we classify a lymphoma as follicular regardless of the degree
or extent of the follicular pattern. That is, any vestige of a
follicular pattern constitutes a follicular lymphoma.
Second, the subtypes of follicular lymphoma cannot be reproducibly determined.
Third, follicular large-cell is an uncommon histology. In order to
have adequate numbers of patients for analysis, many investigators
have incorporated the complete spectrum of stages and treatments into
studies, thereby confounding interpretation of outcome.[8-10]
Fourth, most reported series have a relatively short follow-up period
(less than the known median survival [approximately 8 years] of
follicular lymphoma), thereby creating the appearance of a
tail or plateau in the survival curve.[9-10]
We have recently analyzed outcome of 53 patients with follicular
large-cell lymphoma (expert review by multiple hematopathologists),
having stages III and IV disease, treated with CHOP (cyclophosphamide
[Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine [Oncovin],
and prednisone), and followed for up to 25 years. We compared the
outcome of these patients with follicular large-cell to 336
follicular small-cleaved-cell and follicular mixed small- and
large-cell patients similarly matched for stage and treatment. There
is no evidence of a plateau in the survival curve, and nearly every
patient eventually relapsed with lymphoma (Figure
1). Furthermore, the survival curves for the other histologic
subtypes of follicular lymphoma are not significantly different.
Thus, our study suggests that follicular large-cell lymphoma fails
the test for intermediate-grade classification in the sense that it
is not curable. The Nebraska Lymphoma Study Group has reported
similar findings for all stages of follicular large-cell lymphoma.
This lymphoma is relatively uncommon in the United States and seems
to be disappearing as a distinct entity. The original entity was a
heterogeneous group of diseases, and at least two distinct clinical
and biologic subtypes have been split off from the original category,
namely, lymphoblastic lymphoma and mantle-cell lymphoma.[13,14] These
histologic subtypes require special treatment considerations; neither
do well with standard cyclic combination chemotherapy (see articles
in this ONCOLOGY supplement by Magrath
and Armitage . In addition, some
small-cleaved-cell lymphomas have intact follicular dendritic cells
detectable on immunohistochemical staining and indicative of
persistent follicular center cell architecture that is not evident
histologically. The remaining small number of patients seem to have
an outcome similar to large-cell lymphoma.
This category of lymphoma is highly heterogeneous and is not easily
separated from diffuse large-cell lymphoma. Ideally, it is a disease
of B cells with admixed small and large malignant cells. On occasion,
the admixed small cells are reactive and the condition is referred to
as T-cell-rich B-cell lymphoma. Many peripheral T-cell lymphomas are
included in this group, and these lymphomas have a different outcome
than the B-cell counterpart.
There are no recent data concerning this histologic subtype to
suggest that outcome, of at least the B-cell lymphomas (approximately
70%), differs significantly from that of diffuse large-cell lymphoma.
Recent unpublished updates of the Intergroup Lymphoma Study that
compared CHOP to other second- and third-generation regimens
demonstrate that survival curves for diffuse mixed small- and
large-cell lymphoma and for diffuse large-cell lymphoma are virtually
superimposable. For that reason, the new Revised
European-American Lymphoma (REAL) Classification does not distinguish
diffuse mixed as a separate entity.
Diffuse large-cell lymphoma is by far and away the most common
intermediate-grade histologic subtype. It is the prototype of
potentially curable lymphomas demonstrating a relatively flat
survival curve after 6 or 7 years of disease-free follow-up. The
relevant question for clinicians is whether diffuse large-cell,
immunoblastic subtype (Group H), constitutes a significantly
different disease. In that regard there is some controversy, but most
investigators believe that: 1) the two entities are difficult to
distinguish reproducibly, and 2) survival in prospective studies is
virtually identical.[1,17] For these reasons, the name diffuse
large-cell lymphoma is frequently used to include Working
Groups G and H.
In summary, intermediate-grade lymphomas, from a clinicians
perspective, constitute a different subset of diseases than the
Working Formulation originally defined. Our expectations are that the
disease has aggressive growth characteristics and a potential for
cure. In that regard, Working Groups E, F, G, and H probably best fit
All patients with intermediate-grade non-Hodgkins lymphoma are
initially treated with CHOP chemotherapy. Patients with localized
disease (stages I, IE, and non-bulky II and IIE) generally receive
three cycles of CHOP followed by involved-field radiotherapy (CHOP-3
plus RT) based on a randomized trial of 401 patients treated with
either CHOP-3 plus RT or eight cycles of CHOP (CHOP-8) alone.
CHOP-3 plus RT has been shown to result in better overall survival,
better time to treatment failure, and less toxicity than CHOP-8.
Estimates of overall survival at 5 years were 86% for patients with
stages I and IE disease treated with CHOP-3 plus RT, and 74% for
patients with stages II and IIE disease (non-bulky). Furthermore,
there was less overall toxicity, especially left ventricular failure,
for patients treated with CHOP-3 plus RT.
Patients with advanced disease (stages bulky-II, III, and IV)
received eight cycles of CHOP based on a randomized Intergroup Study
of 899 patients treated with either CHOP or one of three second- or
third-generation regimens including m-BACOD (methotrexate
[Rheumatrex], leucovorin, bleomycin [Blenoxane], doxorubicin,
cyclophosphamide, vincristine, dexamethasone), ProMACE-CytaBOM
(prednisone, doxorubicin, cyclophosphamide, etoposide [VePesid],
cytarabine [Cytosar], bleomycin, vincristine, mitoxantrone,
leucovorin), or MACOP-B (methotrexate, leucovorin, doxorubicin,
cyclophosphamide, vincristine, bleomycin, prednisone). In that
study, overall survival and time to treatment failure rates were
similar for all treatment arms, but patients treated with CHOP had
less life-threatening and fatal toxic events. Estimates of overall
survival at 5 years for patients treated on any of the four arms were
49% for stage bulky-II and 46% for stages III and IV (combined).
These two studies define standard treatment for intermediate-grade
non-Hodgkins lymphoma and establish a benchmark for future
comparisons (Table 1). They
don't, however, conclude the search for effective and safe therapy
for patients with intermediate-grade non-Hodgkins lymphoma. At
least 25% of patients with localized disease, and 50% of patients
with advanced disease, will relapse and die of lymphoma within 5
years following treatment with CHOP-based regimens.
Following relapse patients with recurrent intermediate-grade
non-Hodgkins lymphoma are treated with a variety of
salvage regimens and simultaneously evaluated for
high-dose chemotherapy and autologous transplant. Patients with
drug-sensitive lymphoma who are free of any complicating medical
problems generally receive high-dose chemotherapy and autotransplant
based on a randomized trial by Philip et al. In that study, for
the transplantation group, the event-free survival at 5 years was 46%
and overall survival was 53%; for the standard salvage chemotherapy
group, the event-free survival at 5 years was 12%, and overall
survival was 32%.
Attempts to broaden the role of high-dose chemotherapy and
autotransplant by treating patients with chemotherapy-resistant
disease, or by treating patients in complete remission, have not led
to convincing proof of benefit. In randomized trials of patients with
chemotherapy-resistant disease, high-dose chemotherapy has not been
shown to be better than conventional chemotherapy.[20-21] Likewise,
Haioun et al, in a trial of patients in complete remission, have
shown no difference in disease-free survival or overall survival
among 541 patients randomized to receive consolidation by either
sequential chemotherapy or autotransplant. In that study, a
subgroup analysis of 236 randomized high-risk patients (defined as
high-intermediate and high-risk according to the International
Prognostic Index, see Table 2)
revealed a significant difference in disease-free survival, but not
in overall survival.
There are a large number of standard-dose chemotherapy regimens in
use for treating recurrent intermediate-grade lymphoma, and there are
little data to distinguish them from each other. Two platinum-based
regimens developed by the M. D. Anderson group have gained wide
acceptance and have a singular advantage as preinduction treatment
prior to autotransplant by limiting exposure to anthracyclines.
The DHAP (dexamethasone, cytarabine, and cisplatin [Platinol])
regimen is most frequently used, yielding a 44% to 59% overall
response rate in recurrent intermediate- and high-grade
lymphoma.[19,23] (The response rates to DHAP vary widely, 21% to 64%,
as they do in all salvage studies, depending on whether patients had
primary chemotherapy-resistance or relapsed after obtaining an
initial response to a doxorubicin-containing regimen.) However, a
recent update including long-term follow-up, compares DHAP to ESHAP
(etoposide, solumedrol [methylprednisolone], cytarabine, and
cisplatin), and demonstrates an advantage for patients treated with
ESHAP in regard to time to treatment failure and overall survival.
There are many clinical features associated with survival duration of
patients with intermediate-grade non-Hodgkins lymphoma, and
many more publications attempting to determine the optimum
combination of risk factors (see Moore and Cabanillas ).
Shipp et al have recently completed an analysis of the most commonly
reported clinical prognostic factors by assessing outcome in 2,031
patients treated with potentially curative therapy. This
International Prognostic Index has been largely successful by
allowing a standardized application of clinical variables to trial
design and interpretation of result reporting. Two examples of its
use are detailed to demonstrate the potential for use in this group
of intermediate-grade lymphomas.
First, a consistent and reproducible system of determining prognosis
can be helpful in designing future trials by honing the patient group
to be studied. The recently published Southwest Oncology Group study
of localized lymphoma provides an example. Inasmuch as a large
number of patients were cured with relatively well-tolerated
treatment (CHOP-3 plus RT), it makes little sense to include those
cured patients in future trials of more intensive or costly treatment
designed for the subset of patients who failed treatment. In our
planned study of localized lymphoma, we have applied the
International Prognostic Index modified for localized disease by
specifying non-bulky II as a poor risk factor (rather than stage III
and IV). Analysis reveals that for patients without any risk factors
(stage I, less than 60 years, normal LDH, good performance status,
and less than two extranodal sites of disease) 5-year survival is
95%, whereas patients having any adverse risk factor(s) have a 5-year
survival of 69%. By eliminating patients without any risk factors, we
will spare about 30% of patients more intensive therapy, and we will
target patients having a reasonable possibility of relapse with
current standard therapy.
Second, a system using clinically available data allows comparisons
between studies to help explain apparent inconsistencies and avoid
unnecessary time and resource allocation to large randomized trials.
The Intergroup Lymphoma Study comparing CHOP to second- and
third-generation regimens was controversial from the time of
conception, and the results remained controversial long after
completion. Pilot data suggested that ProMACE-CytaBOM was superior to
CHOP (the justification for the randomized comparison). The
randomized comparison result showed no difference in outcome and was
presumed by some investigators to reflect lack of experience with the
regimen, and thus, an inadequate test of the regimen. Early
application of the International Prognostic Index might have changed
the design of that study. The International Prognostic Index
Comparison of Risk Group Composition allows for comparison of risk
group composition between different studies and may help explain
observed differences in outcome. As Table
2 summarizes, there was a remarkable disparity in patient
selection between institutions participating in the Intergroup
Lymphoma Study and at the NCI.[15, 25] The proportion of patients in
the lowest risk group (one adverse prognostic factor) was 44% at the
NCI, twice that of the Intergroup Study. The cause of the disparate
results between the pilot study and the randomized trial is no longer mysterious.
Approximately 12% of patients with intermediate-grade lymphoma will
have a T-cell malignancy, and 88% will have a B-cell disease.[26,27]
The importance of determining cell lineage was historically
controversial, but the vast majority of recent reports, as summarized
by Gascoyne, document a shortened disease-free survival, shortened
survival, or both.  The issue is consequential, as getting the
facts straight is the first step toward improving therapy.
Vose et al have changed therapy for patients with T-cell lineage by
increasing the dose-intensity with autotransplants and report an
early experience of possible improved outcome. Increasing the
dose-intensity might be a correct solution if one extrapolates from
work by Klimecki et al who showed that normal circulating blood cells
displayed a quantifiable hierarchy with regard to drug-resistant
protein expression. T-cell subsets consistently expressed more
p-glycoprotein than B-cells, and therefore, might benefit from
increased dose-intensity. Regardless, clinicians should exercise
caution when treating a younger patient with a T-cell
Clinicians look forward to the opportunity to treat patients with
intermediate-grade non-Hodgkins lymphoma. Most patients respond
to treatment and there is that opportunity to effect a cure. However,
there is only one small subset of patients for whom standard therapy
is acceptable. Those patients have stage I disease, are less than 60
years old, have a normal LDH, and are generally asymptomatic. We can
offer such patients a 95% probability of cure, and thats not
bad in medicine. However, for all other patients, the outcome
afforded by standard therapy is not acceptable, and until more of
these patients are enrolled in clinical trials, the longer we have to
look forward to offering unacceptable treatment.
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