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Chemotherapy of Intermediate-Grade Non-Hodgkin's Lymphoma: Is "More" or "Less" Better?

Chemotherapy of Intermediate-Grade Non-Hodgkin's Lymphoma: Is "More" or "Less" Better?

ABSTRACT: While it would seem obvious that dose intensity is an important determinant of treatment outcome in aggressive lymphomas, actually there are very few prospective data to support this hypothesis. Circumstantial evidence derived from retrospective analyses suggests that dose intensity is of clinical significance. However, based on available phase II and III data and the one prospective randomized trial to date that has specificially addressed this issue, it remains unclear what impact dose intensity has on treatment outcome. [ONCOLOGY 9(12):1273-1286, 1995]

Introduction

While it would appear to be intuitively obvious that dose intensity
is an important determinant of treatment outcome in aggressive
lymphomas, actually very few prospective data support this hypothesis.
There is, however, considerable circumstantial evidence that dose
intensity may be an important variable in treatment outcome. Unfortunately,
this is not adequate to prove the hypothesis.

DeVita et al were among the first investigators to discuss the
relationship of dose intensity to lymphoma treatment outcome [1].
These investigators proposed a model to relate the projected relative
dose intensities of nine drugs (as defined by a treatment protocol)
to the outcome realized by using various other regimens that incorporated
some or all of these agents. Using this model, they demonstrated
a significant correlation between dose intensity and treatment
outcome. Problems inherent in a model such as this, which uses
projected dose intensity, include the following:

  1. Generally, all agents are considered to be equally effective.
  2. There is no way to take into account possible effects related
    to drug scheduling.
  3. The projected dose intensity is usually not fully delivered.

Several authors have attempted to analyze the contribution of
dose intensity to outcome in retrospective analyses of completed
trials. In a preliminary analysis of results obtained with M-BACOD
and m-BACOD (both regimens employing methotrexate [in different
doses], bleomycin, Adriamycin, cyclosphophamide, Oncovin, and
dexamethasone), Shipp et al reported that delivery of more than
80% of projected doses of doxorubicin, vincristine, and cyclophosphamide
(Cytoxan, Neosar) was associated with improvement in remission
rates and survival [2]. A subsequent analysis noted, however,
that in patients who successfully completed eight cycles of therapy,
this relationship of received dose intensity and outcome was no
longer observed.

The results obtained with the LNH-84 regimen were reported by
Coiffier et al [3]. Received dose intensity data were available
for 720 of 737 patients treated. While the authors were unable
to show statistically significant differences in outcome, they
did demonstrate a trend toward a lower relapse rate in those receiving
higher dose-intense therapy. It should also be noted that a trend
toward a higher death rate also was seen in this same group of
patients.

Epelbaum et al analyzed a series of 78 patients with diffuse large-cell
lymphoma treated with the CHOP (cyclophosphamide, doxorubicin
HCl, Oncovin, and prednisone) regimen to ascertain the contribution,
if any, of dose intensity to outcome [4]. These authors were able
to demonstrate a statistically significant association between
survival and the received dose intensity of doxorubicin.

Kwak et al reported results of a multivariate analysis of 115
patients with diffuse large-cell lymphoma treated with three different
chemotherapy regimens: CHOP, M-BACOD, and MACOP-B (methotrexate,
Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin)
at different periods of time [5]. Similar survival curves were
noted for each of the three regimens. However, the authors did
observe a correlation between average relative dose intensity
and the received dose intensities of doxorubicin and cyclophosphamide
and survival. Using the statistical technique of recursive partitioning,
the authors found that after pretreatment hemoglobin, the dose
intensity of doxorubicin proved to be the most discriminating
prognostic variable.

The technique of meta-analysis also has been employed in an attempt
to define the relationship between dose intensity and treatment
outcome. Meyer et al performed a meta-analysis on pooled data
from 22 studies, of which 14 were randomized trials [6]. High-
and low-intensity treatment groups within the 14 trials, which
included 2,366 patients, were pooled and compared.

The results of the analysis demonstrated that the relative probability
of achieving a complete response was 1.34 in favor of the pooled
arm of high dose intensity. Unfortunately, because of the variable
length of follow-up, long-term disease-free survival, which is
a more meaningful measure of treatment outcome than is complete
remission rate, could not be compared in the analysis. The authors
correctly point out that any conclusions drawn from this analysis
must be accepted with caution because the groups are heterogeneous,
the treatments are varied, and considerable assumptions are made
at the outset in the performance of such an analysis.

Hence, whereas these retrospective analyses have, in some cases,
suggested a correlation between dose intensity and outcome, they
do have to be interpreted cautiously, in large part, because they
are retrospective. Although there is circumstantial evidence that
dose intensity may be an important predictor of outcome, there
is very little direct evidence available from prospective studies.
Four of the regimens in the model proposed by DeVita-m-BACOD,
ProMACE/CytaBOM (prednisone, methotrexate, Adriamycin, cyclophosphamide,
etoposide, cytarabine, Oncovin, and methotrexate) ProMACE-MOPP
(prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide,
mechloroethamine, Oncovin, procarbazine, and prednisone) and MACOP-B-have
greater projected dose intensity than CHOP. These regimens have
been studied extensively in clinical trials.

In this review, we will focus on results obtained in phase II
and III studies employing these regimens. It should be noted that,
in many of the earlier phase II studies, received dose intensity
data was not reported, and thus, the database is incomplete. It
should also be noted that none of the phase III studies we will
review that employed these four regimens or CHOP were prospectively
stratified by dose intensity. Finally, we will review the single
prospective phase III study that has directly tested the question
of dose intensity and has been reported in the literature. Key
terms that will be used in this article are defined in Table 1.

Phase II Studies

m-BACOD

M-BACOD is a regimen that was developed and piloted at the Dana-Farber
Cancer Institute [7]. The regimen employs high-dose methotrexate
with leucovorin rescue given at mid-cycle, that is, at the time
of maximal bone marrow suppression secondary to the myelotoxic
drugs that are given at the beginning of the cycle (see Table
2
). Although this regimen proved to be effective and appeared
to be a significant improvement over prior chemotherapy regimens,
it was also costly and required hospitalization.

The m-BACOD regimen, which employs moderate-dose methotrexate
(see Table 2), was therefore piloted by the same group, and results
similar to those seen with the high-dose regimen were achieved
[8]. Of the 134 patients with diffuse histiocytic or undifferentiated
lymphoma who were treated, 75% had either stage III or IV disease.
The median age of the treated patients was 49 years. Eighty-two
patients (62%) achieved a complete response and 62 (76%) of these
remain in complete remission with a median follow-up of 3.6 years.
The predicted 1-, 3-, and 5-year survival rates were 80%, 63%,
and 60% respectively. The disease-free survival rate at 5 years
for patients achieving a complete response was 74%.

As noted above, in a preliminary analysis of the data, Shipp et
al noted a correlation between dose intensity and outcome. This
correlation, however, was no longer found to be of importance
when patients completing eight cycles of therapy were analyzed.

The Southwest Oncology Group (SWOG) conducted a confirmatory phase
II trial of the m-BACOD regimen [9]. By study design, patients
were stratified at registration as having either normal or impaired
bone marrow reserve. Of the 106 eligible patients, 28 were in
the impaired category and received decreased doses of cyclophosphamide
and doxorubicin. In the study population as a whole, 76% had diffuse
large-cell lymphoma, 75% had stage III or IV disease, and 46%
had B symptoms.

The overall complete response rate was 56%. There was, however,
a marked difference in complete response rates in the normal and
marrow-impaired groups. At 3 years, 64% of the normal marrow group
who achieved a complete response were disease-free, as compared
with 29% in the marrow-impaired group. It should be noted that
despite decreased dosages, the marrow-impaired group experienced
toxicity similar to those treated with full-dose therapy.

The relative dose intensity on the normal marrow reserve arm was
.76 for cyclophosphamide, .75 for doxorubicin, .90 for vincristine,
.85 for dexa-methasone, and .55 for methotrexate. On the impaired-marrow
reserve arm, as would be expected, the values for all drugs were
lower. In addition to being given decreased doses of cyclophosphamide
and doxorubicin by study design, patients with marrow impairment
also had more dose reductions and treatment delays, as compared
to patients with normal marrow reserve.

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