LUGANO, SwitzerlandAlthough a decades worth of
phase II studies in advanced large-cell lymphoma have suggested that
new, multidrug regimens could nearly double both the complete
response rate and the proportion of long-term survivors, appearances
can be deceiving, Richard Fisher, MD, Coleman Professor of Oncology,
Loyola University Medical Center, Maywood, Illinois, said at the VII
International Conference on Malignant Lymphoma.
Dr. Fisher underscored this contention with new long-term follow-up
data from the 1993 SWOG/ECOG 8516 trial, which compared CHOP with
three intensive chemotherapy regimens, m-BACOD, Pro-MACE-CytaBOM, and
MACOP-B. After 7 years, progression-free survival was 33% to 38% and
overall survival was 45% to 46%, with none of the third-generation
regimens exhibiting any significant advantage over CHOP.
The misleadingly favorable results of earlier phase II studies, Dr.
Fisher said, are probably attributable to the inadvertent inclusion
of more low-risk patients in nonrandomized trials.
Although CHOP remains the standard, as good as any with the
least toxicity, it is unacceptable for the long term because it fails
to cure more than half of patients, Dr. Fisher stressed.
Four New Strategies
At least four strategies are being explored in an attempt to boost
the disappointing cure rates in lymphoma. Whether doubling the dose
intensity of CHOP with the use of cytokines will be enough to modify
the natural history of lymphoma was the focus of the just-completed
SWOG 9349 trial.
Another approach that has aroused considerable interest is to
surmount drug resistance with chemosensitizing agents.
However, Dr. Fisher said, the efficacy of drug
resistance modification has not yet been borne out in the
Since the CD20 antibody is expressed in about 85% of large-cell
lymphomas, it represents a logical target for monoclonal antibody
treatment. As a single agent, rituximab [Rituxan] yields a
response rate of about 33%, Dr. Fisher noted. However,
preliminary results have suggested that when this monoclonal antibody
is coupled with CHOP, the complete response rate may be as high as
73%. Prospective randomized studies using rituximab are now being
conducted by ECOG, CALGB, and SWOG.
Role of Transplantation
Dr. Fisher called ablative chemotherapy with bone marrow or
peripheral blood stem cell support the glass thats half
full and half empty. He reminded the audience of the PARMA
study, which showed that transplant clearly prolonged survival in
patients who achieved a complete response, subsequently relapsed, and
remained sensitive to chemotherapy. While this strategy is
effective for the individual who meets these criteria, it will not
have a statistically major impact on overall survival, he maintained.
In contrast, Dr. Fisher said, the study of Verdonck and colleagues
failed to show any advantage of transplant over CHOP in slow
responders. A small study from the Milan group, on the other hand,
indicated that high-dose sequential chemotherapy was superior to
MACOP-B in terms of both freedom from progression and overall survival.
Retrospective subset analysis in several prospective studies
has suggested that the benefits of high-dose chemotherapy with
transplant may be limited to high-risk patients, Dr. Fisher
said. He acknowledged, nonetheless, that this finding has not been
universal and that the picture is complicated.
The hypothesis that I would generate for you is that
intermediate-risk and high-risk patients with aggressive lymphoma who
receive full-course standard induction therapy will benefit from the
addition of a high-dose therapy program, Dr. Fisher said.
To test this hypothesis, a US cooperative intergroup study will be
randomizing patients with high-intermediate risk and high-risk
lymphoma who have responded to five cycles of CHOP to receive either
one additional cycle of CHOP followed by high-dose chemotherapy with
autologous stem cell rescue (early transplant) or three additional
cycles of CHOP, with salvage transplant carried out in cases of
relapse (late transplant).
In nonbulky early-stage large-cell lymphoma, a large-scale SWOG trial
has demonstrated that three cycles of CHOP followed by involved-field
radiation is superior to standard-dose, full-course chemotherapy
alone. A companion study conducted by ECOG has obtained similar
results in patients with bulky early-stage disease.
I believe that we should vary the amount of chemotherapy based
on tumor bulk and use involved-field consolidation in all early-stage
patients, Dr. Fisher said. He pointed out that the cure rate in
early-stage disease is in the range of 80% to 90%, comparable to that
achieved in Hodgkins lymphoma.