conducting trials comparing
CHOP (cyclophosphamide [Cytoxan,
Neosar], doxorubicin HCl,
vincristine [Oncovin], prednisone)
with and without etoposide and
varying time intervals, the German
High-Grade Non-Hodgkin's Lymphoma
Study Group concluded that
CHOP plus etoposide is the new
standard regimen for younger patients
with low-risk non-Hodgkin's
lymphoma (NHL), and CHOP at
2-week intervals is the new standard
regimen for aggressive NHL in older
The two trials had the same objectives,
though with different age
groups: to improve treatment results
in patients with aggressive NHL by
shortening treatment intervals and/
or adding CHOP to etoposide.
Among the group of 18- to 60-yearolds,
CHOEP (CHOP plus
etoposide) achieved the objective.
Among the group of 61- to 75-yearolds,
shortening the time interval
between CHOP treatment courses
from 3 to 2 weeks achieved the objective.
Michael G. Pfreundschuh,
MD, of Medizinische Klinik I,
Universitt des Saarlands, Homburg, Germany, reported the results
at the 43rd Annual Meeting of the
American Society of Hematology
(abstracts 3026 and 3027).
Same Regimens and
In both studies, patients were
randomized to receive six cycles of
CHOP(21) (CHOP every 3 weeks),
CHOP(14) (CHOP every 2 weeks),
CHOEP(21) (3-weekly CHOEP), or
CHOEP(14) (2-weekly CHOEP). In
both CHOEP groups, the etoposide
was administered at 100 mg/m2 on
days 1 to 3. Patients in the 2-weekly
regimens also received granulocyte
colony-stimulating factor (G-CSF
[Neupogen]) starting on day 4.
The primary end point for both
studies was time to treatment failure.
The interim analyses for both
studies included patients who had
either follow-up of more than 3
months after therapy, or an event
(defined as disease progression, relapse,
death, or initiation of alternative
Younger and Low Risk
The younger age group included
18- to 60-year-olds with untreated
low-risk aggressive NHL. Low risk
was defined as normal pretreatment
lactate dehydrogenase (LDH). Inclusion
criteria also included an
Eastern Cooperative Oncology
Group (ECOG) performance status
of 0 to 3, normal white blood count
and platelets, and no major organ
Dr. Pfreundschuh presented interim
data from July 2001 on 659
patients with a median age of 48.
Sixty-six percent had no risk factors,
according to the age-adjusted International
Prognostic Index, 31% had
one risk factor, and 3% had two risk
factors. Twenty-eight percent of patients
had bulky disease, defined as
greater than 7.5 cm, and received 36
Gy of radiotherapy to the site. "All
four regimens had a high relative dose
intensity, clearly above 95%," Dr.
Better Response in Etoposide-
At nearly 84%, "the etoposidecontaining
regimens had a complete
remission rate of 89.3%, vs 83.9%
with CHOP," Dr. Pfreundschuh said.
"In contrast, in this population,
which did not have patients with elevated
LDH indicating relatively fastgrowing
tumors, the effect of the time
interval reduction was not significant.
Similarly, there is no difference
in time to treatment failure between
the 2-weekly and 3-weekly regimen,
but there is significant difference in
the time to treatment failure with
respect to the addition of etoposide."
At a median time of observation of
40 months, time to progression was
72.8% for CHOEP vs 67.5% for
CHOP. "The difference is not judged
significant for overall survival," Dr.
Adding etoposide had the greatest
effect-increasing the remission
rate by 17%-among patients with
one risk factor. "We are suggesting
that the addition of etoposide compensates
for one risk factor," Dr.
Pfreundschuh said. After 40 months,
there was also a 22% difference in
time to treatment failure and a 15%
difference in overall survival.
"CHOEP regimens have somewhat
more hematologic toxicities,"
Dr. Pfreundschuh reported, and required
more transfusions. There
were no major differences in
"We conclude that CHOP plus
etoposide is superior to CHOP in
young low-risk (low-LDH) patients,"
Dr. Pfreundschuh said. "Interval reduction
did not improve outcome in
patients with aggressive lymphoma
and normal LDH. "CHOEP is no
more toxic than CHOP, is well tolerated
in this population of younger
patients. We should therefore consider
CHOEP(21) as the new standard
regimen for low-risk (low-LDH)
Older and Higher Risk
Patients in the second trial reported
by Dr. Pfreundschuh were
not only older (61 to 75 years old)
but more likely to have elevated
LDH and advanced disease (50%)
and bulky disease (40%) requiring
additional radiotherapy. Other inclusion
criteria were the same as for
the younger patients.
"Adherence to the protocol was
quite good," Dr. Pfreundschuh reported,
"except for the double-intensive
CHOEP(14), where the relative
dose dropped to 87%."
The interim analysis included 612
patients, with a median age of 67
years. Complete response rates
ranged from 63.2% for CHOP(21)
to 77% for CHOP(14), with the
CHOEP rates in between (Table 1).
"It is mostly patients with elevated
LDH, a surrogate model for aggressive
growth, that profit from this
time interval reduction," Dr.
Pfreundschuh said. "Whereas complete
response rate only increased
by 8% in patients with normal LDH,
complete remission rate for patients
with elevated LDH increased from
48% to 70%. This translates into
significant differences in time to
treatment failure. With a median
time of observation of 40 months,
difference in time to treatment failure
is 14% between the worst arm-
CHOP(21)-and the best arm-
CHOP(14). This difference is similar
for overall survival."
Hematologic toxicities in the 2-
weekly regimen were not increased
significantly, due to G-CSF. Patients
in the CHOEP regimens had more
cycles with platelets below 50,000/μL.
New Reference Standard
"In summary, CHOP(14) is
superior to CHOP(21)," Dr.
Pfreundschuh said. "It is the best of
the tested arms in elderly patients
with aggressive NHL. The 2-weekly
regimen is feasible and toxicity is
not increased over CHOP(21) due
to the use of G-CSF. CHOP(14) is
our new reference standard for this