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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4560-4567
Moderate Dose Escalation for Advanced Stage Hodgkin's Disease
Using the Bleomycin, Etoposide, Adriamycin, Cyclophosphamide,
Vincristine, Procarbazine, and Prednisone Scheme and Adjuvant
Radiotherapy: A Study of the German Hodgkin's Lymphoma Study Group
By
H. Tesch,
V. Diehl,
B. Lathan,
D. Hasenclever,
M. Sieber,
U. Rüffer,
A. Engert,
J. Franklin,
M. Pfreundschuh,
K.P. Schalk,
G. Schwieder,
G. Wulf,
G. Dölken,
P. Worst,
P. Koch,
N. Schmitz,
U. Bruntsch,
C. Tirier,
U. Müller, and
M. Loeffler for the German Hodgkin's Lymphoma Study Group (Chairman Prof V. Diehl)
From the Klinik I für Innere Medizin, Universität
Köln, Köln, Germany; the Institute for Medical Informatics,
Leipzig, Germany; Med. Klinik Homburg, Stuttgart, Germany;
Lübeck, Germany; Göttingen, Germany; Freiburg, Germany;
Mannheim, Germany; Münster, Germany; Kiel, Germany;
Nürnberg, Germany; Essen-Werden, Germany; and München re.
d. Isar, Germany.
 |
ABSTRACT |
The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide,
vincristine, procarbazine, and prednisone) regimen, a rearranged and
accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been
shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a
maximum practicable dose of three drugs, ie, etoposide, adriamycin, and
cyclophosphamide, for which acute toxicities were acceptable and to
assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study.
Radiotherapy was given in 44 patients (73%) after chemotherapy to
initial bulk lesions and residual disease. Granulocyte-colony
stimulating factor (G-CSF) was given from day 8 to prevent prolonged
neutrocytopenia and severe infections. The intended doses of
adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule
could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and
thrombocytopenia with considerable heterogeneity between individual
patients. Of 60 patients, 56 (93%) achieved a complete remission (CR).
At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95%
confidence interval 83% to 99%) and 90% (82% to 98%). These
results show that a moderate dose escalation of adriamycin,
cyclophosphamide, and etoposide of the baseline BEACOPP regimen is
feasible. The escalated BEACOPP regimen shows very encouraging results
in advanced stage HD and is now being compared in a randomized phase
III study with BEACOPP at baseline dose level.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
THE TREATMENT OF CHOICE for patients with
advanced Hodgkin's disease (HD) is polychemotherapy. A number of
regimens induce complete remission (CR) rates in 70% to 90% of
patients.1 However, about one third of those achieving CR
will subsequently relapse. For more than 20 years, the MOPP
chemotherapy regimen (mustargen, vincristine, procarbazine, and
prednisone), introduced by DeVita et al,2 had been
considered standard treatment for advanced stages. The analysis of
regimens which are not crossreactive with MOPP led to the development
of the ABVD scheme (adriamycin, bleomycin, vinblastine, and
dacarbacine) by Bonadonna et al.3 Subsequently, several
other chemotherapy combinations were analyzed, which did not improve
the results of MOPP- and ABVD-like regimens.2
Large randomized studies have compared MOPP or MOPP-like regimens with
MOPP alternating with ABVD, and the superiority of alternating
MOPP/ABVD over MOPP alone has been
demonstrated.3,4 However, it is not yet clear whether
MOPP/ABVD is superior to ABVD alone. Hybrid regimens such as MOPP/ABV,
in which all cytostatic drugs are given within 8 days, did not show
better remission or relapsefree survival rates when compared with
the alternating MOPP/ABVD standard therapy or ABVD, but were
more toxic.5,6
One possible way of improving treatment results is by dose escalation
of effective cytostatic drugs. The relationship between the total dose
of chemotherapy and antitumor response has been demonstrated in certain
experimental tumor models where the response curve for several
cytotoxic drugs is steep in the linear phase.7 A positive
correlation between the dose of antineoplastic drugs and response rate
was also demonstrated in human tumors in retrospective analyses.2,7 In HD, the dose of vincristine has been shown to affect the results of treatment in the MOPP scheme.8,9 Prospective clinical trials proving the role of dose in HD, however, do
not exist.
To study dose escalation in HD, two main questions have to be
addressed: (1) which group of patients may profit from dose-escalated therapy? (2) To what extent can the doses of key drugs be safely escalated within the limits of a predefined rate of toxicities? Despite
several attempts, no subgroup of patients with a very high risk of
treatment failure (who may be candidates for primary high-dose
chemotherapy with stem cell support) could be identified in HD. Thus,
the question remained whether moderate dose escalation applied to all
advanced-stage patients is possible with defined tolerable toxicities
and whether this strategy could improve treatment results. A
mathematical model of lymphoma growth and chemotherapy effects has been
recently developed.10 The model was based on assumptions of
an exponential tumor growth, chemotherapy sensitivity, the potential
treatment efficacy as a function of total dose, and a net treatment
efficacy at the end of treatment. It extended the simple, well-known
model of chemotherapy by incorporating heterogeneity concerning tumor
growth and chemosensitivity. The model allows estimation of the
distribution of latency times (time until the tumor can be clinically
detected) and the distribution of chemosensitivity in a patient
population. The model was fitted to the data of 705 patients of stage
IIIB/IV HD of the German Hodgkin's Lymphoma Study Group (GHSG). It
predicted that moderate dose escalation of 30% may lead to a potential
benefit of 10% to 15% in tumor control at 5 years.
To prepare a series of studies on the role of moderate dose escalation
in the treatment of advanced stage HD, the GHSG initiated a phase II
study with a new scheme: BEACOPP in baseline dose.11 The
BEACOPP regimen incorporates most active drugs of COPP/ABVD regimen,
ie, adriamycin, cyclophosphamide, vincristine, procarbazine, bleomycin,
and prednisone (Table 1). Etoposide was
added, because it was assumed to have a high activity in HD and can be
escalated substantially. Time schedule of application was rearranged in that (1) all cytotoxic drugs were given within 8 days and recycled after 21 days. The rescheduling of drugs allows a longer therapy-free interval with a better regeneration of hematopoiesis.11
In a first phase-II trial, BEACOPP was applied at baseline level (doses
for adriamycin, cyclophosphamide, and etoposide were 25, 650, and
100 × 3 mg/m2, respectively) without
granulocyte colony-stimulating factor (G-CSF). Thirty patients were
recruited for this study, and 29 were evaluable for response and
toxicity. Toxicities were tolerable with no treatment-related deaths.
Of 29 patients, 27 reached CR. At a median follow-up of 40 months, the
freedom from treatment failure (FFTF) rate was 89%.11
The objective of the present study was to escalate the doses of
adriamycin, cyclophosphamide, and etoposide up to a predefined rate of
acceptable hematotoxicity. The dose of adriamycin was increased at a
fixed level to 35 mg/m2, whereas the doses of
cyclophosphamide and etoposide were increased stepwise. This was done
in an adaptive strategy to identify a maximum practicable dose level,
which could be safely applied with a predefined rate of maximal
hematologic and nonhematologic toxicities. G-CSF was given from day 8 to reduce neutropenia and the rate of infections.
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MATERIALS AND METHODS |
Patient eligibility and pretreatment diagnosis.
Patients between 16 and 65 years of age with biopsy-confirmed HD in
untreated stages IIB and IIIA were eligible for this study if they had
one of the following risk factors: extranodal involvement or large
mediastinal mass (more than one third of thoracic diameter), massive
spleen involvement, high erythrocyte sedimentation rate (ESR) (over
30), or more than three involved lymph node sites). Patients in stages
IIIB and IV with or without risk factors were also eligible. Exclusion
criteria included a positive human immunodeficiency virus (HIV) test,
pregnancy, creatinine-clearance below 60 mL/minute, white blood cell
(WBC) count less than 3,000/µL, platelet count less than
100,000/µL, serum bilirubin greater than 2 mg/dL, concurrent
infections, and severe cardiac, pulmonary, or cerebral dysfunction.
Each patient provided written informed consent.
Pretreatment evaluation included medical history and physical
examination, complete blood count, liver and renal functional tests;
ESR, chest x-ray, abdomen ultrasound, chest, abdominal and pelvic
computed tomography (CT), and bone marrow biopsy. A liver biopsy was
performed in 42 patients. For analysis of toxicity, echocardiography
and lung functional tests were also performed. Staging laparotomy was
not required to enter the study and was performed in five cases only.
Treatment protocol.
Patients were scheduled to receive eight cycles of chemotherapy.
Chemotherapy was administered as described in Table 1. G-CSF (filgrastim, 300 µg for patients <70 kg body weight, 480 µg for patients >70 kg, subcutaneously [SC] once daily) was
applied from day 8 for at least 3 days. G-CSF application was stopped
when leukocytes exceeded 2,000/µL for 3 days after nadir or when
leukocytes exceeded 50,000/µL once. The following cycle was applied
on day 21 if leukocytes were above 2,500/µL and platelets above
80,000/µL.
Dose levels of adriamycin, cyclophosphamide, and etoposide are given in
Table 1. The individual level was planned for all eight cycles except
if the patient had a toxic event, in which case, a dose reduction was
performed (see below). A toxic event occurring in one treatment cycle
was defined as a WBC less than 1,000/µL for more than 4 days
and/or a platelet count less than 25,000/µL and/or
fever/infection World Health Organization (WHO) grade 4 and/or mucositis WHO grade 4.
We developed a generalized version of the up-and-down method of
Storer12 adapted to multiple cycle chemotherapy and
simultaneous treatment of patients.13 In addition to
baseline level, six dose levels were also specified (Table 1). A
patient was selected for an individual dose level by the study
coordination center starting at level 1. The initial dose level for the
subsequent patient was determined on the basis of each toxicity result
(yes or no) of the previously treated patients. A toxic event at a given dose level reduced the actual dose level by 1. When two patients
treated at a given level were recorded to have no toxic events, the
actual level for the subsequent patient was increased by 1. At least
two cycles of chemotherapy without toxic events had to elapse in two
patients before assignment was made to the next level. Thus, the
procedure approximated the maximum practicable level with a 33%
probability of toxic events per cycle.
If a treatment delay of 1 to 2 weeks or a toxic event had occurred, a
dose reduction of one level was performed for the individual patient
for all subsequent cycles. In case a second toxic event or treatment
delay occurred in the subsequent cycle, the dose was reduced to the
baseline level; if the event occurred not in the subsequent, but in a
later cycle, the dose level was reduced by two levels. If a
therapy-related delay of more than 2 weeks occurred, a reduction to the
baseline level was performed. If a therapy-related delay of more than a
week occurred at baseline level, the doses of cyclophosphamide,
adriamycin, procarbazine, and etoposide were reduced to 75%.
Consolidative radiotherapy.
Bulky disease areas (initially more than 5 cm measured by CT scan) were
irradiated with 30 Gy; residual disease that appeared enlarged (> 2cm) clinically or by CT scan after eight cycles of chemotherapy was
treated with 40 Gy.
Response assessment and follow up.
All patients had a physical examination, complete blood cell count,
blood chemistry including ESR, CT scans of involved areas after four
cycles and eight cycles of chemotherapy, and after radiotherapy.
Follow-up examinations were performed within the first 2 years in
3-month intervals, at years 3 and 4 in 4-month intervals, and from year
5 in 6-month intervals.
Treatment was documented after each cycle of chemotherapy and after
radiotherapy. Documentation included dose schedule, dose given, and
toxicities. All data were carefully checked by two data managers and a
physician. The success of treatment was determined by restaging 4 weeks
after chemotherapy and 4 to 8 weeks after the termination of the
protocol treatment. Restaging consisted of a controlled and careful
documentation of all initial disease manifestations by adequate
clinical and histologic methods. CR was defined as the disappearance of
all clinical disease manifestations for at least 4 weeks; partial
remission (PR) was defined as the reduction in all disease
localizations by at least 50% as detected by the products of
perpendicular diameters. Residual disease (>2cm) with suspected
active disease after chemotherapy was allocated for radiotherapy;
residual disease after chemo- and radiotherapy was considered as
CRR (CR with residual lesion), which was to be observed,
but not treated further.
Biometry.
Dose intensity was calculated as total dose per m2 divided
by the duration of the entire therapy in weeks. Because the "last day of therapy" was not documented as such, this was taken to be 21 days after the beginning of the last cycle.
FFTF was defined as the time from the start of therapy to the first of
the following events: death, progressive disease, non-CR status at the
end of the protocol treatment or relapse. Survival times were obtained
and included all deaths, whether disease-related or not. Kaplan-Meier
estimates are given for the probabilities of survival beyond a given
time.
A statistical model for the probability of a toxic event in a given
BEACOPP cycle as a function of dose level was fitted to the toxicity
data. The probability of toxic response was assumed to increase
logistically (ie, in an S-shaped curve) with increasing dose. The
"random effects" model allows for patient heterogeneity in
susceptibility to toxicity. The influence of the parameters dose level,
sex, and cycle was analyzed.
| |
RESULTS |
Patient characteristics.
Table 2 lists the clinical characteristics
of the 60 patients recruited. Median age was 31 years with a range
between 16 and 62. Thirteen percent of the patients were in stage IIB
and had additional risk factors, either large mediastinal mass, massive spleen, or extranodal involvement. Fifty percent were in stage III and
37% in stage IV, respectively. Thus, most patients had both advanced
stage disease and additional clinical risk factors such as bulky
disease (68%), a large mediastinal mass (25%), extranodal involvement
(48%) including bone, skin, pleura, and lung. Among patients with
stage IV (n = 21), there were 10 patients with liver involvement, six
with infiltration in the bone marrow, eight with lung infiltration, and
six with bone infiltration. The histologic subtype in most patients was
nodular sclerosis (NS, 80%), followed by mixed cellularity (MC, 15%),
whereas lymphocyte predominant (LP) subtype was rare (2%).
Dose escalation within the BEACOPP scheme.
The evolution of dose levels of this adaptive escalation study is given
in Fig 1. Because the information about
whether a toxic event had occurred was not always available at the
beginning of the treatment for an individual patient, more than three
patients were recruited at levels 1 and 2.
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| Fig 1.
Evolution of dose levels in the BEACOPP scheme. Each dot
represents the initial dose level of a patient recruited in the study.
Dose escalation in the cohort of patients was performed as described.
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The intended dose levels of cyclophosphamide and etoposide were
compared with the actual given levels achieved on average in all cycles
(Fig 2). Intended dose refers to the
initial dose level in the first cycle for each patient and to the
intended course duration of 8 × 21 days. Actual dose intensities
refer to the total given dose and to the actual duration of the course of all given cycles (last cycle taken as 21 days). Given dose intensities of cyclophosphamide and etoposide were lower than intended
dose intensities, because (1) not all cycles were repeated after 21 days and (2) reduction of dose levels was performed in some patients
due to toxicities. Sixty-eight percent of cycles were given after 21 to
25 days, and 85% of cycles were given within 30 days. Although the
intended dose intensities could not be reached, the given dose
intensities increased parallel to the intended levels. G-CSF
administration was documented in 66% of all cycles, with a mean
duration of administration of 7.4 days (maximum, 23 days).
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| Fig 2.
Comparison of the intended dose levels of
cyclophosphamide and etoposide with the actual given levels achieved on
average in all cycles. Intended dose refers to the initial dose level
in the first cycle for each patient and to the intended course duration
of 8 × 21 days. Actual dose intensities refer to the total given dose
and to the actual duration of the course of all given cycles (last
cycle taken as 21 days). Patients separated according to sex and
arranged in order of increasing initial dose level. ( ) Given DI of
C; ( ) given DI of E; () intended DI of C;
() intended DI of E.
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Radiotherapy.
A total of 44 patients (73%) received radiotherapy for initial bulky
disease alone (n = 12), residual disease alone (n = 2), both bulky and
residual disease (n = 28), or erroneously without either documented
bulky or residual disease (n = 2). Two patients terminated chemotherapy
before remission status could be determined, and one could not be
irradiated due to severe toxicity after chemotherapy, from which he
died.
Toxicities.
Table 3 lists the frequency of toxicities
(WHO grade III and IV) observed in 452 cycles. Major toxicities
included leukocytopenia, thrombocytopenia, and anemia. Leukocytopenia
and thrombocytopenia occured more frequently at dose levels 4 to 6 as
compared with levels 1 to 3. However, the high percentage of
leukocytopenia (71% to 76%) was not accompanied by a similar rate of
infections, which only occurred in 2% of all cycles. Platelet
substitutions were performed in 7.5% and erythrocyte substitutions in
23% of cycles. Nausea, gastrointestinal toxicities, pain, and
respiratory toxicities were reported with low frequencies.
When the rate of toxic events (as defined above) was compared in
individual patients, it appeared that there was substantial heterogeneity (Fig 3). First, female
patients suffered more frequently from toxic events than male patients
(P < .0001). Second, the rate of toxic events increased
steadily from the second to the eighth cycle, which suggests a
cumulative effect (P < .001). However, the first cycle was
significantly more toxic than the following two cycles. Third, toxic
events occurred in some patients during several successive cycles,
although these patients had been subsequently treated at lower dose
levels or at baseline level. The statistical analysis also showed a
significant effect of dose level (P < .01). The probability
of toxic events increased with dose level, giving a maximum practical
dose at level 4. At this level, the probability of a toxic event was
about 33% averaging over all treatment cycles.
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| Fig 3.
Occurence of toxic events in individual patients treated
at different dose levels. ( ) Toxic response; ( ) no toxicity.
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Treatment results.
After chemotherapy alone, clinical CR was reported in 25 and PR in 30 of 60 patients. All patients in PR received additional radiotherapy at
residual sites. In addition, initial bulky disease was irradiated.
After consolidating radiotherapy, 56 of 60 patients (93%) were in CR
(Table 4). The four patients who did not reach a CR were as follows:
one patient was treated initially with two cycles of BEACOPP and was in
PR. Due to toxicities, he was then treated with two cycles COPP/ABVD
and went into CR (considered as failure). One patient developed a
progressive lymphoma during therapy, which was diagnosed as a
non-Hodgkin's lymphoma (NHL) and died of lymphoma. One patient died of
septicemia during therapy. One patient stopped treatment and died of
HD.
Furthermore, two patients developed acute leukemia after chemotherapy:
one patient was treated originally at level 4 and developed myelodysplastic syndrome 18 months after the beginning of chemotherapy. Ten months later, a secondary leukemia was diagnosed. A second patient
initially treated at level 3 developed a secondary leukemia 35 months
after chemotherapy and died of leukemia. One patient developed a colon
carcinoma 15 months after treatment and died. So far, six of 60 patients died due to relapse of HD (n = 1), progression (n = 1), toxicity (n = 1), development of a NHL (n = 1), secondary
leukemia (n = 1), and colon carcinoma (n = 1).
At a median observation of 32 months, FFTF and overall survival rates
were estimated to be 91% (95% confidence interval 83% to 99%) and
90% (82% to 98%). Kaplan-Meier plots are given in Fig 4.
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| Fig 4.
Estimates of FFTF and SV for patients treated with
BEACOPP. FFTF, freedom from treatment failure; SV, overall survival.
( ) FF; ( ) 7 failed/60; () SV; (+) 6 dead/60.
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DISCUSSION |
Role of dose escalation in the treatment of HD.
The role of dose escalation in HD is not yet clear. A retrospective
analysis showed that the total dose of mustargen, vincristine, and
procarbazine correlated with the CR rate.8,9 Prospective clinical studies analyzing the role of dose escalation, however, have
not yet been performed.
The predominant dose-limiting toxicity of many combination chemotherapy
regimens is myelosuppression, particularly neutrocytopenia. G-CSF
promotes the proliferation and differentiation of neutrophil precursors
and enhances the effector functions of mature neutrophils in vitro and
in vivo.14 It has been shown that G-CSF can lead to a
reduced duration of neutrocytopenia, reduction in the number of febrile
days, a reduced incidence of infections, and as a result, fewer days on
antibiotics.15,16 Furthermore, clinical trials have shown
that G-CSF facilitates the delivery of cytotoxic chemotherapy and leads
to fewer treatment delays or dose reduction.
The use of hematopoietic growth factors may allow a significant
escalation of dose intensity when a regimen is used with
myelosuppression as the dose-limiting side effect. In a randomized
study in NHL, patients treated with chemotherapy plus G-CSF achieved a
greater dose intensity than control patients without growth
factor.16 The role of G-CSF in dose escalation, however, is
still controversial and previous studies have reported both positive
and negative results with respect to the efficacy of colony-stimulating
factors.15-18 Interestingly, none of these studies could
demonstrate a significant increase in tumor control or overall
survival.
Dose escalation within the BEACOPP scheme.
The BEACOPP scheme was originally designed to study the role of a
moderate dose escalation in advanced stage HD in a comprehensive way. A
parametric model was developed to describe tumor growth and
chemotherapy effects and was fitted to data from more than 700 patients
treated with COPP/ABVD or COPP/ABV/IMEP in the HD6 study of the GHSG.
The model predicted that a moderate dose increase by about 30% of the
standard chemotherapy doses would raise the CR rate by about
15%.10
The standard COPP/ABVD scheme has a number of disadvantages in studying
the role of dose escalation of key cytotoxic drugs. Therefore, the GHSG
developed a new regimen, which contains the most active drugs in the
same doses as COPP/ABVD. Dacarbazine was replaced by etoposide, and
vinblastine was omitted. Etoposide was incorporated because studies
showed a single-agent response rate of 25% in refractory
HD.19 In addition, etoposide has been used successfully in
a variety of second-line regimens in HD and is an essential part of the
commonly used high-dose myeloablative regimens BEAM (BCNU, etoposide,
cytosine arabinoside and melphalan) and CVB (cyclophosphamide,
etoposide and BCNU).20,21
The schedule within the BEACOPP scheme was rearranged so that all major
myelosuppressive drugs were applied within the first 3 days of the
cycle. G-CSF was introduced from day 8 to reduce prolonged
leukocytopenia. The BEACOPP scheme was planned to be repeated at day 21 (as compared with day 28 in COPP/ABVD), which resulted in a dose
intensification by approximately 30%.
In a phase-II study presented elsewhere,11 30 patients in
advanced stage HD were treated with the BEACOPP regimen at baseline level without G-CSF application. Twenty-five of 30 patients received more than 80% of the planned dosage of drugs. Twenty-seven of 29 evaluable patients reached a CR. The FFTF rate was 89% at a median
follow-up time of 40 months.
The major result of the present study is that a moderate yet
potentially effective dose escalation of three major cytotoxic drugs is
possible at controlled levels of tolerable toxicities. The dose
increase is in the order of magnitude required for testing the model
prediction of a 10% to 15% outcome improvement.13
Toxicities of BEACOPP.
Although transient leukocytopenias grade 3 to 4 were more common with
BEACOPP than detected with COPP/ABVD, there were only a few serious
infections. Whether this low incidence is due to the prophylactic
application of G-CSF is not clear. Toxic events in female patients
occurred more frequently than in male patients, and a considerable
cumulative effect was detected after multiple cycles.
The most serious late complication of HD therapy is the development of
a second cancer. In this study, four patients developed secondary
malignancies: two leukemias 28 months and 35 months after therapy, one
high-grade NHL 8 months and one colon carcinoma 31 months after
therapy. The overall risk of acute myeloid leukemia after HD ranges
from 0.5% to 2% per year for the first 10 years.22 Alkylating agents are probably associated with leukemia. There may also
be an enhanced risk for secondary leukemia and lymphomas after
treatment with etoposide. However, most cases of
epipodophyllotoxin-associated leukemia have occurred at a cumulative
etoposide doses significantly greater than those used in our study and
in patients who received the drug on a weekly or biweekly
schedule.23,24 The most commonly observed second cancers in
patients with HD are solid tumors, which are related to the use of
radiotherapy and which develop in up to 13% of patients after 15 years.22 Thus, the final evaluation of chronic toxicities
requires a very long follow-up time.
We have as yet no data on fertility following BEACOPP, but it is
expected that, as with COPP/ABVD, a high proportion of male patients
will be sterile.25
Results of BEACOPP in comparison to other regimens.
The CR, FFTF, and survival rates of the BEACOPP chemotherapy in
combination with adjuvant radiotherapy are very encouraging. When
compared with the standard COPP/ABVD regimen of the GHSG used in a
similar cohort of patients, the results compare favorably and show a
significantly higher response and FFTF rate. Most interestingly, the
rate of patients with primary progressive disease who have a very
unfavorable prognosis is 16% in COPP/ABVD, but less than 2% in the
present BEACOPP study. Whether adjuvant radiotherapy to bulky
sites and residual disease is necessary is unknown. A recent
meta-analysis indicates that combined modality treatment in patients
with advanced HD has a significantly inferior long-term survival
outcome than chemotherapy alone, if chemotherapy is given over an
appropriate number of cycles.26
Reports from randomized trials suggest that ABVD alone is equally
effective to MOPP/ABVD and to hybrid MOPP/ABV.4,6 In addition, ABVD has only moderate toxicities with respect to fertility and secondary leukemia in contrast to MOPP.6 However
cardiopulmonary toxicities of ABVD could be considerable.27
Recently, other promising regimens have been developed such as Stanford
V, in which a brief chemotherapy regimen including doxorubicin,
vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and
prednisone plus consolidative radiotherapy for most patients was
applied over 12 weeks. Treatment results showed an actuarial 3-year
failure-free survival rate of 87%, a survival rate of 96%, and no
treatment-related deaths.28 Because this trial was
performed at a single institution, prospective randomized multicenter
trials are required to compare efficacy and toxicities of Stanford V
and BEACOPP with standard protocols.
Conclusions.
Taken together, the results of this study show that with controlled
tolerable toxicities, the doses of adriamycin, etoposide, and
cyclophosphamide of the 21-day BEACOPP regimen can be escalated considerably in patients with advanced HD. Dose-escalated BEACOPP chemotherapy with additional radiotherapy is safe and shows promising tumor control. In the HD9 study of the GHSG, the BEACOPP scheme at dose
level 4 with G-CSF is being currently compared with standard COPP/ABVD
and with BEACOPP at baseline dose without G-CSF. To date, more than 900 patients have been recruited in this prospective randomized trial.
| |
APPENDIX |
Participating study centers: Münster, Med. Klinik (P. Koch); Köln, Med. Klinik (H. Tesch, B. Lathan, M. Sieber, V. Diehl); Göttingen, Med. Klinik (G. Wulf); Homburg, Med. Klinik
(M. Pfreundschuh); Kiel, Med. Klinik (N. Schmitz); Stuttgart,
Städt. Klinik (K. P. Schalk); Lübeck, Med. Klinik (G. Schwieder); Freiburg, Med. Klinik (G. Dölken); Mannheim, (P. Worst); Nürnberg, Klinik V (U. Bruntsch); Essen-Werden, Ev. KH
(T. Tirier); München, Klinik re. d. Isar (U. Müller).
Responsibilities: Data monitoring, M. Sieber, H. Nisters-Backes; biometry, M. Loeffler, D. Hasenclever; Writing
committee, H. Tesch, J. Franklin, D. Hasenclever, M. Loeffler.
| |
FOOTNOTES |
Submitted February 17, 1998;
accepted August 6, 1998.
Supported by a grant of the Deutsche Krebshilfe, Bonn, Germany.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to V. Diehl, MD, Klinik I
für Innere Medizin, Universität Köln, 50924 Köln, Germany.
| |
REFERENCES |
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DeVita V, Hubbard SM:
Hodgkin's disease.
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Abstract
Introduction