Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.
ABSTRACT The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD).
Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy.
Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis
The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.
- SourceAvailable from: Monique W M Jaspers[Show abstract] [Hide abstract]
ABSTRACT: Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival. However, childhood cancer survivors (CCS) are at great risk for developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is one of these known (acute) side effects of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate impairment, proteinuria, tubulopathy and hypertension. However, evidence about the long-term effects of these treatments on renal function remains inconclusive. To reduce the number of (long-term) nephrotoxic events in CCS, it is important to know the risk of, and risk factors for, early and late renal adverse effects, so that ultimately treatment and screening protocols can be adjusted. To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment. We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011). With the exception of case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment) in children and adults who were treated for a paediatric malignancy (aged 18 years or younger at diagnosis) with cisplatin, carboplatin, ifosfamide, radiation including the kidney region and/or a nephrectomy. Two review authors independently performed study selection, risk of bias assessment and data extraction using standardised data collection forms. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The search strategy identified 5504 studies, of which 5138 were excluded on the basis of title and/or abstract. The full-text screening of the remaining 366 articles resulted in the inclusion of 57 studies investigating the prevalence of and sometimes also risk factors for early and late renal adverse effects of treatment for childhood cancer. The 57 studies included at least 13,338 participants of interest for this study, of whom at least 6516 underwent renal function testing. The prevalence of renal adverse effects ranged from 0% to 84%. This variation may be due to diversity in included malignancies, prescribed treatments, reported outcome measurements and the methodological quality of available evidence.Chronic kidney disease/renal insufficiency (as defined by the authors of the original studies) was reported in 10 of 57 studies. The prevalence of chronic kidney disease ranged between 0.5% and 70.4% in the 10 studies and between 0.5% and 18.8% in the six studies that specifically investigated Wilms' tumour survivors treated with a unilateral nephrectomy.A decreased (estimated) glomerular filtration rate was present in 0% to 50% of all assessed survivors (32/57 studies). Total body irradiation; concomitant treatment with aminoglycosides, vancomycin, amphotericin B or cyclosporin A; older age at treatment and longer interval from therapy to follow-up were significant risk factors reported in multivariate analyses. Proteinuria was present in 0% to 84% of all survivors (17/57 studies). No study performed multivariate analysis to assess risk factors for proteinuria.Hypophosphataemia was assessed in seven studies. Reported prevalences ranged between 0% and 47.6%, but four of seven studies found a prevalence of 0%. No studies assessed risk factors for hypophosphataemia using multivariate analysis. The prevalence of impairment of tubular phosphate reabsorption was mostly higher (range 0% to 62.5%; 11/57 studies). Higher cumulative ifosfamide dose, concomitant cisplatin treatment, nephrectomy and longer follow-up duration were significant risk factors for impaired tubular phosphate reabsorption in multivariate analyses.Treatment with cisplatin and carboplatin was associated with a significantly lower serum magnesium level in multivariate analysis, and the prevalence of hypomagnesaemia ranged between 0% and 37.5% in the eight studies investigating serum magnesium.Hypertension was investigated in 24 of the 57 studies. Reported prevalences ranged from 0% to 18.2%. A higher body mass index was the only significant risk factor noted in more than one multivariate analysis. Other reported factors that significantly increased the risk of hypertension were use of total body irradiation, abdominal irradiation, acute kidney injury, unrelated or autologous stem cell donor type, growth hormone therapy and older age at screening. Previous infection with hepatitis C significantly decreased the risk of hypertension.Because of the profound heterogeneity of the studies, it was not possible to perform any meta-analysis. The prevalence of renal adverse events after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region and/or nephrectomy ranged from 0% to 84%. With currently available evidence, it was not possible to draw any conclusions with regard to prevalence of and risk factors for renal adverse effects. Future studies should focus on adequate study design and reporting and should deploy multivariate risk factor analysis to correct for possible confounding. Until more evidence becomes available, CCS should be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.Cochrane database of systematic reviews (Online) 10/2013; 10:CD008944. · 5.94 Impact Factor
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ABSTRACT: Zusammenfassung Die Prognose für Patienten mit Hodgkin-Lymphom hat sich in den letzten 30 Jahren erheblich verbessert. In Abhängigkeit von dem Stadium bei Erstdiagnose können mittlerweile Heilungsraten von über 80% erzielt werden. Moderne Therapiestrategien sollen insbesondere das Auftreten von therapiebedingten Spätfolgen bei gleichzeitiger Beibehaltung der guten Tumorkontrolle verringern. Offene Fragen in den fortgeschrittenen Stadien betreffen die optimale Zyklusanzahl bei einer effektiven Chemotherapie und die Notwendigkeit einer zusätzlichen Bestrahlung. Der Stellenwert der PET bezüglich der Unterscheidung zwischen residualen narbigen Veränderungen und aktivem Lymphomgewebe nach intensiver Chemotherapie wird in der aktuellen Studie (HD15) untersucht.Der Onkologe 09/2005; 11(9):942-947. · 0.13 Impact Factor
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ABSTRACT: Das maligne Hodgkin-Lymphom (HL) ist durch die fortschreitende Entwicklung der Behandlungsintensität eine heilbare Erkrankung geworden. Allerdings kann dieses aggressive Vorgehen, das häufig Strahlen- und Chemotherapie kombiniert, u. a. sekundäre Neoplasien zur Folge haben.Der Pathologe 02/2006; 27(1):47-52. · 0.64 Impact Factor
Annals of Oncology 15: 276–282, 2004
© 2004 European Society for Medical Oncology
Treatment of advanced Hodgkin’s disease with COPP/ABV/IMEP
versus COPP/ABVD and consolidating radiotherapy: final results
of the German Hodgkin’s Lymphoma Study Group HD6 trial
M. Sieber*†, H. Tesch†, B. Pfistner, U. Rueffer, U. Paulus, R. Munker, R. Hermann, G. Doelken,
P. Koch, J. Oertel, S. Roller, P. Worst, H. Bischof, A. Glunz, R. Greil, K. von Kalle, K. P. Schalk,
D. Hasenclever, O. Brosteanu, E. Duehmke, A. Georgii, A. Engert, M. Loeffler & V. Diehl
On behalf of the German Hodgkin’s Lymphoma Study Group‡
*Correspondence to: Dr M. Sieber, Klinik I für Innere Medizin, University
of Cologne, 50924 Cologne, Germany. Tel: +49-221-478-4400;
Fax: +49-221-478-5455; E-mail: firstname.lastname@example.org
†Joint first authors for this publication.
‡Participants are listed in Acknowledgements.
Klinik I für Innere Medizin, University of Cologne, Cologne, Germany
Received 14 March 2003; revised 25 July 2003; accepted 4 September 2003
Background: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen
ifosfamide–methotrexate–etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV,
dacarbacine) (CA) in the treatment of advanced-stage Hodgkin’s disease (HD).
Patients and methods: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB
and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of
CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both
groups then received consolidating radiotherapy.
Results: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were
similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and
freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73%
and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were
significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index
and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated
with a poor prognosis
Conclusion: The rapidly alternating hybrid CAI did not give superior results when compared with the standard
regimen CA in advanced-stage HD.
Key words: advanced stage, chemotherapy, COPP/ABV/IMEP, Hodgkin’s disease, randomized clinical
Unlike most other malignancies, Hodgkin’s disease (HD) can be
cured with polychemotherapy, even in advanced stages. The first
highly successful chemotherapy regimen used in HD was MOPP
(mustargen–vincristine–procarbazine–prednisone) introduced by
DeVita and Serpick in 1967 . In 1974, the Milan group
introduced a treatment strategy of alternating cycles of MOPP and
ABVD (doxorubicin–bleomycin–vinblastine–dacarbacine) .
This was based on the efficacy of ABVD in certain patients refrac-
tory to MOPP as well as the therapeutic limitations of MOPP in
others. The results of this trial were striking and statistically signifi-
cant. Subsequently, several large cooperative group trials were
carried out confirming the Milan group’s findings and establish-
ing the superiority of MOPP/ABVD over MOPP and MOPP
derivatives in the treatment of advanced-stage HD [3–5].
Goldie and Coldman  proposed a mathematical model
describing the relationship between tumor drug sensitivity and
spontaneous mutation rates. This model was the basis for the
development of hybrid chemotherapeutic regimens. Groups in
Vancouver and Milan independently developed a MOPP/ABV
hybrid scheme in which all cytostatic agents were given within
8 days. The MOPP/ABV hybrid regimen did not, however, show
better remission or relapse-free survival rates when compared
with standard ABVD or MOPP/ABVD and, in fact, was shown to
be more toxic [7–9].
The purpose of this trial was to compare the efficacy of a new
rapid alternating hybrid scheme COPP/ABV/IMEP (cyclophos-
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CAI with that of the standard COPP/ABVD (cyclophosphamide–
vinblastine–dacarbacine) or CA in the treatment of advanced-
stage HD. The rationale for the new CAI scheme is as follows. It
contains the most active substances of the standard CA regimen
with the exception of dacarbacine, which is highly emetic and
whose activity in HD is thus far not proven. Ifosfamide, metho-
trexate and etoposide were added based on their activity in
relapsed lymphomas [10, 11]. Methotrexate was also a component
of MOMP, a MOPP derivative proposed by DeVita and Serpick .
In 1989, the German Hodgkin’s Lymphoma Study Group began
two multicenter trials to evaluate the COPP/ABV/IMEP scheme
in comparison with COPP/ABVD: the HD5 trial for patients with
intermediate stage HD and the HD6 trial for advanced stages. This
paper presents the final results of the HD6 trial. The results of the
HD5 trial were reported by Sieber et al. .
Patients and methods
Between January 1988 and January 1993, 622 patients with advanced-stage
HD were recruited from 92 participating centers in Germany, Switzerland and
Austria (see Acknowledgements for a list of participating centers). Previously
untreated patients between 15 and 75 years of age with biopsy-proven HD in
stages IIIB and IV were eligible. Exclusion criteria included a positive HIV
test, previous malignant disease, pregnancy, creatinine clearance <60 ml/min,
leukocyte count <3000/µl, platelet count <100 000/µl, serum bilirubin >2 mg/dl,
concurrent infections and severe cardiac, pulmonary or cerebral dysfunction.
Disease staging was determined according to the Ann Arbor classification.
Pretreatment evaluation included medical history, physical examination, com-
plete blood count, liver and renal function tests, erythrocyte sedimentation
rate, chest X-ray, abdominal ultrasound, thoracic, abdominal and pelvic com-
puted tomography (CT) and bone marrow biopsy. In 86 patients a staging
laparotomy was carried out. A liver biopsy was required if staging laparotomy
was not carried out.
Of 622 patients who were registered, 588 were eligible and randomly assigned;
17 patients were ineligible due to concurrent disease, 11 due the review diag-
nosis as non-Hodgkin’s lymphoma and six due to staging errors or previous
treatment. In addition, four patients were ineligible for arm comparison: two
terminated before starting therapy, one received another treatment. Another
was lost before starting therapy and was therefore not included in the overall
results. Patients characteristics for those 584 informative patients are given in
Table 1. Age, sex, histological subtype, stage and clinical risk factors were
evenly balanced in both arms. More than 80% of patients had B symptoms and
>50% were in stage IV. Patients in stage IV had diffuse infiltrations of non-
lymphoid organs such as liver (97 patients), lung (96 patients) and/or bone
(62 patients). Localized extra-nodal disease was detected in 325 patients
A pathology review of the biopsies taken before treatment was also
requested. Biopsy materials were reviewed by four expert pathologists who
examined 439 out of 584 cases (75%) and revealed predominance of nodular
sclerosis (59% of reviewed cases), followed by mixed cellularity (18%),
lymphocyte depletion (2%) and lymphocyte predominance (2%). In 47 speci-
mens (11%) the subtype could not be classified by the review panel and in 36
cases (8%) HD was not certain.
The study design is shown in Figure 1. After informed consent was obtained,
the eligible patients were randomly assigned to receive four treatment cycles
with either CA or CAI. The doses and schedules are given as shown in Table 2.
Patients treated in centers in Switzerland received mustargen instead of
cyclophosphamide (MOPP instead of COPP). They were included in the
analysis of treatment results but not in those of drug delivery and toxicity. In
eight patients, the therapy was switched mid-treatment because of either
excessive toxicity or for unknown reasons: two patients randomly assigned to
CA were switched to CAI and six patients from CAI to CA. These patients are
retained in the assigned treatment group for data analysis purposes (intention-
Table 1. Patient characteristics
aThe histological subtype was reviewed in 75% cases for each arm; the
percentages given refer to reviewed cases only.
CS/PS, clinical stage/pathological stage; ESR, erythrocyte sedimentation
(n = 291)
(n = 293)
Male sex171 (59%)165 (56%)
IIIB143 (49%)147 (50%)
IVA40 (14%)54 (18%)
IVB 108 (37%)92 (31%)
B symptoms251 (86%)239 (82%)
Bulky disease155 (53%)164 (56%)
Staging laparotomy41 (14%)45 (15%)
Histological subtype (reviewed)a
Lymphocyte predominance 3 (1%)6 (3%)
Nodular sclerosis139 (63%)118 (54%)
Mixed cellularity34 (15%)46 (21%)
Lymphocyte depletion5 (2%)5 (2%)
Unclassified22 (10%)25 (11%)
Hodgkin’s disease uncertain16 (7%) 20 (9%)
Large mediastinal mass67 (23%) 80 (27%)
Extra-nodal involvement165 (57%)160 (55%)
High ESR224 (77%)228 (78%)
International Prognostic Indexb
0–3161 (55%)180 (61%)
4–755 (19%)58 (20%)
Missing75 (26%)55 (19%)
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All drugs were given in full doses if the leukocyte count was >2500/µl and
the platelet count >80 000/µl. If the leukocyte or platelet counts following a
treatment cycle were below these values, subsequent cycles were delayed by
2 weeks and doses of cyclophosphamide, doxorubicin, vinblastine, ifosfamide,
methotrexate and etoposide were adjusted. If myelosuppression caused a delay
between 1 and 2 weeks, the doses were reduced by 25%. If the delay was
>2 weeks, the doses were reduced by 50%.
Bulky disease areas (initially >5 cm measured by CT scan) and slow-responding
lymph node sites which appeared enlarged (>2 cm) after two cycles of CA or
CAI were irradiated locally with 30 Gy; residual disease that appeared
enlarged (>2 cm) clinically or by CT scan after eight cycles of chemotherapy
was treated locally with 40 Gy.
Response assessment and follow-up
Patient data were collected following each cycle of chemotherapy and after
radiotherapy. Data collected included dose schedule, actual doses given and
toxicity. Toxicity data included hematological toxicities (leukocytopenia,
thrombocytopenia and anemia), alopecia, nausea and vomiting, neuropathy,
infections, fever, allergic reactions, gastrointestinal, skin, renal and pulmonary
toxicities and secondary malignancies. The data were checked by two data
managers and a physician.
Response was assessed by physical examination, complete blood cell count,
blood chemistries and CT scans following the fourth and eighth cycles of
chemotherapy and following radiotherapy. Restaging consisted of an analysis
and documentation of all initial disease manifestations by adequate clinical and
histological methods. Complete remission (CR) was defined as the absence of
all clinical disease manifestations 3 months following the completion of treat-
ment. Partial remission (PR) was defined as an at least 50% reduction in all
disease sites (measured by the products of perpendicular diameters). Residual
disease was defined as suspected active disease >2 cm after the completion of
eight cycles of chemotherapy. Patients with residual disease after radiotherapy
were considered to be in CR with residual lesions and were observed but not
treated further. Follow-up examinations were then carried out every 3 months
during the first 2 years following treatment, every 4 months during the subse-
quent 2 years and every 6 months beginning with the 5th year.
Randomization was carried out centrally by computer. Five hundred and eight-
four patients were evaluable for arm comparison analyses. All analyses are
based on intention-to-treat. The major end point was freedom from treatment
failure (FFTF), which was defined as the time from the start of randomization
to the first of the following events: death, progressive disease, non-CR status at
the end of the protocol treatment or relapse. Overall survival (OS) analysis
included all deaths whether disease-related or not. Kaplan–Meier estimates are
given for the probabilities of survival beyond a given time. The significance of
comparisons of survival were calculated with the log-rank test.
For the comparison of treatment delivery the analysis was restricted to
patients who had received the intended treatment. Drug delivery was assessed
by comparing given dose intensity and full protocol dose without reduction.
Dose intensity (mg/m2/week) was defined as the total dose given divided by
the product of the body surface area and the number of weeks of treatment
(number of weeks from the first day of treatment to the last day of drug delivery).
The International Prognostic Index was calculated as described by Hasen-
clever and Diehl .
Four cycles of the CA treatment scheme were administered over a
median time of 34 weeks (113% of the intended time). Four cycles
of CAI were administered over 28 weeks (121% of the intended
time). Vincristine was applied at 75% and 80% of the intended
doses in the CA and CAI regimens, respectively. All other drugs
were applied on average >92% of the intended doses. The median
dose intensity for vincristine was 67% of the intended intensity.
All other drugs had a median dose intensity >78%. The median
dose intensities of most drugs (cyclophosphamide, vincristine,
prednisone, procarbacine, doxorubicin, bleomycin, vinblastine)
were slightly, but not significantly, lower in the CAI group.
Three hundred and twenty-three patients received consolidating
radiotherapy, 156 patients (79%) in the CA arm and 167 (78%) in
the CAI arm. Patients with bulky disease areas (52% of CA and
53% of CAI patients) received 30 Gy in these areas. Slow-
responding areas received also 30 Gy (59% of CA and 61%
of CAI patients). Patients with residual disease (disease >2 cm
following chemotherapy, 38% of each group) received 40 Gy.
Eighteen patients in CR (11 of CA and seven of CAI) who did not
meet any of the above criteria also received radiation without an
Figure 1. Flow diagram for the HD6 trial.
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The World Health Organization (WHO) grade of acute toxicity
was documented in 223 patients in the CA group and in 245
patients in the CAI group. Patients treated in Switzerland were
excluded from this comparison because of the switch from COPP
to MOPP. WHO grade 3/4 toxicity is compared in Table 3 for the
two groups. Leukocytopenia grade 3/4 (<1000/µl) occurred in
63% of patients treated with CA and 71% of those treated with
CAI (not statistically significant). Thrombocytopenia grade 3/4
(<25 000/µl) was also more frequent with CAI (5%) than CA (1%)
(P = 0.01). Alopecia occurred in 51% of the CAI group compared
with 33% of the CA group (P <0.001). Emesis was more pro-
nounced in the CA group with an incidence of 34% versus 19%
(P < 0.001). Neuropathy, anemia, infections, pain, gastrointestinal
toxicity, fever, allergic reactions, skin toxicity, renal toxicity,
cardiac toxicity and pulmonary toxicity all occurred in <5% of
patients without significant differences between the two treatment
A total of 29 secondary malignancies were documented, includ-
ing eight acute myelogenous leukemias (AMLs), 11 non-Hodgkin’s
lymphomas, four lung cancers and six other solid tumors. AML
occurred more frequently in the CA group (six versus two patients)
and solid tumors more frequently in CAI group (seven versus
three patients), but both differences are not significant due to
CR was reached by 78% of CA patients and 77% of CAI patients.
PR was achieved by 3% of patients with CA and 5% of patients
with CAI. Progressive disease was seen in 17% of those in the CA
group and 15% of those in the CAI group. Relapses occurred in
18% of CA patients and 19% of CAI patients.
Kaplan–Meier estimates of FFTF and OS are compared in
Figures 2 and 3. At a median observation time of 7 years, OS was
73% ± 5% [95% confidence interval (CI)] in both groups and
FFTF was 56% ± 6% (95% CI) for CA group and 54% ± 6% (95%
CI) for the CAI group. There was no significant difference
between the two groups with regard to OS or FFTF.
Table 2. Planned dosage and schedule of the COPP/ABVD and COPP/ABV/IMEP regimens
aMaximal 2 mg.
Dose (mg/m2)RouteDays Dose (mg/m2) RouteDays
Cyclophosphamide 650 i.v.1, 8800 i.v.1
i.v. 1, 8 1.4a
Procarbazine100 p.o.1–14 100p.o.1–10
Prednisone40 p.o.1–14 40p.o.1–15
Doxorubicin25 i.v. 29, 4340i.v. 15
Bleomycin10i.v. 29, 4310i.v. 15
Vinblastine6 i.v.29, 436i.v. 15
Methotrexate––– 30i.v. 31
Table 3. Percentage of patients with acute toxicity (WHO grade 3/4)
WHO, World Health Organization.
(n = 223)
(n = 245)
Leucocytopenia 63 71
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Causes of death
One hundred and fifty-nine patients (27%) have died at the time of
this analysis (median observation time 7 years). HD was the most
frequent cause accounting for 95 deaths (60%). This was followed
by acute toxicity during primary chemotherapy or salvage chemo-
therapy (13%), secondary neoplasias (12%) and cardiac failure
(7%). Seventeen patients died during therapy, eight receiving CA
and nine receiving CAI. There was no statistically significant
difference between the CA and CAI groups with regard to any
category of cause of death.
The primary goal of this clinical trial was to compare the efficacy
of the time-abbreviated, rapidly alternating CAI hybrid scheme
with that of the standard alternating CA regimen in patients with
advanced-stage HD. In this trial, CAI did not yield superior
results. The CR rates, FFTF and OS rates at 7 years were similar
for the two groups. In general, toxicity was moderate with both
schemes and thrombocytopenia and alopecia were more pro-
nounced in the CAI group, while emesis was more pronounced in
the CA group.
What can we conclude from this trial? Both regimens have a
similar backbone of chemotherapeutic drugs with some important
differences. Dacarbazine was included in the CA regimen and
excluded from the CAI scheme. In CAI, three new drugs were
introduced: methotrexate, etoposide and ifosfamide. Another
important difference is the time frame: one cycle of CAI was
applied over 6 weeks and one cycle of CA over 8 weeks. It is diffi-
cult to distinguish between the effects of these changes.
The results of this trial agree with those from other groups com-
paring hybrid regimens with conventional ones in HD. Groups in
Vancouver and Milan independently developed a MOPP/ABV
hybrid which was compared by the National Cancer Institute with
alternating MOPP/ABVD in patients with stages IIIB and IV HD.
At 5 years, there was no significant difference in the OS rates
between the two groups; however, the hybrid scheme was asso-
ciated with greater hematological and non-hematological toxicity
. The Milan group trial comparing MOPP/ABV with MOPP/
ABVD also showed no significant difference in OS rates at 10 years
. A large USA intergroup trial comparing MOPP/ABV with
ABVD in patients with advanced-stage or recurrent HD was pre-
maturely stopped by the Data and Safety Monitoring Board when
excessive treatment-related deaths and secondary malignancies
were observed in the hybrid regimen group . At 3 years, both
regimens had shown similar failure-free survival rates. The poten-
tial relevance of dose and scheduling was shown in a British
National Lymphoma Investigation trial comparing the LOPP/
EVA hybrid scheme with alternating LOPP/EVA. Both regimens
contained identical doses. There was a significantly lower CR rate
in the hybrid group and this trial was also stopped prematurely .
In summary, the Goldie–Coldman hypothesis predicting that
multidrug chemotherapeutic regimens utilizing larger number of
drugs in rapid alternation would yield superior results has not been
validated by randomized clinical trials in advanced-stage HD.
ABVD has been considered the standard regimen against which
all new regimens are compared. ABVD-based regimens have been
shown to yield a 60–70% FFTF rate at 5 years. Compared with the
hybrid schemes tested thus far, ABVD is equally effective and
appears to cause less myelotoxicity, acute leukemias and sterility.
However, this could be due to the fact that the optimal hybrid regi-
men has not yet been identified.
Although ABVD is considered the standard regimen for
advanced-stage HD, the treatment results are not satisfactory,
especially in comparison with the results in limited stages. Prim-
ary treatment fails in more than one-third of patients and these
patients have a dismal prognosis. Furthermore, the pulmonary tox-
icity of bleomycin, which is more pronounced in children and in
combination with mediastinal radiation, remains a concern with
Two new promising regimens are currently under study. At
Stanford University, a new regimen was developed including
Figure 2. Freedom from treatment failure for COPP/ABVD (Arm A)
versus COPP/ABV/IMEP (Arm B).
Figure 3. Overall survival for COPP/ABVD (Arm A) versus COPP/ABV/IMEP
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etoposide–prednisone . The drug regimen, known as Stanford
V, was applied weekly over a total of 12 weeks. Consolidating
radiotherapy to initial bulky disease sites was essential. In a single-
center trial which included 142 patients, the estimated freedom
from progression at 5 years was 89% and the OS 96% years of
observation . Lower toxicity and preserved fertility were
major goals of this regimen and were achieved in both men and
The German Hodgkin’s Lymphoma Study Group developed
the BEACOPP regimen (bleomycin–etoposide–doxorubicin–
cyclophosphamide–procarbazine–prednisone) . In the three-
arm HD9 trial, BEACOPP in standard and escalated doses were
compared with standard COPP/ABVD in patients with advanced-
stage HD . At the time of a planned interim analysis, the
COPP/ABVD arm was closed to accrual due to observed superior
outcomes in the BEACOPP arms.
The role of consolidating radiotherapy in advanced-stage HD
remains highly controversial . Although the contribution of
radiotherapy is unclear, many large clinical trials include radio-
therapy as an integral part of their protocols. In this study, no
significant difference in outcome was observed between patients
who received radiotherapy and those who did not (data not shown).
This is in agreement with results from other groups and a meta-
analysis of 14 studies including over 1700 patients [20, 21]. It
seems likely, therefore, that radiotherapy is not essential in
patients with advanced-stage HD after a sufficient amount of
anthracycline-containing chemotherapy is applied.
In conclusion, the hybrid regimen CAI did not give superior
results when compared with the standard regimen CA. ABVD
should still be considered the standard treatment protocol in patients
with advanced-stage HD against which promising new regimens
like BEACOPP and the Stanford V should be compared. The role
of adjuvant radiotherapy after chemotherapy remains unproven
and is currently being analyzed in the HD12 trial of the German
Hodgkin’s Lymphoma Study Group.
This clinical trail was supported by a grant from the Federal Min-
ister of Science and Technology, Bundesministerium für Fors-
chung und Technologie, Germany. Writing committee: H. Tesch,
M. Sieber, B. Pfistner; biometry: B. Pfistner, U. Paulus, D. Hasen-
clever, M. Loeffler, O. Brosteanu; radiotherapy panel: E. Duehmke,
R. P. Mueller, N. Willich; pathology panel: A. Georgii, R. Fischer,
M. L. Hansmann, H. Stein; data management: T. Schober, B.
The study participants (listed according to recruitment with at
least three randomly assigned patients) were: SAKK Koordinations-
zentrum, Schweiz (R. Hermann); Klinikum Großhader, Medizinische
Klinik III, München (R. Munker); Med. Universitätsklinik,
Hämatologie/Onkologie, Freiburg (G. Dölken); Med. Univ.-Klinik,
Münster (P. Koch); Klinik I für Innere Medizin, Universität zu
Köln (V. Diehl); Campus Virchow-Klinikum, Hämato-Onkok-
logische Ambulanz, Berlin (J. Oertel, S. Sonntag); Universitätsk-
linik Ulm Med. Klinik und Poliklinik/Innere III, Ulm (S. Roller);
Klinikum Mannheim, III Med. Klinik, Mannheim (P. Worst);
Thorax-Klinik der LVA-Baden, Abt. Onkologie, Heidelberg (H.
Bischoff); Med. Univ.-Klinik Essen, Hämatologie, Essen (A.
Glunz); Landeskrankenhaus, Innsbruck (R. Greil); Robert-Bosch-
Krankenhaus, Innere Medizin II, Stuttgart (K.-P. Schalk); Medizin-
ische Klinik und Poliklinik V, Heidelberg (K. v. Kalle); Univers.
Klinikum B. Franklin, Hämatologie/Onkologie, Berlin (S. Schwartz);
Med. Klinik I Rechts der Isar Abt. Hämatologie u. Onkologie,
München (H. D. Schick); Klinikum Krefeld, Med. Klinik II,
Krefeld (M. Planker); UKE Eppendorf, Hämatologie/Onkologie,
Hamburg (R. Zschaber); Med. Klinik III mit Poliklinik, Univer-
sität Erlangen-Nürnberg, Erlangen (Rösler); Städt. Krankenhaus,
II Med. Klinik und Poliklinik, Kiel (P. Dreger); Städt. K H.
München-Schwabing, I Med. Abt., München (W. Enne, Szeimies);
St Johannes Hospital, Med. Klinik II, Duisburg (J. Selbach);
Evang. Krankenhaus Essen-Werden, Abt. Hämatologie, Essen
(C. Tirier); Med. Universitätsklinik Hämatologische Poliklinik,
Lübeck (G. Schwieder); Städt. Klinikum Med. Klinik II, Hämato-
logie, Karlsruhe (S. Wilhelm); Med. Hochschule, Hämatologie/
Onkologie, Hannover (H. Kirchner); Krankenhaus Moabit, II.
Innere Abteilung, Berlin (G. Kühn, B. Ramsauer); Klinikum Lahn-
berge, Philipps Universität, Innere Med. Hämatologie, Marburg
(J. Heymanns); Mutterhaus der Borromäerinnen, Trier (W. Dorn-
hoff); Krankenhaus Neukölln, Innere Medizin II, Berlin (M. Wil-
helmy); Zentralklinikum Augsburg, Hämatologische Ambulanz,
Augsburg (Müller, Ch. Pawlik); Caritasklinik St Theresia, Klinik
für Hämatologie/Onkologie, Saarbrücken (Heck); Med. Univer-
sitätsklinik, Klinik u. Poliklinik, Bonn (U. Loos); Klinikum Kreis
Herford, Medizinische Klinik II, Herford (M. Just); Ev. Stift St
Martin, Klinik für Innere Medizin, Koblenz (A. Selenka); Städt.
Krankenhaus Süd, Medizinische Poliklinik, Lübeck (H. Bartels);
Lukaskrankenhaus Neuss, Med. Klinik II, Neuss (P. Czygan, Kanz);
St Elisabethen, Med. Klinik, Ravensburg (S. Mende); Klinik II
für Innere Medizin, Poliklinik, Köln (M. Schrappe-Bächer); Kranken-
haus Barmherzige Brüder, I. Med. Abteilung, Trier (Orth, Ren-
denbach); St Bernward Krankenhaus, Med. Klinik II, Hildesheim
(Heide); Städt. Krankenhaus, 1. Med. Klinik, Heilbronn (K.
Koniczek); Med. Poliklinik der Universität, Innere Med., Bonn
(O. Göbel); Marienhospital Hagen, Hämatologie/Onkologie, Hagen
(H. Eimermacher); Evang. Krankenhaus, Med. Klinik, Hämatol-
ogie, Oldenburg (G. Nassauer); Gemeinschaftspraxis Kleeberg,
Hamburg (E. Engel); Gemeinschaftspraxis Innere Medizin/
Hämatologie, Aachen (U. Essers, L. Habets); Gemeinschaftpraxis
Hämatologie/Intern. Onkologie, Hannover (B. Gaede, J. Wysk);
Städtische Kliniken, Medizinische Klinik, Duisburg (Terhorst);
St Elisabeth Krankenhaus, Medizinische Abteilung, Köln (Ham-
mann); St Antonius Hospital, Hämatologie/Onkologie, Eschweiler
(R. Fuchs); Westpfalz-Klinikum GmbH, Medizinische Klinik I,
Kaiserslautern (R. Kirsch); Bethesda Krankenhaus, Medizinische
Klinik, Wuppertal (D. Böttcher); Klinikum Innenstadt, Med.
Klinik/Abt. Hämatologie, München (P. Nöcker); Kreiskranken-
haus Lüdenscheid, Innere Abt./Onkologie, Lüdenscheid (J. Bade);
Internistische Praxis, Köln (R. Zankovich); Kreiskrankenhaus
Günzburg, Abt. Innere Medizin, Günzburg (W. Schreml); St
Johannes Hospital, Medizinische Klinik II, Dortmund (V. Hagen);
by guest on June 1, 2013
Klinikum Lippe-Lemgo, Medizinische Klinik II, Lemgo (U.
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