1. No category

SYSTEMATIC OVERVIEW ARTICLE
A Systematic Overview of Chemotherapy Effects in
Hodgkin’s Disease
Lars Brandt, Eva Kimby, Peter Nygren and Bengt Glimelius for the SBU-group1
From the Department of Oncology, University Hospital, Lund (L. Brandt), Department of Haematology,
University Hospital, Huddinge (E. Kimby), and Department of Oncology, Radiology and Clinical
Immunology, University Hospital, Uppsala (P. Nygren, B. Glimelius), Sweden
Correspondence to: Bengt Glimelius, Department of Oncology, Radiology and Clinical Immunology, Section of
Oncology, University Hospital, SE-751 85, Uppsala, Sweden. Tel: »46 186115513 . Fax: »46 186115528. Email:
[email protected]
Acta Oncologica Vol. 40, No. 2:3, pp. 185 – 197, 2001
A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment
in Health Care (SBU). The procedures for the evaluation of the scientiŽ c literature are described separately (Acta Oncol 2001; 40:
155 –65). This synthesis of the literature on chemotherapy for Hodgkin’s disease (HD) is based on 113 scientiŽ c reports including four
meta-analyses, 44 randomised studies, 18 prospective studies and 40 retrospective studies. These studies involve 69 196 patients. The
conclusions reached can be summarised into the following points:
Chemotherapy is of utmost importance for the cure of HD.
At early stages, extended Ž eld radiotherapy cures most patients. For the majority of patients with relapse after radiotherapy,
chemotherapy is curative and the total proportion of cured early stage patients is 75 – 90%. Chemotherapy in addition to extended Ž eld
radiotherapy reduces recurrences but does not improve long-term survival.
In early stage HD with a large mediastinal mass and:or with systemic symptoms, combined treatment with chemotherapy and
radiotherapy is recommended.
It is likely that chemotherapy will play a greater role in the future in the treatment also of early stage patients in order to reduce late
consequences from extended Ž eld radiotherapy. However, this conclusion remains to be better documented in the literature.
At advanced stages, chemotherapy or a combination of chemotherapy and limited Ž eld radiotherapy are effective treatment options
and, using the regimens available 10 – 20 years ago, 40 – 50% of the patients are cured. Based upon more favourable short-term (three
to eight years) results of more recently developed regimens, it can be expected that today a higher proportion of the patients will
become long-term survivors.
Several chemotherapy regimens containing four to eight drugs are effective in HD. The best regimen considering both antitumour
activity and acute and late side-effects is not known. The choice of regimen is probably best done after considering various
pre-treatment factors such as the number of poor prognostic signs, concomitant diseases and individual preferences.
The results of chemotherapy are more favourable in young than in elderly patients. The development of less toxic but still effective
treatment programmes is therefore particularly important for the elderly.
High dose chemotherapy with stem cell support is presently often used in patients who are chemotherapy induction failures, who
relapse after a short initial remission or after a longer initial remission and treated initially with seven or eight drugs, or who have had
multiple relapses. However, this use is based on data from uncontrolled or small controlled studies, not being fully convincing with
respect to effect on survival.
Persistent side-effects of treatment are common among long-term survivors, although most patients have an apparently normal life.
The relative contributions of chemotherapy and radiotherapy to the persistent effects are not well documented.
1
Other members of the SBU-group were: Jonas Bergh, Radiumhemmet, Stockholm; Bengt Brorsson, SBU, Stockholm; Barbro Gunnars,
Dept of Oncology, University Hospital, Lund; Larsolof Hafström, Dept of Surgery, University Hospital, UmeaÊ ; Ulf Haglund, Dept of
Surgery, University Hospital, Uppsala; Thomas Högberg, Dept of Gynaecological Oncology, University Hospital, Linköping; Karl G.
Janunger, Dept of Surgery, University Hospital, UmeaÊ ; Per-Ebbe Jönsson, Dept of Surgery, Helsingborgs lasarett, Helsingborg; Göran
Karlsson, Handelshögskolan, Stockholm; Gunilla Lamnevik, SBU, Stockholm; Sten Nilsson, Radiumhemmet, Stockholm; Johan
Permert, Dept of Surgery, University Hospital, Huddinge; Peter Ragnhammar, Radiumhemmet, Stockholm; Sverre Sörenson, Dept of
Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
© Taylor & Francis 2001. ISSN 0284-186 X
Acta Oncologica
186
Acta Oncologica 40 (2001)
L. Brandt et al.
In Sweden, 172 cases of Hodgkin’s disease (HD) were
diagnosed in 1997, corresponding to 0.4% of all newly
diagnosed malignant tumours (1). Like in other countries,
there is a biphasic age distribution with one peak around
20 – 30 years of age and another peak around the age of 70
years. Twenty-thirty % of the patients are older than 60
years at diagnosis.
Until the 1960s, HD was considered almost inevitably
fatal but rapid advances in radiotherapy changed the
outlook for many patients. Effective chemotherapy programmes were also introduced in the late 1960s and in
later years the majority of patients with HD have been
cured with radiotherapy, chemotherapy or a combination
of these modalities. Population-based data support improvement in overall survival from the early 1970s when
chemotherapy had been widely introduced to the 1990s (2,
3).
For the choice of treatment it is important to determine
the stage of the disease (Table 1) (4). In Sweden, the
following distribution has been described (Swedish National Care Programme, 1995) (Table 2).
Histologically, HD is classically divided into four major
groups: Lymphocyte predominance (LP), Nodular sclerosis (NS), Mixed cellularity (MC) and Lymphocytic depletion (LD). A new group has recently been added,
Lymphocyte-rich classical HD, separating LP from the
others (5).
LOCALISED DISEASE: STAGES I –II
It is well documented that radiotherapy will induce complete remission (CR) in about 95% of the patients with HD
stage I – II. About 15 –35% relapse but most of them
(75–90%) experience a new remission with chemotherapy
or a combination of chemotherapy and radiotherapy. With
Table 1
The Cotwolds Staging ClassiŽ cation (4)
Stage I: Involvement of a single lymph node region or
lymphoid structure (e.g. spleen, thymus, Waldeyer’s ring).
Stage II: Involvement of two or more lymph node regions on
the same side of the diaphragm (the mediastinum is a single
site).
Stage III: Involvement of lymph node regions or structures on
both sides of diaphragm. III:1: With or without splenic hilar,
coeliac or portal nodes. III:2: With paraaortic, iliac, mesenteric nodes.
Stage IV: Involvement of extranodal site(s) beyond that designated ‘E’.
A: No B-symptoms.
B: Fever, drenching sweats, weight loss.
X: Bulky disease (\1:3 widening of mediastinum, \10 cm
maximum dimension of nodal mass).
E: Involvement of a single extranodal site contiguous or
proximal to known nodal site.
Table 2
Distribution into stages 1
Stage
Stage
Stage
Stage
I
II
III
IV
A (no general
symptoms)
B (general symptoms)
21%
21%
10%
4%
3%
12%
15%
14%
1
The Swedish National Care Programme experience 1984 – 1993.
radiotherapy as the initial treatment, about 75 – 90% are
alive after 10 –20 years. These results were reviewed and
evaluated in SBU-report no. 129:12, 1996, pp. 185– 202.
In order to further improve relapse-free and overall
survival following initial radiotherapy in the early stages, a
number of studies of combined radiotherapy-chemotherapy have been performed (6–15). According to these studies and two metaanalyses (16, 17), combined treatment
results in an improved relapse-free survival after ten years
being about 65% with radiotherapy and 85% with the
combined treatment modality. However, overall long-term
survival is comparable, approximately 80% after ten years,
because most patients with a relapse after radiotherapy are
cured with chemotherapy. In the most recently reported
meta-analysis (17), individual patient data on 1 688 patients in 13 trials were analysed. Crude mortality data on
226 patients in two other trials were also reviewed. The
addition of chemotherapy to radiotherapy halved the ten
year risk of failure (15.8% vs 32.7%; pB 0.00001) , with a
small, non-signiŽ cant improvement in survival (79.4% vs
76.5% alive; p ¾ 0.7). The recurrences seen after radiotherapy were thus generally salvageable by re-treatment with
chemotherapy.
In a small (n ¾ 78) randomised trial in patients with
favourable clinical stage I or II, comparable results after a
median follow-up of four years were seen after radiotherapy alone (subtotal nodal irradiation) or two courses of a
relatively mild chemotherapy regimen (VBM, vinblastine,
methotrexate, bleomycin) followed by less extensive radiotherapy and four additional VBM courses (18). Two
courses of the ABVD regimen (see below) prior to extended Ž eld radiotherapy resulted in a signiŽ cantly superior freedom from treatment failure (96% vs 87% at 24
months) due to a reduced number of relapses (1 vs 17)
when compared with the same radiotherapy alone (19).
Survival rates were not different (97% vs 98%) in this
German Hodgkin Study Group trial (GHSG HD 7 trial)
including 640 patients in stage I and II without clinical risk
factors.
Some patients with localized HD present with systemic
symptoms, i.e. are in stages I –IIB. For these, radiotherapy
Acta Oncologica 40 (2001)
alone has been found to be insufŽ cient. Following radiotherapy, most of them, or about 75%, will relapse within
Ž ve years and chemotherapy as part of the primary treatment has therefore been recommended (6, 7, 20, 21). A
combined treatment with chemotherapy and radiotherapy
has been found to be effective, resulting in relapse-free and
long-term survival for about 90% of the patients (22, 23).
In more than 50% of patients with HD, mediastinal
lymph nodes are affected and sometimes a large mediastinal mass has developed, i.e. bulky mediastinum. Most
investigators recommend a combined treatment in this
situation. With radiotherapy alone 40 – 50% or more may
relapse in the bulky area or in adjacent lung tissue (24–
26). With initial chemotherapy followed by radiotherapy
the local relapse rate is about 10% (2, 27 –31).
The results thus indicate that only about 10% of the
patients with early stage disease are expected to die of
HD. Results from large co-operative groups after prolonged follow-up indicate, however, that long-term survival is not so favourable. There is an increased risk of
late, sometimes fatal, complications, above all secondary
malignancies (32, 33) and cardiac toxicity (34). The magnitude of these fatal complications is still poorly known.
Most evidence indicates that the extended-Ž eld radiotherapy is responsible for a signiŽ cant proportion of the late
complications.
Two randomised trials have compared radiotherapy
alone with combination chemotherapy as initial treatment
for early stage HD. In an Italian trial, 89 patients with
pathological stage I – IIA were randomly allocated to receive either radiotherapy with subtotal nodal irradiation
or six courses of MOPP (see below) (35). With a median
follow-up of eight years, the overall survival rate is higher
in the radiotherapy than in the chemotherapy group (93%
vs 56%; p¾ 0.001). In the second trial, 106 patients with
pathological stage IB –IIIA:1 were randomised between
total nodal irradiation and a minimum of six MOPP
cycles (36). Patient inclusion started in 1978. In 1981
patients with bulky mediastinal disease, and in 1983, patients in stage IIIA were excluded from randomisation due
to unexpectedly high recurrence rates after radiotherapy
alone. The projective ten year overall survival for randomised patients tended to be higher for those randomised
to chemotherapy compared with those randomised to radiotherapy (92% vs 76%; p ¾ 0.05). When the randomised
patients with bulky mediastinal disease or stage IIIA were
excluded, the overall survival was not different (90% vs
85%; p-value not stated). These two studies, mainly recruiting patients during the 1980s thus reached different
results. The overall conclusion was then that radiotherapy
continued to be the preferred treatment to early stage
HD except for subgroups with a high risk of recurrence.
Combination chemotherapy could, however, be a relevant treatment in countries with limited radiotherapy facilities.
Chemotherapy effects in Hodgkin’s disease
187
Even if the above mentioned two trials today mainly
have historical interest, several international groups are
exploring whether chemotherapy followed by limited Ž eld
radiotherapy, or no radiotherapy at all, will result in the
same high curability rates as extended Ž eld radiotherapy
but with less late toxicity. Preliminary results from a
randomised GHSG trial (HD 8) including 742 patients
with early stage HD and unfavourable prognostic signs
also indicate that, following two cycles of COPP: ABVD
(see below), limited Ž eld radiotherapy results in the same
high freedom from treatment failure as extended Ž eld
radiotherapy (91% vs 94%, median follow-up 26 months)
(37).
The literature shows that:
At early stages of HD most patients are cured by
extended Ž eld radiotherapy.
For a majority of patients with relapse after radiotherapy chemotherapy is curative.
Initial chemotherapy in addition to extended Ž eld radiotherapy reduces recurrence rates but does not increase
overall survival.
Patients presenting with a large mediastinal mass should
be recommended an initial combined treatment with
chemotherapy and radiotherapy since otherwise too
many patients will suffer from a relapse. Chemotherapy
should also be given to patients with B-symptoms.
Efforts to minimize treatment without compromising
the cure rate are important due to the risk of late
and sometimes fatal treatment-related complications. These efforts will probably mean that chemotherapy will play an increased role in all early stage
patients with a decreased relative importance of radiotherapy.
Chemotherapy of localised disease: Stages I– II:
ScientiŽ c evidence*
1 ¾ High 2¾ Moderate 3¾ Low Total
Number of studies: number of patients
M
C
P
R
L
1:3888
6:5057
2:477
8:14866
1
1:2999
4:1404
3:572
1:92
–
–
4:1560
–
1:5519
–
2:6887
14 :8021
5:1049
10 :20477
1
Total
18 :24288
9:5067
5:7079
32 :36434
*The weight of scientiŽ c evidence for each publication was graded
as described (Acta Oncol 2001; 40: 155 – 65). M ¾meta-analysis,
C¾controlled clinical trial, P¾prospective trial, R ¾ retrospective study, L ¾literature review and O ¾other studies. The classiŽ cation of each publication is given in the reference list.
188
Acta Oncologica 40 (2001)
L. Brandt et al.
ADVANCED DISEASE: STAGE IIIA
ADVANCED DISEASE: STAGES IIIB– IV
Relapses Ž ve to ten years even after extended Ž eld radiotherapy have been reported in 50 – 75% of patients with
HD stage IIIA (21, 38 –41). Despite this high relapse rate,
65 – 95% of the patients are alive at ten years due to
effective chemotherapy in the relapse situation. With combined chemotherapy and radiotherapy as primary treatment, the relapse rate may be reduced to about 15% and
long-term survival is about 75 – 95% (38, 40, 42).
According to one controlled (21) and one retrospective
study (43) comparable results may be obtained if radiotherapy alone or chemotherapy alone is the primary treatment. It has not been settled in randomised studies
whether overall survival after primary combination therapy is better than after primary treatment with radiotherapy or chemotherapy alone. Since radiotherapy alone
means that large tissue volumes must be irradiated, this
treatment is no longer an accepted primary treatment
because of a high risk of late adverse effects (32, 34). If
radiotherapy is the primary treatment, a substantial proportion of the patients will Ž rst be treated with extended
Ž eld radiotherapy and then with chemotherapy upon
relapse.
The literature shows that:
Initial chemotherapy is standard treatment for these patients. CR may be obtained for 60 – 90% (21, 44 – 46) and
40 – 50% of the patients become long-term survivors (46).
The prognosis is dependent upon a number of prognostic
factors, among which age is one of the most important.
Through the years several groups have developed prognostic indices for freedom from disease progression or overall
survival. Recently, data from 25 centres and study groups
on a total of 5 141 patients treated with combination
chemotherapy for advanced HD were used to create a
prognostic score (47). Based upon the number of adverse
prognostic factors, freedom from progression after Ž ve
years ranged from 84% if no prognostic factor was present
to 42% if Ž ve or more (maximum seven) were present. Five
years overall survival ranged between 90% and 56%. In the
total material it was 78%.
In order to achieve the overall results presented above,
most centres have used eight cycles of chemotherapy,
however, ranging from six to 12 cycles. Besides two early
studies with a limited number of patients, showing that
maintenance chemotherapy did not improve treatment results (48, 49), only one randomised study has addressed
the importance of the number of cycles (50). Eighty-eight
patients were randomised to either eight cycles (4 MOPP,
4 ABVD, see below) or to treatment until CR was reached.
The predicted ten-year progression-free survival was 81%
in the Ž xed group (mean number was 7.2 cycles) and 68%
in the response-adapted group (mean 5.1 cycles) (p B 0.05).
Controlled studies have indicated that the addition of
radiotherapy will not signiŽ cantly improve relapse-free or
overall survival (51). However, in one study, relapse-free
survival at seven years was 45% with the combined treatment and 21% for those treated with chemotherapy alone
(p¾ 0.002). Overall survival was not signiŽ cantly different,
71% vs 58% (p ¾ 0.15) (41). In a German study of patients
in remission following chemotherapy, the addition of lowdose radiotherapy or a further consolidating course of
chemotherapy yielded similar results in terms of relapsefree and overall survival (52). Data on 1 740 patients
treated on 14 different trials have been analyzed in a
meta-analysis (53). Eight comparisons were designed to
evaluate whether radiotherapy in a combined modality
setting could be substituted by chemotherapy using either
more cycles of the same chemotherapy or regimens that
contain additional drugs. Forty-Ž ve per cent of the patients had stage I –IIIA in these comparisons. Additional
radiotherapy showed an 11% overall improvement in tumour control rate after 10 years (p¾0.0001). No difference
could be detected with respect to overall survival (p¾0.6).
In the remaining trials, combined modality treatment
was compared with chemotherapy alone. In these comparisons, more than 80% of the patients had stage IIIB –IV.
No difference could be detected in tumour control rates
(p¾ 0.4), but overall survival was signiŽ cantly better after
Relapse after radiotherapy alone of stage IIIA is common but chemotherapy is effective in this situation.
Initial combination of radiotherapy and chemotherapy
reduces the relapse rate but does not seem to increase
long-term survival.
Overall survival after initial chemotherapy is comparable with survival after initial radiotherapy.
In the light of the most recent knowledge about longterm effects from particularly extended Ž eld radiotherapy, these patients should be treated with primary
chemotherapy, and limited Ž eld radiotherapy should be
provided to selected patients.
Chemotherapy of advanced disease: stage IIIA:
ScientiŽ c evidence*
1 ¾High
2 ¾Moderate
3 ¾ Low Total
Number of studies:number of patients
M
C
P
R
L
–
1:743
–
1:12411
1
–
–
1:179
4:505
–
–
1:151
–
–
–
–
2:894
1:179
5:12916
1
Total
3:13154
5:684
1:151
9:13989
*For abbreviations, see above.
Acta Oncologica 40 (2001)
Chemotherapy effects in Hodgkin’s disease
10 years in the group that did not receive any radiotherapy
(8% difference; p¾ 0.045). There were signiŽ cantly fewer
fatal events among patients in continuous CR if no radiotherapy was given (53). Similarly, the French group
Groupe d’Etudes des Lymphomes de l’Adulte (GELA)
randomised 418 patients in stages IIIB– IV in complete or
good partial remission (PR) after six chemotherapy
courses to either a further two consolidating chemotherapy
courses or extended Ž eld radiotherapy without detecting
any difference in event-free (70 and 72%) and overall (90
and 83%) survival, respectively (54). Like in the less advanced stages of HD, a large mediastinal mass is associated with a pronounced risk of relapse and for these
patients radiotherapy is usually added to chemotherapy as
primary treatment (55). In order to avoid relapse the
addition of radiotherapy has also been recommended with
bulky lesions located elsewhere (56, 57). Strong supportive
evidence for these recommendations from randomised trials is not, however, available.
In elderly patients, the acute side-effects of chemotherapy are particularly obvious and often prevent conventional therapy in advanced stages resulting in a relatively
poor outcome for patients \ 60 years of age (58, 59). For
the elderly patients, reduction of doses and the use of
drugs with limited acute toxicity may permit more treatment courses. Preliminary data suggest that such a strategy
may improve the outcome (59, 60). However, the treatment results of elderly patients with HD are not well
documented in the literature.
The literature shows that:
Initial chemotherapy is standard treatment for stage
IIIB –IV and 40 –50% of the patients become long-term
survivors.
The addition of radiotherapy does not improve relapsefree or overall survival in randomised trials.
The outcome for elderly patients with current treatment
is less favourable. The development of regimens causing
less acute toxicity is particularly important for the
elderly.
Chemotherapy of advanced disease: stage IIIB– IV:
ScientiŽ c evidence*
1 ¾High
2 ¾Moderate
3 ¾ Low Total
Number of studies:number of patients
M
C
P
R
L
O
1:1740
3:1321
–
3:975
1
1
–
1:226
1:79
1:154
–
–
–
5:1033
1:18
1:49
–
–
1:1740
9:2580
2:97
5:1178
1
1
Total
9:4036
3:459
7:1100
19:5595
*For abbreviations, see above.
189
RECOMMENDED CHEMOTHERAPY REGIMENS
MOPP (mechlorethamine, vincristine, procarbazine, prednisone) is a well established, effective treatment of HD. In
advanced stages CR rates range from 82 –90% and longterm survival (cure) has been reported for 60 –70% of the
patients (61, 62). The original drug combination has been
modiŽ ed, with chlorambucil substituting mechlorethamine
and vinblastine substituting vincristine, by several investigators in attempts to improve the efŽ cacy and to reduce
side-effects. These modiŽ cations failed to improve response rates and overall survival (63, 64) but reduced
vomiting (63) and neurotoxicity (64).
ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is another widely used effective drug combination.
In a controlled study of advanced HD, the treatment
results appeared better with ABVD than with MOPP (65).
CR rates were 82% for ABVD and 67% for MOPP (relative risk 0.83; 95% CI 0.71– 0.96). Survival at 5 years was
73 and 66%, respectively, a non-signiŽ cant difference.
However, the dose intensity of the MOPP therapy was
lower than in the previous studies cited (61, 62) and it has
been argued that the original MOPP regimen and ABVD
give similar results (55, 66).
Treatment with MOPP alternating with ABVD did not
improve the results compared with MOPP or ABVD in a
controlled study (65) and, based upon this, it was concluded that there is no Ž rm evidence that the use of sevenor eight-drug regimens is more effective than the standard
four-drug regimens MOPP and ABVD (66). Several other
randomised studies have, however, also addressed the
question whether alternating regimens designed in accordance with the Goldie and Coldman hypothesis (67) are
superior to single regimens. Alternating MOPP:CABS
(CCNU, doxorubicin, bleomycin, streptozocin) was not
found to be superior to MOPP alone in a small trial
including 125 patients (68). Disease-free survival was 72%
and 65%, respectively, and overall survival 68% and 66%,
respectively, after ten years. Similarly, in 113 patients
relapsing from a radiotherapy induced CR, 12 cycles of a
MOPP-like regimen (CVPP), an ABVD-like regimen
(ABOS) or CVPP alternating with ABOS all produced
about 60% Ž ve-year survival (69).
A British group randomised 594 patients to either
ChlVPP (chlorambucil, vincristine, procarbazine, prednisone) or ChlVPP alternating with a doxorubicin combination EVAP (etoposide, vinblastine, doxorubicin,
prednisone). After initial chemotherapy, CR rates were
57% and 65%, respectively (not signiŽ cant), but 65% and
75%, respectively, after the subsequent administration of
radiotherapy to residual masses (pB 0.01). The relapsefree survival and overall survival at 5 years were superior
in the alternating group (72% vs 52%; pB 0.001 and 75%
vs 66%; p B 0.05, respectively) (70). A joint EORTCFrench trial randomised, after two courses of MOPP, 192
190
L. Brandt et al.
patients to either six further courses of MOPP or to two
courses of ABVD followed by two courses of MOPP and
two courses of ABVD. They noted a longer failure-free
survival in the MOPP:ABVD arm (60% vs 43% at six
years; p ¾ 0.03). There was no statistically signiŽ cant difference in overall survival (p ¾ 0.13) (71). A French group
randomised 70 patients with stages IIIB and IV to either
four cycles of MOPP or MOPP alternating with ABVD
followed by extended Ž eld radiotherapy (STNI or TNI).
No signiŽ cant differences were seen in either response rates
(overall 84%), eight-years disease-free survival (70%) or
survival (65%) (72). Finally, in a randomised Norwegian
study of 100 patients, one group was treated with a
MOPP-derived regimen, and another group was treated
with this regimen alternating with an ABVD-derived regimen. The results in terms of relapse-free and overall
survival were almost identical (73). Taken together, some
studies indicate that there is a slightly higher activity in
alternating regimens than in conventional 4-drug regimens,
but Ž rm evidence is lacking.
So-called hybrid regimens, i.e. regimens containing
drugs originating from both MOPP-like and ABVD-like
programmes, have been introduced in recent years (74). In
one study with a short follow-up (Ž ve years), survival
following treatment with a MOPP:ABV-hybrid regimen
was 81% and similar to the survival achieved with alternating MOPP and ABVD (75). Also Ž ve-year failure-free
survival was similar (71% and 57%; p¾ 0.87). In another
study of 427 patients, comparing a hybrid regimen with
alternating MOPP and ABVD, survival at ten years was
the same, or 74% and 72%, respectively, with the two
regimens (76). In a large study of 691 patients (77), a
hybrid regimen, MOPP:ABV, was compared with sequential treatment with six or eight courses of MOPP followed
by three courses of ABVD. The eight-year survival was
79% with the hybrid and 71% with the sequential treatment (p¾ 0.02). In another large US co-operative group
trial, comparing ABVD with the MOPP:ABV-hybrid, no
differences were seen in CR-rates, freedom from progression and survival (78). However, only preliminary results
have been presented after a short follow-up. Improved
progression-free survival was seen in a randomised trial
comparing the ChlVPP:EVA (etoposide, vincristine, doxorubicin)-hybrid with MVPP (80% vs 66%; p¾ 0.005 at
Ž ve years). There was no statistically signiŽ cant difference
in overall survival (80% vs 71%; p¾ 0.28 at Ž ve years) in
this trial including 423 patients (79). The trial has been
updated after a median follow-up of almost ten years. At
eight years, freedom from progression remains superior for
the hybrid regimen (78% vs 65%; p¾ 0.005), whereas there
is no overall survival beneŽ t (74% vs 69%; p¾ 0.18) (80).
In a subsequent trial, so far only preliminarily reported
(80), 282 patients were randomised between either six
cycles of ChlVPP: EVA or an 11-week cycle regimen,
VAPEC-B
(vincristine,
doxorubicin,
prednisolon,
Acta Oncologica 40 (2001)
etoposide, cyclophosphamid and bleomycin). The ChlVPP:
EVA regimen produced similar results in the two trials. It
was superior to the VAPEC-B regimen in terms of both
freedom from progression (80% vs 61%; pB 0.002 and
survival (90% vs 77%; pB 0.03) at a median follow-up of
3.5 years. The trial was prematurely interrupted when the
inferior results of the short weekly regimen were noted.
Although long-term survival can be achieved for 70 –
80% of patients with advanced HD using current treatment programmes, the goal is to improve these results.
Thus, several new regimens are currently under investigation. For example, an intensiŽ ed treatment with
bleomycin, etoposide, doxorubicin, cyclophosphamide,
vincristine, procarbazine and prednisone (BEACOPP) was
developed by the GHSG (81). A pilot study of 30 patients
has been reported and 89% were in CR after a median
follow-up time of 40 months (82).
In order to further improve treatment results, the same
drugs at higher doses and with a shorter time-interval and
with growth factor support (BEACOPP-escalated) have
been tested in 60 patients (83). With a short follow-up
(median 32 months), freedom from treatment failure and
overall survival were 90 and 91%, respectively. The results
were considered encouraging. However, only three patients
were over 60 years (61 –65) and the tolerance of elderly
patients is unknown. Moreover, the potential for serious
late complications might be high. With a short median
observation period of less than three years, two patients
have developed acute leukaemia.
The GHSG has randomised 1 200 patients with an
alternating regimen, COPP:ABVD, the BEACOPP regimen at standard doses and BEACOPP-escalated. Eight
cycles were given followed by irradiation of initial bulky
and residual disease. The trial has so far only been preliminarily analysed and mainly presented at several scientiŽ c
meetings (84– 86). In the fourth interim analysis (85),
BEACOPP is signiŽ cantly superior to COPP:ABVD in all
end-points, and BEACOPP-escalated is superior to BEACOPP-standard in terms of progression-free survival.
Acute toxicities were similar between COPP:ABVD and
BEACOPP-standard, and increased, but manageable with
BEACOPP-escalated. Leukaemogenicity remains a concern with Ž ve cases of acute myeloid leukaemia in
the BEACOPP-escalated arm, one in BEACOPP-standard
and none in the COPP:ABVD-arm. Non-Hodgkin’s
lymphomas were, however, more commonly seen after
COPP:ABVD and BEACOPP-standard.
In another German trial, 264 patients (data available for
211) were randomised between standard COPP:ABVD or
dose-intensiŽ ed COPP: ABVD supported by GM-CSF
(87). CRs were observed for 62 vs 77% (p ¾ 0.02). The
data are preliminary and no information was given about
survival.
Acute and late side-effects are different for MOPPderived regimens and ABVD-like regimens. Neurotoxicity
is more pronounced with MOPP, whereas vomiting is
Acta Oncologica 40 (2001)
more common with ABVD. Bone marrow depression is
more pronounced with MOPP than with ABVD. There are
also major differences in late toxicities. MOPP is associated with infertility in men and women. Recovery is uncertain and has been reported for only 14% of men (88). With
ABVD the risk of infertility is considerably lower and a
100% recovery has been reported. Within the Ž rst 15 years
there is an up to 10% risk of acute leukaemia or myelodysplastic syndrome in patients treated with MOPP-like regimens plus radiation therapy (88, 89). With ABVD and
radiotherapy this risk is considerably lower, about 1%.
Treatment with ABVD and radiotherapy may induce pulmonary Ž brosis in about 60% of the patients (88) and
cardiac disease may also result. It has been hypothesized
that fatal pulmonary or cardiac disease will be similar in
magnitude to the risk of leukaemia after MOPP but precise data are not available (66).
Because the patterns of late toxicity are quite different
with MOPP- and ABVD-derived regimens it is not possible to recommend any of them for universal use in HD. It
has been proposed that the choice depends on the toxicity
proŽ le the patient is willing to accept. In patients in whom
fertility is an overriding concern, ABVD is the treatment
of choice. For patients who are less concerned about
fertility, MOPP or MOPP-derived regimens are reasonable
choices, although concerns about secondary leukaemias
and slightly inferior treatment results can be expressed.
The alternating or hybrid regimens, in which lower total
doses of MOPP- and ABVD-derived drugs are given, may
provide advantages concerning late toxicity but Ž rm evidence for this from clinical studies is not available. In one
of the randomised studies mentioned above (77), 9:344
cases of acute myeloid leukaemia or myelodysplasia were
reported after sequential six to eight courses of MOPP
followed by three courses of ABVD as compared with
1:347 after MOPP:ABV-hybrid (8 –12 cycles). Fewer secondary malignancies were seen with ABVD (two cases)
than with MOPP:ABV-hybrid (12 cases) in a trial including 856 patients (78). In the British trials using the
ChlVPP:EVA hybrid with a median follow-up of almost
ten years, 15:355 patients have developed a second malignancy (80).
The literature shows that:
Several chemotherapy regimens, e.g. MOPP, ABVD,
several alternating or so-called hybrid regimens and
BEACOPP (standard and escalated) are effective in
HD.
MOPP and ABVD have been standard regimens and
have also been used in combination.
Regimens containing drugs originating from both
MOPP-like and ABVD-like regimens (hybrid regimens)
might be more effective than the original standard
regimens, although superiority over ABVD has not
been shown.
Chemotherapy effects in Hodgkin’s disease
191
It is possible that BEACOPP is the presently most
active regimen, but this conclusion is based upon preliminary data from one large trial.
Acute and late side-effects are different for the original
regimens.
Chemotherapy regimens:
ScientiŽ c evidence*
1 ¾High
2 ¾Moderate
3 ¾Low Total
Number of studies:number of patients
M
C
P
R
L
O
–
10 :5228
1:52
5:1005
2
–
–
3:743
2:90
–
–
1
–
5:2099
–
–
–
–
–
18:8070
3:142
5:1005
2
1
Total
18 :6285
6:833
5:2099
29:9217
*For abbreviations, see above.
HIGH-DOSE THERAPY AT RESISTANCE TO
CONVENTIONAL TREATMENT
Patients who fail to achieve a CR to primary chemotherapy have a very poor prognosis, as have patients with
relapse within 12 months after an initial chemotherapy-induced CR. These groups of patients are generally considered resistant to conventional combination chemotherapy
because only about 10% of them will become long-term
disease-free survivors to conventionally dose salvage
chemotherapy (90 –92). For patients with resistant HD,
high-dose regimens with stem cell support have been proposed. The results of ten studies were summarized in 1994
(93). Treatment-related death rate was about 10 – 15%. An
overall long-term, disease-free survival may be achieved in
20 – 30% of these patients. Similar results have been presented also in numerous other reports (94 –103; only selected major recent trials have been reviewed). Two studies
have recently reported results from transplanted patients
who never achieved a CR to primary chemotherapy or
who relapsed within 90 days. The patients have been
reported to international transplantation registers (104,
105). Overall survival at Ž ve years was 35 –40% in these
studies. Although the results using high-dose therapy seem
superior there is a possibility that selection bias is acting to
make high-dose therapy appear more effective than conventional salvage chemotherapy.
A randomised study of 40 patients compared a dose-intensive regimen requiring stem cell support (BEAM;
BCNU, etoposide, cytarabine, melphalan) with the same
drugs used at doses not requiring stem cell support (mini-
192
Acta Oncologica 40 (2001)
L. Brandt et al.
BEAM) (106). At 3 years the progression-free survival was
superior in the BEAM-arm (53% vs 10%; p ¾ 0.025). There
was no signiŽ cant difference in total survival, but 4 patients randomised to mini-BEAM were transplanted after
relapse. The GHSG and the European Bone Marrow
Transplantation Group jointly randomised 161 patients
less than 60 years with relapsed HD between 1993 and
1997. Patients who relapsed early (3– 12 months after
initial treatment), relapsed late ( \ 12 months and treated
with seven or eight drugs) or patients with multiple relapses could be included. Treatment was either four
courses of Dexa-BEAM (dexametason, BCNU, etoposide,
ara-C and melphalan) or two courses of Dexa-BEAM
followed by high-dose BEAM. Only patients with
chemosensitive disease, i.e. CR or PR after two courses of
Dexa-BEAM, continued treatment as randomised. The
results have only been reported as an abstract (107).
Among 142 evaluable patients, 115 were considered
chemosensitive, i.e. proceeded to Dexa-BEAM three and
four or high-dose therapy. Reasons for not proceeding
were mainly toxic death, other life threatening toxicity or
less than PR. Median follow-up is 33 months. When data
were analysed based on intended treatment, time to treatment failure for all chemosensitive patients (p¾ 0.03) and
for the subgroups with early or late relapse (p¾ 0.04 each)
was signiŽ cantly longer with high-dose treatment. Overall
survival did not differ signiŽ cantly (p¾ 0.3). Eight control
patients have been transplanted after another relapse.
A French group (108) has performed a retrospective
case-control study in 86 HD patients who underwent
high-dose treatment after failure of the Ž rst chemotherapy
regimen. Matching was done with 258 conventionally
treated patients from international databases. In the
grafted patients, the Ž ve-year event-free survival and overall survival after transplantation were 25% and 35%, respectively. The Ž ve-year overall survival rates of the
grafted patients and the 258 matched conventionallytreated patients were 38% and 29%, respectively (p ¾ 0.06).
Median follow-up is short or 29 months (8 –106 months)
since the diagnosis of HD and 15 months (1– 93 months)
since the autologous stem cell transplantation. Toxicity
was acceptable with seven (8%) procedure-related deaths.
Yet another retrospective case-control study was performed on primarily refractory HD patients (109). Eventfree survival at four years was 52% in transplanted patients
(n¾ 13) compared with 19% for those who received conventional-dose salvage therapy.
The literature shows that:
The value of high-dose chemotherapy has not been
documented in large controlled trials with long followup.
The results of large uncontrolled single centre and
multicentre studies, two case-control studies, and two
small randomised studies show trends for improved
survival from the use of high-dose chemotherapy in HD
patients who are chemotherapy induction failures, who
relapse after a short initial remission or after a longer
initial remission and treated with a seven to eight drug
combination or who have had multiple relapses. A
recommendation of routine use of such treatment does
not seem to be fully justiŽ ed given the quality of data
available and the observed effect on survival.
High-dose chemotherapy:
ScientiŽ c evidence*
1 ¾High
2 ¾Moderate
3 ¾Low Total
Number of studies:number of patients
M
C
P
R
–
–
1:122
4:846
–
2:182
5:322
3:270
–
–
1:26
2:130
–
2:182
7:470
9:1246
Total
5:968
10 :774
3:156
18:1898
*For abbreviations, see above.
QUALITY OF LIFE FOR LONG-TERM SURVIVORS
In a French study of 93 patients with a mean age of 32
years at diagnosis and free from relapse on an average ten
years after treatment, late psychosocial sequelae were evaluated (110). The results were compared with a matched
population-based control group. Radiation was given in
34% of patients, chemotherapy alone in 4% and 62% were
treated with a combination of irradiation and chemotherapy. Compared with controls HD patients reported more
physical impairments, e.g. dyspnoea (p B 0.001) and fatigue (p¾ 0.03). They were more often childless (p ¾ 0.04).
Psychologic, familial and professional status was not inferior among the former HD patients. The global health
status was rated as equally good by patients and controls.
Similar proportions of patients and controls worked, 74
and 72%, respectively. The sequelae of different treatment
modalities were not analysed separately.
In a Norwegian study, 459 HD survivors aged 19 –74
years treated at the Norwegian Radium Hospital 1971–
1991 were approached in 1994 and compared with norms
from 2 214 individuals approached in 1996. The mean time
since diagnosis among the HD survivors was 12.2 years
(range 3– 23 years). Health-related quality of life (QoL)
was assessed by the short form 36 (SF 36). Previous studies
from the same group had demonstrated that the former
HD patients reported high levels of anxiety and fatigue
(111). Compared with the norms of the control group,
being representative of the general Norwegian population,
the HD survivors had lower scores, i.e. worse health state,
Acta Oncologica 40 (2001)
on all scales after adjustment for age, gender and educational levels. Statistically signiŽ cant differences were thus
found in general health, physical functioning, role limitations, social functioning and in vitality. When analyzed
according to previous treatment, no statistically signiŽ cant
differences were found. Patients treated with chemotherapy
had, however, the highest scores on all scales, intermediate
scores were found for those treated with chemotherapy and
radiotherapy and the lowest scores for those treated with
radiotherapy alone as primary treatment (112, 113).
When the psychosocial adaptation of 273 advanced stage
HD survivors off treatment for one year or more (mean six
years) was compared with that of 206 adult acute leukaemia
survivors, HD survivors reported a distress score on the
brief symptom inventory scale that was almost twice that
found for the acute leukaemia survivors (p ¾ 0.05) (114).
HD survivors also reported more fatigue, conditioned
nausea, greater impact of cancer on their family life and
poorer sexual functioning than acute leukaemia survivors.
All leukaemia patients had received chemotherapy only,
whereas 20% of the Hodgkin disease survivors had received
radiation therapy. The HD patients had relapsed more
frequently than the leukaemia patients (29% vs 7%; p ¾
0.01). The relative contributions of these differences to the
late problems are not known.
In a Swedish study (115), a questionnaire was sent to 110
HD patients surviving 4.6 –19.3 (mean 10.3) years after
treatment. The median age at diagnosis was 32 years and
the former HD patients were asked about possible therapyrelated side-effects. Ninety-nine (90%) responded. Thirty
were treated with chemotherapy as the sole modality and
this group was analysed separately. Shortness of breath and
a reduced physical condition were the most common complaints (19 patients, 63%). Sixteen (53%) reported numbness
in hands:feet. Muscle weakness was experienced by 14
(47%). Mouth dryness was reported by 12 (40%), and 13
(43%) had problems with teeth. Ten out of the 30 patients
treated with chemotherapy were involuntarily childless. In
the total material of 99 former patients, 17% experienced a
reduced capacity for work. The results of this study were
not compared with any control material.
The health-related QoL Ž ndings re ect the treatment
practices of the 1970s and 1980s and the consequences of
giving either chemotherapy, radiotherapy or both. Since
advances have been made in the treatment, as well as in the
treatment of side-effects, it is possible that the results might
be quite different from those treatments used today. The
relative contributions of chemotherapy and radiotherapy
on the late effects are not known, although it may be
suspected that the extended Ž eld radiotherapy, used more
previously, is more responsible for some late effects than the
chemotherapy.
This assumption is supported by a study of late sequelae
after mantle Ž eld irradiation for supradiaphragmatic HD in
221 Norwegian patients (116). The patients were studied
Chemotherapy effects in Hodgkin’s disease
193
more than three years (mean 12 years) after treatment.
Respiratory symptoms, cardiac disease and dental complications were compared with a group of 201 former HD
patients treated with chemotherapy only for advanced-stage
disease and followed for a comparable period. Dyspnoea on
exertion was reported by 30% of the irradiated patients and
9% in the chemotherapy group (p¾ 0.0001). Myocardial
infarction was about equally common in the two groups,
4% and 3%, respectively, but valvular disease was reported
by 11% and 0%, respectively. Increased expenses for dental
care were reported by 48% of the irradiated patients and
21% of patients treated with chemotherapy only (p¾
0.0001). Moreover, the impact of chemotherapy in addition
to irradiation could be evaluated for the respiratory and
dental sequelae. The addition of chemotherapy did not
cause an increase in these complications.
The literature shows that:
Persistent side-effects of treatment are common among
long-term survivors. For some of these side-effects,
radiotherapy contributes more than chemotherapy.
Social and professional status are not impaired.
75 – 85% of former HD patients have a preserved capacity for work.
Quality of life for long-term survivors:
ScientiŽ c evidence*
1 ¾High
2¾ Moderate
3¾ Low
Total
Number of studies:number of patients
R
–
6:1964
–
1:99
–
–
–
7: 2063
Total
6:1964
1:99
–
7: 2063
*For abbreviations, see above.
LITERATURE
The articles included in the reference list were classiŽ ed and graded
as follows:
ScientiŽ c evidence*
1 ¾ High
2 ¾ Moderate
3 ¾ Low
Total
Number of studies:number of patients
M
C
P
R
L
O
3:18039
19 :11930
4:651
26 :19656
5
1
1:2 999
8:2131
12: 1242
10: 1120
–
1
–
17: 5686
2:44
4:5698
–
–
4:21038
44:19747
18:1937
40:26474
5
2
Total
58 :50276
32: 7492
23: 11428
113 :69196
*For abbreviations, see above.
194
Acta Oncologica 40 (2001)
L. Brandt et al.
REFERENCES
1. Cancer incidence in Sweden 1997. Stockholm: National
Board of Health and Welfare, Centre for Epidemiology, The
Cancer Registry, 1999.
2. Abrahamsen AF, Hannisdal E, Nome O, et al. Clinical stage
I and II Hodgkin’s disease: Long-term results of therapy
without laparotomy. Ann Oncol 1996; 7: 147 – 50. (P1:313)
3. Van Spronsen DJ, Dijkema IM, Vrits LW, et al. Improved
survival of Hodgkin’s patients in South-East Netherlands
since 1972. Eur J Cancer 1997; 33: 436 – 41. (L1)
4. Lister AT, Crowther D. Staging for Hodgkin’s disease.
Semin Oncol 1990; 17: 696 – 703.
5. Diehl V, Sextro M, Franklin J, et al. Clinical presentation,
course, and prognostic factors in lymphocyte-predominant
Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s
disease: report from the European task force on lymphoma
project on lymphocyte-predominant Hodgkin’s disease. J
Clin Oncol 1999; 17: 776 – 83. (O1)
6. Anderson H, Deakin D, Wagstaff J, et al. A randomised
study of adjuvant chemotherapy after mantle radiotherapy
in supradiaphragmatic Hodgkin’s disease PS IA-IIB: A report from the Manchester lymphoma group. Br J Cancer
1984; 49: 695 – 702. (C2: 114)
7. Andrieu JM, Dana M, Desprez-Curely JP, et al. MOPP
chemotherapy plus irradiation for Hodgkin’s disease, stages
IA to IIIB. Long-term results of the prospective trial H72
(1972-1976 , 334 patients). Hematol Oncol 1985; 3: 219 – 31.
(P2:334)
8. Anselmo A, Bove M, Cartoni C, et al. Combined modality
(ABVD plus radiotherapy) versus radiotherapy in the management of early stage (IIA) Hodgkin’s disease with mediastinal involvement. Haematol 1992; 77: 177 – 9. (C3:73)
9. Bonfante V, Santoro A, Viviani S, et al. Early stage
Hodgkin’s disease: Ten-year results of a non-randomised
study with radiotherapy alone or combined with MOPP. Eur
J Cancer 1993; 29A: 24 – 9. (P2:201)
10. Carde P, Burgers J, Henry Amar M, et al. Clinical stages I
and II Hodgkin’s disease: A speciŽ cally tailored therapy
according to prognostic factors. J Clin Oncol 1988; 6: 239 –
52. (C1:494)
11. Cosset M, Henry Amar M, Meerwaldt J, et al. The EORTC
trials for limited Hodgkin’s disease. Eur J Cancer 1992; 28A:
1847 – 50. (C1:1641)
12. Nordentoft A, Nissen N, Bjorn Jensen K. Experiences from
the national Danish study group (LYGRA) with respect to
diagnosis, classiŽ cation and treatment of Hodgkin’s disease.
Acta Radiol Oncol 1984; 23: 163 – 7. (C1:310)
13. Rosenberg S, Kaplan H. The evolution and summary results
of the Stanford randomised clinical trials of the management
of Hodgkin’s disease 1962-1984 . Int J Radiat Oncol Biol
Phys 1985; 11: 5 – 22. (C2:835)
14. Straus D, Yahalom J, Gaynor J, et al. Four cycles of
chemotherapy and regional radiation therapy for clinical
early-stage and intermediate stage Hodgkin’s disease. Cancer
1992; 69: 1052 – 60. (C2: 120)
15. Tubiana M, Henry-Amar M, Carde P, et al. Toward comprehensive management tailored to prognostic factors of
patients with clinical stages I and II in Hodgkin’s disease.
The EORTC Lymphoma Group controlled clinical trials:
1964-1987. Blood 1989; 73: 47 –56. (C1:1579)
16. Shore T, Nelson N, Weinerman B. A meta-analysis of stages
I and II Hodgkin’s disease. Cancer 1990; 65: 1155 – 60.
(M2:2999)
17. Specht L, Gray RG, Clarke MJ, et al. In uence of more
extensive radiotherapy and adjuvant chemotherapy on long-
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
term outcome of early stage Hodgkin’s disease: A meta-analysis of 23 randomised trials involving 3 888 patients.
International Hodgkin’s Disease Collaborative Group. J
Clin Oncol 1998; 16: 830 – 43. (M1:3888)
Horning SJ, Hoppe RT, Mason J, et al. Stanford-Kaiser
permanent G1 study for clinical stage I to IIA Hodgkin’s
disease: Subtotal lymphoid irradiation versus vinblastine,
methotrexate, and bleomycin chemotherapy and regional
irradiation. J Clin Oncol 1997; 15: 1736 – 44. (C2:78)
Tesch H, Sieber M, Rüffer JU, et al. 2 cycles ABVD plus
radiotherapy is more effective than radiotherapy alone in
early stage HD – Results of the HD7 trial of the GHSG.
VII Int Conf Malign Lymph, Lugano, 1999; 249 Abstr.
(C3:640)
Gospadarowicz M, Sutcliffe S, Bergsagel D, et al. Radiation
therapy in clinical stage I and II Hodgkin’s disease. Eur J
Cancer 1992; 28A: 1841 – 6. (R1:731)
Haybittle J, Easterling M, Benett M, et al. Review of British
National Lymphoma Investigation studies of Hodgkin’s disease and development of prognostic index. Lancet 1985; 1:
967 – 72. (C1:743)
Brusamolino E, Lazzarino M, Orlandi E, et al. Early stage
Hodgkin’s disease: Long term results with radiotherapy
alone or combined radiotherapy and chemotherapy. Ann
Oncol (Suppl) 1994; 5: 101 – 6. (P1:164)
Ziltoun R, Audebert A, Hoerni B, et al. Extended versus
involved Ž eld irradiation combined with MOPP chemotherapy in early clinical stages of Hodgkin’s disease. J Clin
Oncol 1985; 3: 207 – 14. (C2:335)
Hartsen W, Sarin P, Recine D, et al. Long-term results of
curative irradiation in pathologically staged IA and IIA
Hodgkin’s disease. Radiol 1993; 186: 565 – 8. (R1:176)
Mauch P, Tarbell N, Weinstein H, et al. Stage IA and IIA
supradiaphragmatic Hodgkin’s disease: Prognostic factors in
surgically staged patients treated with mantle and paraaortic
irradiation. J Clin Oncol 1988; 6: 1576 – 83. (R1:315)
Wirth A, Chao M, Corry J, et al. Mantle irradiation alone
for clinical stage I– II Hodgkin’s disease: Long-term followup and analysis of prognostic factors in 261 patients. J Clin
Oncol 1999; 17: 230 – 40. (R1:261)
Glimelius B, Kälkner M, Enblad G, et al. Treatment of early
and intermediate stages of supradiaphragmatic Hodgkin’s
disease: The Swedish National Care Program experience.
Ann Oncol 1994; 5: 809 –16. (R1:210)
Hughes-Davies L, Tarbell NJ, Coleman CN, et al. Stage
IA-IIB Hodgkin’s disease: Management and outcome of
extensive thoracic involvement. Int J Radiat Oncol Biol Phys
1997; 39: 361 – 9. (R1:172)
Leopold K, Canellos G, Rosenthal D, et al. Stage IA-IIB
Hodgkin’s disease: Staging and treatment of patients with
large mediastinal adenopathy. J Clin Oncol 1989; 7: 1059 –
65. (R2:92)
Tarbell N, Thomson L, Mauch P. Thoracic irradiation in
Hodgkin’s disease: Disease control and long-term complications. Int J Radiat Oncol Biol Phys 1990; 18: 275 – 81.
(R1:590)
Zinzani P, Mazza P, Gherlinzoni F, et al. Massive mediastinal involvement in stage I– II Hodgkin’s disease: Response
to combined modality treatment. Leuk Lymphoma 1992; 8:
81 – 5. (P2:37)
Henry-Amar M. Second cancer after the treatment for
Hodgkin’s disease: A report from the international database
on Hodgkin’s disease. Ann Oncol (Suppl) 1992; 3 (4): 117 –
28. (R1:12411)
Acta Oncologica 40 (2001)
33. Swerdlow AJ, Barber JA, Vaughan Hudson G, et al. Risk of
second malignancy after Hodgkin’s disease in a large cohort
of patients in Britain. Leuk Lymphoma 1998;29 (Suppl 1):
O12 Abstr. (R3:5519)
34. Hoppe RT. Hodgkin’s disease. Complications of therapy
and excess mortality. Ann Oncol (Suppl) 1997; 8: 115 – 8.
(L1)
35. Biti GP, Cimino G, Cartoni C, et al. Extended-Ž eld radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I– IIA Hodgkin’s disease:
eight-year update of an Italian prospective randomized
study. J Clin Oncol 1992; 10: 378 – 82. (C3:89)
36. Longo DL, Glatstein E, Duffey PL, et al. Radiation therapy
versus combination chemotherapy in the treatment of earlystage Hodgkin’s disease: seven-year results of a prospective
randomized trial. J Clin Oncol 1991; 9: 906 –17. (C3:105)
37. Rüffer U, Sieber M, PŽ stner B, et al. Involved Ž eld radiation
is as effective as extended Ž eld radiation following
chemotherapy for intermediate stage Hodgkin’s disease expecting a reduction of long term side-effects: Interim analysis
of the HD8 trial (GHSG). VII Int Conf Malign Lymph,
Lugano 1999; 250 Abstr. (C3:742)
38. Brada M, Ashley S, Nichols J, et al. Stage III Hodgkin’s
disease-long term results following chemotherapy, radiotherapy and combined modality therapy. Radiother Oncol 1989;
14: 185 – 98. (R2:215)
39. Levitt S, Lee C, Aeppli D, et al. The role of radiation
therapy in Hodgkin’s disease: Experience and controversy.
The 54th annual Janeway lecture 1989. Cancer 1992; 70:
693 – 703. (P2:179)
40. Mauch P, Goffman T, Rosenthal D, et al. Stage III
Hodgkin’s disease: Improved survival with combined modality therapy as compared with radiation therapy alone. J Clin
Oncol 1985; 3: 1166 – 73. (R2:120)
41. Pavlovsky S, Santarelli M, Sackman MF, et al. Randomised
trial of chemotherapy versus chemotherapy plus radiotherapy for stage III– IVA & B Hodgkin’s disease. Ann Oncol
1992; 3: 533 – 7. (C3:151)
42. Prosnitz L, Cooper D, Cox E, et al. Treatment selection for
stage IIIA Hodgkin’s disease patients. Int J Radiat Oncol
Biol Phys 1985; 11: 1431 – 7. (R2:85)
43. Oza A, Leahy M, Lim J, et al. The treatment of stage IIIA
Hodgkin’s disease-total nodal irradiation versus combination
chemotherapy: Either or neither. J Clin Oncol 1991; 9:
1514 – 6. (R2:85)
44. Hancock B, Vaughan Hudson G, Vaughan Hudson B, et al.
British National Lymphoma Investigation randomised study
of MOPP (mustine, Oncovin, procarbazine, prednisolone)
against LOPP (Leukeran substituted for mustine) in advanced Hodgkin’s disease-long term results. Br J Cancer
1991; 63: 759 – 82. (C1:290)
45. Oza A, Ganesan T, Doreen M, et al. Patterns of survival in
patients with advanced Hodgkin’s disease (HD) treated in a
single centre over 20 years. Br J Cancer 1992; 65: 429 – 37.
(R1:164)
46. Urba W, Longo D. Hodgkin’s disease. N Engl J Med 1992;
326: 678 – 87. (L1)
47. Hasenclever D, Diehl V. A prognostic score for advanced
Hodgkin’s disease. N Engl J Med 1998; 339: 1506 – 14. (O1)
48. Frei E, Luce JK, Gamble JF, et al. Combination chemotherapy in advanced Hodgkin’s disease. Induction and maintenance of remission. Ann Intern Med 1973; 79: 376 – 82.
(C3:178)
49. Young RC, Canellos GP, Chabner BA, et al. Maintenance
chemotherapy for advanced Hodgkin’s disease in remission.
Lancet 1973; 1: 1339 – 43. (C3:57)
Chemotherapy effects in Hodgkin’s disease
195
50. Björkholm M, Axdorph U, Grimfors G, et al. Fixed versus
response-adapted MOPP:ABVD chemotherapy in Hodgkin’s
disease. Ann Oncol 1995; 6: 895 – 9. (C3:88)
51. Yelle L, Bergsagel D, Baseo V, et al. Combined modality
therapy of Hodgkin’s disease: 10-year results of National
Cancer Institute of Canada Clinical Trials Group multicenter clinical trial. J Clin Oncol 1991; 9: 1983 – 93. (C2:226)
52. Diehl V, Loef er M, Pfreundschuh M, et al. Further
chemotherapy versus low-dose involved-Ž eld radiotherapy as
consolidation of complete remission after six cycles of alternating chemotherapy in patients with advanced Hodgkin’s
disease. Ann Oncol 1995; 6: 901 – 10. (C1:288)
53. Loef er M, Brosteanu O, Hasenclever D, et al. Meta-analysis of chemotherapy versus combined modality treatment
trials in Hodgkin’s disease. J Clin Oncol 1998; 16: 818 – 29.
(M1:1740)
54. Fermé C, Mounier N, Diviné M, et al. Extended Ž eld
irradiation does not improve survival in stage IIIB-IV
Hodgkin’s disease (HD) in complete remission or good
partial response: A randomised study from the GELA. VII
Int Conf Malign Lymph, Lugano, 1999; 60 Abstr. (C3:559)
55. Longo D, Russo A, Duffey P, et al. Treatment of advancedstage massive mediastinal Hodgkin’s disease: The case for
combined modality treatment. J Clin Oncol 1991; 9: 227 – 35.
(R3:49)
56. Brizel D, Winer E, Prosnitz L, et al. Improved survival in
advanced Hodgkin’s disease with the use of combined
modality therapy. Int J Radiat Oncol Biol Phys 1990; 19:
535 – 42. (R2:154)
57. Sutcliffe S. Role of radiation therapy in advanced Hodgkin’s
disease-as yet, an answer? Still a question? Ann Oncol 1992;
3: 499 – 501. (O1)
58. Enblad G, Glimelius B, Sundström C. Treatment outcome in
Hodgkin’s disease in patients above the age of 60: A population based study. Ann Oncol 1991; 2: 291 – 302. (R1:163)
59. Glimelius B, Enblad G, Kälkner M, et al. Treatment of
Hodgkin’s disease: The Swedish National Care Program
experience. Leuk Lymphoma 1996; 21: 71 –8. (R1:648)
60. Taylor P, Jackson G, Lucraft H, et al. A novel treatment for
Hodgkin’s disease in the elderly: P. Come. Leuk Lymphoma
1998; 29 (Suppl 1): 97 Abstr. (P3:18)
61. DeVita VT Jr, Simon RM, Hubbard SM, et al. Curability of
advanced Hodgkin’s disease with chemotherapy: Long-term
follow up of MOPP-treated patients at the National Cancer
Institute. Ann Intern Med 1980; 92: 587 – 95. (R1:198)
62. Longo DL, Young RC, Wesley M, et al. Twenty years of
MOPP therapy for Hodgkin’s disease. J Clin Oncol 1986; 4:
1295 – 306. (R1:198)
63. Selby P, Patel P, Milan S, et al. ChlVPP combination
chemotherapy for Hodgkin’s disease: Long term results. Br J
Cancer 1990; 62: 279 – 85. (R1:284)
64. Sutcliffe SB, Wrigley PF, Peto J, et al. MVPP chemotherapy
regimen for advanced Hodgkin’s disease. Br Med J 1978; 1:
679 – 83. (R1:133)
65. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD or
MOPP alternating with ABVD. N Engl J Med 1992; 327:
1478 – 84. (C2:361)
66. Williams ME, Lister TA, Longo DL. Hodgkin’s disease and
non-Hodgkin’s lymphoma. In: McArthur JR, ed. Hematology 1993. Education Programme American Society of Hematology. St Louis, Missouri: 1993:49-61 . (L1)
67. Goldie JH, Coldman AJ. The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res 1984; 44: 3643 – 53.
196
L. Brandt et al.
68. Longo DL, Duffey PL, DeVita VT, et al. Treatment of
advanced-stage Hodgkin’s disease: Alternating non cross-resistant MOPP:CABS is not superior to MOPP. J Clin Oncol
1991; 9: 1409 – 20. (C1:125)
69. Vinciguerra V, Propert KJ, Coleman M, et al. Alternating
cycles of combination chemotherapy for patients with recurrent Hodgkin’s disease following radiotherapy. A prospectively randomised study by the Cancer and Leukemia Group
B. J Clin Oncol 1986; 4: 838 – 46. (C3:113)
70. Hancock BW, Vaughan Hudson G, Vaughan Hudson B, et
al. LOPP alternating with EVAP is superior to LOPP alone
in the initial treatment of advanced Hodgkin’s disease: Results of a British National Lymphoma Investigation Trial. J
Clin Oncol 1992; 10: 1228 – 52. (C1:594)
71. Somers R, Carde D, Henry-Amar M, et al. A randomised
study in stage IIIB and IV Hodgkin’s disease comparing
eight courses of MOPP versus an alternation of MOPP with
ABVD: A European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe
Pierre-et-Marie-Curie controlled clinical trial. J Clin Oncol
1994; 12: 279 – 87. (C1:192)
72. Fermé C, Lepage E, Brice P, et al. Combined chemotherapyradiotherapy in advanced Hodgkin’s disease: Results of a
prospective clinical trial with 70 stage IIIB– IV patients. Int
J Radiat Oncol Biol Phys 1993; 26: 397 – 405. (C3:70)
73. Holte H, Mella O, Witt E, et al. ChlVPP is as effective as
alternating ChlVPP:ABOD in advanced stage Hodgkin’s
disease. Acta Oncol 1996; 35 (Suppl 8): 73 – 80. (C2:100)
74. Klimo P, Connors J. An update of the Vancouver experience
in the management of advanced Hodgkin’s disease treated
with the MOPP:ABV hybrid programme. Semin Hematol
(Suppl) 1988; 2 (2): 34 – 40. (P2:79)
75. Connors JM, Klimo P, Adams G, et al. Treatment of
advanced Hodgkin’s disease with chemotherapy-comparison
of MOPP: ABV hybrid regimen with alternating courses of
MOPP and ABVD: A report from the National Cancer
Institute of Canada Clinical Trials Group. J Clin Oncol
1997; 15: 1638 – 45. (C1: 301)
76. Viviani S, Bonadonna G, Santoro A, et al. Alternating
versus hybrid MOPP and ABVD combinations in advanced
Hodgkin’s disease: Ten-year results. J Clin Oncol 1996; 14:
1421 – 30. (C1:427)
77. Glick JH, Young ML, Harrington D, et al. MOPP:ABV
hybrid chemotherapy for advanced Hodgkin’s disease signiŽ cantly improves failure-free and overall survival: The 8-year
results of the Intergroup trial. J Clin Oncol 1998; 16: 19– 26.
(C1:691)
78. Duggan D, Petroni G, Johnson J, et al. MOPP:ABV versus
ABVD for advanced Hodgkin’s disease-a preliminary report
of CALGB 8952 (with SWOG, ECOG, NCIC). Proc Am
Soc Clin Oncol 1997; 16: 43 Abstr. (C3:856)
79. Radford JA, Crowther D, Rohatiner AZ, et al. Results of a
randomised trial comparing MVPP chemotherapy with a
hybrid regimen, ChlVPP:EVA, in the initial treatment of
Hodgkin’s disease. J Clin Oncol 1995; 13: 2379 – 85. (C1:423)
80. Radford JA, Rohatiner AZ, Ryder WD, et al. Fourteen
years clinical trial experience with the CHLVPP:EVA hybrid
regimen as Ž rst line treatment for advanced Hodgkin’s disease (HD). VII Int Conf Malign Lymph, Lugano, 1999; 59
Abstr. (C3:419 » C3:282)
81. Reuss K, Engert A, Tesch H, et al. Current clinical trials in
Hodgkin’s disease. Ann Oncol (Suppl) 1996; 7 (4): 109 – 13.
(O2)
82. Diehl V, Sieber M, Ruffer U, et al. BEACOPP: An intensiŽ ed chemotherapy regimen in advanced Hodgkin’s disease.
Ann Oncol 1997; 8: 143 – 8. (P2:30)
Acta Oncologica 40 (2001)
83. Tesch H, Diehl V, Lathan B, et al. 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. Blood 1998; 92: 4560 – 7. (P2:60)
84. Diehl V, Franklin J, Hasenclever D, et al. BEACOPP, a new
dose-escalated and accelerated regimen, is at least as effective
as COPP:ABVD in patients with advanced-stage Hodgkin’s
lymphoma: interim report from a trial of the German
Hodgkin’s Lymphoma Study Group. J Clin Oncol 1998; 16:
3810 – 21. (C1:1200)
85. Diehl V, Sieber M, Franklin J, et al. Dose escalated BEACOPP chemotherapy for advanced Hodgkin’s diseae:
Promising results of the fourth interim analysis of the HD9
trial. VII Int Conf Malign Lymph, Lugano, 1999; 61 Abstr.
(C3:1200)
86. Tesch H, Diehl V, Lathan B, et al. Interim analysis of the
HD9 study of the German Hodgkin study group (GHSG)
— BEACOPP is more effective than COPP: ABVD in
advanced stage Hodgkin’s disease. Leuk Lymphoma 1998;
29 (Suppl 1): I-5 Abstr. (C3:505)
87. Gerhartz HH, Schwenke H, Bazarbashi S, et al. Randomised
comparison of COPP: ABVD versus dose-and time-escalated
COPP:ABVD with GM-CSF support for advanced
Hodgkin’s disease. Blood 1997; 90 (Suppl 1) Abstr 1731.
(C3:211)
88. Bonadonna G. Modern treatment of malignant lymphomas:
A multidisciplinary approach. The Kaplan Memorial Lecture. Ann Oncol (Suppl) 1994; 5 (2): 5 – 16. (P1:52)
89. Blaney DW, Longo DL, Young RC, et al. Decreasing risk of
leukemia with prolonged follow up after chemotherapy and
radiotherapy for Hodgkin’s disease. N Engl J Med 1987;
316: 710 – 4. (R1:192)
90. Bonfante V, Santoro A, Viviani S, et al. Outcome of patients
with Hodgkin’s disease failing after primary MOPP-ABVD.
J Clin Oncol 1997; 15: 528 –34. (P2:115)
91. Enblad G, Glimelius B, Hagberg H, et al. Methyl-GAG,
Ifosfamide, Methotrexate and Etoposide (MIME) as salvage
therapy for Hodgkin’s disease and non-Hodgkin’s
lymphomas. Acta Oncol 1990; 29: 297 – 301. (P2:68)
92. Longo DL, Duffey PL, Young RC, et al. Conventional dose
salvage combination chemotherapy in patients relapsing with
Hodgkin’s disease after combination chemotherapy: The low
probability for cure. J Clin Oncol 1992; 10: 210 – 8. (R1:107)
93. Armitage JO. Early bone marrow transplantation in
Hodgkin’s disease. Ann Oncol (Suppl) 1994; 5 (2): 161 – 3.
(R1:442)
94. Ahmed T, Lake DE, Beer M, et al. Single and double
autotransplants for relapsing:refractory Hodgkin’s disease:
Results of two consecutive trials. Bone Marrow Transplant
1997; 19: 449 – 54. (P1:122)
95. Andersson PO, Brune M, Ekman T. Remission inversion
and no transplant-related mortality — A single centre experience of autologous stem cell transplantation in malignant
lymphoma. Acta Oncol 2000; 39: 849 – 56.
96. Burns LJ, Daniels KA, McGalve PB, et al. Autologous stem
cell transplantation for refractory and relapsed Hodgkin’s
disease: Factors predictive of prolonged survival. Bone Marrow Transplant 1995; 16: 13 – 8. (R2:62)
97. Horning SJ, Chao NJ, Negrin RS, et al. High-dose therapy
and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: Analysis
of the Stanford University results and prognostic indices.
Blood 1997; 89: 801 – 13. (R2:119)
Acta Oncologica 40 (2001)
98. Josting A, Katay I, Rueffer U, et al. Favorable outcome of
patients with relapsed or refractory Hodgkin’s disease treated
with high-dose chemotherapy and stem cell transplantation
at the time of maximal response to conventional salvage
therapy (Dexa-BEAM). Ann Oncol 1998; 9: 289 – 95. (P3:26)
99. Josting A, Reiser M, Rueffer U, et al. Treatment of primary
progressive Hodgkin’s and aggressive non-Hodgkin’s
lymphoma: Is there a chance for cure? J Clin Oncol 2000; 18:
332 – 9. (P2:67, 25 transpl)
100. Lancet JE, Rapoport AP, Brasacchio R, et al. Autotransplantation for relapsed or refractory Hodgkin’s disease:
Long-term follow up and analysis of prognostic factors. Bone
Marrow Transplant 1998; 22: 264 – 71. (R3:70)
101. O’Brien ME, Milan S, Cunningham D, et al. High-dose
chemotherapy and autologous bone marrow transplant in
relapsed Hodgkin’s disease-a pragmatic prognostic index. Br
J Cancer 1996; 73: 1272 – 7. (R2:89)
102. Reece DE, Barnett MJ, Shepherd JD, et al. High-dose
cyclophosphamide, carmustine (BCNU), and etoposide
(VP16-213) with or without cisplatin (CBV 9P) and autologous transplantation for patients with Hodgkin’s disease
who fail to enter a complete remission after combination
chemotherapy. Blood 1995; 86: 451 – 6. (P2:30)
103. Ribrag V, Nasr F, Bouhris JH, et al. VIP (etoposide, ifosfamide and cisplatinum) as a salvage intensiŽ cation program
in relapsed or refractory Hodgkin’s disease. Bone Marrow
Transplant 1998; 21: 969 – 74. (P2:42)
104. Lazarus HM, Rowlings PH, Zhang MJ, et al. Autotransplants for Hodgkin’s disease in patients never achieving
remission: A report from the autologous blood and marrow
transplant registry. J Clin Oncol 1999; 17: 534 – 45. (R1:122)
105. Sweetenham JW, Carella AM, Taghipour G, et al. High-dose
therapy and autologous stemcell transplantation for adult
patients with Hodgkin’s disease who do not enter remisson
after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow
Transplantation. J Clin Oncol 1999; 17: 3101 – 9. (R1:175)
106. Linch DC, WinŽ eld D, Goldstone AH, et al. Dose intensiŽ cation with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI
randomised trial. Lancet 1993; 341: 1051 – 4. (C2:40)
Chemotherapy effects in Hodgkin’s disease
197
107. Schmitz N, Sextro M, PŽ stner B, et al. High-dose therapy
(HDT) followed by hematopoietic stem cell transplantation
(HSCT) for relapsed chemosensitive Hodgkin’s disease (HD).
Final results of a randomised GHSG and EBMT trial (HDR1). Proc Am Soc Clin Oncol, 1999; 18: 5 Abstr. (C3: 142)
108. André M, Henry-Amar M, Pico J-L, et al. Comparison of
high-dose therapy and autologous stem-cell transplantation
with conventional therapy for Hodgkin’s disease induction
failure: A case-control study. J Clin Oncol 1999; 17: 222 – 9.
(R3:86)
109. Yuen AR, Rosenberg SA, Hoppe RT, et al. Comparison
between conventional salvage therapy and high-dose therapy
with autografting for recurrent or refractory Hodgkin’s disease. Blood 1997; 89: 814 – 22. (R3:60)
110. Joly F, Henry-Amar M, Arveux P, et al. Late psychosocial
sequelae in Hodgkin’s disease survivors: A French population based case-control study. J Clin Oncol 1996; 14: 2444 –
53. (R1:93)
111. Loge JH, Abrahamsen AF, Ekeberg O, et al. Psychological
distress after cancer cure: a survey of 459 Hodgkin’s disease
survivors. Br J Cancer 1997; 76: 791 – 6. (R1:459)
112. Abrahamsen AF, Loge JH, Hannisdal E, et al. Socio-medical
situation for long-term survivors of Hodgkin’s disease: a
survey of 459 patients treated at one institution. Eur J Cancer
1998; 34: 1865 – 70. (R1:459)
113. Loge JH, Abrahamsen AF, Ekeberg O, et al. Reduced
health-related quality of life among Hodgkin’s disease survivors: A comparative study with general population norms.
Ann Oncol 1999; 10: 71 –7. (R1:459)
114. Kornblith AB, Herndon II JE, Zuckerman E, et al. Comparison of psychosocial adaptation of advanced stage Hodgkin’s
disease and acute leukemia survivors. Ann Oncol 1998; 9:
297 – 306. (R1:273)
115. Johansson AS, Erlanson M, Lenner P, et al. Late side effects
common after treatment for Hodgkin’s disease; muscular
atrophy following radiotherapy a neglected risk. Läkartidningen (Swedish) 1998; 95: 44 – 7. (R2:99)
116. Abrahamsen AF, Loge JH, Hannisdal E, et al. Late medical
sequelae after therapy for supradiaphragmatic Hodgkin’s
disease. Acta Oncol 1999; 38: 511 – 5. (R1:221)