A Systematic Overview of Chemotherapy Effects in Hodgkin’s Disease SYSTEMATIC OVERVIEW ARTICLE

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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 scienti 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 scienti 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 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 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 eld radiotherapy. However, this conclusion remains to be better documented in the literature.
At advanced stages, chemotherapy or a combination of chemotherapy and limited 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 Classi 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-signi 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 eld radiotherapy resulted in a signi 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
alone has been found to be insuf cient. Following radiotherapy, most of them, or about 75%, will relapse within
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- eld radiotherapy is responsible for a signi 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 eld
radiotherapy, or no radiotherapy at all, will result in the
same high curability rates as extended 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 eld radiotherapy results in the same
high freedom from treatment failure as extended 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 eld radiotherapy.
For a majority of patients with relapse after radiotherapy chemotherapy is curative.
Initial chemotherapy in addition to extended 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:
Scienti 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 scienti 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 classi cation of each publication is given in the reference list.
188
L. Brandt et al.
ADVANCED DISEASE: STAGE IIIA
ADVANCED DISEASE: STAGES IIIB– IV
Relapses ve to ten years even after extended 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 rst be treated with extended
eld radiotherapy and then with chemotherapy upon
relapse.
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 ve
years ranged from 84% if no prognostic factor was present
to 42% if 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 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 signi 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 signi 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- 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 signi 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 eld radiotherapy, these patients should be treated with primary
chemotherapy, and limited eld radiotherapy should be
provided to selected patients.
Chemotherapy of advanced disease: stage IIIA:
Scienti 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.
10 years in the group that did not receive any radiotherapy
(8% difference; p¾ 0.045). There were signi 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 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.
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:
Scienti c evidence*
1 ¾High
2 ¾Moderate
3 ¾ Low Total
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
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
modi ed, with chlorambucil substituting mechlorethamine
and vinblastine substituting vincristine, by several investigators in attempts to improve the ef cacy and to reduce
side-effects. These modi 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-signi 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 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% 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 signi 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 signi 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 eld radiotherapy (STNI or TNI).
No signi 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 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 ( 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 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
ve years). There was no statistically signi cant difference
in overall survival (80% vs 71%; p¾ 0.28 at 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 bene 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,
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 intensi 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 scienti c
meetings (84– 86). In the fourth interim analysis (85),
BEACOPP is signi 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 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-intensi 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
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 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 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
pro 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 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).
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.
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:
Scienti c evidence*
1 ¾High
2 ¾Moderate
3 ¾Low Total
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
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 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
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 signi 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 signi cantly longer with high-dose treatment. Overall
survival did not differ signi 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 rst chemotherapy
regimen. Matching was done with 258 conventionally
treated patients from international databases. In the
grafted patients, the ve-year event-free survival and overall survival after transplantation were 25% and 35%, respectively. The 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 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 justi ed given the quality of data
available and the observed effect on survival.
High-dose chemotherapy:
Scienti c evidence*
1 ¾High
2 ¾Moderate
3 ¾Low Total
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
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,
on all scales after adjustment for age, gender and educational levels. Statistically signi 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 signi 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 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 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 eld irradiation for supradiaphragmatic HD in
221 Norwegian patients (116). The patients were studied
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.
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:
Scienti c evidence*
1 ¾High
2¾ Moderate
3¾ Low
Total
R
–
6:1964
–
1:99
–
–
–
7: 2063
Total
6:1964
1:99
–
7: 2063
LITERATURE
The articles included in the reference list were classi ed and graded
as follows:
Scienti c evidence*
1 ¾ High
2 ¾ Moderate
3 ¾ Low
Total
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
194
L. Brandt et al.
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A Systematic Overview of Chemotherapy Effects in Hodgkin’s Disease SYSTEMATIC OVERVIEW ARTICLE

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