Br. J. Cancer(1993), 68, 767-774
Macmillan Press Ltd.,
Combination chemotherapy for intermediate and high grade
H.S. Dhaliwal, A.Z.S. Rohatiner, W. Gregory, M.A. Richards, P.W.M.Johnson, J.S.Whelan,
C.J. Gallagher, J. Matthews, T.S. Ganesan, M.J. Barnett, J.H. Waxman, A.G. Stansfeld,
P.F.M. Wrigley, M.L. Slevin, J.S. Malpas, & T.A. Lister
ICRF Department ofMedical Oncology, St Bartholomew's Hospital, London, ECIA 7BE, UK.
non-Hodgkin's lymphoma were treated with chemotherapy comprising Doxorubicin, Cyclophosphamide,
Vincristine and Prednisolone with mid-cycle Methotrexate (MTX) and leucovorin rescue ('CHOP-M'). Int-
rathecal MTX was given with each treatment cycle as central nervous system (CNS) prophylaxis. 'Clinical
remission' was achieved in 70/110 evaluable patients (64%), complete remission: 45/110, (41%), good partial
remission: 25/110 (23%). Twenty two patients (19%) died prior to completion of therapy, 18 patients had
persistent disease. Hyponatremia (<137 mmol I'), advanced age and hypoalbuminaemia (<32 g I') cor-
related adversely with achievement of CR (P =0.0007, 0.0005 and 0.04 respectively).
With a minimum follow up of 41 years, 47 of the seventy patients (67%) in whom clinical remission was
achieved remain well, 19 havL
developed recurrent disease, resulting in an actuarial projected remission
duration of 70% at ° years. Four died in CR. There has been only one isolated CNS recurrence. On univariate
analysis, hAypoalbuminaemia, hyponatremia and P2 microglobulin (> 3) correlated with unfavourable outcome
in terms of duration of remission (P =0.0009, 0.007 and 0.04 respectively). On multivariate analysis, only the
serum sodium (0.002) and advanced age (0.01) were predictive for remission duration.
Fifty patients (45%) are alive, the overall actuarial projected survival is thus 42% at 8 years. On univariate
analysis, age, hypoalbuminaemia, hyponatraemia, liver involvement and the presence of B symptoms cor-
related unfavourably with survival. On multivariate analysis, hypoalbuminaemia, advanced age, hyponat-
raemia, male gender (aged >50) and diffuse large cell or large cell, immunoblastic histology (Working
Formulation) had an adverse effect (P=0.003, <0.0001, <0.0001, 0.002, and 0.03). It was further possible,
using cut-off points of 32 g 1- I
and 136 mmol I` for albumin and sodium respectively to define prognostic
categories for patients who differed significantly in terms of survival.
One hundred and eighteen consecutive adults with newly diagnosed intermediate and high-grade
The concept of curability of advanced high-grade
Hodgkin's lymphoma (HG-NHL) has been amply confirmed
since the first pioneering reports were published nearly 15
years ago (De Vita et al., 1975; Berd et al., 1975; De Vita et
al., 1987). Increasingly complex and intensive regimens, using
up to nine drugs have since been developed in an effort to
improve results (Cabannillas et al., 1983; Skarin et al., 1983;
Fisher et al., 1983; Klimo & Connors, 1985; Boyd et al.,
1988). Compared with a response rate of 50% and prolonged
survival of approximately 30%
(48-69% long-term survival), although the follow-up time is
relatively short (Coiffier et al., 1987). However, since recent
reports have also defined pre-treatment variables of marked
prognostic significance (Armitage et al., 1982; Shipp et al.,
1986; Jagannath et al., 1986; Danieu et al., 1986; Coleman et
al., 1987), this apparent improvement could in part be due to
patient selection as well as improved care.
In June 1980, an open study began at St Bartholomew's
Hospital (SBH) in which patients with advanced intermediate
(IG) and HG-NHL were treated with the CHOP-M protocol.
300 mgm2) and leucovorin rescue were given in combina-
tion with a treatment programme derived from CHOP, with
intrathecal methotrexate (IT-MTX) as central nervous system
a compromise between the M-BACOD regimen
(Skarin et al., 1983) and conventional CHOP could avoid the
toxicities of bleomycin and high-dose methotrexate, without
compromising efficacy. The results achieved in 110 patients
form the basis of this report.
for patients treated with
first generation regimens,
dose methotrexate (MTX,
1). The objective
Patients and methods
Between June 1980 and July 1986, 118 consecutive, newly
diagnosed adults (age > 15 years) with biopsy proven IG or
HG-NHL (confirmed by one of us, AGS) were treated with
CHOP-M. There were no patients with Burkitt lymphoma or
HTLV-1 associated NHL. Eight patients have been excluded
from the analysis; five because of procotol violation and
three because of concurrent second malignancy (Hodgkin's
disease, two; gastric carcinoma, one).
Clinicopathological characteristics are shown in Tables I
'bulky' disease (a mass > 10 cm in diameter or a mediastinal
mass > 1/3 of the intrathoracic diameter), multiple sites of
involvement, or gut involvement considered unsuitable for
radiotherapy were included. Multiple extranodal sites were
involved in 40/71 (56%) patients with Stage IV disease, the
liver being the most common site (22 patients). Liver involve-
II. Patients with stage IE,
II and IIE disease who had
300 mg m-2
6hourly x 8
12.5 mg I/T
Treatment schedule I/T = intrathecal.
Oncology, St. Bartholomew's Hospital, London ECIA 7BE, UK.
Received 14 December 1992; and in revised form 25 May 1993.
'."Macmillan Press Ltd., 1993
Br. J. Cancer (1993), 68, 767-774
H.S. DHALIWAL et al.
Number of PTS (%)
Age ( Years)
Sodium (mmol I`')
Albumin (g 1- )
P2 Microglobulin (ng ml- ')
Large cell anaplastic
High grade T Cell
Sclerosing mediastinal B cell
When these patients were originally treated the diagnosis was
made in terms of the Kiel Classification as shown above. The slides
were subsequently reviewed by AGS in terms of the Working
Formulation. At that time slides for 16 patients were not available,
all had originally been classified
immunoblastic, 3 centroblastic,
unclassified). Both classifications are therefore shown. Histology for
Formulation. In 6/16 cases in which slides were not available for
review, AGS did not feel that Kiel histology could be directly
changed to Working Formulation.
as high grade lymphoma (10
1 lymphoblastic T & 2 high grade
ment was deemed to be present if the liver was palpable with
two abnormal LFTs, or, if the CT scan showed focal defects.
Bone marrow (BM, 11 patients) and gastro-intestinal (GI)
tract involvement (13 patients) were pathologically proven in
all cases but other sites were not routinely biopsied if there
was evidence of disease at a more accessible site. One patient
presented with a fifth cranial nerve palsy without lymphoma
cells in the cerebro-spinal fluid (CSF).
The extent of disease at presentation was determined by
clinical examination, full blood count, bone marrow aspirate
and trephine biopsy, biochemical tests of liver and renal
function, and radiography of the chest and abdomen supp-
lemented by computed axial tomography (CT).
underwent laparotomy when necessary as a diagnostic proce-
dure or to relieve obstruction, but not solely for staging
therapy, except when this was considered necessary to deter-
mine management. Formal restaging was undertaken one
month after completion
previously abnormal tests including BM biopsy but other
sites were not biopsied to document CR pathologically.
therapy by repeating
The drug doses and schedule for CHOP-M are shown in
methotrexate (300mgm-2) on days 8 and 15 of each cycle.
This was subsequently changed because of unacceptably
severe mucositis. In debilitated, elderly patients (>65 years
old), drug doses were reduced by 25-50% from the outset
and escalated later according to tolerance. Similar reductions
were instituted in a few patients following recurrent, life
threatening infections. Intrathecal methotrexate (12.5 mg on
1) was given with each cycle of treatment as CNS
The plan was to administer six cycles of therapy to all
patients at 3 weekly intervals. Treatment was delayed by
week in the presence of severe neutropenia (absolute neutro-
phil count <1 x IO'
with a 50% reduction in the dose of myelosuppressive drugs
for that cycle, if a further 1 week delay was necessary. Two
responding patients received an extra two cycles because of
residual radiological abnormalities at the completion of six
cyclesof therapy. Two patients
radiotherapy to the site of bulky mediastinal disease.
'Dose intensity' was calculated for the five drugs for each
patient by dividing the total dose given by the time in which
treatment was administered. This was then converted to a
percentage of the intended 'dose intensity' (six cycles at full
dose every 3 weeks). An overall percentage 'dose intensity'
was obtained by averaging the five percentage dose intensities
for the different drugs. Dose intensities were not calculated
for the 22 patients who died before completion of therapy
because only 6/22 received more than one cycle of treatment.
For seven patients, detailed dosage data were not available,
and these patients were thus excluded from the calculation.
first received intravenous
-1) or severe mucositis and reinstituted
Definition of response
Patients in whom 'clinical remission' was achieved were
subdivided into two categories:
Complete Remission (CR): patient in normal health with
Good Partial Remission (GPR): patient in normal health
with no clinical evidence of disease but persistent, equivocal
radiological abnormalities (for example, equivocal media-
significance of which is uncertain.
The response of patients in whom clinical remission was
not achieved was regarded as Poor Partial Remission (PPR)
provided that the tumour volume was reduced by at least
50%. Any response less than PPR or progression of disease
during treatment was documented as treatment failure.
Survival was calculated from the first day of treatment until
documented remission to the time of objective evidence of
relapse or progression. Overall survival and remission dura-
tion curves were plotted according to the method of Kaplan
and Meier (1958) and the log rank method (Peto et al., 1977)
was used to test for significance of differences in survival
distributions. A stepwise regression method based on Cox's
proportional hazards model (Cox, 1972) was used to perform
multivariate analyses to determine the significance of prog-
nostic factors affecting duration of remission and survival. A
stepwise logistic regression model was used to examine the
COMBINATION CHEMOTHERAPY FOR NON-HODGKIN'S LYMPHOMA
significance of factors affecting achievement of remission.
The following 'patient factors' were analysed: age, stage,
Immunophenotype (B vs T), hepatomegaly, bone marrow
infiltration, gut involvement, serum albumin, sodium and P2
microglobulin, and 'bulk', together with the treatment fac-
tors: number of cycles to outcome, and the average dose/
cycle of Doxorubicin, Cyclophosphamide and Methotrexate.
LDH was not in the past measured routinely at St Bar-
tholomew's Hospital, it has therefore not been evaluated as a
nor has performance
buminaemia and hyponatraemia have thus been used as sur-
rogates for the latter. Data were analysed using the BMDP
and SUREAL statistical software package.
Outcome of therapy (Table III)
'Clinical remission' was achieved in 70/110 (64%) of patients
overall: CR 45 (41%), GPR 25 (23%). Sixty-eight per cent of
patients entering clinical remission had no clinical evidence of
disease after three cycles of therapy. There was unequivocal
persistent disease in 18 patients at completion of therapy
(PPR 5, failure 13) although most had shown a degree of
response at some stage. None of these patients subsequently
had a durable response with alternative regimens and all but
one patient (who survived 15 months) died within
advanced age correlated with failure to enter clinical remis-
sion on multivariate analysis; elderly patients (aged >50
years) with either a low serum albumin (< 33 g 1-1) or a low
serum sodium (< 137 mmol 1`) had a clinical remission rate
of 17% (5/30) compared with 81% (65/80) in the remaining
patients (P<0.0001). The presence of B symptoms and liver
involvement also had a negative impact (P= 0.02 and 0.012
respectively). However, both of the latter factors correlated
with low albumin and sodium levels and were thus not
independent predictors of response. None of the other factors
considered were significant.
The mean percentage 'dose intensity' for each of the drugs
is shown according to response in Table IV. 'Dose intensities'
were the same for patients in whom CR and GPR was
achieved and for those in whom treatment failed, though the
latter group probably received less Methotrexate (P=0.02,
t-test). However, the five patients in whom treatment resulted
in a PPR had significantly lower 'dose intensities' for all the
drugs except Vincristine (P values shown in Table IV). For
patients achieving CR and GPR, the lowest overall 'dose
intensity' was 50%, only five patients having values lower
than 70%. Patients aged >60 had significantly lower mean
Outcome of therapy
aAs defined at autopsy.
NA Not fully assessable, i.e. autopsy not performed but six patients
had evidence of marked clinical response.
NED No evidence of disease.
Mean % 'dose intensity' by response to therapy
CR + GPR + Prog.
Dis. vs PPR, P =
% dose intensities than those aged <60 (78.6% vs 90.8%,
P< 0.01, t-test).
Twenty two patients died before therapy could be com-
pleted resulting in a treatment related mortality of 20%. The
majority (19/22) were over 50 years of age (median age 63
years) with advanced disease and poor performance status.
Most were also found
to be hyponatraemic and hypo-
albuminaemic. Bulky disease at presentation was present in
12/22 and ten required a laparotomy for diagnosis. One
young man with gastro-oesophageal disease had had two
laparotomies prior to treatment and died of oesophageal
rupture at the site of disease resolution, with no evidence of
residual disease at autopsy. Twelve of the 22 patients who
died 'early' did so of infective complications whilst pan-
evidence of disease; a further six were obviously responding
although autopsy was not performed.
Duration ofremission (Figure 2)
Forty-seven out of 70 (67%) patients entering clinical remis-
sion remain well, 19 have developed recurrent disease, four
died in remission. Apart from four late recurrences (at 3+, 4,
5+ and 7 years), all occurred within the first 2+ years. Only
three of the patients with recurrent disease are alive, the
majority having died within 6 months of recurrence without
a durable response to second or third line chemotherapy
having been achieved. Four other patients in whom a second
complete remission was achieved subsequently received Cyc-
lophosphamide and whole body irradiation with autologous
bone marrow transplantation. One died of pneumonia on
day 10, two died following further recurrence and one in
whom the histology had originally been centroblastic but at
the time of recurrence showed follicular lymphoma, remains
well at 6 years.
Recurrence always involved at least one of the initial sites
of disease. There has been only 1 isolated CNS recurrence to
date in the patient (mentioned above) who originally present-
ed with a
fifth nerve palsy without cerebrospinal
radiculopathy, but no evidence of malignant cells in the CSF.
The patient eventually died of clinically progressive CNS
disease as well as systemic lymphoma. Four patients died in
remission; two of cardiac failure, one of pneumococcal septi-
caemia having had a splenectomy and another who developed
acute leukaemia within 2 years of treatment and died without
recurrence of lymphoma.
The only factors correlating unfavourably with duration of
(< 137) and advanced aged (> 50) (Table V). (Hypoalbumin-
aemia was significant on univariate analysis but correlated
with hyponatraemia). There was a trend for longer duration
of remission in patients in whom CR as opposed to GPR
significance. There was no correlation between remission
duration and dose intensity for any of the drugs, individually
in combination, on either univariate or multivariate
analysis. In contrast, there was a trend on both univariate
and multivariate analysis for patients receiving five or more
cycles of treatment to have more durable remissions than
those receiving four or less, though this did not reach statis-
tical significance (P = 0.08, univariate; P = 0.05 multivariate).
770H.S. DHALIWAL et al.
Figure 2 Duration of remission for patients in whom 'clinical remission' was achieved.
Univariate and multivariate analyses of factors affecting
duration of remission and survival
(lb + cb vs rest)
(<3 vs >3)
Abbreviations: U/V=Univariate; M/V= Multivariate
NS=not significant.aSerum albumin (g- 1'): <32 v 33-39 v > 40.
bAge (years): < 50 v > 50. cSerum sodium mmol1-: < 137 v > 137.
'Stage: I and II vs III and IV.
Survival (Figures 3, 4, 5, 6 and 7)
Fifty patients (45%) are alive with a minimum follow up of
over 4 years and a median follow up of 61 years (Figure 3).
Four patients died in remission (vide supra). Survival accord-
ing to stage is shown in Figure 4; on univariate analysis,
survival was better for patients with stage I and stage II
disease, but this difference was not maintained on mul-
tivariate analysis. The median survival of those in whom
clinical remission (CR + GPR) could not be achieved was
durable remission with second line therapy. There was no
significant difference in survival beween patients in whom CR
as compared to GPR was achieved (Figure 5). Failure free
survival is shown in Figure 6.
1 year; all died within 2 years, none achieving a
Apart from response to therapy (i.e. CR + GPR vs PPR or
no response), by univariate analysis, age, serum albumin,
serum sodium, liver involvement and the presence of B symp-
toms correlated with survival (Table V). However, by mul-
advanced age, male gender and histology other than diffuse
large cell and large cell, immunoblastic (Working Formula-
variables. The significance of histology (P= 0.07) was con-
siderably less than that of the other four variables (P values
The four main factors were then used to define three
distinct subgroups whose survival differed markedly (Figure
7). Thus, in group A (patients with sodium and albumin
values above 136 and 32 respectively), there were no 'early
deaths' and the actuarial survival at 5 years was excellent at
85%. In contrast, in group C (either albumin < 32 or sodium
< 136) only 5/41 patients survived beyond 3 years and 17/41
(42%) died 'early' during treatment. The survival of the
remaining patients (group B) was intermediate, with
actuarial five year survival of 42%.
an adverse effect
All patients developed alopecia and the majority experienced
nausea or vomiting with the first day of each treatment cycle.
Approximately one third of patients developed oral mucositis
in relation to the mid-cycle MTX. The majority of patients
had a fall in the total white cell count and a concomitant fall
in the absolute neutrophil count, the platelet count was
The results presented above, with almost half the initial
group of patients alive five years from presentation, and little
likelihood of recurrence thereafter, appear better than those
previously reported from St Bartholomew's Hospital (SBH)
for a broadly comparable group of patients (Gallagher et al.,
1982). The disappointment that it has not proved possible to
achieve the same excellent results as initially reported with
the M-BACOD regimen (Skarin et al., 1983), must however
be tempered by the results of the subsequent analysis from
Boston, and comparison of the m-BACOD and M-BACOD
regimens (Shipp et al., 1990).
Comparison of the overall results for CHOP-M with those
for CHOP suggests that it may be as good or marginally
If II ,,,H
COMBINATION CHEMOTHERAPY FOR NON-HODGKIN'S LYMPHOMA
Figure 4 Survival according to stage.
better, but unfortunately, the same may be said when com-
parison of the 'CHOP' data is made with other major second
(Schein et al., 1976; Boyd et al., 1988; Guglielmi et al., 1991)
and third generation (Fisher et al., 1987; Gordon et al., 1989;
Miller et al., 1990) chemotherapy programmes. Moreover,
the recent South West Oncology group randomised study
which compared CHOP and the third generation regimens
m-BACOD, ProMACE-cytaBOM and MACOP-B showed
no advantage in terms of response rate, time to treatment
failure or overall survival for the more intensive regimens
(Fisher1993). The findings that 'completeness' of
remission did not correlate with survival has important prac-
continuing/stopping therapy when 'equivocal'
abnormalities of questionable significance remain.
treatment-related mortality of 20%, particularly since there
was clinical and/or autopsy evidence of response in 12 of
these patients. The reported mortality of < 10%
North American (Cabannillas et al., 1983; Klimo & Connors,
1985) and one European series (Guglielmi et al., 1991) con-
trasts sharply with this experience and with that in a com-
parable study in which 25% patients died during therapy.
MACE-MOPP and MACOP-B either contain more drugs or,
higher doses of MTX. Thus, the higher mortality observed
with CHOP-M and that reported by the Central Lymphoma
Group, England (Stuart et al., 1988), may in part have been
due to the inclusion of a large proportion of patients with
poor prognostic factors. The age distribution in both series
On multivariate analysis, age was an independent prognos-
tic factor for both achievement of remission and survival.
The finding that advanced age (Dixon et al., 1986; Jagganath
et al., 1986; Velasquez et al., 1989; Kwak et al., 1990; Hos-
kins et al.,
1991) and hypoalbuminaemia (Coiffier et al.,
1991) correlate with a low remission rate has been reported
previously, although the relevance of hyponatraemia appears
as M-BACOD, F-MACHOP,
N = 110
H.S. DHALIWAL et al.
GPR N = 16
Li CR N = 23
CHI = 1.844
P = 0.174
Survival of patients in whom CR or GPR was achieved.
N = 110
Failure free survival.
new. All of these may reflect general debility and have been
used here collectively to represent performance status. A
report from the Christie Hospital, Manchester, has shown
albumin to be a significant factor affecting survival in high
grade NHL (Steward
albumin has been shown to influence both overall survival
and achievement of CR in intermediate and high grade lym-
phoma (Cowan et al., 1989). An analysis of serum albumin in
Hodgkin's disease showed
stage, B symptoms,
(Gobbi et al., 1985); serum albumin has also been demon-
strated to be an important prognostic factor in other malig-
nancies (Kawai, 1973; Osterlind & Anderson, 1986). A mul-
titude of reasons for low albumin levels including reduced
synthesis by the liver, and gut loss have been suggested but
albumin haemodynamics in malignant lymphoma have not
been investigated extensively.
The three major prognostic factors (serum albumin, serum
sodium and age) were then used to delineate patient sub
1984) and more
it to correlate with advanced
liver involvement and bulky disease
groups with markedly different outcomes (Figure 5). Previous
studies (Daneiu et al., 1986; Jagganath et al., 1986; Shipp et
al., 1986) have used other known prognostic factors to con-
struct similar models but there has been some conflict in the
reported importance of individual factors. The recently pub-
lished International Index defines five features which have
been shown to correlate independently with survival, namely:
age, stage, performance status, LDH and the number of
extra-nodal sites (Shipp et al., 1992). Whether these factors
therapeutic strategies remains to be determined.
Multivariate analysis of factors predicting for freedom
from recurrence also revealed advanced age and hyponat-
raemia at presentation to be significant. Hypo-albuminaemia
analysis because of very close correlations with the sodium
would have remained significant had performance status been
It is, of course, not known whether serum sodium
COMBINATION CHEMOTHERAPY FOR NON-HODGKIN'S LYMPHOMA
LLJ Good N =27
Intermediate N = 54
BAD N = 29
either males aged <50 or females Group B = patients not falling into categories A or C Group C = patients with: sodium
< 136 mmol I-' or albumin < 32 g 1-'.
Overall survival according to prognostic groups. Group A = patients with: sodium> 136 mmol 1', albumin> 32 g 1-',
considered since the two are usually closely related. Surpris-
ingly, and in contrast to the findings of others (Shipp et al.,
1986; Velasquez et al., 1989; Kwak et al., 1990), the 'bulk' of
tumour at presentation was not relevant.
amount of chemotherapy received did not influence duration
of remission, possibly because so many patients received the
majority of treatment as planned.
The precise contribution of Methotrexate to the efficacy of
CHOP-M cannot be defined, as the optimal dose in combina-
tion chemotherapy is not known, although a clear dose re-
sponse relationship has been demonstrated in single-agent
studies (Tattersall et al., 1975). The lack of any effect of dose
intensity suggests that with this regimen, the total amount of
therapy administered was probably more important than
avoidance of modest dose reduction. However, it should be
remembered that 93% of patients received dose intensities
> 70% and reductions below this level may still be detrimen-
These results demonstrate the influence of pre-treatment
variables on response and survival in a large series of con-
secutive patients managed at a single centre. Two objective
and easily measurable prognostic factors of major impor-
tance, serum sodium and serum albumin were identified. It is,
however, very clear that for 37 patients in this series this
treatment was either inappropriate or inadequate. It is hoped
that a flexible approach to treatment incorporating such
prognostic indices may result in cure for a greater number of
patients without undue toxicity and a better quality of life
for those in whom intensive therapy will not be beneficial.
We are pleased to aknowledge the contribution of the medical and
nursing staff of Annie Zunz and Dalziel ward, St Bartholomew's
Hospital. We thank Dr Amess and the staff of Haematology and Dr
Reznek and the staff of Radiology for their help in staging patients.
We are grateful to Jane Ashby, Shirley Wragg and Claire Hole for
typing many drafts of this manuscript.
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