International Journal of Clinical Medicine, 2011, 2, 246-253
doi:10.4236/ijcm.2011.23039 Published Online July 2011 (
Copyright © 2011 SciRes. IJCM
Clinical Presentation and Outcome in Patients of
over 75 Years Old with Malignant Lymphoma
—Clinical Presentation and Outcome in Elderly Lymphoma Patients
Noriyasu Fukushima1, Hideaki Itamura1, Chisako Urata1, Mariko Tanaka1, Takashi Hisatomi1,
Yasushi Kubota1, Eisaburo Sueoka2, Shinya Kimura1*
1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga Univer-
sity, Saga, Japan; 2Department of Transfusion Medicine, Saga University Hospital, Sage, Japan.
Email: *
Received March 25th, 2011; revised June 5th, 2011; accepted July 1st, 2011.
We analyzed the relationship between the clinical charac teristics, comorbidity, average relative dose intensity (aRDI)
and outcome in patients of over 75 years old with malignant lymphoma. Of the 98 patients studied, the m ean age wa s
79.9 years, and 68 patients (69.4%) had B-cell lymphomas, corresponding to mainly diffuse large B-cell lymphoma.
The 5-year overall survival rate was 32.2% in 97 malignant lymphoma patients. T/NK subtype, poor performance
status (PS) and high-intermediate/high international prognostic index (IPI) were found to be predictive of significantly
poorer overall survival, as is the case in young patients. Correlation between como rbidity index and surviva l rate was
not observed. We also analyzed the aRDI of cyclophosphamide and pirarubicin for 64/97 patients. The proportion of
patients receiving 84% of the planned DI during five cycles gradually increased. Most patients could not maintain
aRDI 85%. However, overall survival was not significantly different between patients with aRDI 0.85 and those
with aRDI 0.84. In conclusion, the prognoses of very elderly patients with malignant lymphoma were not so poor
when they were appropriately treated with modification of the applied dose and the duration of chemotherapy ac-
cord in g to their s tatus.
Keywords: Malignant Lymphoma, Elderly, Comorbidity, Relative Dose Intensity
1. Introduction
The medical burden of the elderly Japanese population is
increasing very rapidly, with people aged > 75 years now
accounting for >10% of the population [1]. With an in-
creasingly aged population, morbidity and mortality due
to various cancers, including malignant lymphoma,
among people aged > 70 years will also increase. In 2000,
the age-specific incidence rates of malignant lymphoma
in Japan were 56 - 81 per 100,000 populations among
men aged > 75 years and approximately 30 per 100,000
populations among women aged > 75 years [2].
Patients with malignant lymphoma can follow various
clinical courses and prognoses, depending on their histo-
logical subtype. Some of subtypes of malignant lym-
phoma are now curable with the development of new
therapeutic options. However, age has been recognized
as one of the strongest adverse prognostic indicators in
patients with malignant lymphoma [3-5]. One of reasons
for this is that elderly patients sometimes receive insuf-
ficient therapy due to factors such as chronic comorbid
conditions, poor performance status (PS), and abnormal
organ function. In practice, physicians can have diffi-
cultly choosing the optimal management for very elderly
patients, in terms of which medication and what dose.
Although many studies have reported data for lymphoma
patients aged 60 - 80 years, there is relatively little evi-
dence for the management of very elderly patients. We
have therefore analyzed the relationships between clini-
cal characteristics, comorbidities, treatment and outcome
in patients with malignant lymphoma aged > 75 years.
2. Patients and Methods
2.1. Patients, Clinical Assessment and
From January 1998 to March 2007, 435 patients with
malignant lymphoma, diagnosed according to REAL
Clinical Presentation and Outcome in Patients of over 75 Years Old with Malignant Lymphoma247
classification [6]/the World Health Organization (WHO)
classification [7], were followed in our institution. For
this study, we conducted a retrospective review of the
results from 98 patients (22.5%) aged > 75 years. Of
these, 97 patients were candidates for survival analysis,
and one patient had no available clinical data except for
pathological findings. Clinical variables were age, sex,
Eastern Cooperative Oncology Group (ECOG) PS, Ann
Arbor stage, number of extra nodal involved sites, serum
lactate dehydrogenase (LDH), international prognostic
index (IPI) and comorbidity index (Charlson’s comor-
bidity index [CCI] [8,9]) and the hematopoietic cell
transplantation comorbidity index (HCTCI) [10].
Over the study period, the standard treatment at our
institute was a pirarubicin, cyclophosphamide, vincristine
and prednisolone (THP-COP) or THP-COP-like regimen
with or without rituximab. The doses and schedules of
THP-COP and rituximab according to age are shown in
Table 1. Some patients with localized lymphoma re-
ceived three cycles of THP-COP following involved field
irradiation. Patients with advanced lymphoma were
planned to receive at least six cycles of THP-COP. For
patients with poor PS, physicians modified the dose ac-
cording to their own judgment. The cycle duration was
also modified at the physician’s discretion (21 days,
depending on the grade of myelosuppression and adverse
events). For some patients, in the absence of institutional
policy, the choice of treatment (including palliative care)
was based on the referring physician’s judgment and the
patient’s wishes. General condition and coexisting organ
dysfunction were the major criteria that affected treat-
ment decisions. The patients and their outcomes have
been followed closely, and where possible, the cause of
death has been identified.
2.2. Relative Dose Intensity
We analyzed the agent-specific relative dose intensity
(RDI) [11] as the ratio of the dose actually delivered to
the planned dose intensity in 64 malignant lymphoma
patients who received a THP-COP or THP-COP-like
regimen ± rituximab. The average RDI (aRDI) was cal-
culated by averaging the delivered RDI of cyclophos
phamide and pirarubicin for THP-COP ± rituximab. We
analyzed overall survival comparisons of three groups
Table 1. Chemotherapy regimen reference planned doses and
79 years 80 years
Pirarubicin 40 mg/m2 (Day 3) 30 mg/m2 (Day 3)
Cyclophosphamide 650 mg/m2 (Day 3) 400 mg/m2 (Day 3)
Vincristine 1 mg/m2 (Day 3) 1 mg/m2 (Day 3)
Prednisolone 40 mg/m2 (Days 3 - 7) 30 mg/m2 (Days 3 - 7)
Rituximab 375 mgmg/m2 (Day 1) 375 mgmg/m2 (Day 1)
that were categorized as 0.85 of RDI, 0.84 of RDI and
incomplete chemotherapy for 31 advanced aggressive
lymphoma patients. This cutoff was based on an analysis
by Lyman et al. [12].
2.3. Statistical Analysis
The relationships between age and sex, PS, stage, IPI,
therapy and comorbidity index was analyzed using the
student’s t-test. Overall survival was calculated from the
date of diagnosis to the date of death according to the
method of Kaplan and Meier [13]. Comparisons were
made using a log-rank test with the following variables:
age, sex, PS, stage, serum LDH level, immunophenotype
of lymphoma, IPI and comorbidity index (by HCTCI
and CCI) in all patients. We also analyzed overall
survival comparisons of the above variables, except for
comorbidity index, along with use or not of rituximab in
patients with diffuse large B-cell lymphoma.
3. Results
3.1. Patient Characteristics and Relationship
between Age and Clinical Variables
The clinical characteristics of the patients are summa-
rized in Table 2. The median follow-up period was 659
days. The mean age was 79.9 years (range 75 - 89 years).
Poor PS (2-4), advanced stage (III or IV), raised LDH
and high-intermediate and high risk IPI were seen in 41%,
56%, 55%, and 53% of patients, respectively. According
to the WHO classification, 68 of 98 patients (69.4%)
presented a B-cell lymphoma (Table 3). The most fre-
quent histological subtype was diffuse large B-cell lym-
phoma (n = 48). It is noteworthy that the proportion of
adult T-cell leukemia/lymphoma (ATL) was relatively
high (n = 12), because the Saga prefecture area of Japan,
where the study was carried out, is an endemic area of
human T-cell leukemia virus type 1 (HTLV-I).
When patients were divided into three groups (stan-
dard chemotherapy, radiation alone, and palliative ther-
apy), there was a trend towards a relationship between
age and palliative care versus chemotherapy (p = 0.056),
but no relationship between age and other combinations
of treatment. This suggests that physicians tended not to
select aggressive chemotherapy for older patients. There
was no significant correlation between age and other
clinical variables (sex, subtype, PS, stage and IPI).
3.2. Survival Analysis
The 5-year overall survival rate was 32.2% among 97
malignant lymphoma patients (Figure 1(a)). Median
survival time was 378 days among 62 deceased patients.
The main reasons for death were malignant lymphoma
(n = 27, 43.5%), infection ( = 4, 6.5%) and other ma- n
Copyright © 2011 SciRes. IJCM
Clinical Presentation and Outcome in Patients of over 75 Years Old with Malignant Lymphoma
Copyright © 2011 SciRes. IJCM
Table 2. Clinical characteristics and outcomes in all lymphoma and diffuse large B-cell lymphoma patients.
All patients (n = 97) Diffuse large B-cell lymphoma (n = 48)
n 5-year OS% p n 5-year OS% p
Age NS <0.05
7943 26.3 26 20.9
8054 42.1 22 57.3
Sex <0.05 0.088
Male54 23.1 20 N.R.
Female43 44.2 28 47.5
PS 0.005 NS
0-157 42.3 28 43.1
2-440 18.1 20 30.7
LDH <0.03 0.01
normal44 41.0 19 55.6
>normal53 26.4 29 26.2
Stage <0.005 <0.0001
I, II43 45.3 26 55.6
III, IV54 21.9 22 N.R.
Immunologic phenotype <0.0001
B-cell68 41.9
NK/T cell26 5.6
Other3 N.R
IPI <0.001 <0.005
Low 22 45.0 13 60.4
Low-INT24 50.7 12 52.5
High-INT18 18.1 7 N.R.
High33 18.5 16 N.R.
Rituximab <0.05
yes 23 40.9
no 16 16.7
N.R. Observation time does not reach 5 years.
Table 3. Subtypes of lymphoma.
All patients (n = 98)
B-cell 68
Burkitt’s like 1
Other B-cell 6
NK/T cell 27
ATL(indolent) 2
ATL (aggressive) 10
Nasal NK/T 2
Other T 2
HD 1
Unclassified 2
Abbrevation; FCL; follicular lymphoma, MCL; mantle cell lymphoma,
MALT; extranodal mucosal associated tissue type lymphoma, DLBCL;
diffuse large B-cell lymphoma, IVL; intravascular lymphoma, PTCL, peri-
pheral T-cell lymphoma, not otherwise specified, AITL; angioimmu-
noblastic T-cell lymphoma, ATL; adult T-cell leukemia/lymphoma, ALCL;
anaplastic large cell lymphoma, HD; Hodgkin’s lymphoma.
lignant disease (n = 3, 4.8%). The overall survival rate
was significantly higher in the following groups: female,
PS 0-1, stage I/II, normal serum LDH level, B-cell sub-
type, and low/low-intermediate IPI, but there was no
significance difference between those aged 79 vs. 80
years (Table 2).
Among DLBCL patients, 5-year overall survival rate
was 36.6% (Figure 1(b)). The overall survival rate was
significantly higher in the following groups: female, stage
I/II, normal serum LDH level, low/low-intermediate IPI,
and age 80 vs. 79 years (Table 2).
Thirty-nine patients with DLBCL received a THP-
COP or THP-COP-like regimen, and 23 of these also
received rituximab. The 5-year overall survival rate was
significantly higher among patients who received che-
motherapy in combination with rituximab than among
those who did not receive rituximab (40.9% vs 16.7%, p
< 0.05).
3.3. Relationship between Comorbidity and
Major comorbidities according to HCTCI and CCI are
summarized in Table 4. Seventy-three patients (75%) had
more than one comorbidity. A previous history of cardio-
vascular diseases (including arrhythmia, angina pectoris,
myocardial infarction, cardiac failure, pacemaker, and
valve disease) was found in 28 patients. Diabetes
Clinical Presentation and Outcome in Patients of over 75 Years Old with Malignant Lymphoma249
Table 4. Major comorbidity-dening organ or disease categories according to HCTCI and CCI.
n 5-years OS(%) p HCTCI score CCI score
Yes 22 12.7
Arrythmia No 75 38.2 n.s. 1 0
Yes 14 27.9
Cardiac No 83 33.4 n.s 1 1
Yes 0 -
Inflammatory bowel disease No 97 32.2 n.s. 1 0
Yes 10 25.4
Diabetes No 87 32.4 N.E 1 1
Yes 19 31.5
Cerebrovascular disease No 78 35.4 n.s. 1 1
Yes 2 N.R.
Psychiatric disturbance No 95 32.6 n.s. 1 Not included
Yes 0 -
Obesity No 97 32.2 n.s. 1 Not included
Yes 6 0.0
Infection No 91 34.9 0.001 1 Not included
Yes 8 0.0
Mild pulmonary No 89 43.0 n.s. Not included 1
Yes 3 0.0
Rheumatologic No 94 33.8 n.s. 2 1
Yes 6 16.7
Peptic ulcer No 91 33.2 0.07 2 1
Yes 0 -
Moderate/severe renal No 97 32.2 n.s. 2 2
Yes 5 20.0
Moderate pulmonary No 92 32.8 n.s. 2 2
Yes 22 32.9
Prior solid tumor No 75 32.1 n.s. 3 2
Yes 3 50.0
Heart valve disease No 94 31.3 n.s. 3 0
Yes 1 N.R.
Severe pulmonary No 96 31.8 n.s. 3 1
Yes 5 N.R.
Moderate/severe hepatic No 92 33.4 <0.01 3 3
CCI, Charlson’s comorbidity index; HCTCI, hematopoietic cell transplantation morbidity index; N.E., Not evaluated; N.R., Not reached; n.s., not significant. co
(a) (b)
Figure 1. Overall survival in (a) all malignant lymphoma patients and (b) diffuse large B-cell lymphoma patients.
Copyright © 2011 SciRes. IJCM
Clinical Presentation and Outcome in Patients of over 75 Years Old with Malignant Lymphoma
was found in 10 and cerebrovascular disease was found
in 19 patients. Prior or simultaneous malignnant disease
was found in 22 patients. Patients were separated into
three categories: 0, 1, 2, and 3 according to the original
description of the HCTCI and CCI scoring systems.
Overall survival was significantly poorer among patients
with infection and moderate/severe liver dysfunction
(Table 4), but the HCTCI and CCI score did not impact
overall survival. (Figure 2)
3.4. Relative Dose Intensity in Elderly Malignant
In this study, 64 or 97 patients received a THP-COP or
THP-COP-like regimen. We analyzed aRDI for these
patients. Status, subtype, and outcome profiles in these
patients are shown in Figure 3. Of 31 patients with ad-
vanced aggressive lymphoma, 21 had B-cell lymphomas
and 10 had T-cell lymphomas. Sixteen patients accom-
plished six cycles of THP-COP. However, only three
patients (9.7%) with these advanced aggressive lym-
phomas had an aRDI for cyclophospamide and pirarubi-
cin 0.85. Fifteen patients stopped THP-COP, due to
exacerbation of lymphoma (n = 9), adverse effects (n =
2), changing hospital (n = 3), and patient’s decision (n =
1). The proportion of patients receiving 0.85 of the
planned dose intensity during five cycles of treatment
decreased gradually across cycles of chemotherapy
(Figure 4). Furthermore, the proportions of patients with
RDI 0.85 in the first cycle of chemotherapy were <
50% in all patient who received THP-COP and in the
(a) (b)
Figure 2. The overall survival by (a) hematopoietic cell transplantation specific comorbidity index (HCTCI) and (b) Charlson
comorbidity index (CCI) in all malignant lymphoma patients.
Figure 3. Profile of lymphoma patients who received a THP-COP or THP-COP-like regimen. Subtypes of aggressive lym-
phoma are DLBCL (n = 20), Burkitt-like (n = 1), AITL (n = 2), PTCL-u (n = 1) and ATL (n = 7).
Copyright © 2011 SciRes. IJCM
Clinical Presentation and Outcome in Patients of over 75 Years Old with Malignant Lymphoma251
Figure 4. Proportions of patients receiving relative dose intensity 85% and 84% during the first five cycles of
31 patients with advanced aggressive lymphoma. The
prognosis of patients with advanced aggressive lym-
phoma who completed their THP-COP regimen was
better than those who did not complete the regimen.
However, overall survival was not significant different
between those with aRDI 0.85 or 0.84.
4. Discussion
The population in Saga prefecture where our hospital is
located is approximate 852,000 in the 2009 national
population census. Of these, 12.9% were >75 years old,
which is higher than average in Japan. However, this is
likely to be the case in the rest of Japan in near future.
The consultation rate of elderly hematological patients at
our hospital is high, and the number of patients with
lymphoma was 2 to 3-fold higher in 2005-2007 than it
was in 1998-2000. Numerous studies about clinical
presentation for very elderly patients with malignant
lymphoma have been reported from western countries
[14-19], but there is limited practical information in
Japan. It is therefore very important to analyze the
current picture of lymphoma patients in Japan and to be
aware of this issue, in order to be prepared for the aging
Japanese society.
We analyzed a relationship between age and clinical
index, including PS, stage, comorbidity, histology, and
initial therapy. There were no significant differences
between age and clinical indexes, except for initial ther-
apy. Some of patients, their family and physician chose
palliative or no chemotherapy rather than aggressive
chemotherapy for older patients on ground of patients’
will and lack confidence in receiving chemotherapy.
They tended to select the therapy based on age, even if
PS and comorbidities were not poor. Elderly patients
could not always understand the benefits and detriments
of therapy, despite adequate information, because most
of them have a reduced emotional tolerance about their
disease diagnosis and its treatment. Therefore, a pa-
tient’s family often decided the best therapy for the pa-
tient. Also, some of the patients were conscious of their
age, and some refused chemotherapy on the basis of
their advanced age. However, there was no significant
difference between those aged 79 years compared with
those aged 80 years group in our study. Furthermore,
the prognosis of the elderly patients was actually quite
reasonable. These factors may make the chance of cure
less likely, and shorten the survival time for patients
with curable lymphoma. Aging is not a reason not to
choose aggressive chemotherapy, as has been showed in
other studies [17,20].
Comorbidity index (using HCTCI and CCI) is an im-
portant prognostic factor in elderly acute myelogenous
leukemia (AML) patients and stem cell transplantation [9,
21-23]. However, there are few data on whether comor-
bidity index is a useful prognostic factor in elderly lym-
phoma patients. We found that both HCTCI and CCI
were not significantly prognostic, except for infection
and severe liver disease. This finding suggests that some
of subtypes of lymphoma are curable, if elderly patients
receive reduced-intensity chemotherapy. Comorbidity
index is, therefore, a useful predictive prognostic marker
in diseases that require strong chemotherapy, such as
elderly AML and stem cell transplantation, but not for
elderly malignant lymphoma. Once a complete remis-
sion has been achieved, the disease-free survival can be
similar to that of a younger patient, even if the first-line
chemotherapy regimen was less aggressive [24]. Other
studies have also reported that CCI is not associated
with survival in retrospective analyses [14,18].
In contrast, PS was one of the most important vari-
Copyright © 2011 SciRes. IJCM
Clinical Presentation and Outcome in Patients of over 75 Years Old with Malignant Lymphoma
ables predictive of survival. PS reflects tolerance of pa-
tients, organ function, and disease progression, and it is
the most important factor for judging whether patients
can receive aggressive chemotherapy. Comorbidity index
may be prognostic factor, as with PS, in some lymphoma
subtypes, but comorbidity index needs to be evaluated in
prospective trials of patients with each subtype to con-
firm this.
Our data suggest that lymphoma phenotype is a strong
prognostic factor. Patients with T/NK cell lymphoma
had a very inferior prognosis compared with patients
with B-cell lymphoma. Our geographic area is endemic
for HTLV-I, and elderly ATL is frequently diagnosed.
Aggressive ATL generally has a poor prognosis and it is
difficult to prolong the survival time even with intensive
chemotherapy [25]. Allogeneic hematopoietic stem cell
transplantation is now considered a promising treatment
for young patients with ATL [26,27], but is not indicated
in elderly patients due to higher toxicities and poor
completion rates. Currently, chemotherapy for elderly
ATL patients should focus on safety above efficacy,
because this disease is not curable.
Some reports have shown that maintaining a high RDI
of doxorubicin provides a survival benefit [11,12,28].
Lyman et al. showed that a subset of patients aged > 60
years who were treated with doxorubicin at dose intensi-
ties > 10 mg/m2/week had a 5-year survival rate similar
to that seen in younger patients [12]. However, in pa-
tients aged > 75 years old, it is difficult to maintain dose
intensity because most elderly patients have some co-
morbid disease and poor PS. Indeed, only 10% of the
patients with aggressive lymphoma in our study who
received a THP-COP or THP-COP-like regimen man-
aged to maintain RDI > 0.85. This was partly due to a
prolonged recovery of bone marrow after chemotherapy,
but also due to insufficient dosing. This is particularly
problematic for elderly patients due to problems getting
to the hospital and the absence of a care assistant at
home. However, patients treated at RDI 0.84 in the >
75-year old group did not have a significantly poorer
outcome. This may be due to the small number of pa-
tients in this study. However, to the best of our knowl-
edge, this is the first study to focus on very elderly
lymphoma patients. Our findings suggest that it is pref-
erable to carry on treatment at a lower dose, thereby
minimizing adverse events, rather than strictly adhering
to high dose intensity. However, a large-scale study is
recommended in order to validate this proposal.
In conclusion, age is not always an adverse prognostic
factor, if the patient has good PS, favorable histology,
and lower-risk IPI. As is the case in younger patients,
the most important prognostic factors were lymphoma
subtype, PS, and IPI. Comorbidity index, however, did
not have an impact on survival. Maintaining a high RDI
during chemotherapy is recommended, but in practice,
this can be difficult. Modification of the applied dose
and the duration of chemotherapy may be required to
improve survival in very elderly patients.
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