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ORIGINALES
Non-Hodgkin´s lymphoma in the elderly.
Age is not always an adverse prognostic factor
Ángel Segura Huerta, José Gómez-Codina, Miguel Pastor Borgoñón, Ana Yuste Izquierdo,
Pedro López-Tendero, Regina Gironés Sarrió, José A. Pérez-Fidalgo and Constantino Herranz
Fernández
Department of Medical Oncology. Hospital Universitario La Fe. Valencia.
A retrospective study analyzing non-Hodgkin’s
lym-phoma (NHL) diagnosed in patients in our
center above 65 years of age between the years
1977-1991 is reported. Histological classification has been completed following the criteria of the Working Formulation. Of 521 patients, 427 were candidates for evaluation.
Those above 65 years of age comprised the subject of our study, with a total of 95 cases.
Population: 43/52 male/female, 47 intermediate-grade
NHL, 38 low-grade NHL, Ann Arbor stages I-II/III-IV
36/59, performance status (PS) 0-1/2-3 39/56, B symptoms yes/no 47/48, lactic dehydrogenase (LDH) normal/high 33/62, albumin normal/low 75/20, Cu normal/
high 44/37 (the rest not available), B2 microglobuline normal/high 17/11 (the rest not available), tumor burden (MD Anderson) high/intermediate/low
41/28/26.
The median range of cause specific survival was
30 months (50 for the low-grade NHL, 17 for the
intermediate-grade). Significant prognostic factors: histological grade (low versus high and intermediate), PS 0/1 versus 2/3, presence versus absence of B symptoms, normal versus high LDH,
tumor burden (low versus high and intermediate). There is no significant statistical difference
between elderly patients and young patients
with a poor PS, phases I and IV, low albumin level
and high and low tumor burden. Age as an adverse prognostic factor is evident in patients with a
strong PS, phases II and III, normal albumin and
intermediate tumor burden.
The characteristics and prognostic factors of elderly patients with NHL are similar to those of
the young. Age does not always function as an independent prognostic factor; age has no effect on
groups with favorable or unfavorable prognostic
factors and it is in the intermediate prognostic
groups in which age plays a part in survival.
Key words: non-Hodgkin´s lymphoma, elderly, prognostic factors, survival, treatment.
Correspondence: Dr. A. Segura Huerta.
Department of Medical Oncology.
Hospital Universitario La Fe.
Avda. Campanar, 21.
46009 Valencia.
Received 5 February 2002; Accepted 11 April 2002.
436
Segura Huerta A, Gómez-Codina J, Pastor Borgoñón M, Yuste Izquierdo A, López-Tendero P, Gironés Sarrió R, Pérez-Fidalgo JA, Herranz Fernández C. Non-Hodgkin´s lymphoma in the elderly. Age is
not always and adverse prognostic factor. Rev Oncol 2002;4(8):436-42.
Linfomas no Hodgkin en el anciano. La edad
no es siempre un factor de mal pronóstico
Hemos analizado de forma retrospectiva los pacientes diagnosticados de linfoma no Hodgkin (LNH)
mayores de 65 años en nuestra institución entre los
años 1977-1991. La clasificación histológica empleada
sigue los criterios de la Working Formulation. De 521
patients, 427 fueron candidatos para la revisión; los 95
mayores de 65 años son el objeto de nuestro estudio.
Población: 43/52 hombres/mujeres, 47 LNH de grado intermedio, 38 LNH de bajo grado, estadios de
Ann Arbor I-II/III-IV 36/59, PS 0-1/2-3 39/56, síntomas B si/no 47/48, LDH normal/elevada 33/62, albúmina normal/baja 75/20, cobre normal/elevado
44/37 (no disponible en el resto), B2 microglobulina normal/elevada 17/11 (no disponible en el
resto), masa tumoral del MD Anderson: alta/intermedia/ baja 41/28/26. La mediana de supervivencia causa-específica fue de 30 meses (50 meses en
los LNH de bajo grado y 17 meses en los de grado
intermedio). Factores pronósticos significativos
fueron: grado histológico (bajo frente a intermedio y alto), PS 0/1 frente 2/3, presencia frente a
ausencia de síntomas B, LDH normal frente a elevada, carga tumoral del MD Anderson baja frente a alta e intermedia. No hubo diferencias estadísticamente significativas entre los pacientes
ancianos y jóvenes con pobre PS, estadios I y IV,
albúmina baja y cargas tumorales alta y baja. La
edad empeora el pronóstico de los pacientes con
PS intermedios, estadios II y III, albúmina normal
y carga tumoral intermedia.
Las características clínicas y los factores pronósticos de los pacientes ancianos con LNH son
similares a las de los pacientes jóvenes. La edad
no se comporta siempre como un factor pronóstico independiente. En los grupos con otros factores de buen o mal pronóstico la influencia de la
edad se diluye y ésta se manifiesta en los grupos
con pronóstico intermedio.
Rev Oncol 2002;4(8):436-42
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SEGURA HUERTA Á, GÓMEZ-CODINA J, PASTOR BORGOÑÓN M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
Palabras clave: linfoma no Hodgkin, ancianos, factores pronósticos, supervivencia, tratamiento.
INTRODUCTION
Non-Hodgkin’s lymphoma (NHL) composes between
3% and 4% of all cancers1. Its incidence increases
exponentially with age and actually 1/3 of all cases of NHL occur in patients above 70 years of age2.
In a retrospective study no difference has been
found in the prevalence of intermediate or highgrade NHL among patients above and below 70 years
of age, the percentage of advanced phases is similar
in the two groups3. In order to adapt cytostatic treatment to the patients it is necessary to take into account prognostic factors that adequately determine
individual risk factors. In spite of no intrinsic difference in the illness itself, age is considered an adverse prognostic factor in those patients
affected with an intermediate or high-grade NHL4.
The International Prognostic Index (IPI) has confirmed age as a principal prognostic factor5.
Diverse factors such as the coexistence of systematic illness common in the elderly or hematological tolerance to chemotherapy has been used to
explain the adverse prognostic in elderly patients. This tolerance to chemotherapy conditions
a higher number of toxic deaths and the use of
schemes that are less aggressive than those used
in younger patients with the subsequent decrease
in response and increase of relapse6. In this moment, the concept of age as an adverse prognostic
factor is being reviewed. A study completed by the
Non-Hodgkin’s Lymphoma Classification Project7
concludes that age alone is not enough to determine a patient’s prognosis; histological type and
clinical characteristics determine a favorable or
an unfavorable prognosis in each age group.
We have analyzed retrospectively those patients
in our center above 65 years of age diagnosed with
NHL with three objectives in mind: to study the
characteristics of NHL that appear in this population, to study prognostic factors that influence
survival and to study the influence of age in relation to other known prognostic factors.
MATERIAL AND METHOD
Non-Hodgkin’s lymphoma patients above 65 years of age
trea-ted in the department of medical oncology at the
University Hospital La Fe between the years 1977 and 1991
are inclu-ded in this study. The NHL is classified according to the Working Formulation but including the inmunoblastic lymphoma with those of intermediate-grade
NHL. Of a total of 521 patients treated in our center, 427
were assessable due to the fact that those patients without histological specimen for review were excluded.
Of these 427 that were examined, 95 were older than 65
years of age and are the object of our study.
The specific cause for survival (SCS) is analyzed as a dependent variable from the moment of the diagnosis until
death due to NHL, which is more suitable than global
survival when the group being studied is the elderly8.
The generally accepted prognostic factors such as the
existence of B symptoms, performance status (PS) according to the criteria of the World Health Organization,
location and size of the nodal and extra-nodal involvement, level of lactic dehydrogenase (LDH), level of albumin, cupremia, beta-2 microglobine, the Ann Arbor stages,
tumor burden, according to the criteria of MD Anderson9
and the IPI are all analyzed as independent variables.
First, all of the patients are studied as a group and then
those patients with low and intermediate-grade NHL are
studied. The patients included in the database who are
younger than 65 years of age are compared with those
above 65 years of age in order to observe the differences
among the two groups with respect to the elderly.
The statistical analysis includes descriptive statistics
and an univariable study of survival as per the KaplanMeier me-thod10 with the habitual 5% (p > 0.05) considered as level of signification. A multivariable analysis
was done according to the Logistic Linear Regression
Method or the Cox Method11 but the results lack statistical value because of insufficient sample size.
RESULTS
TABLE 1. Characteristics of the elderly patients
with non-Hodgkin’s lymphoma
Intermediate
Low-grade NHL
Global series
grade NHL
above 65 years
above 65 years
above 65 years
of age
of age
of age
(n = 38)
(n = 95)
(n = 47)
(40%)
(49%)
Men
Women
Ann Arbor stages
I
II
II
IV
Performance status
0
1
2
3
4
B symptoms
Yes
No
LDH
Normal
High
Tumor burden
Low
Intermediate
High
Complete response
43 (45%)
52 (55%)
18 (47%)
20 (53%)
23 (49%)
24 (51%)
16 (17%)
20 (21%)
7 (7%)
52 (55%)
7 (18%)
3 (8%)
3 (8%)
25 (66%)
8 (17%)
14 (30%)
4 (8%)
21 (45%)
8 (8%)
30 (22%)
31 (33%)
25 (26%)
1 (1%)
6 (16%)
12 (32%)
13 (34%)
7 (18%)
0
2 (4%)
15 (32%)
15 (32%)
14 (30%)
1 (2%)
47 (49%)
48 (51%)
23 (60%)
15 (40%)
21 (45%)
26 (55%)
62 (65%)
33 (35%)
30 (79%)
8 (21%)
29 (62%)
18 (38%)
23 (24%)
28 (29%)
44 (46%)
48 (53%)
12 (32%)
8 (21%)
18 (47%)
25 (66%)
10 (21%)
17 (36%)
20 (46%)
22 (48%)
NHL: non-Hodgkin’s lymphoma; LDH: lactic dehydrogenase.
Rev Oncol 2002;4(8):436-42
437
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SEGURA HUERTA Á, GÓMEZ-CODINA J, PASTOR BORGOÑÓN M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
65 years of age reach a median survival of 140
months compared with 50 months in the elderly
group; in the intermediate-grade NHL the median
rates of the young and the elderly are 88 and 17
months respectively (figs. 2 and 3).
A high or intermediate histological grade, a PS
equal to or above 1, the presence of B symptoms,
high LDH, low albumin, a high or intermediate tumor burden of the MD Anderson, and the Ann-Arbor stages II, III, IV were proven significant in the
global series as adverse prognostic indicators.
In the elderly low-grade LHH patients, the only
adverse prognostic factors were the presence of B
symptoms, and a cupraemia above 150. In the intermediate-grade NHL patients a PS equal to or above
1, the presence of B symptoms, a high LDH, albumin
below 3 g/dl, a high or intermediate tumor burden
of the MDA and a cupraemia above 150 were deemed significant. A summary of the prognostic factors is included in table 2.
When we stratify by age and prognostic factors
we find different situations. There is no significant difference in SCS between the young and the
elderly patients with PS above or equal to 2 (fig.
4), phases I and IV, low albumin, the presence of B
symptoms and high and low tumor burden. The
significant differences appear in groups with PS 1,
phases II and III, normal albumin, absence of B
symptoms and intermediate tumor burden.
In the patients with intermediate-grade NHL,
Of the 427 patients chosen, 208 (49%) had intermediate-grade NHL and 134 (31%) had low-grade
NHL. The 95 patients above 65 years of age compose
22% of the total number, there were 47 (49%) with
intermediate-grade NHL and 38 (40%) with lowgrade NHL. The characteristics of the series are
presented in table 1.
While analyzing the treatment and the response
to the treatment we found that of the 427 patients, in the under 65 years of age group 322 of
332 (97%) received treatment and 227 obtained a
complete response (CR) (70%). In the over 65 years
of age group 91 of 95 were treated (96%) and 48
were evaluated as a CR (53%).
In the under 65 years of age group 155 of 161 with intermediate-grade NHL (96%) were treated, 119 (77%)
of them reached CR. Of the low-grade NHL 95 of 96
(99%) were treated and 75 (78%) of them obtained
CR. In those older than 65 years of age, 46 of 47 with
intermediate-grade NHL (98%) were treated and 22
of them (48%) reached CR; of the low-grade NHL 35 of
38 (92%) were treated and 23 (66%) obtained CR.
In the SCS analysis age is maintained as an important prognostic factor in the global series; those
younger than 65 years of age have a median survival of 75 months in comparison with the 30 month
survival of those older than 65 (fig. 1). The influence of age upon survival remains the same
when the groups are separated according to histology; in the low-grade NHL group those under
Cause-specific survival
1
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0
0
20
40
60
80
100
120
Months
Age < 65
438
140
160
180
Age > 65
Rev Oncol 2002;4(8):436-42
200
220
Fig. 1. Survival of the global series stratified by age.
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SEGURA HUERTA Á, GÓMEZ-CODINA J, PASTOR BORGOÑÓN M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
Cause-specific survival by age and histological grade
Low grade
1
0.900
0.800
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0
0
20
40
60
Fig. 2. Survival of the patients with low-grade lymphoma stratified by age.
80
100
120
Months
140
Age < 65
160
180
200
220
Age > 65
rences appear in the groups with PS 1, phases II
and III, normal albumin, absence of B symptoms
and intermediate tumor burden.
In the low-grade NHL group, there are no signifi-
there is no significant difference in SCS between the young and the elderly with PS above or
equal to 2, phases I and IV, low albumin, presence
of B symptoms and low and high tumor burden.
The significant diffe-
Cause-specific survival by age and histological grade
Intermediate grade
1
0.900
0.800
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0
0
Fig. 3. Survival of the patients with intermediate-grade lymphoma stratified by
age.
20
40
60
80
100
120
Months
Age < 65
Rev Oncol 2002;4(8):436-42
140
160
180
200
220
Age > 65
439
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SEGURA HUERTA Á, GÓMEZ-CODINA J, PASTOR BORGOÑÓN M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
TABLE 2. Prognostic factors in elderly patients
DISCUSSION
Prognostic factors
Prognostic factors
Prognostic factors
above 65 years of age above 65 years of age above 65 years of age
global series
low-grade NHL
intermediate-grade NHL
Histological grade
Performance status
B symptoms
LDH
Albumin
MDA tumor burden
B sypmtoms
Cupraemia
Performance status
B symptoms
LDH
Albumin
MDA tumor burden
Cupraemia
NHL: non-Hodgkin’s lymphoma; LDH: lactic dehydrogenase.
cant differences in SCS between young and elderly patients with PS 0 or PS ≥ 2, low albumin, infiltration of the bone marrow, low and high tumor burden, presence/absence of B symptoms. The
significant differences appear in groups with PS 1,
normal LDH, normal albumin and intermediate
tumor burden.
More than 50% of cancers occur in patients above
65 years of age12 and between 18% and 38% of NHL
are diagnosed in the elderly13. NHL is currently
an important cause of mortality in the elderly.
The age at which a patient is considered elderly
varies among different studies, but always it is
between 60-70 years. Nevertheless, aging is not
homogeneous and cannot always be defined by chronological age14.
The histologies and Ann Arbor stages are similar
in both the young and the elderly although certain situations, such as the primary cerebral, gonadal, and cutaneous NHL occur more frequently
at advanced age15.
Classically, age has been considered an adverse
prognostic factor for patients affected with
NHL. The development of the IPI in 1993 identified old age (above 60 years of age) as the most
important prognostic factor in survival. Other
studies confirm the poor recovery of elderly patients, but already point out the possibility that it
Cause specific survival by age and perfomance status
1
0.900
PS 0
PS 1
0.800
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0
0
20
40
60
80 100 120 140 160 180 200 220
Months
Age < 65
Age > 65
1
0.900
0
20
40
60
80 100 120 140 160 180 200 220
Months
Age < 65
Age > 65
PS 2
PS 3
0.800
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0
0
20
40
60
80 100 120 140 160 180 200 220
Months
Age < 65
Age > 65
0
20
Fig. 4. Survival according to age and performance status (PS).
440
Rev Oncol 2002;4(8):436-42
40
60
80 100 120 140 160 180 200 220
Months
Age < 65
Age > 65
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SEGURA HUERTA Á, GÓMEZ-CODINA J, PASTOR BORGOÑÓN M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
is not the only factor to take into account3.
Currently, there is a consensus about the management of young patients with NHL, but in the elderly the therapeutic attitude and response is heterogeneous and lacks protocol. The chemotherapic
schemes based on antracyclines (CHOP) result in a
complete response of the group infected with NHL
in approximately 45%-55% of the patients with a cure rate of 30%-35%16. In spite of reaching similar response percentages in those above 70 years of age,
the survival is shorter due to the elevated amount
of deaths as a result of toxicity (close to 30%)17; due
to this many elderly patients are not candidates
for receiving treatment with antracyclines.
A retrospective multicenter study found a statistically significant difference in the percentage of
toxic deaths among those patients treated with an
aggressive scheme as opposed to those with more
conservative treatment3.
These results have led to the consideration of treatment with a modified scheme for elderly patients. Various randomized studies have been realized to evaluate a reduced dosage in this group of
elderly patients. In all of these studies, the results of the schemes without antracyclines are inferior in degrees of response and survival, although the number of toxic deaths is less in the
schemes without antracyclines18-20. These results demonstrate that the adapted measures are inferior
to the CHOP scheme and therefore are not the
most suitable in the elderly, who can receive more
aggressive therapy. At the moment there is no way
to predict the toxicity level of the elderly who
undergo chemotherapy with antracyclines, the
principal risk factor associated with toxic death is
a performance status equal to or greater than 221;
the adapted schemes should be reserved for the elderly patients in a poor condition overall.
The elderly patients who receive intense doses
above the norm reach a significantly better survival22. Due to the importance of the dose intensity, studies have been developed with growth
factors care in the elderly with NHL23. The results demonstrate greater dose intensity in the
branch with growth factors; the responses are similar in both groups and the impact of treatment
with cytoquines on survival is still unknown. In
this moment the use of growth factors in this
group of patients should be individualized24.
Our series presents 22% elderly patients (95 of
427), and among these, the median age is 74. This
percentage is inferior to that described in other
studies, which is around 40%25, but the median of
those above 70 years of age is data that has appeared in other works. The phase and histological
distribution is similar to that which appears in patients under 65 years of age.
The median survival is significantly worse in elderly patients due to the fact that these have a median survival of 30 months as opposed to 75 months
in patients under 65 years of age. Dividing by the
groups of the Working Formulation the elderly
low-grade NHL patients had a median survival of 50
months and the intermediate-grade NHL patients
of 17 months. The median survival in our series is superior to those that appear in other articles25, the
survival obtained in the Dutch study is global while we have calculated the SCS in our data. The differences found reflect deaths that occur as a result of causes other than NHL in the elderly
population, estimated to be approximately 20%25.
In the global series of elderly NHL patients, indicators of adverse prognostic factors are a high
or intermediate histological grade, PS above 1,
the presence of B symptoms, high LDH, albumin
below 3 g/dl, high/intermediate tumor burden of
the MDA and an Ann-Arbor stage above 1. In the
elderly patients with a low-grade NHL the only
adverse prognostic factors are the presence of B
symptoms and a cupraemia above 150; in the elderly with intermediate-grade NHL, the adverse
prognostic factors are a high or intermediate histological grade, PS above 1, the presence of B
symptoms, high LDH, albumin below 3 g/dl, high
and intermediate tumor burden of the MDA, AnnArbor stage above 1 and a cupraemia above 150.
The percentage of elderly patients treated in our
series is high (96%), but only 53% reached complete
response criteria. This percentage is inferior to
that reached in young patients and is related to the
chemotherapic scheme employed. The substitution
of adriamycine for mitoxantrone is frequent in our
series and there is data in the bibliography that
confirms the decrease of elderly patient response
of those treated without antracyclines18-20. When
the data is observed according to histology, the lower effectiveness of the scheme adapted to the elderly and the lower survival in comparison to
young patients is confirmed. It seems necessary to
treat the elderly patients taking into account not
only their age, but also effective programs that benefit a group of patients with favorable factors.
When the influence of age is analyzed along with other prognostic factors we find that in the elderly
a
n
d
the young patients the SCS is similar in groups with
poor PS, phases I and IV, low albumin and high and
low tumor burden. The elderly patients with a favorable PS, intermediate phases (II-III), normal albumin
and intermediate tumor burden have a significantly
worse SCS. Therefore it seems that there are prognostic factors that have a greater influence than
age in the patient’s development and it is in groups
with intermediate prognostic factors where advan-
Rev Oncol 2002;4(8):436-42
441
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SEGURA HUERTA Á, GÓMEZ-CODINA J, PASTOR BORGOÑÓN M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
ced age worsens the patient’s development. Only elderly patients with a poor PS should be given adapted treatments, as the risk of toxic death from treatment with antracycline is very high in this group21.
The results of the elderly group with intermediate-grade NHL are similar to those extracted from
the global series. The elderly with a PS greater
than or equal to 2, phases I and IV, low albumin, the
presence of B symptoms and high and low tumor
burden have a SCS similar to the young patients
with the same characteristics. In the low grade
NHL group, the elderly with PS above or equal to
2, low albumin, presence of B symptoms, infiltration of the bone marrow and high and low tumoral
burden have a SCS similar to that of the young patients with the same characteristics. Age worsens
the prognosis in patients with PS 1, normal LDH, normal albumin and intermediate tumor burden.
Our study confirms that the onset of NHL is similar
in the young and the elderly. The survival of patients above 65 years of age is below that of the
younger groups. Age is not the only factor that affects the SCS, as there are also other factors that
determine a prognosis. In those patients with favorable prognostic factors and those with a very unfavorable initial prognosis it seems that age is not
an important prognostic factor. Nevertheless, in the
intermediate risk factor group, age acts as an independent prognostic variable of first order. At this
moment, the biological situation and the presence of
other known prognostic factors and not chronological age should orient the treatment directed at
the elderly patient with lymphoma and the chemotherapic schemes should not be adapted except in unfavorable cases with a high risk of toxic death.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
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SEGURA A GÓMEZ-CODINA J, PASTOR M, ET AL. NON-HODGKIN´S LYMPHOMA IN THE ELDERLY.
AGE IS NOT ALWAYS AN ADVERSE PROGNOSTIC FACTOR
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