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Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis
EJINME-02716; No of Pages 6 European Journal of Internal Medicine xxx (2014) xxx–xxx
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis S. Diem a,⁎, S. Ess b, Th. Cerny a, M. Früh a, F. Hitz a a b
Department of Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland Swiss Cancer League, Flurhofstrasse 7, 9000 St. Gallen, Switzerland
a r t i c l e
i n f o
Article history: Received 12 October 2013 Received in revised form 14 March 2014 Accepted 1 May 2014 Available online xxxx Keywords: DLBCL Elderly R-CHOP
a b s t r a c t Background: Few data on patterns of care and outcomes are available for elderly patients with diffuse large B-cell lymphoma (DLBCL) outside of clinical trials. Methods: We identified patients with DLBCL older than 60 years from a regional cancer registry between 2000 and 2010. Based on registry data and chart review, 128 patients from the oncology network of Eastern Switzerland were analysed for patient characteristics, treatment and outcomes of DLBCL. Three age groups were compared: 60–69, 70–79 and over 80 years old. Results: Median age was 73 years (range: 60 to 95 years). 52/121 treated patients received 6 cycles of R-CHOP/ CHOP, of those 30 (58%), 18 (35%) and 4 (7%) patients were 60–69 years, 70–79 years or older than 80 years respectively, with a significant difference by age group, p = 0.001. Median OS of patients 60–69, 70–79, and 80 years and older receiving 6 cycles of R-CHOP/CHOP were: 54 months, 31 months and 24 months respectively. In comparison, patients receiving other than 6 cycles of R-CHOP/CHOP treatment regimens had a median OS of 22 months, 17 months and 6 months, respectively. In the multivariable analysis other than 6 cycles of RCHOP/CHOP were significantly associated with poor survival. The risk of dying increased by a mean of 6% for each year of age from age 60 years onwards. Conclusion: In conclusion, treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival in our oncology network. The possibility of using R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction The past century has seen a rapid expansion in the population older than 65 years. Over the next 50 years, this group is expected to double in number. Furthermore, the number of individuals above 85 years of age is expected to quadruple [1]. Alongside this demographic shift, age-related disorders are on the rise. Amongst these, diffuse large Bcell lymphoma (DLBCL) is one of the most frequently occurring subtypes of aggressive B-cell non-Hodgkin lymphoma. The incidence of these neoplasms increases with age, reaching a peak in the seventh decade of life and beyond [2]. The international prognostic index (IPI) indicates age to be a strong risk factor and is prognostic of the outcome of patients with DLBCL [3]. However, data suggest that age is not the only factor involved in determining outcome [4]. In an analysis of risk factors for treatment-related deaths in elderly patients with aggressive lymphoma, Gomez et al. found a stronger association between survival and poor performance status, rather than age [5]. Indeed, the heterogeneity in individuals' general health statuses reflects the diverse fitness levels that can be found in the elderly population [6]. Therefore a
major issue in the treatment of the elderly is the recognition of comorbidities and functional status [7]. The immune-chemotherapy regimen R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) has been established as standard treatment for aggressive B-cell lymphomas with excellent outcomes for patients between 60 and 80 years of age [8–10]. Nevertheless, both R-CHOP pivotal trials excluded patients who were frail or above 80 years of age. Peyrade et al. included patients aged 80 years and older treated with rituximab and dose-reduced conventional 3-weekly CHOP. Efficacy and acceptable safety were shown [2]. In light of the paucity of clinical trial data in the elderly, retrospective population-based analyses provide another means to gain insight into the factors that influence treatment and outcomes [4,11]. The aim of this retrospective analysis was to describe the patterns of disease and prognostic impact of treatment regimen, comorbidities and toxicities in DLBCL patients older than 60 years who were treated within a regional health oncology network in Switzerland. 2. Patients and methods
⁎ Corresponding author. Tel.: +41 71 494 11 11. E-mail address: [email protected] (S. Diem).
We retrospectively analysed the outcomes of patients with newly diagnosed, histologically confirmed DLBCL. Data from the cancer
http://dx.doi.org/10.1016/j.ejim.2014.05.001 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
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Response to treatment was evaluated on the basis of imaging by CTscan [13]. Isolated missing data, such as CCI, IPI and response to treatment were added on the basis of available information. The study was approved by the local ethics committee.
registry of the Canton St. Gallen-Appenzell (Switzerland) were used to identify patients. We included patients aged 60 years or older, any stage of disease, diagnosed and treated between 2000 and 2010 in the oncology network of the Cantonal Hospital St. Gallen and its regional public network hospitals. Medical history was reviewed for patient characteristics, treatment and outcomes. Patients were categorized into three age groups: 60–69, 70–79 and over 80 years old and were assessed for the Charlson comorbidity-index (CCI) score defined as follows: low disease score 0–2 and high disease score 3–5 [12], and International Prognostic Index (IPI) [3]. The upper limit of normal lactate dehydrogenase (LDH) was 265 U/l. Patients were analysed by age groups for type of therapy, the number of administered cycles and reasons for drop out. Treatment regimens with 6 cycles of R-CHOP/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) were compared to anthracycline containing regimens as modified R-CHOP/ CHOP regimens with less than 6 cycles and other treatment regimens as rituximab-bendamustine, rituximab monotherapy, R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) or single agents as epirubicine, gemcitabine and navelbine. Causes for treatment interruption were defined as follows: patient wish, treatment-related toxicity, progressive disease and death. Treatment-related toxicity included patients with infection confined to hospitalization due to fever with grades 3 and 4 neutropenia. Granulocyte stimulating factor was administered at the physician's discretion.
3. Statistical analysis The primary endpoint was overall survival (OS) defined as the time form diagnosis to death or last contact. Survival data was computed using the Kaplan Meier method. The following predictive covariates of survival were used: gender, IPI, Ann Arbor stage, age, treatment type (“R-CHOP/CHOP × 6” versus “other than R-CHOP/CHOP × 6”). A multivariate analysis (Cox proportional hazard model) was adjusted for prognostic factors. All analyses were performed using the software STATA version 12. 4. Results 4.1. Patient characteristics Between 2000 and 2010, 128 patients with newly diagnosed DLBCL, treated at the oncology network and 60 years of age or older were identified. Patient characteristics are summarized in Table 1. Median age of patients was 73 years (range: 60–95 years). Age distribution was as follows: 60–69 years (n = 48; 38%), 70–79 years
Table 1 Patient characteristics. All patients n Total number of patients Gender Male Female Ann Arbor stage I II III IV Ann Arbor Stage I–II (localized) III–IV (advanced) B-symptoms Yes No Involvement Exclusively nodal Exclusively extranodal Nodal & extranodal CCI 0 1–2 3–4 N4 Missing IPI score Low Low–intermediate High–intermediate High Missing LDH level Normal Elevated Missing Inclusion into ongoing trials No Yes
60–69 %
128
n 48
70–79 %
n a
48
38
80+ %
n
%
a
32
25
38
59 69
46 54
24 24
50 50
21 27
44 56
14 18
44 56
34 27 38 29
27 21 30 22
13 13 9 13
27 27 19 27
10 10 19 9
21 21 40 19
11 4 10 7
34 13 31 22
61 67
48 52
26 22
54 46
20 28
42 58
15 17
47 53
33 95
26 74
9 39
19 81
15 33
31 69
9 23
28 72
49 28 51
38 22 40
21 9 18
44 19 37
19 9 20
40 19 42
9 10 13
28 31 41
55. 45 16 10 2
43 35 13 7 2
28 15 3 1 1
58 31 6 2 2
16 18 8 6 0
33 37 17 13 0
11 12 5 3 1
35 37 16 10 3
22 41 35. 28 2
17 32 27 22 2
10 16 13 8 1
21 33 27 17 2
7 16 13 12 0
15 33 27 25 0
5 9 9 8 1
16 28 28 25 3
38 85 5
30 66 4
11 35 2
23 73 4
19 28 1
40 58 2
8 22 2
25 69 6
118 10
92 8
44 4
92 8
42 6
87 13
32 0
100 0
p-value p = 0.98 p = 0.97
p = 0.24
p = 0.34
p = 0.39
p = 0.42
p = 0.20
p = 0.92
p = 0.27
Abbreviations: CCI (Charlson comorbidity index). IPI (international prognostic index). a Due to rounding not exactly 100%.
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
S. Diem et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx
(n = 48; 38%), and 80 years and older (n = 32, 25%). No significant difference of gender, disease stage, localized or advanced disease, nodal– extranodal involvement, B-symptoms and LDH, IPI and CCI were observed between the age groups. There were trends towards higher CCI and higher disease stage with increasing age (p = 0.2 and 0.24). CCI showed a low score (score 0–2) for the majority of the patients. No difference in high disease scores (score 3 and more) was observed for the age groups 70–79 and more than 80 years of age. IPI including information on stage of disease, extranodal involvement, LDH, performance status and age were similar in the three age groups. Only 10 (8%) patients were included into an ongoing trial. Patients older than 80 years of age were not eligible for this trial. Median follow-up for all patients was 29 months (range: 0– 136 months) and 54 months for those still alive (range: 24– 136 months). 4.2. Treatment characteristics Of the 128 analysed patients, 7 patients never were treated with an immuno-chemotherapy, chemotherapy or radiotherapy regimen. Significant differences in treatment characteristics for application of 6 cycles of R-CHOP/CHOP regimen occurred between the age groups, p = 0.001 (Table 2). 52 out of 121 patients received 6 cycles of R-CHOP/CHOP as a standard therapy. Of those 30 (58%), 18 (35%) and 4 (7%) patients were 60–69, 70–79 or older than 80 years, respectively. The remaining 69 patients underwent other treatments for DLBCL; 23 of them were older than 80 years. 5 of the 32 patients older than 80 years were never treated. Response assessment of all treatment regimens showed a complete remission (CR) in 56 (46%) patients; thereof 9 patients were older than 80 years. In 23 (19%) patients the extent of the response remained unclear due to missing data. In the group treated with 6 cycles of RCHOP/CHOP regimen 36 (69%) patients reached a CR, of those 4 patients were 80 years and older. The extent of the response was unclear in 8 patients older than 80 years. Compared to the group treated with other treatment regimens 20 (29%) patients reached a CR with 5 patients older than 80 years. 23 patients had unclear response. Progressive disease (PD) was documented in 1 (2%) patient in the group with 6 cycles of R-CHOP/CHOP compared to 9 (13%) patients in the remaining treatment groups for DLBCL.
3
4.3. Survival analysis At the time of analysis 66 (51%) patients were alive, 52 (41%) patients died of lymphoma and 10 (8%) patients died of unrelated causes. In total 26 of 121 treated patients were hospitalized due to neutropenic fever. Five of these died as a direct consequence of the infection. Median OS of all patients 60–69, 70–79 and more than 80 years was 51, 26 and 8.5 months respectively. Median OS of all patients receiving 6 cycles of R-CHOP/CHOP regimen was 50 months compared to 38 months, 8 months and 1 month in patients undergoing anthracycline containing regimens as modified R-CHOP/CHOP regimens with less than 6 cycles, other therapy regimens or no therapy, respectively. Among the groups of 60–69, 70–79 and more than 80 years median OS in patients with 6 cycles of RCHOP/CHOP treatment regimens was 54 months, 31 months and 24 months, respectively (Fig. 1). Cox regression was performed for risk of dying within 2 years. In the univariate analysis increased age (patients 80 years and older; HR 4.77, p = 0.001), high IPI 3–5 (HR 2.26, p = 0.004), CCI ≥ 3 (HR 2.05, p = 0.02), elevated LDH (HR 3.19, p = 0.003) and treatment other than 6 cycles of R-CHOP/CHOP were associated with an increased risk of dying: anthracycline containing regimens as modified R-CHOP/CHOP regimens with less than 6 cycles HR 4.94, CI 95% 1.74–14.02, p = 0.001 and other treatment regimens HR 14.49, CI 95% 5.59–37.59, p = 0.0001. The presence of B-symptoms or extranodal involvement did not significantly impact overall survival (Table 3). In the multivariable analysis other than 6 cycles of R-CHOP/CHOP (HR 6.65, p = 0.001) were significantly associated with poor survival (Table 4). 5. Discussion The present study investigated patterns in patient characteristics and outcomes in patients older than 60 years of age with newly diagnosed DLBCL within a regional oncology network in Switzerland over a 10 year period. Patient and disease characteristics were not significantly different amongst the various age groups. However, in our study significant differences in the disease management strategies
Table 2 Treatment characteristics and differences according to age. All patients
Treatment No treatment R-CHOP/CHOP × 6 R-CHOP/CHOP b6 Other treatment Response R-CHOP/CHOP × 6 CR PR SD PD Unknown R-CHOP/CHOP b6 CR PR SD PD Unknown Other CR PR SD PD Unknown
60–69
70–79
80+
p-value
n
%
n
%
n
%
n
%
121 7 52 31 38
100
48
100
46
100
27
100
43 26 31
30 11 7
62 23 15
18 11 17
39 24 37
4 9 14
15 33 52
22 6 1 0 1
73 20 3 0 1
10 7 0 1 0
56 39 0 6 0
4 0 0 0 0
100 0 0 0 0
4 2 0 1 4
37 19 0 9 36
2 4 0 2 3
18 37 0 18 27
2 4 0 0 3
22 45 0 0 33
p = 0.79
2 0 0 1 4
29 0 0 14 57
7 3 0 4 3
41 18 0 23 18
3 3 2 1 5
21 21 7 14 36
p = 0.52
p b 0.001
p = 0.52
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
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S. Diem et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx
Fig. 1. Survival by age group and treatment regimen.
were observed in the different age groups. Similar findings have been reported in another population-based study evaluating treatment of lymphoma [11]. In a comparison of lymphoma patients across varying age groups, the Italian cancer registry reported that 60 years of age was the cut-off point for the application of an adequate or standard therapeutic approach [14]. These trends in clinical practice are in sharp contrast to the findings from pivotal studies, which have demonstrated that clinically fit patients 60–80 years of age have excellent outcomes using a standard RCHOP regimen [8–10].
5.1. Patient characteristics and treatment regimens Fewer than half of the patients in our analysis were treated with a standard approach for DLBCL, defined as 6 cycles of an R-CHOP/CHOP regimen. Most of these patients were in the 60–69 year age group, where 62% (n = 30) were treated with R-CHOP/CHOP. A surprising high proportion of patients in this age group did not receive standard therapy. Most of them had limited stage DLBCL with a short course of R-CHOP/CHOP treatment with or without consolidation radiotherapy;
some were early progressive and did not complete the planned treatment. Patients 70 years and older were more likely to be treated with a non R-CHOP/CHOP approach for DLBCL, substantially altering patient outcomes (Fig. 1). This fact is worrisome as the decision for non RCHOP/CHOP treatment seems to be based on age by itself rather than on objective factors. In our study population, 75% had either no comorbidities or a low CCI score. The majority of these were in the group of patients aged 60– 69 years. The subsequent two age groups (70–79 years and N 80 years) had a similar distribution of CCI and IPI-score. Although patient and disease characteristics were not significantly different in these two age groups, patients 80 years and older were treated more often with regimens other than 6 cycles of R-CHOP/CHOP (85%; n = 23), compared to those 70–79 years of age (60%; n = 28; p b 0.001). There is evidence suggesting that older patients undergo chemotherapy less frequently, and when they do, the frequency and intensity of chemotherapy are reduced compared to younger patients. Co-morbidities and poor performance status are among the most common reasons for reducing the intensity of chemotherapy in the elderly [15]. Further compounding the problem, the bulk of the evidence upon which treatment guidelines are based is obtained in younger patients, since the elderly are rarely included in clinical trials. Therefore, the rationale for reduction of treatment intensity is often based on age by itself rather than on a systematic evaluation of performance status [16]. To this end, comprehensive geriatric assessments were developed to facilitate evaluation of a patient's general health status, and are currently used in the management of elderly cancer patients [7]. Response assessment in our study population revealed that in a large proportion of patients treated with other treatment regimens, the response remained unclear due to missing data. More patients older than 80 years (29%) wished to stop treatment compared to patients within the 70–79 year (6%) and 60–69 year (11%) age groups. This decision was mostly based on treatment-related adverse events or remained unclear. It is known that frail and vulnerable patients not only have limited physical resources, but also fewer psychological and social resources to sustain complications [17]. Nevertheless, 14 out of 60 patients older than 70 years achieved a CR using an anthracycline containing regimens as modified R-CHOP/CHOP regimens with less than 6 cycles and other treatment regimens. In the pre-rituximab era, the capacity of similar approaches to cure or at
Table 3 2-year overall survival in univariate analysis. Univariate Haz. ratio Age 60–69 70–79 80+ IPI0–2 IPI3–5 CCI 0–2 CCI N3 LDH normal LDH elevated B-symptoms No Yes Involvement Exclusively nodal Exclusively extranodal Nodal & extranodal Treatment R-CHOP/CHOP × 6 Other than R-CHOP/CHOP × 6a
p value
[95% conf. interval]
0.05 b0.001
1.00 2.32
4.34 9.84
0.004
1.30
3.92
0.02
1.15
3.63
0.003
1.50
6.78
1 (ref) 1.15
0.64
0.63
2.09
1 (ref) 1.63 1.71
0.18 0.09
0.79 0.90
3.34 3.23
1 (ref) 9.16
b0.001
3.62
23.21
1 (ref) 2.08 4.77 1 (ref) 2.26 1 (r.ef) 2.05 1 (ref) 3.19
Abbreviations: CCI (Charlson comorbidity index). IPI (International Prognostic Index). a Including 7 patients without treatment.
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
S. Diem et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx
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Table 4 2-year overall survival in multivariable analysis. Multivariate haz. ratio Age 60–69 70–79 80+ IPI0–2 IPI3–5 CCI 0–2 CCI N3 LDH normal LDH elevated B-symptoms No Yes Involvement Exclusively nodal Exclusively extranodal Nodal & extranodal Treatment R-CHOP/CHOP × 6 Other than R-CHOP/CHOP × 6a
p value
1 (ref) 1.06 2.14 1 (ref) 1.65 1 (ref) 1.68 1 (ref) 2.14
[95% conf. interval]
0.90 0.07
0.44 0.94
2.51 4.87
0.20
0.76
3.55
0.17
0.81
3.48
0.11
0.85
5.38
1 (ref) 1.85
0.09
0.91
3.76
1.51 1.44
0.35 0.35
0.64 0.67
3.54 3.07
b0.001
2.40
18.42
|
1 (ref) 6.65
Abbreviations: CCI (Charlson comorbidity index). IPI (International Prognostic Index). a Including 7 patients without treatment.
least to prolong progression free survival has been demonstrated in a small proportion of patients [18]. Immuno-chemotherapy regimens such as mini-R-CHOP, R-bendamustine or new agents in combination with rituximab [2,19] are not only clinically active but provide a balance between toxicity and efficacy, giving patients the opportunity to remain disease free for months or even years. 5.2. Survival Median survival by age group declined dramatically with each decade of life beyond 60 years (51 months, 26 months and 8.5 months, respectively, for each subsequent decade). In the univariate analysis age over 80 years, poor IPI, CCI ≥3, elevated LDH and treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival. In the multivariable analysis only treatment regimens other than 6 cycles of R-CHOP/CHOP were significant.
Treatment of elderly patients, however, should be tailored according to the patient's comorbidities, performance status, individual wishes and therapeutic goals. The possibility of using curative R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL. Learning points • R-CHOP standard treatment should be considered for DLBCL irrespective of the patient age. • In patients eligible for R-CHOP/CHOP objective facts such as a geriatric assessment or CCI maybe more relevant than age alone. • Reasons for deviations of the standard regimen should carefully be documented in the patient file both for medical and legal reasons. Conflict of interest None.
5.3. Limitations The findings from our study are limited by the retrospective nature of the analysis. The definition of CCI is based on chart review and may not accurately capture the actual patients' comorbidities. Furthermore, the value of CCI is somewhat controversial as the diagnoses of certain comorbid conditions do not reflect the extent of the concomitant disease. The performance status as defined by the clinician is also a prognostic factor that represents the clinician's perception of a patient's functional status and is often underreported in patients' records. Furthermore patient numbers within the age and treatment groups are limited and diverge substantially, restricting statements on patient's outcome. Limited is also the conclusion on disease specific survival as death is only documented in the death certificate. 6. Conclusions In conclusion, treatment regimens other than 6 cycles of R-CHOP were significant predictors for survival in our oncology network. It seems in our study that chronological age was mainly used as the decision factor to select chemotherapy regimens other than R-CHOP/CHOP, although other clinical factors such as frailty, patient preferences and comorbidities as detected by the CCI or biological age could have been taken into consideration.
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Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
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Original Article
Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis S. Diem a,⁎, S. Ess b, Th. Cerny a, M. Früh a, F. Hitz a a b
Department of Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland Swiss Cancer League, Flurhofstrasse 7, 9000 St. Gallen, Switzerland
a r t i c l e
i n f o
Article history: Received 12 October 2013 Received in revised form 14 March 2014 Accepted 1 May 2014 Available online xxxx Keywords: DLBCL Elderly R-CHOP
a b s t r a c t Background: Few data on patterns of care and outcomes are available for elderly patients with diffuse large B-cell lymphoma (DLBCL) outside of clinical trials. Methods: We identified patients with DLBCL older than 60 years from a regional cancer registry between 2000 and 2010. Based on registry data and chart review, 128 patients from the oncology network of Eastern Switzerland were analysed for patient characteristics, treatment and outcomes of DLBCL. Three age groups were compared: 60–69, 70–79 and over 80 years old. Results: Median age was 73 years (range: 60 to 95 years). 52/121 treated patients received 6 cycles of R-CHOP/ CHOP, of those 30 (58%), 18 (35%) and 4 (7%) patients were 60–69 years, 70–79 years or older than 80 years respectively, with a significant difference by age group, p = 0.001. Median OS of patients 60–69, 70–79, and 80 years and older receiving 6 cycles of R-CHOP/CHOP were: 54 months, 31 months and 24 months respectively. In comparison, patients receiving other than 6 cycles of R-CHOP/CHOP treatment regimens had a median OS of 22 months, 17 months and 6 months, respectively. In the multivariable analysis other than 6 cycles of RCHOP/CHOP were significantly associated with poor survival. The risk of dying increased by a mean of 6% for each year of age from age 60 years onwards. Conclusion: In conclusion, treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival in our oncology network. The possibility of using R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction The past century has seen a rapid expansion in the population older than 65 years. Over the next 50 years, this group is expected to double in number. Furthermore, the number of individuals above 85 years of age is expected to quadruple [1]. Alongside this demographic shift, age-related disorders are on the rise. Amongst these, diffuse large Bcell lymphoma (DLBCL) is one of the most frequently occurring subtypes of aggressive B-cell non-Hodgkin lymphoma. The incidence of these neoplasms increases with age, reaching a peak in the seventh decade of life and beyond [2]. The international prognostic index (IPI) indicates age to be a strong risk factor and is prognostic of the outcome of patients with DLBCL [3]. However, data suggest that age is not the only factor involved in determining outcome [4]. In an analysis of risk factors for treatment-related deaths in elderly patients with aggressive lymphoma, Gomez et al. found a stronger association between survival and poor performance status, rather than age [5]. Indeed, the heterogeneity in individuals' general health statuses reflects the diverse fitness levels that can be found in the elderly population [6]. Therefore a
major issue in the treatment of the elderly is the recognition of comorbidities and functional status [7]. The immune-chemotherapy regimen R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) has been established as standard treatment for aggressive B-cell lymphomas with excellent outcomes for patients between 60 and 80 years of age [8–10]. Nevertheless, both R-CHOP pivotal trials excluded patients who were frail or above 80 years of age. Peyrade et al. included patients aged 80 years and older treated with rituximab and dose-reduced conventional 3-weekly CHOP. Efficacy and acceptable safety were shown [2]. In light of the paucity of clinical trial data in the elderly, retrospective population-based analyses provide another means to gain insight into the factors that influence treatment and outcomes [4,11]. The aim of this retrospective analysis was to describe the patterns of disease and prognostic impact of treatment regimen, comorbidities and toxicities in DLBCL patients older than 60 years who were treated within a regional health oncology network in Switzerland. 2. Patients and methods
⁎ Corresponding author. Tel.: +41 71 494 11 11. E-mail address: [email protected] (S. Diem).
We retrospectively analysed the outcomes of patients with newly diagnosed, histologically confirmed DLBCL. Data from the cancer
http://dx.doi.org/10.1016/j.ejim.2014.05.001 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
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Response to treatment was evaluated on the basis of imaging by CTscan [13]. Isolated missing data, such as CCI, IPI and response to treatment were added on the basis of available information. The study was approved by the local ethics committee.
registry of the Canton St. Gallen-Appenzell (Switzerland) were used to identify patients. We included patients aged 60 years or older, any stage of disease, diagnosed and treated between 2000 and 2010 in the oncology network of the Cantonal Hospital St. Gallen and its regional public network hospitals. Medical history was reviewed for patient characteristics, treatment and outcomes. Patients were categorized into three age groups: 60–69, 70–79 and over 80 years old and were assessed for the Charlson comorbidity-index (CCI) score defined as follows: low disease score 0–2 and high disease score 3–5 [12], and International Prognostic Index (IPI) [3]. The upper limit of normal lactate dehydrogenase (LDH) was 265 U/l. Patients were analysed by age groups for type of therapy, the number of administered cycles and reasons for drop out. Treatment regimens with 6 cycles of R-CHOP/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) were compared to anthracycline containing regimens as modified R-CHOP/ CHOP regimens with less than 6 cycles and other treatment regimens as rituximab-bendamustine, rituximab monotherapy, R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) or single agents as epirubicine, gemcitabine and navelbine. Causes for treatment interruption were defined as follows: patient wish, treatment-related toxicity, progressive disease and death. Treatment-related toxicity included patients with infection confined to hospitalization due to fever with grades 3 and 4 neutropenia. Granulocyte stimulating factor was administered at the physician's discretion.
3. Statistical analysis The primary endpoint was overall survival (OS) defined as the time form diagnosis to death or last contact. Survival data was computed using the Kaplan Meier method. The following predictive covariates of survival were used: gender, IPI, Ann Arbor stage, age, treatment type (“R-CHOP/CHOP × 6” versus “other than R-CHOP/CHOP × 6”). A multivariate analysis (Cox proportional hazard model) was adjusted for prognostic factors. All analyses were performed using the software STATA version 12. 4. Results 4.1. Patient characteristics Between 2000 and 2010, 128 patients with newly diagnosed DLBCL, treated at the oncology network and 60 years of age or older were identified. Patient characteristics are summarized in Table 1. Median age of patients was 73 years (range: 60–95 years). Age distribution was as follows: 60–69 years (n = 48; 38%), 70–79 years
Table 1 Patient characteristics. All patients n Total number of patients Gender Male Female Ann Arbor stage I II III IV Ann Arbor Stage I–II (localized) III–IV (advanced) B-symptoms Yes No Involvement Exclusively nodal Exclusively extranodal Nodal & extranodal CCI 0 1–2 3–4 N4 Missing IPI score Low Low–intermediate High–intermediate High Missing LDH level Normal Elevated Missing Inclusion into ongoing trials No Yes
60–69 %
128
n 48
70–79 %
n a
48
38
80+ %
n
%
a
32
25
38
59 69
46 54
24 24
50 50
21 27
44 56
14 18
44 56
34 27 38 29
27 21 30 22
13 13 9 13
27 27 19 27
10 10 19 9
21 21 40 19
11 4 10 7
34 13 31 22
61 67
48 52
26 22
54 46
20 28
42 58
15 17
47 53
33 95
26 74
9 39
19 81
15 33
31 69
9 23
28 72
49 28 51
38 22 40
21 9 18
44 19 37
19 9 20
40 19 42
9 10 13
28 31 41
55. 45 16 10 2
43 35 13 7 2
28 15 3 1 1
58 31 6 2 2
16 18 8 6 0
33 37 17 13 0
11 12 5 3 1
35 37 16 10 3
22 41 35. 28 2
17 32 27 22 2
10 16 13 8 1
21 33 27 17 2
7 16 13 12 0
15 33 27 25 0
5 9 9 8 1
16 28 28 25 3
38 85 5
30 66 4
11 35 2
23 73 4
19 28 1
40 58 2
8 22 2
25 69 6
118 10
92 8
44 4
92 8
42 6
87 13
32 0
100 0
p-value p = 0.98 p = 0.97
p = 0.24
p = 0.34
p = 0.39
p = 0.42
p = 0.20
p = 0.92
p = 0.27
Abbreviations: CCI (Charlson comorbidity index). IPI (international prognostic index). a Due to rounding not exactly 100%.
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
S. Diem et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx
(n = 48; 38%), and 80 years and older (n = 32, 25%). No significant difference of gender, disease stage, localized or advanced disease, nodal– extranodal involvement, B-symptoms and LDH, IPI and CCI were observed between the age groups. There were trends towards higher CCI and higher disease stage with increasing age (p = 0.2 and 0.24). CCI showed a low score (score 0–2) for the majority of the patients. No difference in high disease scores (score 3 and more) was observed for the age groups 70–79 and more than 80 years of age. IPI including information on stage of disease, extranodal involvement, LDH, performance status and age were similar in the three age groups. Only 10 (8%) patients were included into an ongoing trial. Patients older than 80 years of age were not eligible for this trial. Median follow-up for all patients was 29 months (range: 0– 136 months) and 54 months for those still alive (range: 24– 136 months). 4.2. Treatment characteristics Of the 128 analysed patients, 7 patients never were treated with an immuno-chemotherapy, chemotherapy or radiotherapy regimen. Significant differences in treatment characteristics for application of 6 cycles of R-CHOP/CHOP regimen occurred between the age groups, p = 0.001 (Table 2). 52 out of 121 patients received 6 cycles of R-CHOP/CHOP as a standard therapy. Of those 30 (58%), 18 (35%) and 4 (7%) patients were 60–69, 70–79 or older than 80 years, respectively. The remaining 69 patients underwent other treatments for DLBCL; 23 of them were older than 80 years. 5 of the 32 patients older than 80 years were never treated. Response assessment of all treatment regimens showed a complete remission (CR) in 56 (46%) patients; thereof 9 patients were older than 80 years. In 23 (19%) patients the extent of the response remained unclear due to missing data. In the group treated with 6 cycles of RCHOP/CHOP regimen 36 (69%) patients reached a CR, of those 4 patients were 80 years and older. The extent of the response was unclear in 8 patients older than 80 years. Compared to the group treated with other treatment regimens 20 (29%) patients reached a CR with 5 patients older than 80 years. 23 patients had unclear response. Progressive disease (PD) was documented in 1 (2%) patient in the group with 6 cycles of R-CHOP/CHOP compared to 9 (13%) patients in the remaining treatment groups for DLBCL.
3
4.3. Survival analysis At the time of analysis 66 (51%) patients were alive, 52 (41%) patients died of lymphoma and 10 (8%) patients died of unrelated causes. In total 26 of 121 treated patients were hospitalized due to neutropenic fever. Five of these died as a direct consequence of the infection. Median OS of all patients 60–69, 70–79 and more than 80 years was 51, 26 and 8.5 months respectively. Median OS of all patients receiving 6 cycles of R-CHOP/CHOP regimen was 50 months compared to 38 months, 8 months and 1 month in patients undergoing anthracycline containing regimens as modified R-CHOP/CHOP regimens with less than 6 cycles, other therapy regimens or no therapy, respectively. Among the groups of 60–69, 70–79 and more than 80 years median OS in patients with 6 cycles of RCHOP/CHOP treatment regimens was 54 months, 31 months and 24 months, respectively (Fig. 1). Cox regression was performed for risk of dying within 2 years. In the univariate analysis increased age (patients 80 years and older; HR 4.77, p = 0.001), high IPI 3–5 (HR 2.26, p = 0.004), CCI ≥ 3 (HR 2.05, p = 0.02), elevated LDH (HR 3.19, p = 0.003) and treatment other than 6 cycles of R-CHOP/CHOP were associated with an increased risk of dying: anthracycline containing regimens as modified R-CHOP/CHOP regimens with less than 6 cycles HR 4.94, CI 95% 1.74–14.02, p = 0.001 and other treatment regimens HR 14.49, CI 95% 5.59–37.59, p = 0.0001. The presence of B-symptoms or extranodal involvement did not significantly impact overall survival (Table 3). In the multivariable analysis other than 6 cycles of R-CHOP/CHOP (HR 6.65, p = 0.001) were significantly associated with poor survival (Table 4). 5. Discussion The present study investigated patterns in patient characteristics and outcomes in patients older than 60 years of age with newly diagnosed DLBCL within a regional oncology network in Switzerland over a 10 year period. Patient and disease characteristics were not significantly different amongst the various age groups. However, in our study significant differences in the disease management strategies
Table 2 Treatment characteristics and differences according to age. All patients
Treatment No treatment R-CHOP/CHOP × 6 R-CHOP/CHOP b6 Other treatment Response R-CHOP/CHOP × 6 CR PR SD PD Unknown R-CHOP/CHOP b6 CR PR SD PD Unknown Other CR PR SD PD Unknown
60–69
70–79
80+
p-value
n
%
n
%
n
%
n
%
121 7 52 31 38
100
48
100
46
100
27
100
43 26 31
30 11 7
62 23 15
18 11 17
39 24 37
4 9 14
15 33 52
22 6 1 0 1
73 20 3 0 1
10 7 0 1 0
56 39 0 6 0
4 0 0 0 0
100 0 0 0 0
4 2 0 1 4
37 19 0 9 36
2 4 0 2 3
18 37 0 18 27
2 4 0 0 3
22 45 0 0 33
p = 0.79
2 0 0 1 4
29 0 0 14 57
7 3 0 4 3
41 18 0 23 18
3 3 2 1 5
21 21 7 14 36
p = 0.52
p b 0.001
p = 0.52
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
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S. Diem et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx
Fig. 1. Survival by age group and treatment regimen.
were observed in the different age groups. Similar findings have been reported in another population-based study evaluating treatment of lymphoma [11]. In a comparison of lymphoma patients across varying age groups, the Italian cancer registry reported that 60 years of age was the cut-off point for the application of an adequate or standard therapeutic approach [14]. These trends in clinical practice are in sharp contrast to the findings from pivotal studies, which have demonstrated that clinically fit patients 60–80 years of age have excellent outcomes using a standard RCHOP regimen [8–10].
5.1. Patient characteristics and treatment regimens Fewer than half of the patients in our analysis were treated with a standard approach for DLBCL, defined as 6 cycles of an R-CHOP/CHOP regimen. Most of these patients were in the 60–69 year age group, where 62% (n = 30) were treated with R-CHOP/CHOP. A surprising high proportion of patients in this age group did not receive standard therapy. Most of them had limited stage DLBCL with a short course of R-CHOP/CHOP treatment with or without consolidation radiotherapy;
some were early progressive and did not complete the planned treatment. Patients 70 years and older were more likely to be treated with a non R-CHOP/CHOP approach for DLBCL, substantially altering patient outcomes (Fig. 1). This fact is worrisome as the decision for non RCHOP/CHOP treatment seems to be based on age by itself rather than on objective factors. In our study population, 75% had either no comorbidities or a low CCI score. The majority of these were in the group of patients aged 60– 69 years. The subsequent two age groups (70–79 years and N 80 years) had a similar distribution of CCI and IPI-score. Although patient and disease characteristics were not significantly different in these two age groups, patients 80 years and older were treated more often with regimens other than 6 cycles of R-CHOP/CHOP (85%; n = 23), compared to those 70–79 years of age (60%; n = 28; p b 0.001). There is evidence suggesting that older patients undergo chemotherapy less frequently, and when they do, the frequency and intensity of chemotherapy are reduced compared to younger patients. Co-morbidities and poor performance status are among the most common reasons for reducing the intensity of chemotherapy in the elderly [15]. Further compounding the problem, the bulk of the evidence upon which treatment guidelines are based is obtained in younger patients, since the elderly are rarely included in clinical trials. Therefore, the rationale for reduction of treatment intensity is often based on age by itself rather than on a systematic evaluation of performance status [16]. To this end, comprehensive geriatric assessments were developed to facilitate evaluation of a patient's general health status, and are currently used in the management of elderly cancer patients [7]. Response assessment in our study population revealed that in a large proportion of patients treated with other treatment regimens, the response remained unclear due to missing data. More patients older than 80 years (29%) wished to stop treatment compared to patients within the 70–79 year (6%) and 60–69 year (11%) age groups. This decision was mostly based on treatment-related adverse events or remained unclear. It is known that frail and vulnerable patients not only have limited physical resources, but also fewer psychological and social resources to sustain complications [17]. Nevertheless, 14 out of 60 patients older than 70 years achieved a CR using an anthracycline containing regimens as modified R-CHOP/CHOP regimens with less than 6 cycles and other treatment regimens. In the pre-rituximab era, the capacity of similar approaches to cure or at
Table 3 2-year overall survival in univariate analysis. Univariate Haz. ratio Age 60–69 70–79 80+ IPI0–2 IPI3–5 CCI 0–2 CCI N3 LDH normal LDH elevated B-symptoms No Yes Involvement Exclusively nodal Exclusively extranodal Nodal & extranodal Treatment R-CHOP/CHOP × 6 Other than R-CHOP/CHOP × 6a
p value
[95% conf. interval]
0.05 b0.001
1.00 2.32
4.34 9.84
0.004
1.30
3.92
0.02
1.15
3.63
0.003
1.50
6.78
1 (ref) 1.15
0.64
0.63
2.09
1 (ref) 1.63 1.71
0.18 0.09
0.79 0.90
3.34 3.23
1 (ref) 9.16
b0.001
3.62
23.21
1 (ref) 2.08 4.77 1 (ref) 2.26 1 (r.ef) 2.05 1 (ref) 3.19
Abbreviations: CCI (Charlson comorbidity index). IPI (International Prognostic Index). a Including 7 patients without treatment.
Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001
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Table 4 2-year overall survival in multivariable analysis. Multivariate haz. ratio Age 60–69 70–79 80+ IPI0–2 IPI3–5 CCI 0–2 CCI N3 LDH normal LDH elevated B-symptoms No Yes Involvement Exclusively nodal Exclusively extranodal Nodal & extranodal Treatment R-CHOP/CHOP × 6 Other than R-CHOP/CHOP × 6a
p value
1 (ref) 1.06 2.14 1 (ref) 1.65 1 (ref) 1.68 1 (ref) 2.14
[95% conf. interval]
0.90 0.07
0.44 0.94
2.51 4.87
0.20
0.76
3.55
0.17
0.81
3.48
0.11
0.85
5.38
1 (ref) 1.85
0.09
0.91
3.76
1.51 1.44
0.35 0.35
0.64 0.67
3.54 3.07
b0.001
2.40
18.42
|
1 (ref) 6.65
Abbreviations: CCI (Charlson comorbidity index). IPI (International Prognostic Index). a Including 7 patients without treatment.
least to prolong progression free survival has been demonstrated in a small proportion of patients [18]. Immuno-chemotherapy regimens such as mini-R-CHOP, R-bendamustine or new agents in combination with rituximab [2,19] are not only clinically active but provide a balance between toxicity and efficacy, giving patients the opportunity to remain disease free for months or even years. 5.2. Survival Median survival by age group declined dramatically with each decade of life beyond 60 years (51 months, 26 months and 8.5 months, respectively, for each subsequent decade). In the univariate analysis age over 80 years, poor IPI, CCI ≥3, elevated LDH and treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival. In the multivariable analysis only treatment regimens other than 6 cycles of R-CHOP/CHOP were significant.
Treatment of elderly patients, however, should be tailored according to the patient's comorbidities, performance status, individual wishes and therapeutic goals. The possibility of using curative R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL. Learning points • R-CHOP standard treatment should be considered for DLBCL irrespective of the patient age. • In patients eligible for R-CHOP/CHOP objective facts such as a geriatric assessment or CCI maybe more relevant than age alone. • Reasons for deviations of the standard regimen should carefully be documented in the patient file both for medical and legal reasons. Conflict of interest None.
5.3. Limitations The findings from our study are limited by the retrospective nature of the analysis. The definition of CCI is based on chart review and may not accurately capture the actual patients' comorbidities. Furthermore, the value of CCI is somewhat controversial as the diagnoses of certain comorbid conditions do not reflect the extent of the concomitant disease. The performance status as defined by the clinician is also a prognostic factor that represents the clinician's perception of a patient's functional status and is often underreported in patients' records. Furthermore patient numbers within the age and treatment groups are limited and diverge substantially, restricting statements on patient's outcome. Limited is also the conclusion on disease specific survival as death is only documented in the death certificate. 6. Conclusions In conclusion, treatment regimens other than 6 cycles of R-CHOP were significant predictors for survival in our oncology network. It seems in our study that chronological age was mainly used as the decision factor to select chemotherapy regimens other than R-CHOP/CHOP, although other clinical factors such as frailty, patient preferences and comorbidities as detected by the CCI or biological age could have been taken into consideration.
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Please cite this article as: Diem S, et al, Diffuse large B-cell lymphoma in elderly patients: A retrospective analysis, Eur J Intern Med (2014), http:// dx.doi.org/10.1016/j.ejim.2014.05.001