Original Study

What Determines Therapeutic Choices for ElderlyPatients With DLBCL? Clinical Findings of a

Multicenter Study in PortugalRute Alvarez,1 Susana Esteves,1 Sérgio Chacim,2 José Carda,3 Alexandra Mota,4

Manuel Guerreiro,5 Inês Barbosa,1 Filipa Moita,1 Adriana Teixeira,3 Jorge Coutinho,4

Fernando Príncipe,5 José Mário Mariz,2 Maria Gomes Silva1

AbstractThis study aimed to characterize Portuguese elderly patients with diffuse large B-cell lymphoma (DLBCL) andinvolved 5 hematology departments in which 378 patients older than 60 years with DLBCL were retrospectivelyanalyzed. We compared the treatment and outcomes of patients younger than 80 years and those older than 80years. Treatment choice was frequently based on age and not toxicities or comorbidities. R-CHOP (rituximab,cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) was prescribedless often in patients > 80 years but showed similar benefit in both age groups.Background: Age is a negative prognostic factor in lymphomas, and elderly patients are often undertreated becauseof toxicity concerns. The pattern of treatment in elderly patients with diffuse large B-cell lymphoma (DLBCL) in Portugalhas not been previously described. Patients and Methods: We conducted a multicenter retrospective study including378 elderly patients with DLBCL receiving alkylating agentecontaining regimens between 2003 and 2010. We comparedthe outcome of patients aged 60 to 79 years with patients > 79 years and analyzed the second group according totreatment. Results: R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin],prednisolone) was prescribed in only 60% of patients and was prescribed significantly less in patients > 79 years,despite no significant differences being found in comorbidities between the 2 age groups. Similarly, dose reductionsfrequently were instituted because of chronologic age and not always because of toxicity. When different regimenswere compared, multivariate analysis showed an independent beneficial effect of R-CHOP in treatment outcomes.Additionally, treatment with anthracyclines and rituximab predicted a better progression-free survival (PFS) and time toprogression (TTP) in patients > 79 years. Conclusion: This was the first characterization of the clinical care of elderlyPortuguese patients with DLBCL. We showed that R-CHOP is effective even in patients > 79 years, emphasizing thattreatment decisions based on age alone can compromise treatment efficacy and outcome in fit patients.

Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved.Keywords: DLBCL, Elderly, R-CHOP, Treatment

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common

Non-Hodgkin lymphoma subtype, with a rising incidence in the

1Instituto Português de Oncologia de Lisboa de Francisco Gentil, Lisbon, Portugal2Instituto Português de Oncologia do Porto de Francisco Gentil, Porto, Portugal3Hospital Universitário de Coimbra, Coimbra, Portugal4Hospital de Santo António, Porto, Portugal5Hospital São João, Porto, Portugal

Submitted: Dec 13, 2013; Revised: Jan 15, 2014; Accepted: Jan 23, 2014

Address for correspondence: Rute Alvarez, MD, Serviço de Hematologia, InstitutoPortuguês de Oncologia de Lisboa de Francisco Gentil, Rua Professor Lima Basto,1099-023, Lisboa, PortugalFax: 351-217249048; e-mail contact: rutealv@gmail.com

2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.clml.2014.01.008

Western world.1 More than half of patients are older than 60 yearsat diagnosis. Age has been found to be a negative prognostic factorfor most types of lymphomas, including DLBCL. Indeed the In-ternational Prognostic Index (IPI), which has been shown to be themost significant determinant of clinical outcomes for patientsreceiving modern treatments, includes age as an important stratifi-cation factor, with a cutoff of 60 years.2,3

Currently, it is well recognized that the treatment of patients withDLBCL should be stratified by age and prognostic factors.4 Duringthe past decade, several studies have demonstrated a clear benefit forregimens containing anthracyclines and rituximab in patients withDLBCL younger than 80 years. As a consequence, R-CHOPbecame the standard of care for this patient population.1,4-8

Clinical Lymphoma, Myeloma & Leukemia Month 2014 - 1

Therapeutic Choices for Elderly Patients With DLBCL

2 - Cli

Multiple studies have shown that patients aged 60 to 80 yearsbenefit from 6 to 8 cycles of R-CHOP administered every 14 to 21days provided that they have no contraindications for any of thedrugs in this regimen.4,9 In patients with cardiac dysfunction,anthracycline dose reductions, the use of liposomal formulations,and the substitution of other drugs (etoposide, mitoxantrone) havebeen used at the cost of reduced efficacy.9

In contrast, the treatment of very old patients is currently notwell defined. Patients older than 80 years would benefit from asystematic comprehensive geriatric assessment before treatmentdecisions are made. In fit patients, a regimen including rituximaband reduced-dose CHOP has shown an encouraging 72% responserate and 59% survival at 2 years10; however, this regimen has notbeen compared to more intensive treatments.

Nevertheless, part of the elderly population may not be receivingoptimal therapy (anthracyclines and rituximab-based treatment)because of the chronologic age factor. Physicians fear a lowertolerance to chemotherapy, even when there is no formal demon-stration of an increased risk for specific toxicities or the performanceof a global geriatric assessment showing a high comorbidity risk.11-14

This undertreatment might in some cases be responsible for theadverse prognostic impact assigned to age.11-13 Outside clinicaltrials, chemotherapy dose reductions and omission or substitution ofeffective drugs are frequently undertaken on the basis of chronologicage.15,16 These practices may vary in different countries and areprobably underreported.

The pattern of treatment of elderly patients with DLBCL inPortugal has not been previously evaluated. We hypothesize that itmay be common practice to administer suboptimal chemotherapyregimens and to reduce doses or omit (or both) anthracyclines orrituximab (or both) without contraindications or evidence oftoxicity. To evaluate the compliance with treatment guidelines andthe therapeutic approach and outcomes in these patients, we con-ducted a retrospective multicenter study aiming to obtain a de-mographic, clinical, and therapeutic characterization of Portuguesepatients with DLBCL who were older than 60 years. To evaluatethe impact of age in the clinical course of the disease, we furthercompared the outcomes of patients younger than 80 years and thoseolder than 80 years who were treated with R-CHOP, and weseparately analyzed the course of very old patients (� 80 years)receiving different chemotherapy regimens.

Patients and MethodsWe conducted a multicenter retrospective observational study

involving 5 hematology departments at university hospitals from thenorth, center and south of Portugal. The protocol was approved bythe ethics committees and institutional review boards of allparticipating centers.

All consecutive elderly patients (� 60 years old) diagnosed withDLBCL between January 2003 and January 2010 were retrospec-tively reviewed. We excluded from the analysis patients with aprevious history of indolent lymphoma, patients selected for palli-ative care alone and not receiving chemotherapy, patients treatedwith experimental drugs in the setting of clinical trials, patientsreceiving regimens not containing alkylating agents, and patientslost to follow-up. The study population included patients receiv-ing first-line treatment with alkylating agentecontaining regimens,

nical Lymphoma, Myeloma & Leukemia Month 2014

with or without anthracyclines (doxorubicin) or anthracenediones(mitoxantrone) and with or without rituximab (CHOP � R,CNOP [cyclophosphamide, mitoxantrone {Novantrone}, vincris-tine {Oncovin}, prednisone] � R, or CVP [cyclophosphamide,vincristine, prednisone] � R).

Diagnostic pathologic specimens were not centrally reviewed.Information concerning stage of disease, prognostic factors accord-ing to the IPI, Charlson comorbidity score,17 first-line therapeuticregimen, number of cycles, doses of drugs administered, prematuresuspension of treatment according to intent-to-treat (ITT), toxicity,response assessment, relapse, and survival data was retrospectivelycollected from clinical charts.

Chemotherapy regimens used were CHOP, CVP, and CNOP,with or without rituximab.18-21 Granulocyte colony-stimulatingfactor (G-CSF) was used at the discretion of the treating physi-cian, according to the common clinical practice in each center.

Relative dose delivered (RDD) was calculated for each chemo-therapy agent and defined as the actual cumulative dose adminis-tered to a patient relative to the planned cumulative dose for theintended first-line chemotherapy (the ITT dose). RDD (%) wascalculated as follows: cumulative dose administered (mg/m2)/ITTdose (mg/m2) � 100. ITT was established by the treating physician.When this information could not be readily assessed from theclinical charts, ITT was established according to the stage ofdisease: stages I and II, 4 cycles of chemotherapy þ radiotherapyor 6 cycles of chemotherapy; stages III and IV, 6 to 8 cycles ofchemotherapy.

The average relative dose delivered (ARDD) for each regimen wasthen calculated (as a percentage) by averaging the RDDs of cyclo-phosphamide and doxorubicin for R � CHOP regimens and theRDDs of cyclophosphamide and mitoxantrone for R � CNOPregimens. For R � CVP regimens, we considered only the RDD ofcyclophosphamide.13

The efficacy outcomes evaluated were overall and completeresponse rate, time to progression (TTP), progression-free survival(PFS), overall survival (OS) and premature suspension of chemo-therapy because of toxicity, according to ITT. Assessment ofresponse and outcomes were defined according to the Chesoncriteria.22 Time-to-event end points were analyzed using Kaplan-Meier methodology. The log-rank test was used to compare sur-vival curves, including the impact of ARDD in time-to-eventoutcomes within the therapeutic groups. A multivariate analysis(Cox proportional hazards regression) was used to assess the effectof treatment regimens on OS and PFS, taking into account thecovariates specified in advance: IPI risk group, age, and Charlsoncomorbidity score. Categorical data were compared using the c2

test or Fisher exact test, as appropriate. Group comparisons forquantitative variables were based on the Mann-Whitney testbecause these did not follow a normal distribution. All significancetests were 2-sided and were not adjusted for multiple comparisons.P ¼ .05 was considered the limit of significance. Results werecomputed using R software.23

ResultsPatients and Treatment Characterization

During the 7-year period of the study, 475 patients with DLBCLwere identified in the 5 centers. Ninety-seven patients were

Rute Alvarez et al

excluded for the reasons depicted in Figure 1. After applying in-clusion and exclusion criteria, 378 elderly patients with newlydiagnosed DLBCL were retrospectively analyzed.

Patient characteristics are summarized in Table 1. Median agewas 72 years, 56% were women, 60% had advanced-stage diseaseat presentation, and 56% had a Charlson comorbidity indexscore < 3. When comparing baseline characteristics between pa-tients younger or older than 79 years, no significant differenceswere found in stage at diagnosis, IPI risk, Charlson comorbidityindex score, cardiovascular or respiratory comorbidities, albuminlevel, or performance status. However, when we compared base-line characteristics in the different treatment subgroups, weobserved that patients with Charlson comorbidity index score > 2and Eastern Cooperative Oncology Group performance status > 1received R-CHOP less frequently (P ¼ .008 and P < .001,respectively). The same association was found for preexistingcardiovascular disease (P ¼ .020). Nevertheless, 13% of patientswithout any history of heart disease did not receive doxorubicin.

Although baseline cytopenia was reported in 48% of patients,most cases (86%) were attributed to anemia, and only 35% of anemicpatients had hemoglobin levels< 10 g/dL. Leukocytes< 1000/mL orplatelets < 100 000/mL, or both, which could limit the adminis-tration of chemotherapy, were present in only 1% and 4% of pa-tients, respectively.

Despite some heterogeneity in the choice of treatment amongcenters, there was a sustained increase in R-CHOP prescription overtime, from 24% in 2003% to 81% in 2009 (data not shown).

Table 2 depicts the treatments administered by age group.R-CHOP was prescribed less in patients > 79 years compared withthe younger group (33% vs. 65%, respectively; P < .001). Doses ofchemotherapy were available in 65% of cases (n ¼ 246). Whenanalyzing the individual chemotherapy agents administered,vincristine was found to be the most frequently reduced drug, bothin the first and subsequent cycles. Seventeen percent of patients hadat least 1 drug reduced in their first cycle. Dose reductions weremainly because of age (34%) and comorbidities (19%). In subse-quent cycles, the proportion of patients with dose reductionsincreased to 39%, and age appeared as the commonest causetogether with neurologic toxicity (22% each). Other reasons fordose reductions in subsequent cycles were heart disease (4%), renal

Figure 1 Patient Flow Diagram

failure (2%), diabetes (1%), and other medical conditions (10%). In39% of cases, a reason for dose reduction was not identified. Dosereductions both in first and subsequent cycles were overall morefrequent in patients � 80 years for R-CHOP and noneR-CHOPgroups (P ¼ .005 and P < .001, respectively). Additionally, agegroup differences regarding the number of cycles and ARDD weresignificant only in the R-CHOPetreated patients.

The distribution of the relative frequencies of ARDD by age andtreatment group is shown in Figure 2. Seventy percent of patientsaged 60 to 79 years (Fig. 2B) and 70% of patients treated with R-CHOP (Fig. 2C) received between 90% and 105% ARDD. In veryelderly and noneR-CHOP treatment subgroups, the percentage ofpatients receiving 90% to 105% ARDD decreased to 43% and55%, respectively (Fig. 2, A, and D).

Overall, G-CSF was administered to 179 patients (47%), with nosignificant differences seen between treatment (R-CHOP andnoneR-CHOP) or age groups.

Twenty-three percent of patients interrupted chemotherapyprematurely. The most commonly reported causes were death(29%) and toxicity (22%). In one third of cases, the reason for thepremature withdrawal of treatment could not be established.Overall, the premature interruption of treatment was more frequentin patients > 79 years (39% vs. 19%; P ¼ .001).

The best responses were observed with R-CHOP (92% overallresponse rate; 80% complete response [CR]). R-CNOP was inferiorto R-CHOP (CR rates 71% vs. 80%, respectively) and CNOP wasinferior to CHOP (CR rates 48% vs. 62%, respectively), althoughthe differences did not reach statistical significance. Only 20 pa-tients received CVP � R and attained a low response rate (CR,35%). Patients who interrupted treatment prematurely had lowerCR rates than did those who completed treatment (49% vs. 79%,respectively; P < .001). Globally, dose reductions did not seem toaffect CR in this very heterogeneously treated population (P ¼ .9).

Median follow-up time for patients who were alive at the last visitwas 3.6 years. As can be seen in Table 3, there were 149 deaths. Themajority of deaths were related to lymphoma progression (58%);23% were caused by toxicity and 14% resulted from other causes.Causes of death for patients > 80 years, namely, toxicity and diseaseprogression, were similar to the causes in the overall sample. OS ofthe whole cohort was 63% at 3 years (95% confidence interval [CI],58%-69%) and depended on the IPI risk (84% in the low-riskgroups and 50% in the high-risk groups). The observed 3-yearPFS was 56% (95% CI, 51%-62%) with a median OS and PFSof 6.5 and 4.8 years, respectively. As can be seen in Table 4,multivariate analysis showed a clear benefit for R-CHOP comparedwith other treatments in the reduction of the hazard of death whencontrolling for the IPI risk group, age, and Charlson comorbidityindex score (hazard ratio, 0.58; 95% CI, 0.40-0.83). The R-CHOPregimen also had a beneficial effect on PFS (hazard ratio, 0.51; 95%CI, 0.36-0.72) when controlling for the same covariates.

Clinical Outcome of Patients According to Age andTreatment

We wanted to compare treatment outcomes with R-CHOP inpatients younger than 79 years and those older than 79 years. Twohundred twenty-three patients received R-CHOP. As can be seen inTable 5, 90% of those (n ¼ 200) were 60 to 79 years old and only

Clinical Lymphoma, Myeloma & Leukemia Month 2014 - 3

Table 1 Clinical and Demographic Patient Characteristics at Diagnosis

VariableAll Patients(n [ 378)

Age Groups Treatment Groups

60-79 Years(n [ 309)

‡80 Years(n [ 69) P Value

R-CHOP(n [ 223)

Other(n [ 155) P Value

Age (years)

Median (range) 72 (60-92) 71 (60-79) 82 (80-92) <.001 71 (60-86) 75 (60-92) <.001

Sex, n (%)

Male 168 (44) 147 (48) 21 (30) .014 108 (48) 60 (39) .061

Female 210 (56) 162 (52) 48 (70) 115 (52) 95 (61)

Comorbidities, n (%)

Cardiovascular 52 (14) 39 (13) 13 (19) .261 26 (12) 26 (17) .020

Congestive heart failure 13 (3) 10 (3) 3 (4) 4 (2) 9 (6)

Arrhythmias 17 (5) 15 (5) 2 (3) 8 (4) 9 (6)

Ischemic heart disease 22 (6) 14 (5) 8 (12) 14 (6) 8 (5)

Respiratory 19 (5) 14 (5) 5 (7) .358 9 (4) 10 (6) .259

Charlson Comorbidity Index, n (%) (n [ 363)

<3 202 (56) 170 (57) 32 (48) .247 133 (61) 69 (47) .008

�3 161 (44) 127 (43) 34 (52) 84 (39) 77 (53)

ECOG PS, n (%) (n [ 270)

0-1 221 (82) 190 (84) 31 (72) .070 143 (89) 78 (72) <.001

�2 49 (18) 37 (16) 12 (28) 18 (11) 31 (28)

Stage, n (%) (n [ 376)

I/II 152 (40) 119 (39) 33 (49) .171 81 (36) 71 (46) .050

III/IV 224 (60) 189 (61) 35 (51) 142 (64) 82 (54)

B Symptoms, n (%) (n [ 346)

Absent 208 (60) 163 (58) 45 (68) .178 117 (58) 91 (63) .323

Present 138 (40) 117 (42) 21 (32) 85 (42) 53 (37)

Extranodal Involvement, n (%) (n [ 375)

Nodal disease 119 (32) 98 (32) 21 (30) .963 75 (34) 44 (29) .100

Nodal and extranodal disease 151 (40) 123 (40) 28 (41) 94 (42) 47 (37)

Extranodal disease 105 (28) 85 (28) 20 (29) .948 53 (24) 52 (34) .915

No. extranodal sites, median (range) 1 (1-9) 1 (1-9) 1 (1-4) 1 (1-5) 1 (1-9)

More than 1 extranodal site 77 (21) 63 (21) 14 (20) 45 (20) 32 (21)

Bulky Disease (‡ 7.5 cm), n (%) (n [ 310)

Yes 93 (30) 72 (38) 21 (37) .277 64 (33) 29 (25) .158

No 217 (70) 181 (72) 36 (63) 131 (67) 86 (75)

IPI Risk Group, n (%) (n [ 354)

1 49 (14) 38 (13) 11 (19) .651 28 (13) 21 (15) .339

2 111 (31) 92 (31) 19 (32) 63 (30) 48 (34)

3 110 (31) 94 (32) 16 (27) 74 (35) 36 (26)

4/5 84 (24) 71 (24) 13 (22) 48 (23) 36 (26)

Serum Albumin, n (%) (n [ 307)

�3.5 g/dL 90 (29) 69 (28) 21 (36) .239 49 (26) 41 (35) .071

>3.5 g/dL 217 (71) 179 (72) 38 (64) 142 (74) 75 (65)

Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IPI ¼ International Prognostic Index; R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin),vincristine (Oncovin), prednisolone.

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10% (n ¼ 23) were older than 79 years. Patient characteristics inthe 2 age groups, namely, the IPI risk distribution, Charlson co-morbidity index, performance status, and serum albumin levels, didnot differ significantly except for cardiac comorbidity, with morefrequent ischemic heart disease in the most elderly subgroup(P ¼ .029). Both age groups seemed to benefit from R-CHOP

nical Lymphoma, Myeloma & Leukemia Month 2014

treatment. Three-year PFS and OS of R-CHOPetreated patientswere 65% (95% CI, 58%-72%) and 72% (95% CI, 66%-78%),respectively. Overall response rate and CR rate did not differ be-tween patients who were younger than 79 years and those who wereolder (92% vs. 96%; P ¼ 1.00 and 80% vs. 77%; P ¼ .68,respectively). Similarly, we could not demonstrate a significant

Table 2 Treatment Characterization

Variable All Patients (n [ 378) 60-79 Years (n [ 309) >79 Years (n [ 69) P ValueFirst-Line Treatment Regimen, n (%)

R-CHOP 223 (59) 200 (65) 23 (33) <.001

NoneR-CHOP 155 (41) 109 (35) 46 (67)

CHOP 70 (19) 58 (19) 12 (17)

R-CNOP 32 (8) 19 (6) 13 (19)

CNOP 25 (7) 19 (6) 6 (9)

R-CVP 7 (2) 2 (1) 5 (7)

CVP 21 (6) 11 (4) 10 (15)

Number of Cycles, median (IQR)

R-CHOP 6 (6-8) 6 (6-8) 6 (5-6) .007

NoneR-CHOP 6 (4-8) 6 (4-8) 5.5 (3-6) .286

Early Termination of Therapy, n (%)

R-CHOP 34 (16) 27 (14) 7 (30) .062

NoneR-CHOP 47 (35) 28 (30) 19 (44) .108

Dose Reduction in Cycle 1, n (%)

R-CHOP 29 (13) 21 (11) 8 (35) .005

NoneR-CHOP 29 (24) 11 (13) 18 (46) <.001

Dose Reduction After Cycle 1, n (%)

R-CHOP 61 (38) 50 (35) 11 (73) .005

NoneR-CHOP 35 (41) 16 (28) 19 (70) <.001

ARDD %, median (IQR)

R-CHOP 100 (89-100) 100 (100-100) 83 (45-100) .0008

NoneR-CHOP 97 (68-100) 98 (79-100) 83 (45-100) .146

Use of G-CSF, n (%)

R-CHOP 100 (48) 89 (48) 11 (48) .983

NoneR-CHOP 79 (52) 60 (56) 19 (43) .149

Abbreviations: ARDD ¼ average relative dose delivered; CVP ¼ cyclophosphamide, vincristine, prednisone; G-CSF ¼ growth colony-stimulating factor; IRQ ¼ interquartile range (quartile 1 to quartile3); R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisolone; R-CNOP ¼ cyclophosphamide, mitoxantrone (Novantrone), vincristine (Oncovin),prednisone.

Rute Alvarez et al

difference in TTP (Fig. 3A), PFS (Fig. 3B), and OS between pa-tients younger than 79 years and those older than 79 years, despitedose reductions and premature treatment interruption being morefrequent in the most elderly group. However, in the R-CHOPetreated patients, the global impact of the chemotherapy dosesmeasured by ARDD was evident, with a significant benefit in 3-yearPFS (Fig. 3D) and OS (Fig. 3C) for patients receiving more than85% average relative doses when compared with patients treatedwith lower doses (PFS, 73%; 95% CI, 66%-82% and 32%; 95%CI, 19%-54% respectively, and OS, 79%; 95% CI, 72%-87% and6%; 95% CI, 31%-66%, respectively). It should be noted thatsimilar results were found in the noneR-CHOP group.

We especially focused on patients> 79 years. In our cohort, therewere only 69 patients in this age group (18% of the global sample)who underwent treatment with CHOP� R, CNOP� R, or CVP�R. In this very elderly population, 78% of patients received anthra-cyclines/anthracenediones (AC): doxorubicin, n ¼ 35 and mitox-antrone, n ¼ 19; 59% received rituximab (n ¼ 41). Patients treatedwith or without AC and with or without rituximab were comparableregarding IPI risk groups (P ¼ .46 and P ¼ .61, respectively) andcomorbidity index (P ¼ .53 and P ¼ .62, respectively). Interestingly,we observed that patients treated with rituximab had more frequent

dose reductions both in the first (57% vs. 19%; P ¼ .013) andsubsequent cycles (82% vs. 33%; P ¼ .0092) when compared withpatients not receiving the antibody.

CR rates were higher in the AC- and rituximab-treated subgroups(67% in both) compared with the non-AC and nonrituximabgroups (33% and 50%, respectively), although the differences werenot statistically significant. Patients receiving AC had longer TTP(median not reached vs. 9 months) (Fig. 4A), PFS (median 30 vs. 7months; P ¼ .057) (not shown), and OS (median, 35 vs. 8 months)(Fig. 4C) when compared with patients not receiving these drugs.Treatment with rituximab also increased both TTP (median notreached vs. 59 months) (Fig. 4B), PFS (23 months vs. 12 months;P ¼ .29) (not shown), and OS (35 vs. 19 months) (Fig. 4D).Median OS observed in these very elderly patients was 35 months.

DiscussionWe performed a multicenter characterization of the clinical

care of 378 elderly patients with DLBCL treated with alkylatingagentecontaining regimens. In this cohort with a median age of72 years and a predominance of advanced-stage disease, patientswere treated heterogeneously. Responses were obtained in thevast majority of patients (89%) with a variety of treatments,

Clinical Lymphoma, Myeloma & Leukemia Month 2014 - 5

Figure 2 Relative Frequency Distribution of Average Relative Dose Delivered (ARDD) (%). (A) Patients Older Than 79 Years.(B) Patients 60 to 79 Years. (C) Patients Treated With R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin[Hydroxydaunorubicin], Vincristine [Oncovin], Prednisolone). (D) Patients Treated With NoneR-CHOP Regimens

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including regimens not containing anthracyclines or rituximab.As expected, overall and complete response rates were higher withR-CHOP (92% and 80%, respectively) and comparable to pre-viously published results.7,8,24 Prolonged disease control, asmeasured by PFS and OS in patients receiving R-CHOP, wasalso similar to that described in other series with the same riskprofile.18,19,25

We registered some delay in the adoption of R-CHOP as stan-dard treatment for DLBCL. In a population in which a low numberof patients had significant heart disease (14%) and with a Charlsoncomorbidity index that was predominantly low, only 60% of pa-tients were treated with R-CHOP. This cannot be explained by thehematologic status at diagnosis, because although mild anemia waspresent in the majority of patients, moderate and severe cytopeniaoccurred in < 5%. In addition, patients older than 79 years receivedR-CHOP less frequently (33% vs. 65%; P < .001) and had morefirst-cycle dose reductions than did the younger group. However,

Table 3 Causes of Death

Primary Cause of DeathAll Patients

N (%)Patients ‡80 Years

n (%)

Progressive disease 86 (58) 19 (56)

Toxicity 35 (23) 9 (26)

Other cause 21 (14) 4 (12)

Unknown 7 (5) 2 (6)

Total deaths 149 (100) 34 (100)

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this age group had a performance status, albumin levels, Charlsoncomorbidity index, and respiratory comorbidities similar to those inyounger patients. The small differences observed between agegroups suggests that treatment decisions were frequently made onthe basis of chronologic age and reflect physicians’ fears ofchemotherapy toxicity in the elderly. In our study, chronologic agealso arose as a determining factor in the decision to reduce dosesboth in first and subsequent cycles of chemotherapy.14,26,27 In thisretrospective analysis, no systematic evaluation of activities of dailyliving through a standardized scale was used. Nevertheless, webelieve that the information gathered on the previously mentionedprognostic factors can be considered a reliable indicator of patientfitness and validates the conclusion that elderly fit patients couldbenefit from more aggressive therapy without excessive risks. Otherauthors have shown that activities of daily living are not indepen-dent predictors of prognosis and emphasized the importance ofrespiratory comorbidity and albumin levels.28,29

Interestingly, even acknowledging that our global population washeterogeneously treated and did not always receive standard treat-ment, we observed a PFS of 56% and an OS of 63% at 3 years,similar to previously published results in more homogeneouslytreated patients.6 Mortality mainly resulted from lymphoma pro-gression (57%). It should be emphasized that patients > 79 yearshad a toxicity death rate similar to that of the overall sample. Thesefindings may be caused by uncontrolled factors related to theeligibility criteria for this study (patients not candidates forchemotherapy treatment and those receiving palliative care wereexcluded) but may also reflect improved patient supportive care in

Table 4 Multivariate Analysis for Treatment Outcomes Con-trolling for Age, Charlson Comorbidity Index and IPI

Variable Hazard Ratio95% Confidence

IntervalOverall Survival

First-line treatment

R-CHOP versus other 0.58 0.40-0.83

IPI risk category

Intermediate-low versus low 1.98 0.99-3.98

High intermediate-high versus low 2.47 1.27-4.81

Age

Per additional year 1.03 1.00-1.05

Charlson comorbidity index

�3 versus <3 1.19 0.67-1.30

Progression-Free Survival

First-line treatment

R-CHOP versus other 0.51 0.36-0.72

IPI risk category

Intermediate-low versus low 1.74 0.92-3.29

High intermediate-high versus low 2.52 1.37-4.63

Age

Per additional year 1.01 0.99-1.04

Charlson comorbidity index

�3 versus <3 0.93 0.67-1.30

Abbreviations: IPI ¼ International Prognostic Score; R-CHOP ¼ rituximab, cyclophosphamide,doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisolone.

Table 5 Characterization of Patients Treated With R-CHOP(n [ 223)

Variable60-79 Years(n [ 200)

>79 years(n [ 23)

PValue

IPI Risk Group, n (%) (n [ 213)

1 26 (13) 2 (11)

2 57 (29) 6 (32)

3 66 (34) 8 (42) .829

4/5 45 (23) 3 (16)

IPI Risk Group, n (%) (n [ 160)

0 17 (11) 0 .568

1 56 (38) 4 (33)

2 64 (43) 7 (58)

3 11 (7) 1 (8)

Cardiac Comorbidity, n (%)(n [ 212)

No 169 (89) 17 (74) .029

Congestive heart failure 4 (2) 0

Arrhythmia 7 (4) 1 (4)

Ischemia 9 (5) 5 (22)

Respiratory Comorbidity, n (%)(n [ 218)

No 188 (96) 21 (91) .243

Yes 7 (4) 2 (9)

Charlson Comorbidity Index, n(%)(n [ 217)

<3 121 (62) 12 (52) .342

�3 73 (38) 11 (48)

ECOG PS, n (%) (n [ 161)

0-1 132 (89) 11 (92) 1.000

�2 17 (11) 1 (8)

Serum Albumin, n (%) (n [ 191)

�3.5 g/dL 41 (24) 8 (36) .221

>3.5 g/dL 128 (76) 14 (64)

Response to Treatment (n [ 215)

Complete response 155 (80%) 17 (77%) .688

Partial response 22 (11%) 4 (18%)

No response/disease progression 16 (8%) 1 (5%)

Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status;IPI ¼ International Prognostic Index; R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin(hydroxydaunorubicin), vincristine (Oncovin), prednisolone.

Rute Alvarez et al

recent years and strengthen the need for objective comorbidityevaluation before treatment decisions are made. It should be notedthat in common with other prospective series,6,24 myeloid growthfactors were not used in half of our patients.

Despite being the most frequently used regimen, R-CHOP wasprescribed significantly less in patients > 79 years. Not surprisingly,it was associated with the best response rates and disease control.Survival, as shown in multivariate analysis, was worse in patients notreceiving R-CHOP regardless of age, IPI, and Charlson comorbidityindex.5,7,26 It should be emphasized that patients treated withCHOP (with or without rituximab) received cumulative doses closeto the intended ones. This was not the case for patients treated withthe other regimens, probably revealing that those were mostly usedwithout curative intent.

Vincristine was undoubtedly the drug most frequently reduced,which is understandable because of the high risk of neurotoxicity inthe elderly. The importance of chemotherapy cumulative doses andintensities for treatment efficacy is well known,16,24,30-32 andregimen modifications and dose adjustments have been shown tohave a negative impact on disease control and survival in elderlypatients with DLBCL.9,13,14,28-30,33 Although more frequent pre-mature suspension of therapy and individual drug dose reductionsin patients older than 79 years occurred in our R-CHOPetreatedcohort, we could not demonstrate an adverse impact in quality ofresponse and duration of benefit. However, when analyzing theoutcomes based on ARDD, both R-CHOP- and noneR-CHOPetreated patients receiving ARDD � 85% had a significantbenefit in 3-year PFS and OS.

We still could not demonstrate significant differences in TTP,PFS, and OS between patients 60 to 79 years old and those olderthan 79 years despite more frequent dose reductions and prematuretreatment interruption in the most elderly group, which may berelated to the retrospective nature of the data and patient selection.Our results are in line with the ones published by Peyrade et al,10

who used a reduced-dose R-CHOP regimen with favorable out-comes at 2 years (OS, 72%; PFS, 59%) and with Trebouet et al,34

who demonstrated that despite the problems associated with frailtyand comorbidities, very elderly patients (> 90 years) with aggressivelymphoma benefit from treatment.

We hypothesize that when the maximum tolerated treatmentwith best supportive care is administered, disease control translates

Clinical Lymphoma, Myeloma & Leukemia Month 2014 - 7

Figure 3 Clinical Outcomes in Patients Treated With R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin [Hydroxydaunorubicin],Vincristine [Oncovin], Prednisolone). (A) Time to Progression (TTP). (B) Progression-free Survival (PFS) by age Group.(C) Overall Survival (OS). (D) PFS by Average Relative Dose Delivered (ARDD %)

Figure 4 Clinical Outcomes in Very Elderly Patients (‡ 80 years) According to First-line Treatment. (A) Time to Progression(TTP) According to Treatment With Regimens Containing Anthracycline/Anthracenediones (AC). (B) TTP According toTreatment Regimens Containing Rituximab (Rtx). (C) Overall Survival (OS) According to Treatment With RegimensContaining Anthracycline/Anthracenediones. (D) OS According to Treatment With Regimens Containing Rituximab

Therapeutic Choices for Elderly Patients With DLBCL

8 - Clinical Lymphoma, Myeloma & Leukemia Month 2014

Rute Alvarez et al

into a measurable benefit for very elderly patients; ongoing trials inthis patient population and longer follow-up may clarify this issue inthe future.1 Recently, the European Society for Medical Oncologyguidelines suggested R-miniCHOP as the new standard of carefor patients with DLBCL older than 80 years without cardiacdysfunction.4

In the most elderly subgroup, we compared the outcome of pa-tients treated with AC and those treated without AC and with andwithout rituximab. We observed that the CR rate doubled in theAC-treated group. Median TTP was also significantly better forpatients receiving AC, and a trend for a better PFS was also seen inthis group (30 months and 7 months, respectively, P ¼ .056).Rituximab-treated patients also showed a trend for a better CR rateand longer TTP and PFS. The fact that this difference did notreach statistical significance may be explained not only by thelow number of patients in this subgroup (n ¼ 69) but also becauseoctogenarians treated with rituximab received considerably lesschemotherapy than those not treated with the antibody. This sug-gests the use of rituximab as a chemotherapy “saver” in this settingand explains the unexpected limited benefit of the association.

ConclusionAlthough limited by its retrospective nature, this is the first

characterization of the clinical care of elderly patients with DLBCL inPortugal in a multicenter setting. We observed an impact of chro-nologic age in therapeutic decisions that was not always supported byobjective evidence of organ dysfunction or treatment toxicity. Theoutcomes observed with R-CHOP are in agreement with publishedresults,18,19 and our study has shown that R-CHOP is as effective inthe group > 79 years as in patients aged 60 to 79 years. This suggeststhat treatment decisions based on the age factor alone can compro-mise treatment efficacy and outcome in otherwise fit patients.

Clinical Practice Points

� This manuscript is the first characterization of the clinical careof elderly Diffuse large B-cell Lymphoma (DLBCL) patients in amulticenter setting in Portugal.

� We analysed the course of 378 elderly DLBCL patients treatedwith alkylating-containing regimens, with and without anthra-cyclines and/or rituximab. We showed that R-CHOP was themost effective regimen and was equally beneficial in the two agegroups: 60-79 and � 80 years old. We also have shown thatchemotherapy choice, in patients above 79 years old, was frequentlybased on chronological age alone and not on comorbidities.

� Treatment efficacy can be seriously compromised due to un-dertreatment based on age alone. Chemotherapy choice in theelderly should be made in accordance with comorbidities andgeriatric assessments.

DisclosureThe authors have stated that they have no conflicts of interest.

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