1
ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.788176
Correspondence: Dr. Francesco Merli, MD, Hematology Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifi co, Viale Risorgimento, 80 – 42123 Reggio Emilia, Italy. Tel: ⫹ 39-0522-296618. Fax: ⫹ 39-0522-295655. E-mail: merli.francesco@asmn.re.it
Received 24 July 2012 ; revised 8 February 2013 ; accepted 17 March 2013
ORIGINAL ARTICLE: CLINICAL
Outcome of frail elderly patients with diff use large B-cell lymphoma
prospectively identifi ed by Comprehensive Geriatric Assessment:
results from a study of the Fondazione Italiana Linfomi
Francesco Merli
1, Stefano Luminari
2, Giuseppe Rossi
3, Caterina Mammi
1, Luigi Marcheselli
2, Angela Ferrari
1,
Michele Spina
4, Alessandra Tucci
3, Caterina Stelitano
5, Isabella Capodanno
1, Alberto Fragasso
6, Luca Baldini
7,
Chiara Bottelli
3, Elisa Montechiarello
5, Stefano Fogazzi
3, Cinzia Lamorgese
3, Lara Cavalli
3& Massimo Federico
2;
for the Fondazione Italiana Linfomi
1 Hematology Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifi co, Reggio Emilia, Italy,
2 Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy, 3 Division of Hematology,
Spedali Civili, Brescia, Italy, 4 Division of Medical Oncology A, National Cancer Institute, Aviano, Italy, 5 Hematology Department,
Azienda Ospedaliera “ Bianchi, Melacrino, Morelli ” , Reggio Calabria, Italy, 6 Department of Internal Medicine, Hematology Unit,
Ospedale Madonna delle Grazie, Matera, Italy and 7 Hematology Unit 1, IRCCS Foundation, Ca Granda Hospital “ Maggiore
Policlinico ” , University of Milan, Milan, Italy
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most fre-quent subtype of non-Hodgkin lymphoma (NHL) and frequently affects elderly people [1]. With the use of
immunochemotherapy, elderly fit patients can be safely treated with a 50 – 60% chance of cure and with manage-able toxicity [2 – 4]. In most elderly patients, however, the choice of treatment is a challenge for clinicians, mainly due to the presence of one or more comorbid conditions and/or functional status impairments. In contrast to fit patients, the chance of cure for frail patients with DLBCL is poor [5,6]. This is a result of the negative effect of con-comitant diseases on patients ’ outcome or treatment morbidity and the lack of standard therapies. Most frail patients are frequently treated with modified versions of standard regimens, reducing doses of drugs, or using less toxic drugs [7 – 9].
Although some tools are available to identify fi t versus frail patients among the elderly population, published clinical trials usually leave the decision of whether or not to include a patient or to prescribe full-dose chemotherapy to the clinician ’ s judgment. Th e Comprehensive Geriatric Assessment (CGA) is a formal evaluation of an older indi-vidual ’ s functional status, comorbid medical conditions, psychological state, social support and nutritional status and a review of the patient ’ s medications. Recently the CGA has been proposed as an objective tool to support medical decisions [10 – 13].
In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program to investigate initial treatment for elderly patients with DLBCL. Before starting treat-ment all patients had to complete the CGA assesstreat-ment. Fit patients could be treated with full-dose chemotherapy
Abstract
In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program for investigating initial treatment of frail elderly patients with diff use large B-cell lymphoma (DLBCL) identifi ed by Comprehensive Geriatric Assessment (CGA). From 2003 to 2006, 334 elderly patients underwent CGA assessment, and 99 patients were classifi ed as frail. Frail patients had a median age of 78 years, stage III – IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) of 2 – 3 in 53%. Treatment consisted of several diff erent regimens according to physician discretion. After a median follow-up of 36 months, 5-year overall survival (OS) was 28%. In multivariate analysis, aaIPI 2 – 3 ( p ⴝ 0.005) and the presence of respiratory comorbidity ( p ⴝ 0.044) were
the only factors that showed independent correlation with OS. Frail patients had a poorer outcome compared with fi t patients also if they were treated with rituximab-containing combination chemotherapy (hazard ratio 2.37, 95% confi dence interval 1.48 – 3.78; p ⬍ 0.001). CGA is a valid tool to prospectively identify frail subjects among elderly patients with DLBCL.
Keywords: Diff use large B-cell lymphoma (DLBCL) ,
elderly patients , frail patients , Comprehensive Geriatric Assessment (CGA) , chemotherapy , rituximab
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and were enrolled in the NCT01148446 randomized trial that compared R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) versus R-miniCEOP (rituximab, cyclophosphamide, epirubicin, vinblastine, prednisone). Frail patients were treated according to physi-cian ’ s choice. Results of the phase III study were recently published, and showed no diff erence in outcome between the study arms [14]. Here we describe the results achieved in the group of frail patients.
Materials and methods
Th e trial was conducted in compliance with the Declaration of Helsinki. It was also accepted by the appropriate Research Ethics Committee and required each patient to give written informed consent prior to registration. Th e randomized part of the study was registered on the Clinicaltrial.gov website and assigned the code NCT01148446.
Previously untreated patients older than 65 years of age, with a histologically confirmed diagnosis of DLBCL, fol-licular lymphoma grade IIIb, clinical Ann Arbor stage II – IV disease and Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 3 were eligible. All patients were required to undergo a CGA that included evaluation of the following parameters: (1) Activities of Daily Living (ADL), that is, loss of any activity, including personal hygiene and grooming, dressing and undressing, self-feeding, functional transfer, bowel and bladder management and ambulation; (2) comorbidity score according to the Cumu-lative Illness Rating Score for Geriatrics (CIRS-G) [15] and evaluated in all organs/systems as detailed by Bal-ducci and Beghe [10 – 12]. Patients were classified as “ fit ” if they were younger than 80 years and had an ADL score of 6, fewer than three grade 3 CIRS-G comorbidities and no grade 4 comorbidities (hematological comorbidities were not investigated), and none of the criteria defining the presence of geriatric syndrome. Patients older than 80 years were classified as frail; moreover, patients younger than 80 years who were not fit according to one or more of the previous features were also considered as frail. Moreover, Instrumental Activities of Daily Living (IADL) were also tested for each patient; IADL included patient ability to use the telephone, shop, cook, do housework or laundry, use private or public transport, comply with medical prescriptions and use money. The IADL score did not affect the definition of patient status. Patients were also excluded if affected by a concomitant cancer other than lymphoma, another cancer diagnosed within 5 years before the lymphoma diagnosis, or if they were positive for human immunodeficiency virus (HIV).
Fit patients were enrolled in a randomized trial compar-ing two diff erent chemoimmunotherapy regimens (R-CHOP vs. R-miniCEOP), while frail patients were assigned to treat-ment according to their physician ’ s discretion.
Th e main objectives of the present study were to describe the outcome of frail patients, to evaluate which among the CGA components could help better identify patients at a higher risk of death and to compare the outcomes of fi t versus frail patients.
Th e principal study endpoint was overall survival (OS), which was calculated for all patients as the time from study registration to death from any cause, or last clinical observa-tion. OS was estimated using the Kaplan – Meier method and compared using the log-rank test. Additional study endpoints were relative survival (RS) and standardized mortality rate (SMR). Relative survival for healthy subjects was calculated from life tables of the Italian population (source ISTAT, Isti-tuto Italiano di Statistica; http://demo.istat.it/) for a cohort of patients matched by age, gender and calendar time. Rela-tive survival was estimated using the Ederer II method with a complete cohort approach [16]. Th e SMR was calculated from the ratio between the observed and expected number of deaths. Th e expected number of deaths was obtained using as a reference the mortality table of the Italian population extracted from the ISTAT database (http://demo.istat.it/), matched with demographic characteristics of the study pop-ulation. Ninety-fi ve percent confi dence intervals (95% CIs) were based on the assumption that the observed numbers of deaths were distributed as Poisson variables. SMR was mod-eled by means of Poisson regression, where the exposure was the expected number of deaths.
All statistical analyses were two-sided and were performed using Stata 10/SE software (StataCorp, College Station, TX). Proportions were compared using Fisher ’ s exact test or χ 2
test, when appropriate, and continuous variables using the Mann – Whitney test. Multivariable analysis was performed using the Cox proportional hazards model. No sample size was planned in advance.
Results
From 2003 to 2006, 334 elderly patients with DLBCL were prospectively registered in the study and underwent CGA assessment; seven patients were not included due to lack of data, 228 were considered fi t and 224 of these were fully eligible for the randomized trial. According to CGA, the remaining 99 patients were classifi ed as frail. Clinical data were available for 94 frail patients.
Clinical characteristics, treatment and oucome of frail patients
Th e frail patients had a median age of 78 years (range 65 – 93), stage III – IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) [17] of 2 – 3 in 53%. A list of clinical characteristics of frail and fi t patients is reported in Table I. Reasons for considering patients as frail included age greater than 80 years (34%), comorbidity (54%), impaired ADL (32%) and geriatric syndrome (25%). Overall results of CIRS-G, ADL, assessment of geriatric syndrome and IADL were avail-able in 90%, 86%, 81% and 53% of the cases, respectively. Th e most common comorbidities were hypertension (34%), car-diac disease (31%), diabetes (16%), respiratory disease (15%) and musculoskeletal disorders (15%). Th e most frequent inabilities present were personal hygiene and grooming (28%), dressing and undressing (23%), functional transfer (17%) and self-feeding (17%); among the recorded geriatric syndrome items the most frequent were depression (16%) and incontinence (14%) (Table II).
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Seventy-three patients were treated with polychemother-apy regimens that consisted of several diff erent therapies. In the remaining 21 patients treatment consisted of mono-chemotherapy, radiotherapy or palliation. Interestingly, 71% of patients received doxorubicin-containing regimens. Over-all, 31 patients were treated with anthracycline-based poly-chemotherapy combined with rituximab (33% of all patients) and fi ve were treated with rituximab and polychemotherapy regimens without anthracyclines (5%) (Table III). Seventy four percent and 66% of patients younger and older than 80 years, respectively, were treated with anthracyclines ( p ⫽ 0.472). Overall, rituximab was administered in 48% and 22% of patients younger and older than 80 years, respectively ( p ⫽ 0.015).
At the time of the last follow-up, 62 patients had died among the frail patients; of these, 35 were as a result of lymphoma progression, 13 due to treatment-related com-plications/toxicity (22% of deaths, 18% of treated patients) and 14 due to diff erent causes not related to initial treatment and/or lymphoma (hepatic failure in two, sepsis in two, lung failure in one, heart disease in one, stroke in one, cachexia in
one, pneumonia in one, multiple organ dysfunction in one, sudden death in one and unknown cause in three).
After a median follow-up of 36 months for living patients (range 1 – 70), 3- and 5-year OS was 33% (95% CI 23 – 43%) and 28% (95% CI 17 – 39%), respectively. In univariate analysis the clinical factors that infl uenced OS were aaIPI (coded 2 – 3 vs. 0 – 1, p ⫽ 0.001) and stage (III – IV vs. II, p ⫽ 0.017) (Table IV). Regarding single CGA items, the following were also predictive of overall survival in univariate analysis: respira-tory comorbidity ( p ⫽ 0.013), ambulation ADL ( p ⫽ 0.038) and functional transfer ADL ( p ⫽ 0.020), predictive of worse survival, and diabetes, predictive of better survival ( p ⫽ 0.014). Regarding therapy among patients treated with Table I. Patient characteristics and comparison with fi t elderly
patients. Variable † Status Frail ( n ⫽ 94) Fit ( n ⫽ 224) p -Value n % n % Age, median (range) 78 (65 – 93) 72 (65 – 80) ⬍ 0.001 Gender F 62 66 120 54 0.047 M 32 34 104 46 AA stage II 36 38 70 31 0.242 III – IV 58 62 154 69 Symptoms A 75 80 135 60 0.001 B 19 20 89 40 aaIPI 0 16 18 34 16 0.339 1 26 29 80 37 2 34 38 81 38 3 13 15 19 9 ADL 6 55 68 224 100 * ⬍ 6 26 32 — — IADL 8 20 40 176 79 ⬍ 0.001 ⬍ 8 30 60 48 21 GS No 57 75 224 100 * Yes 19 25 — — CIRS-G Grade 1 – 2 17 19 195 87 * Grade 3 ⬍ 3 7 8 29 13 Grade 3 ⱖ 3 48 53 — Grade 4 ⱖ 1 18 20 —
F, female; M, male; AA, Ann Arbor; aaIPI, age-adjusted International Prognostic Index; ADL, Activities of Daily Living; IADL, Instrumental Activities of Daily Living; GS, geriatric syndrome; CIRS-G, Cumulative Illness Rating Scale for Geriatrics.
* p -Value was not calculated because CIRS-G assessment was part of frailty defi nition.
† Missing: aaIPI (frail n ⫽ 5; fi t n ⫽ 10), IADL (frail n ⫽ 44), ADL (frail n ⫽ 13), GS
(frail n ⫽ 18), CIRS-G (frail n ⫽ 9).
Table II. Rate of comorbid conditions included in CGA, ADL and geriatric syndrome. CIRS-G ( n ⫽ 85) % with grade III – IV Hypertension 34 Cardiac 31 Diabetes 16 Musculoskeletal system 15 Respiratory system 15 Liver 14 Nervous system 12 Circulatory system 9 Gastrointestinal system 8 Genitourinary tract 5 Endocrine-metabolic system 5 Kidneys 4 Eyes/ears/nose/throat 1
ADL ( n ⫽ 81) % with inability
Personal hygiene and grooming 28
Dressing and undressing 23
Functional transfer 17
Self-feeding 17
Ambulation 16
Bowel and bladder management 16
IADL ( n ⫽ 50) % with inability
Shopping 60 Cooking 48 Transport 42 Medicine 42 Laundry 36 Money 24 Housework 22 Phone 16
Geriatric syndrome ( n ⫽ 76) % with syndrome
Depression 16
Urinary/fecal incontinence 14
Neglect and abuse 8
Failure to thrive 7
Dementia 5
Falls 5
Osteoporosis 3
Delirium 0
CGA, Comprehensive Geriatric Assessment; CIRS-G, Cumulative Illness Rating Scale for Geriatrics; ADL, Activities of Daily Living; IADL, Instrumental Activities of Daily Living.
Table III. Treatment of frail patients.
Th erapy R ⫹ R ⫺ Total (%)
Polychemotherapy with anthracyclines * 31 36 67 (71%)
Polychemotherapy without anthracyclines † 5 1 6 (6%)
Mono-chemotherapy, radiotherapy, palliation 1 20 21 (22%)
Total (%) 37 (39%) 57 (61%) 94
R, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CEOP, cyclophosphamide, epirubicin, vinblastine, prednisone; CNOP, cyclophosphamide, mitoxantrone, vincristine, prednisone; P-VEBEC, prednisone, vinblastine, epirubicin, bleomycin, etoposide, cyclophosphamide; CVP, cyclophosphamide, vincristine, prednisone.
* Includes CHOP, mini-CEOP, CNOP, P-VEBEC.
† Includes CVP.
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rituximab and anthracycline-based immunochemotherapy (data not shown).
Univariate and multivariate analyses were conducted for all frail and fi t patients enrolled in the entire research pro-gram, considering clinical features and single CGA scales. Th is analysis confi rmed age ( ⬎ 80 years), aaIPI (2 – 3), B symptoms, the use of rituximab and ADL as independent prognostic factors for OS. ADL, IADL and geriatric syndrome, however, were strongly correlated to each other and mutu-ally exclusive. When a diff erent multivariate analysis was conducted substituting the results of single CGA scales with the defi nition of frail status as defi ned in the protocol, aaIPI (2 – 3), B symptoms, the use of rituximab and frail status were the only independent covariates (HR for frail status 2.85, 95% CI 1.8 – 4.6) (Table V).
In order to consider competing risks of death in the study population we also calculated the SMR for the frail and fi t groups; SMR was 12.5 (95% CI 9.8 – 16.1) and 4.7 (95% CI 3.7 – 5.9) for frail and fi t patients, respectively, compared with the mortality of the Italian population. Th e 5-year relative survival was 85.3%, 71.5% (95% CI 62.9 – 79.2) and 23.8% (95% CI 11.7 – 39.4) for healthy, fi t and frail patients, respectively (Figure 2).
Discussion
Treatment of elderly patients with DLCBL represents a chal-lenge for hemato-oncologists, as standard treatment modali-ties studied in randomized trials cannot always be proposed to patients.
So far, most published studies investigating the treat-ment of elderly patients have approached the problem from a treatment-oriented perspective. Th ere are cur-rently several regimens that are proposed to patients not fi t enough to receive standard therapy. Th ese include treatments that use lower doses of active drugs [8,14] and/ or the use of drugs with a better reported toxicity profi le [7,18]. In our study we decided to approach the problem starting from a patient-oriented perspective, focusing fi rst on the defi nition of patient status. All elderly patients with DLBCL were administered a simple CGA test to defi ne their ability to undergo systemic treatment before defi ning the chemotherapy, rituximab only showed a trend for a better
survival benefi t ( p ⫽ 0.152), with an OS at 3 years of 43% vs. 26% for patients treated with monoclonal antibody or not, respectively (Figure 1).
In multivariate analysis, aaIPI 2 – 3 (hazard ratio [HR] 2.24, p ⫽ 0.005) and the presence of respiratory comorbidity (HR 2.00, p ⫽ 0.044) were factors that showed correlation with a poorer OS, as reported in Table IV. Th e presence of diabetes was also an independent prognostic factor for OS; however, this covariate was unstable at bootstrapping analysis and was not confi rmed as a study result (data not shown).
Comparison of frail and fi t patients
Frail patients showed clinical characteristics that were diff er-ent from fi t patier-ents in terms of age, gender and B symptoms, as reported in Table I; interestingly, aaIPI was similar in the two groups.
Compared with fi t patients, frail patients had a worse OS, with an HR of 3.09 (95% CI 2.20 – 4.33; p ⬍ 0.001). Frail patients had a poorer outcome compared to fi t patients even if they were treated with rituximab-containing combination chemotherapy (HR 2.37, 95% CI 1.48 – 3.78; p ⬍ 0.001). In Figure 1 the OS is reported, stratifi ed by fi t and frail patients and by rituximab use. Similarly, a poorer outcome for frail patients compared to fi t patients was confi rmed when the analysis was limited to patients who were treated with
Table IV. Results of univariate and multivariate analyses for OS for frail patients.
Variable Status
Univariate analysis Multivariate analysis
HR 95% CI p -Value HR 95% CI p -Value Age ⬎ 80 1.08 0.65 – 1.70 0.782 aalPI 2 – 3 2.49 1.46 – 4.25 0.001 2.24 1.28 – 3.91 0.005 AA stage III – IV 1.96 1.13 – 3.41 0.017 Rituximab ⫹ 0.68 0.40 – 1.16 0.152 ADL ⬍ 6 1.59 0.91 – 2.77 0.103
Geriatric syndrome Yes 1.04 0.53 – 2.00 0.914
Comorbidity Grade 3 ⬎ 3 1.31 0.69 – 2.49 0.412
Grade 4 ⬎ 1 1.56 0.69 – 3.50 0.282
Single CGA item
CIRS-G (diabetes) Grade ⬎ 3 0.35 0.15 – 0.81 0.014 0.38 0.16 – 0.90 0.029
CIRS-G (respiratory syndrome) Grade ⬎ 3 2.31 1.19 – 4.49 0.013 2.00 1.02 – 3.93 0.044
ADL (ambulation) Unable 2.04 1.04 – 4.01 0.038
ADL (functional transfer) Unable 2.24 1.13 – 4.43 0.020
OS, overall survival; aaIPI, age-adjusted International Prognostic Index; AA, Ann Arbor; ADL, Activities of Daily Living; CGA, Comprehensive Geriatric Assessment; CIRS-G, Cumulative Illness Rating Scale for Geriatrics; HR, hazard ratio; CI, confi dence interval.
Figure 1. Overall survival (OS) stratifi ed by fi t and frail patients.
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treatment program. With this approach we could formally defi ne patients as fi t or frail.
Looking at the study results we fi rst confi rmed that the outcome of frail patients is poor, and observed that OS in these patients can be further predicted by the presence of severe respiratory disease, one of the CGA items and aaIPI. Of note, in this analysis, age was not helpful in further pre-dicting survival of the subgroup of frail patients. To our knowledge, the prognostic role of comorbidities has not been extensively studied in elderly patients with lymphoma, but the prognostic role of respiratory disease has been reported previously in patients with myelodysplastic syndrome (MDS) and in patients addressed to hematopoietic stem cell trans-plant [19,20]. In our analysis, among other CGA items, none was correlated with survival, and the role of diabetes as a protective factor was not adequately validated by bootstrap-ping, and likely explained by a type I error. Due to the small numbers analyzed, we cannot exclude that some of the CGA items analyzed are predictors of patient outcome. Our study suggests that a further, more accurate assessment of respira-tory function is warranted in patients with elderly lymphoma to better defi ne the quality of respiratory disease and to iden-tify a role for preventive measures.
Interestingly, then, we were able to compare the clini-cal features and outcome of frail patients with those of fi t patients of the whole clinical research program conducted by the FIL. As a fi rst result we found that the main diff erences between frail and fi t patients were mostly related to patient
status (age, gender and, as expected, comorbidity). Interest-ingly, lymphoma diagnosed in frail patients did not show worse features (stage, symptoms, aaIPI). Th is fi nding could be biased by the limited number of cases considered, but confi rms that CGA can add useful information that would not otherwise be available.
Comparing the outcome of fi t versus frail patients who were prospectively enrolled in our program, we confi rmed that the defi nition of patient status (fi t vs. frail) provides useful information as an independent prognostic factor. Th e same result was achieved either when patients were catego-rized as frail according to protocol defi nition or when the results of single CGA scales were considered; in this latter case, however, ADL, IADL and CIRS scales were correlated to each other and were mutually exclusive. Similar results were recently published by Nabhan et al ., who conducted a retrospective analysis of 330 patients older than 80 years with NHL (143 DLBCL); also in this study, loss of ADL was an independent prognostic factor for OS and progression-free survival (PFS), along with advanced stage and lack of com-plete response (CR) in the subgroup of aggressive lympho-mas [13]. Loss of ADL was confi rmed as a prognostic factor for OS also in the subgroup of indolent lymphomas and in elderly patients with HL [21].
Among possible limitations of our study, it is important to acknowledge that the treatment decision in the study was based on CGA results, and that most frail patients were not treated with standard regimens. Of note, one unexpected fi nding of our study was the low rate of frail patients who were treated with immunochemotherapy (ICT); when the study was conducted, rituximab was approved for the initial therapy of elderly patients with DLBCL in combination with CHOP, and few or no data were available to support diff erent or personalized ICT regimens. Th e lack of evidence together with the high costs of ICT could be reasons why frail patients who were less likely candidates for full-dose therapy were not treated with rituximab.
Some suggestions come from the analysis of SMR, which provides details on how a patient ’ s frailty may aff ect treat-ment results. First, the excess risk of death decreases with an inverse ratio to age. Age is one of the strongest adverse prognostic factors of NHL, as several studies have described that older age was signifi cantly correlated with shorter Table V. Univariate and multiple Cox proportional hazards regression analysis for OS across cohort of 318
elderly patients (224 fi t patients and 94 frail patients).
Variable Status
Univariate analysis Multivariate analysis *
HR 95% CI p -Value HR 95% CI p -Value Age ⬎ 80 2.53 1.64 – 3.92 ⬍ 0.001 1.95 1.06 – 3.63 0.033 aaIPI 2 – 3 3.10 2.15 – 4.48 ⬍ 0.001 2.51 1.70 – 2.73 ⬍ 0.001 AA stage III – IV 1.46 1.01 – 2.13 0.048 Symptoms B 1.67 1.19 – 2.33 0.003 1.98 1.33 – 2.94 0.001 Rituximab ⫹ 0.30 0.21 – 0.44 ⬍ 0.001 0.49 0.27 – 0.87 0.015 Patients Frail 3.09 2.20 – 4.33 ⬍ 0.001 2.85 1.76 – 4.61 ⬍ 0.001 ADL ⬍ 6 3.66 2.26 – 5.94 ⬍ 0.001 2.40 1.36 – 4.21 0.002
Geriatric syndrome Yes 2.55 1.40 – 4.65 0.002
Comorbidity Grade 3 ⬎ 3 1.37 0.89 – 2.10 0.149
Grade 4 ⬎ 1 3.34 1.82 – 6.10 ⬍ 0.001
OS, overall survival; aaIPI, age-adjusted International Prognostic Index; AA, Ann Arbor; ADL, Activities of Daily Living; HR, hazard ratio; CI, confi dence interval.
* Multiple regression was performed over 303 complete cases.
Figure 2. Relative survival (RS) for frail and fi t patients and for a matched population of healthy subjects.
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assessment is more eff ective than clinical judgment to identify elderly diff use large cell lymphoma patients who benefi t from aggressive therapy . Cancer 2009 ; 115 : 4547 – 4553 .
Boehme V , Schmitz N , Zeynalova S , et al . CNS events in elderly
[25]
patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) . Blood 2009 ; 113 : 3896 – 3902 . disease-free survival (DFS) and OS [17,22,23]. Th e excess
mortality due to age is explained not only by a lymphoma-related component (i.e. it is harder to cure lymphoma in elderly patients) but also by competing causes of death that are expected in elderly patients. Actually, most of the frail patients died due to lymphoma progression (60% of deaths); this was observed also in the subgroup of patients treated with full-dose regimens, and confi rmed the observation already reported by Tucci et al . [24]. Moreover, in our study we found a very high treatment-related mortality (TRM) among frail patients who were addressed to chemotherapy (18%), which confi rms how diffi cult is to treat this popula-tion of frail subjects. Th is TRM is highest compared to the 8% TRM rate observed for fi t patients and to published data from randomized trials with ICT [2,3,25]. Clinical trials specifi -cally addressed to frail patients and with regimens primarily designed to preserve safety are warranted as a strategy to improve the outcome or the quality of life of these subjects.
In conclusion, treatment of frail patients with DLBCL is largely unsatisfactory, and CGA is a valid tool to prospec-tively identify frail subjects among elderly patients with DLBCL. Also, based on this fi rst experience, all ongoing and future clinical trials conducted by the Fondazione Italiana Linfomi and designed for elderly patients will include a preliminary defi nition of patient status using CGA. Diff erent from the present study, in new studies a novel category of “ unfi t ” patients is identifi ed, with charac-teristics intermediate between fi t and frail subjects, defi ned by advanced age for otherwise fi t patients or by intermedi-ate CGA scores for younger patients. With this new method we will try to verify whether it is possible to better plan the treatment approach according to a more accurate func-tional risk assessment.
Potential confl ict of interest: Disclosure forms provided
by the authors are available with the full text of this article at www.informahealthcare.com/lal.
Th is work was supported by grants from the Associazi-one Angela Serra per la Ricerca sul Cancro, Modena, Italy, GR.A.D.E. Onlus (Gruppo Amici Dell ’ Ematologia-Onlus), Reggio Emilia, Italy and Fondazione Italiana Linfomi-Onlus, Alessandria, Italy.
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