Comprehensive geriatric assessment in elderly patients with newly diagnosed aggressive non-Hodgkin lymphoma treated with multi-agent chemotherapy

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Comprehensive geriatric assessment in elderly patients with newly diagnosed aggressive non-Hodgkin lymphoma treated with multi-agent chemotherapy Seha Parka , Junshik Hongb,⁎, Incheol Hwangc , Jeong-Yeal Ahnd , Eun Yeong Chob , Jinny Parkb , Eun Kyung Chob , Dong Bok Shinb , Jae Hoon Leeb a

Department of Medicine, Gachon University School of Medicine, Incheon 405-760, Republic of Korea Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon 405-760, Republic of Korea c Department of Family Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon 405-760, Republic of Korea d Department of Laboratory Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon 405-760, Republic of Korea b

AR TIC LE I N FO

ABS TR ACT

Article history:

Objectives: The purpose of this prospective observational study is to evaluate the relation of the

Received 6 June 2015

comprehensive geriatric assessment (CGA) to tolerability and survival of multi-agent chemo-

Received in revised form

therapy for curative intent in elderly patients with aggressive non-Hodgkin lymphoma (NHL).

23 September 2015

Materials and Methods: Patients who were 1) age ≥ 65 years, 2) newly diagnosed aggressive

Accepted 14 October 2015

NHL, and 3) treated with multi-agent chemotherapy within 2 weeks from the time of

Available online 27 October 2015

diagnosis were enrolled from January 2011 to June 2014. Baseline clinical, laboratory, and CGA data being composed of Mini Nutritional Assessment-Short Form (MNA-SF), Korean

Keywords:

version of Mini Mental Status Exam, Korean-Geriatric Depression Scale, and Groningen

Non-Hodgkin lymphoma

Frailty Index (GFI), were collected and analyzed for the relation to the outcome factors.

Geriatric assessment

Results: Seventy patients were included; the median age was 73.5 years, 27 (38.6%) patients

Chemotherapy

were Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or more, and

Elderly

half of the patients were high or high-intermediate risk by age-adjusted international prognostic index (aaIPI). Most patients received CHOP or CHOP-like chemotherapy. Factors affecting discontinuation of chemotherapy within 12 weeks were poor MNA-SF, poor GFI, poor PS, and presence of B symptom. Among those, poor MNA-SF was independent of other variables in multivariate analysis. Poor MNA-SF, bone marrow involvement, and baseline anemia of hemoglobin < 10 g/dL were found to be independent factors associated with inferior overall survival whereas aaIPI factors were not. Conclusion: MNA-SF predicted tolerability to multi-agents chemotherapy and overall survival in elderly patients with aggressive NHL who were treated with multi-agent chemotherapy. © 2015 Elsevier Ltd. All rights reserved.

⁎ Corresponding author at: Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdongdae-ro 774-gil, Namdong-gu, Incheon 405-760, Republic of Korea. Tel.: +82 70 4735 6016; fax: +82 32 460 3233. E-mail address: [email protected] (J. Hong).

http://dx.doi.org/10.1016/j.jgo.2015.10.183 1879-4068/© 2015 Elsevier Ltd. All rights reserved.

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1. Introduction

2. Materials and Methods

The incidence of cancer increases with age. In the West, currently approximately 60% of cancer occurs in people over 65 years, and approximately 80% of cancer mortality of also occurred in the elderly.1 Unlike young patients, many elderly patients have systemic diseases as well as loss of body function and cognition. Therefore, older patients are less likely to receive standard chemotherapy in terms of duration and intensity, compared with the young, and clinicians prefer to reduce the dose of drugs or delay the schedule of chemotherapy.

2.1. Patients

Because reductions in chemotherapy dose intensity compromise disease control and survival,2 older patients may have unsatisfactory outcomes. Because of this problem, conduct of clinical trials in the elderly population is also difficult. It has been reported that there are many restrictions in cases of elderly patients participating in clinical trials.3 For assessment of general health status of elderly patients, comprehensive geriatric assessment (CGA) provides information on the overall health status of older individuals, consisting of functional status, comorbid medical condition, cognition, psychological state, nutritional status, and a review of the patient's medications, etc. The United States National Comprehensive Cancer Network (NCCN) selected ‘older adult oncology’ as a sector of independent guidelines and well noted the need for CGA.4,5 Use of biological age as an indicator for treatment in elderly patients with cancer seems to be beneficial, because in many situations, chronological age is distinct from functional age and may not represent an individual's actual general medical condition 6–9. Aaldriks et al.10 evaluated the association between the results of CGA using mini-nutritional assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Index (GFI), the Mini-Mental Status Examination (MMSE), and treatment outcomes of 202 patients with cancer, who have undergone at least four cycles of chemotherapy. As a result, they concluded that the MNA and the GFI were associated with mortality. Such CGA has also been reported to affect selection of treatment method in actual clinical treatment.11,12 Non-Hodgkin lymphoma (NHL) is the most prevalent hematologic malignancy and the International Prognostic Index (IPI) is a well-known prognostic indicator of aggressive NHLs including diffuse large B-cell lymphoma (DLBCL).13,14 In elderly patients with aggressive NHL who receive multi-agent chemotherapy for curative intent, substantial cases of unsatisfactory outcomes are derived from morbidity or even mortality during treatment. Although the IPI includes chronological age (over 60 years or not) as one of five components, it is for anticipating overall survival (OS) of patients with NHL, but not for predicting tolerability of the planned chemotherapy or immunochemotherapy with the maintenance of good performance status (PS). Thus, reliable predictors of suitability for the treatment need to be defined. Therefore, we conducted a prospective observational study to evaluate the relation of the CGA to treatment tolerability and survival of elderly patients with aggressive NHL treated with multi-agent chemotherapy for curative aim.

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The inclusion criteria of the current study were 1) age ≥65 years, 2) newly diagnosed aggressive NHL according to the 2008 World Health Organization Classification, 3) initially treated with multi-agent systemic chemotherapy for curative intent within 2 weeks from the time of diagnosis at a single institution, Gachon University Gil Medical Center (GUGMC), 4) signed informed consent with the understanding of the purpose of the current study, and 5) willing to cooperate with CGA. ‘Aggressive’ NHL subtypes include DLBCL, mantle cell lymphoma, and peripheral T-cell lymphomas (PTCLs). Patients with subtypes of NHLs usually classified as indolent NHL, such as follicular lymphoma, marginal zone lymphoma, or lymphoplasmacytic lymphoma, could not be included in principle. However, if a patient with those subtypes had aggressive biological (for example, FL with histologic grade 3) and/or clinical nature (for example, significant growth of multiple masses in 2 ~ 3 weeks that necessitates immediate systemic chemotherapy), participation in the current study was allowed. Patients with a difficulty of oral feeding caused by tumorous obstruction, any central nervous system (CNS) involvement of lymphoma, or human immunodeficiency virus-associated lymphoma, were not included. CGA was performed after the clinical decision of curative treatment by the attending physician and no intervention was conducted according to CGA outcomes. The current study was reviewed and approved by the Institutional Review Board of the GUGMC (approval number: GIRBA 2436).

2.2. Chemotherapy Multi-agent chemotherapy was defined as systemic therapy composed of three or more cytotoxic drugs with or without corticosteroids; mainly cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) combination, or ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) combination,15 or their modifications. Rituximab was added to patients with B-cell lymphomas. Because large amount of initial dose reduction might not be considered chemotherapy of a real curative intent, primary dose reduction up to 20% of conventional dose was allowed. Any drugs of R-CHOP can be initially reduced according to the physician's discretion. For example, reduction of both cyclophosphamide and adriamycin for fear of infectious episodes, adriamycin alone for patients with decreased heart function, or vincristine alone for those with preceding neuropathy. However, only up to 20% reduction of reduction was allowed and patients with >20% of initial dose reduction were excluded. For patients who had severe lymphoma related symptom with high tumor burden, 20–100 mg of oral prednisolone or intravenous administration of methylprednisolone for 3–7 days was allowed for cytoreduction as well as alleviation of the symptoms. Prophylactic antibiotics were not applied. Granulocyte colony stimulating factor (G-CSF) was administered according to the recommendations of the Korean National Health Insurance Guideline; daily from the first day of absolute neutrophil count (ANC) <1000/μL to the third consecutive day of ANC >3000/μL in

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each cycle. Response evaluation to chemotherapy was estimated using the Revised Response Criteria for NHL.16

2.3. Comprehensive Geriatric Assessment MNA is a validated tool for assessment of the nutritional status of geriatric patients age 65 and above.17–19 The MNA is known for its usefulness in predicting mortality of elderly hospitalized patients19,20 and is now used as a part of CGA in patients with cancer.10 We used a short form of MNA (MNA-SF) developed by Rubenstein et al., which also has good diagnostic accuracy.18 The investigators were permitted to use the MNA-SF for clinical study by copyright owner, Nestlé Nutrition Institute, Vevey, Switzerland, and obtained permission before publication of the current study. Because there was no Korean version of the MNA-SF at the time of planning the current study, the investigators translated the MNA-SF into Korean language, and the translated version was submitted to Nestlé Nutrition Institute, then the accuracy was checked and accredited. MMSE, a test designed for evaluation of various cognitive functions, is a valid and reliable tool for identification of moderate and/or advanced dementia.21 Because of its clinical convenience and excellence, Korean version of the MMSE (K-MMSE) was translated and validated by Kang et al.22 and it has been used clinically for 20 years in Korea. The current study also used the K-MMSE. Korean-Geriatric Depression Scale (K-GDS) is the evaluation index for elderly patients with depression, which was developed by Sheikh and Yesavage,23 and modified by Kee24 based on Geriatric Depression Scale (GDS) to suit the elderly Koreans. GFI25 was developed for evaluation of frailty but has hardly ever been used in studies conducted in Korea until the planning period of this study. It is a 15-question measurement tool to assess the degree of frailty, and its Korean version was translated into Korean language by investigators and was validated through the process of translation followed by back-translation. Before initiation of the current study, investigators conducted a pilot CGA in five elderly patients aged from 65 to 87, and concluded that at least 15 minutes was required to obtain CGA outcomes of good quality. Therefore, investigators made every effort to observe the rule of 15 minutes as a minimal duration with the sincere progress of CGA with the patient. To maintain the integrity and good quality, the investigators who actually conducted CGA were limited to four persons (Park SH, Hong J, and two research nurses) and had a separate meeting time for reviewing what the investigators need to know for the proper outcomes of CGA.

(0–7 points). To evaluate the question of whether pre-treatment CGA can predict the tolerability of patients to multi-agent chemotherapy, we investigated the relations of CGA outcomes and other baseline characteristics to the capability of maintaining the planned chemotherapy for 12 weeks or more. The Chi-square test was used for estimation of the relationship between two dichotomous variables. Among factors with a p < 0.1 in the Chi-square test, backward conditional multiple binary logistic regression tests were performed as multivariable analysis. Event-free survival (EFS) denotes the period from the time of initiation of therapy to any treatment failure, including progression of disease or discontinuation of the therapy for any reason. Overall survival (OS) was defined as the time of initiation of treatment until death from any cause. Survival analysis was performed according to the Kaplan–Meier method and compared by log-rank test. Factors with a p < 0.1 in the longrank test were included for multivariate analysis for OS by entering into a backward conditional Cox regression model. The values were two sided, and statistical significance was accepted at the level of p < 0.05.

3. Results 3.1. Patient Characteristics From January 2011 to June 2014, 94 elderly (age ≥65 years) patients were diagnosed as NHL at the GUGMC. Among them, 24 patients were excluded from the current study because of treatment of palliative aim (n = 9), indolent subtype (n = 5), refused CGA (n = 3), CNS involvement (n = 2), received concurrent chemoradiation (n = 2; patients with nasal type of extranodal NK/T-cell lymphoma), profound hearing loss which resulted in failure of appropriate CGA (n = 2), and very aggressive subtype (n = 1; final biopsy result changed from DLBCL to Burkitt lymphoma). The median age of the 70 included patients was 73.5 years. Twenty-seven (38.6%) patients were Eastern Cooperative Oncology Group (ECOG) PS of 2 or more, and half of the patients were high or high-intermediate risk by age-adjusted IPI. Fifty-three patients with B-cell lymphomas received CHOP plus rituximab. IMEP chemotherapy was used in 4 patients with extranodal NK/T-cell lymphoma because CHOP-based chemotherapy is not recommended for the subtype26,27 and one patient with angioimmunoblastic T-cell lymphoma who had heart failure and expected to intolerant to anthracycline. The other 12 patients with PTCLs received CHOP chemotherapy. Detailed information on the analyzed patients is summarized in Table 1.

3.2. Overall Treatment Outcomes 2.4. Statistical Analysis For the accuracy and convenience of the analyses of CGA, the results were dichotomized along with other clinical and laboratory parameters. For example, according to the scoring of MNA-SF, nutritional status of a patient is classified as follows: normal nutritional status for patients with 12–14 points, at risk of malnutrition for those with 8–11 points, and malnutrition for those with 0–7 points.18 We dichotomized the analyzed patients as good MNA-SF group (8–14 points) and poor MNA-SF group

Among 59 evaluable patients, 45 patients (76.3%) achieved a complete remission. Seven patients showed a partial response, four patients had a stable disease, and three patients showed progressive disease. More than 90% of the patients (64; 91.4%) reported G4 neutropenia during chemotherapy and 16 of them suffered from febrile neutropenia (22.9%). Twenty-seven (38.6%) and 29 (41.4%) patients experienced grade ≥ 3 or 4 anemia and thrombocytopenia, respectively. Ten patients were admitted to intensive care unit with the

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Table 1 – Patient characteristics. N = 70 Gender Age (years)

Subtypes of NHL

ECOG performance status Serum lactate dehydrogenase Ann Arbor stage

Age-adjusted IPI

Bone marrow involvement B symptom Type of chemotherapy

Initial chemotherapy dose

N Male Median (range) ≥ 70 years ≥ 75 years Diffuse large B-cell lymphoma Mantle cell lymphoma Follicular lymphoma, grade 3 Lymphoplasmacytic lymphoma Extranodal marginal zone lymphoma Peripheral T-cell lymphomas (PTCLs) –Angioimmunoblastic T-cell lymphoma –PTCL, not otherwise specified –Extranodal NK/T-cell lymphoma a 2, 3, and 4 Elevated I II III IV Low Low-intermediate High-intermediate High Yes Yes CHOP or CHOP-rituximab –CHOP-rituximab –CHOP IMEP 100% dose Reduction up to 20%

38 73.5 (65-92) 51 34 44 6 1 1 1 17 (11) (2) (4) 27 34 7 23 17 23 23 12 16 19 12 16 65 (53) (12) 5 26 44

% 54.3 72.8 48.6 64.3 8.6 1.4 1.4 1.4 24.3

38.6 48.6 10.0 32.9 24.3 32.9 32.9 17.1 22.9 27.1 17.1 22.9 92.9 75.8 17.1 7.1 37.1 62.9

Footnotes: Abbreviations used: NHL = Non-Hodgkin's lymphoma; ECOG = Eastern Cooperative Oncology Group; IPI = International Prognostic Index; CHOP = cyclophosphamide, hydroxydaunorubicin (Doxorubicin), oncovin (Vincristine), and prednisolone; IMEP; ifosphamide, methotrexate, etoposidie, and prednisolone. a Three patients with nasal type and one patient with non-nasal type.

support of mechanical ventilation during chemotherapy and 8 of them expired.

3.3. CGA Outcomes The CGA was conducted successfully in all of the 70 enrolled patients (Table 2).

was an independent parameter in multivariate analysis regarding maintenance of chemotherapy for ≥ 12 weeks (Table 3). Out of 53 patients who successfully maintained ≥4 cycles of chemotherapy, 42 patients experienced no additional (i.e., subsequent to initial) dose reduction during chemotherapy and among the other 11 patients, the extent of additional dose reduction of cyclophosphamide and adriamycin was limited to ≤20% of baseline doses.

3.4. CGA and Chemotherapy Tolerability 3.5. Survival Analysis Seventeen patients discontinued chemotherapy within 12 weeks after treatment initiation; nine patients gave up continuing treatment by patients or physicians due to intolerable toxicities and its resultant decline in PS, five patients experienced treatment-related mortality (TRM) within 12 weeks, and two patients showed early disease progression within 12 weeks. Excluding two patients with early progressive disease, 15 patients were regarded as failure of continuing chemotherapy for 12 weeks, i.e., unsuitable for multi-agent chemotherapy. Among the 68 patients, factors affecting give-up of chemotherapy within 12 weeks were poor MNA-SF, poor GFI, higher Ann Arbor stage, poorer PS, and presence of B symptom (Table 3). Among those, only MNA-SF

During the median follow-up period of 21.5 months (95% confidence interval 11.8–31.3), 25 events (35.7%) and 20 deaths (28.5%) were observed. Seven patients (10%) experienced TRM, whereas another 11 patients died of progression of lymphoma. Two other patients expired of rupture of aortic aneurysm and heart failure, respectively, not directly related to lymphoma. Estimated 2-year EFS and OS were 55.2% and 70.5%, respectively, and 3-year EFS and OS were 45.3% and 63.2%, respectively. Univariate and multivariate analysis for OS were performed with the CGA results in addition to various clinical and laboratory parameters (Table 4). Poor MNA-SF group along

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Table 2 – Results of comprehensive geriatric assessment of the analyzed patients.

Mean score

Mini-nutritional assessment-short form (MNA-SF)

Mini mental status exam (MMSE)

Geriatric depression scale (GDS)

Groningen Frailty index (GFI)

9.1 ± 2.9

24.4 ± 4.6

11.8 ± 7.0

3.8 ± 2.9

Interpretation 12–14; normal nutrition (19) (N) 8–11; at risk of malnutrition (26) 0–7; malnourished (25)

In the current Good MNA-SF (45) study (N) Poor MNA-SF (25)

24–30; no cognitive dysfunction (44) 18–23; mild-degree dysfunction (18) 0–17; significant dysfunction (8) Good MMSE (44) Poor MMSE (26)

with bone marrow involvement and baseline anemia of Hb < 10 g/dL was found to be an independent factor associated with inferior OS, whereas age-adjusted IPI was not (Table 4).

3.6. Subgroup Analysis Among Patients with Diffuse Large B-Cell Lymphoma Relations of baseline characteristics including CGA outcomes to the maintenance of the immunochemotherapy for ≥12 weeks were evaluated among 44 patients with DLBCL treated with CHOP-rituximab. There were 9 patients who gave up CHOPrituximab within 12 weeks and five of them (55.5%) belonged to poor MNA-SF group. By contrast, 10 (28.6%) out of 35 patients who maintained CHOP-rituximab for ≥12 weeks were classified to poor MNA-SF group. However, this difference was statistically insignificant (p = 0.128) probably due to small patient number. All the other CGA outcomes and baseline parameters presented in Table 3 were not related to the maintenance of CHOP-rituximab for ≥12 weeks except PS ≥2 (data not shown). Poor MNA-SF group was still an independent prognostic factor when the analysis was limited in patients with DLBCL treated with CHOP-rituximab (Table 4).

4. Discussion A few previous studies have incorporated CGA into the treatment of elderly patients with lymphoma.28–33 The majority of the studies were conducted by Italian investigators and they used CGA in order to classify patients according to two (fit vs. unfit,28 or fit vs. frail32) or three (fit vs. unfit vs. and frail29,30,33, or fit vs. intermediate vs. frail31) subgroups, as a tool for stratification according to the suitability for curative treatment approach (Table 5). Those studies consistently showed difference of outcomes according to the stratification by CGA.28–33 To evaluate the role of CGA, we used a different approach compared to previous studies. Instead of stratifying patients into two or three categories according to CGA outcomes, eligibility was limited to elderly patients who decided to receive multi-agent chemotherapy with a curative intent based on physicians' judgment. Therefore, we could not evaluate the significance of CGA among very frail patients who received low-intensity palliative therapy or only supportive care; for those definitely frail patients, a phase II

0–13; normal (41)

0–3; not frail (37)

14–18; mild-degree ≥4; with frailty (33) depression (14) 19–21; moderate depression (8) ≥22; severe depression (7) Good GDS (55) Good GFI (37) Poor GDS (15) Poor GFI (33)

EORTC trial showed overall poor treatment outcome and the importance of CGA.34 Instead, the current study focused on defining a part of patients who were selected to receive multi-agent chemotherapy by clinical decision, but were actually not suitable for it, in order to gain insight to avoid dropping out from chemotherapy due to decline in PS or even TRM. Outcomes of the current study suggest that some elderly patients who were expected to tolerate multi-agent chemotherapy by physicians but actually unfit to intensive therapy can be successfully selected by CGA. It is in line with a previous study by Tucci et al.28: they conducted CGA in 84 consecutive patients with DLBCL aged > 65 years although treatment with curative vs. palliative aim was decided according to clinical judgment with the blindness of CGA outcomes. In their study, only 50% of patients were classified as the ‘fit’ group by CGA, whereas 75% of patients were considered fit enough to receive aggressive treatment for cure by clinical decision. Because outcomes of 20 patients classified as unfit by CGA but fit by clinical judgment and treated with multi-agent chemotherapy were as poor as those of unfit patients with palliative care, they concluded that CGA was more conservative and better than clinical judgment in assigning patients to aggressive multi-agent chemotherapy with curative intent.28 Putting the results of the study by Tucci et al. and those of the current study together, CGA could be an objective and accurate tool for selection of patients who are unfit for multi-agent chemotherapy, at least in the field of aggressive NHL. We selected four parameters as a component of CGA, and in some aspects, this study is closer to multidimensional geriatric assessment (MGA) rather than true CGA, which is a more comprehensive work and usually conducted by an experienced geriatrician who interprets and can act upon the MGA results.35,36 MNA-SF and GFI were selected because we thought that they contain various aspects of life. For example, although MNA-SF focuses on nutritional status which is assessed by questionnaires regarding loss of appetite, weight loss, and body mass index, it also briefly includes questions on PS, psychological distress, and neurologic or psychiatric problems such as dementia or depression.19 The aim of GFI is to evaluate frailty of elderly patients but it also contains questions on cognition and psychological status.25 Those two tests seem to reflect treatment tolerability, as in the study conducted by Aaldriks et al.,10 and in particular, MNA-SF was found to be a helpful parameter. In addition, because they have relatively brief and easily understandable

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Table 3 – Relations of baseline characteristics including comprehensive geriatric assessment outcomes to the maintenance of chemotherapy for 12 weeks or more: univariate and multivariate analysis. Univariate analysis (n = 68; excluding two patients who experienced early progressive disease) Continuing chemotherapy ≥ 12 weeks

MNA-SF Good Poor Mini mental status examination Good Poor Geriatric depression scale Good Poor Groningen frailty index Good Poor Ann Arbor stage I or II III or IV Serum lactate dehydrogenase Normal Elevated Performance status 0 or 1 2 or more Diagnosis Diffuse large B-cell lymphoma Others Initial dose reduction up to <20% No Yes B symptom No Yes Bone marrow involvement No Yes Serum albumin ≥ 3.5 g/dL <3.5 g/dL Body mass index ≥ 21 kg/m2 <21 kg/m2 Baseline hemoglobin ≥ 10. 0 g/dL <10.0 g/dL

No

Yes

5 10

40 13

p = 0.002

p = 0.873 9 6

33 20 p = 0.510

10 4

43 11 p = 0.015

4 11

33 20

3 12

26 27

p = 0.045

p = 0.314 6 9

29 24

6 9

37 16

9

35

6

18

p = 0.035

p = 0.666

p = 0.100 3 12

23 30

8 7

44 9

p = 0.017

p = 0.211 11 4

46 7

7 8

18 35

5 10

15 38

10 5

39 14

p = 0.368

p = 0.706

p = 0.598

Multivariate analysis (by multiple binary logistic regression tests)

MNA-SF

Odds ratio

95% confidence interval

p-value

6.2

1.8–21.3

0.004

Footnotes: Abbreviations used: MNA-SF = Mini Nutritional Status-Short Form.

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questions, we had an ease for translation (linguistic validation) and less burden on the problem of insufficient cultural validation (e.g. for appropriateness of wording or potential misunderstanding due to different ways of thinking). We chose K-MMSE and K-GDS because we thought that cognitive function and mood of depression were important aspects to elderly patients and they had already been well validated and widely used in Korea. In designing a study of geriatric assessment, the time required to CGA is a major consideration. It is like a doubleedged sword: to achieve high-quality CGA outcomes, a sufficient amount of time is required because a patient should have enough time for understanding and contemplating the questions, and then describing answers appropriately. On the other hand, in actual clinical practice of oncology, only short and rapid screening tools can be widely accepted.5,33,37 Therefore, optimal selection of parameters of CGA is of importance. Because MNA-SF yielded good correlation to tolerability to chemotherapy and survival with a short period of time, it is a promising parameter to be incorporated into future studies as a part of CGA or a pre-screening tool for full time CGA, such as G-8 geriatric screening test37 or abbreviated CGA.38 The lower limit of age for inclusion in the current study was 65 years. Because the average life expectancy is increasing, particularly in the developed countries of the aged society, some may argue that it is no longer appropriate to include those aged in their late sixties. Indeed, recent definition of the elderly is moving toward age 70 years or older and several CGA studies in lymphoma were conducted in patients with ≥70 or even ≥75 years old. Winkelmann et al.39 analyzed the association of results of CGA with survival in patients with malignant lymphoma. They included patients aged ≥18 years and 61 of 143 patients (43%) were aged 18–59 years. Although the study conducted by Winkelmann et al. included younger patients and thus should not be considered as a real ‘geriatric’ assessment, CGA outcomes such as IADL and comorbidity were independent prognostic factors for survival, whereas age (<60 versus ≥60) was not.39 Considering the results, including patients aged ≥65 but <70 years does not seem to invalidate outcomes of the current study. Aside from the issue on the adequate lower limit of age in conducting CGA, very old age itself can be a crucial factor affecting frailty and inferior treatment outcome. In a prospective multicenter CGA study for patients with DLBCL conducted by the Lymphoma Italian Foundation, Tucci et al. classified patients with age > 80 years into frail category irrespective of the results of other CGA parameters.33 It is supported by recently published study of NCCN-IPI for patients with DLBCL treated with rituximab-contained therapy that showed a significant difference of survival according to the age stratification (>40 to ≤ 60 vs. > 60 to ≤ 75 vs. > 75 years).40 Future studies on searching for a subgroup that are actually suitable for chemotherapy among very old patients could be expected. 88.6% of the included patients were either DLBCL or PTCLs because we excluded patients with very aggressive lymphoma or indolent lymphoma, and 92.9% of patients received either CHOP or CHOP-rituximab. Notwithstanding, heterogeneous subtypes of aggressive lymphoma are obvious limitations of the current study. Instead, to get the most out of the setting of single institutional research, we focused on conducting CGA of good quality by conducting pilot CGA, setting a minimal

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Table 4 – Univariate and multivariate analysis for overall survival in the analyzed patients. Among entire patients (n = 70)

Univariate analysis Age-adjusted IPI factors Elevated serum lactate dehydrogenase Ann Arbor stage III or IV ECOG performance status ≥2 Comprehensive geriatric assessments Poor mini-nutritional assessment Poor mini mental status examination Poor geriatric depression scale Poor Groningen frailty index Diffuse large B-cell lymphoma Presence of B symptom Bone marrow involvement Serum albumin <3.5 g/dL Pre-treatment Hb <10.0 g/dL Multivariate analysis Elevated serum lactate dehydrogenase Ann Arbor stage III or IV ECOG performance status ≥2 Poor mini-nutritional assessment Bone marrow involvement Pre-treatment Hb <10.0 g/dL

Among patients with DLBCL with CHOP-rituximab (n = 44)

Hazard ratio (95% CI)

p-value

Hazard ratio (95% CI)

p-value

2.6 (1.0–6.6) 2.5 (0.9–6.5) 4.7 (1.9–12.2)

0.044 0.067 0.001

4.0 (1.3–12.1) 2.8 (0.9–8.1) 7.0 (2.3–21.4)

0.015 0.062 0.001

4.6 1.5 1.1 2.2 1.0 2.2 4.8 2.6 5.0

0.001 0.417 0.827 0.084 0.940 0.108 0.001 0.034 < 0.001

4.0 1.4 1.8 2.4 – 5.9 5.2 2.1 3.3

0.011 0.760 0.368 0.105 – 0.006 0.003 0.179 0.026

–

6.0 (1.0–36.0) 8.9 (1.1–74.5) 17.4 (3.4–88.7) 3.6 (1.1–12.0) – –

– – 2.5 4.4 3.4 3.8

(1.8–11.4) (0.6–3.9) (0.4–3.4) (0.9–5.5) (0.4–2.4) (0.8–5.9) (1.9–11.7) (1.1–6.3) (2.0–12.4)

(0.8–7.4) (1.7–11.5) (1.2–9.5) (1.5–9.4)

0.097 0.003 0.022 0.004

(1.4–11.5) (0.2–10.5) (0.5–6.9) (0.8–7.0) (1.6–21.2) (1.7–15.8) (0.7–5.9) (1.2–9.5)

0.043 0.049 0.001 0.037 – –

Footnotes: Abbreviations used: DLBCL = diffuse large B-cell lymphoma; CHOP-rituximab; cyclophosphamide, hydroxydaunorubicin (Doxorubicin), oncovin (Vincristine), and prednisolone plus rituximab; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group.

time requirement and limitation of investigators with actual involvement in CGA. Although we did not estimate required time of CGA for each patient, we experienced that for some patients, particularly for patients with very old age or who had decreased hearing, much more time, even more than 30 minutes were actually required, mostly during MMSE, as previously reported.41 Again noted, a time-consuming CGA

cannot be widely accepted in real-world practice. For the purpose of successful patient stratification, we can cautiously suggest that parameters for evaluating a certain individual aspect other than functional status, for example, MMSE for cognitive function, could be abbreviated by a shortened version, at least at initial stage, because of economy of time and low probability of direct correlation to treatment outcomes. This is

Table 5 – Summary of studies regarding comprehensive geriatric assessment in elderly patients with malignant lymphoma. Studies

N

Age (years)

Tucci et al. 28

84

>65

Diffuse large B-cell lymphoma

Olivieri et al. 29

91

≥ 65

Diffuse large B-cell lymphoma

Spina et al. 30

100

≥ 70

Marchesi et al.31

73

≥ 75

Merli et al. 32

≥ 65

Tucci et al. 33

99 frail patients (of 334 patients) 173

Diffuse large B-cell lymphoma Aggressive B-cell lymphomas Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma

Current study

70

≥ 65

>69

Subtype(s)

Aggressive non-Hodgkin lymphoma

Key findings Among patients considered ‘unfit’ by comprehensive geriatric assessment (CGA), no difference of outcomes were observed between those who received curative vs. palliative treatment Tailored treatment according to stratification of patients by CGA showed 5-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) rates of 46%, 31%, and 41%, respectively, and multivariate analysis showed prognostic role of CGA Adjustment of immunochemotherapy based on CGA resulted to manageable toxicity and 5-year DFS and OS of 80% and 60%, respectively Patients classified as ‘fit’ and ‘intermediate’ by CGA showed better OS compared to those classified as ‘frail’ Frail patients had a poorer outcome compared with fit patients if they were treated with rituximab-containing combination chemotherapy Two-year OS of patients treated with curative or palliative aim was 88% vs. 25% (p = 0.0001) in fit, 75% vs. 45% (p = 0.32) in unfit, and 44% vs. 39% (p = 0.75) in frail patients, respectively Shortened form of Mini Nutritional Assessment predicts the tolerability to chemotherapy for ≥12 weeks and prognostic of OS

J O U RN A L OF GE RI A T RI C O NC O L O G Y 6 ( 2 01 5 ) 4 7 0 –47 8

in line with a recent suggestion of two-step approach in CGA studies.37,38,42 We did not use pegylated G-CSF but only administered unpegylated G-CSF daily until recovery because the Korean National Insurance System did not allow its use during the study period. However, we believe that G-CSF was used sufficiently enough to alleviate the risk of infectious events during chemotherapy considering the result of a study that the use of pegylated G-CSF once per cycle and plain G-CSF for 7 or 10 days showed similar overall outcomes among patients with B-cell lymphoma treated with CHOP-14 regimen.43 In this study, we excluded 2 patients with a profound deafness because we regarded the efficiency of CGA with economy of time highly. However, in a prospective multicenter study to predict chemotherapy toxicity in older patients, Hurria et al. reported that poor hearing was identified as a risk factor for chemotherapy toxicity.44 Therefore, those patients might have been benefitted from CGA if included in more comprehensive and patient manner. In conclusion, MNA-SF, a component of CGA, predicts the tolerability to chemotherapy for ≥ 12 weeks and even prognostic of OS, in spite of heterogeneous subtypes of lymphoma, in elderly patients with aggressive NHL who were treated with multi-agent chemotherapy. CGA could be an objective and reliable tool for selection of patients who are not suitable for chemotherapy with a curative intent. By incorporating CGA into clinical practice, unnecessary chemotherapyinduced morbidities and mortalities could be avoided. Larger scale future prospective clinical trials, especially with twostep approach in more homogeneous population such as DLBCL,45 would give shape to CGA of optimal components and feasibility.

Funding Source This work was supported by a grant of Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1731).

Disclosures and Conflict of Interest Statements JH reports grants from Ministry of Health & Welfare, Republic of Korea (HI14C1731). All other authors have no conflict of interest to disclose.

Author Contributions Study Concept and Design: J Hong Data Collection: S Park and J Hong Data Analysis and Interpretation: S Park and J Hong Manuscript Writing: S Park and J Hong Manuscript Editing and Review: I Hwang, J-Y Ahn, EY Cho, J Park, EK Cho, DB Shin and JH Lee Approval of final article: S Park, J Hong, I Hwang, J-Y Ahn, EY Cho, J Park, EK Cho, DB Shin, and JH Lee All authors have approved the final article.

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