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Predicting systemic therapy toxicity in older adult patients with advanced non-small cell lung cancer: A prospective multicenter study of National Hospital Organization in Japan

Open AccessPublished:August 22, 2022DOI:https://doi.org/10.1016/j.jgo.2022.07.011

      Abstract

      Introduction

      Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients.

      Materials and methods

      Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

      Results

      In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%).

      Discussion

      A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients.

      Keywords

      1. Introduction

      Lung cancer is the leading cause of cancer-related death worldwide, and the majority of diagnosed lung cancer patients have non-small cell lung cancer (NSCLC) [
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2020.
      ]. About 70% of patients with NSCLC are diagnosed at an advanced stage, and the median age at diagnosis is 70 years [
      • Owonikoko T.K.
      • Ragin C.C.
      • Belani C.P.
      • Oton A.B.
      • Gooding W.E.
      • Taioli E.
      • et al.
      Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database.
      ]. Although systemic therapy is one of the therapeutic options available for advanced NSCLC patients, the standard first-line treatment for older adult patients is still debated. Previous trials suggested that older adult NSCLC patients benefit from platinum doublet therapy, but its superiority is controversial [
      • Quoix E.
      • Zalcman G.
      • Oster J.P.
      • Westeel V.
      • Pichon E.
      • Lavolé A.
      • et al.
      Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.
      ,
      • Okamoto I.
      • Nokihara H.
      • Nomura S.
      • Niho S.
      • Sugawara S.
      • Horinouchi H.
      • et al.
      Comparison of carboplatin plus pemetrexed followed by maintenance pemetrexed with docetaxel monotherapy in elderly patients with advanced nonsquamous non-small cell lung cancer: a phase 3 randomized clinical trial.
      ,
      • Abe T.
      • Takeda K.
      • Ohe Y.
      • Kudoh S.
      • Ichinose Y.
      • Okamoto H.
      • et al.
      Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L.
      ]. An explanation for this discrepancy is that there is considerable heterogeneity in physiological changes that occur with aging. Furthermore, only a low number of older adult patients are enrolled in clinical trials, although enrollment disparity has been improved in older adult NSCLC patients [
      • Pang H.H.
      • Wang X.
      • Stinchcombe T.E.
      • Wong M.L.
      • Cheng P.
      • Ganti A.K.
      • et al.
      Enrollment trends and disparity among patients with lung cancer in national clinical trials, 1990 to 2012.
      ]. It is difficult to predict the tolerability of general older adult patients who are more vulnerable to adverse events from systemic therapy in clinical practice.
      Age is an important factor in management decisions because of the complex interplay between normal age-related decline and comorbidities. The Karnofsky Performance Status or the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is used in patients to predict treatment toxicity and survival [
      • Albain K.S.
      • Crowley J.J.
      • LeBlanc M.
      • Livingston R.B.
      Survival determinants in extensive-stage non-small-cell lung cancer: the southwest oncology group experience.
      ,
      • Sweeney C.J.
      • Zhu J.
      • Sandler A.B.
      • Schiller J.
      • Belani C.P.
      • Langer C.
      • et al.
      Outcome of patients with a performance status of 2 in eastern cooperative oncology group study E1594: a phase II trial in patients with metastatic nonsmall cell lung carcinoma.
      ]; however, these tools were validated in younger adults and are not suitable for predicting vulnerability to chemotherapy in older adult patients. Other factors such as comorbidity, nutrition, physical and cognitive function, and social support also correlate with toxicity to therapy and cancer outcomes [
      • Dale W.
      • Mohile S.G.
      • Eldadah B.A.
      • Trimble E.L.
      • Schilsky R.L.
      • Cohen H.J.
      • et al.
      Biological, clinical, and psychosocial correlates at the interface of cancer and aging research.
      ]. Comprehensive geriatric assessment (CGA), a compilation of standardized tools to assess these factors, can help predict mortality in older adult cancer patients [
      • Extermann M.
      • Hurria A.
      Comprehensive geriatric assessment for older patients with cancer.
      ,
      • Kanesvaran R.
      • Li H.
      • Koo K.N.
      • Poon D.
      Analysis of prognostic factors of comprehensive geriatric assessment and development of a clinical scoring system in elderly Asian patients with cancer.
      ,
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • Topinkova E.
      • Janssen-Heijnen M.L.
      • Extermann M.
      • et al.
      International society of geriatric oncology consensus on geriatric assessment in older patients with cancer.
      ,
      • Corre R.
      • Greillier L.
      • Le Caër H.
      • Audigier-Valette C.
      • Baize N.
      • Bérard H.
      • et al.
      Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non-small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08-02 study.
      ].
      As CGA is complicated for daily clinical practice, it has been validated for community oncologist [
      • Mohile S.G.
      • Dale W.
      • Somerfield M.R.
      • Schonberg M.A.
      • Boyd C.M.
      • Burhenn P.S.
      • et al.
      Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
      ,
      • Gajra A.
      • Jeune-Smith Y.
      • Fortier S.
      • Feinberg B.
      • Phillips Jr., E.
      • Balanean A.
      • et al.
      The use and knowledge of validated geriatric assessment instruments among US community oncologists.
      ]. Furthermore, several reports predicted the risk of treatment associated toxicity and indicated that a certain subgroup of older adult patients with cancer were more vulnerable to adverse events from chemotherapy [
      • Extermann M.
      • Boler I.
      • Reich R.R.
      • Lyman G.H.
      • Brown R.H.
      • DeFelice J.
      • et al.
      Predicting the risk of chemotherapy toxicity in older patients: the chemotherapy risk assessment scale for high-age patients (CRASH) score.
      ,
      • Hurria A.
      • Togawa K.
      • Mohile S.G.
      • Owusu C.
      • Klepin H.D.
      • Gross C.P.
      • et al.
      Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study.
      ,
      • Hurria A.
      • Mohile S.
      • Gajra A.
      • Klepin H.
      • Muss H.
      • Chapman A.
      • et al.
      Validation of a prediction tool for chemotherapy toxicity in older adults with cancer.
      ]. In this study, we completed a pre-first-line systemic therapy assessment, including the following: patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables, focused on older adult NSCLC patients. From these factors, we aimed to develop a risk stratification to predict vulnerability to systemic therapy in older adult NSCLC patients.

      2. Methods

      2.1 Patients

      This prospective observational study was performed at 24 National Hospital Organization (NHO) institutions. The main eligibility criteria were age ≥ 70 years, histologically or cytologically proven advanced NSCLC (according to the TNM classification, the 7th edition), and a schedule to receive first-line systemic therapy (cytotoxic chemotherapy or targeted therapy). Patients with active malignancy within the past five years, history of systemic therapy, massive pleural effusion, and pericardial effusion or ascites who received radiation therapy to the lung were excluded from the study. All patients provided written informed consent before enrollment. This study was approved by the NHO Central Review Board and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines (UMIN000010384).

      2.2 Study schema

      All patients completed a pre-first-line systemic therapy assessment, including the following parameters: cancer characteristics (tumor type, stage, and driver mutation status), treatment variables, laboratory test values, and geriatric assessment variables. The Barthel Index [
      • Mahoney F.I.
      • Barthel D.W.
      Functional evaluation: the Barthel index.
      ] was used to evaluate activities of daily living. Independence of daily living and limitation of daily life due to dementia were evaluated by the physicians in terms of whether or not patients needed assistance. The evaluation of hearing and falls within six months were made by patients' self-report or their families. The patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.

      2.3 Statistical Analysis

      Descriptive analyses were performed to summarize the patients' treatment variables and geriatric assessment results. The incidence of the specific categories (hematologic and non-hematologic) and toxicity of NCI-CTCAE grade 3, 4, or 5 were calculated.
      The χ2 test was used to examine the association between patient characteristics and hematologic or non-hematologic toxicity. The best combined sets of risk factors that predicted systemic therapy toxicity were evaluated using a multivariate logistic regression model with a backward elimination procedure. A risk score for each risk factor was calculated by dividing the β-coefficient of the variable by the lowest β-coefficient in the model and then rounding off to the nearest whole number [
      • Concato J.
      • Feinstein A.R.
      • Holford T.R.
      The risk of determining risk with multivariable models.
      ,
      • Walter L.C.
      • Brand R.J.
      • Counsell S.R.
      • Palmer R.M.
      • Landefeld C.S.
      • Fortinsky R.H.
      • et al.
      Development and validation of a prognostic index for 1-year mortality in older adults after hospitalization.
      ]. The sum of the scores for each patient was calculated. The discrimination and calibration of the predictive model were assessed using the total score as a predictor of systemic therapy toxicity. The difference was considered significant at a two-sided p-value of 0.05 or less. All statistical analyses were performed by SAS 9.4 (SAS Institute, Cary, NC).

      3. Results

      3.1 Patient and treatment characteristics

      Between April 2013 and March 2017, 354 patients were enrolled from 24 NHO institutions. Four patients were discontinued before receiving the first-line systemic therapy. One patient was subsequently excluded because of concurrent radiotherapy to the lung, and another patient was excluded due to being classified as non-advanced (Stage IIIA) NSCLC. As a result, 348 patients were included in the analysis (Table 1). The median age of patients was 76 years (range, 70–95 years). The ratio of patients with stage IIIB NSCLC was 11.8%, and stage IV and recurrence was 88.2%. About two-thirds of the patients were male (69.8%), and the most common tumor type was adenocarcinoma (71.8%). One hundred patients (28.7%) had epidermal growth factor receptor (EGFR) mutations, and only three patients (0.9%) had anaplastic lymphoma kinase (ALK) fusion gene-rearrangements. Eighty-six patients (24.7%) received tyrosine kinase inhibitor (TKI) therapy (EGFR-TKIs: 85 patients; ALK-TKI: one patient). As for first-line cytotoxic chemotherapy, more patients received combination chemotherapy (54.9%) than single-agent chemotherapy (20.4%). About two-thirds of the patients (62.1%) were treated with standard doses.
      Table 1Patient characteristics (N = 348).
      CharacteristicsNo. of patients%Patients
      Age<7513639.1
      ≥7521260.9
      SexMale24369.8
      Female10530.2
      StageIIIB4111.8
      IV27378.4
      recurrence349.8
      HistologyAdenocarcinoma25071.8
      Squamous cell carcinoma7220.7
      Non-small cell carcinoma267.5
      EGFR・ALKWild type24570.4
      EGFR10028.7
      (Exon18/19/20/21/compound/unknown)(4/34/2/57/1/2)
      ALK30.9
      ECOG-PS013037.4
      118854.0
      2257.2
      ≥351.4
      CCI018352.6
      111232.2
      24312.4
      ≥3102.9
      Regimen forTKI8624.7
      1st line therapySingle agent7120.4
      Combination19154.9
      Dose of therapyStandard21662.1
      Reduction13237.9
      Body weight loss<5%25673.5
      5–10%7220.7
      ≥5%195.5
      Unknown10.3
      BMI<2216246.6
      ≥2218653.4
      MMSE<3023968.7
      309928.4
      Unknown102.9
      Barthel Index≥8532392.8
      <85236.6
      Unknown20.6
      Independence ofNot limited28481.6
      daily livingLimited6318.1
      Unknown10.3
      Daily life due toNot limited32794.0
      dementiaLimited205.8
      Unknown10.3
      HearingFair30186.5
      Worse4613.2
      Unknown10.3
      Falls within032192.2
      six months1 or more267.5
      Unknown10.3
      Managing his/herPossible31690.8
      medicationNeed assistance318.9
      Unknown10.3
      Hemoglobin≥10 g/dL33094.8
      <10185.2
      Albumin≥3 g/dL29785.3
      <35114.7
      CreatinineNormal31690.8
      Abnormal329.2
      LDH<460 IU/L33696.6
      ≥460123.4
      CRP<3 mg/dL28080.5
      ≥36719.3
      Unknown10.3
      EGFR = epidermal growth factor receptor; ALK = anaplastic lymphoma kinase; ECOG-PS = Eastern cooperative oncology group performance status; CCI = Charlson comorbidity index; TKI = tyrosine kinase inhibitor; BMI = body mass index; MMSE = mini-mental state examination.

      3.2 Geriatric assessment

      The most common comorbid conditions were hypertension (46.3%), diabetes mellitus (16.7%), and chronic obstructive pulmonary disease (14.4%). Fifty-three patients (15.3%) were at high risk of complications (the Charlson Comorbidity Index [CCI] [
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ] was 2 points or more). The patients' body mass indexes (BMI) ranged from 13.9 to 34.0 kg/m2, with about half (53.4%) of the patients having a BMI >22 kg/m2. Ninety-one patients (26.2%) had a body weight loss of 5% or more within six months.
      Although most patients showed good PS (ECOG-PS =0/1: 91.4%), patients with poor PS (ECOG-PS ≥2: 8.6%) were also enrolled. Sixty-three patients (18.2%) were limited in activities of daily living. According to the Barthel Index, 23 patients (6.6%) had a score of <85 points. As for cognitive function, about two-thirds of the patients (68.7%) could not get the perfect score of the mini-mental state examination (MMSE) [
      • Folstein M.F.
      • Folstein S.E.
      • McHugh P.R.
      ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician.
      ]. Twenty patients (5.8%) had trouble in daily living because of their cognitive dysfunction.

      3.3 Systemic therapy toxicity and development of a risk stratification system

      Severe adverse events, grade 3 to 5 according to NCI-CTCAE, version 4.0, occurred in 136 patients (39.1%). Among them, severe hematologic toxicity occurred in 103 patients (29.6%), and severe non-hematologic toxicity occurred in 57 patients (16.4%). The most common severe adverse events were neutropenia (24.7%), leucopenia (18.1), and infection (6.6%) (Supplementary Table 1). About one-third of the patients (29.9%) required a dose reduction in systemic therapy or postponing of the next cycle. Moreover, 53 patients (15.2%) discontinued treatment due to adverse events or unexpected events during one cycle of therapy.
      The treatment variables CCI ≥2, BMI ≥22, limitation in daily living due to dementia, and anemia were associated with severe hematologic toxicity in the univariate analysis (Table 2). As per the calculated odds ratio from the multivariate analysis, single-agent regimen as first-line systemic therapy, BMI ≥22, body weight loss of 5% or more within six months, and limitation of daily life due to dementia were extracted as the risk factors. These risk factors distinguished the risk levels of hematologic toxicity ≥grade 3 (Fig. 1A ); 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Area under the receiver operating characteristics curve (AUC) was 0.66.
      Table 2Association between patient characteristics and Hematologic toxicity.
      VariableNo. of Grade 0–2 toxicity (N = 245)No. of Grade 3–5 toxicity (N = 103)(N = 348)p-value
      N (%)N (%)N (%)
      Age<7598 (40.0)38 (36.9)136 (39.1)0.5877
      ≥75147 (60.0)65 (63.1)212 (60.9)
      SexMale199 (68.4)44 (77.2)243 (69.8)0.1852
      Female92 (31.6)13 (22.8)105 (30.2)
      ECOG-PS0–1226 (92.2)92 (89.3)318 (91.4)0.3749
      ≥219 (7.8)11 (10.7)30 (8.6)
      CCI0–1214 (87.3)81 (78.6)295 (84.8)0.0391
      ≥231 (12.7)22 (21.4)53 (15.2)
      Regimen forTKI85 (34.7)1 (1.0)86 (24.7)< 0.0001
      1st line therapySingle agent34 (13.9)37 (35.9)71 (20.4)
      Combination126 (51.4)65 (63.1)191 (54.9)
      Dose of therapyStandard158 (64.5)58 (56.3)216 (62.1)0.1512
      Reduction87 (35.5)45 (43.7)132 (37.9)
      Body weight loss<5%185 (75.5)71 (68.9)256 (73.6)0.3328
      ≥5%59 (24.1)32 (31.1)91 (26.1)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      BMI<22122 (49.8)40 (38.8)162 (46.6)0.0613
      ≥22123 (50.2)63 (61.2)186 (53.4)
      MMSE<30165 (67.3)74 (71.8)239 (68.7)0.6898
      3073 (29.8)26 (25.2)99 (28.4)
      Unknown7 (2.9)3 (2.9)10 (2.9)
      Barthel Index≥85227 (92.7)96 (93.2)323 (92.8)0.6535
      <8516 (6.5)7 (6.8)23 (6.6)
      Unknown2 (0.8)0 (0.0)2 (0.6)
      Independence ofNot limited206 (84.1)78 (75.7)284 (81.6)0.1277
      daily livingLimited38 (15.5)25 (24.3)63 (18.1)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      Daily life due toNot limited234 (95.5)93 (90.3)327 (94.0)0.0990
      dementiaLimited10 (4.1)10 (9.7)20 (5.7)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      HearingFair211 (86.1)90 (87.4)301 (86.5)0.7894
      Worse33 (13.5)13 (12.6)46 (13.2)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      Falls within0225 (91.8)96 (93.2)321 (92.2)0.7694
      six months1 or more19 (7.8)7 (6.8)26 (7.5)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      Managing his/herPossible226 (92.2)90 (87.4)316 (90.8)0.2376
      medicationNeed assistance18 (7.3)13 (12.6)31 (8.9)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      Hemoglobin≥10 g/dL237 (96.7)93 (90.3)330 (94.8)0.0132
      <108 (3.3)10 (9.7)18 (5.2)
      Albumin≥3 g/dL212 (86.5)85 (82.5)297 (85.3)0.3347
      <333 (13.5)18 (17.5)51 (14.7)
      CreatinineNormal225 (91.8)91 (88.4)316 (90.8)0.3041
      Abnormal20 (8.2)12 (11.7)32 (9.2)
      LDH<460 IU/L236 (96.3)100 (97.1)336 (96.6)0.7225
      ≥4609 (3.7)3 (2.9)12 (3.4)
      CRP<3 mg/dL201 (82.0)79 (76.7)280 (80.5)0.3824
      ≥343 (17.6)24 (23.3)67 (19.3)
      Unknown1 (0.4)0 (0.0)1 (0.3)
      ECOG-PS = Eastern cooperative oncology group performance status; CCI = Charlson comorbidity index; TKI = tyrosine kinase inhibitor; BMI = body mass index; MMSE = mini-mental state examination; LDH = lactate dehydrogenase; CRP = C-reactive protein.
      Fig. 1
      Fig. 1Risk scores were assigned to each risk factor from odds ratio for grade 3 to 5 adverse events, and the sum of the scores for each patient was calculated. This score predicted the percentage of patients who experienced grade 3 to 5 (A) hematologic toxicity and (B) non-hematologic toxicity.
      Non-hematologic toxicity was associated with sex (male), functional status (ECOG-PS, Barthel Index, and limitation in activities of daily living), hypoalbuminemia (<3 g/dL), and high lactate dehydrogenase levels (≥460 IU/L) in the univariate analysis (Table 3). Based on the odds ratio from the multivariate analysis, sex (male), limitation in activities of daily living, and high lactate dehydrogenase levels were extracted as the risk factors. When risk scores were assigned to each factor, this scoring system could predict the frequency of severe non-hematologic toxicity (Fig. 1B); 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), and 3 points (75.0%) (AUC = 0.69).
      Table 3Association between patient characteristics and Non-hematologic toxicity.
      VariableNo. of Grade 0–2 toxicity (N = 291)No. of Grade 3–5 toxicity (N = 57)(N = 348)p-value
      N (%)N (%)N (%)
      Age<75108 (37.1)28 (49.1)136 (39.1)0.0893
      ≥75183 (62.9)29 (50.9)212 (60.9)
      SexMale161 (65.7)82 (79.6)243 (69.8)0.0099
      Female84 (34.3)21 (20.4)105 (30.2)
      ECOG-PS0–1272 (93.5)46 (80.7)318 (91.4)0.0017
      ≥219 (6.5)11 (19.3)30 (8.6)
      CCI0–1247 (84.9)48 (84.2)295 (84.8)0.8977
      ≥244 (15.1)9 (15.8)53 (15.2)
      Regimen forTKI73 (25.1)13 (22.8)86 (24.7)0.8810
      1st line therapySingle agent60 (20.6)11 (19.3)71(20.4)
      Combination158 (54.3)33 (57.9)191 (54.9)
      Dose of therapyStandard178 (61.2)38 (66.7)216 (62.1)0.4340
      Reduction113 (38.8)19 (33.3)132 (37.9)
      Body weight loss<5%219 (75.3)37 (64.9)256 (73.6)0.2263
      ≥5%71 (24.4)20 (35.1)91 (26.1)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      BMI<22133 (45.7)29 (50.9)162 (46.6)0.4740
      ≥22158 (54.3)28 (49.1)186 (53.4)
      MMSE<30200 (68.7)39 (68.4)239 (68.7)0.9513
      3083 (28.5)16 (28.1)99 (28.4)
      Unknown8 (2.7)2 (3.5)10 (2.9)
      Barthel Index≥85274 (94.2)49 (86.0)323 (92.8)0.0403
      <8515 (5.2)8 (14.0)23 (6.6)
      Unknown2 (0.7)0 (0.0)2 (0.6)
      Independence ofNot limited246 (84.5)38 (66.7)284 (81.6)0.0045
      daily livingLimited44 (15.1)19 (33.3)63 (18.1)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      Daily life due toNot limited275 (94.5)52 (91.2)327 (94.0)0.5129
      dementiaLimited15 (5.2)5 (8.8)20 (5.7)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      HearingFair253 (86.9)48 (84.2)301 (86.5)0.7491
      Worse37 (12.7)9 (15.8)46 (13.2)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      Falls within0270 (92.8)51 (89.5)321 (92.2)0.5758
      six months1 or more20 (6.9)6 (10.5)26 (7.5)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      Managing his/herPossible24 (8.2)7 (12.3)31 (8.9)0.5662
      medicationNeed assistance266 (91.4)50 (87.7)316 (90.8)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      Hemoglobin≥10 g/dL275 (94.5)55 (96.5)330 (94.8)0.5351
      <1016 (5.5)2 (3.5)18 (5.2)
      Albumin≥3 g/dL254 (87.3)43 (75.4)297 (85.3)0.0207
      <337 (12.7)14 (24.6)51 (14.7)
      CreatinineNormal265 (91.1)51 (89.5)316 (90.8)0.7037
      Abnormal26 (8.9)6 (10.5)32 (9.2)
      LDH<460 IU/L284 (97.6)52 (91.2)336 (96.6)0.0160
      ≥4607 (2.4)5 (8.8)12 (3.4)
      CRP<3 mg/dL237 (81.4)43 (75.4)280 (80.5)0.4948
      ≥353 (18.2)14 (24.6)67 (19.3)
      Unknown1 (0.3)0 (0.0)1 (0.3)
      ECOG-PS = Eastern cooperative oncology group performance status; CCI = Charlson comorbidity index; TKI = tyrosine kinase inhibitor; BMI = body mass index; MMSE = mini-mental state examination; LDH = lactate dehydrogenase; CRP = C-reactive protein.

      4. Discussion

      We developed a risk stratification to predict vulnerability to systemic therapy in older adult NSCLC patients, using patient backgrounds and parameters often used in daily clinical practice. A previous report indicated that several risk factors could predict the frequency of severe adverse events. These factors include age, treatment dose, number of systemic therapy drugs, hearing status, number of falls in the last six months, medication administration, limitation during walking one block, decreased social activity, and hemoglobin and creatinine clearance [
      • Hurria A.
      • Togawa K.
      • Mohile S.G.
      • Owusu C.
      • Klepin H.D.
      • Gross C.P.
      • et al.
      Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study.
      ,
      • Hurria A.
      • Mohile S.
      • Gajra A.
      • Klepin H.
      • Muss H.
      • Chapman A.
      • et al.
      Validation of a prediction tool for chemotherapy toxicity in older adults with cancer.
      ]. Although these results are very interesting, the study is not specific to lung cancer, and there is no discrimination of the risk factors between hematological and non-hematological toxicities. In another report, several factors, such as ECOG-PS, the Lawton 9-item Instrumental Activities of Daily Living (IADL) [
      • Lawton M.P.
      Scales to measure competence in everyday activities.
      ], mini-nutritional assessment (MNA) [
      • Vellas B.
      • Guigoz Y.
      • Garry P.J.
      • Nourhashemi F.
      • Bennahum D.
      • Lauque S.
      • et al.
      The mini nutritional assessment (MNA) and its use in grading the nutritional state of elderly patients.
      ], MMSE, and high lactate dehydrogenase levels (≥ 460 IU/L), predicted the frequency of hematologic and non-hematologic toxicities [
      • Extermann M.
      • Boler I.
      • Reich R.R.
      • Lyman G.H.
      • Brown R.H.
      • DeFelice J.
      • et al.
      Predicting the risk of chemotherapy toxicity in older patients: the chemotherapy risk assessment scale for high-age patients (CRASH) score.
      ]. To improve the convenience in daily practice and assist in decision making, we also assessed the usefulness of the alternative measures: limitation in activities of daily living instead of IADL; albumin, BMI, and body weight loss instead of MNA; and independence of dementia instead of MMSE.
      Single-agent chemotherapy as first-line therapy, BMI ≥ 22, body weight loss of ≥5% within six months, and limitations in daily living due to dementia were identified as the risk factors of hematologic toxicity. Docetaxel is one of the standard therapeutic options for older adult patients with NSCLC in Japan, although the Japanese population seems more susceptible to its toxicity [
      • Kenmotsu H.
      • Tanigawara Y.
      Pharmacokinetics, dynamics and toxicity of docetaxel: why the Japanese dose differs from the Western dose.
      ]. In a recent randomized phase III trial comparing docetaxel with carboplatin plus pemetrexed in Japan, severe hematologic toxicities were higher in the docetaxel group compared with those in the latter group [
      • Okamoto I.
      • Nokihara H.
      • Nomura S.
      • Niho S.
      • Sugawara S.
      • Horinouchi H.
      • et al.
      Comparison of carboplatin plus pemetrexed followed by maintenance pemetrexed with docetaxel monotherapy in elderly patients with advanced nonsquamous non-small cell lung cancer: a phase 3 randomized clinical trial.
      ]. In our study, docetaxel or docetaxel plus bevacizumab were administered to about half of the patients treated with single-agent chemotherapy (Supplementary Table 2). This large number of patients in the docetaxel group may be the reason for single-agent chemotherapy to appear as one of the risk factors. There was no significant difference in the risk of toxicity and prognosis between high and low BMI groups among the Japanese patients with cancer [
      • Miya T.
      • Goya T.
      • Yanagida O.
      • Nogami H.
      • Koshiishi Y.
      • Sasaki Y.
      • et al.
      The influence of relative body weight on toxicity of combination chemotherapy with cisplatin and etoposide.
      ,
      • Kashiwabara K.
      • Yamane H.
      • Tanaka H.
      Toxicity and prognosis in overweight and obese women with lung cancer receiving carboplatin-paclitaxel doublet chemotherapy.
      ]. However, dose adjustment by only BMI or body surface area, as with young patients, may lead to an overdose in older adult patients. As for cognitive function, platinum doublet chemotherapy was previously shown to be less effective in groups with low MMSE scores [
      • Quoix E.
      • Zalcman G.
      • Oster J.P.
      • Westeel V.
      • Pichon E.
      • Lavolé A.
      • et al.
      Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.
      ]. We should consider the patients' cognitive function during shared decision making.
      Sex, limitation in activities of daily living, and high lactate dehydrogenase levels were identified as risk factors of non-hematologic toxicity. In the ECOG 1594 trial, adverse events were more frequent in female than in male patients with NSCLC receiving platinum doublet chemotherapy [
      • Wakelee H.A.
      • Wang W.
      • Schiller J.H.
      • Langer C.J.
      • Sandler A.B.
      • Belani C.P.
      • et al.
      Survival differences by sex for patients with advanced non-small cell lung cancer on eastern cooperative oncology group trial 1594.
      ]. However, male patients had more non-hematologic toxicities in our study. As the number of patients with dose reduction did not differ between the male and female patient groups (data not shown), the contradictory results may be attributed to the overdose of systemic therapy in older adult male patients who had a higher BMI compared with females. Physical function [
      • Albain K.S.
      • Crowley J.J.
      • LeBlanc M.
      • Livingston R.B.
      Survival determinants in extensive-stage non-small-cell lung cancer: the southwest oncology group experience.
      ,
      • Sweeney C.J.
      • Zhu J.
      • Sandler A.B.
      • Schiller J.
      • Belani C.P.
      • Langer C.
      • et al.
      Outcome of patients with a performance status of 2 in eastern cooperative oncology group study E1594: a phase II trial in patients with metastatic nonsmall cell lung carcinoma.
      ,
      • Dale W.
      • Mohile S.G.
      • Eldadah B.A.
      • Trimble E.L.
      • Schilsky R.L.
      • Cohen H.J.
      • et al.
      Biological, clinical, and psychosocial correlates at the interface of cancer and aging research.
      ,
      • Extermann M.
      • Hurria A.
      Comprehensive geriatric assessment for older patients with cancer.
      ,
      • Kanesvaran R.
      • Li H.
      • Koo K.N.
      • Poon D.
      Analysis of prognostic factors of comprehensive geriatric assessment and development of a clinical scoring system in elderly Asian patients with cancer.
      ,
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • Topinkova E.
      • Janssen-Heijnen M.L.
      • Extermann M.
      • et al.
      International society of geriatric oncology consensus on geriatric assessment in older patients with cancer.
      ,
      • Corre R.
      • Greillier L.
      • Le Caër H.
      • Audigier-Valette C.
      • Baize N.
      • Bérard H.
      • et al.
      Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non-small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08-02 study.
      ] and high levels of lactate dehydrogenase [
      • Lee D.S.
      • Park K.R.
      • Kim S.J.
      • Chung M.J.
      • Lee Y.H.
      • Chang J.H.
      • et al.
      Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes.
      ,
      • Ulas A.
      • Turkoz F.P.
      • Silay K.
      • Tokluoglu S.
      • Avci N.
      • Oksuzoglu B.
      • et al.
      A laboratory prognostic index model for patients with advanced non-small cell lung cancer.
      ] correlated with clinical outcomes as supported by the previous reports. Our findings indicated that these factors were useful for assessing the vulnerability of older adult patients with advanced NSCLC to systemic therapy.
      This study had several limitations. First, there is a bias in treatment variables because the decision of selecting the first-line therapy regimen or dose de-escalation was made by the physicians, as suitable in clinical practice. Although the analysis considered treatment variables, TKIs exhibit different levels of toxicity and contribute to clinical outcomes, compared to cytotoxic chemotherapy. Second, there were few cases of severe adverse events among several of the risk factors investigated at this time. Further investigation is required to determine whether risk stratification using our method may be useful in clinical practice. Moreover, patients with NSCLC treated with immune checkpoint inhibitors (ICIs) as first-line systemic therapy were not included in our study. As reported by previous studies, pembrolizumab showed clinical benefit for patients with advanced NSCLC, regardless of the patient's age [
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • Hui R.
      • Csószi T.
      • Fülöp A.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      ,
      • Nosaki K.
      • Saka H.
      • Hosomi Y.
      • Baas P.
      • de Castro G.
      • Jr Reck M.
      • et al.
      Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
      ]. Although the combination therapy of platinum doublet chemotherapy and ICIs has emerged as one of the standard therapies for advanced NSCLC patients [
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • Esteban E.
      • Felip E.
      • De Angelis F.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      ,
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • Stroyakovskiy D.
      • Nogami N.
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      ,
      • West H.
      • McCleod M.
      • Hussein M.
      • Morabito A.
      • Rittmeyer A.
      • Conter H.J.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Nishio M.
      • Barlesi F.
      • West H.
      • Ball S.
      • Bordoni R.
      • Cobo M.
      • et al.
      Atezolizumab plus chemotherapy for first-line treatment of nonsquamous NSCLC: results from the randomized phase 3 IMpower132 trial.
      ], the safety of the combination therapies in older adult patients is controversial. For choosing a therapeutic strategy involving ICIs, the assessment of the individual older adult patient's vulnerability to systemic therapy is of utmost importance.

      5. Conclusion

      This prospective multicenter study demonstrated that many older adult patients with advanced NSCLC experienced severe adverse events in daily practice. Our findings emphasize that careful dose adjustment needs to be performed for such vulnerable patients with advanced disease. A risk stratification using our method may be useful to predict the vulnerability to systemic therapy in older adult patients with NSCLC.

      Author contribution

      Conceptualization: Masaki Kanazu, Shinji Atagi.
      Data curation: Masaki Kanazu, Ryusei Saito, Masahide Mori, Atsuhisa Tamura, Yoshio Okano, Yuka Fujita, Takeo Endo, Mitsuru Motegi, Shohei Takata, Toshiyuki Kita, Noriaki Sukoh, Mitsuhiro Takenoyama, Shinji Atagi.
      Formal analysis: Masaki Kanazu, Mototsugu Shimokawa.
      Funding acquisition: Masaki Kanazu
      Investigation: Masaki Kanazu, Mototsugu Shimokawa.
      Methodology: Masaki Kanazu, Mototsugu Shimokawa, Shinji Atagi.
      Project administration: Masaki Kanazu, Shinji Atagi.
      Supervision: Shinji Atagi
      Validation: Mototsugu Shimokawa
      Visualization: Masaki Kanazu, Mototsugu Shimokawa
      Writing: Masaki Kanazu, Mototsugu Shimokawa
      Review and editing: Ryusei Saito, Masahide Mori, Atsuhisa Tamura, Yoshio Okano, Yuka Fujita, Takeo Endo, Mitsuru Motegi, Shohei Takata, Toshiyuki Kita, Noriaki Sukoh, Mitsuhiro Takenoyama.

      Category

      Prospective observational study.

      Funding

      This study was supported by National Hospital Organization in Japan.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      We thank all investigators and patients, including their families, for their participation in this study.

      Appendix A. Supplementary data

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