Prediction of chemotherapy adverse reactions and mortality in older patients with primary lung cancer through frailty index based on routine laboratory data

Figures & data

Figure 1 Study profile including patients’ selection and mortality information.

Figure 2 Survival curves 926 patients with primary lung cancer receiving chemotherapy according to baseline frailty status assessed by FI-LAB.

Abbreviation: FI-LAB, frailty index based on laboratory variables.

Table 1 Characteristics of the study population according to frailty assessed by FI-LAB

N=1020	Robust(n=701)	Pre-frail(n=269)	Frail(n=50)	P*
Age (years)	64 (61,69)	65 (63,69)	67 (62,70)	0.136
Female, n (%)	213 (30.4)	65 (24.2)	14 (28.0)	0.158
Marital Status, n (%)				0.925
married	678 (96.7)	261 (97.0)	48 (96.0)
single/widowed	23 (3.3)	8 (3.0)	2 (4.0)
Occupation, n (%)				0.594
technician/worker	41 (5.8)	16 (5.9)	5 (10.0)
civil Servants	50 (7.1)	21 (7.8)	7 (14.0)
farmer	92 (13.1)	29 (10.8)	5 (10.0)
retiree	166 (23.7)	60 (22.3)	9 (18.0)
others	352 (50.2)	143 (53.2)	24 (48.0)
BMI (kg/m^2), mean ± SD	22.70±3.14	22.42±3.01	22.44±2.68	0.413
Health Insurance, n (%)				0.052
no	343 (48.9)	155 (57.6)	25 (50.0)
yes	358 (51.1)	114 (42.4)	25 (50.0)
Smoking Status, n (%)				0.053
non-smoker	287 (73.0)	89 (33.1)	17 (34.0)
former smoker	216 (30.8)	79 (29.4)	15 (30.0)
current smoker	198 (28.2)	101 (37.5)	18 (36.0)
Pack-years of cigarettes	15 (0,40)	24 (0,40)	20 (0,40)	0.013
Alcohol Drinking, n (%)				0.942
never	419 (49.8)	157 (58.4)	27 (54.0)
sometimes	148 (21.1)	60 (22.3)	12 (24.0)
always	134 (19.1)	52 (19.3)	11 (22.0)
Number of chronic diseases^@	1.64±1.53	1.56±1.46	1.50±1.27	0.627
Patients with lung cancer surgery, n (%)	242 (80.4)	55 (18.3)	4 (1.3)	<0.001
Histology, n (%)				0.052
adenocarcinoma	515 (73.5)	171 (63.6)	34 (68.0)
squamous carcinoma	97 (13.8)	52 (19.3)	8 (16.0)
small cell carcinoma	89 (12.7)	46 (17.1)	8 (16.0)
Regimen of Chemotherapy, n (%)				0.001
single	48 (6.8)	32 (11.9)	10 (20.0)
combination	653 (93.2)	237 (88.1)	40 (80.0)
Metastasis, n (%)	595 (85.0)	245 (91.1)	49 (98.0)	0.003
Clinical Stage, n (%)				<0.001
I	61 (8.7)	9 (3.3)	1 (2.0)
II	68 (9.7)	15 (5.6)	0 (0.0)
III	215 (30.7)	77 (28.6)	9 (18.0)
IV	357 (50.9)	168 (62.5)	40 (80.0)
Radiotherapy, n (%)	189 (27.0)	103 (38.3)	18 (36.0)	0.002

Notes: Data are the Median (Q1, Q3) unless otherwise indicated. *Significance testing of the differences between groups were carried out using Kruskal-Wallis test, Pearson’s chi-square analysis or Fisher’s exact test or one-way analysis of variance as appropriate. ^@chronic diseases include hypertension, coronary heart disease, chronic obstructive pulmonary disease, asthma, digestive system diseases, diabetes mellitus, thyroid diseases, nervous system diseases, immunological diseases, renal diseases, urinary tract diseases, osteoarticular diseases and other chronic diseases (except lung cancer).

Abbreviations: BMI, body mass index; FI-LAB, frailty index based on laboratory variables.

Table 2 The differences of short-term chemotherapy adverse reactions according to baseline frailty status

N=1020	Robust (n=701)	Pe-frail (n=269)	Frail (n=50)	P*
Any adverse reactions	83 (11.8)	53 (19.7)	15 (30.0)	0.001
Digestive reactions	40 (5.7)	17 (6.3)	3 (6.0)	0.935
All infections	40 (5.7)	33 (12.3)	9 (18.0)	<0.001
Fungus infection	7 (1.0)	10 (3.7)	1 (2.0)	0.619
Other adverse reactions	9 (1.3)	7 (2.6)	4 (8.0)	0.020

Notes: Any adverse reactions include digestive reactions, infection, non-infection fever or rash; other adverse reactions include non-infection fever or rash. *Significance testing of the differences between groups were carried out using Pearson’s chi-square analysis or Fisher’s exact test as appropriate.

Table 3 The associations between frailty and risk of short-term chemo adverse reactions

N=1020	Robust (N=701)		Pre-frail (N=269)		Frail (N=50)
	OR (95%CI)	P	OR (95%CI)	P	OR (95%CI)	P
Any adverse reactions
Model 1	1	-	1.83(1.25,2.67)	0.002	3.19(1.67,6.09)	<0.001
Model 2	1	-	1.85(1.26,2.72)	0.002	3.19(1.67,6.12)	<0.001
Model 3	1	-	1.86(1.25,2.77)	0.002	3.48(1.77,6.87)	<0.001
All infections
Model 1	1	-	2.31(1.42,3.75)	0.001	3.63(1.65,7.98)	0.001
Model 2	1	-	2.37(1.45,3.88)	0.001	3.72(1.68,8.26)	0.001
Model 3	1	-	2.24(1.35,3.74)	0.002	3.58(1.55,8.26)	0.003
Other adverse reactions
Model 1	1	-	2.05(0.76,5.57)	0.157	6.69(1.98,22.53)	0.002
Model 2	1	-	2.04(0.74,5.60)	0.169	6.03(1.75,20.72)	0.004
Model 3	1	-	1.95(0.69,5.51)	0.205	5.65(1.52,20.93)	0.010

Notes: Any adverse reactions include digestive reactions, infection, non-infection fever or rash; other adverse reactions include non-infection fever or rash. Model 1: Unadjusted model. Model 2: Adjusted for age, sex, occupation, health insurance, BMI, pack-years of cigarettes and drinking history. Model 3: Further adjusted for number of chronic diseases (except lung cancer), histology, regimen of chemotherapy, metastasis, clinical stage, radiotherapy and lung cancer surgery.

Abbreviations: OR, odds ratio; CI, confidence intervals; BMI, body mass index.

Table 4 The prognostic role of frailty in predicting all-cause mortality

N=926	All-cause mortality
	Crude HR	95%CI	P	Adjusted HR*	95%CI	P
Frailty status
Robust	1	-	-	1	-	-
Pre-frail	1.66	1.39–1.98	<0.001	1.30	1.08–1.57	0.006
Frail	3.00	2.15–4.18	<0.001	2.13	1.51–3.00	<0.001
Frailty as a continuous variable
FI-LAB (per SD)	1.40	1.29–1.52	<0.001	1.23	1.13–1.34	<0.001
FI-LAB (per 0.01)	1.03	1.03–1.04	<0.001	1.02	1.01,1.03	<0.001

Note:*Adjusted for age, sex, occupation, health insurance, BMI, pack-years of cigarettes, drinking history, number of chronic diseases (except lung cancer), histology, regimen of chemotherapy, metastasis, clinical stage, radiotherapy and lung cancer surgery.

Abbreviations: HR, hazards ratio; CI, confidence intervals; SD, standard deviation; FI-LAB, frailty index based on laboratory variables.

Table S1 Laboratory variables for frailty index

	Item	No frailty (Normal)*	+1 Frailty risk (Abnormal)
Routine blood test
1	RBC(*10^12/L)	3.8–5.1 (F) 4.3–5.8 (M)	<3.8 or >5.1 (F) <4.3 or >5.8 (M)
2	Hb (g/L)	115–150 (F) 130–175 (M)	<110 or >150 (F) <130 or >175 (M)
3	HCT (L/L)	0.35–0.45 (F) 0.40–0.50 (M)	<0.35 or >0.45 (F) <0.40 or >0.50 (M)
4	MCV (fL)	82–100	<82 or >100
5	MCH (pg)	27–34	<27 or >34
6	MCHC (g/L)	316–354	<316 or >354
7	RDW-CV (%)	11.5–14.5	<11.5 or >14.5
8	RDW-SD (fL)	37.0–54.0	<34.0 or >54.0
9	PLT (*10^9/L)	100–300	<100 or >300
10	WBC (*10^9/L)	3.5–9.5	<3.5 or >9.5
11	NEUT (*10^9/L)	1.8–6.3	<1.8 or >6.3
12	LYMPH (*10^9/L)	1.1–3.2	<1.1 or >3.2
13	MONO (*10^9/L)	0.1–0.6	<0.1 or >0.6
14	EO (*10^9/L)	0.02–0.52	<0.02 or >0.52
15	BASO (*10^9/L)	0.0–0.06	<0.0 or >0.06
Hepatic Function
16	TBil (umol/L)	5.0–28.0	<5.0 or >28.0
17	DBil (umol/L)	<8.8	≥8.8
18	IDBil (umol/L)	<20	≥20
19	ALT (IU/L)	<50	≥50
20	AST (IU/L)	<40	≥40
21	TP (g/L)	65–85	<65 or >85
22	ALB (g/L)	40–55	<40 or >55
23	ALP (IU/L)	50–135 (F) 51–160 (M)	<50 or >135 (F) <51 or >160 (M)
24	GGT (IU/L)	<45 (F) <60 (M)	≥45 (F) ≥60 (M)
25	CK (IU/L)	20–140 (F) 19–226 (M)	<20 or >140 (F) <16 or >226 (M)
26	LDH (IU/L)	110–220	<110 or >220
Fast Blood Glucose
27	GLU (mmol/L)	3.9–5.9	<3.9 or >5.9
Renal Function
28	UREA (mmol/L)	3.82–8.86	<3.82 or >8.86
29	CREA (umol/L)	53.0–140.0	<53.0 or >140.0
30	URIC (umol/L)	240.0–490.0	<240.0 or >490.0
Blood Lipid
31	TG (mmol/L)	0.29–1.83	<0.29 or >1.83
32	CHOL (mmol/L)	2.8–5.7	<2.8 or >5.7
33	HDL-C (mmol/L)	>0.9	≤ 0.9
34	LDL-C (mmol/L)	<4.0	≥4.0
Blood Electrolyte
35	NA (mmol/L)	137.0–147.0	<137.0 or >147.0
36	K (mmol/L)	3.5–5.5	<3.5 or >5.5
37	CL (mmol/L)	99.0–110	<99 or >110
38	MG (mmol/L)	0.67–1.04	<0.67 or >1.04
39	CA (mmol/L)	2.1–2.7	<2.1 or >2.7
40	P (mmol/L)	0.81–1.45	<0.81 or >1.45
Blood Coagulation
41	PT (s)	9.6–12.8	<9.6 or >12.8
42	INR	0.88–1.15	<0.88 or >1.15
43	APTT (s)	20.0–40.0	<20.0 or >40.0
44	Fib (g/L)	2.0–4.0	<2.0 or >4.0

Notes: *The standard was according to the lab in West China Hospital, Sichuan University.

Abbreviations: F, female; M, male; RBC, red blood cell; Hb, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW-CV, red cell distribution width-coefficient of variation; RDW-SD, red cell distribution width-standard deviation; PLT, platelets; WBC, white blood cell; NEUT, neutrophil; LYMPH, lymphocyte; MONO, monocyte; EO, eosinophil; BASO, basophil; TBil, total bilirubin; DBil, direct bilirubin; IDBil, indirect bilirubin; ALT, alanine transaminase; AST, aspartate aminotransferase; TP, total protein; ALB, albumin; ALP, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase; CK, creatine kinase; LDH, lactate dehydrogenase; GLU, glucose; UREA, urea; CREA, creatinine; URIC, uric acid; TG, triglyceride; CHOL, cholesterol; HDL-C, high-density lipoprotein cholesterol-C; LDL-C, low-density lipoprotein cholesterol-C; NA, sodium; K, potassium; CL, chlorinum; MG, magnesium; CA, calcium; P, phosphorus; PT, prothrombin time; INR, international normalized ratio; APTT, activated partial thromboplastin time; Fib, fibrinogen.