Epidemiology, risk factors and impact of cachexia on patient outcome: Results from the Japanese Lung Cancer Registry Study

Abstract

Background

Cancer cachexia is a syndrome that does not fully recover with nutritional support and causes appetite loss and body weight loss. It worsens a patient's quality of life and prognosis. In this study, the epidemiology of cachexia in lung cancer, its risk factors and its impact on chemotherapy response rate and prognosis were examined using the national database of the Japan Lung Cancer Society. Understanding these things related to cancer cachexia is important as a starting point in overcoming cancer cachexia in patients with lung cancer.

Methods

In 2012, 12 320 patients from 314 institutions in Japan were registered in a nationwide registry database (Japanese Lung Cancer Registry Study). Of these, data on body weight loss within 6 months were available for 8489 patients. We defined the patients with body weight loss ≥ 5% within 6 months, which is one of the three criteria listed in the 2011 international consensus definition of cancer cachexia, as cachectic in this study.

Results

Approximately 20.4% of the 8489 patients had cancer cachexia. Sex, age, smoking history, emphysema, performance status, superior vena cava syndrome, clinical stage, site of metastasis, histology, epidermal growth factor receptor (EGFR) mutation status, primary treatment method and serum albumin levels were significantly different between patients with and without cachexia. Logistic analyses showed that smoking history, emphysema, clinical stage, site of metastasis, histology, EGFR mutation, serum calcium and albumin levels were significantly associated with cancer cachexia. The response to initial therapy, including chemotherapy, chemoradiotherapy or radiotherapy, was significantly poorer in the patients with cachexia than in those without cachexia (response rate: 49.7% vs. 41.5%, P < 0.001). Overall survival was significantly shorter in the patients with cachexia than in those without cachexia in both univariate and multivariable analyses (1‐year survival rate: 60.7% vs. 37.6%, Cox proportional hazards model, hazard ratio: 1.369, 95% confidence interval: 1.274–1.470, P < 0.001).

Conclusions

Cancer cachexia was seen in approximately one fifth of the lung cancer patients and was related to some baseline patient characteristics. It was also associated with a poor response to initial treatment, resulting in poor prognosis. The results of our study may be useful for early identification and intervention in patients with cachexia, which may improve their response to treatment and their prognosis.

Introduction

Globally, the number of lung cancer cases and deaths has been increasing. In 2020, the Global Cancer Observatory estimated 2.2 million new cases (11.4% of the total cancer cases) and 1.79 million deaths (18.0% of the total cancer deaths), making it the most frequently diagnosed cancer and cause of cancer‐related death. ¹ The 5‐year overall survival (OS) rate for non‐small‐cell lung cancer (NSCLC) remains poor, from 68% in patients with stage IB disease to 0–10% in those with stage IVA/IVB disease. ²

Body weight loss in cancer patients worsens prognosis ³ and is often associated with cancer cachexia, which is a syndrome characterized by weight loss (with or without fat loss) and anorexia that cannot be completely reversed by conventional nutritional support. Fearon et al. defined cancer cachexia as weight loss > 5% over the past 6 months (in the absence of simple starvation), or body mass index (BMI) < 20 kg/m² and any degree of weight loss > 2%, or appendicular skeletal muscle index consistent with sarcopenia (<7.26 kg/m² in males and <5.45 kg/m² in females). ⁴ One of the main pathophysiological mechanisms of body weight loss/cancer cachexia is systemic inflammation, which causes weight loss due to the degradation of skeletal muscle and adipose tissue and suppression of appetite. ⁴ A high frequency of cachexia is also observed in patients with advanced lung cancer, ⁵ and in patients with NSCLC, greater weight loss and lower BMI after diagnosis have been associated with worse prognosis and quality of life (QOL). ⁶ Understanding the epidemiology of cachexia in lung cancer, its risk factors and its impact on chemotherapy and prognosis is important as a starting point in overcoming cancer cachexia in patients with lung cancer. Therefore, the objective of this study was to determine the frequency of ≥5% weight loss during the previous 6 months and its relationship to baseline patient characteristics and OS.

Megestrol acetate is the only drug approved by the US Food and Drug Administration for the treatment of AIDS‐related cachexia. Anamorelin hydrochloride (ONO‐7643), a ghrelin‐like agonist, was developed for the treatment of cancer cachexia and approved for its treatment in January 2021 in Japan. In a randomized, double‐blind, phase II study (ONO‐7643‐04) of anamorelin in Japanese NSCLC patients with cachexia, significant improvements in lean body mass, weight gain and appetite‐related QOL were observed in the anamorelin group. ⁷ Phase III trials of anamorelin in patients with NSCLC in the United States and Europe (ROMANA 1 and 2 trials) showed similar results. ⁸ In addition to ghrelin analogues, selective androgen receptor modulators as well as anti‐inflammatory drugs such as thalidomide, OHR, anti‐interleukin antibody, cannabinoids and omega‐3 supplements are in development and currently under investigation in phase I or II studies. ⁹ As there are limited therapeutic agents available at this time, the identification of risk factors for cancer cachexia is important for the prevention of cancer cachexia and the effective use of multidisciplinary treatment, including early rehabilitation and therapeutic agents. However, at present, only small retrospective or single‐centre studies have been conducted to investigate the risk factors for cancer cachexia, making it difficult to accurately predict them. Thus, in the present study, we used a large Japanese database of advanced lung cancer patients to investigate the epidemiology, prognosis and impact of cancer cachexia on the course of treatment in patients clinically defined as cachectic.

Methods

Patient selection and data collection

Medical records of patients with lung cancer were obtained from the Japanese Joint Committee of Lung Cancer Registry (JJCLCR). The committee invited 846 teaching institutions in Japan to participate in this study, of which 314 complied. This registry was opened on 1 January 2012, and a follow‐up survey was completed on 30 April 2016. The institutions participated in this registry by accessing a website established by the JJCLCR. The inclusion criteria for patients were as follows: (1) pathological or cytological diagnosis of advanced NSCLC or small‐cell lung cancer (SCLC) at a participating institution; (2) diagnosis obtained from 1 January to 31 December 2012; and (3) receipt of non‐curative intent surgical treatment, including chemotherapy, chemoradiotherapy or supportive care alone. Patients who underwent palliative surgery for metastatic sites (e.g., brain metastasis) and those who underwent salvage surgery after chemoradiotherapy for locally advanced disease were eligible. Patients who developed recurrence after curative primary surgery were also excluded. The registered patient information was as follows: (1) patient demographic characteristics, including (a) date of registry, (b) sex, (c) birth month and year and (d) month and year of diagnosis; (2) general conditions at diagnosis, including (a) smoking status, (b) body weight loss, (c) presence of concomitant lung disease, (d) Eastern Cooperative Oncology Group performance status (PS), (e) serum calcium and (f) serum albumin; (3) tumour‐related factors, including (a) clinical tumour, node and metastasis (TNM) factors and stage, (b) presence of superior vena cava syndrome, (c) metastatic sites, (d) histology and (e) epidermal growth factor receptor (EGFR) mutation status; (4) therapeutic factors, including (a) first‐line therapy and (b) second‐line or later therapy; and lastly, (5) prognostic information, including (a) vital status, (b) final follow‐up month and year and (c) cause of death. This study included patients with data on body weight loss and stage III or IV disease. The clinical TNM factors and stage were classified according to the Union for International Cancer Control TNM Classification of Malignant Tumours, 7th Edition (2009). ¹⁰ The histology was classified according to the World Health Organization Histological Typing of Lung and Pleural Tumours, 3rd Edition (1999).

This study was conducted in accordance with the principles of the Declaration of Helsinki. This registry study followed the ethical guidelines for epidemiological studies published jointly by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Japan Ministry of Health, Labour and Welfare on 17 June 2002 and was revised on 16 August 2007. The study protocol was further amended to follow the ethical guidelines for human medical studies issued on 22 December 2014. According to the guidelines, the requirement of informed consent was waived. The study was approved by the Institutional Review Board of Osaka University Hospital, where the registry office was located.

Statistical analyses

We compared the baseline patient characteristics with and without body weight loss ≥ 5% within 6 months of treatment initiation using Fisher's exact test. We also performed logistic analyses to identify factors related to body weight loss ≥ 5% within 6 months. Patients with body weight loss ≥ 5% within 6 months were defined as cachectic in this study.

Survival curves were estimated using the Kaplan–Meier method for clinical subset groups. Differences in survival rates were assessed using the log‐rank test. OS was defined as the interval between the pathological diagnosis and patient death or last follow‐up. Survival curves were plotted using the Kaplan–Meier method. We performed multivariable analysis of OS using baseline patient characteristics and the Cox proportional hazards model.

Lesions were evaluated using plain chest radiography, computed tomography (CT) of the chest and abdomen, positron emission tomography or bone scintigraphy, and CT or magnetic resonance imaging of the cranium. Tumour control was assessed according to the Response Evaluation Criteria in Solid Tumors (Version 1.1). The response and disease control rates were compared using Fisher's exact test. All statistical analyses were performed using SPSS software (Version 23.0; IBM Corp., Armonk, NY, USA) for Windows. Statistical significance was set at P < 0.05.

Results

Patient characteristics and factors related to body weight loss ≥ 5% within 6 months

A total of 12 320 patients from 314 institutions in Japan were registered in a nationwide registry database (the Japanese Lung Cancer Registry Study) in 2012. Of these, 8489 patients met the criteria of data availability for body weight loss and stage III or IV disease.

Table 1 shows the patient characteristics of this study. There were more male patients (72.4%) and smokers (current smoker 41.7%; past smoker 37.8%) in this study. Approximately 75% of the patients had a PS of 0–1, and approximately 70% had stage IV disease. Approximately 20.4% of the 8489 patients had body weight loss ≥ 5% within 6 months of treatment initiation. Table 2 shows patient characteristics according to status of body weight loss ≥ 5% within 6 months. Sex, age, smoking history, emphysema, PS, superior vena cava syndrome, clinical stage, site of metastasis, histology, EGFR mutation status, primary treatment method and serum albumin level were all significantly different between the patients with and without body weight loss ≥ 5% within 6 months. Table 3 shows the results of logistic analyses performed to identify factors related to body weight loss ≥ 5% within 6 months of treatment initiation. Current smoking, emphysema, higher clinical stage, site of metastases, adenocarcinoma, squamous cell carcinoma, large‐cell carcinoma histology, unknown EGFR mutation, higher calcium level and serum albumin < 3.2 g/dL were associated with higher frequency of weight loss > 5%. Logistic regression was also used to identify factors related to body weight loss ≥ 5% within 6 months of treatment initiation stratified by sex (Tables S1 and S2 ). In male patients, the risk factors were the same as those in the study patients overall, whereas in female patients, only emphysema, distant organ metastases and serum albumin level were associated with body weight loss ≥ 5% within 6 months of treatment initiation.

Table 1.

Patient characteristics

		n	%
Sex	Male	6143	72.4
	Female	2346	27.6
Age	Median (range)	69	(22–102)
Smoking history	Never	1742	20.5
	Past	3211	37.8
	Current	3536	41.7
Emphysema	No	6328	74.5
	Yes	2161	25.5
Interstitial pneumonia	No	7691	90.6
	Yes	798	9.4
Performance status	0	2749	32.4
	1	3951	46.5
	2	997	11.7
	3	575	6.8
	4	217	2.6
Superior vena cava syndrome	No	8243	97.1
	Yes	246	2.9
Clinical stage	IIIA	1173	13.8
	IIIB	1318	15.5
	IV	5998	70.7
Distant metastasis	Yes	5604	66.0
	No	2885	34.0
M1a	Pleural nodule	1071	12.6
	Pleural effusion	1645	19.4
	Pericardial effusion	213	2.5
	Ipsilateral pulmonary metastasis	914	10.8
M1b	Lung	561	6.6
	Bone	2261	26.6
	Liver	974	11.5
	Brain	1487	17.5
	Adrenal gland	751	8.8
Histology	Small‐cell lung cancer	1578	18.6
	Adenocarcinoma	4250	49.5
	Squamous cell carcinoma	1602	18.9
	Large‐cell carcinoma	113	1.3
	Others	527	6.2
	Missing value	419	4.9
EGFR	Mutant	1442	17.0
	Wild	3519	41.5
	Unknown	3528	41.6
Primary treatment	Palliative treatment	1979	23.3
	Chemotherapy	4934	58.1
	Sequential chemoradiotherapy	141	1.7
	Concurrent chemoradiotherapy	1158	13.6
	Radiotherapy	275	3.2
	Others	2	0.0
Body weight loss ≥ 5% within 6 months	No	6760	79.6
	Yes	1729	20.4
Serum calcium level (N = 7746)	Mean (SD)	9.2087	(0.77574)
Serum albumin level (N = 8111)	Mean (SD)	3.703	(0.6099)

Note: Past smokers were defined as those who had quit smoking more than 1 year ago. A current smoker was defined as a patient who had smoked within 1 year.

Abbreviations: EGFR, epidermal growth factor receptor; SD, standard deviation.

Table 2.

Patient characteristics according to body weight loss ≥ 5% within 6 months

		Body weight loss < 5% within 6 months		Body weight loss ≥ 5% within 6 months		P value
		n	%	n	%
Sex	Male	4851	71.8	1291	74.7	0.015
	Female	1909	28.2	437	25.3
Age	Mean (SD)	68.30	(10.299)	69.07	(9.799)	0.004
Smoking history	Never	1452	21.5	290	16.8	<0.001
	Past	2594	38.4	617	35.7
	Current	2714	40.1	822	47.5
Emphysema	No	5131	75.9	1197	69.2	<0.001
	Yes	1629	24.1	532	30.8
Interstitial pneumonia	No	6123	90.6	1568	90.7	0.926
	Yes	637	9.4	161	9.3
Performance status	0	2473	36.6	276	16.0	<0.001
	1	3157	46.7	794	45.9
	2	666	9.9	331	19.1
	3	336	5.0	239	13.8
	4	128	1.9	89	5.1
Superior vena cava syndrome	No	6579	97.3	1664	96.2	0.020
	Yes	181	2.7	65	3.8
Clinical stage	IIIA	1016	15.0	157	9.1	<0.001
	IIIB	1074	15.9	244	14.1
	IV	4670	69.1	1328	76.8
M1a	Pleural nodule	865	12.8	206	11.9	0.351
	Pleural effusion	1240	18.3	405	23.4	<0.001
	Pericardial effusion	153	2.3	60	3.5	0.006
	Ipsilateral pulmonary metastasis	695	10.3	219	12.7	0.005
M1b	Lung	426	6.3	135	7.8	0.026
	Bone	1701	25.2	560	32.4	<0.001
	Liver	685	10.1	289	16.7	<0.001
	Brain	1145	16.9	342	19.8	0.006
	Adrenal gland	536	7.9	215	12.4	<0.001
Histology	Small‐cell lung cancer	1316	19.6	344	20.1	0.001
	Adenocarcinoma	3598	53.5	829	48.3
	Squamous cell carcinoma	1291	19.2	391	22.8
	Large‐cell carcinoma	86	1.3	31	1.8
	Others	440	6.5	120	7.0
EGFR	Mutant	1212	17.9	230	13.3	<0.001
	Wild	2826	41.8	693	40.1
	Unknown	2722	40.3	806	46.6
Primary treatment	Palliative treatment	1411	20.9	568	32.9	<0.001
	Chemotherapy	4038	59.7	896	51.8
	Sequential chemoradiotherapy	116	1.7	25	1.4
	Concurrent chemoradiotherapy	974	14.4	184	10.6
	Radiotherapy	219	3.2	56	3.2
	Others	2	0.0	0	0
Serum calcium level (N = 7746)	Mean (SD) (mg/dL)	9.2359	(0.99477)	9.2019	(0.71013)	0.204
Serum albumin level (N = 8111)	Mean (SD) (g/dL)	3.765	(0.5861)	3.460	(0.6403)	<0.001

Note: Past smokers were defined as those who had quit smoking more than 1 year ago. A current smoker was defined as a patient who had smoked within 1 year.

Abbreviations: EGFR, epidermal growth factor receptor; SD, standard deviation.

Table 3.

Logistic analyses to find factors related to body weight loss ≥ 5% within 6 months

All values
		n	OR	95% CI	P value
Sex	Male	5478
	Female	2085	1.080	0.918–1.270	0.353
Age	<75 years	5418
	≥75 years	2145	1.032	0.905–1.179	0.636
Smoking history	Never	1520
	Past	2857	1.132	0.919–1.394	0.243
	Current	3186	1.311	1.155–1.751	0.001
Emphysema	No	5629
	Yes	1934	1.311	1.145–1.500	<0.001
Interstitial pneumonia	No	6841
	Yes	722	0.877	0.717–1.074	0.205
Superior vena cava syndrome	No	7344
	Yes	219	1.336	0.972–1.835	0.074
Clinical stage	IIIA	1031
	IIIB	1167	1.412	1.113–1.791	0.004
	IV	5365	1.311	1.046–1.644	0.019
M1a	Pleural nodule	991	0.899	0.748–1.080	0.255
	Pleural effusion	1457	1.337	1.143–1.564	<0.001
	Pericardial effusion	189	1.308	0.932–1.836	0.121
	Ipsilateral pulmonary metastasis	814	1.245	1.033–1.501	0.022
M1b	Lung	503	1.037	0.826–1.304	0.752
	Bone	2023	1.343	1.165–1.548	<0.001
	Liver	863	1.548	1.300–1.843	<0.001
	Brain	1323	1.205	1.027–1.413	0.022
	Adrenal gland	503	1.340	1.108–1.620	0.003
Histology	Small‐cell lung cancer	1490
	Adenocarcinoma	3971	1.265	1.031–1.551	<0.001
	Squamous cell carcinoma	1497	1.324	1.092–1.605	0.004
	Large‐cell carcinoma	104	1.648	1.031–2.632	0.037
	Others	501	1.206	0.921–1.581	0.174
EGFR	Mutant	1313
	Wild	3163	1.149	0.947–1.393	0.159
	Unknown	3087	1.445	1.149–1.817	0.002
Serum calcium level (N = 7563)	mg/dL		1.143	1.060–1.232	0.001
Serum albumin level	<3.2 g/dL	1349
	≥3.2 g/dL	6214	0.453	0.393–0.521	<0.001

Stepwise method
		n	OR	95% CI	P value
Smoking history	Never	1520
	Past	2857	1.072	0.889–1.291	0.467
	Current	3186	1.349	1.120–1.625	0.002
Emphysema	No	5629
	Yes	1934	1.298	1.136–1.483	<0.001
Superior vena cava syndrome	No	7344
	Yes	219	1.349	0.983–1.853	0.064
Clinical stage	IIIA	1031
	IIIB	1167	1.412	1.114–1.790	0.004
	IV	5365	1.295	1.037–1.618	0.022
M1a	Pleural effusion	1457	1.342	1.148–1.568	<0.001
	Ipsilateral pulmonary metastasis	814	1.247	1.035–1.501	0.020
M1b	Bone	2023	1.346	1.169–1.549	<0.001
	Liver	863	1.554	1.306–1.849	<0.001
	Brain	1323	1.223	1.044–1.432	0.012
	Adrenal gland	503	1.344	1.112–1.624	0.002
Histology	Small‐cell lung cancer	1490
	Adenocarcinoma	3971	1.261	1.029–1.546	0.025
	Squamous cell carcinoma	1497	1.314	1.084–1.592	0.005
	Large‐cell carcinoma	104	1.625	1.018–2.595	0.042
	Others	501	1.204	0.920–1.576	0.177
EGFR	Mutant	1313
	Wild	3163	1.132	0.935–1.370	0.205
	Unknown	3087	1.420	1.132–1.781	0.002
Serum calcium level (N = 7563)	mg/dL		1.142	1.059–1.231	0.001
Serum albumin level	<3.2 g/dL	1349
	≥3.2 g/dL	6214	0.451	0.392–0.519	<0.001

Note: Past smokers were defined as those who had quit smoking more than 1 year ago. A current smoker was defined as a patient who had smoked within 1 year.

Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; OR, odds ratio.

First‐line treatment response and overall survival according to existence of body weight loss ≥ 5% within 6 months of treatment initiation

Table 4 shows differences in the response to first‐line treatments between patients with and without body weight loss ≥ 5% within 6 months of treatment initiation. The response and disease control to initial therapy including chemotherapy, chemoradiotherapy or radiotherapy was significantly lower in the patients with body weight loss ≥ 5% within 6 months of treatment initiation than in those without it (response rate: 49.7% vs. 41.5%, P < 0.001; disease control rate: 74.1% vs. 64.3%, P < 0.001).

Table 4.

Differences in the response to first‐line treatment

	Body weight loss < 5% within 6 months (n = 5218)		Body weight loss ≥ 5% within 6 months (n = 1129)
	n	%	n	%
CR	168	3.2	21	1.9
PR	2426	46.5	448	39.7
SD	1270	24.3	257	22.8
PD	939	18.0	262	23.2
NE	415	8.0	141	12.5
Response rate	49.7%		41.5%
Disease control rate	74.1%		64.3%

Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 1 shows Kaplan–Meier curves of OS of the patients included in this study. OS was significantly longer in patients with stage IIIA, IIIB and IV, in that order. OS was also significantly longer in patients with NSCLC than in those with SCLC. Figure 2 A shows Kaplan–Meier curves of OS of patients with body weight loss ≥ 5% within 6 months of treatment initiation compared to those without it. Body weight loss was associated with significantly shorter OS in each stage group (IIIA, IIIB and IV), in patients with both NSCLC and SCLC histologies and in patients with the EGFR mutation treated with EGFR tyrosine kinase inhibitor (EGFR‐TKI) (Figure 2 B–F ). Table 5 shows multivariable analysis of OS, which was significantly shorter in patients with body weight loss ≥ 5% within 6 months of treatment initiation than in those without (Cox proportional hazards model, hazard ratio: 1.369, 95% confidence interval: 1.274–1.470, P < 0.001). The multivariable analysis of OS revealed that in patients with stage IV disease, positive for the EGFR mutation and treated with EGFR‐TKI, there was a trend towards shorter OS in those with body weight loss ≥ 5% within 6 months of treatment initiation than in those without (Table S3 , Cox proportional hazards model, hazard ratio: 1.219, 95% confidence interval: 0.974–1.526, P = 0.084).

Figure 1.

Kaplan–Meier curve of overall survival of all the patients, and the patients according to clinical stage and histology. (A) Kaplan–Meier curve of overall survival of the patients included in this study. (B) Kaplan–Meier curves of overall survival of the patients according to clinical stage. (C) Kaplan–Meier curves of overall survival of the patients according to histology. NSCLC, non‐small‐cell lung cancer; SCLC, small‐cell lung cancer.

Figure 2.

Kaplan–Meier curves of overall survival of patients according to existence of body weight loss ≥ 5% within 6 months of treatment initiation. (A) Kaplan–Meier curves of overall survival of patients with (red) or without (blue) body weight loss ≥ 5% within 6 months of treatment initiation. (B) Kaplan–Meier curves of overall survival of patients with stage IIIA or IIIB disease. Red and blue lines represent patients with or without body weight loss ≥ 5% within 6 months of treatment initiation, respectively. (C) Kaplan–Meier curves of overall survival of patients with stage IV disease. Red and blue lines represent patients with or without body weight loss ≥ 5% within 6 months of treatment initiation, respectively. (D) Kaplan–Meier curves of overall survival of patients with small‐cell lung cancer. Red and blue lines represent patients with or without body weight loss ≥ 5% within 6 months of treatment, respectively. (E) Kaplan–Meier curves of overall survival of the patients with non‐small‐cell lung cancer. Red and blue lines represent the patients with or without body weight loss ≥ 5% within 6 months of treatment initiation, respectively. (F) Kaplan–Meier curves of overall survival of the patients with stage IV, positive epidermal growth factor receptor (EGFR) mutation treated with EGFR tyrosine kinase inhibitor (EGFR‐TKI). The red and blue lines represent body weight loss ≥ 5% within 6 months before treatment initiation and those without body weight loss ≥ 5%, respectively.

Table 5.

Multivariable analysis of overall survival

		n	Univariate analysis			Multivariable analysis
			HR	95% CI	P value	HR	95% CI	P value
Sex	Male	5477
	Female	2085	0.628	0.589–0.670	<0.001	0.777	0.715–0.846	<0.001
Age	<75 years	5418
	≥75 years	2144	1.403	1.322–1.489	<0.001	1.256	1.175–1.343	<0.001
Smoking history	Never	1520
	Past	2856	1.574	1.454–1.703	<0.001	1.100	0.991–1.211	0.074
	Current	3186	1.653	1.529–1.788	<0.001	1.140	1.026–1.267	0.015
Emphysema	No	5628
	Yes	1934	1.354	1.273–1.440	<0.001	1.065	0.994–1.142	0.074
Interstitial pneumonia	No	6841
	Yes	721	1.743	1.598–1.902	<0.001	1.441	1.311–1.583	<0.001
Performance status	0	2426
	1	3565	1.491	1.397–1.593	<0.001	1.293	1.204–1.388	<0.001
	2	895	3.079	2.812–3.371	<0.001	1.966	1.775–2.178	<0.001
	3	499	3.990	3.578–4.450	<0.001	2.521	2.224–2.858	<0.001
	4	177	6.771	5.795–7.912	<0.001	5.004	4.175–5.998	<0.001
Clinical stage	IIIA	1031
	IIIB	1166	1.230	1.101–1.373	<0.001	1.285	1.140–1.450	<0.001
	IV	5365	1.841	1.686–2.011	<0.001	1.703	1.524–1.904	<0.001
Histology	Small‐cell lung cancer	1490
	Adenocarcinoma	3970	0.737	0.686–0.792	<0.001	0.899	0.811–0.997	0.043
	Squamous cell carcinoma	1497	1.122	1.031–1.220	0.007	1.155	1.051–1.269	0.003
	Large‐cell carcinoma	104	1.283	1.031–1.596	0.025	1.472	1.164–1.862	0.001
	Others	501	1.109	0.983–1.251	0.093	1.211	1.057–1.387	0.006
EGFR	Mutant	1313
	Wild	3162	2.035	1.865–2.221	<0.001	1.926	1.745–2.125	<0.001
	Unknown	3087	2.398	2.198–2.616	<0.001	2.120	1.884–2.385	<0.001
Primary treatment	Palliative treatment	1709
	Chemotherapy	4437	0.473	0.444–0.504	<0.001	0.607	0.564–0.654	<0.001
	Sequential chemoradiotherapy	130	0.330	0.263–0.415	<0.001	0.398	0.311–0.508	<0.001
	Concurrent chemoradiotherapy	1050	0.252	0.228–0.280	<0.001	0.370	0.325–0.422	<0.001
	Thoracic radiotherapy	236	0.583	0.495–0.687	<0.001	0.618	0.512–0.746	<0.001
Body weight loss ≥ 5% within 6 months	No	6041
	Yes	1521	1.806	1.694–1.926	<0.001	1.369	1.274–1.470	<0.001
Serum calcium level (N = 7746)	mg/dL		0.953	0.916–0.991	0.016	1.045	1.005–1.087	0.028
Serum albumin level	<3.2 g/dL	1349
	≥3.2 g/dL	6213	0.489	0.468–0.512	<0.001	0.622	0.576–0.672	<0.001

Note: Past smokers were defined as those who had quit smoking more than 1 year ago. A current smoker was defined as a patient who had smoked within 1 year.

Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio.

Figure 3 shows Kaplan–Meier curves of OS of patients according to body weight loss ≥ 5% within 6 months of treatment initiation (BW loss +) and serum albumin value (alb) ≥ 3.2 or <3.2 mg/dL. In all patients and those with stage IV disease, OS was significantly longer in the order of ‘BW loss −, alb ≥ 3.2 mg/dL’, ‘BW loss +, alb ≥ 3.2 mg/dL’, ‘BW loss −, alb < 3.2 mg/dL’ and ‘BW loss +, alb < 3.2 mg/dL’ (Figure 3 A,C ). In the patients with stage IIIA or IIIB, the trend of OS was similar, although the difference between ‘BW loss −, alb < 3.2 mg/dL’ and ‘BW loss +, alb < 3.2 mg/dL’ was not statistically significant (Figure 3 B ).

Figure 3.

Kaplan–Meier curves of overall survival of patients according to cachexia status and serum albumin value. (A) Kaplan–Meier curves of overall survival of patients according to cachexia status and serum albumin value. (B) Kaplan–Meier curves of overall survival of patients with stage IIIA or IIIB disease. The curves were drawn according to cachexia status and serum albumin value. (C) Kaplan–Meier curves of overall survival of patients with stage IV disease. The curves were drawn according to cachexia status and serum albumin value.

Discussion

This is the one of the largest studies to investigate baseline patient characteristics, prognosis and impact on the course of treatment in patients with cancer‐associated cachexia, defined clinically as a weight loss of ≥5% within 6 months of treatment initiation. The definition of cancer cachexia has changed over time. The early definitions focused on weight, physical performance and patient function. Most recently, in 2011, an international Delphi consensus definition and classification of cancer cachexia was published, provisionally defining cancer cachexia as ≥5% weight loss within 6 months, or 2–5% weight loss with either a BMI of 20 kg/m² or reduced muscle mass. ¹¹ In 2011, the European Palliative Care Research Collaborative published a consensus on the definition and diagnostic criteria for cancer cachexia. Cancer cachexia is classified into three stages: pre‐cachexia, cachexia and refractory cachexia. The need for early intervention from the first stage, pre‐cachexia, is recommended. The reason for and degree of weight loss in cancer patients vary depending on the type of cancer, comorbidities and treatment. However, because there is no accurate and simple way to diagnose pre‐cachexia, it has been proposed to suspect cancer cachexia through weight loss and treat it. As described in the Introduction, body weight loss in patients with cancer worsens their prognosis. ³

Few studies have investigated the risk factors of cancer cachexia. One retrospective study investigated the clinical association between cachexia, tumour characteristics (such as metastatic burden and mutational status) and treatment in 394 lung cancer patients. ¹² A French nationwide cross‐sectional survey (performed across 55 geriatric oncology clinics) of 1030 cancer patients aged ≥70 years investigated the relationship between cachexia and patient characteristics, including demographic, clinical and nutritional data. ¹³ Out of the 29% gastrointestinal cancer patients and 16% breast cancer patients, those with breast, gynaecological, urinary, skin or haematological cancers were less likely to have cachexia than patients with colorectal cancer. In addition, patients with previous surgery for metastatic cancer, poor PS, low food intake, poor timed up‐and‐go test results, cognitive disorders or risk of depression were more likely to have cachexia. Our study, which included only lung cancer patients, found that smoking history, emphysema, clinical stage, site of metastases, histology, EGFR mutation, serum calcium and albumin levels were significantly correlated to body weight loss ≥ 5% within 6 months. As EGFR mutations are found exclusively with other driver oncogenes, including KRAS, our study is consistent with prior studies as well as the clinical stage. The EGFR mutation is known not only as a predictive factor of EGFR‐TKI effectiveness but also as a favourable prognostic factor in patients with lung cancer who receive surgery. ¹⁴ This suggests that lung cancers with EGFR mutations may grow more slowly than those without EGFR mutations and that patients with lung cancers with EGFR mutations are less likely to develop cancer cachexia. In addition, the risk of cancer cachexia was associated with the tumour histology. This suggests that the nature of the tumour is associated with cancer cachexia. In terms of emphysema and smoking history, it is well established that the prevalence of cachexia is high in chronic obstructive pulmonary disease. Triggers of muscle wasting include hypoxemia, oxidative stress, inflammation, impaired growth factor signalling, oral glucocorticoids, disuse and malnutrition, some of which are influenced by smoking. ¹⁵ Logistic regression analyses to identify factors related to body weight loss ≥ 5% within 6 months of treatment initiation were also performed stratified by sex. In male patients, the risk factors were the same as those in the study patients overall, whereas in female patients, emphysema, distant organ metastases and serum albumin level were the only risk factors identified. The differences of factors related to cancer cachexia according to sex have not been comprehensively explored, and to our knowledge, this study is the first to show such differences.

In a pharmacokinetic study of NSCLC patients treated with pembrolizumab, there was a trend towards shorter OS with faster drug clearance in patients with cancer cachexia. ¹⁶ In addition, a retrospective study evaluating the treatment response of patients with advanced NSCLC treated with a single immune checkpoint inhibitor divided by the presence or absence of cancer cachexia showed that response rate, progression‐free survival (PFS) and OS were significantly worse in the group with cachexia. ¹⁷ Another retrospective study evaluating the impact of body weight loss at diagnosis on PFS and OS in patients with EGFR‐TKI‐treated sensitive mutant advanced NSCLC patients showed shorter PFS and OS in patients with body weight loss at diagnosis. ¹⁸ Our study included patients before the advent of immune checkpoint inhibitors; however, cytotoxic anticancer agents, molecularly targeted drugs and chemoradiotherapy might also be significantly less effective in patients with cancer cachexia.

There are several definitions of cancer cachexia, including one by Evans et al. ¹⁹ who defined it as weight loss (>5%) in addition to three of the following symptoms: decreased grip strength, fatigue, low‐energy intake, low muscle mass, abnormal biochemical tests [C‐reactive protein (CRP) > 5 mg/L, haemoglobin < 12.0 g/dL or albumin < 3.2 g/dL]. In our study, the presence of hypoalbuminemia (<3.2 g/dL) in addition to weight loss resulted in a neatly demarcated Kaplan–Meier curve for OS.

This study had several limitations. First, as the data are extracted from a registry and not from clinical trials, assessments were probably in some way incomplete. For example, there were 3260 stage III and 8171 stage IV patients in the original registry, but the data of body weight loss were available in 8489 patients. We had no access to the details of treatment protocols and laboratory data such as the CRP level, which was used by Evans et al. ¹⁹ as one of the criteria for cancer cachexia, for each patient. Patients with cancer cachexia defined as body weight loss > 2% with either BMI < 20 kg/m² or sarcopenia were not included in our study because the data for BMI, muscle mass and body weight loss > 2% were not collected in the Japanese Lung Cancer Registry Study. Second, even with the large number of patients included in this study, we did not have another independent dataset to validate the results, which weakens our conclusion.

In conclusion, this is one of the largest studies to investigate the relationships between baseline patient characteristics, body weight loss ≥ 5% and OS in patients with advanced lung cancer. The results of this study should be validated in the current situation with the introduction of immune checkpoint inhibitors. We hope that the results of our study will be useful for early identification and intervention in patients with cachexia, as early therapeutic intervention may improve their prognosis. Further investigation is needed to overcome cancer cachexia to improve the QOL and prognosis of patients with lung cancer.

Conflict of interest

Dr. Takahashi received grants from the Ono Pharmaceutical Company. The other authors of this manuscript have no conflicts of interest that could be positively or negatively influenced by the content of this article.

Supporting information

Table S1. Logistic regression analyses to find factors related to body weight loss ≥ 5% within 6 months in male patients

Table S2. Logistic regression analyses to find factors related to body weight loss ≥ 5% within 6 months in female patients

Table S3. Multivariable analysis of overall survival in patients with Stage 4, positive EGFR mutation, treated with EGFR‐TKI

Shukuya T., Takahashi K., Shintani Y., Miura K., Sekine I., Takayama K., et al (2023) Epidemiology, risk factors and impact of cachexia on patient outcome: Results from the Japanese Lung Cancer Registry Study, Journal of Cachexia, Sarcopenia and Muscle, 14, 1274–1285, 10.1002/jcsm.13216