Received: 23 January 2023

Accepted: 21 March 2023

DOI: 10.1111/1759-7714.14881

ORIGINAL ARTICLE

Prognostic effect of cachexia in patients with non-small cell lungcancer receiving immune checkpoint inhibitors
Norikazu Matsuo 1 | Koichi Azuma 1| Kenta Murotani 2 | Daiki Murata 1 |Goushi Matama 1 | Akihiko Kawahara 3 | Takashi Kojima 1 | Takaaki Tokito 1 |Tomoaki Hoshino 1
1
Division of Respirology, Neurology, andRheumatology, Department of Internal Medicine,
Kurume University School of Medicine, Kurume,
Fukuoka, Japan
2
Biostatistics Center, Kurume University School of
Medicine, Fukuoka, Japan3
Department of Diagnostic Pathology, Kurume
University Hospital, Fukuoka, Japan

Correspondence
Koichi Azuma, Division of Respirology,
Neurology, and Rheumatology, Department ofInternal Medicine, Kurume University School of
Medicine, 67 Asahi-machi, Kurume, Fukuoka
830-0011, Japan.
Email: azuma@med.kurume-u.ac.jp
Funding information
JSPS KAKENHI, Grant/Award Number:
JP20K16317

Abstract
Background: The presence of cachexia in cancer patients negatively affects the qualityof life and survival. However, the impact of cachexia on immunotherapy, such as
PD-1/L1 inhibitors, is not fully understood. Therefore, we examined whether cancer
cachexia affects the prognosis of patients with non-small cell lung cancer (NSCLC)
treated with PD-1/PD-L1 inhibitors.
Methods: We retrospectively screened patients with pathologically confirmed
advanced or recurrent NSCLC who were treated with PD-1/PD-L1 monotherapy at
Kurume University Hospital. We defined cancer cachexia as weight loss of at least 5%
during the past 6 months or any degree of weight loss more than 2% and BMI <20.
Results: Among 182 patients, 74 had cancer cachexia. The presence of cachexia wassignificantly associated with females, poor performance status (PS), never-smokers,
and driver mutations. Multivariate analysis revealed that poor PS and being a smoker
were associated with the presence of cachexia. Patients with cancer cachexia had significantly shorter progression-free survival (PFS) and overall survival (OS). In themultivariate analysis, PS and sex were significantly correlated with PFS, whereas PS
and cachexia were significantly correlated with OS. Subanalysis revealed that patientsin the PS0/without cachexia group had longer PFS and OS than those in the cachexia
or PS1-3 group.
Conclusions: In NSCLC patients, cachexia was associated with a worse prognosis,
irrespective of tumor PD-L1 expression, indicating that cachexia is a predictive factor
for NSCLC patients receiving immune checkpoint inhibitors.
KEYWORDS
cachexia, NSCLC, PD-1 inhibitor

INTRODUCTION
Cachexia is a multifactorial syndrome that causes reduced
food intake, progressive bodyweight loss via skeletal muscle
and adipose tissue loss, and an imbalance in metabolic regulation, resulting in reduced physical function.1 It is caused by acancer-associated catabolic state in the systemic circulation as
well as physiological factors, such as imbalanced inflammatory
activation, proteolysis, autophagy, and lipolysis.2 Cachexia is acommon complication in non-small cell lung cancer (NSCLC),
occurring in almost 38.7%–48.1% of patients with advanced orrecurrent disease.3–6 Since the presence of cachexia negatively
affects the quality of life and decreases survival, the assessmentof cachexia is important in the management of patients withcancer.7
Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have demonstrated promising clinical outcomes in patients withThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.
Thorac Cancer. 2023;1–6.

wileyonlinelibrary.com/journal/tca

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NSCLC.8–11 Notably, a subgroup of NSCLC patients treatedwith PD-1/PD-L1 inhibitors has long-duration tumor
responses.12 However, PD-1/PD-L1 inhibitors are often ineffective in vulnerable patients, such as those with poor performance status (PS).13 Given that the presence of cancer
cachexia worsens the patient’s condition and is associatedwith altered inflammatory dynamics, the impact of cachexia
on immunotherapy efficacy should be clarified. In the present study, we investigated whether cancer cachexia affects
the prognosis of patients with NSCLC treated with PD-1/
PD-L1 inhibitors. The primary endpoint of this study was toinvestigate the prognostic impact of cachexia on PD-1/PD-L1
inhibitors treatment, and secondary endpoint was to explore
predictors of therapeutic response to PD-1/L1 inhibitors in
NSCLC patients with cachexia.

study was performed in accordance with the provisions of
the Declaration of Helsinki and was approved by theInstitutional Review Board of Kurume University Hospital (IRB No 20100).

Definition of cancer cachexia
The cancer cachexia definition used in our study wasderived from the original definition by Fearon et al., whichstates the presence of weight loss of at least 5% during thepast 6 months or any degree of weight loss more than 2%
and BMI <20. We did not include skeletal muscle mass inthe definition of cancer cachexia.1

Statistical analysis
METHODS
Patients and clinical analysis
We retrospectively screened patients with pathologicallyconfirmed advanced or recurrent NSCLC who were treatedwith PD-1/PD-L1 inhibitors at Kurume University Hospital between February 2016 and December 2020. PD-L1
expression on tumor cells was assessed by the PD-L1
immunohistochemistry (IHC) 22C3 pharm Dx assay(Agilent Technologies) in archived biopsy specimens. The

Comparisons for categorical variables were evaluated using
the chi-squared or Fisher’s exact tests and identified the factors significantly related to cachexia. Multivariate analysis
was performed to identify the risk factors for cancer
cachexia using the stepwise logistic regression method. With
respect to the factors, PS (0 vs. 1–3), age (≥75 years
vs. <75 years), sex, smoking status, and driver mutation(positive versus negative) were analyzed.
Objective tumor responses were evaluated in accordancewith Response Evaluation Criteria in Solid Tumors(b)Progression-free Survival (%)(a)
All NSCLC patients who received PD-1/L1 inhibitorsn = 197

Excluded patientsn = 14

Cachexia +Cachexia P < 0.001

100

50

0

Eligible Patients

0

12

24

36

48

60

Month

n = 183(c)Cachexia +Cachexia P < 0.001

With Cachexia

Without Cachexia

n = 74n = 109

NSCLC:non-small cell lung cancer
PD-1/L1:Programmed cell death protein 1/ligand 1

Overall Survival (%)

100

50

0

0

12

24

36

48

60

Month

F I G U R E 1 (a) A total of 197 patients were identified with advanced or recurrent NSCLC who had been treated with PD-1/PD-L1 inhibitors at Kurume
University Hospital between February 2016 and December 2020. Of the 197 patients, 183 were included. Fourteen patients were excluded because theirbodyweight before treatment was not recorded and cachexia could not be assessed. Kaplan–Meier curves displaying (b) progression-free survival and(c) overall survival of NSCLC patients receiving PD-1/PD-L1 inhibitors with or without cancer cachexia.

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MATSUO ET AL.

2

3

T A B L E 1 Clinical characteristics of NSCLC patients receiving PD-1/
PD-L1 inhibitors with and without cachexia.
VariableWith cachexia Without cachexia(N = 74)(N = 109)
p-value

Age, median (range), years 72 (48–89)

70 (41–87)

Sex

0.010

TABLE 2Multivariate analysis of cachexia prevalence.

Variable

p-value

OR (95% CI)

PS ≥1 vs. 0<0.0015.441 (2.648–11.179)

Smoker vs.never

0.012

0.375 (0.175–0.805)

0.011

Male

47 (62.7)

88 (80.7)

Female27 (37.3)

21 (19.3)

ECOG performance status

RESULTS<0.0010

13 (17.6)

59 (54.1)

1

28 (37.8)30 (27.5)

2

21 (28.4)

13 (11.9)

3

12 (16.2)

7 (6.4)Former or current

49 (66.2)

91 (83.5)

Never

25 (33.8)

18 (16.5)

Smoking status

0.007

Histology

0.141

Squamous

17 (23.0)

36 (33.0)

Nonsquamous

57 (77.0)

73 (67.0)

Driver mutation

0.027

EGFR or ALK

22 (29.7)

17 (15.6)

Wild-type

52 (70.3)

92 (84.4)

Treatment line

0.724

First

18 (24.3)

24 (22.0)

Second or later

56 (75.7)

85 (78.0)

PD-L1 TPS

(N = 57)(N = 82)<1%

16 (28.1)

20 (24.4)

1%–49%

14 (24.6)

27 (32.9)≥50%

27 (42.1)

35 (42.6)

Nivolumab

42 (56.8)

52 (47.7)

Pembrolizumab

29 (39.2)

42 (38.5)

Atezolizumab

3 (4.1)15 (13.8)

PD-1/PD-L1 inhibitor

0.566

0.085

Note: Data represent numbers (%) unless otherwise indicated.
Abbreviations: ALK, anaplastic lymphoma kinase; ECOG, Eastern Cooperative
Oncology Group; EGFR, epidermal growth factor receptor; NSCLC, non-small celllung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed cell deathligand 1; TPS, tumor proportion score.

(RECIST) 1.1.14 Progression-free survival (PFS) and overall
survival (OS) were compared using the log-rank test. Multivariate analysis was performed which factors were associatedwith PFS and OS using the stepwise logistic regression
method. With respect to the factors, cancer cachexia, PS(0 vs. 1–3), age (≥75 years vs. <75 years), sex, smoking status, histology (nonsquamous vs. squamous), driver mutation(positive vs. negative) and PD-L1 tumor proportion score(TPS) (≥50% vs. <50%) were analyzed. All tests were twosided, and differences were considered statistically significant at p < 0.05. Statistical analyses were conducted using
JMP version 11 (SAS Institute Inc.) or GraphPad Prism version 6.07 for Windows (GraphPad Software; www.
graphpad.com).

Association between cancer cachexia and patientcharacteristics
We identified 197 patients with advanced or recurrent
NSCLC who had been treated with PD-1/PD-L1 inhibitors
at Kurume University Hospital between February 2016 andDecember 2020. Of 197 patients, 183 were included. Fourteen patients were excluded because their bodyweight before
treatment was not recorded and cachexia could not be
assessed (Figure 1a). All patients received PD-1/PD-L1
inhibitors monotherapy. Of these 183 patients, 74 (40.4%)
were diagnosed with cancer cachexia. Relevant patient characteristics related to the presence of cachexia are summarized in Table 1. The presence of cachexia was significantly
associated with females ( p = 0.011), poorer PS (p < 0.001),
never-smokers (p = 0.007), and driver mutations (p = 0.027),
whereas no significant association was observed with histology, treatment line, PD-L1 expression, or PD-1/L1 inhibitor
treatment. Multivariate analysis was performed using step
wise regression with factors that were found to be significantly related to cachexia as variables. Multivariate analysis
revealed that poorer PS and smoker were was associatedwith the presence of cachexia (PS 1–3 vs. PS 0, p < 0.001,
OR = 5.441, and smoker vs. never smoker, p = 0.012,
OR = 0.375) (Table 2).

Association between cancer cachexia andoutcomes of PD-1/PD-L1 inhibitor treatment
There was no difference in the overall response rate between
patients with (25.4%) or without (28.7%) cancer cachexia(p = 0.622). However, the disease control rate tended to beworse in those with cancer cachexia (43.7%) than in those
without cachexia (58.3%) (Table S1). The median length offollow-up was 8.5 months (range, 0.1–71.6) for censoredcases. The median PFS and OS were 3.0 months (95% CI:
2.2–4.9) and 12 months (95% CI: 9.1–15.0), respectively.
Patients with cancer cachexia had significantly shorter PFS(median, 2.1 vs. 5.1 months, p < 0.001) and OS (median, 5.6
vs. 15.0 months, p < 0.001) (Figure 1b, c).

Multivariate analyses for PFS and OS
We performed multivariate analyses to identify the prognostic importance of clinical characteristics and cancer
cachexia. In the multivariate analysis, PS (hazard ratio

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MATSUO ET AL.

[HR] 1.964, 95% CI: 1.403–2.749, p < 0.001) and sex (hazard
ratio [HR] 0.67, 95% CI: 0.470–0.957, p < 0.028) were significantly correlated with PFS (Table 3), whereas PS (hazard
ratio [HR] 1.990, 95% CI: 1.344–2.968, p < 0.001) andcachexia (hazard ratio [HR] 1.488, 95% CI: 1.018–2.175,
p = 0.040) were significantly correlated with OS (Table 4).

Exploratory analyses of cachexia and PS
Given the positive association between cancer cachexia andPS, we analyzed the relationship between cachexia and
PS. We divided the patients into four groups based on PS
0 or 1–3 as well as the presence or absence of cachexia. The
median PFS was 5.6 in the PS 0/with cachexia group,
6.5 months in the PS 0 /without cachexia group, 1.9 months
in the PS 1–3/with cachexia group, and 2.8 months in the
PS 1–3/without cachexia group ( p < 0.001, Figure 2a). The
median OS was 13.6 months in the PS 0/with cachexia
group, 18.5 months in the PS 0 /without cachexia group,
5.4 months in the PS 1–3/with cachexia group, and11.9 months in the PS 1–3/without cachexia group(p < 0.001, Figure 2b).

Multivariate analysis of progression-free survival (PFS).

Variable

p-value

OR (95% CI)

PS ≥1 vs. 0<0.001

1.964 (1.403–2.749)

Male vs. female

0.028

0.67 (0.470–0.957)

TABLE 4Multivariate analysis of overall survival (OS).
p-value

OR (95% CI)

Cachexia+ vs. cachexia

0.040

1.488 (1.018–2.175)

PS ≥1 vs. 0<0.0011.990 (1.334–2.968)

Progression-free Survival (%)

Variable(a)

Cancer cachexia worsens the patient’s condition and reduces
patient survival due to its high incidence and mortality rate.
However, the impact of cachexia on immunotherapy, suchas PD-1/L1 inhibitors, is not fully understood. Therefore, weinvestigated whether cancer cachexia affects the prognosis ofpatients with NSCLC treated with PD-1/PD-L1 inhibitors.
We found that patients with cachexia had a worse prognosis,
irrespective of tumor PD-L1 expression, indicating thatcachexia is a predictive prognostic factor for NSCLC
patients receiving immune checkpoint inhibitors.
Cachexia is common, with rates of 38.7%–48.1% inpatients with NSCLC,3–6 and it is more common in patientswith poor PS.4,15 Consistent with these results, we also
found correlations between cancer cachexia and poorer
PS. Cancer patients with cachexia experience numerous
complications, including reduced functionality of muscledependent systems and mobility. These complications interfere with the patient’s ability to perform daily activities,
which in turn may be related to a poor PS. Notably, cachexia
is also a complication in populations with good PS. Several
studies have reported that 18.9%–40% of patients with PS0
have cachexia.3,4 In accordance with this result, of thepatients with cachexia, 17.6% patients had PS0. The survival
curves show little difference in patients with cachexia at PS0
treated with ICI from patients without cachexia at PS0 in
terms of PFS, but who are worse in terms of OS. These
results indicate that patients with PS0 and cachexia are considered to have potentially progressing cachexia, although it
does not interfere with their daily activities. This combination of factors can be used to more accurately stratify
patients for treatment outcomes of PD-1/PD-L1 inhibitors.
It should be noted that cachexia is potentially present evenin patients who have the ability to perform daily activities.
We found that patients with cancer cachexia had significantly shorter PFS and OS than those without cachexia.
Multivariate analysis has shown that poorer PS and sex are(b)a. Cachexia + / PS 0
b. Cachexia + / PS 1-3
c. Cachexia - / PS 0
d. Cachexia - / PS 1-3
P<
0.001

100

50

Overall Survival (%)

TABLE 3DISCUSSION

P<
0.001

0
0

12

24

36

Month

48

60

MonthsF I G U R E 2 (a) The patients were divided into four groups based on PS 0 or 1–3 as well as the presence or absence of cachexia. The median PFS was 5.6
in the PS 0/with cachexia group, 6.5 months in the PS 0 /without cachexia group, 1.9 months in the PS 1–3/with cachexia group, and 2.8 months in the PS
1–3/without cachexia group ( p < 0.001). (b) The median OS was 13.6 months in the PS 0/with cachexia group, 18.5 months in the PS 0 /without cachexia
group, 5.4 months in the PS 1–3/with cachexia group, and 11.9 months in the PS 1–3/without cachexia group.

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MATSUO ET AL.

4

prognostic factors for shorter PFS, and the presence of cancer cachexia and poorer PS are independently associatedwith shorter OS. A previous study showed that PFS and OS
were significantly shorter in the cachexia than in the noncachexia group.16 In our analysis, cachexia was not a prognostic factor for PFS, and the possible reasons why cancer
cachexia was not significant in the multivariate analysis withrespect to PFS, unlike previous reports, could be due to thesmall number of cases and the fact that this was a retrospective study and the timing of imaging evaluation. Immune
checkpoint inhibitors enhance antitumor immunity byblocking a negative regulator of T cell activation, thus promoting the host immune system’s ability to attack cancer
cells. Cancer cachexia is caused by tumor and host-derived
factors that lead to inflammation and systemic metabolism,
resulting in catabolism, energy expenditure, and muscle
decline.17–19 Our results may indicate that cancer
cachexia promotes tumor progression and resistance toPD-1/L1 inhibitors by interrupting antitumor immunity.
Indeed, a previous study reported that patients withcachexia had shorter PFS, irrespective of PD-L1 expression.16 In accordance with these results, we also found a
reduced efficacy of PD-1/L1 inhibitors in patients withcachexia, regardless of PD-L1 expression (Figure S1).
Although the mechanisms underlying these effects are notfully understood, several studies have reported that
endogenous glucocorticoids and inflammatory cytokines,
such as IL-6, TNF-α, and IL-1β, may suppress tumorinfiltrating lymphocytes through the immunosuppressive
tumor microenvironment.20–27 Ghrelin, a peptide secretedby the stomach, is an endogenous agonist of the growth
hormone receptor, which regulates energy metabolism bypromoting growth hormone secretion.28 Amamorelin, aghrelin receptor agonist, is thought to improve cancer
cachexia by increasing appetite and insulin-like growth
factor-1,29,30 and has been approved and introduced into
clinical practice in Japan. However, because there are few
treatment options, further studies to better understandcancer-associated cachexia are needed to assess novel
therapeutic strategies for NSCLC patients with cachexia.
Although our study was retrospective in nature and hada relatively small sample size, our results provide a rationale
for future clinical investigations into cancer cachexia as atarget for NSCLC patients who receive immune checkpoint
inhibitors. Further large-scale studies of patients with similar
characteristics are warranted to confirm our findings.
In summary, we have demonstrated that 40.4% of
patients who received PD-1/PD-L1 inhibitors had cachexia,
which was associated with a poor prognosis. Our subanalysis indicated that the presence of cachexia in combination with poor PS predicts worse survival in thesepatients. This combination of factors can be used to moreaccurately stratify patients for treatment outcomes of
PD-1/PD-L1 inhibitors. Given the expanding clinical use
of immune checkpoint inhibitors, further studies are warranted to evaluate the role cachexia plays in cancer immunotherapy efficacy.

5

AU T H O R C O N T R I B U T I O N S
All authors contributed to the study conception and design.
Material preparation, data collection and analysis were performed by Norikazu Matsuo, Koichi Azuma, Daiki Murata,
Goushi Matama, Takashi Kojima, and Takaaki Tokito.
Akihiko Kawahara performed Immunohistchemical Staining. Kenta Murotani performed the biostatistics. The firstdraft of the manuscript was written by Norikazu Matsuo,
Koichi Azuma, and Tomoaki Hoshino, and all authors commented on previous versions of the manuscript. All authors
reviewed and approved the final version of the manuscript.
ACKNOWLEDGMENTS
We would like to thank the participating patients for theircontributions to this study.
This study was supported by the Japan Society for the Promotion of Science. Grant sponsor: JSPS KAKENHI; Grant
numbers: JP20K16317.
CONFLICT OF INTEREST STATEMENT
Norikazu Matsuo reports receiving personal fees from Ono
Pharmaceutical outside the submitted work; Koichi Azuma
reports receiving personal fees from Ono Pharmaceutical,
Chugai Pharmaceutical, AstraZeneca, MSD Oncology, andBristol Myers Squibb, outside the submitted work; Takaaki
Tokito reports receiving personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, and Boehringer Ingelheim, outside the submitted work; The remaining authors have noconflicts of interest to disclose.
DA T A A V A I L A B I L I T Y S T A T E M E N T
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
OR CI D
Koichi Azuma

https://orcid.org/0000-0001-5040-5856

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SU PP O RT I NG IN FO RM A T I ON
Additional supporting information can be found online in
the Supporting Information section at the end of this article.
How to cite this article: Matsuo N, Azuma K,
Murotani K, Murata D, Matama G, Kawahara A,
et al. Prognostic effect of cachexia in patients with
non-small cell lung cancer receiving immune
checkpoint inhibitors. Thorac Cancer. 2023. https://doi.org/10.1111/1759-7714.14881

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