TYPE Original Research

PUBLISHED 04 November 2024

DOI 10.3389/fimmu.2024.1463655

Dynamics trajectory of patient-

OPEN ACCESS reported quality of life and its
EDITED BY
Georgios Germanidis,
University General Hospital of Thessaloniki
associated risk factors among
AHEPA, Greece

REVIEWED BY
hepatocellular carcinoma
Mohammad Imran K. Khan,
Columbia University, United States
Mansoor-Ali Vaali-Mohammed,
patients receiving immune
King Saud University, Saudi Arabia
Yunpeng Hua, checkpoint inhibitors: a
The First Affiliated Hospital of Sun Yat-sen
University, China

*CORRESPONDENCE
prospective cohort study
Rong-Rui Huo
huorongrui@sr.gxmu.edu.cn Xue-Mei You 1,2,3†, Fei-Chen Lu 4†, Fan-Rong Li 1,
†
These authors have contributed equally to Feng-Juan Zhao 5 and Rong-Rui Huo 6*
this work
1
Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China,
RECEIVED 12 July 2024 2
Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical
ACCEPTED 16 October 2024 University), Ministry of Education, Nanning, China, 3Guangxi Key Laboratory of Early Prevention and
PUBLISHED 04 November 2024 Treatment for Regional High Frequency Tumor, Nanning, China, 4Medical Imaging Department, Guangxi
Medical University Cancer Hospital, Nanning, China, 5Head and Neck Surgery Department, Guangxi Medical
CITATION
University Cancer Hospital, Nanning, China, 6Department of Experimental Research, Guangxi Medical
You X-M, Lu F-C, Li F-R, Zhao F-J and University Cancer Hospital, Nanning, China
Huo R-R (2024) Dynamics trajectory of
patient-reported quality of life and its
associated risk factors among
hepatocellular carcinoma patients
Objective We aimed to characterize quality of life (QOL) trajectories among
receiving immune checkpoint inhibitors:
a prospective cohort study. patients with intermediate and advanced hepatocellular carcinoma patients
Front. Immunol. 15:1463655. treated with immunotherapy.
doi: 10.3389/fimmu.2024.1463655
Methods Barcelona Clinic Liver Cancer (BCLC) stage B-C HCC patients receiving
COPYRIGHT
© 2024 You, Lu, Li, Zhao and Huo. This is an immunotherapy at Guangxi Medical University Cancer Hospital were included.
open-access article distributed under the terms Trajectories of QOL, assessed using the Functional Assessment of Cancer
of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction
Therapy-Hepatobiliary (FACT-Hep) questionnaire, were identified through
in other forums is permitted, provided the iterative estimations of group-based trajectory models. Associations with
original author(s) and the copyright owner(s) trajectory group membership were analyzed using multivariable multinomial
are credited and that the original publication
in this journal is cited, in accordance with logistic regression.
accepted academic practice. No use,
distribution or reproduction is permitted
Results Three trajectory groups were identified (n=156): excellent (35.3%), poor
which does not comply with these terms. (43.6%), and deteriorating (21.1%) QOL. The deteriorating trajectory group
reported a mean QOL score of 124.79 (95% CI, 116.58–133.00), but then
declined significantly at month-2 (estimated QOL score 98.67 [95% CI, 84.33–
113.00]), and the lowest mean score is reached at month-6 (estimated QOL
score 16.58 [95% CI, 0–46.07]). Factors associated with membership to the
deteriorating group included no drinking (odds ratio [OR] vs yes [95% CI], 3.70
[1.28–11.11]), no received radiotherapy (OR vs yes [95% CI], 8.33 [1.41–50.00]),
diabetes (OR vs no [95% CI], 6.83 [1.57–29.73]), and extrahepatic metastasis (OR
vs no [95% CI], 3.08 [1.07–8.87]). Factors associated with membership to the poor
group also included body mass index ≤24.0 kg/m2 (OR vs no [95% CI], 4.49
[1.65–12.22]).

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You et al. 10.3389/fimmu.2024.1463655

Conclusions This latent-class analysis identified a high-risk cluster of patients

with severe, persistent post-immunotherapy QOL deterioration. Screening
relevant patient-level characteristics may inform tailored interventions to
mitigate the detrimental impact of immunotherapy and preserve QOL.

KEYWORDS

hepatocellular carcinoma, quality of life, trajectory analysis, immunotherapy, immune

checkpoint inhibitors

1 Introduction similar longitudinal trajectories, offering a more comprehensive

understanding of the impact of cancer and its treatment over time
Hepatocellular carcinoma (HCC), the most common primary (21, 22). To our best knowledge, no studies have attempted to
liver cancer, is a significant global cause of morbidity and mortality identify distinct groups of HCC patients who experience
(1, 2). Recent years have witnessed a substantial transformation in distinct QOL trajectories after immunotherapy using this
the HCC treatment landscape, particularly with an expanded array methodological approach.
of therapeutic options for advanced disease (2–4). However, a Early identification of high-risk groups for QOL deterioration is
predominant challenge remains as most HCC patients are crucial for timely, patient-specific supportive care interventions.
diagnosed at an advanced stage, precluding them from curative This study was conducted among intermediate and advanced HCC
treatments (5). The past decade has seen significant advancements patients who received immunotherapy, with the following aims: (1)
in pharmacotherapy for advanced HCC (2, 5, 6). Notably, the oral to describe dynamics of patient-reported QOL over six months after
small molecule multikinase inhibitors (MTKis) — sorafenib, immunotherapy; (2) to identify patients at high risk of QOL
cabozantinib, regorafenib, and lenvatinib — along with the deterioration; and (3) to focus on factors are associated with
monoclonal antibody (mAb) ramucirumab, have demonstrated distinct patterns of QOL.
effectiveness in phase III clinical trials as first- or second-line
treatments (7–12). These drugs have received approval from the
United States Food and Drug Administration (FDA) for use in 2 Methods
advanced HCC. Concurrently, immunotherapies, particularly
nivolumab and pembrolizumab, have shown promising outcomes, 2.1 Study design and patients
leading to their conditional FDA approval for second-line use (13,
14). Despite these advancements, which have improved overall Barcelona Clinic Liver Cancer (BCLC) stage B-C HCC patients
survival (OS) rates for advanced HCC patients, these therapies receiving immunotherapy at Guangxi Medical University Cancer
are not curative. Additionally, their unique treatment-related Hospital from January to July 2023 were initially included.
toxicities can exacerbate patients’ already fragile health. Therefore, Enrollment criteria were as follows: diagnosis of HCC confirmed
treatment strategies that also prioritize maintaining an adequate by postoperative histopathology; no prior immunotherapy; age 18-
quality of life (QOL) are of paramount importance. 75 years; Eastern Cooperative Oncology Group (ECOG)
QOL encompasses complete physical, mental, and social well- performance score of 0-1; Child-Pugh score ≤7; Karnofsky
being, extending beyond the mere absence of disease or infirmity. performance score (KPS) >60; estimated survival time ≥6 months;
The European Society of Medical Oncology (ESMO) emphasizes no family history or history of mental illness, no consciousness
the importance of QOL, incorporating it as a critical parameter in disorders, and normal cognitive function. Exclusion criteria were:
evaluating the clinical value of anticancer treatments (15, 16). presence of other malignant tumors; tumor-related surgery within
Despite this recognition, QOL assessments are often overlooked the last two months; concurrent use of Chinese herbal medicines
or inadequately reported in phase III clinical trials (17, 18). Previous with anti-tumor effects; active or historical autoimmune systemic
research has shown that immunotherapy generally has a transient diseases with potential relapse; discontinuation of subsequent
negative impact on QOL (19, 20). However, traditional analytic treatment due to severe immune-related adverse reactions (e.g.,
methods, which describe average outcomes at the population level, immune-related myocarditis, hepatitis, colitis).
may fail to capture the individual variability in the longitudinal The study protocol was approved by the Ethics Review
trajectory of cancer-related QOL. But, more detailed and nuanced Committee of Guangxi Medical University Cancer Hospital
exploration of this variability is possible through clustering (KY2024397) and conformed to the Declaration of Helsinki. All
techniques, such as growth mixture models or latent class enrolled patients provided informed consent prior to project
analyses. These methods can identify patient subgroups with initiation. This study was conducted in accordance with the

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You et al. 10.3389/fimmu.2024.1463655

Strengthening the Reporting of Observational Studies in described using frequencies and percentages. Baseline characteristics,
Epidemiology (STROBE) guidelines (23). summarized by QOL trajectory groups, were compared using the c2
test or analysis of variance, as appropriate.
Longitudinal variations in the FACT-Hep Summary Score were
2.2 Immunotherapy regimen analyzed using Group-Based Trajectory Modeling (GBTM) (21, 22,
25). This approach enabled the identification of polynomial
Treatment plans for all patients are evaluated and determined by a trajectories and latent trajectory groups, which are clusters of
minimum of two attending physicians based on the patient’s condition. individuals with similar outcome progressions. Model selection
Medication may be discontinued in cases of disease progression or was meticulous, involving iterative estimations to determine the
intolerable adverse reactions. The immune checkpoint inhibitors optimal fit. This included deciding on the number of trajectory
include PD-1 inhibitors such as sintilimab, toripalimab, groups and the shape or order of each group using maximum
camrelizumab, pembrolizumab, and nivolumab, all administered likelihood methods. Time was categorized in weeks for estimating
intravenously at a dosage of 200 mg every three weeks. Additionally, trajectory groups. A detailed description of the model selection
the PD-L1 inhibitor atezolizumab is administered intravenously at a process is provided in the Supplementary Methods. Each identified
dosage of 1200 mg every three weeks. trajectory group was assigned a descriptive label to succinctly
represent its QOL outcome patterns. Following this, we
characterized the demographics of participants in each group. To
2.3 Outcome variable and follow-up enhance insights from the FACT-Hep Summary Score and provide
a detailed view of the dynamics of its components, mean scores
The primary outcome was the QOL, which was determined across all FACT-Hep Questionnaire scales were compiled and
through the use of the Functional Assessment of Cancer Therapy- summarized by trajectory group.
Hepatobiliary questionnaire (FACT-Hep) (24). The 45-item FACT- A multivariable multinomial logistic regression model was
Hep consists of five subscales: physical well-being; social and family subsequently used to estimate the associations between baseline
well-being; emotional well-being; functional well-being; and the covariates and trajectory group membership, the association size
hepatobiliary cancer subscale (HepCS). The HepCS includes 18 was expressed as odds ratio (OR) and its 95% confidence interval
items that assess specific symptoms of hepatobiliary carcinoma and (CI). The optimal pattern of the FACT-Hep Summary Score was
side-effects of its treatment. Aggregate scores can also be formed, selected as the reference point. This approach was adopted to
from 0 to 180, higher scores on all scales of the FACT-Hep reflect concentrate on identifying factors associated with clustering into
better quality of life or fewer symptoms. groups characterized by less favorable patterns.
Following immunotherapy, patients undergo follow-up Analyses were performed using R, v4.3.0 (R Foundation), and
examinations every two months. These examinations comprise the GBTM model was fitted using lcmm package. Statistical
blood routine tests, liver and kidney function tests, key tumor significance was defined with a P value < 0.05.
markers, enhanced abdominal CT or MRI, and chest CT. QOL
assessments occur at four intervals: baseline (prior to
immunotherapy), two months post-immunotherapy, four months 3 Results
post-immunotherapy, and six months post-immunotherapy. The
study includes patients with a minimum of two measurement OQL. 3.1 Cohort characteristics

Of the 256 HCC patients at study baseline, we excluded 52 who

2.4 Variables of interest did not receive immunotherapy, 3 who declined to participate, and
45 who were lost to follow-up. Consequently, 156 patients were
Data collected by medical record review at diagnosis included included in the analysis. A detailed description of the selection
age, sex, drinking status, income; history of family cancer, diabetes, process is provided in Figure 1. In the whole cohort (n=156), the
and hypertension; hepatitis B surface antigen, hepatitis C antibody, mean age was 50.81 years (SD 10.48), 140(89.7%) and 16(10.3%)
liver cirrhosis, body mass index, tumor number, tumor size, patients were male and female, respectively; 37(23.7%) and 119
extrahepatic metastasis, vascular invasion, a-fetoprotein, BCLC (76.3%) patients were BCLC B and C stage, respectively. Overall,
stage, targeted therapy regimens, immunotherapy regimens, liver 67.9% received targeted therapy with Lenvatinib, 67.3% received
resection, transarterial chemoembolization, and radiotherapy. Body immunotherapy with Tislelizumab, 13.5% received liver resection,
mass index was calculated as weight in kilograms divided by height 81.4% received transarterial chemoembolization therapy, and 13.5%
in meters squared. received radiotherapy (Supplementary Table S1).

2.5 Statistical analyses 3.2 QOL trajectory groups

Data for normally distributed continuous variables were presented Our final model identified three trajectory groups (Figure 2).
as means and standard deviations (SDs). Categorical variables were Model selection metrics are presented in Supplementary Tables S2,

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You et al. 10.3389/fimmu.2024.1463655

158.39) at month 6. The second trajectory group included the majority

of patients (n=68, 43.6%; poor), who reported a consistently low QOL
from baseline, with an estimated QOL score of 126.60 (95% CI, 123.83
to 129.36), declining to 115.16 (95% CI, 103.47 to 126.86) at month 6.
In the third trajectory group (n=33, 21.1%; deteriorating), QOL at
baseline was comparable to that of the second group, with a mean QOL
score of 124.79 (95% CI, 116.58 to 133.00). However, a significant
decline occurred by month 2, with an estimated QOL score of 98.67
(95% CI, 84.33 to 113.00), and the lowest mean score was recorded at
month 6, at 16.58 (95% CI, 0 to 46.07). The detail estimated score and
respective 95% CIs for the trajectory groups are available in the
Supplementary Table S4. The trend of five subscalew of QOL in
different trajectories was basically the same (Figure 3).

3.3 Trajectory group membership

Table 1 displays patient characteristics by trajectory group.

Univariabel analysis (Supplementary Table S6) revealed that sex,
drinking status, diabetes, body mass index, extrahepatic metastasis,
vascular invasion, BCLC stage, transarterial chemoembolization,
and radiotherapy may be the trajectory group membership. We
incorporated these factors into multivariable multinomial logistic
regression model (Table 2) for further validation, we excluded sex,
due to the sample size of women is very small. Patients with no
alcohol consumption were significantly associated with poor and
deteriorating trajectory groups, with OR of 5.55 (95% CI: 2.44–
FIGURE 1
12.50) and 3.70 (95% CI: 1.28–11.11), respectively. Similarly, those
Consort diagram of patient population. QOL, quality of life. who did not receive radiotherapy had ORs of 5.00 (95% CI: 1.54–
16.67) for poor and 8.33 (95% CI: 1.41–50.00) for deteriorating
outcomes. Patients with a BMI ≤24.0 kg/m² were more likely to be
S3. The first trajectory group (n=55, 35.3%; excellent) demonstrated in poor QOL trajectory groups (OR: 4.49; 95% CI: 1.65–12.22).
consistently QOL over time, with an estimated QOL score of 139.52 Additionally, patients with diabetes and extrahepatic metastasis had
(95% CI, 135.71 to 143.33) at baseline and 154.32 (95% CI, 150.26 to ORs of 6.83 (95% CI: 1.57–29.73) and 3.08 (95% CI: 1.07–8.87),

FIGURE 2
Trajectory groups according to best-fitting model (n=156). Solid lines represent the predicted trajectories, shadow shapes represent the respective
95% CIs, and dotted gray lines represent the mean score at basleline. FACT-Hep Summary Scores were available for 156 patients at baseline, and
then among 156 at 2 months follow-up; 143 at 4 months follow-up; and 141 patients at 6 months follow-up. Higher scores reflect better QOL.
FACT-Hep, Functional Assessment of Cancer Therapy - Hepatobiliary questionnaire; QOL, quality of life.

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You et al. 10.3389/fimmu.2024.1463655

FIGURE 3
Mean QOL scores by trajectory group and by time point for FACT-Hep subscales. Solid lines represent the predicted trajectories, dotted gray lines
represent the mean score at basleline. Higher scores indicate greater functionality. Respective 95% CIs for the means are available in Supplementary
Table S5. FACT-Hep, Functional Assessment of Cancer Therapy - Hepatobiliary questionnaire; QOL, quality of life.

TABLE 1 Distribution of patient characteristics at baseline by quality of life trajectory group (n=156).

a
Characteristic Excellent (n=55) Poor (n=68) Deteriorating (n=33) P value
Age, years
Mean ± SD 52.20 ± 10.18 50.25 ± 11.28 49.67 ± 9.23 0.462

<60 43 (78.2%) 52 (76.5%) 30 (90.9%) 0.211

≥60 12 (21.8%) 16 (23.5%) 3 (9.1%)

Sex 0.001

Male 53 (96.4%) 54 (79.4%) 33 (100.0%)

Female 2 (3.6%) 14 (20.6%) 0 (0.0%)

Drinking status <0.001

No 20 (36.4%) 49 (72.1%) 20 (60.6%)

Yes 35 (63.6%) 19 (27.9%) 13 (39.4%)

(Continued)

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You et al. 10.3389/fimmu.2024.1463655

TABLE 1 Continued

a
Characteristic Excellent (n=55) Poor (n=68) Deteriorating (n=33) P value
Monthly household income, yuan 0.800

<6000 44 (80.0%) 57 (83.8%) 28 (84.8%)

≥6000 11 (20.0%) 11 (16.2%) 5 (15.2%)

Family history of cancer 0.957

No 43 (78.2%) 52 (76.5%) 26 (78.8%)

Yes 12 (21.8%) 16 (23.5%) 7 (21.2%)

Diabetes 0.008

No 49 (89.1%) 64 (94.1%) 24 (72.7%)

Yes 6 (10.9%) 4 (5.9%) 9 (27.3%)

Hypertension 0.344

No 41 (74.5%) 57 (83.8%) 28 (84.8%)

Yes 14 (25.5%) 11 (16.2%) 5 (15.2%)

Hepatitis B surface antigen 0.228

Negative 5 (9.1%) 5 (7.4%) 6 (18.2%)

Positive 50 (90.9%) 63 (92.6%) 27 (81.8%)

Hepatitis C antibody 0.053

Negative 51 (92.7%) 68 (100.0%) 32 (97.0%)

Positive 4 (7.3%) 0 (0.0%) 1 (3.0%)

Liver cirrhosis 0.844

No 16 (29.1%) 23 (33.8%) 10 (30.3%)

Yes 39 (70.9%) 45 (66.2%) 23 (69.7%)

Body mass index, kg/m2

Mean ± SD 23.02 ± 3.51 21.55 ± 2.55 21.65 ± 3.21 0.022

≤24.0 36 (65.5%) 58 (85.3%) 27 (81.8%) 0.026

>24.0 19 (34.5%) 10 (14.7%) 6 (18.2%)

Tumor number 0.996

Single 10 (18.2%) 12 (17.6%) 6 (18.2%)

Multiple 45 (81.8%) 56 (82.4%) 27 (81.8%)

Tumor size, cm 0.452

<5 12 (21.8%) 9 (13.2%) 6 (18.2%)

≥5 43 (78.2%) 59 (86.8%) 27 (81.8%)

Extrahepatic metastasis 0.001

No 39 (70.9%) 51 (75.0%) 13 (39.4%)

Yes 16 (29.1%) 17 (25.0%) 20 (60.6%)

Vascular invasion 0.096

No 20 (36.4%) 22 (32.4%) 5 (15.2%)

Yes 35 (63.6%) 46 (67.6%) 28 (84.8%)

a-Fetoprotein, ng/ml 0.664

(Continued)

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You et al. 10.3389/fimmu.2024.1463655

TABLE 1 Continued

a
Characteristic Excellent (n=55) Poor (n=68) Deteriorating (n=33) P value
≤400 27 (49.1%) 32 (47.1%) 13 (39.4%)

>400 28 (50.9%) 36 (52.9%) 20 (60.6%)

BCLC stage 0.134

B 17 (30.9%) 16 (23.5%) 4 (12.1%)

C 38 (69.1%) 52 (76.5%) 29 (87.9%)

Targeted therapy regimens 0.807

Donafenib 9 (16.4%) 13 (19.1%) 5 (15.2%)

Lenvatinib 35 (63.6%) 47 (69.1%) 24 (72.7%)

Regorafenib 0 (0.0%) 1 (1.5%) 0 (0.0%)

Apatinib 2 (3.6%) 3 (4.4%) 2 (6.1%)

Anrotinib 1 (1.8%) 0 (0.0%) 0 (0.0%)

Bevacizumab 8 (14.5%) 4 (5.9%) 2 (6.1%)

Immunotherapy regimens 0.585

Atezolizumab 2 (3.6%) 1 (1.5%) 0 (0.0%)

Cetuximab 7 (12.7%) 3 (4.4%) 3 (9.1%)

Camrelizumab 10 (18.2%) 12 (17.6%) 8 (24.2%)

Tislelizumab 36 (65.5%) 48 (70.6%) 21 (63.6%)

Penpulimab 0 (0.0%) 2 (2.9%) 1 (3.0%)

Pembrolizumab 0 (0.0%) 2 (2.9%) 0 (0.0%)

Liver resection 0.787

No 49 (89.1%) 58 (85.3%) 28 (84.8%)

Yes 6 (10.9%) 10 (14.7%) 5 (15.2%)

Transarterial chemoembolization 0.033

No 7 (12.7%) 10 (14.7%) 11 (33.3%)

Yes 48 (87.3%) 58 (85.3%) 22 (66.7%)

Radiotherapy 0.066

No 43 (78.2%) 61 (89.7%) 31 (93.9%)

Yes 12 (21.8%) 7 (10.3%) 2 (6.1%)

Data are presented as n(%), unless otherwise indicated.

BCLC, Barcelona clinic liver cancer; SD, standard deviation.
a
P value was based on c2, t-test where appropriate.

respectively, indicating higher likelihoods of deteriorating QOL poor, and deteriorating. Our findings indicate that a significant
patterns compared to those with excellent trajectories. portion of patients experienced severe and sustained declines in
QOL, with the lowest scores observed at the six-month mark.
Factors such as no alcohol consumption, absence of radiotherapy,
4 Discussion diabetes, and extrahepatic metastasis were significantly associated
with membership in the deteriorating group. These results highlight
This study aimed to characterize the QOL trajectories among the necessity for targeted interventions to mitigate the adverse
patients with intermediate and advanced HCC treated with impacts of immunotherapy on patient QOL.
immunotherapy. Through the use of group-based trajectory QOL in HCC patients is influenced by medical factors,
modeling, we identified three distinct QOL trajectories: excellent, including the disease itself, its complications, treatments such as

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TABLE 2 Multinomial logistic regression of factors associated with utilization of QOL in HCC patients included description of
FACT-Hep score trajectory group membership (vs reference Excellent).
symptomatology and QOL of patients, treatment endpoint in
clinical trial, and health care valuation (17, 32). QOL
Poor (n=68) Deteriorating (n=55)
Factors measurement provides valuable information in clinical practice
OR (95% CI) P value OR (95% CI) P value and research. Future research into utilization in clinical trials as
Drinking status well as routine clinical practice are warranted. While novel
immunotherapies have improved overall survival in HCC patients
Yes Reference Reference
in recent years, their unique side effects may reduce overall
No 5.55 (2.44–12.50) <0.001 3.70 (1.28–11.11) 0.016 treatment efficacy and perceived benefits (33). Therefore, regular
Diabetes monitoring of changes in quality of life can provide important clues
to the long-term prognosis of patients. Previous studies have shown
No Reference Reference
that immunotherapy often has a transient negative effect on QOL
Yes 0.65 (0.15–2.78) 0.566 6.83 (1.57–29.73) 0.010 (19, 20). However, traditional analytic methods, which describe
Body mass index, kg/m2 average outcomes at the population level, may fail to capture the
individual variability in the longitudinal trajectory of cancer-related
>24.0 Reference Reference
QOL. Therefore, this study used latent categorical analysis to
≤24.0 4.49 (1.65–12.22) 0.003 3.22 (0.91–11.42) 0.071 identify subgroups of patients with similar longitudinal
Extrahepatic metastasis trajectories, thereby providing a more comprehensive picture of
the quality of life of HCC patients after immunotherapy and its
No Reference Reference
impact over time.
Yes 0.70 (0.27–1.79) 0.458 3.08 (1.07–8.87) 0.037 In our cohort, the deteriorating trajectory group exhibited
Vascular invasion significant declines in QOL as early as three weeks post-
treatment, with the lowest scores at six months. This rapid
No Reference Reference
deterioration underscores the severe impact of immunotherapy
Yes 0.69 (0.25–1.87) 0.463 2.48 (0.60–10.20) 0.208 on patients’ well-being and highlights the necessity for early
BCLC stage intervention. Our findings contribute to the growing body of
literature on the short-term effects of cancer treatments on
B Reference Reference
patient-reported outcomes. While previous studies have often
C 2.15 (0.72–6.45) 0.173 2.21 (0.49–9.94) 0.299 focused on QOL at only one time point (19, 20), our research
Transarterial chemoembolization
provides a comprehensive assessment of overall QOL trajectories
over an extended period. This approach allows for a more nuanced
No Reference Reference
understanding of the short-term impact of immunotherapy on
Yes 0.73 (0.21–2.49) 0.617 0.29 (0.08–1.08) 0.064 HCC patients and underscores the need for continuous
Radiotherapy
monitoring and intervention to support patients’ well-being
throughout their treatment journey.
Yes Reference Reference
The identification of modifiable or non-modifiable factors, as
No 5.00 (1.54–16.67) 0.008 8.33 (1.41–50.00) 0.019 predictors of deteriorating QOL trajectories underscores the
OR, odds ratio; CI, confidence interval. importance of personalized care strategies. Patients who abstained
from alcohol were more likely to be in the deteriorating QOL group
oncological and immunotherapy, underlying liver conditions, and (OR=3.70, 95% CI, 1.28–11.11). Moderate alcohol consumption is
psychological, social, or spiritual responses. One interesting use of often associated with positive social interactions and emotional
QOL data in HCC patients is prognostication for OS. A study support. It serves as a part of social activities, enhancing social
identified worse scores in appetite loss, physical function, and role connections which can positively impact mental health (34, 35).
function from the EORTC QLQ-C30 as independent risk factors for However, the relationship between alcohol consumption and QOL
shorter OS in advanced HCC patients (26). Another study using the requires further study, as it varies individually and is influenced by
EORTC QLQ-C30 found that a better baseline role function score factors such as quantity consumed, drinking patterns, and personal
was a significant prognostic factor for longer OS in advanced HCC health status (36). Patients who did not receive radiotherapy were
patients (27). The baseline Spitzer QoL index was reported as more likely to be in the deteriorating QOL group (OR=8.33, 95% CI,
prognostic for survival in 538 advanced HCC patients, with 1.41–50.00). Radiotherapy plays a significant role in controlling
higher scores associated with longer OS (28). Attempts have been tumor growth and alleviating symptoms, and enhances
made to enhance existing staging systems with QOL data (27, 28). immunotherapeutic sensitivity (37, 38). Patients who do not
Addition of EORTC QLQ-C30 data has been shown to improve the undergo radiotherapy may experience more pain and other
performance of the Cancer of the Liver Italian Program (CLIP) (29), symptoms due to inadequate tumor control, directly lowering
the BCLC system (30), the Groupe d’É tude et de Traitement du their QOL (39). Additionally, patients receiving radiotherapy
Carcinome Hé patocellulaire system (31). Spitzer QOL index could often have higher expectations and confidence in treatment
improve the prognostic value of CLIP (28). In addition, important outcomes, which positively influences QOL (39). Although

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You et al. 10.3389/fimmu.2024.1463655

radiotherapy may have some side effects, the benefits in symptom The strengths of our study include its prospective, longitudinal
relief and QOL improvement generally outweigh the negatives. design and the use of a robust higher-order QOL outcome measure
Patients with a low BMI (≤24.0 kg/m²) were more likely to be in the that summarizes multiple scales into a multidimensional response
poor QOL group (OR=4.49, 95% CI, 1.65–12.22). A low BMI often profile. This approach avoids the limitations of multiple
indicates malnutrition or insufficient body weight, leading to comparisons and offers a comprehensive view of patients’ QOL
compromised immune function, physical decline, and worsening over time. Moreover, the use of group-based trajectory modeling
health conditions, thereby impacting QOL (40, 41). Moreover, a low allows for the identification of clinically relevant latent groups,
BMI could signify underlying conditions such as cachexia, a providing valuable insights into the diverse experiences of HCC
complex metabolic syndrome further reducing patient QOL (42). patients undergoing immunotherapy. We acknowledge several
Patients with diabetes were more likely to be in the deteriorating limitations in this study. First, being a longitudinal investigation,
QOL group (OR=6.83, 95% CI, 1.57–29.73). Diabetes commonly it is subject to the common constraint of escalating response
accompanies multiple complications such as cardiovascular disease, attrition as time progresses from study entry. Consequently, we
kidney disease, neuropathy, and retinopathy (43, 44), significantly recognize the potential for selection and attrition bias evolving over
affecting both health and QOL (45, 46). Managing diabetes requires time. However, it is noteworthy that GBTM can effectively
long-term medication and strict dietary control, placing high accommodate missing outcome data (25). Second, there are some
demands on patients’ lifestyle and mental state, thereby increasing well-known determinants of QOL that could not be explored,
their burden of living (47). Additionally, diabetes patients often including psychologic measures such as depression and fatigue
experience psychological distress such as anxiety and depression (57). Third, our models describe a population of patients with
(48), further impacting QOL. Patients with extrahepatic metastasis intermediate and advanced HCC, and the findings may not be
were more likely to be in the deteriorating QOL group (OR=3.08, generalizable to patients with early-stage disease. Further research is
95% CI, 1.07–8.87). Extrahepatic metastasis typically indicates needed to confirm our findings in larger and more diverse patient
advanced disease and poor prognosis, significantly impacting populations and to explore the long-term impact of
patient QOL (49–51). It signifies tumor spread beyond the liver, immunotherapy on QOL beyond the six-month period examined
accompanied by more severe symptoms and worse prognosis. These in this study. Fourth, our study population exclusively comprised
patients often require complex and invasive treatments, which Chinese survivors, limiting the generalizability of results. Fourth, we
themselves may negatively affect QOL (52). fitted the latent class model with a smaller sample size. Although
In summary, the results of this study indicate that abstaining our sample size may be relatively modest for latent class modeling,
from alcohol, not receiving radiotherapy, low BMI, diabetes, and but our model evaluation metrics support the suitability of the fitted
extrahepatic metastasis are critical factors influencing patient QOL. latent trajectory model. Finally, it is pertinent to note that the risk
These factors collectively contribute to a significant decline in QOL models for membership in specific trajectory groups may
among patients in the deteriorating group. Recognizing and underestimate the uncertainty inherent in the trajectory modeling
intervening in these high-risk factors is crucial in clinical practice during the initial stage.
to improve patient QOL. For instance, providing nutritional
support for malnourished patients (53), comprehensive
management for diabetes patients (54), and considering 5 Conclusions
radiotherapy (55) when appropriate may help enhance patient
QOL. Additionally, offering psychological support and social Our study identifies a high-risk cluster of HCC patients with
resources could also positively impact the QOL of these patients severe, persistent QOL deterioration following immunotherapy.
(56). Future research should further explore the causal relationships Screening for relevant patient-level characteristics can inform
between these factors and QOL, as well as assess the effectiveness of tailored interventions to mitigate the detrimental impact of
different interventions. This will provide more scientific and immunotherapy and preserve QOL. Future research should focus
comprehensive guidance for clinical practice. Through integrated on developing and testing targeted interventions that address both
management and personalized treatments, it is possible to improve modifiable and non-modifiable factors associated with QOL
patient QOL and enhance their overall health outcomes. declines in this patient population. This will be crucial in
From a clinical perspective, our findings are particularly improving long-term outcomes and enhancing the overall quality
relevant for informing patient care strategies. Greater treatment- of life for HCC patients undergoing immunotherapy.
related symptom burden is among the main reasons for non-
adherence and discontinuation of treatment, which ultimately can
contribute to poorer clinical outcomes. In the context of Data availability statement
immunotherapy, it is crucial to identify patients at risk of
significant QOL deterioration early in the treatment process. By The data analyzed in this study is subject to the following
doing so, healthcare providers can implement timely interventions licenses/restrictions: Data available on request due to privacy/
to manage symptoms and support patients, potentially improving ethical restrictions. Requests to access these datasets should be
adherence to treatment and overall outcomes. directed to Rong-Rui Huo, huorongrui@sr.gxmu.edu.cn.

Frontiers in Immunology 09 frontiersin.org

You et al. 10.3389/fimmu.2024.1463655

Ethics statement was supported by the National Natural Science Foundation of

China (81960308).
The study protocol was approved by the Ethics Review
Committee of Guangxi Medical University Cancer Hospital
(KY2024397) and conformed to the Declaration of Helsinki. All Conflict of interest
enrolled patients provided informed consent prior to project
initiation. This study was conducted in accordance with the The authors declare that the research was conducted in the
Strengthening the Reporting of Observational Studies in absence of any commercial or financial relationships that could be
Epidemiology (STROBE) guidelines. construed as a potential conflict of interest.

Author contributions Publisher’s note

X-MY: Funding acquisition, Writing – original draft, Writing – All claims expressed in this article are solely those of the authors
review & editing. F-CL: Data curation, Resources, Writing – original and do not necessarily represent those of their affiliated
draft, Writing – review & editing. F-RL: Data curation, Formal organizations, or those of the publisher, the editors and the
analysis, Investigation, Visualization, Writing – review & editing. F- reviewers. Any product that may be evaluated in this article, or
JZ: Data curation, Formal analysis, Visualization, Writing – review & claim that may be made by its manufacturer, is not guaranteed or
editing. R-RH: Conceptualization, Supervision, Writing – original endorsed by the publisher.
draft, Writing – review & editing.

Supplementary material
Funding
The Supplementary Material for this article can be found online at:
The author(s) declare that financial support was received for the https://www.frontiersin.org/articles/10.3389/fimmu.2024.1463655/
research, authorship, and/or publication of this article. This work full#supplementary-material

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