Joint modeling of longitudinal health-related quality of life during concurrent chemoradiotherapy period and long-term survival among patients with advanced nasopharyngeal carcinoma.

Background

Nasopharyngeal carcinoma (NPC) is endemic in Southeastern Asia, especially in China [ 1 ]. Different from other head and neck cancers, NPC is significantly associated with Epstein-Barr virus infection and its major pathological type is non-keratinizing. Most NPC patients present at locally advanced stage at their initial diagnosis due to the conceal tumor-related symptoms on anatomical structure. Radical radiotherapy, such as intensity modulated radiotherapy (IMRT), is the current recommended treatment for NPC patients, and IMRT combined with chemotherapy is the primary treatment modality for locally advanced NPC patients [ 2 ]. Along with the improvements in early diagnosis and multimodality therapy, the prognosis of NPC has been largely improved in recent decades. The 5-year overall survival (OS) is over 90% for early-stage NPC patients and around 68–90% for locally advanced NPC patients [ 3 , 4 ]. However, the treatment-related late side effects and sequela considerably reduce NPC survivors’ health-related quality of life (HRQOL) [ 5 ]. Our previous study has proved a substantially deteriorated trend of HRQOL during the concurrent chemoradiotherapy (CCRT) period among advanced NPC patients [ 6 ].

Previous studies have reported positive associations between pretreatment HRQOL and survival outcomes among patients with advanced lung carcinoma, breast carcinoma, multiple myeloma, melanoma, esophageal carcinoma, and head and neck carcinoma [ 7 – 14 ]. A few of studies reported that scores of some domains/items of HRQOL could predict distant metastasis and tumor recurrence in NPC and other head and neck cancers [ 15 , 16 ]. One limitation of these studies is that HRQOL was measured at one time point (i.e., pretreatment) without considering its dynamic fluctuation during and after treatment. The longitudinal trend rather than only one measure of HRQOL might provide a more accuracy prediction of NPC prognosis. It has been reported that every 10-point increase of appetite loss during treatment and survival period resulted in a 13% increased risk of death in anaplastic oligodendrogliomas patients [ 17 ]. However, how the longitudinally deteriorated HRQOL could affect the long-term survival of NPC patients is still unclear. It is therefore necessary to investigate the effect of longitudinal HRQOL on long-term survival of NPC patients.

HRQOL is dynamically changing during the treatment and survival period of NPC patients, and often correlated with the length of survival period. Treatment and treatment-related impairment of HRQOL might affect survival. Separate analysis of longitudinal and survival data would lead to biased estimations [ 18 ]. Joint modeling, which brings both longitudinal measures and time-to-event outcomes together (simultaneously) into a single model, could provide unbiased estimations for longitudinal HRQOL, survival processes, and their association [ 18 ] [ 19 ]. Therefore, it could be a promising approach to better characterize the effect of longitudinal HRQOL on long-term survival outcomes [ 20 ]. Using the updated follow-up data from a multicenter clinical trial conducted in China, this study is objectively to investigate the impact of longitudinal HRQOL during treatment period on the long-term survival outcomes among advanced NPC patients using joint modeling approach.

Methods

Study design and participants

This study was based on an open-label, noninferiority, multicenter randomized clinical trial during 2012–2014 in China [ 21 ]. In the trial, patients, who were aged 18–65 years with non-keratinizing clinical stage of II-IVB (T 1–4 N 1–3 or T 3–4 N 0 ) NPC, no evidence of distant metastasis, a Karnofsky score ≥ 70, and adequate hematological, renal, hepatic functions, were randomly allocated (1:1) to cisplatin-based or nedaplatin-based concurrent chemoradiotherapy groups. The exclusion criteria include prior or synchronous malignant disease, primary relapse/distant metastasis, previously received radiotherapy or chemotherapy, pregnancy and lactating mothers, the presence of uncontrolled life-threatening illness, or with any mental disorder or somatic comorbidities of clinical concerns. In this study, a subsample of 145 patients who completed European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORCT QLQ-C30) at baseline were involved, and their survival outcomes were updated from 31 June 2017 to 31 December 2020. Details of participants in this study has been reported previously [ 6 ].

Measures of health-related quality of life

HRQOL was measured at baseline (i.e., before treatment initiation) and repeatedly evaluated weekly to week 6 (around the end of CCRT) during the CCRT period, using the Chinese version of the EORCT QLQ-C30 (version 3.0). The EORCT QLQ-C30 has been widely used in several international cancer clinical trials [ 22 , 23 ]. All assessments were carried out by a well-trained clinical research coordinator at the clinic. The fifteen domains of HRQOL, including a global quality of life, five multi-item functioning scales (i.e., physical, role, emotional, cognitive, and social functioning), three multi-item symptom scales (fatigue, pain, and nausea/vomiting), and six single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), were measured by 30 items. All domain scores were normalized into the range from 0 to 100, with higher scores indicating a better global health status, better performance of functioning, or higher levels of symptoms.

Survival outcomes

This study focused on three survival outcomes, including OS, progression-free survival (PFS), and distant metastasis-free survival (DMFS). OS was defined as the time interval from the date of random assignment to the date of death from any cause or censored at the date of last follow-up. PFS was defined as the time interval from the date of random assignment to the date of local or regional relapse, distant metastasis, or death from any cause, whichever occurred first. DMFS was defined as the time interval from the date of random assignment to the date of distant metastasis, or death from any cause.

Statistical analysis

Descriptive statistics (e.g., means and standard deviation (SD), frequency and percentage) were presented when appropriate. We firstly assessed the associations between baseline HRQOL domains and survival outcomes by cox regression models. Secondly, the associations between longitudinal assessments of HRQOL during the CCRT period and subsequently long-term survival outcomes were estimated using joint modeling method [ 18 ]. Joint modeling could simultaneously analyze the longitudinal data of the covariates and time-to-event data, which consists of a longitudinal component to model longitudinal trend of HRQOL and a survival component to model time-to-event outcomes. A linear mixed-effect model that expands the time effect into a B-spline basis matrix was used for longitudinal trend of HRQOL, and an exponential hazard model was used for time-to-event outcomes. The longitudinal and survival components were jointed through a random slope effect as shared parameter with a time lag of 12 months, to associate the true levels of longitudinal trend of HRQOL domains with the risk of a survival outcome (i.e., OS, PFS, or DMFS) [ 24 ]. The hazard ratios (HRs) with 95% confidence intervals (95% CIs) were reported as the 10-point increase of HRQOL domain scores, which is the minimal clinically important difference of the scales [ 25 ]. The SAS macro JM was applied for the joint modeling analyses [ 26 ].

All models were adjusted for age, sex, percentage of weight loss during CCRT period, AJCC stage, EBV-DNA copies before treatment, and treatment group. All data analyses were performed using SAS software (version 9.4, SAS Institute, Cary, NC, USA), and a two-sided p value < 0.05 was considered as statistically significant.

Ethical approval

This study was approved by the institutional review board of Sun Yat-sen University Cancer center. The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit ( www.researchdata.org.cn ), with the approval RDD number as RDDA2022748620.

Results

Patients’ characteristics

Among 145 patients, the mean age was 44.7 years (SD: 9.3) in the cisplatin group and 43.8 years (SD: 10.3) in the nedaplatin group. Most patients were female, 74.7% in the cisplatin group and 74.3% in the nedaplatin group, 30.7% in cisplatin group and 27.1% in nedaplatin group reported more than 10% of weight loss during CCRT period. (Table 1 ). Table 1 Descriptions of sample characteristics Cisplatin group ( n = 75) Nedaplatin group ( n = 70) Age, years Mean ± SD 44.7 ± 9.3 43.8 ± 10.3 Rang 20–64 22–65 ≤ 45 39 (52.0) 41 (58.6) > 45 36 (48.0) 29 (41.4) Sex Male 19 (25.3) 18 (25.7) Female 56 (74.7) 52 (74.3) Percentage of weight loss during CCRT period No change or increase 9 (12.0) 16 (22.9) < 5% 20 (26.7) 17 (25.7) 5–10% 23 (30.7) 18 (25.7) > 10% 23 (30.7) 19 (27.1) AJCC stage II 7 (9.3) 8 (11.4) III 48 (64.0) 47 (67.1) IV 20 (26.7) 15 (21.4) Epstein-Barr virus DNA test DNA < 1500 copies per mL 44 (58.7) 35 (50.0) DNA ≥ 1500 copies per mL 31 (41.3) 35 (50.0) CCRT, concurrent chemoradiotherapy; AJCC, American joint committee on cancer; SD, standard deviation

Updated long-term survival rate

After a median follow-up of 83.4 months (range: 5.0, 100.7 months), 20 dead cases, 30 progressed cases, and 16 distant metastasis cases were observed. The 5-year and 8-year overall survival rates were 90.8% (95% CI: 84.7, 94.5) and 82.9% (95% CI: 73.2, 89.3), respectively. The 5-year and 8-year PFS rates were 82.5% (95% CI: 75.2, 87.8) and 75.9% (95% CI: 66.0, 83.3), while the 5-year and 8-year DMFS rates were 90.2% (95% CI: 84.0, 94.1), and 88.5% (95% CI: 81.9, 92.8), respectively. (Fig. 1 ). Fig. 1 Kaplan–Meier survival curve of progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS)

Joint modeling of longitudinal scores of HRQOL with survival outcomes

After adjustment of potential covariates, the results in Table 2 showed significant effects of longitudinal trend in fatigue and appetite loss during CCRT period on DMFS: a 10-point increase in scores of fatigue and appetite loss domains over time was associated with 75% (HR: 1.75, 95%CI: 1.01, 3.02; p = 0.047) and 59% (HR: 1.59, 95%CI: 1.09, 2.59; p = 0.018) increase in the risk of distant metastasis, respectively. The associations of other domains of HRQOL with DMFS were not statistically significant. The scores of HRQOL domains, neither at baseline nor longitudinal trend, showed statistical significance with OS and PFS (Table S1 and Table S2). Table 2 Associations between health-related quality of life and distant metastasis-free survival among advance nasopharyngeal carcinoma Univariate Adjusted † HR (95% CI) p HR (95% CI) p Global quality of life Baseline 0.94 (0.76, 1.16) 0.56 0.98 (0.79, 1.23) 0.876 Longitudinal 0.72 (0.48,1.07) 0.10 0.71 (0.48,1.04) 0.081 Psychical function Baseline 0.81 (0.59, 1.12) 0.205 0.82 (0.57, 1.17) 0.262 Longitudinal 0.60 (0.36,0.99) 0.046 0.65 (0.39,1.09) 0.102 Role function Baseline 1.15 (0.88, 1.49) 0.303 1.15 (0.88, 1.52) 0.309 Longitudinal 0.72 (0.51,1.01) 0.06 0.71 (0.50,1.00) 0.053 Emotional function Baseline 0.93 (0.71, 1.22) 0.614 0.97 (0.73, 1.29) 0.841 Longitudinal 0.60 (0.32,1.11) 0.104 0.61 (0.32,1.15) 0.125 Cognitive function Baseline 0.84 (0.65, 1.11) 0.217 0.90 (0.68, 1.19) 0.456 Longitudinal 0.63 (0.36,1.10) 0.103 0.68 (0.38,1.22) 0.196 Social function Baseline 1.07 (0.88, 1.31) 0.482 1.09 (0.90, 1.33) 0.391 Longitudinal 0.65 (0.38,1.12) 0.121 0.66 (0.37,1.16) 0.143 Fatigue Baseline 0.94 (0.74, 1.21) 0.632 0.91 (0.70, 1.17) 0.453 Longitudinal 1.78 (1.04, 3.06) 0.036 1.75 (1.01, 3.02) 0.047 Nausea and vomiting Baseline 0.93 (0.77, 1.12) 0.438 0.92 (0.76, 1.11) 0.385 Longitudinal 1.76 (0.89, 3.50) 0.105 1.68 (0.86, 3.30) 0.13 Pain Baseline 1.05 (0.83, 1.34) 0.675 1.01 (0.78, 1.33) 0.92 Longitudinal 1.31 (0.95, 1.81) 0.096 1.30 (0.94, 1.80) 0.119 Dyspnea Baseline 0.87 (0.64, 1.18) 0.377 0.87 (0.64, 1.18) 0.369 Longitudinal 4.59 (1.10, 19.09) 0.037 3.97 (0.96,16.44) 0.058 Sleep disturbance Baseline 1.12 (0.94, 1.32) 0.199 1.20 (0.99, 1.46) 0.068 Longitudinal 1.80 (0.83,2.16) 0.235 1.30 (0.80,2.11) 0.288 Appetite loss Baseline 0.95 (0.81, 1.12) 0.546 0.92 (0.77, 1.09) 0.326 Longitudinal 1.59 (1.09, 2.33) 0.018 1.59 (1.09, 2.59) 0.018 Constipation Baseline 0.94 (0.77, 1.15) 0.551 0.98 (0.79, 1.23) 0.88 Longitudinal 1.28 (0.95,1.74) 0.107 1.30 (0.95,1.78) 0.105 Diarrhea Baseline – – Longitudinal 1.44 (0.07,31.60) 0.815 1.62 (0.16,16.12) 0.68 Financial difficulties Baseline 0.97 (0.84, 1.12) 0.654 0.90 (0.76, 1.06) 0.203 Longitudinal 1.47 (0.52, 4.17) 0.465 1.33 (0.40, 4.38) 0.637 The bold values indicate statistically significant 95% CI: 95% confidence interval † Models were adjusted of age, sex, weight loss during CCRT period, AJCC stage, EBV-DNA copies before treatment, and treatment group

Discussion

To the best of our knowledge, this is the first study to investigate the prognostic effects of longitudinal HRQOL on the long-term survival outcomes in advanced NPC patients, showing that the deteriorated trends of fatigue and appetite loss during CCRT period were significantly associated with lower rates of DMFS.

Fatigue is one of the most prevalent cancer-related symptoms, especially for locally advanced NPC patients [ 6 , 27 ], and few studies explored its associations with long-term survival in cancer patients. Antolín et al. reported that intensity of fatigue was associated with decreased quality of life but not with metastasis status among prostate cancer [ 28 ]. One possible mechanisms of our findings could be the inflammatory changes. Fatigue was found to be significantly associated with the increases of inflammation markers (e.g., IL6, sTNFR2) in head and neck cancer patients during treatment [ 29 ].These inflammatory changes could suppress the immune system [ 30 , 31 ], and increase the risk of distant metastasis. Another possible mechanism might be hyponatremia. Fatigue is associated with hyponatremia, which was reported to be linked with lower survival rate in patients with lung cancer [ 32 , 33 ], epithelial ovarian cancer [ 34 ], gastric cancer [ 35 ], and colorectal cancer [ 36 ]. Besides, Workeneh et al. indicated that hyponatremia can reduce the likelihood of survival [ 37 ], it is therefore necessary to take care of hyponatremia during anti-cancer treatment.

We also found that longitudinal trend of appetite loss during treatment period was significantly associated with lower DMFS in advanced NPC patients, which highlighted the importance of appetite and nutritional support for advanced NPC patients during treatment period. One possible reason could be that appetite loss could directly reduce patients’ nutrition intake and could cause clinically significant weight loss [ 38 , 39 ], which was associated with a lower rate of DMFS among head and neck patients [ 40 , 41 ]. Such weight loss, or even malnutrition, could downregulate the immune system, which might lead to unidentified micro-metastasis of metastatic cancer cells. Specifically, tumor immune escape and the initiation of metastasis are critical steps in the malignant progression of tumors [ 42 ]. Recruitment of immunosuppressive cells to tumors could protect metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis [ 43 ].

The main advantage of our study is that the dynamic effects of longitudinal measures of HRQOL on survival outcomes were estimated by joint modeling, which should have less bias than using only one single measure of HRQOL without considering its dynamic changes. However, there are several limitations in our study. First, the sample is small, especially for limited events of disease progress, distant metastasis, and death. Future studies with large sample size are warranted to confirm our findings. Second, HRQOL in our study was only weekly measured during treatment period, which could not reflect their long-term dynamic profiles after the treatment, and the impact of their dynamic changes during long-term survival period on prognosis of NPC patients is still unclear, and warranted in further research. Third, the generalizability of our finding might be limited by the representativeness of the sample, considering that patients only from one cancer center of epidemic region.

In conclusion, our findings indicate that the longitudinal deteriorated trends in fatigue and appetite loss during treatment period were significantly associated with higher risks of distant metastasis among advanced NPC patients. Proper psychological supportive care nutritional support during treatment period could potentially benefit treatment effects and long-term prognosis of NPC patients.

Supplementary Information

Additional file 1. Additional file 2.

Publisher's Note

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Ji-Bin Li, Shan-Shan Guo, Hai-Qiang Mai and Qiu-Yan Chen have contributed equally to this study.

Acknowledgements

We greatly appreciated all participants and their families, as well as the medical, nursing, and research staff at the study centers.

Author contributions

QY Chen, JB Li, and SS Guo conceived and designed the study; JB Li, SS Guo, T Liu, and LQ Tang acquired the data; JB Li, and ZC Lin conducted the statistical analyses; JB Li, and SS Guo drafted the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content, and approved the final version of the manuscript.

Funding

This study was partly supported by grants from the National Natural Science Foundation of China (No.81803105, No.81425018, No.81672868, No.82002852 and No.81802775), National Key Research and Development Program of China (2022YFC2705005), Natural Science Foundation of Guangdong Province (No. 2018A030310238, No.2017A030312003), Medical Science and Technology Research Fund of Guangdong Province (No. A2018201), the Sun Yat-sen University Clinical Research 5010 Program, the Fundamental Research Funds for the Central Universities of Sun Yat-sen University (No. 22qntd4001), and China Medical Board, USA (No. 22–484).

Availability of data and materials

The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit ( www.researchdata.org.cn ), with the approval RDD number as RDDA2022748620.

Declarations

Ethics approval and consent to participate

This study was approved by the institutional review board of Sun Yat-sen University Cancer center and all the participates approved the inform consent.

Consent for publication

All the authors approved the consent for publication.

Competing interests

All authors declare no conflict of interest.

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