Abstract
Background/Aim: Malnutrition and inflammation are common conditions in patients with head and neck cancer (HNC). This study aimed to evaluate the predictive value of albumin combined with neutrophil-lymphocyte ratio (NLR), referring to the albumin-NLR score (ANS), in the prediction of treatment completeness and safety profiles in HNC patients receiving definitive concurrent chemoradiotherapy (CCRT). Patients and Methods: 461 consecutive HNC patients who received CCRT between 2016 and 2017 at three medical centers in Taiwan were prospectively enrolled and divided into three different groups based on their pretreatment ANS (ANS 0, high albumin and low NLR; ANS 1, low albumin or high NLR; and ANS 2, low albumin and high NLR) for treatment completeness and safety profiles comparison. Results: Overall, 46 patients (10.0%) had incomplete CCRT treatment. Patients in the ANS 2 group experienced a higher rate of incomplete CCRT (20.9%) than those in the ANS 1 (7.4%) and ANS 0 (3.5%) groups. ANS had a better discriminatory ability in predicting CCRT completeness in terms of −2 log-likelihood value, chi-square value, and c-index than the prognostic nutritional index. Patients in the ANS 2 group had significantly higher incidences of grade 3 or higher leukopenia, anemia, neutropenia, thrombocytopenia, non-neutropenic infection, and hypokalemia than those in the other two ANS groups. Conclusion: Our study showed that the ANS can accurately predict the treatment completeness of CCRT in patients with HNC and can be widely used as a simple predictor of treatment tolerance and safety profiles in patients with HNC undergoing CCRT.
More than 60% of head and neck cancers (HNC) are diagnosed with locally advanced disease (1), for which radical resection does not lead to a cure. The overall 5-year survival for the advanced stages is 40%-50% and has not markedly improved in the past decades due to the frequent relapse at the primary site, distant metastases, and second primary tumors after definitive treatment (2, 3).
Definitive concurrent chemoradiotherapy (CCRT) with a platinum-based regimen is currently the standard of care for patients with locally advanced HNC (4). However, grade 3 or higher grade serious adverse events (SAEs) are common in patients receiving definitive CCRT, including 41%-47% incidence of stomatitis, 37%-43% of dysphagia, 35% of odynophagia, 20%-32% of nausea or vomiting, and 15% of neutropenia (4-7). Because of the high toxicity profiles of CCRT, dose reduction of chemotherapeutic agents is common, and 6%-17% of patients fail to complete the planned CCRT (4-7), which inevitably compromises the treatment efficacy of CCRT. Therefore, avoidance of treatment interruption and elucidation of the risk of SAEs of CCRT are important issues that need to be addressed to maximize treatment efficacy for HNC patients.
Several inflammation-based biomarkers have been used to predict the mortality and morbidity of various cancers undergoing antitumor therapies (8, 9). Among these biomarkers, the albumin and neutrophil-to-lymphocyte ratio (NLR) has been extensively investigated for use in HNC (10, 11). Albumin is commonly used as a surrogate for nutritional status. Previous studies have revealed a significant association between pretreatment nutritional status and treatment completeness of CCRT in patients with HNC receiving CCRT (11, 12). NLR is a biomarker for systemic inflammation, with a higher NLR associated with a higher risk of SAEs (13) and tumor recurrence in HNC patients receiving definitive radiotherapy (14) or CCRT (15).
Since albumin and NLR have been separately used to predict morbidity and mortality in HNC patients receiving CCRT, our study hypothesized that the combination of albumin and NLR, i.e., the albumin-NLR score (ANS), might serve as a predictive tool in predicting treatment completeness and safety profiles in HNC patients undergoing definitive CCRT.
Patients and Methods
Patient selection. We prospectively enrolled 461 consecutive patients who received CCRT for the treatment of locally advanced HNC between September 2016 and December 2017 at three medical centers in Taiwan. The inclusion criteria were as follows: 1) age >20 years; 2) pathologically diagnosed primary HNC with stage II to IVa disease; 3) received CRRT as the curative-intent treatment, and 4) provided a written informed consent. Patients who received chemotherapy/radiotherapy alone or surgery before CCRT were excluded.
Concurrent chemoradiation therapy and follow-up. All patients received intensity-modulated or arc technique radiation therapy at a conventional fractionated daily dose of 200 cGy for five consecutive days per week, with a total prescribed radiation therapy dose of 7,000-7,400 cGy over seven weeks. The initial treatment volume included the tumor bed and regional lymphatics. After receiving 4,600-5,000 cGy, the treatment area was reduced to only the tumor bed and regional nodes. Chemotherapy regimens, including cisplatin (40 mg/m2 every week or 100 mg/m2 every three weeks) (16), the PF regimen (cisplatin 60 mg/m2 plus continuous infusion of 5-fluorouracil 800 mg/m2 on days 1-5, every two weeks) (17), and the PUL regimen [cisplatin 50 mg/m2, Tegafur-uracil (UFUR, TTY Biopharm Co. Ltd, Taipei, Taiwan, ROC) 300 mg/m2/day, and oral leucovorin 60 mg/m2/day on days 1-14, every two weeks] (18) were administered concurrently with radiation therapy, according to the treatment guidelines at our institution. Patients who received less than 90% of the specified protocol radiation therapy dose or those treated with a cumulative cisplatin dose of less than 200 mg/m2 for any reason were considered to have incomplete radiotherapy and chemotherapy (19), respectively. Incompletion of CCRT was defined as patients having either incomplete radiotherapy or chemotherapy.
The patients’ vital signs and grades for any adverse event were evaluated at least weekly between the first day and one month after the end of CCRT. Treatment-related toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Albumin and neutrophil-lymphocyte-ratio score. The patients’ demographic and clinicopathological characteristics and laboratory data were obtained within seven days before the beginning of CCRT. An NLR value less or higher than the median was assigned to 0 or 1 point, respectively, whereas an albumin value higher or less than the median was assigned to 0 or 1 point, respectively (20).
The prognostic nutritional index (PNI) was calculated using the following formula: 10×serum albumin value (g/dl)+0.005×total lymphocyte count in the peripheral blood (per mm3). A PNI cut-off point of 45 was used for comparison according to a previous study (21).
Ethics approval and consent to participate. This study was approved by the institutional review board of Chang Gung Memorial Hospital in September 2016 (ethic code: 201600916B0) and has been conducted in compliance with the Helsinki Declaration (1996). A written informed consent was obtained from all subjects.
Statistical analysis. Basic patient demographic data are presented as frequency (%) for categorical variables and as median with range for continuous variables. Comparisons among the ANS groups were performed using the Kruskal-Wallis test for continuous and ordinal variables and chi-square or Fisher’s exact tests for categorical variables. A logistic regression model was used to estimate the relative risk (RR) and 95% confidence interval (CI) for variables associated with CCRT incompletion. We adjusted for age, sex, education, tumor site, tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, and chemotherapy regimens to calculate the adjusted RR in the multivariate analysis. To compare the performance of the model, linear chi-square test, −2 log-likelihood, and c-index were used. In general, a higher linear chi-squared and lower −2 log-likelihood value indicate a more accurate model, with a higher c-index value indicating an increased discriminative ability of the model. SPSS software (version 17.0; SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. All statistical assessments were 2-sided and had a p-value of <0.05, which was considered the threshold for statistical significance.
Results
Table I presents the basic characteristics of the 461 patients included in this study. The median albumin value in the present study was 4.2 g/dl, and the NLR was 2.6. Accordingly, patients with both albumin ≥4.2 g/dl and NLR <2.6 were allocated ANS 0, patients with either albumin <4.2 g/dl or NLR ≥2.6 were allocated ANS 1, and patients with both albumin <4.2 g/dl and NLR ≥2.6 were allocated as ANS 2, respectively. Among 461 patients, 142 (30.8%), 190 (41.2%), and 129 (28.0%) patients were allocated to the ANS 0, 1, and 2 groups, respectively. No statistical differences were observed among the three ANS groups in terms of sex, age, marital status, education, occupation, main caregiver, smoking, alcohol drinking, and betel quid-chewing. In our ANS 0, 1, and 2 groups, 52.8%, 53.2%, and 53.3% of patients had no comorbidity. There was no statistical difference among these three groups in those with comorbidities (p=0.26). However, patients in the ANS 2 group had significantly lower body mass index, poorer ECOG performance, a higher percentage of primary tumors from the oropharynx, higher percentage of stage IV disease, lower PNI value, and were less likely to receive platinum doublet treatment than the other two ANS groups.
Basic patient characteristics.
In total, 46 patients (10.0%) had incomplete CCRT treatment. Marital status, main caregiver, ECOG performance, albumin, NRL, ANS, and PNI were significant predictors of incomplete CCRT in univariate analysis (Table II). Patients in the ANS 2 group experienced a higher rate of incomplete CCRT (20.9%) than those in the ANS 0 (3.5%) and ANS 1 groups (7.4%). The crude relative risks (RRs) for incomplete CCRT treatment were 2.18 (95%CI=0.77-6.20; p=0.14) and 7.25 (95%CI=2.70-19.5; p<0.001) when the patients in the ANS 1 and ANS 2 groups were compared with those in the ANS 0 group, respectively. In multivariate analysis, patients in the ANS 1 and ANS 2 groups had a 2.30-fold (95%CI=0.78-6.75; p=0.13) and 8.12-fold (95%CI=2.74-24.1; p<0.001) increased likelihood of incomplete CCRT compared with those in the ANS 0 group (Figure 1).
Univariate analysis for incomplete concurrent chemoradiotherapy.
The relative risk of incomplete concurrent chemoradiotherapy among the different albumin-neutrophil-to-lymphocyte ratio score (ANS) groups.
The CCRT-related SAEs in our patient cohort are shown in Table III. In total, 128 patients (27.8%) and 340 patients (73.8%) experienced at least one hematological and non-hematological SAE, respectively. Patients in the ANS 1 and ANS 2 groups were significantly associated with higher incidences of hematological and non-hematological SAEs than patients in the ANS 0 group (Figure 2). Furthermore, patients in the ANS 2 group had significantly higher incidences of grade 3 or higher leukopenia, anemia, neutropenia, thrombocytopenia, non-neutropenic infection, and hypokalemia than those in the other two groups.
Grade 3 or higher adverse events of concurrent chemoradiotherapy.
Incidence of any grade 3-4 hematological and non-hematological toxicities among the different albumin-neutrophil-to-lymphocyte ratio score (ANS) groups.
Table IV shows the predictive performance of albumin, NLR, ANS, and PNI in predicting CCRT incompleteness. The PNI had the lowest predictive power and discrimination ability in terms of the lowest −2 log-likelihood value (257.9 for ANS, 290.6 for albumin, 279.6 for NLR, and 294.9 for PNI), highest chi-square value (23.4 for ANS, 8.64 for albumin, 19.7 for NLR, and 4.36 for PNI), and highest c-index (0.70 for ANS, 0.61 for albumin, 0.67 NLR, and 0.66 for PNI), while ANS had the highest values.
Performance of PNI, albumin, NLR, and ANS in predicting chemoradiotherapy incompleteness.
Discussion
The present study demonstrated that albumin and NLR were both significant predictors of CCRT completeness in patients with locally advanced HNC. Furthermore, our study showed that albumin combined with the neutrophil-lymphocyte ratio had a better performance in predicting CCRT completeness than albumin or NLR alone. Furthermore, ANS was significantly associated with CCRT-related SAEs in patients with locally advanced HNC. The results of the present study showed that the ANS can be widely used as a simple predictor of treatment tolerance and safety profiles in HNC patients undergoing definitive CCRT.
More than 20% of patients with HNC are malnourished at the time of diagnosis (22, 23), and CCRT subsequently exacerbates their nutritional status (24). Plasma albumin, which decreases with inflammation, extreme starvation, increased age, or advanced tumor stage, is an important nutrient for the human body and is broken down to produce amino acids needed for energy supply and synthesis of tissue proteins (25). In several retrospective studies, serum albumin level was proven to be a predictive marker for poor survival outcomes in patients with HNC undergoing CCRT (26). Moreover, hypoalbuminemia, an index of malnutrition and cachexia, is associated with alterations in drug metabolism (27) and makes patients vulnerable to chemotherapy-related toxicities (28), which eventually affects the patients’ tolerance to definitive CCRT. In one retrospective study, the majority (62.5%) of patients did not complete three scheduled cisplatin courses of CCRT due to prolonged myelosuppression, which strongly correlated with pretreatment serum albumin level (12).
The NLR, a systemic inflammatory marker, is associated with more advanced disease and poorer prognosis in patients with oral cavity squamous cell carcinoma (29). HNC is characterized by cancer-related inflammation with increased production of proinflammatory cytokines (30), which enhances neutrophil recruitment to the tumor microenvironment (31). In other words, a higher NLR may coincide with systemic symptoms related to cancer inflammation (32), which subsequently exacerbates the toxicities of CCRT. One retrospective study revealed that grade 3 radiation-induced mucositis significantly occurred in hypopharyngeal or laryngeal cancer patients with NLR >5 (13).
In our cohort, patients in the ANS 2 group generally had a lower body mass index (BMI) and prognostic PNI, as well as poorer ECOG performance. It is reasonable that patients in the ANS 2 group were more malnourished due to the higher prevalence of T4 stage cancer (83.7%) and oral cavity/oropharyngeal primary tumors (74%). Advanced tumors in the upper aerodigestive tract frequently cause mechanical obstruction and swallowing dysfunction, leading to marked weight loss at the time of diagnosis. In addition, tumor-derived factors, including immunosuppressive cytokines (33) and exosomes (34), interfere with immune cell functions and result in immune suppression as the disease progresses, especially in HNC patients (35). Therefore, patients in the ANS 2 group were more vulnerable to opportunistic infections during CCRT, which may have led to their inability to endure CCRT in this study. As a result, concurrent platinum monotherapy was the preferred treatment compared to doublet therapy for these vulnerable patients in our clinical practice. However, even such a lower treatment intensity of CCRT resulted in a higher incidence of SAEs in ANS 2 patients than in ANS 0.
The 10% CCRT incomplete treatment rate in our entire cohort was comparable to that reported in the literature (4-7). In our study, patients in the ANS 2 group had a 20.9% probability of CCRT incompleteness rate, which was 8.1-fold higher than that in the ANS 0 group. Our study recommends that pretreatment ANS be widely utilized as a simple predictive tool for treatment completeness and safety profiles in patients with HNC undergoing definitive CCRT, and to determine appropriate alternative treatments for vulnerable patients. As a result, HNC patients with ANS 2 may be considered for radiotherapy alone because of poor treatment compliance and high toxicity profiles of standard CCRT.
Several albumin and white blood cell-based biomarkers, including the Glasgow Prognostic Score (GPS) and PNI (36), have been evaluated as prognostic or predictive models in HNC patients (23). The GPS is calculated from the C-reactive protein (CRP) and albumin levels, while PNI is calculated using albumin level and total lymphocyte count in peripheral blood. Both measures show comparable accuracy in predicting the length of hospital stay and grade 3 or higher surgical complications in gastric cancer patients who underwent radical gastrectomy and D-2 dissection (21). The present study showed that the ANS is more accurate than the PNI in predicting CCRT treatment completeness in patients with HNC. Unfortunately, information regarding the ability of GPS to predict CCRT tolerance is lacking, because data regarding CRP levels are not routinely collected in our patient cohort. As both albumin levels and NLR are easily measurable, ANS can be more widely utilized than GPS as a predictor of treatment tolerance and toxicity profiles in HNC patients at the beginning of definitive CCRT.
To the best of our knowledge, this study is the first to demonstrate the predictive value of the ANS on CCRT completeness and safety profiles in HNC patients undergoing definitive CCRT. This study was strengthened by the prospective design and inclusion of a large number of patients. However, some limitations merit further discussion. First, we arbitrarily allocated the median values of albumin and NLR as cut-off values in the present study, because it is easier to use in clinical practice and allowed the division of the patients into three groups with relatively equal patient numbers. Furthermore, the absence of in vivo experiments to confirm the ratio of optimum albumin and NLR is a limitation of this study. In a univariate analysis for incomplete CCRT (Table II), the relative risks of albumin and NLR were 4.2 and 2.6, respectively. These data suggested that albumin and NLR may disproportionally predict the completeness of CCRT. Huang et al. also used the median albumin and NLR to stratify their cohort (20); hence, we used the same albumin and NLR values for comparison in this study. There is currently no consensus on the optimal cut-off value of albumin and NLR used as the prognostic factor in patients with HNC. Further studies are necessary to reach a consensus on the optimal albumin and NLR cut-off values for predicting CCRT tolerance and safety profiles in patients with HNC. Second, the ANS was developed based on HNC patients treated with definitive CCRT in the present study, but whether the results could be applied in HNC patients receiving other treatment strategies, such as surgery, adjuvant CCRT, bio-radiotherapy, or immune-radiotherapy remains uncertain. Furthermore, the performance of the ANS, as observed in the present study, requires external validation to confirm its ability to predict patients’ treatment tolerances and safety profiles of various antitumor treatments.
Conclusion
The results of the present study showed that the ANS, which is a combination of albumin and NLR, demonstrated better prognostic accuracy than albumin alone, NLR alone, or PNI in HNC patients undergoing definitive CCRT. Patients with higher ANS were more likely to have incomplete treatment with CCRT and had a higher incidence of SAEs than those with lower ANS. The ANS may be widely used as a simple predictor of treatment tolerance and safety profiles in patients with HNC treated with CCRT.
Acknowledgements
The Authors gratefully acknowledge the assistance of the patients who participated in this study.
Footnotes
Authors’ Contributions
Conception and design of study: HCC, CWC, HYS, LSY, LCH; Acquisition of data: YKY, LCH; Analysis and interpretation of data: HCC, WHM, CWC; Drafting of the manuscript: HCC, CWC, HYS, LSY, HCY, YKY, WMH, LCH.
Conflicts of Interest
The Authors declare that no competing interests exist regarding this study.
- Received September 2, 2022.
- Revision received September 22, 2022.
- Accepted September 23, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
