|Year : 2021 | Volume
| Issue : 6 | Page : 295-304
Pretreatment body mass index and serum uric acid and albumin levels as prognostic predictors in patients with oral squamous cell carcinoma
Wei-Chin Chang1, Cheng-Yu Yang2, Yu-Chun Lin3, Chun-Shu Lin4, Chin-Shan Kuo1, Yu-Hsuan Li1, Yuan-Wu Chen1
1 Department of Oral and Maxillofacial Surgery, Tri Service General Hospital; School of Dentistry, National Defense Medical Center, Taipei, Taiwan, Republic of China
2 School of Dentistry, National Defense Medical Center, Taipei, Taiwan, Republic of China
3 School of Dentistry, National Defense Medical Center; Department of Pathology, Tri Service General Hospital, Taipei, Taiwan, Republic of China
4 Department of Radiation Oncology, Tri Service General Hospital, Taipei, Taiwan, Republic of China
|Date of Submission||04-Oct-2020|
|Date of Decision||03-Feb-2021|
|Date of Acceptance||04-Mar-2021|
|Date of Web Publication||15-May-2021|
Dr. Yuan-Wu Chen
Division of Oral and Maxillofacial Surgery, Tri-Service General Hospital, 2F, No. 325, Sec. 2, Chenggong Road, Neihu District, Taipei City 114
Republic of China
Source of Support: None, Conflict of Interest: None
Background: Oral squamous cell carcinoma (OSCC) is the most frequently found malignant tumor of the oral cavity, and the annual death rate of OSCC patients has been increasing rapidly among the Taiwanese population. Aim: The aim of this study is to evaluate if poor nutrition is a potential adverse prognostic factor in patients with OSCC. Methods: This cross-sectional study included 322 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The pretreatment body mass index (BMI) and serum uric acid and albumin levels were measured as common indicators of the nutritional status, and overall survival (OS) was analyzed using the Kaplan–Meier method and a Cox regression model. Results: The optimal cut-off values were 24.0 kg/m, 5.05 mg/dL, and 3.85 g/dL for BMI, serum uric acid, and serum albumin, respectively. The multivariate Cox regression analysis indicated lower BMI (hazard ratio [HR] = 1.557, 95% confidence interval [95% CI]: 1.070–2.265; P = 0.021), lower serum uric acid (HR = 1.857, 95% CI: 1.265–2.724; P = 0.002), and lower serum albumin (HR = 2.011, 95% CI: 1.278–3.163; P = 0.003) as independent and significant prognosticators of OS. Advanced stage, depth of invasion of more than 5 mm, and extranodal extension were prognostic predictors of poor OS. Conclusion: A lower preoperative BMI and lower serum uric acid and albumin levels are predictors of significantly worse survival among OSCC patients. Maintaining a healthy nutritional status is crucial to improving the survival of patients with oral cancer. The treatment for patients with poor nutritional status should be more aggressive and cautious.
Keywords: Body mass index, nutrition, uric acid, albumin, oral squamous cell carcinoma
|How to cite this article:|
Chang WC, Yang CY, Lin YC, Lin CS, Kuo CS, Li YH, Chen YW. Pretreatment body mass index and serum uric acid and albumin levels as prognostic predictors in patients with oral squamous cell carcinoma. J Med Sci 2021;41:295-304
|How to cite this URL:|
Chang WC, Yang CY, Lin YC, Lin CS, Kuo CS, Li YH, Chen YW. Pretreatment body mass index and serum uric acid and albumin levels as prognostic predictors in patients with oral squamous cell carcinoma. J Med Sci [serial online] 2021 [cited 2022 Jan 16];41:295-304. Available from: https://www.jmedscindmc.com/text.asp?2021/41/6/295/315910
| Introduction|| |
Oral squamous cell carcinoma (OSCC) is the sixth-most prevalent type of malignancy worldwide, and the most frequently occurring malignant tumor of the oral cavity. In Taiwan, OSCC is the fourth-most prevalent cancer among men, and the sixth-most prevalent cancer overall. Accordingly, the number of annual deaths attributable to OSCC has been increasing rapidly among Taiwanese men, and most cases of OSCC recurrence are observed within 2 years.
Current guidelines for the treatment and management of OSCC recommend resection, either alone or in combination with adjuvant concurrent chemoradiotherapy. These guidelines have not been updated in the past 10 years; therefore, the 5-year OSCC survival rate has not improved significantly in recent decades. Conventionally, long-term prognoses and selective treatment decisions are related to tumor, node, and metastasis (TNM) staging and adverse features; however, we sought to identify other poor prognostic factors and individual patient conditions as interesting research targets. Moreover, early-stage oral cancer patients can be treated with simple surgical excision without a prolonged period of admission compared with advanced-stage patients who may remain hospitalized for months; when severe complications develop, the therapeutic duration may be even longer. Therefore, the preoperative nutritional status of patients with oral cancer becomes very important for tolerating the treatment course, and pretreatment nutritional factors need to be analyzed.
The outcomes of surgical treatment for OSCC may induce facial muscle dysfunction and cause defects in the chewing apparatus. Consequently, patients who have undergone surgical resection for OSCC may experience more difficulty in coping with the negative effects of both the disease and its treatment. Although surgical resection is undertaken to remove the primary lesions from the oral cavity, both the preoperative tumor size and surgical outcomes can lead to insufficient food intake and malnutrition.,
Previous studies have addressed the effects of the nutritional status on survival among cancer patients; for example, patients with hepatocellular carcinoma who had serum albumin levels exceeding 3.5 g/dL were likelier to experience prolonged survival. Among patients with gastric cancer, patients with a higher body mass index (BMI) were found to experience prolonged survival, while those with head and neck cancer who had a higher BMI and albumin level could better tolerate further treatment complications. The protein metabolic end-product, uric acid, is derived exclusively from the oxidation of xanthine and hypoxanthine by xanthine oxidoreductase. The resulting serum uric acid level is a useful biomarker in the evaluation of the treatment options of patients with nasopharyngeal carcinoma, with a high value suggesting prolonged survival.
To date, no other study has addressed the effects of nutritional markers on oral cancer prognoses. Accordingly, this study is aimed to investigate the preoperative nutritional statuses of patients with OSCC in Taiwan, using parameters such as BMI and serum albumin and uric acid levels. These parameters were further investigated to explore the simple clinical predictors of survival in patients with oral cancer.
| Materials and Methods|| |
In this retrospective study, the medical records of patients with oral cancer who were treated at the Tri-service General Hospital between 2002 and 2015 were evaluated. The study inclusion criteria were as follows: (1) previously untreated oral cancer, (2) histologically proven squamous cell carcinoma, (3) an Eastern Cooperative Oncology Group performance status of 0 or 1, and (4) surgical resection and curative surgery with or without adjuvant postoperative therapy. The exclusion criteria were as follows: (1) unavailable data regarding hematologic and BMI parameters before curative surgery, (2) identification of distant metastasis at the initial visit, (3) history of treatment for other cancers, (4) contraindication to undergo curative surgery, (5) history of chronic renal failure with or without hemodialysis, and (6) final event of death and recurrence caused by an event of noncancer etiology. In our study, 389 patients met the inclusion criteria; of these, 67 were excluded because of insufficient data, including of the censored event defined as absence of records for the last 3 months, and death attributed to noncancer causes. Accordingly, data of 322 patients were obtained and analyzed in this study [Table 1]. The 322 patients included 296 men and 26 women, and their median age was 51 years (range, 23–84 years). The primary tumor sites were the lip, retromolar region, gingiva, tongue, buccal mucosa, the floor of mouth, and palate. The survivors were followed up for a median of 3.7 years (range, 0.0–11.9 years), and except in cases of death, all of them were followed up for at least 2 years, until December 2015.
All patients with primary OSCC underwent, at the minimum, selective neck lymphatic node dissection, and resection with safe margins. Adjuvant radiotherapy or concurrent chemoradiotherapy was administered after staging if adverse features were present. All patients were followed up and registered in an institutional database that was corrected and updated to include patients' latest treatment conditions. The Ethical Committee of the Tri-Service General Hospital (Taipei, Taiwan) approved this retrospective study (institutional review board protocol no: 2-106-05-082), and all patients provided written informed consent.
Definitive tumor staging relied on pathological features in accordance with the American Joint Committee on Cancer Staging guidelines. Definitive nodular staging was based on the pathological analysis of specimens from selective neck dissections. The following nutritional parameters were evaluated within 2 weeks before curative excision and lymphatic dissection: BMI, serum uric acid, and serum albumin. BMI was determined as the body mass weight divided by the square of the body height, and the unit is expressed in kg/m. The concentrations of serum albumin and serum uric acid were measured in the serum examination.
A receiver operating characteristic (ROC) curve was plotted for overall survival (OS) at 2 years postoperatively to verify the optimal cut-off values for BMI, serum albumin, and serum uric acid, due to the most cases of OSCC recurrence are observed within 2 years. The relationships between patients' clinical characteristics and their BMI and serum uric acid and albumin levels were examined using a Chi-square test. The Kaplan–Meier method was used to estimate OS and disease-free survival (DFS). OS was calculated from the date of the therapeutic surgery to the date of the last follow-up or death from cancer-related causes. The event of death was recorded in the patient's medical chart at our hospital, and the event of survival was defined the presence of follow-up in the last 3 months. All cases were also verified and registered by the cancer recording group. DFS was measured from the date of surgery to the date of tumor recurrence, which was defined as locoregional or distant metastasis. OS and DFS were measured according to different albumin, BMI, and uric acid categories. Further adverse features in the OSCC survival analysis were enrolled to stratify patients and compare the OS values obtained in different adverse feature situations. Multivariate Cox proportional hazards regression model analysis was performed to identify the prognostic factors affecting OS among patients treated with surgery, with or without adjuvant therapy, with factors such as TNM stage, carcinogen exposure, sex, age, and nutritional status as independent variables. Statistical analyses were conducted using SPSS statistical software (IBM SPSS, version 20.0; IBM Corp., Armonk, NY, USA).
| Results|| |
Optimal continuous body mass index, serum uric acid, and serum albumin cut-off values
In this study, mean (standard deviation) values of 23.8 (3.9) kg/m, 6.2 (1.7) mg/dL, and 4.2 (0.6) g/dL were obtained for BMI, serum uric acid, and serum albumin, respectively. ROC curves for OS and Youden's index were used to determine the optimal cut-off values for continuous BMI, serum uric acid, and serum albumin, and the corresponding areas under the curves were 0.643, 0.572, and 0.557, respectively. Optimal cut-off values of 24.0 kg/m, 5.05 mg/dL, and 3.85 g/dL were identified for BMI, serum uric acid, and serum albumin, respectively, and the corresponding highest Youden's index values (specificity and sensitivity) were 1.224 (0.646 and 0.578), 1.145 (0.323 and 0.823), and 1.108 (0.223 and 0.885), respectively. The patients were subsequently divided according to the cut-off values into two subgroups per parameter for further analyses. As a result, 165 (51.2%) and 157 patients (49.8%) had BMI values <24.0 kg/m and ≥24.0 kg/m, respectively; 80 (24.8%) and 242 patients (75.2%) had serum uric acid levels <5.05 mg/dL and ≥ 5.05 mg/dL, respectively; 51 (15.8%) and 271 patients (84.2%) had serum albumin levels <3.85 g/dL and ≥3.85 g/dL, respectively.
Patient characteristics and nutritional markers
To examine the correlations between BMI, serum uric acid, serum albumin, and clinical parameters, we compared the patients' characteristics with respect to the subgroups classified according to BMI, serum uric acid, and serum albumin levels [Table 2]. Accordingly, we identified a significant relationship between the serum uric acid level and cancer stage (P = 0.022), and between the serum albumin level and cancer stage (P = 0.010), age (P = 0.040), and tobacco exposure (P = 0.017). In contrast, no significant differences were observed with respect to BMI.
|Table 2: Characteristics of the total patient sample and the subgroups, stratified by the body mass index, serum uric acid, and serum albumin cut-off values|
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The 322 patients were followed up for a mean (standard deviation) of 51.5 (34.8) months. Of all patients, 129 (40.1%) died of cancer-related causes and 149 (46.3%) developed local or distant recurrence. Kaplan–Meier analysis yielded 1-, 3-, and 5-year OS rates of 86.0%, 74.2%, and 62.5%, respectively, and corresponding DFS rates of 74.4%, 58.1%, and 49.8%, respectively. [Figure 1] presents the OS and DFS curves according to the pretreatment BMI and serum uric acid and serum albumin values. In summary, high BMI and serum uric acid and serum albumin values were significantly correlated with superior OS and DFS.
|Figure 1: Univariate analysis of the effects of pretreatment BMI and serum uric acid and albumin levels on overall and disease-free survival. BMI = Body mass index|
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Multivariate Cox proportional hazards regression model analyses indicated that the independent prognostic factors for OS included tumor stage, BMI, serum uric acid level, and serum albumin level [Table 3] Furthermore, we evaluated the stage effect with the three nutritional factors, and we also entered these factors and stages as categorical variables in these factor and stage. Cox regression for the detection of moderator effects showed that, in the case of early-stage OSCC, the hazard ratio (HR) was shifted to reverse with the moderator of stage with the serum albumin from 0.208 to 0.632, denoting that lower serum albumin levels were indicative of adverse effects of a higher degree [Table 4]. In contrast, Cox regression with moderator of stage with serum uric acid and BMI had no relationship, and it not showed in our result. Comparing with the adverse features, only the depth of index more than 5 mm and presence of extranodal extension have the prognostic influence in the OS analysis.
|Table 3: Univariate and multivariate analyses of the prognostic factors related to 5 years overall survival|
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|Table 4: Results of a cox regression analysis for the detection of moderator effects in terms of the association between serum albumin and cancer stage|
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| Discussion|| |
In this multifactorial study, the pretreatment BMI and serum uric acid and serum albumin values were found to be associated with the OS and DFS of patients with OSCC. Although all patients enrolled in this study underwent resection with or without adjuvant therapy, those with a low BMI, low serum uric acid level, and low serum albumin level were likelier to have a poor nutritional status. Although there were some baseline differences between the groups in terms of current oral carcinogen exposure (e.g., chewing betel nuts), the primary treatment modality (surgical resection) was correlated to the clinical stage and adjuvant treatment modality. Furthermore, the result was similar to those of other studies in the literature.
A cancer patient's nutritional status greatly influences OS. Malnutrition frequently affects patients with head and neck cancer, with a prevalence rate of 60% before diagnosis. Previous evaluations of poor nutritional status among patients with oral cavity cancer were based on dynamic changes in various parameters including body weight, dysphagia, and even cachexia.,, However, the individual pretreatment nutritional status is also a useful parameter and along with related factors, could serve as an early marker preceding oral cavity cancer diagnosis as well as a target for the prevention and reduction in the risk of oral cavity cancer among undernourished populations.
Our study showed that multiple nutritional factors, including BMI, serum albumin, and serum uric acid, are associated with OSCC outcomes. Patients with a lower preoperative BMI had lower OS rates than those with higher BMI values. This result is in agreement with the findings of previous studies,,, as well as a large case-control study in which the HR for poor survival was elevated in both the lower BMI and obese groups. However, the HRs in our study's multivariate Cox regression were limited because of the limited sample size; nonetheless, the trend was consistent with the result observed in the univariate analysis.
Our finding that oral cavity cancer was associated with an increased HR of lower serum uric acid levels corroborates the findings of a previous pooled analysis of head and neck cancer. Serum uric acid levels decrease as a consequence of poor nutrition and neurological disorders. In the serum, uric acid may serve as an antioxidant and free radical scavenger in blood vessels. However, its antioxidative abilities remain controversial, and the level of serum uric acid required for anti-oxidation is near the normal range. In contrast, hyperuricemia syndrome may lead to cardiovascular, respiratory, and renal diseases and an increased tumor burden consequent to rapid nucleic acid turnover., Previous cancer studies have indicated that high serum uric acid levels affect patient mortality; this is similar to our findings. Regarding the relationship between tumor stage and serum uric acid [Table 2], the results of the present study, in line with those of a previous study, showed higher serum uric acid levels in patients with higher-grade head and neck carcinoma.
In the present study, it was also observed that lower albumin levels were associated with reduced OS among patients with OSCC; this is in agreement with the findings of other studies focusing on the survival of cancer patients. Serum albumin levels indicate not only the nutritional status, but also inflammatory response status, and this explains the association between advanced tumor stage and lower albumin levels. However, among elderly individuals, a lower serum albumin level is associated with loss of muscle mass and decreased muscle strength; this may explain our finding regarding the association of age with serum albumin [Table 2]. We found that nutritional deficiency, indicated by a lower albumin level, was associated with poor prognosis. Moreover, moderated Cox regression analyses indicated that its effect was weaker among patients with advanced-stage disease than among those with early-stage disease [Table 4].
Pathologic TNM staging, which is based on lesion size and the number of metastatic nodes, is critical in the determination of the appropriate adjuvant treatment for oral cancer. When used alone, the conventional TNM staging category for OSCC is not sufficient for survival analysis; a combination of staging categories, adverse features, and other factors is required. In terms of adverse features, insufficient surgical margin, lymphatic metastasis with extranodal extension, perineural invasion, lymphovascular invasion, and a large tumor invasion depth are well-known indicators of poorer prognosis. These adverse features may shorten patient survival.,, Accordingly, the present study found that pretreatment BMI, serum uric, acid and albumin levels, i.e., markers of the underlying nutritional status, may be useful in the survival analysis of patients with OSCC with the adverse features of depth of invasion of more than 5 mm and extranodal extension.
This study had some limitations. The sample size was limited by patient enrollment and poor cooperation with follow-up. Accordingly, a larger number of patients should be enrolled in future studies, along with the inclusion of other pathologic oral cancer patterns. Future research studies should also consider and compare several pathologic factors as potential predictive factors for OSCC prognoses. Despite these limitations, the age, sex, carcinogen exposure, and cancer sub-site distributions of the patients in our study were very similar to those observed in most oral cancer cases diagnosed in Taiwan.
| Conclusion|| |
Lower BMI and lower serum uric acid and serum albumin levels were found to significantly correlate with poorer survival among patients with OSCC. These findings suggest that a better nutritional status is crucial to improving the survival of patients with oral cancer and that patients with a poor nutritional status should receive more aggressive and cautious treatment.
This study was supported by research grants from Tri Service General Hospital, Republic of China (grant Nos. TSGH-C106-004-006-008-S05, TSGH-C105-164, TSGH C106-144, T S G H - C 1 0 8 0 0 7 0 0 8 S 0 6 , T S G H C 1 0 8 1 8 9 , TSGH D 109159,TSGH-D-110149, TSGH-C05-110035), the Ministry of National Defense, Republic of China (grant No. MAB 106-090), and the National Science Council, Taiwan, Republic of China (grant No. MOST 105 2314 B-016 021 MY3). This research was also supported by the Cancer Registry Group of Tri Service General Hospital. The statistical consulting company – Estat – provided consultation and editing services to this research.
Financial support and sponsorship
This study was supported by research grants from the Tri Service General Hospital, Republic of China (grant numbers:TSGH C106 004 006 008 S05,TSGH C10 5 164,TSGH C106 144,TSGH C108 007 008 S06, TSGH C108 189, TSGH D 109159,TSGH-D-110149, TSGH-C05-110035), the Ministry of National Defense, Republic of China (grant number: MAB 106 090), and the National Science Council, Taiwan, Republic of China (grant number: MOST 105 2314 B 016 021 MY3).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]