A retrospective study on the prognostic value of preoperative C-reactive protein to albumin ratio in patients with oral cavity squamous cell carcinoma

Study patients

We retrospectively reviewed the clinical outcomes of patients newly diagnosed with OSCC and who underwent primary curative surgery with or without adjuvant therapy at the Department of Otorhinolaryngology of Chang Gung Memorial Hospital from January 2008 to December 2017.

We subsequently excluded patients with a history of malignancy, synchronous cancer, infection or inflammatory conditions, or autoimmune disorders; those who had received neoadjuvant therapy; and those with missing CRP or albumin data. Finally, 326 patients were enrolled. Their history of cigaret smoking, betel nut chewing, and alcohol consumption was obtained from clinic notes and patient interviews or from the tumor registry. Cigarette smokers were defined as those who had smoked 1 or more cigarets per day for 1 year or longer; betel nut chewers were defined as those who had chewed 2 betel nuts or more daily for at least 1 year; and alcohol drinkers were defined as those who had consumed more than 1 alcoholic beverage per week for more than 6 months. The Institutional Review Board of Chang Gung Memorial Hospital ratified our study protocol (201901573B0), and the requirement for patient’s informed consent was waived by the Institutional Review Board. All patients were subjected to routine preoperative workups including blood tests, physical examinations, magnetic resonance imaging or computed tomography of the head and neck, abdominal echography, chest X-ray, nuclear bone scans, and the detailed medical histories of the patients were recorded. Concurrent neck dissection and intraoperative frozen section controls were used for tumor excision per institutional guidelines, and plastic surgeons used local, free, or pedicled flaps for reconstruction of surgical defects. Pathological TNM staging was recorded according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual Cancer Staging Manual, Eighth Edition. If indicated, postoperative adjuvant therapy based on the institutional guidelines was administered. Briefly, patients with pathological T4 tumors who had positive lymph nodes underwent adjuvant radiotherapy, and patients with any pathological finding including multiple neck lymph node metastases, positive surgical margin, and ENE received adjuvant concurrent chemoradiotherapy within 6 weeks after surgery. A radiation dose of 66 Gy was administered in 2-Gy daily fractions for 5 days each week, and a cisplatin-based regimen was used for the chemotherapy. Patients were followed up bimonthly for the first year after discharge, at 3-month intervals throughout the second year and at 6-month intervals thereafter. At each follow-up visit, physical examination, laboratory testing, and endoscopy were performed. Follow-up imaging with computed tomography or magnetic resonance imaging was performed every 6 months for 2 years and every 12 months thereafter.

Inflammation-based prognostic scores

To probe the correlation between survival outcomes and systemic inflammatory indices, we performed preoperative blood laboratory tests within 1 week before curative surgery. According to the blood tests and recorded clinical symptoms and signs, severe infection status was excluded in all patients. The medical staff collected the hematological and biochemistrical parameters during the treatment from patient’s charts. Pretreatment biochemistry values of albumin (reference value: 35–55 g/L) and CRP (reference value: <5 mg/L) were measured using biochemistry automated analyzer (Roche Hitachi Cobas 8000, Rotkreuz, Switzerland) during the study period. Hematological results of lymphocyte, neutrophil, hemoglobin, and platelet were measured using the hematology analyzer (Sysmex SE-9000, Kobe, Japan). Preoperative CAR was calculated as follows: CRP level (expressed in mg/L)/albumin level (expressed in g/L). Similarly, we derived the preoperative NLR and PLR as follows: peripheral blood neutrophil count/lymphocyte count and platelet count/lymphocyte count, respectively. Next, mGPS was calculated using previously published methods (McMillan, 2008). Patients with both hypoalbuminemia (<35 g/L) and increased CRP levels (>10 mg/L), with one of these variables, and with none of these variables were assigned the scores of 2, 1, and 0, respectively.

Statistical analysis

By analyzing the receiver operating characteristic (ROC) curves, we determined the statistically optimal cutoff values of prognostic variables on the basis of inflammation, including the CAR, CRP, mGPS, PLR, and NLR. The area under the ROC curve (AUC) was calculated for determining the various indices’ discriminatory ability. We used the Spearman test to investigate the correlation between preoperative CRP and albumin levels and examined the normality of distribution of study data by using Kolmogorov–Smirnov test. Patient follow-up was conducted at the outpatient clinic until death or the cutoff date (December 31, 2018). The log-rank test and Kaplan–Meier analysis were performed to evaluate the long-term survival probability in the high and low CAR groups (defined by the optimal CAR cutoff). The clinicopathological features of the two groups were compared using the Mann–Whitney U and chi-square tests for continuous and categorical variables, respectively. Cox proportional hazards models based univariate and multivariate analyses were used to identify independent prognostic factors by calculating their hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). All aforementioned analyses were performed on SPSS version 21.0 (SPSS, Chicago, IL, USA). Statistical significance was indicated by p < 0.05. A multivariate nomogram model incorporating sex, age, overall pathological stage, cell differentiation, ENE, DOI, and preoperative CAR was generated as described by Kao et al. (2018) by using the “rms” package in R (version 5.1-0; Vanderbilt University, Nashville, TN, USA). Calibration plots were drawn and a concordance index (c-index) of the established nomogram was calculated to assess the predictive accuracy for OS. A c-index of 0.5 denotes the equivalent of random prediction and that of 1.0 indicates perfect prediction (Harrell, Lee & Mark, 1996). We calculated the c-index for traditional OS prediction based on TNM staging alone as well as for prediction with the proposed nomogram models with and without CAR.

Baseline characteristics

Baseline clinicopathological characteristics as well as laboratory data are listed in Table 1. In total, 326 patients—294 (90.2%) of whom were men and 32 (9.8%) were women—who were newly diagnosed as having OSCC and underwent primary radical surgery were included; their median age and follow-up duration were 57 (range, 31–86) years and 48 (range, 3–115) months, respectively. The most common primary tumor site was the tongue (n = 126, 38.7%), followed by the buccal area (n = 104, 31.9%) and gingiva (n = 43, 13.2%). Of these patients, 81.9% were smokers, 79.8% were betel nut chewers, and 66% were alcohol consumers. Nearly half of the patients (n = 152, 46.6%) were diagnosed as having stage IV disease, and 117 (35.8%) patients had pathologically confirmed neck lymph node metastasis. All the enrolled patients completed the planned treatment course, with 43 (13.2%) patients undergoing only adjuvant radiotherapy and 105 (32.2%) receiving adjuvant concurrent chemoradiotherapy.

Inflammation-based prognostic score cutoffs and ROC curves

The median CAR was 0.08 (range, 0.01–5.48). A Spearman test revealed that CRP levels were negatively correlated with albumin levels (r = −0.223; p < 0.001, Fig. 1). By analyzing the ROC curves, we determined the optimal OS cutoff value to be 0.195 for CAR (sensitivity, 65.3%; specificity, 78.4%), 4.505 for NLR, and 165.85 for PLR. We further compared the AUCs of various indices (Fig. 2) to assess their discrimination ability and found that the AUC of CAR (0.718, 95% CI [0.654–0.782], p < 0.001) was higher than that of NLR (0.621, 95% CI [0.550–0.692], p = 0.001), CRP (0.705, 95% CI [0.638–0.766], p = 0.001), PLR (0.610, 95% CI [0.539–0.680], p = 0.002), and mGPS (0.679, 95% CI [0.612–0.746], p < 0.001).

Association of CAR with clinicopathological characteristics

We performed dichotomization of patients by the optimal cutoff of CAR, followed by comparing the two groups’ clinicopathological characteristics (Table 2). The CAR ≥ 0.195 group was determined to have a significant association with advanced TNM stage (p < 0.001), lymph node metastasis with extracapsular nodal extension (ENE, p < 0.001), DOI of >10 mm (p < 0.001), need for adjuvant therapy (p = 0.003), higher mGPS (p < 0.001), higher NLR (p < 0.001), higher PLR (p = 0.034), and shortened survival period (p = 0.01) compared with the other group.

Association of CAR with survival outcomes

In the univariate analysis, the indicators of poor OS were found to be increased T classification, lymph node metastasis with ENE, poor cell differentiation, DOI >10 mm, need for adjuvant chemoradiotherapy, mGPS of 1 or 2, CAR of ≥0.195, NLR of ≥4.505, and PLR of ≥165.85 (Table 3). Furthermore, multivariate analysis indicated increased T classification (p = 0.025 for T3 and 0.003 for T4), ENE (p < 0.001), poor cell differentiation (p < 0.001), CAR of ≥0.195 (p = 0.002), and NLR of ≥4.505 (p = 0.006) to be independent prognostic factors for poor OS (Table 3). In the OS probability analysis, the observed 5-year OS incidence was 80.9% and 46.5% in patients with an optimal CAR cutoff of <0.195 and ≥0.195, respectively; these survival differences were significant according to the executed log-rank test (p < 0.001, Fig. 3A). The median OS times for patients with CARs of ≥0.195 and <0.195 were 40 (95% CI [12–68]) and >99 months, respectively.

Table 4 demonstrates the association of clinicopathological variables with 5-year DFS. In the univariate analysis, T4 classification, ENE, poor cell differentiation, DOI of >10 mm, need for adjuvant chemoradiotherapy, mGPS of 1 or 2, CAR of ≥0.195, NLR of ≥4.505, and PLR of ≥165.85 were significantly associated with poor DFS. Multivariate analysis results indicated that T4 classification (p = 0.031), ENE (p < 0.001), poor cell differentiation (p = 0.009), CAR of ≥0.195 (p = 0.029), and NLR of ≥4.505 (p = 0.02) were independent prognostic indicators of poor DFS. In the DFS probability analysis, the 5-year DFS incidence for patients stratified into the CAR < 0.195 and CAR ≥ 0.195 subgroups was at a proportion of 60.1% and 36.8%, respectively; moreover, the log-rank test results demonstrated these differences in DFS to be significant (p < 0.001; Fig. 3B). The median DFS times for patients with CARs of ≥0.195 and <0.195 were 24 (95% CI [15–33]) and 86 (95% CI [62–110]) months, respectively.

Discrimination ability of CAR in subgroup analysis

CAR was significantly correlated with OS in the subgroups of patients with early- and late-stage disease (HR = 7.06, 95% CI [2.58–19.29], p < 0.001; HR = 2.97, 95% CI [1.86–4.75], p < 0.001, respectively. Fig. 4). Nevertheless, CAR was not significantly associated with OS in the subgroup of patients with lymph node metastasis without ENE.

Nomogram models

To improve OSCC survival prediction, we established a multivariate nomogram model consisting of CAR, TNM stage, and several clinicopathological factors (Fig. 5A). Figure 5B presents nomogram calibration plots for 3-year OS prediction, and Fig. 5C shows the calibration plots for predicting 5-year OS probabilities. The c-index was 0.801 for the nomogram incorporating CAR and clinicopathological prognosticators, higher than that of the nomograms consisting of clinical factors without CAR (0.759) or TNM staging alone (0.685).