The diagnosis of NPC was confirmed by a multidisciplinary tumor board before initiating the treatment. Ninety eight patients with NPC treated with concurrent chemo-radiotherapy between years 2010 and 2018 were included. Inclusion criteria included histologically confirmed NPC by biopsy, no distant metastasis, normal hepatic functions (serum total bilirubin ≤1.6mg/dL and serum transaminase levels <2.5 times higher than upper limit); normal renal functions (serum creatinine ≤1.5mg/dL and creatinine clearance ≥60mL/min); normal complete blood count level (haemoglobin >10g/dL, white blood cells ≥4000μL, platelet ≥100,000μL); Karnofsky Performance Status (KPS) score of >70; and receiving only cisplatin during concurrent chemo-radiotherapy. This study was approved by local research ethics committee and written informed consent was provided by all patients (Local Research Ethics Committee ID: 2019/160 and date: 06.03.2019).

Staging was determined by clinical examination of head and neck, nasoendoscopy with direct fiber optic, Magnetic Resonance Imaging (MRI) and Positron Emission Computed Tomography (PET-CT). All patients were restaged according to the 8th edition of the American Joint Committee on Cancer (AJCC) system.20

2/3D conformal radiotherapy technique was performed before 2012 and IMRT technique was performed after 2012. Standard dose and fractionation for 2/3D conformal RT was 70Gy to the primary tumor; 50–60Gy to involved nodes in 35 daily fractions. The total dose and fraction for IMRT were 70Gy/2.12Gy per fraction for high risk planning target volume (primary tumor volume and involved nodes), 60Gy/1.8Gy per fraction for intermediate risk planning target volume and 54Gy/1.65Gy per fraction for low risk planning target volume. Cisplatin regimen consists of intravenous infusion of 100mg/m2 every 3 weeks or 50mg/m2 intravenous infusion weekly. Chemotherapy was started at the first radiation treatment day for all patients.

Toxicity information was recorded by medical staff during treatment and collected from patients’ charts. Acute toxicity evaluation of the treatment was performed according to National Cancer Institute Common Toxicity Criteria version 3.0.21

Patient follow up was defined from the first day of treatment to the last examination or death. Both MRI and PET-CT were performed to evaluate the response to treatment on the 3rd month after the last treatment day. The evaluation of the response to treatment was done according to Response Evaluation Criteria in Solid Tumors (RECIST criteria).22 The response to treatment was classified as Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). If the response was complete, the patients were monitored every 3 months for the first 2 years with MRI and their follow-up examinations were performed every 6 months thereafter until death.

The site of the first clinical relapse was accepted as local failure, if the relapse site is in the nasopharynx. The site of first clinical relapse was accepted as regional failure, if the relapse site is in the nodal region. If the relapse site was beyond the above-mentioned areas, we accepted it as distant failure. The duration of Disease Free Survival (DFS), Local Recurrence-Free Survival and Regional Recurrence-Free Survival (LRFS and RRFS) and distant metastasis-free survival (DMFS) were calculated from day 1 of the treatment until treatment failure is documented. Overall survival (OS) was calculated from day 1 of the treatment until death or the date of the last follow up. The statistical analysis of the data was performed by using IBM SPSS Statistics 22.0 (IBM Corp., Armonk, New York, USA). All data were expressed as means±SD unless otherwise stated and controlled for normality using Shapiro–Wilk test. Chi-square and Fisher's exact tests were used to compare categorical variables such as different age, gender, T stage, N stage, and chemotherapy regimen. The survival time between groups was compared with Kaplan–Meier analysis and log-rank tests. Differences were considered significant at p<0.05. The effective factors on overall survival and loco-regional relapse-free survival were analyzed using multivariate Cox regression (Backward/Wald method) model. Removal probability for stepwise was taken as p<0.10. The value of p<0.05 denoted statistical significance.

From 2010 to 2018, a total of 98 (28 female and 70 male) eligible patients were evaluated. The median age was 49.5 years (range 16–75). Of the 98 patients, 17 (17.3%), 28 (28.6%), 20 (20.4%) and 33 (33.7%) had T1, T2, T3, and T4 stage cancers, respectively. Of the 98 patients, 20 (20.4%), 28 (28.6%), 38 (38.8%) and 12 (12.2%) had N0, N1, N2, and N3 stage cancers, respectively. Of the 98 patients, 19 (19.4%), 36 (36.7%) and 43 (43.9%) had Stage II, Stage III and Stage IVA cancers, respectively. Sixty-one patients (62.2%) received weekly-cisplatin and 37 (37.8%) patients received 3-weekly cisplatin. Five of 98 patients (5.1%) were treated with 2/3D conformal RT technique. 93 of 98 patients (94.9%) were treated with IMRT technique. After chemo-radiotherapy 80 patients (81.6%) were evaluated as complete response and 18 patients (18.4%) were evaluated as partial response. A cumulative dose of ≥200mg/m2 was achieved in 46 of 61 (74%) patients in weekly cisplatin group and all the patients (100%) in 3 weekly cisplatin group received a cumulative dose of ≥200mg/m2. Median treatment day was found to be 48 days (range: 30–87 days). The characteristics of patients are summarized in Table 1.

Grade 1–2 hematological toxicity was found in 88 of all patients (89.8%) and Grade 3–4 hematological toxicity was found in 10 of all patients (10.2%). Six of the patients with Grade 3–4 hematological toxicity were in the 3 weekly cisplatin group and 4 of the patients with Grade 3–4 toxicity were in the weekly cisplatin group. There was no statistically significant difference between the two groups (p=0.17). Grade 1–2 mucositis was found in 57 of all patients (57.2%) and Grade 3–4 mucositis was found in 41 of all patients (41.8%). Thirteen of the patients with Grade 3–4 mucositis were in 3-weekly cisplatin group and 28 of the patients with Grade 3–4 mucositis were in the weekly cisplatin group. There was no statistically significant difference between in the two groups (p=0.39). Eighty seven of all patients (88.8%) experienced Grade 1–2 dermatitis and 11 of all patients (11.2%) experienced Grade 3–4 dermatitis. Nine patients with Grade 3–4 dermatitis were in the weekly cisplatin group and 2 patients with Grade 3–4 dermatitis were in the 3-weekly cisplatin group. There was no statistically significant difference between the two groups (p=0.199). The most frequently determined toxicity was malnutrition. Compared to weekly-regimen, the 3-weekly cisplatin regimens induced significantly more severe nutrient toxicity. Sixty nine of all patients (69/98) experienced malnutrition. The average percentage of malnutrition in the weekly cisplatin group was 59% (36/61) and in the 3 weekly cisplatin group 89.2% (33/37). The malnutrition was not determined in 25 patients (41%) in the weekly cisplatin group and was not determined in only 4 patients (10.8%) in the 3-weekly cisplatin group. There was statistically significant difference between groups in terms of malnutrition (p=0.001). The weekly cisplatin group was experienced less nutrient toxicity. The characteristics of patients’ toxicity are summarized in Table 2.

Cumulative high-dose cisplatin did not show statistically significant difference in Grade 3–4 toxicities including hematological toxicity, mucositis, dermatitis, and malnutrition compared to cumulative low-dose cisplatin (p=1.00; p=0.09; p=0.38; p=1.00 respectively). For nausea and vomiting, the difference between the groups was close to being statistically significant (p=0.051). The comparison between the toxicities and delivered cumulative dose cisplatin is summarized in Table 3.

Median follow up was found to be 41.5 months (range: 2–93 months). Local recurrence was observed in 23 of 98 patients. The local recurrence rate was 19.4% (19/61) in the weekly cisplatin group and 4.1% (4/37) in the 3-weekly cisplatin groups (p=0.02) (Table 4). The regional-recurrence was observed in 8 of 98 patients. The regional-recurrence rate was 7.1% (7/61) in the weekly-cisplatin group and 1% (1/37) in the 3-weekly-cisplatin groups (p=0.25) (Table 4). Distant metastasis was observed in 17 of 98 patients. The distant metastasis rate was 11.2% (11/61) in the weekly cisplatin group and 6.1% (6/37) in the 3-weekly cisplatin groups (p=1.00) (Table 4).

While ≥200mg/m2 cisplatin dose was achieved in 82 of 98 patients, <200mg/m2 cisplatin dose was achieved in 16 of 98 patients. While the complete response rate was found to be 82.9% in patients achieving a dose of ≥200mg/m2 cisplatin, it was found to be 75% in the patients achieving a dose of <200mg/m2 cisplatin and the difference between groups was not statistically significant (p=0.48) (Table 4). While local-recurrence rate was found to be 19.5% in the patients achieving a dose of ≥200mg/m2 cisplatin, it was found to be 43.8% in the patients achieving a dose of <200mg/m2 cisplatin and the difference between groups was statistically significant (p=0.03) (Table 4). In terms of regional-recurrence rate, the difference was not statistically significant between the patients achieving a dose of ≥200mg/m2 cisplatin and the patients achieving a dose of <200mg/m2 cisplatin (p=0.61) (Table 4). In terms of distant metastasis rate, the difference was not statistically significant between the patients achieving a dose of ≥200mg/m2 cisplatin and the patients achieving a dose of <200mg/m2 cisplatin (p=0.46) (Table 4).

The mean LRFS was found to be 70.7 months for all patients. The 5 years LRFS rates in the weekly-cisplatin group and the 3 weekly-cisplatin group were 66.2% and 81.6% respectively. There was no statistically significant difference between groups (p=0.15) (Fig. 1). The 5 year LRFS rates in the patients achieving dose of ≥200mg/m2 cisplatin and in the patients achieving dose of <200mg/m2 cisplatin were 75.8% and 47.9% respectively. The difference between the groups was close to being statistically significant (p=0.055) (Fig. 2). Clinical parameters consist of gender, age, T category, N category, TNM stage, chemotherapy schedule and cumulative cisplatin dose did not have any effect on LRFS, except for the RT technique. The LRFS was influenced by the RT technique (HR=0.23, 95% CI: 0.068–0.787, p=0.01) (Table 5).

Figure 1.

(A) Overall survival curve between 3 weekly group and weekly group; (B) locally recurrence-free survival curve between 3 weekly group and weekly group; (C) regional recurrence-free survival curve between 3 weekly group and weekly group; (D) distant metastasis-free survival curve between 3 weekly group and weekly group.

(0.22MB).

Figure 2.

Kaplan–Meier curves for patients receiving cisplatin ≥200mg/m2 and <200mg/m2. (A) Overall survival curve between ≥200mg/m2 and <200mg/m2; (B) locally recurrence-free survival curve between ≥200mg/m2 and <200mg/m2; (C) regional recurrence-free survival curve between ≥200mg/m2 and <200mg/m2, (D) distant metastasis-free survival curve between ≥200mg/m2 and <200mg/m2.

(0.2MB).

The mean RRFS was found to be 85.2 months for all patients. The 5 year RRFS rates in the weekly-cisplatin group and the 3 weekly cisplatin group were 87.3% and 95.7% respectively. There was no statistically significant difference between the groups (p=0.18) (Fig. 1). The 5 year RRFS rates in patients achieving a dose of ≥200mg/m2 cisplatin and in patients achieving a dose of <200mg/m2 cisplatin were 91.0% and 87.1% respectively. There was no statistically significant difference between the groups (p=0.46) (Fig. 2). The RRFS was not influenced by any clinical parameters in the univariate analysis (Table 5).

The mean DMFS was found to be 77.1 months for all patients. The 5 year RRFS rates in the weekly cisplatin group and the 3 weekly cisplatin group were 80.1% and 76.1% respectively. There was no statistically significant difference between the groups (p=0.74) (Fig. 1). The 5 year DMFS rates in patients achieving a dose of ≥200mg/m2 cisplatin and in patients achieving a dose of <200mg/m2 cisplatin were 80% and 72.2% respectively. There was no statistically significant difference between the groups (p=0.47) (Fig. 2). The DMFS was not influenced by any clinical parameters in the univariate analysis (Table 5).

The mean OS was found to be 73.6 months for all patients. The 5 year OS rates in the weekly cisplatin group and the 3 weekly cisplatin group were 68.3% and 90.3% respectively. There was no statistically significant difference between the groups (p=0.11) (Fig. 1). The 5 year OS rates in patients achieving a dose of ≥200mg/m2 cisplatin and in patients achieving a dose of <200mg/m2 cisplatin were 78.2% and 49.2% respectively. The difference between the groups was statistically significant (p=0.003) (Fig. 2).

When evaluated in subgroup analysis, there were no statistically significant differences in terms of OS, LRFS, RRFS and DMFS (p=0.40, p=0.36, p=0.22 and p=0.22, respectively) (Fig. 3) between 3-weekly and weekly chemotherapy regimens in patients with cumulative cisplatin dose of ≥200mg/m2.

Figure 3.

Survival curves between 3 week and weekly chemotherapy regimens in patients with cumulative cisplatin dose ≥200mg/m2. (A) Overall survival curve; (B) locally recurrence-free survival; (C) regional recurrence-free survival curve; (D) distant metastasis-free survival curve.

(0.24MB).

The cumulative dose of cisplatin and RT technique were effective on OS in univariate analysis. 2/3D conformal RT and <200mg/m2 cisplatin were associated with shorter OS in univariate analysis (HR=0.21, 95% CI: 0.071–0.628, p=0.005 and HR=0.29, 95% CI: 0.125–0.686, p=0.003, respectively) (Table 6). Among the clinical parameters, only <200mg/m2 cisplatin was a prognostic factor for the OS in multivariate analysis (HR=0.36, 95% CI: 0.146–0.912, p=0.03) (Table 6).