Study subjects

Patients diagnosed with NPC between September 2009 and February 2014 at our institution were considered for enrollment. Inclusion criteria were as follows: 17–73 years old; objective measurement or evaluation of the lesions; Karnofsky Performance Status Scale ≥ 70; blood evaluations: white blood cell (WBC) count ≥ 4.0 × 10⁹/l, platelet count ≥ 100 × 10⁹/l, hemoglobin ≥ 100 g/l; total bilirubin ≤ 1.5 × the upper-normal limit (UNL), aspartate aminotransferase/alanine aminotransferase ≤ 1.5 × UNL, and serum creatinine ≤ 1.5 × UNL; no known allergies; no history of mental illness; and no drug abuse or other unhealthy habits. Patients with metastasis or malignancy in other organs were excluded. Patients were also excluded from the study if they had a history of another malignant tumor, participated in other clinical trials, had severe allergies, were pregnant or lactating, had previously received anti-EGFR therapy, or exhibited no tolerance to therapy.

The initial examination included a detailed medical history, assessment of performance status, physical examination, chest radiography or computed tomography (CT) scan, abdominal B ultrasonic scan or CT scan, bone emission CT scan, blood biochemical analysis, and intensive magnetic resonance imaging (MRI) or CT scan of the nasopharynx and neck. Cases were required to be staged according to the American Joint Committee on Cancer, 2010 Edition (7^th, AJCC 2010).

The study protocol was approved by the Research Ethics Committee of the Eye, Ear, Nose & Throat Hospital of Fudan University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.

Study design and case grouping

This was a prospective, non-randomized trial, and the baseline demographic and clinical pathological characteristics and radiotherapy techniques were well matched. One hundred eighty patients diagnosed with NPC from September 2009 to February 2014 were enrolled, and they were divided into two groups with a sample ratio of 1 : 2 based on administration of Nimo. All the patients in our cohort completed 2–3 cycles of IC followed by CCRT, and 60 of the 180 patients were additionally administered Nimo. According to the application time of Nimo, the patients were divided into three groups: group A (120 patients), IC followed by CCRT; group B (30 patients), in which Nimo was applied at the beginning of IC (IC (+ Nimo) + CCRT); and group C (30 patients), in which Nimo was applied at the beginning of radiotherapy (IC + CCRT (+ Nimo)).

The primary study outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcome was the development of common toxicities, including hematological toxicity, skin reaction, mucositis, nausea/vomiting, and hepatotoxicity. The OS was defined as the time from the date of diagnosis to the date of death from any cause; PFS was defined as the time between the date of diagnosis and the date of local failure or distant metastasis. The investigators who assessed the treatment outcomes were blinded to the patients’ group assignments.

Treatments

All patients received definitive intensity modulation radiation therapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). Prescribed doses were determined according to the tumor volume and stage in reference to IMRT target dose designs and the expert consensus for NPC by the Chinese clinical NPC working committee and Wang’s target delineation protocol [9]. The gross tumor volume doses were delivered with 66–69.75 Gy for the IMRT group and 68–73 Gy for the CRT group, and the treatment dose to involved lymph nodes was 60–70 Gy. The clinical tumor volume dose was delivered with 50–62 Gy.

IC regimens included TPF (docetaxel + cisplatin + 5-fluorouracil (5-FU)), TP (docetaxel + cisplatin), or PF (cisplatin + 5-FU). The TPF protocol consisted of 2–3 cycles of docetaxel 70 mg/m² on day 1 over 1 h, cisplatin 75 mg/m² on day 1 to day 3, and 5-FU 500 mg/m² from day 1 to day 4 as an intravenous infusion every 3 weeks. The PF protocol was the same as the TPF protocol except for the inclusion of docetaxel. Concurrent chemotherapy treatment regimens consisted of 1–3 cycles of cisplatin 80 mg/m² divided evenly across 3 days, and was repeated every 3 weeks. Dose modifications were allowed during chemotherapy according to the patient’s tolerance, and the chemotherapy application time was adjusted appropriately. Chemotherapy was delayed until observation of a WBC count ≥ 3.5 × 10⁹/l and an absolute neutrophil count ≥ 1.5 × 10⁹/l.

Nimo was administered weekly at a dose of 200 mg in 250 ml of physiological saline. Intravenous infusion of Nimo was administered over 60 min. Dexamethasone 5 mg was administered intravenously before Nimo to prevent allergic reactions. After infusion of Nimo, the infusion apparatus was flushed with normal saline to avoid mixed infusion with other drugs. Six to 8 weeks of the targeted therapy was considered a complete dosage schedule.

Follow-up

Post-treatment assessment of patients, including a physical examination, was scheduled every 8 weeks in the first year, every 12 weeks in the second year, and every 4–6 months thereafter. MRI/CT scan of the nasopharynx and neck, chest radiography, and abdominal ultrasound were performed approximately every 6 months during follow-up. An MRI/CT scan was performed for patients with clinical suspicion of local or locoregional recurrence. Distant metastases were diagnosed by clinical symptoms, physical examinations, chest CT, bone scan, MRI, CT, abdominal CT, or positron emission tomography/CT. The last recorded follow-up was August 25, 2017.

Statistical analysis

Numerical variables are expressed as the mean ± standard deviation (M ± SD), and categorical variables are expressed as a percentage (%). Categorized variables were compared using the χ² test. Kaplan-Meier curves were used to characterize OS and PFS, and differences in survival between patient subsets were evaluated using the log-rank test. A two-tailed p-value of less than 0.05 was considered statistically significant. All statistical analysis and graphing were performed using IBM SPSS 20 (IBM Corp., Armonk, NY, USA).

Patient characteristics

A total of 168 patients with complete clinical and follow-up data were included in the analysis, including 126 men and 42 women, and 89.9% (151/168) of patients were diagnosed with advanced stage disease. The median age at diagnosis was 49 years (range: 17–72 years). Clinical data are shown in Table I. All the patients received 2–3 cycles of IC, and 20.8% (35/168) of patients underwent dose or time modification of chemotherapy during the course of CCRT. Fifty-six patients received 6–8 cycles of Nimo, and no dose or time modification occurred.

Efficacy

Through August 25, 2017, the median follow-up time was 61.4 months (range: 1.7–96.5 months). The 5-year OS for patients who did not receive Nimo (group A) and those who did (groups B + C) was 74.8 ±4.1% and 87.0 ±4.6%, respectively (p = 0.043; Figure 1 A). During follow-up, 34 patients who did not receive Nimo and 13 patients who did receive Nimo experienced disease progression, and the median times to disease progression were 26.6 and 45.3 months, respectively. The 5-year PFS for patients who did not receive Nimo and those who did was 72.7 ±4.3% and 83.1 ±5.1%, respectively (p = 0.243) (Figure 1 B).

Figure 1

Kaplan-Meier estimation of 5-year-OS (A), 5-year-PFS (B) for patients who received IC plus CCRT treatment regimen with Nimo (n = 56) or without Nimo (n = 112)

P-values were calculated with log-rank test. IC – induction chemotherapy, CCRT – concurrent chemoradiotherapy, Nimo – nimotuzumab.

There was a striking difference in the 5-year OS rate between group B and group A (93.0 ±4.8% vs. 74.8 ±4.1%, p = 0.038; Figure 2 A). However, no significant difference in 5-year PFS was found between group B and group A (89.3 ±5.9% vs. 72.7 ±4.3%, p = 0.144, Figure 2 B). The 5-year OS and PFS for group C were 80.4 ±7.9% and 76.4 ±8.5%, respectively, and there was no significant difference compared with those of group A (p = 0.257 and p = 0.611, respectively; Figures 2 C and D).

Figure 2

Kaplan-Meier estimation of 5-year-OS (A), 5-year-PFS (B) for patients who received IC concurrent Nimo plus CCRT (n = 56) or IC plus CCRT (n = 112), 5-year-OS (C), 5-year-PFS (D) for patients who received IC plus CCRT concurrent Nimo (n = 56) or IC plus CCRT (n = 112)

P-values were calculated with log-rank test. IC – induction chemotherapy, CCRT – concurrent chemoradiotherapy, Nimo – nimotuzumab.

Adverse events

Graded adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The treatment toxicities were generally mild, and no grade 3–4 acute toxicities occurred in the IC setting in any of the patients. In the concurrent chemotherapy phrase, nausea and vomiting were common in patients who received cisplatin. The other common acute adverse effects were oral mucositis, leukocytopenia, and skin reaction; however, there was no significant difference in toxicities among the different treatment regimens. It was rare to find a specific toxicity that was induced by Nimo. The majority of acute toxicities rapidly disappeared, and most patients recovered in a few months. Detailed adverse effects are displayed in Table II.

Xerostomia was the most common late adverse effect, and the degree of xerostomia appeared to decrease with time. Some patients complained of hearing impairment and recurrent secretory otitis media, and were treated in the Department of Otorhinolaryngology.