The Clinical Research Ethics Committee of Sun Yat-sen University Cancer Center (SYSUCC) approved this retrospective review. We reviewed the inpatient medical records of primary nasopharyngeal carcinoma patients treated with IMRT at SYSUCC between January 2008 and December 2013. A total of 6,908 patients were identified, and eligible patients met the following criteria: (i) III-IVb disease stages; (ii) histologically proven nonmetastatic NPC; (iii) Karnofsky Performance Status (KPS) ≥80; (iv) completion of radical radiotherapy; and (v) no previous anti-cancer treatment. The exclusion criteria were as follows: (a) age >70 years; (b) disease progression during radiotherapy; (c) pregnancy or lactation; (d) lack of concurrent chemotherapy; (e) concurrent chemotherapy is not cisplatin-based; (f) received other anti-EGFR targeting therapy; and (g) previous malignancy or other concomitant malignant disease. The staging workup included an MRI of the head and neck, a chest radiograph, a bone scintigraphy, and an ultrasonography of the abdominal region for all the patients. All the included patients were restaged according to the Seventh Edition of the American Joint Committee on Cancer (AJCC) staging system. From these criteria, 1,274 patients were selected for the matched study (Figure 1).
We performed an analysis of variance as well as a χ2 test on the patients’ baseline demographics and clinical characteristics. Variable differences were identified between the two groups, including gender, age, tumor stage (T stage) and node stage (N stage), clinical stage and chemotherapy regime, all of which were identified as prognostic factors for survival outcomes in a previous study. Using propensity scores to adjust for these 6 factors, we created a well-balanced cohort by matching each patient who underwent nimotuzumab treatment with no more than three patients who underwent chemoradiotherapy without nimotuzumab (Table 1). From this stratification process, we selected a total of 730 patients, including 184 patients in the nimotuzumab arm and 546 patients in the no nimotuzumab arm (Table 1). We first conducted case-matched comparisons between the two arms in terms of efficacy and safety in this well-balanced cohort of 730. Subsequently, we conducted univariable and multivariate analyses of the 730 patients.
All patients received IMRT. The primary nasopharyngeal gross tumor volume (GTVnx) and the involved cervical lymph nodes were determined based on MRI/CT and/or PET-CT imaging, clinical, and endoscopic findings. The enlarged retropharyngeal nodes together with primary gross tumor volume (GTV) were outlined as the GTVnx on the IMRT plans. The clinical tumor volume (CTV) represents the primary tumor with potential subclinical disease. The first clinical tumor volume (CTV1) was defined as the GTV plus a 0.5-1.0 cm margin (0.2 to 0.3 margin posteriorly) to encompass the high-risk sites of microscopic extension and the whole nasopharynx. Clinical target volume 2 (CTV2) was defined as the CTV1 plus a 0.5-1.0 cm margin (0.2 to 0.3 margin posteriorly) to encompass the low-risk sites of microscopic extension, the level of the lymph node, and the elective neck area (bilateral levels IIa, IIb, III, and Va are routinely covered for all N0 patients, whereas ipsilateral levels IV, Vb, or supraclavicular fossae are also included for N1-3 patients). The prescribed doses were 66–70 Gy to the planning target volume (PTV) of the primary gross tumor volume (GTVnx), 60 Gy to PTV1 (PTV of CTV1), 54 Gy to PTV2 (PTV of CTV2), and 60–66 Gy to PTVnd of the involved cervical lymph nodes in 28 to 33 fractions. All patients were treated once daily, with five fractions administered weekly. The doses to critical structures were within the tolerance range according to the RTOG 0225 protocol, and efforts were made to meet the criteria as closely as possible.
During the study period, concurrent chemoradiotherapy (CCRT) ± induction chemotherapy(IC) for stage III to IV disease was recommended according to our institutional guidelines. The study-defined concurrent chemoradiotherapy regimen was 80–100 mg/m2 cisplatin on day 1 every 3 weeks for 2–3 cycles or 30 mg/m2 cisplatin weekly. Patients receiving other chemotherapy regimens or who received only one cycle of induction or concurrent chemotherapy were excluded from this study. The study-defined induction chemotherapy regimens included PF (n=161) (80-100 mg/m2 cisplatin on day 1 and 800 mg/m2 /d fluorouracil civ on days 1–5), TP (n=176) (75 mg/m2 docetaxel on day 1 and 75 mg/m2 cisplatin on day 1 or TPF(142) (75 mg/m2 docetaxel on day 1, 75 mg/m2 cisplatin on day 1 and 800 mg/m2 /d fluorouracil civ on days 1–5), and both regimens were repeated every 3 weeks for 2–3 cycles. The reasons for deviating from the institutional guidelines included organ dysfunction suggesting intolerance to chemotherapy, patient refusal, and the discretion of the doctors in individual cases.
Nimotuzumab was not recommended for NPC patients by the guideline at that time. Therefore, the use of Nimotuzumab was determined by the patients’ willingness and the doctors’ experience. Intravenous Nimotuzumab was administered at an initial dose of 200 mg weekly during the entire radiation period. A total of 184 patients received full doses of Nimotuzumab.
Patient follow-up was measured from the first day of therapy to the last examination or death. Patients were examined at least every 3 months during the first 2 years, with follow-up examinations every 6 months for 3 years or until death. The last follow-up date was 20 April 2019.
The Common Terminology Criteria for Adverse Events (version 4.0) was used to evaluate chemotherapy-related toxic effects, and the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group was used to evaluate radiotherapy-related toxic effects (16). Acute toxicities were defined as those occurring either during the course of IMRT or within 90 days of its completion.
Distant metastasis–free survival (DMFS) and locoregional relapse–free survival (LRRFS) were calculated from day 1 after completion of treatment to the first distant metastasis and locoregional relapse, respectively. Progression–free survival (PFS) was calculated from day 1 after completion of treatment to locoregional relapse, distant relapse or tumor-related death, whichever occurred first. Overall survival (OS) was calculated from day 1 after completion of treatment to the last examination or death.
The clinic-pathologic characteristics of participants are described, and the differences of these characteristics between the Nimotuzumab group and non-Nimotuzumab group were compared by the χ2 test for categorical variables and the t-test for continuous variables. Logistic regression analysis was used to identify confounders between the treatment groups. A propensity score matching method was used. Propensity scores were calculated based on the identified potential confounders and other important factors, such as tumor stage, and then each patient was assigned a score. Using a caliper width of 0.2, 1:3 matching was performed between patients in the Nimotuzumab group and non-Nimotuzumab group based on the propensity scores.
LRRFS, DMFS, PFS and OS were calculated using the Kaplan-Meier method. The differences in LRRFS, DMFS, PFS and OS between the two groups were tested using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards models. All statistical analyses were performed using SPSS 21.0 statistical software (Chicago, IL, USA). A value of P < 0.05 was considered statistically significant.