Patients
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. The eligible patients met the following criteria including: (i) Patients stages III-IVb disease; (ii) Histologically proven nonmetastatic NPC; (iii) Karnofsky Performance Status (KPS) ≥80; (iv) Completion of radical radiotherapy; (v) Without previous anti-cancer treatment. The exclusion criteria were as follows: (a) age is older than 70 years; (b) disease progression during radiotherapy; (c) pregnancy or lactation; (d) not receiving 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 with no more than three patients who underwent chemoradiotherapy without nimotuzumab (Table 1). From this stratification process, we selected a total of 730 patients comprised of 184 patients in the nimotuzumab arm and 546 patients in the no nimotuzumab arm (Table 1). We first conducted case-matched comparison between the two arms in terms of efficacy and safety in this well-balanced cohort of 730. Subsequently, we conducted univariable and multivariate analysis of those 730 patients.
Treatment
Radiation Therapy
All patients received IMRT. The primary nasopharyngeal gross tumor volume (GTVnx) and the involved cervical lymph nodes were determined based on the 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 sub-clinical 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 were also included for N1-3 patients). The prescribed dose was 66–70 Gy to the planning target volume (PTV), 60 Gy to PTV1, 54 Gy to PTV2, and 60–66 Gy to PTV of the involved cervical lymph nodes in 28 to 33 fractions. All patients were treated once daily, five fractions weekly. Dose constrains to the critical structures were within the tolerance according to the RTOG 0225 protocol, and efforts were made to meet the criteria as closely as possible.
Chemotherapy
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 80–100mg/m2 cisplatin on day 1 every 3 weeks for 2–3 cycles or 30mg/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)(75mg/m2 docetaxel on day 1 and 75 mg/m2 cisplatin on day 1 or TPF(142) (75mg/m2 docetaxel on day 1, 75 mg/m2 cisplatin on day 1 and 800 mg/m2 /d fluorouracil civ on days 1– 5); both regimens were repeated every 3 weeks for 2–3 cycles. 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 delivery
Nimotuzumab was not recommended for NPC patients by the guideline at that time. So the uses of Nimotuzumab was determined by the patients’ willing and the experience of doctors. Intravenous Nimotuzumab was administered at an initial dose of 200mg weekly during whole radiation period. A total of 184 patients received full doses of Nimotuzumab.
Follow-up
Patient follow-up was measured from the first day of therapy to the day of 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.
Statistical analysis
Distant metastasis–free survival (DMFS) and locoregional relapse–free survival (LRRFS) were calculated from day 1 after completion of treatment to 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 last examination or death respectively.
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 χ2 test for categorical variables, and 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 0.2-caliper width, 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 of LRRFS, DMFS, PFS and OS between two groups were tested using log-rank test. Multivariate analysis was performed using the Cox proportional hazards models. All statistical analysis was performed using SPSS 21.0 statistical software (Chicago, IL, USA). A p < 0.05 were considered statistically significant.