The Sun Yat-Sen University Cancer Center is the largest therapy and diagnosis center of NPC in southeastern China. According to the institutional electronic medical records, a total of 49,021 patients with NPC were treated by definitive RT in our Cancer Center between January 1970 and December 2009 and information about their pretreatment characteristics, therapy, and outcome is available. From this database we were able to identify 15 male patients for IMRT group who (1) had second primary squamous cell carcinoma (SPSCC) arising in the head and neck, (2) were treated only by IMRT for NPC, (3) had no smoking and excessive alcohol intake history, and (4) had no family history of cancer. We were able to identify 23 male patients for RT group who (1) had SPSCC arising in the head and neck, (2) were treated only by RT for NPC, (3) had no smoking and excessive alcohol intake history, and (4) had no family history of cancer. Prior informed consent was obtained from patients, as was the approval of the Institutional Research Ethics Committee of the Sun Yat-sen University Cancer Center.
All patients in IMRT group were immobilized with a customized thermoplastic head–neck–shoulder cast in the supine treatment position. Two sets of images with and without contrast were obtained from the computed tomography (CT) simulator for treatment planning. The definition of target volumes was in accordance with the International Commission on Radiation Units and Measurements (ICRU) report 50 and 626,7. The gross tumor volume (GTV) is defined as the whole known gross extent of the primary nasopharyngeal tumor and involved lymph nodes determined from magnetic resonance imaging (MRI), physical examination and endoscopy. The first clinical tumour volume (CTV1) was defined as the GTV plus a margin of 5–10 mm for potential microscopic spread, including the entire nasopharyngeal mucosa plus a 5-mm submucosal volume. The second CTV (CTV2) was defined by adding a margin of 5–10 mm to CTV1 and included the following regions, which required prophylactic irradiation: the retropharyngeal lymphnode regions, clivus, skull base, pterygoid fossae, parapharyngeal space, inferior sphenoid sinus, posterior edge of the nasal cavity, maxillary sinuses, and lymphatic drainage area. The planning target volume (PTV) for GTV and CTVs were generated automatically by adding a 5-mm margin after delineation of tumour targets according to the immobilization and localization uncertainties. The prescribed dose was 60–80 Gy (mean ± SD, 70.40 ± 4.48 Gy) to the PTV of the GTV, 54–66 Gy to the PTV of the CTV1 (PTV1), and 50–56 Gy to the PTV of the CTV2 (PTV2) in 28–35 daily fractions, respectively. The doses limited to the major organs at risk (OAR) were as follows: brainstem: Dmax < 54 Gy; spinal cord: Dmax < 45 Gy; optic nerve and chiasm: Dmax < 50 Gy; temporal lobes: Dmax < 60 Gy; parotid glands: Dmean < 26 Gy; mandible: Dmax < 70 Gy; oral cavity: Dmax < 40 Gy; glottis: Dmean < 45 Gy; and cervical esophagus: Dmean < 45 Gy.
All patients in RT group were immobilized in the supine position with a thermoplastic mask and treated with two lateral opposing faciocervical portals to irradiate the nasopharynx and upper neck in one volume followed by application of the shrinking-field technique to limit irradiation of the spinal cord. An anterior cervical field was used to treat the neck with a laryngeal block. The accumulated radiation doses were 59–80 Gy (mean ± SD, 68.09 ± 6.20 Gy), with 2 Gy per fraction applied to the primary tumour and 50–55 Gy applied to the uninvolved areas.
Criteria set by Warren and Gates8 were used to define the SPC. All tumors were confirmed pathologically as distinct malignancies. None were undifferentiated carcinomas, excluding the possibility of locoregional recurrence or distant metastasis of nasopharyngeal origin. For the distinction between a recurrence, metastasis, or SPC, we used case-by-case judgment instead of rigid definitions. All patients were staged according to the 2002 American Joint Committee on Cancer (AJCC) staging system. TNM classification was based on pathological information; clinical information was used if pathology data were missing.
Follow-up data were collected from the outpatient service and complementary data were obtained by telephone inquiry and follow-up letters. They were reviewed every month for the first year postoperatively, every two months during the second year, 4-monthly during the third and fourth years, and 6-monthly thereafter. The cutoff date of the last follow-up was December 31, 2014 for the censored data analysis. Follow-up time was calculated from the time of diagnosis of SPSCC to the last date of contact. At the time of data collection, all of the patients had been followed for a minimum of 5 years after therapy. The median follow-up period for all patients was 61 months (range, 6–288 months).
The ANOVA test were used to examine the difference between groups. Overall survival (OS) was calculated from the diagnosis of SPSCC until death or last follow-up. The Cox proportional hazard model was used for analysis of estimated cumulative risk and OS of all SPSCC from the date of initial treatment. The statistical analysis was performed using SPSS 25.0 software (SPSS Inc., Chicago, IL). The difference was considered statistically significant when the P value was less than 0.05.
Ethical approval
We confirm that all methods were performed in accordance with the relevant guidelines and regulation. The Guangzhou University of Traditional Chinese Medicine First Affiliated Hospital had approved the research, the approval letter number is JY2022-034. Informed consent was obtained from all patients.