Risk of Second Primary Malignancy in Nasopharyngeal Carcinoma Patients: A Single Center Experience from Türkiye

Risk of Second Primary Malignancy in Nasopharyngeal Carcinoma Patients: A Single Center Experience from Türkiye | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 12 June 2025 V1 Latest version Share on Risk of Second Primary Malignancy in Nasopharyngeal Carcinoma Patients: A Single Center Experience from Türkiye Authors : Kübra Özkaya Toraman 0000-0003-2518-5980 [email protected] , Rasim Meral , Makbule Atasoyu , Ahmet Karadeniz , and Musa Altun Authors Info & Affiliations https://doi.org/10.22541/au.174973340.04627568/v1 154 views 74 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Aim: Advances in radiotherapy (RT), chemotherapy (ChT), and prolonged survival have increased the incidence of second primary malignancies (SPMs) in patients with nasopharyngeal carcinoma (NPC). This study evaluated NPC survivors’ SPM incidence and characteristics. Methods: Medical records of patients with NPC treated between 1990 and 2019 were retrospectively reviewed. SPMs were classified by organ, histopathology, and location (in-field or out-of-field RT). All SPMs were histopathologically confirmed. Cumulative SPM incidence was estimated, clinical associations were analyzed, and standardized incidence ratios (SIRs) were calculated. Results: Among 821 patients with NPC, 79 (9.6%) developed SPMs over a median follow-up of 90 months (interquartile range [IQR]:34–157). Independent risk factors included age >40 years (hazard ratio [HR]:4.02; 95% confidence interval [CI]:2.20–7.34) and female sex (HR: 1.73; 95% CI: 1.00–2.98). Synchronous SPMs occurred in 14 patients, while metachronous SPMs occurred in 65. Twenty-five (38.4%) of the 65 metachronous SPMs are located within the radiation field. The overall SPM risk was 73% higher than in the general population (SIR:1.73; 95% CI:1.69–1.77). SPMs were most frequently in the head and neck (n=25) and lungs (n=15). Excess cancer risks were significant for head and neck (SIR:34.69; 95% CI:33.49–35.89), sarcoma (SIR:14.18; 95% CI:13.03–15.33), esophagus (SIR:6.18; 95% CI:5.35–7.01), kidney (SIR:4.62; 95% CI:4.22–5.01), and pancreas (SIR:4.12; 95% CI:3.72–4.51). Conclusion: NPC survivors face an elevated risk of SPMs. Long-term follow-up should monitor both in-field and out-field malignancies. Decades-long comprehensive monitoring is recommended, with emphasis on neoplasms outside the irradiation field. Risk of Second Primary Malignancy in Nasopharyngeal Carcinoma Patients: A Single Center Experience from Türkiye Risk of SPM in NPC patients Kübra Özkaya Toraman a Rasim Meral b Makbule Atasoyu c Ahmet Karadeniz d (Emeritus) Musa Altun e (Emeritus) a Department of Radiation Oncology, Oncology Institute, Istanbul University; Topkapı, Turgut Özal Millet Street No:118, 34093 Fatih/Istanbul , Turkey; [email protected] b Department of Radiation Oncology, Oncology Institute, Istanbul University; Topkapı, Turgut Özal Millet Street No:118, 34093 Fatih/Istanbul , Turkey; [email protected] c Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, the Netherlands; Hanzeplein 1, 9713 GZ Groningen, the Netherlands; [email protected] d Department of Radiation Oncology, Istanbul Faculty of Medicine, Istanbul University; Topkapı, Turgut Özal Millet Street No:118, 34093 Fatih/Istanbul , Turkey; [email protected] e Department of Radiation Oncology, Istanbul Faculty of Medicine, Istanbul University; Topkapı, Turgut Özal Millet Street No:118, 34093 Fatih/Istanbul , Turkey; [email protected] Corresponding author: Kübra Özkaya Toraman Phone: +905422188737 Adress: Topkapı, Turgut Özal Millet Street No:118, 34093 Fatih/İstanbul Condensed abstract: Nasopharyngeal carcinoma survivors exhibit a 73% higher risk of developing second primary malignancies compared with Turkish population—particularly in the head-neck and lungs—with age over 40 and female sex serving as independent risk factors. These findings underscore the necessity for decades-long, comprehensive follow-up that monitors both in-field and out-of-field malignancies to improve early detection and clinical outcomes. Declaration of Conflicting Interests The authors declare that there is no conflict of interest Funding This research did not receive any grant Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Risk of Second Primary Malignancy in Nasopharyngeal Carcinoma Patients: A Single Center Experience from Türkiye Abstract Aim: Advances in radiotherapy (RT), chemotherapy (ChT), and prolonged survival have increased the incidence of second primary malignancies (SPMs) in patients with nasopharyngeal carcinoma (NPC). This study evaluated NPC survivors’ SPM incidence and characteristics. Methods: Medical records of patients with NPC treated between 1990 and 2019 were retrospectively reviewed. SPMs were classified by organ, histopathology, and location (in-field or out-of-field RT). All SPMs were histopathologically confirmed. Cumulative SPM incidence was estimated, clinical associations were analyzed, and standardized incidence ratios (SIRs) were calculated. Results: Among 821 patients with NPC, 79 (9.6%) developed SPMs over a median follow-up of 90 months (interquartile range [IQR]:34–157). Independent risk factors included age >40 years (hazard ratio [HR]:4.02; 95% confidence interval [CI]:2.20–7.34) and female sex (HR: 1.73; 95% CI: 1.00–2.98). Synchronous SPMs occurred in 14 patients, while metachronous SPMs occurred in 65. Twenty-five (38.4%) of the 65 metachronous SPMs are located within the radiation field. The overall SPM risk was 73% higher than in the general population (SIR:1.73; 95% CI:1.69–1.77). SPMs were most frequently in the head and neck (n=25) and lungs (n=15). Excess cancer risks were significant for head and neck (SIR:34.69; 95% CI:33.49–35.89), sarcoma (SIR:14.18; 95% CI:13.03–15.33), esophagus (SIR:6.18; 95% CI:5.35–7.01), kidney (SIR:4.62; 95% CI:4.22–5.01), and pancreas (SIR:4.12; 95% CI:3.72–4.51). Conclusion: NPC survivors face an elevated risk of SPMs. Long-term follow-up should monitor both in-field and out-field malignancies. Decades-long comprehensive monitoring is recommended, with emphasis on neoplasms outside the irradiation field. Keywords: nasopharyngeal carcinoma, second primary malignancy, head-neck, sarcoma, lung carcinoma Introduction Nasopharyngeal carcinoma (NPC) has a distinctive geographic distribution. According to GLOBOCAN’s 2022 estimates, global NPC incidence rates are approximately 1.3 per 100,000 people; however, Southeast Asia, especially in countries such as Indonesia and Malaysia, shows markedly higher rates. In contrast, Türkiye, situated at the crossroads of Asia and Europe, reported a rate of approximately 0.86 cases per 100,000 people (1). With the development of radiotherapy (RT) techniques and systemic therapy, the survival outcomes of patients with NPC have improved. Additionally, the relatively young age at NPC diagnosis has resulted in a large cohort of long-term survivors, making the risk of developing second primary malignancy (SPM) a critical concern for this population (2). Information on SPMs in patients with NPC remains limited and is often derived from studies in endemic regions, where the cancer risk in individuals with NPC has been reported to be higher than that in the general population (3-9). The incidence of SPMs in non-endemic regions remains unclear. Advancements in early cancer screening programs and treatment strategies have significantly enhanced the survival rate of patients with cancer. However, increased longevity has brought new challenges, particularly the emergence of SPMs as major contributors of morbidity and mortality (10). First introduced by Warren and Gates in 1932, the concept of SPMs refers to malignancies that arise after an index cancer and are distinct from metastases or recurrences of the original tumor (11). Certain primary cancers are associated with a significantly increased risk of SPM compared to that in the general population (10). Among patients with head and neck cancer, the incidence of SPMs is approximately 13.2%, a phenomenon extensively studied (12). In patients with NPC, various risk factors contribute to SPM development, including treatments for primary cancer, shared etiological factors, and genetic predispositions (5). Epstein-Barr virus (EBV) is the most significant etiological factor for NPC and is detected in 95% of patients in endemic regions (13). In addition to NPC, EBV infection is associated with the development of various other malignancies, including Burkitt’s lymphoma, Hodgkin’s lymphoma, and gastric carcinoma (14). Tobacco use is also strongly associated with keratinizing-type NPC, which is more common in non-endemic regions (15). Additionally, the theory of field cancerization in head and neck cancers suggests that tobacco-related malignancies in the upper aerodigestive tract increase the risk of SPMs in other anatomical locations (16). Tobacco use is considered to play a role in NPC, particularly in SPM development located in the head, neck, esophagus, and lungs (9). Treatment-related factors are pivotal in SPM development. RT, which is the cornerstone of NPC treatment, is a carcinogenic modality. Radiation-induced DNA damage effectively targets malignant cells while inducing genomic instability in normal tissues, thereby increasing the risk of secondary malignancies (17). Chemotherapy (ChT) has also been implicated in the development of secondary cancers, including both solid tumors and hematological malignancies, such as leukemia and lymphoma (18-21). According to the Warren and Gates criteria, metachronous SPM occurs more than six months after the index cancer diagnosis (11). Unlike synchronous SPM, the most significant contributor to metachronous SPMs is the administration of RT and/or ChT for the primary malignancy. The aim of this study is retrospective investigation of the excess risk of synchronous and metachronous SPMs among patients with NPC, treated and followed at a single center over 29 years, compared with the Turkish population. Material-Method Patient Selection and Evaluation Between January 1990 and December 2019, we retrospectively enrolled all consecutive patients with newly diagnosed, biopsy-proven, and previously untreated NPC at the Istanbul University Oncology Institute. Patient demographics, treatment details, and causes of death were extracted from the institutional databases. Exclusion criteria included: (1) pathologically confirmed non-NPC; (2) incomplete clinical, pathological, or treatment data; and (3) any cancer history before NPC diagnosis (n=12). All NPC patients were re-staged according to the 7th edition of the American Joint Committee on Cancer’s Tumor–Node–Metastasis (TNM) staging system. The histopathology of NPC was classified into (1) keratinizing squamous cell carcinoma (WHO type I NPC), (2) non-keratinizing squamous cell carcinoma (WHO type II NPC), non-keratinizing undifferentiated carcinoma (WHO type III NPC), and (3) squamous cell carcinoma with no specific histological subtype. Leisons which fulfill the following Warren and Gates criteria classified as SPM: histologic confirmation of malignancy for both tumors, a minimum of 6 cm of normal mucosa separating the two tumors, exclusion of metastatic tumors, and a solitary lesion histologically distinct from the index tumor for lung SPMs (11). Accordingly, 3 patients with no histologically confirmed tumors were excluded from the study (one optic glioma, one meningioma, and one skin tumor). None of the second primary tumors were classified as undifferentiated carcinomas, effectively ruling out the likelihood of locoregional recurrence or distant metastases originating from the nasopharynx. All SPMs were recorded, including their anatomical location, cancer type, and diagnosis date. SPM locations were categorized as in-field or out-field depending on whether the tumor was within or outside the previous radiation fields. All leukemia cases were classified as out-field SPMs. Synchronous tumors were defined as those diagnosed within 6 months of NPC diagnosis, and metachronous tumors as those diagnosed more than 6 months later. The histopathology of these malignancies was classified into sarcoma and non-sarcoma types (i.e., squamous cell carcinomas, adenocarcinomas, oncocytic carcinomas, anaplastic carcinomas, papillary carcinomas, and adenosquamous carcinomas). Staging and Treatment Initial evaluations included a comprehensive history, physical examination, blood and biochemical tests, fiberoptic nasopharyngoscopy, biopsy, and magnetic resonance imaging (MRI)/computed tomography (CT) of the nasopharynx and neck. Additional assessments included chest CT, abdominal ultrasound or CT, and bone scans with PET-CT, which were introduced after 2006. Before 2010, patients were treated with two-dimensional radiotherapy (2D-RT) at a daily fraction of 2 Gy. After 2010, intensity-modulated radiotherapy (IMRT) was introduced, delivering 2.12 Gy per fraction using 6-MV X-rays. Patients with stage I disease did not undergo chemotherapy (ChT). For those with stage II or higher disease, platinum-based concurrent chemoradiotherapy (CCRT) was administered. Patients with locally advanced disease received induction chemotherapy (IC) followed by CCRT. The concurrent ChT regimen consisted of either weekly cisplatin (40 mg/m²) or three-weekly cisplatin (100 mg/m² every 3 weeks). The IC regimens included the TP regimen (docetaxel-cisplatin, repeated every 3 weeks), the PF regimen (cisplatin-5-fluorouracil, repeated every 3 weeks), and the GP regimen (gemcitabine-cisplatin, repeated every 3 weeks). For pediatric patients, the primary treatment consisted of three courses of IC (PF regimen, PEB (cisplatin, epirubicin, and bleomycin) or PE (cisplatin and epirubicin)) followed by RT. Concurrent chemotherapy was not administered. ChT was initially administered to all patients with metastasis, if no palliative intervention was required, followed by an evaluation of the radiological response after 3–6 cycles. Patients showing stable, partial, or complete responses subsequently received locoregional radical RT (with or without ChT). Follow-Up Patients were followed up at 3-month intervals during the first two years, every 4–6 months during the third to fifth years, and annually thereafter. Each follow-up visit included a complete medical history, physical examination, and nasopharyngoscopy. Annual evaluations included head and neck imaging with CT or MRI, as well as chest radiography and/or CT. Statistical Analysis The data cut-off for the final follow-up was April 2023. The normality of continuous variables was tested using the Kolmogorov-Smirnov test. Descriptive statistics were used for patients’ demographic and tumor characteristics in terms of median, mean, standard deviation, and interquartile range (IQR) for continuous variables, and frequency and percentages for categorical variables. Overall survival (OS) was calculated from the date of NPC diagnosis until death or last follow-up. OS was analyzed using the Kaplan-Meier method, and log-rank tests were used to compare differences between survival and SPM risk curves. The clinical factors associated with overall survival and SPM risk were evaluated using univariate and multivariate Cox regression analyses, respectively. The Standardized Incidence Ratio (SIR) was calculated by dividing the observed number of cases by the expected number of cases and multiplying by 100. For the SIR calculation, data from the Türkiye Cancer Statistics (2013-2017), published by the Turkish Ministry of Health, were used. All statistical tests were two-tailed, and a p-value<0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS software (version 27.0; IBM Corp., Armonk, NY, USA). This study was approved by the Ethics Committee of Istanbul University Oncology Institute and conducted in accordance with the ethical standards of the Helsinki Declaration. Written informed consent was obtained from all patients. Results Patient Characteristics In total, 821 patients diagnosed with NPC were included in this study. The mean age at NPC diagnosis was 43.84 ± 17.1 years (range 6–85 years), and 69% (n=569) of the patients were male. The patient characteristics are summarized in Table 1. During a median follow-up of 90 months (IQR:34–157), 79 patients (9.6%) had SPM (14 synchronous and 65 metachronous). Survival Analysis Of the whole group, 244 (29.7%) were dead at the time of analysis. The 5-year and 10-year overall survival rates were 79.7% and 68.7%, respectively. Survival has improved over the past 30 years, with patients diagnosed between 1990 and 1999 exhibiting poorer survival rates (p=0.001) in univariate analysis. Advanced age (>40 years) (p<0.001), male sex (p=0.012), and WHO type 1 histopathology (p<0.001) were associated with decreased OS rates (Figure 1). Overall survival worsened with increased tumor stage and lymph node involvement, with pathological T4 and N2-3 tumors significantly impacting OS (P<0.001). Patients diagnosed with SPM also had lower OS rates (p=0.018). In multivariate analysis, diagnosis during 1990–1999, age N3 lymph node involvement were independent prognostic factors for OS. Sex and SPM development were not significantly associated with OS (p>0.05) (Table 2). Risk Factors Associated with SPM in NPC Patients The risk of SPM was significantly higher in patients aged > 40 years (p 40 years (p<0.001) and female sex (p=0.0498) were independent risk factors for SPM (Table 3). Patients with SPM SPM were detected in 79 patients with NPC. The median age at the time of NPC diagnosis was 53 years (range:11–80). Seventeen patients were female and 62 were male (Table 4). Six patients received RT alone for NPC treatment. Fifteen patients received CCRT, and one received adjuvant ChT after CCRT. Fifty-two patients underwent RT or CCRT after IC. Nineteen patients were treated using IMRT, and 55 underwent 2DRT. In 64.6% of patients, SPM occurred within 10 years of RT, and in 35.4%, it occurred more than 10 years later. Metachronous disease was identified in 65 patients, with a median time between NPC and SPM diagnosis of 103 months (range:9–314). In 25 patients, SPM occurred within previously irradiated fields (19 head and neck located non-sarcomatous tumors, 4 head and neck located sarcomas, 2 cervical esophagus tumors). Four patients with in-field SPM had sarcoma histology (one laryngeal liposarcoma, one nasal carcinosarcoma, one neck myxofibrosarcoma, and one paranasal undifferentiated sarcoma). After NPC irradiation, the median latency period for sarcoma development was 94 months (range:41–217). For sarcoma treatment, three patients underwent surgery alone, and one patient underwent multiple surgeries for local recurrence, followed by ChT. One patient diagnosed with metachronous SPM refused further treatment. Three patients did not receive treatment and were followed up with the best supportive care. One patient with low-risk prostate cancer was currently undergoing active surveillance. The remaining 60 patients underwent radical or palliative treatment. Among the patients who developed SPM, 33 (41.8%) died of SPM, and one (1.3%) patient died of NPC. Five (6.3%) patients died of non-cancer-related causes. Forty (50.6%) patients are currently alive. Standardized Incidence Ratios by Cancer Site We compared the observed SPM numbers with the expected numbers from the general Turkish population. Table 5 presents the standardized incidence ratios (SIRs) for SPM by tumor location. The SIR of developing SPM was 1.73 (95% CI:1.69–1.77). The most common site of SPM was the head and neck region (n=21), including four oral cavity cancers (three tongue, one floor of mouth), six larynx cancers, six oropharynx cancers, three thyroid cancers, one salivary gland tumor, and one hypopharynx cancer. Lung was the second most common SPMs location (n=15). The regions with the highest risk of SPM were the head and neck [SIR:34.69 (95% CI:33.49–35.89)], sarcoma [SIR:14.18 (95% CI:13.03–15.33)], esophagus [SIR:6.18 (95% CI:5.35–7.01)], kidney [SIR:4.62 (95% CI:4.22–5.01)], and pancreas [SIR:4.12 (95% CI:3.72–4.51)] (Table 5). Discussion The risk of SPM in NPC has rarely been studied, particularly in endemic regions, with only a limited number of studies available (3-9,24). As new treatment technologies improve the survival rates, SPM is expected to occur more frequently in this patient group. In our study, 9.6% of the 821 patients with NPC were diagnosed with SPM during a median follow-up of 90 months, and the risk of developing SPM increased by 73% compared with the general population. The most common sites for SPMs were the head and neck (n=25) and lungs (n=15). Female sex and age > 40 years were identified as independent risk factors for SPM development. Factors influencing the survival of patients with NPC include WHO type 1 tumors, advanced T and N stages, older age at diagnosis, and diagnosis between 1990 and 1999. Although female sex and the presence of SPM appeared to affect survival in the univariate analysis, these factors were not statistically significant in the multivariate analysis. The incidence of SPMs in patients with NPC varies in the literature, ranging from 3% to 20.1% (7,22,23). These rates differ based on the follow-up duration, diagnostic criteria, and patient characteristics. For example, data from the Taiwan National Cancer Registry, published by Chen et al., showed that 3.01% of 23,639 patients with NPC developed SPM. However, in this study, SPMs that developed within two months of NPC diagnosis were excluded to avoid confusion with potential recurrence or metastasis, which may explain the lower rate compared to other series (4). The highest incidence SPM rate in the literature (20.1%) was found in the Netherlands, which is a non-endemic region (7). A systematic review by Svärd et al. (2023), which included 89,168 patients, estimated that the average risk of developing SPM was 6.6%. In the endemic regions, the average risk was 4.9%, whereas in the non-endemic regions, it increased to 8.7%. (25) In our study, the crude incidence of SPM was calculated as 9.6%, which closely aligned with the rate reported for non-endemic regions. Few studies have investigated the risk of SPM in patients with NPC, particularly when comparing them to the general population, and most of these studies have been published in endemic regions (Table 6). In a study by Scélo et al., data from 13 cancer registries, Singapore showed an SIR of 0.76, whereas the average in other countries was 1.46. In most published studies, the risk of SPM in NPC patients was found to be higher than that in the general population, except for data from Singapore, which reported a decreased risk (24). The lower rate in Singapore may be due to mandatory biopsy requirements for SPM diagnosis (24). In our study, consistent with data from non-endemic regions, the SIR for SPM development was calculated as 1.73, with all diagnoses confirmed by histopathological examination. Studies investigating SPM development have emphasized that the median follow-up duration should be at least a decade. Variations in incidence rates may also arise from differences in follow-up duration (22, 26, 27). The median follow-up duration for patients with NPC in the present study was 7.5 years. Because 28 of the 79 SPM cases were diagnosed after 10 years, the crude incidence of SPM is likely to increase with extended follow-up periods. Advanced age at diagnosis (>40 years) were identified as independent risk factors for SPM development. Similar findings regarding age have been reported in the literature, in which an increased risk of SPM has been observed in individuals diagnosed with NPC at an older age. Kong et al. stated that being ≥50 years old is an independent risk factor for SPM development (23). Tsou et al. indicated that the only factor that increased the risk of SPM in patients with NPC was a diagnosis made after 70 years of age (28). Using national data from the Netherlands, Ooft et al. demonstrated that advanced age was associated with an increased risk of SPM (7). In a 2020 multicenter study conducted in Hong Kong, advanced age was found to be an independent risk factor for SPM development, along with smoking, HBsAg positivity, and reirradiation (9). Female sex was another significant risk factor for SPM development in our study. However, the role of sex in SPM development remains controversial. In a study of 527 patients who underwent IMRT, no significant differences were observed between the sexes regarding SPM development (22). In a 2006 study from China by Kong et al., which included 326 patients, 17 SPMs were identified; although a slight increase in SPM risk was noted in men, the difference was not statistically significant (23). A study involving data from 13 different centers worldwide, including Singapore as the only endemic region, found no difference in risk between sexes, although it showed a reduced risk for men in Singapore compared to the general population (24). In a SEER analysis by Chan JY, women had a much higher risk for oral cavity and pharynx cancers than men, and this was attributed to the higher radiation sensitivity in women (6). Additionally, a systematic review published in 2023 suggested that female sex significantly increases the risk of SPM (25). Our study found female sex to be an independent risk factor for SPM development, but no significant increase in the risk of female cancers. The head and neck region is the most common site of SPM in patients with NPC (23). In this study, the risk of developing these tumors was 34.69 times higher than that in the general population, with the most frequent tumors being oropharyngeal, laryngeal, and oral cavity cancers. RT may play a role in the etiology of SPM development within the radiation field. In our study, patients diagnosed with metachronous SPMs within the radiation field (referred to as ”in-field metachronous”) constitute this group. Of the 79 patients with SPM, 25 met these criteria. The median time to disease development for these patients was 151 months (range:41–309). Metachronous SPMs within the radiation field accounted for 2.9% of the total population of 821 patients. Secondary cancers caused by radiation can be either sarcomatous or non-sarcomatous, with squamous cell carcinoma being the most common (27). In our study, we divided the patients into two groups based on histology: sarcomatous and non-sarcomatous. The nonsarcomatous group predominantly consisted of patients with squamous cell carcinoma, although it also included patients with adenocarcinomas and thyroid papillary carcinomas. Sarcomas within the radiation field are one of the most common complications of RT. The incidence of radiation-induced sarcomas in the head and neck region has been reported to be less than 1% (range:0.03–0.8%) (26,29,30,31). In our study, four of the six identified sarcoma cases were located within the radiation field. Owing to these radiation-induced tumors, a significant increase in sarcoma risk was observed compared with that in the general population (SIR, 14.18). The latent period between RT and sarcoma development is generally considered to be approximately a decade, although this period may vary (29,32,33). According to the modified Cahan criteria, at least 3 years must pass between primary RT and the diagnosis of radiation-associated sarcoma (34). A recent multicenter retrospective study involving 419 patients suggested that concurrent ChT may shorten the latent period (35). In our patients, the median latency was 94 months, with two patients showing a latency of less than 3 years. All patients in our study received RT after IC for NPC. Treatment of SPMs that develop within the radiation field remains a challenging and controversial issue for clinicians. Since tumors develop within the previous radiation field, the likelihood of using an effective radiation dose is low, making surgical treatment more prominent. Some authors suggested that R0 resection (complete resection) of the tumor is an important prognostic factor (26,27,33). However, these tumors are generally diagnosed at an advanced stage. The fibrosis of tissues caused by the radiation used in the treatment of the primary tumor, the disruption of anatomy, the long latent period for SPM development, and the tendency for symptoms to be attributed to late radiation-related complications make the early detection of these tumors very difficult for both physicians and patients (26). Additionally, avoiding imaging in the late period and following up with only clinical examination complicates the early detection of tumors located in areas that may not be visible on physical examination. Another treatment option, ChT, may not be feasible in some patients because of chemoresistance, particularly in those with sarcoma histology. The detection of lung cancer as an SPM in patients with index cancer is common (36). The highest risk occurs in cancers with longer survival rates, such as breast and prostate cancers. Among patients with NPC, lung cancer is the second most commonly diagnosed SPM, after head and neck cancers (37). However, studies from both endemic and non-endemic regions have shown variable results regarding increased risk compared with the general population. A 2022 study by Xue et al., which evaluated 1,102 patients with NPC treated with IMRT, found that the crude incidence of second primary lung adenocarcinoma was 2%, with no significant increase in risk compared to the general population (38). This study focused only on adenocarcinomas due to the low incidence of squamous cell lung carcinoma in China. Chen et al. did not observe a significant increase in lung cancer risk in patients with NPC compared to that in the Taiwanese population (4). However, two studies from Hong Kong found a significant risk increase, and in a study with a smaller sample size, SIR was 1.9 (95% CI 0.87–3.61) (8,9). The highest risk increase was shown in a 2016 SEER analysis, which revealed an increase in the risk of lung cancer compared with the general population (SIR, 2.39) (6). Lung cancer is the most common and fatal cancer in Türkiye in 2022 (1). In this study, the crude incidence rates of lung cancer were 1.8%, and SIR for lung cancer was 2.29, respectively. Two patients in this study developed cervical esophageal cancer as an in-field second primary malignancy, and the risk increased compared to the general population was 6.18 times. Esophageal cancer showed the highest increase in risk among SPMs. In a 2016 SEER analysis by Chan et al., a significant increase in esophageal cancer risk was found 2–11 months after the index NPC diagnosis compared with the American population, which reported an SIR of 3.5 (6). Among SPMs observed in patients with NPC, cancers outside the radiation field, excluding lung cancer, constitute a smaller percentage. In these cancers, the radiation used for the treatment of the index cancer cannot be considered a contributing factor to the etiology. ChT is used in addition to RT in all patients with NPC except those with stage I disease (19-21). Although no high-level evidence is available, some studies have suggested that cisplatin-based ChT may play a role in the development of secondary malignancies. Epstein-Barr virus (EBV), a major etiological factor in NPC, is also known to play a role in the etiology of other cancers, and shared genetic predispositions seem to be the most likely explanation. Several studies have reported an increased risk of leukemia and lymphoma in patients with NPC. Particularly in non-endemic regions, EBV detected in all patients is known to play a role in the etiology of certain lymphomas (14). Furthermore, it has been shown that cisplatin-based ChT leads to a minimal increase in the risk of secondary leukemia and myelodysplastic syndrome (21). In a series published by Wang et al., the risk of leukemia and lymphoma was nine times higher than that in the general population (3). In a 25-year study in Taiwan, SIR for leukemia and lymphoma was 1.66 (4). Another study reporting data from 13 centers showed a 3.85-fold risk increase in non-endemic areas (24). In this study, three cases of leukemia and lymphoma were found as second primary malignancies, and SIR was calculated as 0.96 (95% CI 0.85–1.07). Gastric cancer is also associated with the etiology of EBV (14). Some studies have reported an increase in gastric cancer patients compared to the general population, while others have reported a decrease in NPC patients (3,24). In endemic regions, most cases of NPC are linked to EBV, whereas in data from endemic regions in Singapore, a decrease in gastric cancer risk has been observed (24). In our study, SIR for gastric cancer was found to be 2.25. Similar increases in the risk have been observed for other gastrointestinal cancers. Prostate cancer is among the most prevalent cancers worldwide, and its incidence is particularly high in developed countries owing to widespread screening programs (42). The occurrence of prostate cancer as a SPM in NPC patients has been inconsistently reported in the literature. Some studies suggest a reduced risk compared to the general population, whereas others indicate an elevated risk. For example, in a study using Taiwan’s National Cancer Registry involving 23,639 patients with NPC, Chen et al. reported a 47% reduction in prostate cancer risk (4). Conversely, Chow et al. compared patients with NPC to a Hong Kong population not subjected to PSA screening and observed an increased risk of prostate cancer (8). No screening programs for prostate cancer currently exist in Turkey. In our study, six patients developed prostate cancer as an SPM, representing a 1.84-fold higher risk than that in the general population. Chow et al. have reported an unexplained increase in the risk of liver cancer (8). Similarly, our study identified an elevated risk of liver cancer, with a standardized incidence ratio (SIR) of 1.66. Additionally, significant increases in risk were observed for colon cancer, pancreatic cancer, renal cell carcinoma (RCC), and bladder cancer compared with the general population. However, these findings, which have not been previously documented, are challenging to explain. None of these cancers shares known environmental factors or genetic predispositions with NPC (8). Smoking is the only potential overlapping risk factor associated with NPC and bladder cancer. In our study cohort, thorough history-taking during follow-up was the cornerstone of clinical practice. Patients were also contacted regularly by phone, which reinforced their motivation to participate in ongoing monitoring. One of the most important factors influencing mortality in patients with NPC is SPM development. Approximately 15.3% of deaths occurring after five years were due to secondary malignancies (43). In a study by Chen et al., the survival curves of patients with and without SPMs did not differ before the ninth year (4). A crossover occurred around the 9th year, after which patients with SPMs had significantly poorer survival. Similarly, a study by Lin et al. observed a crossover during the 3rd year. In our study, SPM development did not appear to affect survival; however, a similar crossover occurred around the fifth year. If the follow-up period is extended, differences in the survival rates may occur. This may be related to the predominance of early-stage SPMs, which are unlikely to affect survival. As most recurrences of head and neck cancers occur within the first two years after treatment, close follow-up during this period is critically important. The NCCN treatment guidelines recommend clinical examination and annual imaging for hard-to-access areas in asymptomatic patients more than six months post-treatment (44). Annual thoracic CT scans are recommended for patients with a history of heavy smoking. However, no evidence demonstrates the survival benefit of follow-up conducted beyond five years after treatment for head and neck cancer (45,46). In contrast, some authors have emphasized the importance of long-term follow-up in detecting late recurrences and secondary primary cancers (47). Nevertheless, no recommendations have been made regarding the frequency of imaging. In our study, 40 of the 79 SPM cases occurred in the radiation field or lungs. Before immediately considering the complaints of the patients as long-term side effects of treatment, the second primary should be taken into consideration, and the necessary examinations and imaging should be performed. In contrast, approximately half of the SPMs detected in our study developed outside the radiation field and lungs. Therefore, in addition to a detailed examination of the head and neck region in SPMs, it may be useful to inquire about the symptoms of cancers that occur outside the radiation field. The study’s main limitations were its retrospective design and relatively short median follow-up period. Additionally, changes in technology and treatment approaches over the 29-year period have resulted in patients receiving different treatments. Another limitation is the lack of data on smoking habits, EBV status, and details of previous treatments. However, this is the first study from Türkiye to compare the SPM risk in NPC patients with that in the general population. Conclusion Long-term multidisciplinary follow-up is essential for the prevention and early detection of SPMs in patients with NPC. Particular attention should be paid to monitoring head and neck cancers, lung cancer, and sarcomas. 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Am Soc Clin Oncol Educ Book. 2023 Jan;43:e389718. doi: 10.1200/EDBK_389718. PMID: 37079869. Table 1. Patient characteristics Year of diagnosis 2010-2019 265(32.3) 2000-2009 281(34.2) 1990-1999 275(33.5) Age (year) mean±SD 43.84±17.11 Age group ≤40 302(36.8) >40 519(63.2) Gender Female 252(30.7) Male 569(69.3) Histological type Type 1 35(4.3) Type 2-3 786(95.7) T Stage I 170(20.7) II 333(40.6) III 130(15.8) IV 188(22.9) N Stage 0 96(11.7) I 218(26.6) II 376(45.8) III 131(16) Second primary malignancy No 742(90.4) Yes 79(9.6) Follow-up (month) Median (IQR) 90(34-157) IQR, Interquartile Range; SD, standard deviation. Table 2. Multivariate analysis of significant factors associated with OS in NPC Year of diagnosis 2010-2019 1(reference) 2000-2009 1.28(0.91-1.80) 0.153 1990-1999 1.45(1.02-2.06) 0.039* Age ≤40 1(reference) >40 2.40(1.77-3.25) <0.001* Gender Female 1(reference) Male 1.22(0.91-1.63) 0.191 Histological type Type 2-3 1(reference) Type 1 2.20(1.37-3.52) 0.001* T Stage I 1(reference) II 1.39(0.94-2.07) 0.104 III 1.42(0.88-2.28) 0.150 IV 2.34(1.53-3.58) <0.001* N Stage 0 1(reference) I 1.15(0.69-1.91) 0.603 II 1.66(1.03-2.65) 0.036* III 3.37(2.03-5.62) <0.001* Second primary malignancy No 1(reference) Yes 1.25(0.88-1.78) 0.219 * p<0.05; HR, hazard ratio; CI, confidence interval. Table 3. Risk factors associated with SPM in NPC patients ( Multivariate Cox proportional hazards analysis results) . Year of diagnosis 1990-1999 1(reference) 2000-2009 1.22(0.66-2.25) 0.521 2010-2019 1.92(0.97-3.79) 0.062 Age ≤40 1(reference) >40 4.02(2.20-7.34) <0.001* Gender Male 1(reference) Female 1.73(1.00-2.98) 0.0498* Histological type Type 2-3 1(reference) Type 1 0.63(0.15-2.58) 0.518 T Stage I 1(reference) II 1.67(0.89-3.12) 0.111 III 1.64(0.77-3.51) 0.199 IV 1.71(0.81-3.59) 0.158 N Stage 0 1(reference) I 1.25(0.45-3.49) 0.666 II 1.59(0.68-3.71) 0.280 III 1.22(0.53-2.81) 0.635 * p40 64(81) Gender Female 17(21.5) Male 62(78.5) Histological type WHO type 1 2(2.5) WHO type 2-3 77(97.5) Timing Synchronous 14(17.7) Metachronous 65(82.3) Histology Sarcoma 6(7.6) Non-sarcoma 73(92.4) Table 5. Standardized incidence ratios by cancer site. All Sites 79 1.73 (1.69-1.77) Head-Neck 21 34.69 (33.49-35.89) Lung 15 2.29 (2.18-2.40) Sarcoma 6 14.18 (13.03-15.33) Prostate 6 1.84 (1.69-1.98) Kidney 5 4.62 (4.22-5.01) Gastric 5 2.25 (2.06-2.45) Bladder 5 2.15 (1.97-2.34) Colon 5 1.95 (1.78-2.12) Pancreas 4 4.12 (3.72-4.51) Lymphoma-Leukemia 3 0.96 (0.85-1.07) Esophagus 2 6.18 (5.35-7.01) Breast 1 0.19 (0.15-0.23) Ovary 1 1.40 (1.11-1.67) Liver 1 1.66 (1.34-1.98) SIR, standardized incidence ratio; CI, confidence interval Table 6. Studies compared the SPM rates in NPC and the general population Wang 2000 (3) Taiwan 2.8 Head and neck tumors (16.5), stomach (5.5), leukemia-lymphoma (9) 1549 39 2.5% Scélo 2007 (24) 13 centers (Singapore, Denmark, Finland, Iceland, Norway, Slovenia, Sweden, Spain, Canada, Australia Singapore 0.76 Tongue (11.1) lung (0.4), stomach (0.4), colon (0.2) 5182 76 1.5% Others 1.46 NHL (3.06), tongue (5.29), brain (3.89), myeloid leukemia (3.85), skin (3.47) 3765 215 5.7% Chen 2008 (4) Taiwan 1.24 Oral/pharyngeal (2.67), salivary gland (3.82), sarcoma (4.05), skin (2.43), leukemia/lymphoma (1.68) rectum (0.67), prostate (0.53) 23649 712 3.0% Goggins 2010 (5) Hong Kong 1.93 Tongue (25.7), lung (1.83), nasal +middle ear (30.7), brain (10.5) 1500 84 5.1% Chan 2016 (6) USA 1.47 oral cavity+pharynx (7.11), esophagus (3.5), nose+nasal cavity+middle ear (15.5), lung (2.39) 3162 332 10.5% Ooft 2016 (7) Netherlands - Pharynx (7.5), larynx (3.8), lower airways (0.4) 1175 237 20.2% Chow 2019 (8) Hong Kong 1.84 sarcoma (38.1), tongue (33.3), oropharyngeal (25.0), prostate (3.19), liver (2.80) 759 51 6.7% Chow 2020 (9) Hong Kong 1.9 oral cavity (26.3), sarcoma (15.2), OPC (11.4), nasal+paranasal sinus+middle ear (8.6), salivary gland (6.8), thyroid (3.4), skin (3.6), lung (1.8) 3166 290 9.2% 2024 This study 1.73 Head neck (34.69), sarcoma (14.18), lung (2.29), esophagus (6.18), prostate (1.84), kidney (4.62), colon (1.95), pancreas (4.12) 821 79 9.6% Figure 1. Kaplan–Meier curves for factors significantly associated with the overall survival of patients with NPC. (A) all patients, (B) decade of diagnosis, (C) age group (≤40 vs (G) N stage, and (H) second primary cancer (Yes/No). Figure 1 (continued) Figure 2. Kaplan–Meier curves for factors significantly associated with the SPM-free survival of patients with NPC. (A) All patients (B) age group (≤40 vs >40), (C) gender Information & Authors Information Version history V1 Version 1 12 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Kübra Özkaya Toraman 0000-0003-2518-5980 [email protected] Istanbul Universitesi Onkoloji Enstitusi View all articles by this author Rasim Meral Istanbul Universitesi Onkoloji Enstitusi View all articles by this author Makbule Atasoyu Universitair Medisch Centrum Groningen Afdeling radiotherapie View all articles by this author Ahmet Karadeniz Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Musa Altun Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Metrics & Citations Metrics Article Usage 154 views 74 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Kübra Özkaya Toraman, Rasim Meral, Makbule Atasoyu, et al. Risk of Second Primary Malignancy in Nasopharyngeal Carcinoma Patients: A Single Center Experience from Türkiye. Authorea . 12 June 2025. 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