To investigate the patterns of care for patients with nasopharyngeal carcinoma (NPC) in South Korea.
A multi-institutional retrospective study was performed (Korean Radiation Oncology Group [KROG] 11-06) on a total of 1,445 patients from 15 institutions.
Of the 1,445 patients, more than half were stages III (39.9%) and IV (35.8%). In addition to patterns of care, we also investigated trends over time with the periods 1988-1993, 1994-2002, and 2003-2011. The frequencies of magnetic resonance imaging and positron emission tomography-computed tomography were markedly increased in the third period compared to previous 2 periods. Concurrent chemoradiation (CCRT) was performed on 894 patients (61.9%), neoadjuvant chemotherapy on 468 patients (32.4%), and adjuvant chemotherapy on 366 patients (25.3%). Of stage II-IV patients, CCRT performed on 78.8% in 2003-2011 compared to 15.0% in 1988-1993. For patients treated with CCRT, cisplatin was the most commonly used agent in 81.3% of patients. Over the periods of time, commonly used radiotherapy (RT) techniques were changed from 2-dimensional RT (1988-1993, 92.5%) to 3-dimensional RT (2003-2011, 35.5%) or intensity-modulated RT (IMRT; 2003-2011, 56.5%). Median RT doses given to primary tumors, high-risk lymphatics, and low-risk lymphatics were 70.0 Gy, 58.1 Gy, and 48.0 Gy, respectively. Adoption of IMRT increased the dose per fraction and escalated total radiation dose.
Assessment of the patterns of care for NPC patients in South Korea demonstrated that management for NPC including diagnostic imaging, treatment regimen, RT techniques and dose schedule, advanced in accordance with the international guidelines.
Nasopharyngeal carcinoma (NPC) shows markedly geographic and racial variations in incidence. In southern China, NPC is the most common head and neck cancer, but in the Western world, it is a rare disease with an incidence of less than 1 per 100,000 [
Because of difficulty in surgical resection with an adequate margin, radiotherapy (RT) is the gold standard treatment of NPC [
To assess the patterns of care, a multi-institutional retrospective study of NPC (Korean Radiation Oncology Group [KROG] 11-06) was performed through the head and neck committee of the Korean Society of Radiation Oncology. Data were collected from the medical records of 1,476 primary NPC patients treated at 15 institutions in South Korea between September 1988 and October 2011. Eligible criteria were as follows: 1) pathologically proven NPC; 2) stage I to IVb NPC according to the American Joint Committee on Cancer (AJCC) staging, the 6th edition; 3) age over 18 years; and 4) the Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Patients who had undergone previous surgery or RT to the head and neck, and those with distant metastasis at initial diagnosis were excluded from the study.
In this study, to assess the patterns of care, we collected the data of patient and tumor characteristics, diagnostic modality, RT technique, RT dose schedule, chemotherapy schedule, treatment outcomes, and salvage treatment. Cases with missing data were included in analysis to investigate as many patients as possible. In total, 31 patients were excluded. Reasons for exclusion were as follows: 7 patients below 18 years, 2 patients with ECOG 3, 16 patients given lower than 45 Gy to primary mass, and 6 patients with lack of data of RT dose. Finally 1,445 patients were analyzed.
Prior to patient enrollment, Institutional Review Board approval was obtained at each participating center, and data of eligible patients were collected through web-based system developed by KROG and were transferred to the KROG Data Center (National Cancer Center, Goyang, Korea). RT, chemotherapy, toxicity, recurrence, and survival reports of all patients were reviewed according to a centralized quality-assurance program.
Response was evaluated according to World Health Organization (WHO) criteria. Overall survival (OS) was defined as the time from pathologic diagnosis of NPC to death of all cause. Recurrences were analyzed to evaluate the failure pattern. Recurrences in the primary site and the cervical lymphatic area were defined as locoregional ones. Recurrences involving other sites were regarded as distant metastasis. Survival time was estimated by the Kaplan-Meier method. Survival differences over time were analyzed using the log-rank test. A p-value of <0.05 (two-sided test) was considered significant.
Patient characteristics are listed in
The most common chief complaint was a palpable neck mass(41.4%). Nasal symptoms (epistaxis, nasal stuffiness, and rhinorrhea) were observed in 25.8% of the patients. Aural symptoms (tinnitus, hearing impairment, and otorrhea) were observed in 16.5% of the patients, and cranial nerve palsy was observed in 8.9%. Other complaints were headache (4.7%), incidental finding (1.2%), throat symptom (1.2%), and pain (1.1%).
Neck computed tomography (CT, 94.1%), neck magnetic resonance imaging (MRI, 69.8%), positron emission tomography-computed tomography (PET-CT, 46.6%), bone scan (35.8%), and abdominal ultrasonography (US) or CT (29.4%) were used for diagnostic imaging. Commonly used imaging studies were changed over the periods studied. Neck CT was performed on almost all patients in the 3 periods (1988-1993, 97.5%; 1994-2002, 92.1%; and 2003-2011, 95.1%). The frequency of MRI was markedly increased in the third period compared to previous 2 periods (1988-1993, 13.2%; 1994-2002, 55.2%; and 2003-2011, 81.7%). PET-CT was also used more frequently in the third period compared to previous 2 periods (1988-1993, 2.8%; 1994-2002, 2.9%; and 2003-2011, 72.9%). However, bone scan, abdominal CT, and abdominal US were decreased in the third period compared to previous 2 periods-bone scan (1988-1993, 71.8%; 1994-2002, 71.1%; and 2003-2011, 16.6%), abdominal CT and abdominal US (1988-1993, 80.6%; 1994-2002, 55.7%; and 2003-2011, 14.7%). Details of diagnostic imaging studies are shown in
Of the 1,445 patients, 894 (61.9%) received CCRT and 551 (38.1%) received RT alone. Neoadjuvant chemotherapy was given before RT to 468 patients (32.4%) and adjuvant chemotherapy was given after RT to 366 patients (25.3%). Grouping the patients by the treatment modalities, CCRT alone without neoadjuvant or adjuvant chemotherapy was the most common treatment regimen (27.5%). CCRT followed by adjuvant chemotherapy (21.3%) and RT alone without neoadjuvant or adjuvant chemotherapy (18.5%) were the next common treatment regimens. The more details are presented in
Treatment regimens showed a difference between the AJCC stages. Patients with stage III and IV disease, received CCRT more often than those with stage I and II (stage I, 14.1%; stage II, 53.4%; stage III, 64.6%; and stage IV, 69.9%). Neoadjuvant and adjuvant chemotherapies were also delivered more often to patients with more advanced diseases-neoadjuvant chemotherapy (stage I, 8.5%; stage II, 29.4%; stage III, 35.4%; and stage IV, 34.0%), adjuvant chemotherapy (stage I, 0%; stage II, 21.1%; stage III, 26.5%; and stage IV, 29.7%). Treatment regimens also showed a difference over the periods. CCRT increased remarkably from 15.0% in 1988-1993 to 75.1% in 2003-2011. Neoadjuvant chemotherapy steadily declined from 55.0% to 28.5% during studied period and adjuvant chemotherapy did not show a remarkable change after 1994 (
Of the 894 patients who received CCRT, 768 (85.9%) completed chemotherapy (
As for RT, 98.1% of the patients completed the whole course of treatment. Patients received RT using 4 techniques: the two-dimensional RT (2DRT) technique (24.6%), 2DRT and 3DRT combined technique (11.7%), 3DRT technique (28.0%), and intensity-modulated RT (IMRT) technique (35.7%). Changes in the four RT techniques over time were observed. The 2DRT technique was performed on 92.5% of the patients in 1988-1993. In 2003-2011, the 3DRT and IMRT techniques were on 35.5% and 56.5% of the patients, respectively (
Responses were evaluated by physical examination (62.1%), neck CT (56.5%), neck MRI (32.2%), PET-CT (14.1%), and histopathological examination (5.0%). The number of patients who showed clinical responses was 1,353 (93.6%), and the more details were as follows: complete response, 1,025 (70.9%); partial response, 328 (22.7%); stable disease, 35 (2.4%); and progressive disease, 15 (1.0%). The 5-year OS rates were 73.6% for the whole group and those for individual stages were as follows: stage I, 96.3%; stage II, 86.2%; stage III, 77.4%; and stage IV, 60.4%. The 5-year OS rate showed a significantly better outcome in the third period compared to previous 2 periods (1988-1993, 63.5%; 1994-2002, 64.8%; 2003-2011, 79.9%; p < 0.001) (
In total, 452 patients (31.2%) had recurrences: 235 patients (16.2%) showed locoregional recurrences without distant metastasis, 197 patients (13.6%) showed distant metastases only, and 20 patients (1.4%) showed both. Recurrent patients received salvage treatment including surgery (15.3%), re-irradiation (40.1%), and chemotherapy (50.0%). RT techniques used in re-irradiation was 3DRT (46.4%), fractionated stereotactic radiotherapy (23.2%), or IMRT (21.4%). Patients received other treatments as follows: 3 patients received CyberKnife-based radiosurgery, 1 patient brachytherapy, 1 patient gamma knife-based radiosurgery, and 1 patient proton therapy.
To the best of our knowledge, this is the first report on the patterns of care for patients with NPC in South Korea. This report is based on the data for a large-scaled multi-institutional study that were collected from 1,445 patients. We assessed the patterns of care over time and demonstrated that management for NPC patients in South Korea have been improved in accordance with international guidelines. According to the current guidelines, neck CT, neck MRI, and PET-CT are recommended for stage evaluation at diagnosis. Although CT provides fundamental anatomic information for defining RT target volume, CT has limitations in exact delineation of tumors that extend to adjacent structures. MRI is superior to CT to detect intracranial involvement, skull bone invasion, or parapharyngeal infiltration. Ng et al. [
Changes in treatment regimens over time were also observed. As NPC is not only radiosensitive but chemosensitive tumor, many trials investigated advantage of concurrent chemotherapy for NPC to improve locoregional control. Al-Sarraf et al. [
As most NPC patients present with advanced disease at diagnosis and distant metastasis is the main pattern of failure, efficacy of systemic chemotherapy have been studied extensively. Neoadjuvant chemotherapy was tried to reduce tumor burden before RT and to eradicate micro-metastases. Several phase II trials showed high overall response rate of cisplatin-based combination chemotherapy ranging from 75% to 90% [
Advances in RT techniques were remarkable over the periods studied. In 1988-1993, 92.5% of the patients were treated with the 2DRT technique; in 2003-2011, the 3DRT technique and IMRT were performed on 92.0% of patients. During the whole period of 25 years, the mainstream of RT for NPC patients was changed from the 2DRT through 3DRT, in currently IMRT. RT dose schedules also changed according to advances in RT techniques. Total RT doses given to primary tumor were not quite different between patients treated with 2DRT technique and those treated with IMRT. However, daily doses delivered with 2DRT were 1.8-2.0 Gy in 97.7% of patients, while with IMRT over 2.0 Gy in 81.5%. Also, increase of RT doses given to high risk lymphatic chain was observed; 67.4% of patients received doses below 55 Gy with 2DRT technique but 64.8% of patients over 55 Gy with IMRT.
In the 2DRT era, doses of 66-70 Gy was delivered to primary tumor via laterally opposed fields. It could deliver tumoricidal doses to the primary tumor, but compromise of target coverage was inevitable because of proximity to critical organs such as brainstem or temporal lobe. Delivery of sufficient dose to lymphatic area was also hardly achievable. The 5-year local control was reported as 78%-85% and the 5-year OS was 50%-75% in 2DRT era [
This study has the limitation in terms of data quality because missing data were included in the dataset. This was unavoidable because patient data were collected retrospectively through surveys of multiple institutions. However, this study has a large sample size, which sufficiently showed the patterns of care for NPC patients in South Korea. Also, data on RT planning and dosimetry were not collected so the comparison of the RT plans according to RT techniques could not be done.
In conclusion, there have been advances in the management of NPC patients in South Korea. Diagnostic imaging studies including CT, MRI and PET-CT have been more frequently used and CCRT have been performed in more patients. Also, RT techniques and dose prescription have been advanced remarkably to adopt the IMRT technique and dose escalation. Treatment for NPC patients in South Korea reflected the up-to-date results of trials and advanced in accordance with the international guidelines.
ECOG, Eastern Cooperative Oncology Group; SqCC, squamous cell carcinoma; AJCC, American Joint Committee on Cancer; EBV, Epstein-Barr virus.
Values are presented as number (%).
CT, computed tomography; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; US, ultrasonography.
RT, radiotherapy; CCRT, concurrent chemoradiotherapy; CTx, chemotherapy.
Values are presented as number (%).
RT, radiotherapy; CCRT, concurrent chemoradiotherapy.
FP, 5-fluorouracil + cisplatin; DP, docetaxel + cisplatin; FDP, 5-fluorouracil + docetaxel + cisplatin.
FP, 5-fluorouracil + cisplatin; DP, docetaxel + cisplatin; FDP, 5-fluorouracil + docetaxel + cisplatin.
Values are presented as median (range) or number (%).