In recent years, the radiotherapy techniques for NPC have advanced from 2- to 3-dimensional. The combined use of 3-dimensional conformal IMRT and MRI allows for the vital organs to be clearly defined and the dose to be properly distributed to the target area, leading to a significant increase in the local area control rate of NPC. Tumor centers in China and other countries have reported that the 5-year local area progression-free survival rate for NPC after IMRT was >90%[15, 16].IMRT significantly improved the local area control rate; however, it did not translate into improved patient survival due to the occurrence of distant metastases, which pose as challenges for patients with NPC [2-5]. We investigated the characteristics and prognostic factors of distant metastatic NPC after IMRT and provided experience for appropriate salvage therapies to improve the overall survival rate of NPC.
Various survival rates for patients with distant metastatic NPC have been reported in previous studies. The median survival time and 2-year survival rate ranges from 9–15.6 months and 15.0–34.4%, respectively. The survival rate may be related to whether the patients received treatment and the treatment methods and intensity in the various studies [17-20]. Based on our findings, the median survival was 14 months, and the post-metastasis1-, 2-, and 3-year survival rates were 60.4%, 40.2%, and 27.6%, respectively. The most common metastatic sites were the bones, lungs, and the liver. The 2-year survival rate observed in this study was higher than that previously reported. There are two possible reasons for the differences in our findings and those previously reported. First, although this was a retrospective study, the treatment for all patients was selected by the Multiple Disciplinary Team (MDT), based on the patients’ disease status and physical condition. Thus, there was no bias between different physicians regarding treatment options. Hence, our results are a good representation of the general situation regarding patients with metastatic NPC after IMRT. Second, most of the patients received local radiotherapy after disease remission or control by systemic chemotherapy. Radiotherapy eliminated local residual lesions that were not sensitive or resistant to chemotherapy. Furthermore, the combination of radiotherapy and chemotherapy reduced the overall tumor load and delayed the progression of disease.
The N stage at initial treatment independently affects the survival of patients with metastatic NPC .However, although induction chemotherapy and the N stage at initial diagnosis had effects on survival after metastasis upon univariate analysis, these factors were not found to be significant independent prognostic factors upon multivariate analysis. This could be explained by the fact that 71.1% of patients had N2 or N3 stages at initial diagnosis. Relatively high-risk N2 (>3 cm lymph node or with fusion necrosis) and N3 stage patients were provided 3–6 full cycles of treatment, in conjunction with an adequate amount of induction chemotherapy, which may have balanced the N-stage effects and improved the prognosis of high-risk N stage patients. Therefore, the N-stage did not have a critical impact on patient survival in the current study.
The findings from the multivariate analysis in this study were similar to those reported in previous studies [17-19]. Prognosis can vary according to the different metastatic sites. The median survival time of intrahepatic metastases was only 10.5 months, while that of extrahepatic metastases was 16 months. The median survival time of bone and lung metastases was 18 months and 16 months, respectively, whereas that of multi-organ metastases was only 10 months. The survival rate of multiple organ metastases was significantly lower than that of any single organ metastasis. Previous studies have reported that patients with only lung or bone metastases have a better prognosis and long-term survival [17, 18], but no clear comparisons have been made in respective studies.
Local palliative therapy is a very important method for the treatment of metastatic NPC. For patients with bone metastases, radiotherapy after chemotherapy, combined with bisphosphonate treatment to inhibit osteoclast activity, can effectively relieve pain and prevent fractures. In patients with only lung metastases, chemotherapy combined with targeted therapy is an effective treatment option. After 4–6 cycles of chemotherapy, local radiotherapy is performed for intrapulmonary metastatic lesions. For a single lung metastatic lesion or multiple lesions in a single lobe, surgery or SBRT could also be considered if the patient is in good health. Liver metastasis generally involves multiple lesions and therefore, performing surgery is difficult. The liver poorly tolerates radiation; therefore, chemotherapy has always been used as the preferred treatment option. Patients with oligometastatic can also consider SBRT or radiofrequency ablation. In the current study, SBRT for metastatic lesions was performed in three and two patients with lung and liver metastases, respectively. Furthermore, one patient with liver metastasis was treated with radiofrequency ablation. All patients had long-term survival of >3 years.
Systemic chemotherapy is the preferred treatment choice for metastatic NPC [6, 7]. In this study, the median survival time of patients who received systemic chemotherapy was 18 months, which significantly differed from that of patients who did not receive chemotherapy (9 months). However, the efficacy of chemotherapy may depend on various patient factors. Previous researchers have shown that factors, such as the general condition of patients, hemoglobin levels, and body weight, can affect the treatment efficacy of metastatic NPC. The efficacy of different chemotherapy regimens can also vary. According to the results of multiple phase II clinical studies, the combination of two or three platinum-containing first-line drugs can achieve an efficiency of 50–80%, and a median progression-free and overall survival of 5-11 and 10-14 months, respectively [21-27]. The metastatic NPC chemotherapy regimens used in this study were docetaxel + cisplatin, gemcitabine + cisplatin or cisplatin + fluorouracil + nimotuzumab. There was no difference in the efficacy between these three regimens. However, prospective randomized controlled trials of these chemotherapy regimens are limited and therefore, prospective clinical trials to compare the efficacy between chemotherapy regimens are needed. We did not observe a prognostic effect of the targeted drugs upon univariate analysis; this may be due to the small number of patients (n=14) who underwent chemotherapy in addition to targeted therapy. Therefore, this finding may not reflect the true efficacy of targeted drugs used for metastatic NPC.
There were several limitations in the present study. First, the copy number of serum Epstein-Barr virus DNA is an important prognostic factor in patients with NPC . However, only a small number of patients in this study had the pre-treatment serum Epstein-Barr virus Deoxyribonucleic acid (DNA) copy number and therefore, it was not included in the prognostic analysis of the patients.
In conclusion, the treatment of metastatic NPC remains challenging. Although the treatment has been improved, the overall prognosis of patients remains poor. Presently, systemic chemotherapy with a platinum-based regimen remains an important first-line treatment. The combined application of localized radiotherapy and systemic chemotherapy requires further investigation. We found that there was a potential of cure or long-term remission after 4–6 cycles of chemotherapy and active local treatment of metastases for patients with only bone or lung metastases who were in good general health. For patients with multiple liver metastases or multiple organ metastases who had poor general health, the median survival time was relatively short, thus the best supportive care should be provided. The findings from this study can assist clinicians in more accurately determining the prognosis of patients with metastatic NPC. Additionally, they might provide guidance on the selection of individualized treatment plans, which can prevent excessive or ineffective treatment for patients.