Liver metastasis is a common occurrence at initial diagnosis in patients with metastatic NPC. The survival time in these patients is poor, ranging between 13.0 and 17.0 months [8–10]. Similar to these reports, our analyses gave a median survival time of 19.0 months, and a 3-year OS rate of 14.1%, which is lower than those reported for lung or bone metastasis [11, 12].
The benefits of systemic chemotherapy have been demonstrated in many studies [14–18]. Platinum-based combination treatment with two or three drugs achieves high response rates and is the most widely used regimen . In this study, the patients who received chemotherapy had a median survival time of 20.0 months, compared to 9.0 months in patients who refused treatment.
In cases of metastatic NPC where chemotherapy is the only curative option, it is important that patients undergoing platinum-based combination therapy receive a sufficient number of cycles. A retrospective study involving 20 long-term disease-free survivors with metastatic NPC showed that approximately six cycles of chemotherapy were required . Wang et al. also found that patients who received six cycles of chemotherapy survived longer than those receiving fewer cycles. Furthermore, they showed that the number of chemotherapy cycles was an independent prognostic factor in metastatic NPC . Our results, based on univariate and multivariate analyses, were consistent with both these reports, however due to the retrospective nature of our study, further confirmation is required.
The application of radiotherapy to the primary tumor in NPC patients with synchronous liver metastasis remains controversial. It is generally considered unnecessary due to their short life expectancy and serious late complications. However, due to improvements in techniques, several studies have demonstrated that local control of primary tumors through radiotherapy can improve quality of life and contribute to prolonged survival. Yeh et al. showed that the 2-year OS rate in patients with metastatic NPC at diagnosis was 24.0% when they received radiotherapy alone, compared to 10% in those who received chemotherapy alone . They also showed that local control of the primary tumor reduced necrosis, bleeding, nasal obstruction and severe headaches. Our study supported these findings by showing improved survival rates in patients who responded to chemotherapy of the metastatic lesions when radiotherapy of the primary tumor was administered. Taken together, these findings indicate that better local control may help reduce the tumor burden and lower the risks caused by progression or recurrence in NPC.
Local therapy of metastatic lesions may also prolong survival. Although local therapy is widely applied in patients with liver metastasis from colorectal cancer [19, 20], its application in metastatic NPC remains limited. Pan et al. reported that the median survival of 11 patients with 1–3 metastatic lesions receiving treatment with RFA was 48.1 months, which was higher than those not receiving RFA . Furthermore, procedure-related complications were infrequent. The treatment regimens for local therapy of liver metastases analyzed in this study included RFA, interventional embolization and liver radiotherapy. The median survival for all three modalities was 23.0 months and included three long-term disease-free survivors. RFA was found to be more effective than both interventional embolization and liver radiotherapy, giving a median survival time of 32.0 months compared to 9.0 months; however, this difference may be related to other factors between the patients. Patient with 1-3 metastatic lesions were found to benefit the most from RFA, with a median survival of 36.0 months compared to 21.0 months for those not undergoing RFA. Therefore, local therapy to metastatic liver lesions, particularly with RFA, should be considered in patients with NPC who have ≤3 lesions to further improve their survival when the primary tumor and metastatic diseases are stable.
Patients’ response to chemotherapy was found to be a significant prognostic factor. The overall response rate was 76.4% and was associated with performance status, LDH level, number of metastatic lesions, presence of extrahepatic metastasis and number of chemotherapy cycles, suggesting that these factors could be potential predictors of treatment response. Patients with LDH >245 IU/L, multiple organ metastasis and >3 liver lesions had lower rates of CR or PR to chemotherapy. In clinical practice, the response of metastatic lesions to chemotherapy is a key consideration in the choice of treatment; therefore, patients with CR or PR were recommended for radiotherapy of the primary tumor as this could significantly improve survival.
LDH is a glycolytic enzyme which reversibly catalyzes pyruvate to lactic acid under anaerobic conditions. Elevated levels of LDH are considered a negative prognostic factor in many solid tumors, including advanced NPC, and have been associated with large tumor burden, tumor extension and high risk of metastasis [21–25]. Serum LDH levels twice normal levels are rarely seen in loco-regional disease but are commonly observed in NPC patients with liver metastasis or multiple organ metastases. As such, they have been described as a negative prognostic factor . Studies have found that patients with advanced NPC and elevated baseline LDH levels were more likely to develop liver metastasis following treatment , and elevated LDH levels were reported in over 55.0% of patients with metastatic NPC, with hazard ratios up to 1.8 . In our study, >60.0% of patients had elevated levels of LDH; furthermore, these patients had significantly poorer 3-year OS rates compared to those without elevated LDH levels (9.3% compared to 22.6%). These pretreatment serum levels of LDH may be a potential prognostic indicator.
In conclusion, we identified five independent prognostic factors in NPC patients who initially presented with liver metastasis. These included pretreatment performance status, LDH level, radiotherapy of the primary tumor, the number of chemotherapy cycles and response to chemotherapy. Although survival rates in these patients remains poor, our findings suggest that selected patients may achieve improved survival by undergoing comprehensive treatment, including six or more systemic chemotherapy cycles and radiotherapy of the primary tumor. The application of local therapy to metastatic lesions, in particular by RFA, may also prolong survival.