Nasopharyngeal cancer is a very common malignancy in Southeast Asia and southern China. At least 80% of nasopharyngeal cancer cases worldwide occur in China and Southeast Asian countries, and the incidence rate of nasopharyngeal cancer in China is the highest in the world. Most prominently in Guangdong Province, the incidence rate can reach 30/100,000, so nasopharyngeal cancer is even called “Guangdong cancer”. For early stage and locally advanced nasopharyngeal cancer patients, the standard treatment plan is simultaneous radiotherapy plus chemotherapy. However, the main reason for treatment failure of nasopharyngeal cancer is distant metastasis. The survival of patients with different metastatic sites varies greatly. Patients with simple lung and bone metastases have relatively long survival, while patients with liver metastases have the shortest survival and the worst prognosis. How to improve the treatment effect of patients with liver metastasis of nasopharyngeal carcinoma? There are several treatment methods: surgical resection combined with postoperative chemotherapy: Patients with liver metastases from nasopharyngeal carcinoma are defined as oligometastases if the number of metastases is less than 5. Oligometastasis is a transitional state between local invasion and extensive metastasis, and if the tumor location is more concentrated, hand localization can be considered for resection. The survival rates of patients with oligometastases in the liver of nasopharyngeal carcinoma after surgical resection are 85.7%, 64.2% and 40.2% at 1, 3 and 5 years, which are significantly better than those of patients with non-surgical treatment. Of course, patients still need to receive systemic chemotherapy to prevent tumor recurrence after surgery.
Systemic chemotherapy combined with ablation therapy: For patients with liver metastases of nasopharyngeal carcinoma, if the tumor is located in such a way that surgical resection is not possible, ablation of the metastases combined with systemic chemotherapy can significantly improve the local tumor control rate and prolong survival time. There is no uniform conclusion on the sequence and interval arrangement of chemotherapy and ablative treatment because there are no retrospective or prospective clinical studies for comparison. However, in the current clinical experience, it is recommended to combine local ablation in the interval of chemotherapy to treat liver metastases.
Systemic chemotherapy combined with interventional therapy For patients with liver metastases from non-oligometastatic nasopharyngeal carcinoma, systemic chemotherapy is the main treatment tool. In 2016, the GEM20110714 large phase 3 clinical study published in The Lancet demonstrated for the first time that GP (cisplatin + gemcitabine) chemotherapy regimen is significantly better than the conventional PF (cisplatin + 5-FU) regimen in the first-line treatment of metastatic nasopharyngeal carcinoma, and therefore GP regimen is now the standard first-line chemotherapy regimen for metastatic nasopharyngeal carcinoma. Therefore, GP regimen is now the first-line standard chemotherapy regimen for metastatic nasopharyngeal cancer.
For patients who fail first-line chemotherapy, hepatic artery chemoembolization (interventional therapy) may be considered. Hepatic artery chemoembolization has the advantages of high local chemotherapeutic drug concentration and low systemic adverse effects, and together with local tumor blood supply embolization, it can improve the local control rate of metastatic tumors. From clinical practice, the efficacy of interventional treatment is related to the degree of liver invasion. The smaller the number of intrahepatic lesions and the smaller the extent of invasion, the better the interventional efficacy and the longer the survival time. Patients with nodular liver metastases, where the metastases account for less than 50% of the total liver load, have better interventional outcomes than those with diffuse liver metastases.
Chemotherapy combined with targeted/immunotherapy In previous clinical studies, the efficacy of single targeted therapy for patients with recurrent or metastatic nasopharyngeal carcinoma was poor, and it was difficult for patients to achieve complete remission with an average tumor progression period of 3-4 months. In contrast, targeted combination chemotherapy can extend the overall survival of patients to 8-12 months. Therefore, patients with liver metastases from nasopharyngeal carcinoma, whether diagnosed for the first time or failing treatment, may consider combining targeted drugs during chemotherapy to improve the efficacy. The approved targeted drugs for nasopharyngeal carcinoma are cetuximab and the domestic targeted drug nitrozumab (Tykerb). An international multicenter clinical study (EXTREME) confirmed that cetuximab in combination with platinum/fluorouracil improved survival in patients with metastatic nasopharyngeal cancer. China’s 2013 version of the Chinese Expert Consensus on Nasopharyngeal Cancer also recommends the addition of cetuximab to first-line chemotherapy for patients with recurrent or metastatic nasopharyngeal cancer who are eligible. Nitrozumab is a new humanized anti-EGFR monoclonal antibody, and the results of a prospective multicenter phase II clinical study reported by ASCO in 2017 showed that PF chemotherapy regimens combined with nitrozumab for the treatment of recurrent or metastatic nasopharyngeal cancer had better recent efficacy and treatment tolerability. For patients with advanced nasopharyngeal carcinoma, genetic testing may be considered before receiving targeted therapy, and targeted therapy may be used as appropriate based on the expression of epidermal growth factor receptor (EGFR).
In addition to traditional surgical treatment, chemotherapy, ablation and interventional therapy, the emerging immunotherapy provides more treatment options for patients with advanced nasopharyngeal cancer. The application of immune checkpoint inhibitors in nasopharyngeal cancer has been a popular research topic, and multiple PD-1 antibodies have shown some therapeutic value in the first- or second-line treatment of advanced nasopharyngeal cancer.In 2018, data from a phase I clinical study of karilizumab in combination with a GP regimen showed that patients in the treatment group had an overall effective rate (ORR) of 91% and a disease control rate (DCR) of 100%. No patient stopped using PD-1 antibody due to side effects. The efficacy of karilizumab in advanced nasopharyngeal carcinoma, an immune checkpoint inhibitor developed independently in China, will need to be confirmed by the results of future large phase 3 clinical studies.
Conclusion Overall, the comprehensive treatment of nasopharyngeal carcinoma liver metastases is currently centered on systemic chemotherapy with individualized selection according to the patient’s specific condition, combined with surgery, ablation, interventional therapy and targeted immunotherapy to improve the patient’s survival.