Treatment strategy for de novo metastatic nasopharyngeal carcinoma: a literature review
Review Article

Treatment strategy for de novo metastatic nasopharyngeal carcinoma: a literature review

Qin Liu1, Jishi Li2,3, Wai Tong Ng1,2,3, Anne W. M. Lee2,3

1Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 2Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; 3Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China

Contributions: (I) Conception and design: AWM Lee, WT Ng; (II) Administrative support: AWM Lee; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Q Liu, J Li; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Anne W. M. Lee, MD. Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, No. 1, Haiyuan 1st Road, Futian District, Shenzhen 518053, China; Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Email:

Background and Objective: Nasopharyngeal carcinoma (NPC) with de novo distant metastasis (M1) is classified as stage IVB in the 8th edition of the staging system jointly adopted by the American Joint Committee on Cancer and the International Union against Cancer Control. Patients with M1 disease generally have a relatively short life expectancy. This review discusses the personalized and intensified treatment strategies for de novo metastatic NPC.

Methods: A literature search was conducted on PubMed to identify peer-reviewed publications on subdivisions of M1 disease and treatment of de novo metastatic NPC. and Chinese Clinical Trial Register were searched to identify ongoing clinical trials evaluating systemic or local therapy of previously untreated metastatic NPC.

Key Content and Findings: M1 encompasses a diverse group of diseases. Several important factors, including tumor burden, EBV-DNA levels, location of involvement, the number of metastasis, and treatment strategies, influence the prognosis of NPC patients. Researchers have attempted to define M1 subcategorization to reflect the underlying risk profile and tailor personalized treatment. Recent advancements have brought new hope for this otherwise incurable condition. In the era of immunotherapy, checkpoint inhibitors have become the first-line systemic treatment for metastatic NPC in JUPITER-02, CAPTAIN-1st, and RATIONALE-309. Additionally, the value of radical locoregional radiation therapy and ablative treatment to distant metastatic sites should not be overlooked in patients with de novo metastatic diseases. Locoregional radiation with concurrent chemotherapy, maintenance chemotherapy, and radical local treatment to metastatic sites are emerging as potential treatment options.

Conclusions: Given the diversity of metastatic NPC, a multimodality approach incorporating chemotherapy, immunotherapy, locoregional radiation and ablative treatment to metastatic sites has been shown to improve overall control. Further research is needed to determine the efficacy and optimal duration of maintenance therapy.

Keywords: Metastatic nasopharyngeal carcinoma; radiation therapy; chemotherapy; immunotherapy

Submitted Apr 12, 2023. Accepted for publication Aug 07, 2023. Published online Aug 24, 2023.

doi: 10.21037/cco-23-32


Nasopharyngeal carcinoma (NPC) arises from the epithelial lining of the nasopharynx. According to GLOBOCAN 2020, there were 133,354 new cases and 80,008 cancer deaths globally (1). Although NPC only accounts for 0.7% of all new cancer cases diagnosed globally, it has a skewed geographic distribution, with more than 70% of new cases diagnosed in East and Southeast Asia (2). Historically, approximately 4–6% of patients present with de novo metastasis at diagnosis (3,4). With more sensitive radiological examinations, such as [18F] fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT), 12.9–14.8% of patients were found to have de novo metastatic NPC (5,6).

With contemporary state-of-art treatment, the majority of NPC patients could achieve good outcomes. However, patients with metastatic (M1) disease have a significantly worse prognosis than those without distant metastases at presentation. The 5-year disease-specific survival rate for patients with M1 disease was estimated to be 20%, while the 5-year survival rate for those without metastases was greater than 70% (4). Chemotherapy using gemcitabine and cisplatin (GP) combination was the standard of care in the first line setting before the era of immunotherapy (7). Emerging evidence supports the role of immunotherapy and locoregional radiotherapy in patients with de novo metastatic nasopharyngeal (8-11). However, metastatic NPC is a complex and heterogeneous disease. The prognosis of patients with metastatic NPC differs considerably.

In this article, we discuss the current literature and clinical trials on the risk stratification and treatment of metastatic NPC, focusing on intensifying systemic therapy with immunotherapy and radiotherapy. We present this article in accordance with the Narrative Review reporting checklist (available at


A literature review was conducted to identify studies on the subcategorization and treatment of newly diagnosed metastatic NPC. PubMed, and the Chinese Clinical Trial Register (ChiCTR) were searched separately using combinations of keywords. The PubMed search included the terms “nasopharyngeal carcinoma”, “metastatic nasopharyngeal carcinoma”, “metastasis”, “subdivision”, “locoregional radiotherapy” and “local treatment”. The and ChiCTR searches used the terms “metastatic NPC”, “radiotherapy”, and “interventional study”. Trials that did not include patients with previously untreated de novo metastatic NPC were excluded in the analysis. Table 1 provides a summary of the search strategy.

Table 1

Search strategy summary for literature included in the review

Items Specification
Date of search 10 March 2023
Databases and other sources searched PubMed,, Chinese Clinical Trial Register
Search terms used Search: “nasopharyngeal carcinoma” AND “metastasis” AND “subdivision”, Filters: Filters: Full text, from 2000–2023
Search: “metastatic nasopharyngeal carcinoma”, Filters: Clinical Trial, Randomized Controlled Trial, from 2000–2023
Search: “metastatic nasopharyngeal carcinoma” AND “metastasis” AND “locoregional radiotherapy” OR “local treatment”, Filters: Full text, from 2000–2023
Keywords: “metastatic nasopharyngeal carcinoma”, “radiotherapy”, “interventional study”
Timeframe January 2000 to March 2023
Inclusion and exclusion criteria Prospective and retrospective trials on subcategorization of metastatic NPC and treatment of newly diagnosed metastatic NPC were included. Studies involving only pretreated patients were excluded. Articles in languages other than English were excluded
Selection process The authors conducted literature search and reviewed the selected literature
Any additional considerations Articles were also identified by examining references of pertinent publications and prior knowledge of key studies

Recommendations on management of de novo metastatic NPC by national and international guidelines

There are variations in the recommendation by different major guidelines. The Chinese Society of Clinical Oncology (CSCO) recommends GP with or without camrelizumab or toripalimab (evidence 1A) and local radiotherapy (evidence 1A) as first-line treatment for recurrent and metastatic NPC (12). The National Comprehensive Cancer Network (NCCN) guideline recommends induction chemotherapy followed by radiotherapy (RT) with or without chemotherapy or systemic therapy for oligometastatic disease (13). GP chemotherapy is the preferred first-line regime for patients with widely disseminated disease and good performance status. NCCN recently added GP plus a programmed cell death 1 (PD-1) inhibitor (pembrolizumab or nivolumab) as an “other recommended regimen” for the first-line treatment of recurrent and metastatic NPC, even though no phase 3 data supported the use of these two immune-checkpoint inhibitors (13). Definitive locoregional RT (LRRT) can be considered following a good response to systemic therapy. The European Society of Medical Oncology (ESMO) guideline recommends chemotherapy followed by radiation to the primary tumor and involved lymph nodes for newly diagnosed metastatic disease (14). Consideration should be given to adding immunotherapy to systemic chemotherapy and using it as maintenance therapy as first-line therapy (15).

Controversy about the subcategorization of M1 disease

Many studies have attempted to subcategorize metastatic NPC (Table 2). The prognoses of patients with metastatic NPC depend upon disease burden, locations of involvement, and timing of metastasis. Patients with oligometastatic disease had significantly better clinical outcomes than patients with widely disseminated NPC (28). The Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) level, a surrogate marker of the tumor load, also plays an important role in predicting the prognosis of patients with distant metastasis (29). Elevated levels of plasma EBV-DNA, along with certain clinical parameters such as the number of metastatic lesions, have been found to predict poor prognosis in patients (21-23,25-27). On the other hand, faster clearance rates of plasma EBV-DNA are associated with better treatment response and patient outcomes (30). However, it should be noted that a significant proportion (12% to 29%) of confirmed NPC cases have undetectable EBV-DNA (31), and there is no universal cutoff value for patient segregation based on plasma EBV-DNA levels. As a result, incorporating plasma EBV-DNA levels into the TNM staging system poses a challenge. Furthermore, patients with lung metastasis alone generally have a more favorable prognosis compared to those with metastasis in other organs, as evidenced by the Hong Kong NPC Study Group study, showing a median overall survival (OS) of 3.9 years for patients with metastases to lung versus ≤1.9 years to other sites, respectively (32). A similar observation was recently reported by Chee et al., patients with lung metastases only had the best prognosis with an OS of 51.1 months. In contrast, those with liver or abdominal metastases had the worst clinical outcomes, with an OS of 15.4 and 8.8 months, respectively (28). Regarding the timing of M1 disease, patients with synchronous metastases at presentation had better OS than those with metachronous metastases (33). In summary, most studies proposed an M1 subcategorization system based on the number of metastatic lesions and sites, liver involvement, and EBV-DNA as key prognosticators. Given the variety of definitions proposed, no standard classification is concluded. Nevertheless, it highlighted the importance of characterizing M1 patients according to the underlying risk profile and providing individualized treatment strategies.

Table 2

Summary of proposed M1 subcategorizations

Author Year Proposed subdivision No. patients Survival outcome
Shen et al. (16) 2015 M1a: single extra-liver metastasis 505 Median OS:
M1a: 46 months
M1b: 25.1 months
M1c: 18.3 months
3-year OS rates:
M1a: 62.1%; M1b: 36.1%; M1c: 17.9%; P=0.001
M1b: single liver metastasis or multiple extra-liver metastases
M1c: multiple liver metastases
Jiang et al. (17) 2016 The classifier uses three clinical parameters and seven hematological markers to classify M1a and M1b 347 2-year OS rates:
M1a: 71.4%; M1b: 18.8%, P<0.001
Shen et al. (18) 2016 M1a: a solitary lesion confined in a single organ or site 1,172 M1b vs. M1a:
HR (95% CI): 2.28 (1.71, 3.05)
M1c vs. M1a:
HR (95% CI): 3.65 (2.75, 4.85)
M1b: multiple lesions confined in a single organ or site
M1c: multiple metastatic sites
Tian et al. (19) 2016 M1a: single-organ metastases or oligometastases 263 5-year OS rates:
M1a: 38.7%; M1b: 7.0%, P<0.01
M1b: multi-organ metastases or ≥6 lesions
Zou et al. (20) 2017 M1a: oligometastases with no hepatic metastasis Training: 462 3-year OS rates:
M1a: 54.5% to 72.8%
M1b: 34.3% to 41.6%
M1c: 22.6.0% to 23.6%
M1b: multiple lesions with no hepatic metastasis Internal validation: 272
M1c: presence of liver lesions External validation: 243
Sun et al. (21) 2019 Low risk: ≤ 3 lesions with undetectable EBV DNA after PCT 226 3-year OS rates:
Low risk: 80%
Intermediate risk: 54.9%
High risk: 37.8%
5-year OS rates:
Low risk: 66.7%
Intermediate risk: 41.3%
High risk: 11.6%
Intermediate risk: >3 lesions and undetectable EBV DNA after PCT; or ≤3 lesions and detectable EBV DNA after PCT
High risk: >3 lesions and detectable EBV DNA after PCT
Zheng et al. (22) 2020 M1a: oligometastases with low EBV DNA Training: 613 3-year OS rates:
M1a: 49.9%; M1b: 33.4%
M1c: 22.6%; M1d: 6.7%
M1b: multiple metastatic lesions with low EBV DNA Internal validation: 204
M1c: high EBV DNA without liver involvement
M1d: high EBV DNA with liver involvement
Yang et al. (23) 2021 Low risk: single organ involvement with ≤5 lesions and EBV DNA ≤25,000 copies/mL 498 OS differences with or without LRRT
Low-risk subgroup: P=0.039
Intermediate-risk subgroup: P=0.010
High-risk subgroup: P=0.076
Intermediate risk: single organ involvement with≤5 lesions and EBV DNA >25,000 copies/mL
High risk: >5 lesions or multi-organ involvement or both
Chan et al. (24) 2022 M1a: no co-existing liver-bone metastases Training: 120 Median OS in training cohort:
M1a: 39.5 months
M1b: 23.7 months, P=0.004
Median OS in validation cohort:
M1a: 47.7 months
M1b: 16.0 months, P=0.008
M1b: co-existing liver-bone metastases Validation: 63
Chan et al. (25) 2022 Set 1: 69 Median OS in set 1:
M1a: 28.1 months
M1b: 19.2 months, P=0.023
Median OS in set 2:
M1a: 44.2 months
M1b: 19.7 months, P<0.001
M1a: no co-existing liver-bone metastases
M1b: co-existing liver-bone metastases
Set 2:
M1a: EBV DNA ≤2,500 copies/mL
M1b: EBV DNA >2,500 copies/mL
Qiu et al. (26) 2022 M1a: low risk, low PPS and absence of hepatic involvement 586 3-year OS rates:
M1a: 77% vs. 55%, P=0.00033
M1b: 50% vs. 48%, P=0.103
M1c: 20% vs. 22%, P=0.224
M1b: intermediate risk, low PPS and presence of hepatic involvement, high PPS and low EBV DNA
M1c: high risk, high PPS with high EBV DNA
Yao et al. (27) 2023 Low risk: ≤4 lesions in organs other than the liver Training: 264; validation: 298 3-year OS rates:
Low risk: 80.4%
Intermediate risk: 42.0%
High risk: 20.4%
Intermediate risk: ≤4 lesions involving the liver or >4 lesions with EBV-DNA < 62,000 copies/mL
High risk: >4 lesions with EBV-DNA >62,000 copies/mL

OS, overall survival; HR, hazard ratio; LRRT, locoregional radiotherapy; EBV-DNA, Epstein–Barr virus DNA; PCT, palliative chemotherapy; PPS, PET-CT parameter score.

The evolution of 1st line systemic therapy for de novo metastatic NPC

NPC is a chemo-sensitive tumor; however, head-to-head trials in patients with metastatic NPC were lacking in the past, and most chemotherapy regimens were based on phase 2 trials. The most frequently used regimen was cisplatin plus continuous intravenous infusion of fluorouracil (PF), with an overall response rate (ORR) of 76% (34). Other active agents included taxane, gemcitabine, capecitabine, vinorelbine, and some older drugs, such as bleomycin, epirubicin, and cyclophosphamide (35-40).

The preferred first-line chemotherapy regimen recommended by NCCN guideline, was based on a phase III randomized controlled trial demonstrated that GP was superior to the traditional regimen of PF in 2016 (7). Patients who received GP had longer progression-free survival (PFS) and OS than those who received PF. After a median follow-up time of over 60 months, the median OS was 22.1 months with GP versus 18.6 months with PF. The 5-year OS rate in the GP arm was more than double that of the PF arm (19.2% vs. 7.8%) (41). Two recent randomized phase III trials (JUPITER-02 and CAPTAIN-1st) further demonstrated an improvement in PFS when anti-PD-1 immune checkpoint inhibitors (toripalimab or camrelizumab) were added to first-line treatment with GP, followed by maintenance immunotherapy (8,9). Key results are summarized in Table 3. Adding toripalimab or camrelizumab to GP as the first-line therapy for metastatic NPC reduced the risk of cancer progression or death by nearly half, as evidenced by hazard ratios (HRs) of 0.52 and 0.54, respectively. Pending full publication of RATIONALE-309, tislelizumab is the third PD-1 inhibitor to show PFS benefit when combined with GP (42). This study also provided evidence on optimal treatment-sequencing. PFS after next-line treatment (PFS2) was not reached at the time of data cutoff for tislelizumab plus chemotherapy versus 13.9 months for placebo plus chemotherapy with a 62% reduction in risk of disease progression on first subsequent therapy or death (10). Although the OS data from these three phase 3 trials are not yet mature, the PFS, as a surrogate for survival, provided an early indication of survival benefit. We recommend adding a PD-1 inhibitor to chemotherapy every 3 weeks for up to six cycles, followed by maintenance therapy with a PD-1 inhibitor as first-line treatment for eligible patients with de novo metastatic NPC. Several phase 3 clinical trials are ongoing evaluating the efficacy and safety of other anti-PD1 and anti-CTLA4 monoclonal antibodies (Table 4).

Table 3

Key randomized phase III trials evaluating 1st line systemic therapy for metastatic nasopharyngeal carcinoma

Trial Year Regime No. patients Survival outcome
GEM20110714 (7,41) 2016, 2021 Gemcitabine + cisplatin vs. fluorouracil + cisplatin 362 Median PFS: 7.0 vs. 5.6 months
HR (95% CI), 0.55 (0.44–0.68), P<0.0001
Median OS: 22.1 vs. 18.6 months
1-year OS rate: 79.9% vs. 71.8%
3-year OS rate: 31.0% vs. 20.4%
5-year OS rate: 19.2% vs. 7.8%
JUPITER-02 (8) 2021 Toripalimab + gemcitabine + cisplatin vs. Gemcitabine + cisplatin 289 Median PFS: 11.7 vs. 8.0 months
HR (95% CI), 0.52 (0.36–0.74), P=0.0003
CAPTAIN-1st (9) 2021 Camrelizumab + gemcitabine + cisplatin vs. gemcitabine + cisplatin 263 Median PFS: 9.7 vs. 6.9 months
HR (95% CI), 0.54 (0.39–0.76), P=0.0002
RATIONALE-309 (10,42) 2021 Tislelizumab + gemcitabine + cisplatin vs. gemcitabine + cisplatin 263 Median PFS: 9.6 vs. 7.4 months, P<0.0001
HR (95% CI), 0.50 (0.37–0.68)
Median PFS2 and OS are not reached
PFS2: HR (95% CI), 0.38 (0.25–0.58)
OS: HR (95% CI), 0.60 (0.35–1.01)

PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival.

Table 4

Ongoing phase III trials evaluating 1st line systemic therapy for de novo metastatic nasopharyngeal carcinoma

Trial Enrollment Treatment
NCT05294172 291 KL-A167 Injection + cisplatin + gemcitabine vs. cisplatin + gemcitabine
NCT04974398 298 Penpulimab (AK105) + cisplatin + gemcitabine vs. cisplatin + gemcitabine
NCT04458909 316 Nivolumab + cisplatin or carboplatin + gemcitabine vs. cisplatin or carboplatin + gemcitabine
NCT05576272 460 QL1706 + gemcitabine + cisplatin vs. camrelizumab + gemcitabine + cisplatin
NCT04890522 622 5-Fluorouracil + toripalimab (JS001) + cisplatin vs. gemcitabine + toripalimab (JS001) + cisplatin
NCT03924986 256 Tislelizumab + cisplatin + gemcitabine vs. cisplatin + gemcitabine
NCT02633176 120 Cetuximab + cisplatin + docetaxel vs. cisplatin + docetaxel
NCT05854849 244 Gemcitabine + Camrelizumab + apatinib vs. gemcitabine + camrelizumab + cisplatin
NCT03581786 289 Toripalimab + cisplatin + gemcitabine vs. cisplatin + gemcitabine

Value of adding “radical” locoregional RT to chemotherapy

The natural course of patients with metastatic NPC is commonly perceived as governed by distant disease, and the primary treatment has been palliative systemic therapy. Increasing evidence suggests that LRRT contributes to improved clinical outcomes in patients who responded well to chemotherapy. To date, one phase III randomized controlled trial has evaluated the efficacy and safety of adding LRRT to backbone chemotherapy in de novo metastatic NPC (11). Patients eligible for LRRT were those who achieved partial response (PR) or complete response (CR) after 3 cycles of PF. Additional LRRT reduced the risk of progression by 64% and the risk of death by 58% at 2 years. The majority of patients (69.8%) included in this study had more than 3 metastatic lesions. In addition to the anticipated decrease in locoregional relapses, the rate of distant metastatic recurrences was reduced following LRRT (54.0% vs. 68.3%). The study delivered “radical” doses of 70 Gy to the primary tumor and the retropharyngeal lymph nodes, and 60–66 Gy to the cervical lymph nodes. 16.4% of patients had a CR on completion of radiotherapy. Notably, no survival benefit was observed in patients who are not chemo-sensitive, including those who progressed between 3–6 cycles despite initial response.

Several retrospective trials have reached similar conclusions (Table 5). In addition, it was demonstrated that patients who received a dose greater than 65 Gy had better survival outcomes compared to those who received less than 65 Gy (43). No survival benefit was seen with an RT dose of less than 50 Gy (45). Patients with a single organ metastasis are anticipated to survive longer than those with multiple organ metastases. Yet, patients with multiple metastases also benefited from the addition of LRRT. In contrast, those with liver involvement, regardless of metastatic lesions, did not have a substantial improvement in OS with additional LRRT (20). Consistent with previous findings, the absence of liver involvement and oligometastases were strong predictors of survival (48). Regarding treatment sequencing, concurrent chemoradiation or induction chemotherapy followed by RT offered significant survival advantages over chemotherapy alone (HR 0.629 and 0.573, respectively) (45). RT followed by adjuvant chemotherapy had no survival advantage over chemotherapy alone (45). The patients who underwent LRRT plus systemic chemotherapy exhibited the highest survival rate compared to those who underwent LRRT or systemic therapy alone (44). The 5-year survival rate improved by about 17% with induction chemotherapy following concurrent chemoradiation compared to induction chemotherapy following RT alone (48). The 5-year OS rate improved by nearly 20% in patients receiving 4–6 cycles compared to those receiving only 1–3 cycles of chemotherapy (48). However, chemotherapy over 6 cycles did not prolong survival (44). Therefore, we recommend the use of 4–6 cycles of induction systemic therapy followed by LRRT with a “radical” dose of 66–70 Gy, preferably with concurrent chemotherapy if patients’ tolerance allowed, in those who responded well to induction chemotherapy (undetectable EBV DNA or CR/PR) or those with oligometastases.

Table 5

Retrospective studies evaluating survival benefits by adding locoregional RT/CRT to chemotherapy

Author Duration Treatment No. patients Survival outcome
Lin et al. (43) 1995–2002 Chemotherapy + local regional RT + local treatment to metastatic lesions 105 Median OS: 25 months
2-year OS rate: 50%
5-year OS rate: 17%
Chen et al. (44) 2001–2009 Chemotherapy + local regional RT vs. local regional RT alone 408 Median OS: 34 vs. 17.7 months, P<0.001
Rusthoven et al. (45) 2004–2013 Chemotherapy + local regional RT vs. chemotherapy alone 718 Median OS: 21.4 vs. 15.5 months
5-year OS rate: 28% vs. 10%
HR (95% CI), 0.68 (0.55–0.84), P<0.001
Verma et al. (46) Chemotherapy + local regional RT vs. chemotherapy alone 555 Median OS: 25.8 vs. 13.7 months, P<0.001
Zou et al. (20) 2000–2010 Chemotherapy + local regional RT vs. chemotherapy alone Training: 462 M1b: HR (95% CI), 0.61 (0.33–0.78), P=0.005
Internal validation: 272 M1c: HR (95% CI), 1.81 (0.82–4.03), P=0.144
External validation: 243
Du et al. (47) 2008–2018 Chemotherapy + local regional RT 118 5-year PFS: 34.2%
5-year OS: 44%
5-year DMFS: 41.1%
5-year LRFS: 82.6%
Zheng et al. (48) 2000–2017 Chemotherapy + CCRT vs. chemotherapy + RT 746 5-year OS rate: 55.7% vs. 39.0%, P=0.034
Median DPFS: 29.4 vs. 18.7 months, P=0.052

RT, radiation therapy; CRT, chemoradiation; OS, overall survival; HR, hazard ratio; CI, confidence interval; PFS, progression free survival; DMFS, distant metastasis-free survival; LRFS, local, regional recurrence free survival; CCRT, concurrent chemoradiation; DPFS, distant progression-free survival.

Value of local treatment to metastatic sites

The number of metastases reflects the biological progression of the tumor. Curative treatments have been successfully contemplated in patients with metastatic disease that is not widespread (49). Emerging evidence has supported the value of local treatment, usually by ablative methods, to metastatic sites in oligometastatic diseases, such as non-small cell lung cancer and colon cancer (50,51). A randomized open-label phase 2 study assessed the value of stereotactic ablative radiotherapy (SABR) in patients with a controlled primary tumor and oligometastases (52). Median overall survival time was longer with SABR (41 vs. 28 months; P=0.090). The 5-year OS rate reached 42.3% in the SABR group versus 17.7% in the control group (P=0.006). The 5-year PFS rate remained not reached in the SABR arm after a median follow-up of 51 months (53). This study had a high proportion of breast, colorectal, lung, and prostate cancers. Nevertheless, this work heralds the advent of a new therapy paradigm that could shift the clinical goal from control to cure in patients with metastatic disease.

To date, there is limited but promising evidence supporting the use of local treatment for metastatic sites for NPC. Table 6 summarizes the retrospective trials evaluating the local treatment of metastatic lesions. In those with less than 5 pulmonary lesions, radiofrequency ablation (RFA) and surgical resection doubled the median OS compared to no local treatment (56). The addition of RT to chemotherapy increased the local control rate of distant metastases by 34.2%, while surgery plus chemotherapy increased it by 42.6% (54). Although liver metastases generally have a poor prognosis, local treatment of liver lesions following radical treatment of the primary tumor increased median OS from 16.5 to 48.1 months (55). Moreover, combined RFA and chemotherapy reduced the risk of death and progression in NPC patients with oligometastasis in the liver by 47% and 40%, respectively (58). In another report, 7 out of 15 patients who underwent partial hepatectomy achieved long-term survival over 3 years (57). Furthermore, survival benefits were not limited to patients with oligometastases, as patients with greater than 5 metastases or greater than 2 metastatic sites might still benefit from high-dose RT (60).

Table 6

Studies evaluating local treatment to metastases in addition to systemic chemotherapy

Author Year Study Treatment No. Survival outcome
Ma et al. (54) 1994–2008 Retrospective Local RT to lung metastases ± chemotherapy vs. operation ± chemotherapy vs. chemotherapy alone 105 Local control rate:
53.8% in chemotherapy cohort
88.0% in RT cohort
96.4% in operation cohort, P<0.01
Pan et al. (55) 2000–2008 Retrospective RFA of liver metastases vs. no RFA 376 Median OS:
48.1 vs. 16.5. months, P=0.016
Pan et al. (56) 2000–2009 Retrospective RFA to lung metastases vs. no RFA 480 Median OS:
77.1 vs. 32.4 months, P=0.009
Huang et al. (57) 1993–2010 Retrospective Partial hepatectomy vs. TACE 30 Median OS: 45.2 vs. 14.1 months
1-year OS: 85.7% vs. 53.3%
3-year OS: 64.2% vs. 26.6%
5-year OS: 40.2% vs. 20%, P=0.039
Median PFS: 21.2 vs. 4.2 months
1-year PFS: 70% vs. 27%
3-year PFS: 53% vs. 7%
5-year PFS: 18% vs. 0%, P=0.007
Li et al. (58) 2003–2011 Retrospective RFA of liver metastases + chemotherapy vs. chemotherapy alone 328 OS: HR (95% CI), 0.53 (0.30–0.93), P=0.025
PFS: HR (95% CI), 0.60 (0.36–0.97), P=0.037
Li et al. (59) 2002–2018 Retrospective Palliative vs. radical RT to metastatic bone 300 OS: HR (95% CI), 2.60 (1.40–4.82), P=0.003
PFS: HR (95% CI), 1.57 (1.10–2.24), P=0.013
In-situ bone RFS: HR (95% CI), 3.46 (1.57–7.66), P=0.002
Liao et al. (60) 2010–2017 Retrospective Chemotherapy + local treatment to metastatic lesions vs. chemotherapy alone 147 Entire cohort:
Median OS: 71.7 vs. 16.2 months
3-year OS rate: 55.4% vs. 25.9%, P<0.001
PSM cohort:
Median OS: 55.6 vs. 17.6 months
3-year OS rate: 50.6% vs. 32.55, P=0.011
Lin et al. (61) 2007–2017 Retrospective Chemotherapy + LRRT + local RT vs. chemotherapy + LRRT 131 Median OS: 83 vs. 45 months
Median PFS: 60 vs. 36.5 months, P>0.05

RT, radiation therapy; RFA, radiofrequency ablation; TACE, transcatheter hepatic artery chemoembolization; HR, hazard ratio; CI, confidence interval; LRRT, loc-regional radiation therapy; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; RFS, relapse-free survival; PSM, propensity score matching.

Regarding the optimal radiation dose in treating distant metastases, patients treated with an equivalent dose at 2 Gy (EQD2) of ≥60 Gy had longer OS compared to those with EQD2 <60 Gy (59,60). A fractionated dose of ≤2 Gy increased the bone relapse-free survival rate (88.5% vs. 81.3%, P=0.026). For patients with sclerotic bone metastases, radical irradiation substantially reduced the incidence of in-situ relapse, but not for those with osteolytic lesions or soft tissue involvement (59). Given the emerging role of ablative treatment, especially SBRT, in oligometastatic disease in other cancers, there are many ongoing trials studying the combination of systemic therapy and local ablative treatment in metastatic NPC (Table 7).

Table 7

Ongoing trials

Trial Phase Enrollment Treatment
NCT05417139 II 43 Sintilimab + GP + LRRT
NCT05385926 II 34 Toripalimab + GP + RT
NCT04351282 II 43 Chemotherapy ± immunotherapy + LRRT + SBRT for oligometastatic lesions
NCT05520814 II 50 Immunotherapy + RT for metastatic lesions
NCT05431764 II 38 Camrelizumab + LRRT + SBRT for all oligometastatic lesions
NCT03129412 II 64 Chemotherapy + LRRT + local treatments for oligometastatic lesions
NCT04517214 II 126 Toripalimab + GP + LRRT + maintenance toripalimab and capecitabine
NCT05652192 II 37 Tislelizumab + chemotherapy + LRRT+ SBRT for metastatic lesions
NCT04398056 II 22 Toripalimab + chemotherapy + LRRT
NCT04421469 II 39 Triprilimab + nedaplatin f + local treatment of metastatic lesions
ChiCTR2100046735  II 118 Carrelizumab + GP + LRRT
ChiCTR2100045190  II 32 GP + anlotinib + toripalimab + SBRT

GP, gemcitabine plus cisplatin; LRRT, locoregional radiotherapy; RT, radiotherapy; SBRT, stereotactic body radiation therapy.

As M1 disease can present in a variety of ways, there is currently no available research regarding the optimal timing of local treatment for distant metastases. Our typical strategy is to offer “upfront” ablative treatment either before or after 1–2 cycles of induction to patients with small oligometastasis, particularly solitary lesions in the liver or lung. This approach helps to prevent difficulties in locating completely regressed lesions after intensive induction therapy. For patients with larger distant lesions (e.g., >5 cm), a "deferred" approach is preferred to allow for downsizing of lesions through induction therapy. In this scenario, regular radiological examinations are necessary.

Other treatment strategies

A retrospective study of 64 patients with de novo metastatic NPC who underwent LRRT showed that capecitabine maintenance therapy improved OS for patients with baseline EBV DNA ≤30,000 copies/mL (62). A phase 3 randomized clinical trial recently evaluated this maintenance strategy and found an impressive survival benefit in the capecitabine arm, with a PFS of 35.9 months (63). However, before adopting capecitabine maintenance as the new standard of care, several considerations were suggested (64). First, the trial used paclitaxel, cisplatin, and capecitabine (TPC) as induction chemotherapy, which is not a commonly used first-line regimen. Second, the median PFS in this trial was considerably longer than earlier data reported on capecitabine (65) and immune checkpoint inhibitors (8-10), and it is uncertain whether this difference is due to TPC sensitization. Furthermore, the optimal dose of oral capecitabine needs to be explored, and as the number of first-line therapeutic options increases, treatment sequencing may become crucial. Mature OS data is needed to compare maintenance use of capecitabine with drug holiday and later rechallenge of chemotherapy. Further research is also warranted to assess the value of adding capecitabine to PD-1 inhibitor maintenance, especially when patients were initially treated with GP and a PD-1 inhibitor.

Recommendation on treatment strategy for de novo metastatic NPC

Treatment for de novo metastatic NPC should be individualized. Figure 1 depicts a summary of treatment recommendations. For patients with oligometastases, upfront ablative treatment of metastatic sites should be considered before systemic treatment, whenever possible. Chemotherapy and immunotherapy, followed by radical locoregional RT with concurrent cisplatin are recommended. For patients with widespread metastases, systemic therapy with chemotherapy and immunotherapy should be offered in eligible patients as first-line treatment. High dose locoregional RT with concurrent chemotherapy and local ablative treatment to distant metastases are recommended in those who achieve completed or PR after systemic treatment. Aggressive treatment with radiotherapy is not recommended in those who respond poorly to first-line systemic therapy. Maintenance therapy with checkpoint inhibitor or capecitabine may be considered for both groups.

Figure 1 Summary of recommendations on treatment strategy for de novo metastatic NPC. NPC, nasopharyngeal carcinoma; PD-1, programmed cell death 1; RT, radiotherapy.

Strengths and limitations

In this review, the risk stratification of metastatic NPC is examined, and a summary of research on systemic and local therapies, including radical locoregional radiotherapy to primary cancers and cervical nodes, as well as aggressive local ablative therapy to metastatic sites is presented. It highlights the importance of risk stratification for metastatic NPC and recommends an intensified treatment strategy for metastatic NPC. A key limitation is that most studies evaluating the role of radical locoregional radiotherapy and local ablative treatments were retrospective in nature. In addition, the present review does not provide a systematic evaluation of the quality of the included studies due to lack of high-quality prospective studies on the local treatment of metastatic NPC.


The natural history of metastatic NPC is highly variable, with several crucial factors impacting the prognosis, including tumor burden, EBV-DNA levels, location of involvement, timing of metastasis, and treatment strategies. Therefore, treatment for de novo metastatic NPC should be individualized. Intensifying systemic treatment with immunotherapy has been shown to improve overall control. Additionally, locoregional radiation therapy to the primary tumor and regional nodes can offer a survival benefit for good responders to systemic treatment. In cases of oligometastases, aggressive treatment through ablative means to distant sites should be explored whenever possible. Further studies on maintenance therapy using PD-1 inhibitor and/or capecitabine, and determination of optimal duration, are warranted.


Funding: This work was supported by the Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy (No. ZDSYS20210623091811035) and Shenzhen Key Medical Discipline Construction Fund (No. SZXK014).


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Cite this article as: Liu Q, Li J, Ng WT, Lee AWM. Treatment strategy for de novo metastatic nasopharyngeal carcinoma: a literature review. Chin Clin Oncol 2023;12(4):43. doi: 10.21037/cco-23-32

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