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

Introduction

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 https://cco.amegroups.com/article/view/10.21037/cco-23-32/rc).

Methods

A literature review was conducted to identify studies on the subcategorization and treatment of newly diagnosed metastatic NPC. PubMed, Clinicaltrials.gov 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 Clinicaltrials.gov 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.

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.

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).

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.

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).

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).

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.

Conclusions

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.

Acknowledgments

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).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-23-32/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-32/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-32/coif). AWML serves as an unpaid editorial board member of Chinese Clinical Oncology from January 2023 to December 2024. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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