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Treatment of recurrent and metastatic nasopharyngeal carcinoma

Treatment of recurrent and metastatic nasopharyngeal carcinoma
Authors:
Edwin P Hui, MD
Anthony TC Chan, MD
Quynh-Thu Le, MD
Section Editors:
Bruce E Brockstein, MD
David M Brizel, MD
Marshall R Posner, MD
Marvin P Fried, MD, FACS
Deputy Editor:
Sonali Shah, MD
Literature review current through: Dec 2022. | This topic last updated: Jun 08, 2022.

INTRODUCTION — Nasopharyngeal carcinoma (NPC) arises from the lining of the nasopharynx, the narrow tubular passage behind the nasal cavity. Worldwide, in 2020, there were over 130,000 new cases and over 80,000 deaths from NPC, although the racial and geographic distribution of this disease is variable [1]. While rare in most parts of the world, NPC is endemic in Southern China, Southeast Asia, North Africa, and the Arctic, where undifferentiated, nonkeratinizing squamous cell carcinoma is the predominant histology. The treatment of recurrent and metastatic disease is challenging, since recurrent disease and distant metastases are the most common causes of death among patients with NPC. However, prolonged survival is possible in patients who are carefully selected and appropriately treated.

The treatment of recurrent and metastatic NPC is presented here. The epidemiology and diagnosis of NPC, as well as the treatment of early and locoregionally advanced NPC are discussed separately.

(See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

(See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

STAGING AND HISTOLOGY — The staging and the histopathologic classification of NPC are discussed in more detail separately. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

Staging — NPC is staged according to the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging system (table 1) [2].

Histology — The World Health Organization (WHO) classifies NPC into three histopathologic types [3]:

Keratinizing squamous cell carcinoma (WHO type I)

Nonkeratinizing carcinoma: differentiated (WHO type II) and undifferentiated (WHO type III)

Basaloid squamous cell carcinoma

PRETREATMENT EVALUATION — For patients with locoregionally recurrent NPC, we evaluate with magnetic resonance imaging (MRI) of the head and neck to assess for locoregional disease. We also obtain a whole-body positron emission tomography (PET)/computed tomography (CT) scan to exclude distant metastases [4,5]. This evaluation should be performed prior to initiating therapy, as approximately one-half of patients initially diagnosed with local recurrence will also present with synchronous, distant metastatic disease. The most common site for first distant metastases is the bone, followed by the liver and lung [6]. (See 'Metastatic disease' below.)

Further details on the initial diagnostic evaluation of NPC, including obtaining Epstein-Barr virus (EBV) DNA levels, are discussed separately. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Initial diagnostic evaluation'.)

LOCOREGIONALLY RECURRENT DISEASE — Selected patients with locoregionally recurrent NPC can achieve long-term survival when managed with local therapies, such as surgery and radiation therapy (RT). Our approach to retreatment is influenced by various clinical factors including prior RT, tumor size, and surgical candidacy. Clinical trials are encouraged, where available, as retreatment can be challenging due to tumor location and proximity to critical structures (which can influence surgical candidacy) and limitations arising from prior therapies (eg, reirradiation dosing in the setting of prior RT).

Prior radiation therapy — A vast majority of patients with locoregionally recurrent NPC have previously received RT as part of therapy for their primary tumor, since RT (either alone or in combination with chemotherapy) is an integral part of primary therapy for NPC. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

For such patients, treatment options include salvage surgery or reirradiation. Our treatment approach is as follows:

Resectable disease — Salvage surgery is an option for patients with small local recurrent nasopharyngeal tumors or those with an isolated resectable relapse in the neck [7,8]. (See 'Salvage surgery (cT1 to T2 nasopharyngeal tumors)' below and 'Recurrent nodal disease' below.)

Salvage surgery (cT1 to T2 nasopharyngeal tumors) — For patients with small (ie, cT1 to T2) recurrent local nasopharyngeal tumors who are eligible for resection, we suggest salvage surgery with endoscopic nasopharyngectomy rather than reirradiation with or without concurrent chemotherapy, as this approach improved overall survival (OS) and decreased long-term toxicity in a phase III trial [9]. However, reirradiation is a reasonable alternative for those who are ineligible for or wish to avoid surgery. The decision between surgery and reirradiation is individually tailored, taking into consideration the location and extent of the recurrent tumor and previous therapies. (See 'Unresectable disease' below.)

Surgery for patients with locoregionally recurrent disease in this setting is technically challenging because of limitations of access to the nasopharynx. The goal is to achieve an adequate negative surgical margin while preserving the neurovascular bundle and restoring critical mucosal barriers. While anterior approaches are most commonly used, endoscopic nasopharyngectomy in selected patients may achieve comparable results with reduced complications [10,11]. Robotic surgery may have an application for nasopharyngectomy [12,13].

Serious surgical complications include meningitis (the most common cause of perioperative mortality), osteoradionecrosis, necrosis of the free flap, and aspiration pneumonia [14,15]. Other commonly seen complications include middle ear effusion, hypernasality, nasal regurgitation, cerebrospinal rhinorrhea, ectropion, temporary and permanent infraorbital numbness, trismus, epiphora (watering eyes), impaired swallowing, and oropalatal fistula.

In an open-label phase III trial, 200 patients with recurrent NPC were randomly assigned to either endoscopic nasopharyngectomy or reirradiation with intensity-modulated RT (IMRT) [9]. Tumors were confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. A majority of those treated with surgery (94 percent) did not require adjuvant RT or chemotherapy. Similarly, all except one patient treated with IMRT completed a full course of treatment, and a majority (71 percent) received concurrent chemotherapy with cisplatin.

At a median follow-up of 56 months, endoscopic nasopharyngectomy improved three-year OS compared with IMRT (86 versus 68 percent, HR 0.47, 95% CI 0.29-0.76). OS benefit was seen in those with T1 and T2 tumors, but not those with T3 tumors. Grade ≥3 overall and late adverse events due to radiation were both lower with endoscopic nasopharyngectomy than IMRT (13 versus 37 percent for both outcomes).

Additional studies of carefully selected patients with recurrent NPC have reported three-year survival rates as high as 86 percent after salvage surgery, but survival benefit may be restricted to those with T1 or T2 recurrent disease [9,14,16-18]. In addition to high recurrent T stage (with skull base, cranial nerve, dural, or brain involvement) (table 1), positive surgical margins and concurrent nodal metastases have been associated with poor prognosis [19,20]. (See 'Prognosis' below.)

Recurrent nodal disease — Radical, modified radical, or selective neck dissection is indicated for patients with residual nodal disease after initial RT or for an isolated neck recurrence. In patients with a single nodal recurrence, selective neck dissection has similar OS, disease-free survival, and regional recurrence-free survival compared with radical neck dissection [21]. However, selective neck dissection has the advantage of decreased postoperative morbidity. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck", section on 'Isolated neck recurrence'.)

Is there a role for adjuvant therapy? — Adjuvant chemotherapy and adjuvant RT (including conventional RT, brachytherapy, radiosurgery, and concurrent chemoradiation) are frequently used following surgical salvage. However, there are limited data to support the efficacy of such adjuvant therapy [18,19,22]. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)

Unresectable disease

Reirradiation — For patients with larger (cT3 to T4) locoregionally recurrent nasopharyngeal tumors or those with unresectable disease, we suggest reirradiation rather than surgery or other systemic therapies. Patients who are not candidates for reirradiation can be offered systemic therapy using a similar approach to those with metastatic disease. (See 'Metastatic disease' below.)

The potential for long-term survival with reirradiation has been demonstrated for such carefully selected patients [23-26]. Reirradiation for locally recurrent head and neck cancer is discussed in detail separately. (See "Reirradiation for locally recurrent head and neck cancer".)

However, reirradiation poses a therapeutic challenge, since the dose that can be delivered safely is limited by previous RT treatments and the tolerance of normal tissues. The extent of local recurrence and the ability to deliver an adequate reirradiation dose can limit the success of salvage therapy [27]. Significant acute and late toxicities must be expected.

Various techniques for reirradiation have been investigated in this setting and include:

Three-dimensional conformal RT [28,29]

IMRT [30,31]

Intracavitary and interstitial brachytherapy, including implantation of radioactive gold grains [28,32-36]

Stereotactic radiosurgery [33,35]

Fractionated stereotactic RT [34,37,38]

Proton beam RT [39,40]

Intensity-modulated carbon-ion RT (IMCT) [41,42]

However, these different RT approaches have not been directly compared in clinical trials. The choice of therapeutic approach depends upon local expertise and technical considerations, including the location and extent of recurrent disease.

Grade 3 to 4 late toxicities have been reported in at least 5 to 20 percent in some series and consist of temporal lobe necrosis, cranial nerve palsies, hearing loss, endocrine abnormalities, palatal fibrosis, trismus, chronic pain, and osteoradionecrosis [33,43,44]. Lethal nasopharyngeal necrosis and hemorrhage are major late complications [26,45]. (See "Delayed complications of cranial irradiation" and "Management of late complications of head and neck cancer and its treatment".)

Is there a role for combining reirradiation and chemotherapy? — There is a limited role for combining reirradiation with either induction or concurrent cisplatin-based chemotherapy due to toxicity [43,46,47]. As an example, in a phase II trial of 33 patients with locally recurrent NPC, triplet induction chemotherapy (docetaxel, cisplatin, and fluorouracil [TPF]) followed by chemoradiation (concurrent cetuximab, docetaxel, and IMRT) achieved three-year progression-free and overall survival rates of 36 and 64 percent, respectively, but was associated with high rates of treatment-related deaths and late complications [47]. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

No prior radiation therapy — Patients with locoregionally recurrent nasopharyngeal tumors who did not receive prior RT are rare, as RT (either alone or in combination with chemotherapy) is an integral part of standard therapy for primary NPC.

For patients who declined initial therapy (including RT) for their primary tumor, the treatment approach is similar to those with treatment-naïve early and locoregionally advanced NPC, which is discussed separately. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

Patients with oligometastatic disease who have only received initial systemic therapy without prior RT are candidates for consolidative locoregional RT to the primary tumor and cervical lymph nodes. This approach is discussed below. (See 'Consolidation with radiation therapy' below.)

Others may have received inadequate initial therapy that did not include a complete course of RT (eg, due to treatment-related toxicity), resulting in residual or recurrent disease. For such patients with resectable, locoregionally recurrent disease, we offer salvage surgery rather than other treatment modalities, since surgery is not part of the treatment approach for primary NPC. Patients who are ineligible for or decline surgery may alternatively be offered either concurrent chemoradiation or systemic therapy using a similar approach to those with metastatic disease. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Concurrent chemoradiation' and 'Metastatic disease' below.)

METASTATIC DISEASE — Patients with metastatic NPC are treated with systemic therapy. Patients with metastatic NPC may present with de novo disease or progress with distant metastases after receiving initial therapy for primary NPC. Enrollment in clinical trials are encouraged, where available. (See 'Investigational agents' below.)

Treatment options include systemic chemotherapy and checkpoint inhibitor immunotherapy, either as single agents or in combination. Additionally, patients with limited or oligometastatic NPC and a good performance status who have achieved an at least partial response to systemic chemotherapy are offered consolidation with radiotherapy. (See 'Consolidation with radiation therapy' below.)

Initial therapy — For most patients with metastatic NPC who are treatment naïve in this setting, we suggest initial therapy with cisplatin-based combination therapy, rather than other chemotherapy agents. We prefer the combination of gemcitabine plus cisplatin, which improved overall survival (OS) and progression-free survival (PFS) in a phase III trial. (See 'Gemcitabine plus cisplatin' below.)

Gemcitabine plus cisplatin — NPC is a highly chemosensitive disease with response rates up to 80 percent with cisplatin-based regimens [48-51]. A phase III trial (GEM20110714) established the combination of gemcitabine plus cisplatin as the preferred regimen. In this trial, 362 patients were randomly assigned to gemcitabine (1000 mg/m2 on days 1 and 8) plus cisplatin (80 mg/m2 on day 1) or fluorouracil (4 g/m2 continuous intravenous infusion over 96 hours) plus cisplatin (80 mg/m2 on day 1) [48]. Treatment was given for a maximum of six cycles.

At a median follow-up of 19 months, compared with fluorouracil plus cisplatin, gemcitabine plus cisplatin improved PFS (median 7 versus 5.6 months, hazard ratio [HR] 0.55, 95% CI 0.44-0.68) [48]. At a median follow-up of 70 months, gemcitabine plus cisplatin also improved OS (median 22 versus 19 months, HR 0.72, 95% CI 0.58-0.90) [52]. The gemcitabine plus cisplatin regimen was generally well tolerated, although it was associated with more hematologic toxicity than cisplatin plus fluorouracil.

Alternative agents — For patients with good performance status who are ineligible for or decline initial therapy with gemcitabine plus cisplatin-based therapy, alternative options include combination therapy with fluorouracil plus cisplatin [53]; gemcitabine plus carboplatin; a platinum (carboplatin or cisplatin) plus a taxane (docetaxel or paclitaxel) [54-56]; paclitaxel, cisplatin, and capecitabine [57]; or carboplatin plus cetuximab, an epidermal growth factor receptor (EGFR) inhibitor [58].

For older adults or patients with decreased performance status who are unable to tolerate combination chemotherapy, we offer single-agent chemotherapy. Options include platinum (cisplatin, carboplatin), fluorouracil (including capecitabine), taxanes (paclitaxel, docetaxel), gemcitabine, methotrexate, bleomycin, ifosfamide, anthracyclines, irinotecan, and vinorelbine [59-65].

Is there a role for maintenance chemotherapy? — Further studies are needed to assess the role of maintenance chemotherapy after completion of induction chemotherapy. The decision to offer maintenance chemotherapy rather than observation is based on institutional practice as well as patient and provider preference.

As an example, in a randomized phase III trial of 104 patients with metastatic NPC treated with induction chemotherapy (paclitaxel, cisplatin, and capecitabine) and who achieved either a complete response, partial response, or stable disease, the addition of maintenance capecitabine to best supportive care improved PFS (median 36 versus 8 months, HR 0.44, 95% CI 0.26-0.74) and objective response rates (25 versus 12 percent) with a manageable toxicity profile [57].

Is there a role for combination chemotherapy and immunotherapy? — The combination of checkpoint inhibitor immunotherapy plus chemotherapy is a promising approach to initial therapy for metastatic NPC. This approach remains investigational pending further data on OS and more widespread regulatory approval of these immunotherapy agents.

The addition of checkpoint inhibitor immunotherapy (eg, toripalimab, camrelizumab, or tislelizumab) to gemcitabine plus cisplatin significantly improved PFS in separate phase III trials [66-68]. Extrapolating from these data, the National Comprehensive Cancer Network also suggests the addition of either nivolumab or pembrolizumab to gemcitabine plus cisplatin as an initial treatment option for metastatic NPC [69]. We encourage patients interested in combination chemotherapy and immunotherapy to enroll in clinical trials, where available. (See 'Gemcitabine plus cisplatin and toripalimab' below and 'Gemcitabine plus cisplatin and camrelizumab' below and 'Gemcitabine plus cisplatin and tislelizumab' below.)

Subsequent therapy with checkpoint inhibitor immunotherapy for patients who progress on platinum-based chemotherapy is discussed below. (See 'Checkpoint inhibitor immunotherapy' below.)

Gemcitabine plus cisplatin and toripalimab — The addition of toripalimab, a humanized monoclonal IgG4K antibody against programmed cell death protein 1 (PD-1), to gemcitabine plus cisplatin improved PFS, objective response rates (ORRs), and duration of response in a double-blind, placebo-controlled phase III trial. This approach also offers patients with metastatic NPC the opportunity for subsequent monotherapy with toripalimab to reduce the risk of disease progression after receiving chemotherapy. Toripalimab has regulatory approval in China. These data are promising, and we await longer follow-up of OS data and more widespread, international regulatory approval of toripalimab before incorporating this approach into clinical practice. Further details on the efficacy of toripalimab monotherapy as subsequent-line therapy are discussed below. (See 'Toripalimab' below.)

In a phase III trial (JUPITER-02), 289 patients with recurrent or metastatic NPC without prior systemic therapy in this setting were randomly assigned to either toripalimab or placebo, with gemcitabine plus cisplatin [66]. Patients assigned to combination chemotherapy and immunotherapy received gemcitabine at 1000 mg/m2 on days 1 and 8, cisplatin at 80 mg/m2 on day 1, and toripalimab at 240 mg every three weeks for up to six cycles, followed by monotherapy with toripalimab every three weeks until completion of two years of therapy, disease progression, or intolerable toxicity.

At the prespecified interim analysis, the addition of toripalimab to chemotherapy improved PFS (median 12 versus 8 months, one-year PFS 49 versus 28 percent, HR 0.52, 95% CI 0.36-0.74), ORRs (77 versus 66 percent), and median duration of response (10 versus 6 months). Additionally, PFS benefit was seen across all prespecified subgroups, including all programmed cell death ligand 1 (PD-L1) subgroups. OS was similar between the two treatment groups (two-year OS 78 versus 66 percent, HR 0.60, 95% CI 0.36-0.99), and follow-up of OS is ongoing. Grade ≥3 treatment-related toxicities were similar between the two treatment arms (81 versus 83 percent). Grade ≥3 immune-mediated adverse events were higher for those treated with combination chemotherapy plus immunotherapy arm versus chemotherapy plus placebo (7 versus 1 percent), with no new toxicity profiles noted for toripalimab when combined with immunotherapy.

While promising, this approach remains investigational pending further data on OS. For example, it is unclear whether the addition of immunotherapy to chemotherapy confers a survival advantage over the sequential use of these agents (ie, initial treatment with chemotherapy followed by immunotherapy upon disease progression), as patients enrolled in the placebo arm did not cross over to the treatment arm upon disease progression.

Further studies are also needed to evaluate the optimal regimen to administer after completion of combination chemotherapy plus immunotherapy (ie, chemotherapy versus immunotherapy). (See 'Is there a role for maintenance chemotherapy?' above.)

Gemcitabine plus cisplatin and camrelizumab — In a separate double-blind, placebo-controlled phase III trial (CAPTAIN-1st) of 263 patients with recurrent or metastatic NPC, the addition of the PD-1 inhibitor camrelizumab to gemcitabine plus cisplatin also improved PFS (median 10 versus 7 months, HR 0.54, 95% CI 0.39-0.76) and median duration of response (9 versus 6 months) [67]. OS data are immature.

While camrelizumab has regulatory approval in China, this approach remains investigational pending further follow-up.

Gemcitabine plus cisplatin and tislelizumab — The addition of the PD-1 inhibitor tislelizumab to gemcitabine plus cisplatin improved both PFS and second progression-free survival (PFS2; ie, time from randomization to objective disease progression on subsequent-second line therapy or death from any cause) in a phase III trial. The use of tislelizumab in combination with chemotherapy remains investigational pending further follow-up and regulatory approval.

In a double-blind phase III trial (RATIONALE-309), 263 patients with treatment-naïve, recurrent, or metastatic NPC were randomly assigned to either tislelizumab or placebo, along with gemcitabine plus cisplatin, followed by either tislelizumab monotherapy or placebo until disease progression, intolerable toxicity, or death [68]. Patients assigned to chemotherapy plus placebo were also allowed to cross over to tislelizumab monotherapy upon disease progression.

In preliminary results, at median follow-up of 16 months, the addition of tislelizumab to gemcitabine plus cisplatin improved both PFS (median 10 versus 7 months, HR 0.50, 95% CI 0.37-0.68) and PFS2 (median not reached versus 14 months, HR 0.38, 95% CI 0.25-0.58) [68]. OS was similar for the two treatment arms (median OS not reached versus 23 months, HR 0.60, 95% CI 0.31-1.01) and further follow-up of OS is ongoing. Grade ≥3 toxicity rates were similar for both treatment arms (81 versus 82 percent).

Consolidation with radiation therapy — In patients with de novo oligometastatic NPC and a good performance status who have an at least partial response to systemic chemotherapy, we suggest consolidation with radiation therapy (RT) rather than observation until progression. Intensity-modulated RT (IMRT) is administered after chemotherapy to the primary tumor and cervical lymph nodes up to a dose of 70 Gy with target volumes based on prechemotherapy imaging data. Stereotactic body RT (SBRT) or IMRT can be administered to the oligometastatic disease.

Initial retrospective studies suggested improved long-term outcomes following a multimodality approach involving radical chemoradiotherapy to the primary tumor and ablative treatment to the site of oligometastasis [70-73]. An OS benefit was confirmed in a small, randomized trial that enrolled patients with chemosensitive de novo metastatic disease [74].

In this multicenter open-label phase III trial, 126 patients with de novo metastatic NPC and an at least partial response after three cycles of fluorouracil plus cisplatin (PF) were randomly assigned to an additional three cycles of PF with or without consolidation IMRT to the primary tumor and cervical lymph nodes [74].

At a median follow-up of 27 months, the addition of IMRT improved OS (24-month OS 76 versus 54 percent; HR 0.42, 95% CI 0.23-0.77) and PFS (median 12 versus 7 months; HR 0.36, 95% CI 0.23-0.57). IMRT was associated with the following grade 3 or greater adverse effects: mucositis (34 percent), dermatitis (8 percent), xerostomia (7 percent), hearing loss (5 percent), and trismus (3 percent).

Limitations of this trial include the smaller than planned sample size due to early trial closure for benefit and the use of PF rather than gemcitabine plus cisplatin as the chemotherapy backbone.

Subsequent therapy — For patients who progress on initial platinum-based chemotherapy, subsequent treatment with either checkpoint inhibitor immunotherapy or systemic chemotherapy are reasonable options. The choice of therapy is based upon clinical factors including comorbidities, patient preference, and drug availability.

Checkpoint inhibitor immunotherapy — For patients with metastatic disease who progress on initial platinum-based chemotherapy, we suggest the use of checkpoint inhibitor immunotherapy rather than systemic chemotherapy, as this approach had similar overall survival but less toxicity in a phase III trial [75]. Options include pembrolizumab, nivolumab, and toripalimab (where available). The choice between these agents is based on drug availability, as they have not been directly compared in randomized trials. There are insufficient data to use a combined positive score (CPS) to select therapy. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility'.)

Pembrolizumab — Pembrolizumab is an option for subsequent therapy in patients with PD-L1 positive, recurrent or metastatic NPC, and may be preferred in patients who wish to avoid the toxicities associated with chemotherapy. In a phase III trial, pembrolizumab did not improve OS compared with chemotherapy but had less toxicity [76].

Based on initial data [75], an open-label phase III trial (KEYNOTE-122) was conducted in 233 patients with recurrent or metastatic NPC who had previously received platinum-based chemotherapy [76]. Patients were randomly assigned to either pembrolizumab at 200 mg every three weeks for up to 35 cycles versus standard chemotherapy (capecitabine, gemcitabine, or docetaxel). Among patients receiving pembrolizumab versus chemotherapy, the frequency of a tumor PD-L1 combined positive score (CPS) ≥1 was 74 and 63 percent, respectively. In preliminary results, at median follow-up of 45 months, pembrolizumab did not improve OS (median 17 versus 15 months, HR 0.90, 95% CI 0.67-1.19) or objective response rates (23 versus 26 percent), but had lower rates of grade ≥3 toxicities (10 versus 44 percent).

Nivolumab — Nivolumab is an option for subsequent therapy in patients with nonkeratinizing NPC. In a phase II study (NCI-9742), 44 patients with heavily pretreated recurrent or metastatic disease were treated with nivolumab (3 mg/kg every two weeks) [77]. A majority (>80 percent) had nonkeratinizing disease, and all had previously received platinum-based chemotherapy. At a median follow-up of approximately 13 months, objective responses were seen in nine patients (21 percent), including one complete and eight partial responses; objective responses were also higher among those with PD-L1 positive disease. One-year PFS and OS were 19 and 59 percent, respectively.

A similar ORR was noted in preliminary findings from a separate phase II (CheckMate-358) also conducted in patients with nonkeratinizing disease [78].

Toripalimab — In a phase II trial (POLARIS-02) of 190 patients with treatment-refractory disease treated with toripalimab, the ORR was 21 percent [79]. Median PFS and OS were 2 and 17 months, respectively. A 50 percent or greater decrease in Epstein-Barr virus (EBV) copy number was associated with improved ORR. Additionally, patients with genomic amplification in the 11q13 region or ETV6 genomic alterations had poor responses to toripalimab.

Toripalimab has regulatory approval in China. Further data on the combination of toripalimab with gemcitabine plus cisplatin as initial therapy are discussed above. (See 'Gemcitabine plus cisplatin and toripalimab' above.)

Investigational immunotherapy agents — Various early-phase clinical trials have evaluated immunotherapy with other PD-L1 checkpoint inhibitors in patients with recurrent, platinum-refractory NPC including camrelizumab [80,81] and spartalizumab [82]. Further data are needed before incorporating these agents into the routine clinical treatment of NPC.

Ineligible for immunotherapy (chemotherapy) — For patients who are ineligible for or opt against immunotherapy, we offer systemic chemotherapy as subsequent-line therapy. Options are similar to agents available as alternative initial therapy to gemcitabine plus cisplatin. (See 'Alternative agents' above.)

PROGNOSIS — Recurrent and distant metastases are the most common causes of death among patients with NPC, as survival outcomes have improved for patients with locoregionally advanced disease due to more successful treatment strategies. For patients with recurrent and metastatic disease, the median overall survival ranges between 10 and 36 months [83], although these data were obtained in the era prior to checkpoint inhibitor immunotherapy. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Prognosis'.)

However, prolonged survival may be possible for carefully selected and treated subsets of patients, especially with more contemporary treatments for recurrent and metastatic disease. As such, there is interest in developing prognostic biomarkers (such as pre- and post-treatment Epstein-Barr virus [EBV] DNA levels [54,79,84] and circulating tumor cells [85]) and prognostic indices in patients with recurrent and metastatic disease [86]. Further data are necessary before incorporating these approaches into routine clinical practice.

The use of EBV DNA levels in locoregionally advanced disease is discussed separately. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Is there a role for EBV DNA in posttreatment surveillance?'.)

INVESTIGATIONAL AGENTS — Various treatments are being evaluated for metastatic NPC as follows:

Approaches targeting Epstein-Barr virus – Viral antigens from Epstein-Barr virus (EBV) are potential treatment targets, as EBV is present in virtually all poorly differentiated and undifferentiated nonkeratinizing NPC (World Health Organization [WHO] type II and III) [87,88]. Approaches that are being investigated include adoptive transfer of cytotoxic T cells (CTLs) specific for EBV antigens [89-96], and therapeutic EBV vaccination [97-102], among others.

Targeted therapy – Molecularly targeted therapy such as epidermal growth factor receptor (EGFR) inhibitors [58,103-105] and vascular endothelial growth factor receptor (VEGFR) inhibitors [87,88,106-112] have demonstrated clinical activity in patients with metastatic NPC and remain under investigation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

SUMMARY AND RECOMMENDATIONS

Prognosis for recurrent and metastatic nasopharyngeal carcinoma – For patients with NPC, recurrent and distant metastases are the most common causes of death. However, prolonged survival is possible in patients who are carefully selected and appropriately treated. (See 'Introduction' above and 'Prognosis' above.)

Pretreatment evaluation for locoregionally recurrent disease – For patients with locoregionally recurrent NPC, we evaluate using magnetic resonance imaging (MRI) of head and neck as well as whole-body positron emission tomography (PET)/computed tomography (CT) scan to assess for synchronous, distant metastatic disease.

Locoregionally recurrent disease – For patients with locoregionally recurrent disease, our approach is as follows (see 'Locoregionally recurrent disease' above):

Resectable disease – For those treated with prior radiation therapy (RT) and small local recurrences (clinical stage T1 to T2 disease (table 1)) who are eligible for resection, we suggest salvage surgery with endoscopic nasopharyngectomy rather than reirradiation with or without concurrent chemotherapy (Grade 2C), as this approach improved overall survival (OS) with less toxicity.

Unresectable disease – Reirradiation is a reasonable alternative for those with larger (cT3 to T4) tumors, those with unresectable disease, and those who are ineligible for or wish to avoid surgery. (See 'Locoregionally recurrent disease' above.)

Metastatic disease – For most patients with metastatic NPC, our approach is as follows (see 'Metastatic disease' above):

Initial therapy – For patients with metastatic NPC, we suggest initial therapy with cisplatin-based combination chemotherapy, rather than other chemotherapy agents (Grade 2B). We prefer gemcitabine plus cisplatin, which improved progression-free survival (PFS) and OS compared with cisplatin plus fluorouracil. (See 'Initial therapy' above.)

Is there a role for combination chemotherapy plus immunotherapy? – The addition of checkpoint inhibitor immunotherapy (toripalimab, camrelizumab, or tislelizumab) to gemcitabine and cisplatin as initial therapy in patients with metastatic disease is a promising approach that improved PFS in randomized trials. Such combination therapy remains investigational pending further data on OS and more widespread regulatory approval of these immunotherapy agents. We encourage patients interested in this approach to enroll in clinical trials, where available. (See 'Is there a role for combination chemotherapy and immunotherapy?' above.)

Indications for consolidation radiation therapy – In patients with de novo oligometastatic NPC and a good performance status who have an at least partial response to systemic chemotherapy, we suggest consolidation with RT rather than observation until progression (Grade 2B), as this approach improved overall survival. (See 'Consolidation with radiation therapy' above.)

Subsequent therapy – For patients with metastatic disease who progress on initial platinum-based chemotherapy, subsequent treatment with either checkpoint inhibitor immunotherapy or systemic chemotherapy are reasonable options.

For patients who choose immunotherapy or wish to avoid the potential toxicities of chemotherapy, options include pembrolizumab, nivolumab, and toripalimab (where available). (See 'Subsequent therapy' above.)

Patients who are ineligible for or opt against immunotherapy may alternatively receive chemotherapy agents not previously administered during initial therapy. (See 'Ineligible for immunotherapy (chemotherapy)' above and 'Alternative agents' above.)

  1. Global Cancer Observatory. International Agency for Research on Cancer. World Health Organization. Available at: https://gco.iarc.fr/ (Accessed on June 06, 2021).
  2. Lee AWM, Lydiatt WM, Colevas AD, et al. Nasopharynx. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), Springer, New York 2017. p.103.
  3. Pathology and genetics of head and neck tumors. In: World Health Organization Classification of Tumours, Barnes L, Eveson JW, Reichart P, Sidransky D (Eds), IARC Press, Lyon 2005.
  4. Lee AWM, Ng WT, Chan JYW, et al. Management of locally recurrent nasopharyngeal carcinoma. Cancer Treat Rev 2019; 79:101890.
  5. Perri F, Della Vittoria Scarpati G, Caponigro F, et al. Management of recurrent nasopharyngeal carcinoma: current perspectives. Onco Targets Ther 2019; 12:1583.
  6. Hui EP, Leung SF, Au JS, et al. Lung metastasis alone in nasopharyngeal carcinoma: a relatively favorable prognostic group. A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 2004; 101:300.
  7. Chan JY. Surgical salvage of recurrent nasopharyngeal carcinoma. Curr Oncol Rep 2015; 17:433.
  8. Na'ara S, Amit M, Billan S, et al. Outcome of patients undergoing salvage surgery for recurrent nasopharyngeal carcinoma: a meta-analysis. Ann Surg Oncol 2014; 21:3056.
  9. Liu YP, Wen YH, Tang J, et al. Endoscopic surgery compared with intensity-modulated radiotherapy in resectable locally recurrent nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2021; 22:381.
  10. Chen MY, Wen WP, Guo X, et al. Endoscopic nasopharyngectomy for locally recurrent nasopharyngeal carcinoma. Laryngoscope 2009; 119:516.
  11. Emanuelli E, Albu S, Cazzador D, et al. Endoscopic surgery for recurrent undifferentiated nasopharyngeal carcinoma. J Craniofac Surg 2014; 25:1003.
  12. Tsang RK, To VS, Ho AC, et al. Early results of robotic assisted nasopharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck 2015; 37:788.
  13. You R, Zou X, Hua YJ, et al. Salvage endoscopic nasopharyngectomy is superior to intensity-modulated radiation therapy for local recurrence of selected T1-T3 nasopharyngeal carcinoma – A case-matched comparison. Radiother Oncol 2015; 115:399.
  14. Yu KH, Leung SF, Tung SY, et al. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck 2005; 27:397.
  15. To EW, Lai EC, Cheng JH, et al. Nasopharyngectomy for recurrent nasopharyngeal carcinoma: a review of 31 patients and prognostic factors. Laryngoscope 2002; 112:1877.
  16. Fee WE Jr, Moir MS, Choi EC, Goffinet D. Nasopharyngectomy for recurrent nasopharyngeal cancer: a 2- to 17-year follow-up. Arch Otolaryngol Head Neck Surg 2002; 128:280.
  17. Hsu MM, Hong RL, Ting LL, et al. Factors affecting the overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site: experience with 60 cases. Arch Otolaryngol Head Neck Surg 2001; 127:798.
  18. Chang KP, Hao SP, Tsang NM, Ueng SH. Salvage surgery for locally recurrent nasopharyngeal carcinoma-A 10-year experience. Otolaryngol Head Neck Surg 2004; 131:497.
  19. Hao SP, Tsang NM, Chang KP, et al. Nasopharyngectomy for recurrent nasopharyngeal carcinoma: a review of 53 patients and prognostic factors. Acta Otolaryngol 2008; 128:473.
  20. Chan JYW, Wong STS, Wei WI. Surgical salvage of recurrent T3 nasopharyngeal carcinoma: Prognostic significance of clivus, maxillary, temporal and sphenoid bone invasion. Oral Oncol 2019; 91:85.
  21. Chen JY, Zhang L, Ji QH, et al. Selective neck dissection for neck residue of nasopharyngeal carcinoma: A prospective study. J Craniomaxillofac Surg 2015; 43:1571.
  22. Chen C, Fee W, Chen J, et al. Salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC). Am J Clin Oncol 2014; 37:327.
  23. Agas RAF, Yu KKL, Sogono PG, et al. Reirradiation for Recurrent Nasopharyngeal Carcinomas: Experience From an Academic Tertiary Center in a Low- to Middle-Income Country. J Glob Oncol 2019; 5:1.
  24. Ng WT, Lee MC, Fung NT, et al. Dose volume effects of re-irradiation for locally recurrent nasopharyngeal carcinoma. Head Neck 2020; 42:180.
  25. Leong YH, Soon YY, Lee KM, et al. Long-term outcomes after reirradiation in nasopharyngeal carcinoma with intensity-modulated radiotherapy: A meta-analysis. Head Neck 2018; 40:622.
  26. Kong F, Zhou J, Du C, et al. Long-term survival and late complications of intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma. BMC Cancer 2018; 18:1139.
  27. Lee AW, Foo W, Law SC, et al. Reirradiation for recurrent nasopharyngeal carcinoma: factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 1997; 38:43.
  28. Zheng XK, Chen LH, Chen YQ, Deng XG. Three-dimensional conformal radiotherapy versus intracavitary brachytherapy for salvage treatment of locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004; 60:165.
  29. Zheng XK, Ma J, Chen LH, et al. Dosimetric and clinical results of three-dimensional conformal radiotherapy for locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2005; 75:197.
  30. Chua DT, Sham JS, Leung LH, Au GK. Re-irradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy. Radiother Oncol 2005; 77:290.
  31. Tian YM, Tian YH, Zeng L, et al. Prognostic model for survival of local recurrent nasopharyngeal carcinoma with intensity-modulated radiotherapy. Br J Cancer 2014; 110:297.
  32. Leung TW, Tung SY, Wong VY, et al. Nasopharyngeal intracavitary brachytherapy: the controversy of T2b disease. Cancer 2005; 104:1648.
  33. Low JS, Chua ET, Gao F, Wee JT. Stereotactic radiosurgery plus intracavitary irradiation in the salvage of nasopharyngeal carcinoma. Head Neck 2006; 28:321.
  34. Yau TK, Sze WM, Lee WM, et al. Effectiveness of brachytherapy and fractionated stereotactic radiotherapy boost for persistent nasopharyngeal carcinoma. Head Neck 2004; 26:1024.
  35. Chua DT, Wei WI, Sham JS, et al. Stereotactic radiosurgery versus gold grain implantation in salvaging local failures of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007; 69:469.
  36. Koutcher L, Lee N, Zelefsky M, et al. Reirradiation of locally recurrent nasopharynx cancer with external beam radiotherapy with or without brachytherapy. Int J Radiat Oncol Biol Phys 2010; 76:130.
  37. Wu SX, Chua DT, Deng ML, et al. Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007; 69:761.
  38. Orecchia R, Redda MG, Ragona R, et al. Results of hypofractionated stereotactic re-irradiation on 13 locally recurrent nasopharyngeal carcinomas. Radiother Oncol 1999; 53:23.
  39. Romesser PB, Cahlon O, Scher ED, et al. Proton Beam Reirradiation for Recurrent Head and Neck Cancer: Multi-institutional Report on Feasibility and Early Outcomes. Int J Radiat Oncol Biol Phys 2016; 95:386.
  40. Dionisi F, Croci S, Giacomelli I, et al. Clinical results of proton therapy reirradiation for recurrent nasopharyngeal carcinoma. Acta Oncol 2019; 58:1238.
  41. Hu J, Bao C, Gao J, et al. Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results. Cancer 2018; 124:2427.
  42. Hu J, Huang Q, Gao J, et al. Clinical outcomes of carbon-ion radiotherapy for patients with locoregionally recurrent nasopharyngeal carcinoma. Cancer 2020; 126:5173.
  43. Poon D, Yap SP, Wong ZW, et al. Concurrent chemoradiotherapy in locoregionally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004; 59:1312.
  44. Liu S, Lu T, Zhao C, et al. Temporal lobe injury after re-irradiation of locally recurrent nasopharyngeal carcinoma using intensity modulated radiotherapy: clinical characteristics and prognostic factors. J Neurooncol 2014; 119:421.
  45. Yu YH, Xia WX, Shi JL, et al. A model to predict the risk of lethal nasopharyngeal necrosis after re-irradiation with intensity-modulated radiotherapy in nasopharyngeal carcinoma patients. Chin J Cancer 2016; 35:59.
  46. Chua DT, Sham JS, Au GK. Induction chemotherapy with cisplatin and gemcitabine followed by reirradiation for locally recurrent nasopharyngeal carcinoma. Am J Clin Oncol 2005; 28:464.
  47. Ng WT, Ngan RKC, Kwong DLW, et al. Prospective, Multicenter, Phase 2 Trial of Induction Chemotherapy Followed by Bio-Chemoradiotherapy for Locally Advanced Recurrent Nasopharyngeal Carcinoma. Int J Radiat Oncol Biol Phys 2018; 100:630.
  48. Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet 2016; 388:1883.
  49. Chua DT, Kwong DL, Sham JS, et al. A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. Eur J Cancer 2000; 36:736.
  50. Airoldi M, Gabriele AM, Garzaro M, et al. Induction chemotherapy with cisplatin and epirubicin followed by radiotherapy and concurrent cisplatin in locally advanced nasopharyngeal carcinoma observed in a non-endemic population. Radiother Oncol 2009; 92:105.
  51. Chen C, Wang FH, An X, et al. Triplet combination with paclitaxel, cisplatin and 5-FU is effective in metastatic and/or recurrent nasopharyngeal carcinoma. Cancer Chemother Pharmacol 2013; 71:371.
  52. Hong S, Zhang Y, Yu G, et al. Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study. J Clin Oncol 2021; 39:3273.
  53. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005; 23:3562.
  54. Jin Y, Shi YX, Cai XY, et al. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2012; 138:1717.
  55. Tan EH, Khoo KS, Wee J, et al. Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma. Ann Oncol 1999; 10:235.
  56. Yeo W, Leung TW, Chan AT, et al. A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer 1998; 34:2027.
  57. Liu GY, Li WZ, Wang DS, et al. Effect of Capecitabine Maintenance Therapy Plus Best Supportive Care vs Best Supportive Care Alone on Progression-Free Survival Among Patients With Newly Diagnosed Metastatic Nasopharyngeal Carcinoma Who Had Received Induction Chemotherapy: A Phase 3 Randomized Clinical Trial. JAMA Oncol 2022; 8:553.
  58. Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005; 23:3568.
  59. Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 2003; 39:361.
  60. Ciuleanu E, Irimie A, Ciuleanu TE, et al. Capecitabine as salvage treatment in relapsed nasopharyngeal carcinoma: a phase II study. J BUON 2008; 13:37.
  61. Poon D, Chowbay B, Cheung YB, et al. Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma. Cancer 2005; 103:576.
  62. Ngeow J, Lim WT, Leong SS, et al. Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma. Ann Oncol 2011; 22:718.
  63. Au E, Tan EH, Ang PT. Activity of paclitaxel by three-hour infusion in Asian patients with metastatic undifferentiated nasopharyngeal cancer. Ann Oncol 1998; 9:327.
  64. Foo KF, Tan EH, Leong SS, et al. Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol 2002; 13:150.
  65. Rischin D, Corry J, Smith J, et al. Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 2002; 20:1845.
  66. Mai HQ, Chen QY, Chen D, et al. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. Nat Med 2021; 27:1536.
  67. Yang Y, Qu S, Li J, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2021; 22:1162.
  68. Zhang L, Yang Y, Pan J, et al. RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer. J Clin Oncol 2022; 40; 36S.
  69. NCCN Clinical Practice Guidelines in Oncology, Head and Neck Cancers. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf (Accessed on December 07, 2021).
  70. Zheng W, Zong J, Huang C, et al. Multimodality Treatment May Improve the Survival Rate of Patients with Metastatic Nasopharyngeal Carcinoma with Good Performance Status. PLoS One 2016; 11:e0146771.
  71. Hu J, Kong L, Gao J, et al. Use of Radiation Therapy in Metastatic Nasopharyngeal Cancer Improves Survival: A SEER Analysis. Sci Rep 2017; 7:721.
  72. Huang T, Su N, Zhang X, et al. Systemic chemotherapy and sequential locoregional radiotherapy in initially metastatic nasopharyngeal carcinoma: Retrospective analysis with 821 cases. Head Neck 2020; 42:1970.
  73. Li WZ, Lv SH, Liu GY, et al. Development of a Prognostic Model to Identify the Suitable Definitive Radiation Therapy Candidates in de Novo Metastatic Nasopharyngeal Carcinoma: A Real-World Study. Int J Radiat Oncol Biol Phys 2021; 109:120.
  74. You R, Liu YP, Huang PY, et al. Efficacy and Safety of Locoregional Radiotherapy With Chemotherapy vs Chemotherapy Alone in De Novo Metastatic Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial. JAMA Oncol 2020; 6:1345.
  75. Hsu C, Lee SH, Ejadi S, et al. Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol 2017; 35:4050.
  76. Chan ATC, Lee VHF, Hong R, et al. Results of KEYNOTE-122: A phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy (chemo) for platinum-pretreated, recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Ann Oncol 2021; 32;5S.
  77. Ma BBY, Lim WT, Goh BC, et al. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol 2018; 36:1412.
  78. Delord, Hollebecque A, De Boet JP. An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). J Clin Oncol 2017; 35:15S.
  79. Wang FH, Wei XL, Feng J, et al. Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02). J Clin Oncol 2021; 39:704.
  80. Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol 2018; 19:1338.
  81. Yang Y, Zhou T, Chen X, et al. Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study). J Immunother Cancer 2021; 9.
  82. Lim D, Wang HM, Li S, Ngan R. Abstract CT150: Phase II study of spartalizumab (PDR001) vs chemotherapy (CT) in patients with recurrent/metastatic nasopharyngeal cancer (NPC). Clin Cancer Res 2019; 79:13S.
  83. Qu W, Li S, Zhang M, Qiao Q. Pattern and prognosis of distant metastases in nasopharyngeal carcinoma: A large-population retrospective analysis. Cancer Med 2020; 9:6147.
  84. An X, Wang FH, Ding PR, et al. Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy. Cancer 2011; 117:3750.
  85. Ko JM, Vardhanabhuti V, Ng WT, et al. Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma. Br J Cancer 2020; 123:114.
  86. Li YQ, Tian YM, Tan SH, et al. Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy. J Clin Oncol 2018; 36:891.
  87. Hong M, Tang K, Qian J, et al. Immunotherapy for EBV-Associated Nasopharyngeal Carcinoma. Crit Rev Oncog 2018; 23:219.
  88. Chow JC, Ngan RK, Cheung KM, Cho WC. Immunotherapeutic approaches in nasopharyngeal carcinoma. Expert Opin Biol Ther 2019; 19:1165.
  89. Chua D, Huang J, Zheng B, et al. Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 2001; 94:73.
  90. Straathof KC, Bollard CM, Popat U, et al. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. Blood 2005; 105:1898.
  91. Comoli P, Pedrazzoli P, Maccario R, et al. Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J Clin Oncol 2005; 23:8942.
  92. Louis CU, Straathof K, Bollard CM, et al. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother 2010; 33:983.
  93. Huang J, Fogg M, Wirth LJ, et al. Epstein-Barr virus-specific adoptive immunotherapy for recurrent, metastatic nasopharyngeal carcinoma. Cancer 2017; 123:2642.
  94. Comoli P, De Palma R, Siena S, et al. Adoptive transfer of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-specific immune response in a patient with EBV-related nasopharyngeal carcinoma. Ann Oncol 2004; 15:113.
  95. Li J, Chen QY, He J, et al. Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. Oncoimmunology 2015; 4:e976507.
  96. Chia WK, Teo M, Wang WW, et al. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther 2014; 22:132.
  97. Lin CL, Lo WF, Lee TH, et al. Immunization with Epstein-Barr Virus (EBV) peptide-pulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer Res 2002; 62:6952.
  98. Li F, Song D, Lu Y, et al. Delayed-type hypersensitivity (DTH) immune response related with EBV-DNA in nasopharyngeal carcinoma treated with autologous dendritic cell vaccination after radiotherapy. J Immunother 2013; 36:208.
  99. Chia WK, Wang WW, Teo M, et al. A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. Ann Oncol 2012; 23:997.
  100. Taylor GS, Haigh TA, Gudgeon NH, et al. Dual stimulation of Epstein-Barr Virus (EBV)-specific CD4+- and CD8+-T-cell responses by a chimeric antigen construct: potential therapeutic vaccine for EBV-positive nasopharyngeal carcinoma. J Virol 2004; 78:768.
  101. Hui EP, Taylor GS, Jia H, et al. Phase I trial of recombinant modified vaccinia ankara encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients. Cancer Res 2013; 73:1676.
  102. Taylor GS, Jia H, Harrington K, et al. A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer. Clin Cancer Res 2014; 20:5009.
  103. Chua DT, Wei WI, Wong MP, et al. Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head Neck 2008; 30:863.
  104. Ma B, Hui EP, King A, et al. A phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein-Barr virus DNA as a biomarker of efficacy. Cancer Chemother Pharmacol 2008; 62:59.
  105. You B, Le Tourneau C, Chen EX, et al. A Phase II trial of erlotinib as maintenance treatment after gemcitabine plus platinum-based chemotherapy in patients with recurrent and/or metastatic nasopharyngeal carcinoma. Am J Clin Oncol 2012; 35:255.
  106. Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007; 25:3766.
  107. Xue C, Huang Y, Huang PY, et al. Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol 2013; 24:1055.
  108. Lim WT, Ng QS, Ivy P, et al. A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res 2011; 17:5481.
  109. Hui EP, Ma BB, King AD, et al. Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann Oncol 2011; 22:1280.
  110. Soria JC, Deutsch E. Hemorrhage caused by antiangiogenic therapy within previously irradiated areas: expected consequence of tumor shrinkage or a warning for antiangiogenic agents combined to radiotherapy? Ann Oncol 2011; 22:1247.
  111. Hui EP, Ma BBY, Loong HHF, et al. Efficacy, Safety, and Pharmacokinetics of Axitinib in Nasopharyngeal Carcinoma: A Preclinical and Phase II Correlative Study. Clin Cancer Res 2018; 24:1030.
  112. Li L, Kong F, Zhang L, et al. Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study. Invest New Drugs 2020; 38:1847.
Topic 3381 Version 45.0

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