Treatment of early and locoregionally advanced nasopharyngeal carcinoma

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, but there was remarkable variation in racial and geographic distribution [1]. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Epidemiology'.)

The treatment of locoregional NPC is presented here. The treatment of recurrent and metastatic NPC is discussed separately. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma".)

HISTOLOGY — The World Health Organization (WHO) classifies NPC into three histopathologic types [2] (see "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Histology'):

●Keratinizing squamous cell carcinoma (WHO type I)

●Nonkeratinizing carcinoma, which includes differentiated carcinoma (WHO type II) and undifferentiated carcinoma (WHO type III)

●Basaloid squamous cell carcinoma, which is extremely rare

STAGING — NPC is staged according to the Tumor, Node, Metastasis (TNM) system of the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) [3,4]. The eighth edition of this staging system is shown in the table (table 1). Based on the risk of treatment failure, four prognostic groups can be defined according to the TNM staging system for nasopharyngeal cancer. In brief:

●Stage I (early stage) – This group is limited to patients with a T1 primary tumor (tumor confined to the nasopharynx, or adjacent oropharynx and/or nasal cavity without parapharyngeal involvement), no lymph node involvement (N0), and no distant metastases (M0). (See 'Early (stage I) disease' below.)

●Stage II (intermediate stage) – This group is limited to patients with a T1 or T2 (parapharyngeal extension but without involvement of bony structures) primary tumor, no or unilateral lymph node involvement ≤6 cm in greatest diameter (N0 or N1), and no distant metastases (M0). (See 'Intermediate (stage II) disease' below.)

●Stage III, IVA (advanced stage but without distant metastases [M0]) – Stage III disease is defined by bony involvement (T3) or by bilateral metastases in cervical lymph nodes ≤6 cm that are above the caudal border of the cricoid cartilage (N2).

Stage IVA disease is defined by either a T4 primary tumor (intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit) and N0, N1, or N2 disease; or any T stage primary tumor and N3 disease in the neck (unilateral or bilateral metastasis in cervical lymph node[s] ≥6 cm, and/or extension below the caudal border of the cricoid cartilage). (See 'Advanced (stage III and IVA) disease' below.)

●Stage IVB – Distant metastases present (M1), regardless of stage of primary tumor or status of neck nodes. The treatment approach to patients with distant metastatic disease is discussed separately. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma".)

Of note, patients with stage IVB tumors were previously classified as having locoregionally advanced disease without distant metastases, based on prior versions of the AJCC staging system. Therefore, some studies on locoregionally advanced disease that are presented here include patients with such staging. (See 'Advanced (stage III and IVA) disease' below.)

The eighth edition of the AJCC/UICC staging system is based on clinical data from a study of 1609 patients with NPC [3]. All patients were evaluated with magnetic resonance imaging (MRI), staged with the seventh edition of the AJCC/UICC staging system, and irradiated using intensity-modulated radiation therapy (IMRT) at two centers in Hong Kong and mainland China. Based on these findings, the following changes were integrated into the eighth edition of the AJCC/UICC staging system:

●Changing medial and/or lateral pterygoid involvement from T4 to T2

●Adding prevertebral muscle involvement as T2

●Replacing supraclavicular fossa with the lower neck (defined as extension below the caudal border of the cricoid cartilage)

●Merging lower neck involvement with a maximum nodal diameter >6 cm as N3

●Merging T4 and N3 as stage IVA criteria

These findings led to better distinction of the hazards between adjacent stages/categories and are more aligned with current nodal levels as defined by imaging [3].

Although patients with early-stage disease have good outcomes with RT alone, more intensive treatment strategies combining RT with chemotherapy are required to manage intermediate- and advanced-stage disease.

PRINCIPLES OF RADIATION THERAPY — NPC has traditionally been treated with radiation therapy (RT) because it is a radiosensitive tumor and because its anatomic location limits a surgical approach; RT remains the mainstay of treatment for patients with nasopharyngeal cancer.

The clinical outcomes with RT have improved significantly due to advances in high-precision RT delivery, the integration of chemotherapy, and improvement in tumor imaging and disease monitoring [5]. (See "General principles of radiation therapy for head and neck cancer" and "Radiation therapy techniques in cancer treatment".)

Endemic nasopharyngeal cancer (undifferentiated carcinoma, World Health Organization [WHO] type III) appears to be particularly radiosensitive and may be associated with higher overall survival rates (OS) than nonendemic disease (keratinizing squamous cell carcinoma, WHO type I). However, there is insufficient evidence to suggest that treatment should differ based on histopathologic classification. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Histology'.)

Radiation therapy techniques — More highly conformal external beam RT techniques, such as intensity-modulated RT (IMRT), its iteration volumetric modulated arc therapy, and proton therapy, have demonstrated better long-term disease control and less toxicity and fewer serious complications than older techniques, based on observational data [6,7] and randomized trials [8-10]. These RT techniques are standard of care, where available.

Since the dose gradients for these highly conformal radiation techniques are quite steep, it is important to ensure adequate patient immobilization and verify daily treatment set-up accuracy with imaging called image-guided RT. This is required with verification of set-up accuracy and for consideration of adaptive replanning in cases where there is a significant change in the patient's anatomy due to rapid tumor shrinkage, patient swelling, or weight loss.

The improved disease control with contemporary RT techniques was demonstrated in a phase III trial in which 616 patients with localized or locoregional disease were randomly assigned to treatment with either two-dimensional RT or IMRT [8]. IMRT was associated with improved OS (five-year OS 79.6 versus 67.1 percent) and decreased toxicity and complications (such as blindness and hearing loss). Other randomized trials in patients with NPC have shown that IMRT is superior to conventional RT in preserving parotid function and resulted in less severe late xerostomia without affecting local control in patients with early-stage NPC [9,10].

Although some institutions have performed dosimetric comparisons between IMRT and intensity-modulated proton therapy (IMPT) for NPC [11,12], clinical data on the use of IMPT in NPC are limited. (See "General principles of radiation therapy for head and neck cancer", section on 'External beam radiation therapy'.)

Radiation dosing and schedule

●Dosing – External beam RT (EBRT) is typically given to a total dose of 66 to 70 Gray (Gy) at 2 to 2.12 Gy per fraction to eradicate macroscopic disease and 50 to 60 Gy to treat potential subclinical disease in at-risk sites. EBRT is delivered using a once-daily fraction at five fractions per week [13-15].

The delineation of elective nodal volumes should cover the bilateral neck nodal basins from retropharyngeal lymph nodes to lateral neck levels II to IV and V (figure 1), due to the highly infiltrative nature of NPC within the nasopharyngeal mucosa and the propensity for early and bilateral involvement of regional lymph nodes [14]. Level IB is included when there is either level II or anterior nasal cavity involvement. This approach is consistent with consensus guidelines from the American Society of Clinical Oncology (ASCO) and the Chinese Society of Clinical Oncology (CSCO) [16].

In patients with a clinically and radiographically negative (N0) neck, compared with whole neck prophylactic RT, upper prophylactic RT down to the level III (middle jugular) nodes (figure 1) has demonstrated similar rates of disease control, suggesting that a reduced nodal treatment volume skipping level IV may be feasible and potentially limit toxicity [17-20].

●Schedule – Conventional fractionation using five daily fractions of RT per week remains the standard of care in NPC when delivered with chemotherapy. Although accelerated fractionation has been tested as an alternative, randomized trials suggest that it does not improve survival and may increase toxicity, when compared with a conventionally fractionated schedule of five treatments per week. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

Although one randomized trial suggested improved failure-free survival with accelerated RT, subsequent studies did not confirm a survival benefit and also demonstrated increased toxicity. Accelerated RT was initially evaluated in a randomized trial (NPC-9902) of 189 patients with T3-4, N0-1 disease [21]. In this study the combination of accelerated RT using six fractions per week plus adjunctive chemotherapy improved the five-year failure-free rate compared with accelerated fractionation without chemotherapy or conventional fractionation (five fractions per week) with or without chemotherapy (88 versus 56, 65, and 63 percent, respectively). However, in subsequent trials, altered fractionation schedules have either not improved survival or increased toxicity [22-25]. As an example, in one randomized trial (NPC-0501), compared with conventional fractionation, accelerated fractionation did not confer any survival benefit and was associated with increased toxicity, specifically acute mucositis and dehydration [22,23].

IS THERE A ROLE FOR SURGERY? — Surgery is not used as initial treatment at the primary site because of the relative lack of surgical access to the deep anatomical location of the nasopharynx and its close proximity to critical neurovascular structures [26]. However, neck dissection may be indicated after radiation therapy (RT) for residual nodal disease or for an isolated neck recurrence. However, nasopharyngectomy may be an option for a small, localized recurrence. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma", section on 'Resectable disease'.)

EARLY (STAGE I) DISEASE — For patients with early, stage I disease, we recommend radiation therapy (RT) alone rather than chemoradiation, as this approach provides excellent locoregional control and avoids the potential toxicity of additional chemotherapy [27-29].

The efficacy of intensity-modulated RT (IMRT) in this population was established in a nonrandomized phase II trial (Radiation Therapy Oncology Group 0225) of 68 patients with locoregionally advanced NPC, including a subset of nine patients with stage I disease treated with IMRT alone [29]. At a median follow-up of 2.6 years, none of the patients with stage I disease experienced locoregional failure. For the entire study population, the two-year local progression-free interval and progression-free survival (PFS) and overall survival (OS) rates were 92, 73, and 80 percent, respectively. Further data on the radiation techniques used in this trial are discussed separately. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'Simultaneous integrated boost technique with IMRT'.)

Subsequent studies using more contemporary IMRT techniques have reported improved five-year OS rates of 93 percent or more in those with early-stage disease (table 2) [28]. The prognosis for patients with NPC, based on stage, is discussed below. (See 'Prognosis' below.)

INTERMEDIATE (STAGE II) DISEASE

Risk classification — The management of patients with stage II (T1 to T2, N1 or T2N0 (table 1)) nasopharyngeal carcinoma (NPC) is based on the risk of disease recurrence, as defined by clinical lymph node involvement and/or pretreatment plasma Epstein-Barr Virus (EBV) DNA levels.

●High-risk stage II disease – Patients with high-risk stage II disease have one or more of the following adverse features [16,30,31]:

•Cervical lymph nodes ≥3 cm

•Level IV or VB lymph nodes (figure 1)

•Extranodal extension

•Pretreatment plasma EBV DNA ≥4000 copies/mL

EBV DNA levels are obtained as part the initial diagnostic and staging evaluation of NPC. Of note, test results may be variable across institutions and regions, and further harmonization and validation of this assay is necessary. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Initial diagnostic evaluation'.)

●Low-risk stage II disease – Patients with low-risk stage II disease have none of the above high-risk features.

Low-risk stage II disease — For patients with stage II (T1 to T2, N1 or T2N0 (table 1)) disease who are at low risk for recurrence (see 'Risk classification' above), we suggest intensity-modulated radiation therapy (IMRT) alone rather than concurrent chemoradiation. However, chemoradiation still remains a reasonable alternative in this population, pending further follow-up confirming a long-term survival benefit for radiation therapy (RT) alone. In a randomized phase III trial, RT alone demonstrated noninferior failure-free survival (FFS) and overall survival (OS) and was better tolerated compared with chemoradiation in this patient population as well as those with low-risk T3N0 (stage III) disease [31]. The management of T3N0 disease is discussed below. (See 'Advanced (stage III and IVA) disease' below.)

In a multicenter, open-label phase III trial, 341 patients with AJCC seventh edition T1 to T2, N1M0 or T2N0M0 (stage II) and T3N0M0 (stage III), low-risk NPC were randomly assigned to either IMRT alone or chemoradiation (IMRT with concurrent bolus cisplatin administered at 100 mg/m² on days 1, 22, and 43) [31]. At median follow-up of 46 months, IMRT demonstrated noninferior FFS (three-year FFS 91 versus 92 percent, HR 1.35, 95% CI 0.69-2.64) and OS (three-year OS 98 versus 99 percent, HR 3.22, 95% CI 0.65-15.98) in the entire study population. Noninferior FFS was also seen across all patient subgroups, including those with stage II (HR 1.25) and stage III (HR 1.61) disease. Distant metastasis-free and locoregional relapse-free survival were also similar for the two treatment arms. Grade ≥3 toxicities were more frequent with chemoradiation versus IMRT alone including leukopenia (10 versus 1 percent), neutropenia (7 versus 2 percent), nausea (13 versus 1 percent), vomiting (15 versus 1 percent), anorexia (29 versus 5 percent), weight loss (5 versus 1 percent), and mucositis (19 versus 10 percent). Quality of life scores were also improved with IMRT compared with chemoradiation.

High-risk stage II disease — For patients with stage II (T1 to T2, N1 and T2N0 (table 1)) disease at high risk for recurrence (see 'Risk classification' above), we suggest concurrent chemoradiation rather than RT alone because this approach improved OS and decreased the risk of distant metastatic disease in a randomized trial [32,33]. (See 'Concurrent chemoradiation' below and 'Choice of chemosensitizing agent' below.)

In an open-label phase III trial, 230 patients with previously untreated stage II NPC were randomly assigned to two-dimensional RT plus concurrent weekly cisplatin (30 mg/m²) versus RT alone [32,33]. All patients had T1-2N1M0 or T2N0M0 disease with parapharyngeal space involvement. When patients were restaged according to the 2010 Tumor, Node, Metastasis (TNM) staging system, 31 patients (13 percent) were reclassified as stage III.

With a median follow-up of 10 years, the addition of concurrent cisplatin to RT improved OS (five-year OS 95 versus 86 percent, 10-year OS 84 versus 66 percent, hazard ratio [HR] 0.40, 95% CI 0.23-0.68). The OS benefit was mostly seen in those with T2N1 (more bulky tumor volume and nodal) disease [33]. This difference was mainly due to an improvement in distant metastasis-free survival (94 versus 83 percent), as rates of locoregional relapse-free survival were similar in the two study arms (89 versus 87 percent). Multivariate analysis showed that the number of chemotherapy cycles delivered was the only independent factor that was associated with survival, progression, and distant disease control.

In this trial, the addition of weekly cisplatin to RT was associated with an increase in severe (grade 3 or 4) leukopenia/neutropenia, nausea/vomiting, and mucositis compared with RT alone (12 versus 0, 8.6 versus 0, and 46 versus 33 percent, respectively). There was no significant increase in late toxicity. Reported rates of acute and late toxicities were lower than expected for these treatment protocols.

ADVANCED (STAGE III AND IVA) DISEASE — A combined-modality approach that includes concurrent chemoradiation is the basis for the standard treatment approach of patients with advanced, nonmetastatic NPC (American Joint Committee on Cancer [AJCC] eighth edition stages III and IVA disease (table 1)) [34,35]. Options include either the use of induction chemotherapy followed by concurrent chemoradiation or concurrent chemoradiation with or without adjuvant chemotherapy [36,37].

Of note, in previous versions of the AJCC staging system, stage IVB tumors were classified as locoregionally advanced disease (any T stage, N3) without distant metastases, and some studies presented here on locoregionally advanced disease included patients with such staging.

Selection of therapy — For patients with advanced NPC, our treatment approach is as follows, which is generally consistent with consensus guidelines from the American Society of Clinical Oncology (ASCO) and the Chinese Society of Clinical Oncology (CSCO) [16]:

●Stage III to IVA (except T3N0) disease – For most patients with more advanced NPC (stage III to IVA disease, except those with T3N0 disease) and good performance status (table 3), we suggest induction chemotherapy followed by concurrent chemoradiation rather than concurrent chemoradiation alone, as this approach improved overall survival (OS) in randomized trials. In such patients who are able to tolerate more intense therapy, induction chemotherapy can reduce tumor burden, increase control of both locoregional and systemic disease, and allow for smaller high-dose radiation volumes during concurrent chemoradiation [16,27]. The choice of treatment regimens is discussed below. (See 'Induction chemotherapy' below and 'Concurrent chemoradiation' below.)

●T3N0 disease – For patients with T3N0 disease, the evidence to support induction chemotherapy followed by chemoradiation is weaker [16,27]. These patients have a lower risk of treatment failure [38] and were often excluded from randomized trials assessing the addition of induction or adjuvant chemotherapy to concurrent chemoradiation [16]. Our approach is as follows:

•For patients with T3N0 disease who are at low risk for recurrence (see 'Risk classification' above), we suggest RT alone rather than chemoradiation. However, chemoradiation still remains a reasonable alternative in this population, pending further follow-up confirming a long-term survival benefit for RT alone in a phase III trial [31]. Low-risk T3N0 disease is treated using a similar approach to those with low-risk stage II disease. (See 'Low-risk stage II disease' above.)

•For patients with T3N0 disease at high risk for recurrence (see 'Risk classification' above), we suggest concurrent chemoradiation rather than radiation alone, although trials evaluating chemoradiation have typically excluded these patients. The decision to add either induction chemotherapy or adjuvant chemotherapy is individualized and best made in a multidisciplinary treatment setting. (See 'Concurrent chemoradiation' below.)

●Ineligible for induction chemotherapy – For those patients who are ineligible for or unable to tolerate cisplatin-based induction chemotherapy, we alternatively offer concurrent chemoradiation followed by adjuvant chemotherapy. However, concurrent chemoradiation alone is also a reasonable alternative for patients who chose to forego or cannot tolerate adjuvant chemotherapy (ie, due to decreased performance status (table 3) or comorbidities). The choice of treatment regimens is discussed below. (See 'Concurrent chemoradiation' below and 'Adjuvant chemotherapy' below.)

Induction chemotherapy — For patients who are candidates for induction chemotherapy, we suggest three cycles of gemcitabine plus cisplatin (GP), as this regimen improves OS, has a manageable toxicity profile, and is easier to administer than other available regimens [39,40]. Other alternative induction regimens that may be used in the absence of medical contraindications include cisplatin plus docetaxel and fluorouracil (TPF), cisplatin plus paclitaxel and capecitabine (TPC), cisplatin plus either fluorouracil or oral capecitabine, or cisplatin plus docetaxel. Patients with a contraindication to such cisplatin-based combination chemotherapy should be offered alternative treatment approaches. (See 'Selection of therapy' above.)

Among patients with advanced NPC, the addition of induction chemotherapy to chemoradiation confers an OS advantage. A meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) included 28 randomized controlled clinical trials with 8214 patients with non-metastatic NPC [41]. At median follow-up of 7.6 years, induction chemotherapy plus chemoradiation improved OS compared with chemoradiation alone (HR 0.75, 95% 0.59-0.96 for induction chemotherapy with taxanes; HR 0.81, 95% CI 0.69-0.95 for induction chemotherapy without taxanes) [41].

These randomized studies investigating induction chemotherapy have some limitations. For example, patients with T3-4, N0 disease were excluded from most trials investigating induction chemotherapy. Demographic and dosing differences may affect the generalizability of these results outside of endemic regions such as eastern Asia.

The following phase III trials compared induction regimens followed by concurrent chemoradiation versus concurrent chemoradiation alone:

●In a multicenter phase III clinical trial conducted by Sun Yat-sen University in China, 480 patients with newly diagnosed, stage III to IVB, node-positive disease were randomly assigned to induction chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation alone [39,40].

Induction chemotherapy consisted of three cycles of gemcitabine 1000 mg/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1 of a 21-day cycle. Concurrent chemoradiation used cisplatin at 100 mg/m² on days 1, 22, and 43.

At a median follow-up of 70 months, induction chemotherapy demonstrated the following [40]:

•Improved OS in the entire study population (five-year OS 88 versus 79 percent, HR 0.51, 95% CI 0.34-0.78).

•Improved failure-free survival (FFS; five-year FFS 81 versus 67 percent, hazard ratio [HR] 0.51, 95% CI 0.36-0.73).

•Improved distant metastasis-free survival (DMFS; five-year DMFS 90 versus 78 percent, HR 0.42, 95% CI 0.27-0.67).

•Similar locoregional RFS (five-year RFS 88 versus 83 percent, HR 0.65, 95% CI 0.41-1.02).

Induction chemotherapy was well tolerated, with a majority of patients (97 percent) receiving all three cycles of gemcitabine and cisplatin. Grade 3 or greater toxicities were higher in the induction therapy group (76 versus 56 percent), with higher incidences of neutropenia, thrombocytopenia, anemia, nausea, and vomiting. Grade 3 or greater late toxic effects were similar between the two groups (11 percent each). Grade 1 to 2 late peripheral neuropathy was higher in the induction group, likely reflecting the higher cumulative doses of cisplatin (9 versus 2 percent).

●In a multicenter phase III trial also conducted by Sun Yat-sen University in China, 480 patients with stage III to IVB, node-positive disease were randomly assigned to induction chemotherapy followed by concurrent chemoradiation or concurrent chemoradiation alone [42].

Induction chemotherapy consisted of three cycles of docetaxel (60 mg/m² on day 1), cisplatin (60 mg/m² on day 1), and fluorouracil (600 mg/m² per day as a continuous infusion on days 1 to 5). Concurrent chemoradiation used cisplatin at 100 mg/m² on days 1, 22, and 43. Patients with node-negative disease were excluded, and the TPF dosing was lower than the standard TPF validated in other head and neck cancer clinical trials [43,44].

Induction TPF resulted in the following:

•Improved FFS at three years (80 versus 72 percent, HR 0.68, 95% CI 0.48-0.97).

•Improved three-year OS (92 versus 86 percent, HR 0.59, 95% CI 0.36-0.95).

•Distant metastases were significantly reduced, and locoregional failure was lower, although not significantly, in the induction arm.

•Late toxicities have not yet been reported, and this may be of particular concern because of the higher cumulative cisplatin dose with the induction regimen.

●In a third multicenter trial also conducted at Sun Yat-sen University in China, 476 patients with node-positive, stage III to IVB disease were randomly assigned to either two cycles of induction chemotherapy followed by concurrent chemoradiation or to concurrent chemoradiation alone [45,46].

Induction chemotherapy consisted of two cycles of cisplatin 80 mg/m² on day 1 plus fluorouracil 800 mg/m² continuous intravenous infusion on days 1 through 5 of a 21-day cycle. Concurrent chemoradiation used cisplatin 80 mg/m² on days 1, 22, and 43.

After a median follow-up of 83 months, induction chemotherapy resulted in the following:

•Improved disease-free survival (five-year disease-free survival 73 versus 63 percent, HR 0.65, 95% CI 0.48-0.88).

•Improved DMFS (five-year DMFS 83 versus 73 percent, HR 0.61, 95% CI 0.42-0.90).

•Similar locoregional RFS (five-year RFS 88 versus 85 percent, HR 0.75, 95% CI 0.47-1.19).

•Improved OS (five-year OS 81 versus 77 percent, HR 0.70, 95% CI 0.5-1.0).

•Similar survival among patients receiving two-dimensional RT and intensity-modulated RT (IMRT).

•No difference in grade 3 or greater late toxicities.

●The Taiwan Cooperative Oncology Group evaluated a multiagent induction regimen of mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin given for three cycles followed by weekly cisplatin (30 mg/m²) during RT compared with weekly cisplatin plus RT in 479 patients with stage IV disease [47]. This induction regimen improved disease-free survival (61 versus 50 percent at five years, HR 0.73, 95% CI 0.57-0.97). OS was similar in the two arms (72 versus 68 percent at five years, HR 0.92, 95% CI 0.67-1.27). Owing to increased myelotoxicity, which persists from the induction phase to the RT period, fewer patients in the induction arm (26 percent) completed the planned concurrent cisplatin during RT than in the control arm (73 percent), which may have compromised the therapeutic effect.

●In the phase III GORTEC trial conducted in 83 patients with stage III to IVB NPC, the addition of the full-dose European version of the TPF induction regimen to concurrent chemoradiation improved three-year progression-free survival (PFS; HR 0.44, 95% CI 0.20-0.97), but not OS (HR 0.40, 95% CI 0.15-1.04) [48]. Of note, this trial was prematurely closed due to poor accrual.

●The Hong Kong Nasopharyngeal Cancer Study group (HKNPCSG) 0501 trial evaluated the potential therapeutic gain of reversing the sequence of the United States Intergroup 0099 regimen [49]. It is a six-arm study that includes a comparison of induction-concurrent chemotherapy versus concurrent-adjuvant chemotherapy in stage III to IVB NPC [22]. In subsequent follow-up of this trial, induction chemotherapy plus chemoradiation was compared with chemoradiation plus adjuvant chemotherapy. Data from a subgroup analysis of those treated with conventional fractionation suggested that induction chemotherapy improved five-year OS (84 versus 72 percent) and PFS (78 versus 62 percent), after adjusting for multiple comparisons [23].

Clinical trials that directly compare induction chemotherapy regimens are limited. In one phase III trial, 238 patients with AJCC seventh edition stage IVA and IVB NPC were randomly assigned to induction chemotherapy with either cisplatin plus paclitaxel and capecitabine (TPC) or cisplatin plus fluorouracil, followed by chemoradiation [50]. At median follow-up of 48 months, compared with cisplatin plus fluorouracil, TPC improved failure-free survival (84 versus 69 percent at three years, HR 0.47, 95% CI 0.28-0.79), distant metastasis-free survival (91 versus 80 percent at three years, HR 0.49, 95% CI 0.24-0.98), and locoregional relapse-free survival (94 versus 87 percent at three years, HR 0.4, 95% CI 0.18-0.93), but failed to improve OS (95 versus 89 percent at three years, HR 0.45, 95% CI 0.17-1.18). TPC had lower rates of grade 3 to 4 acute toxicities (58 versus 66 percent) and similar rates of late-onset toxicities (14 versus 18 percent) compared with cisplatin plus fluorouracil.

Concurrent chemoradiation

Rationale for concurrent chemoradiation — For patients with advanced NPC, concurrent chemoradiation (either alone or in combination with adjuvant chemotherapy) improves OS compared with RT alone. Concurrent chemoradiation improves local control at the primary site and neck, and the chemosensitizing agent used with RT may also have a more modest effect on distant micrometastases. (See 'Adjuvant chemotherapy' below.)

The efficacy of concurrent chemoradiation (in combination with adjuvant chemotherapy) was initially demonstrated in a phase III trial (the United States Intergroup 0099 trial), in which 193 patients with advanced nasopharyngeal cancer were randomly assigned to either chemoradiation with cisplatin followed by adjuvant chemotherapy with three cycles of cisplatin plus fluorouracil or RT alone [49]. Among the 147 patients eligible for evaluation, compared with RT alone, chemoradiation plus adjuvant chemotherapy improved both PFS (three-year PFS 69 versus 24 percent) and OS (three-year OS 78 versus 47 percent). Of note, approximately one-half of patients (55 percent) treated with chemoradiation and adjuvant chemotherapy were able to fully comply with the prescribed regimen due to treatment-related toxicity.

The benefit of a concurrent chemoradiation alone was subsequently illustrated by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group [34]. This meta-analysis included data on 1834 patients in seven trials in which concurrent chemotherapy during RT (without induction or adjuvant chemotherapy) was compared with RT alone. At median follow-up of 7.7 years, compared with RT alone, concurrent chemotherapy improved both OS (10-year OS 59 versus 51 percent, HR 0.80, 95% CI 0.70-0.93) and PFS (10-year PFS 52 versus 44 percent, HR 0.81, 95% CI 0.71-0.92).

Choice of chemosensitizing agent — For patients receiving concurrent chemoradiation for NPC, we suggest the concurrent use of cisplatin with RT rather than other chemotherapy agents. Cisplatin is the standard chemosensitizer for concurrent chemoradiation in the treatment of NPC. Patients who are ineligible for cisplatin may be offered alternative agents such as carboplatin or oxaliplatin. (See 'Alternative agents' below.)

Cisplatin — For patients being treated with concurrent chemoradiation using cisplatin, either weekly dosing (40 mg/m² weekly) or bolus dosing (100 mg/m² on days 1, 22, and 43) are acceptable strategies, as both approaches had similar efficacy but varying toxicity profiles in observational data and randomized trials [51-53].

Weekly cisplatin can also be readily administered in the outpatient setting and is less resource intensive. Thus, weekly cisplatin has become the standard of care for patients with locally advanced NPC undergoing chemoradiation in many oncology centers. The delivered cisplatin dose intensity seems more important for disease control than the specific cisplatin schedule, and a cumulative cisplatin dose of 200 mg/m² is the minimum threshold [32,54-56]. The use of cisplatin as a chemosensitizer in other head and neck cancers is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cisplatin'.)

In a phase III trial, 510 patients with locoregionally advanced NPC were randomly assigned to either bolus cisplatin (100 mg/m² every three weeks for two cycles) or weekly cisplatin (40 mg/m² weekly for six cycles) dosing concurrently with IMRT. At a median follow-up of 58 months, there was no significant difference in three-year failure-free survival (85 versus 86 percent). Although both regimens were well tolerated, grade ≥3 toxicity rates were higher in those receiving weekly versus bolus dosing (66 versus 56 percent), including hematologic toxicity and hearing loss [52]. A separate randomized phase II trial demonstrated similar efficacy for the two schedules and a nonsignificant trend towards worsened toxicity with weekly dosing [51]. Despite the results of these two trials, other evidence in head and neck cancer suggests that weekly dosing has better tolerability than bolus dosing of cisplatin. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cisplatin'.)

Alternative agents — The substitution of carboplatin or oxaliplatin as chemosensitizing agents are reasonable alternatives to cisplatin for patients with a poor performance status or comorbidities.

●Carboplatin – For patients with borderline renal function, pre-existing hearing loss or tinnitus, older age, or decreased performance status (Eastern Cooperative Oncology Group [ECOG] 2 or worse (table 3)) who are receiving concurrent chemoradiation, we offer carboplatin as an alternative chemosensitizer to cisplatin. However, data for carboplatin in this setting are limited and further studies are needed before carboplatin-containing regimens can be recommended with the same confidence as cisplatin-containing regimens.

Carboplatin has a more favorable toxicity profile than cisplatin and appears to have similar efficacy. In a single phase III trial, 206 patients were randomly assigned to cisplatin concurrent with RT followed by three cycles of adjuvant cisplatin and fluorouracil or to carboplatin (100 mg/m² on days 1, 8, 15, 22, 29, and 36) concurrent with RT and followed by three cycles of adjuvant chemotherapy consisting of carboplatin (area under the concentration x time curve of 5 on day 1) plus fluorouracil (1000 mg/m² over 96 hours) every four weeks beginning four weeks after the end of RT [57].

At a median follow-up of 26 months, three-year disease-free survival (63 versus 61 percent) and OS (78 versus 79 percent) were similar for both regimens. However, this study had limited follow-up for a disease that has a much longer natural history than other head and neck cancers. Additionally, as the carboplatin regimens used in this study are no longer a standard of care, substitution of cisplatin by carboplatin cannot be considered equivalent based on this study alone [57].

Fewer patients assigned to the cisplatin arm compared with the carboplatin arm completed concurrent chemoradiation (59 versus 73 percent) plus three cycles of adjuvant chemotherapy (42 versus 70 percent). Patients treated with cisplatin had more renal toxicity, nausea and vomiting, and anemia compared with carboplatin (26 versus 0, 59 versus 34, and 47 versus 18 percent, respectively). Weight loss and the need for enteral nutritional support were also more frequent with cisplatin. Thrombocytopenia was less frequent with cisplatin (4 versus 12 percent).

●Oxaliplatin – The addition of weekly oxaliplatin (70 mg/m² over two hours) to RT improved OS in a randomized trial. However, oxaliplatin has not been directly compared with cisplatin [58,59].

Adjuvant chemotherapy — For most patients with locoregionally advanced disease who are ineligible for or unable to tolerate cisplatin-based induction chemotherapy, we suggest concurrent chemoradiation followed by adjuvant chemotherapy. However, concurrent chemoradiation alone is also a reasonable alternative for patients who chose to forego or cannot tolerate adjuvant chemotherapy (ie, due to decreased performance status (table 3) or comorbidities). (See 'Concurrent chemoradiation' above.)

For patients with advanced NPC, chemoradiation plus adjuvant chemotherapy improved OS compared with RT alone. The choice of adjuvant regimen is discussed below. (See 'Choice of adjuvant chemotherapy' below.)

Rationale for adjuvant chemotherapy — The combination of chemoradiation plus adjuvant chemotherapy improved OS compared with RT alone. Initial randomized trials failed to demonstrate a survival benefit of adjuvant chemotherapy following RT alone [60,61]. However, in a meta-analysis (MAC-NPC) of six trials including 1267 patients, concurrent chemoradiation followed by adjuvant chemotherapy improved OS versus RT alone (10-year OS 57 versus 43 percent, HR 0.65, 95% CI 0.56-0.76) [34]. A subsequent network meta-analysis also demonstrated similar results [35].

The clinical benefit for the combination of concurrent chemoradiation plus adjuvant chemotherapy over chemoradiation alone is evolving. In an updated meta-analysis of MAC-NPC that included 28 randomized controlled clinical trials with 8214 patients, at median follow-up of 7.6 years, the addition of adjuvant chemotherapy to chemoradiation demonstrated a non-statistically significant trend towards higher OS, which would be clinically meaningful if true (HR 0.88, 95% 0.75-1.04) [41].

The benefit of concurrent chemoradiation followed by adjuvant chemotherapy may be partially offset by toxicities. In one randomized phase III trial comparing concurrent chemoradiation plus adjuvant chemotherapy with RT alone, grade ≥3 late toxicities were more frequent at three years, but the difference between the treatment arms gradually decreased over time (10-year cumulative incidence 52 versus 47 percent) [62,63].

Choice of adjuvant chemotherapy

Gemcitabine plus cisplatin — For patients receiving chemoradiation followed by adjuvant chemotherapy, we suggest three cycles of adjuvant gemcitabine plus cisplatin rather than cisplatin plus fluorouracil (FU), which improved PFS in a randomized trial [64]

In an open-label phase III trial, 240 patients with locoregionally advanced (AJCC seventh edition stage T1-4 N2-3 M0) treatment-naïve nasopharyngeal carcinoma were randomly assigned to chemoradiation with concurrent cisplatin followed by three cycles of adjuvant therapy with either gemcitabine plus cisplatin or FU plus cisplatin [64].

At median follow-up of 40 months, relative to adjuvant FU and cisplatin, adjuvant gemcitabine plus cisplatin improved PFS (three-year PFS 84 versus 72 percent, HR 0.54, 0.32-0.93) and reduced the risks of locoregional relapse (three-year cumulative incidence 3 versus 13 percent, HR 0.33, 95% CI 0.12-0.90) and distant metastases (three-year cumulative incidence 11 versus 22 percent, HR 0.50, 95% CI 0.26-0.98). OS was similar between the treatment arms (three-year OS 91 versus 94 percent, HR 1.17, 95% CI 0.51 to 2.66). Compliance with all three cycles of adjuvant therapy was similar between the two treatment arms (approximately 71 percent each). However, grade ≥3 hematologic toxicity rates were higher for adjuvant gemcitabine plus cisplatin compared with FU plus cisplatin (leukopenia [52 versus 29 percent] and neutropenia [32 versus 16 percent]), including one death from septic shock due to neutropenic infection.

Platinum plus fluorouracil — For patients receiving adjuvant chemotherapy who decline or are ineligible for gemcitabine plus cisplatin (ie, due to concerns for hematologic toxicity), adjuvant therapy with three cycles of cisplatin plus fluorouracil is an appropriate alternative. For those with a contraindication to cisplatin, we offer three cycles of adjuvant carboplatin plus fluorouracil, which was noninferior to adjuvant cisplatin plus fluorouracil in a randomized trial [57].

The efficacy of adjuvant cisplatin plus fluorouracil following concurrent chemoradiation over RT alone was established in the United States Intergroup 0099 trial [49] and later confirmed in subsequent randomized trials [21,63,65,66]. The data for the United States Intergroup 0099 trial are discussed above. (See 'Concurrent chemoradiation' above.)

What is the role of adjuvant capecitabine? — Adjuvant capecitabine is an active and well-tolerated chemotherapy regimen that improved failure-free survival (after chemoradiation) and OS (after induction chemotherapy plus chemoradiation) in randomized phase III trials [67,68]. While promising, longer follow-up of these data and further randomized studies comparing capecitabine with adjuvant platinum-based chemotherapy are needed before incorporating this approach into routine clinical practice. Patients who are interested in adjuvant capecitabine should be offered enrollment in appropriate clinical trials.

Two dosing strategies for adjuvant capecitabine (metronomic versus standard) have been investigated in separate randomized trials and found to be effective when added to concurrent chemoradiation [67,68]. Compliance rates with these dosing regimens (between 74 and 80 percent) are higher than those reported with adjuvant platinum-based chemotherapy (55 percent for cisplatin plus fluorouracil [49]). However, the optimal dosing strategy is not yet established. Data are as follows:

●Metronomic-dose capecitabine – Metronomic chemotherapy uses frequent, lower doses of chemotherapy over long periods of time to target tumor angiogenesis and minimize toxicity. The addition of adjuvant metronomic capecitabine to concurrent chemoradiation improved OS in a randomized phase III trial of 406 patients with locoregionally advanced (stage III to IVA, excluding those T3 to 4N0 and T3N1) disease [67]. All patients received definitive chemoradiation, and a majority (77 percent) also received cisplatin-based induction chemotherapy, mostly with docetaxel plus cisplatin. After completing chemoradiation, patients were randomly assigned to either oral metronomic capecitabine (650 mg/m² orally twice daily for one year) or clinical observation.

At a median follow-up of 38 months, compared with observation, metronomic chemotherapy improved three-year failure-free survival (85 versus 76 percent, HR 0.50, 95% CI 0.32-0.79) for both locoregional and metastatic disease. Metronomic capecitabine also improved three-year OS (93 versus 89 percent, HR 0.44, 95% CI 0.22-0.88). Grade ≥3 toxicity rates were higher for capecitabine versus observation (17 versus 6 percent), including hand-foot syndrome (9 versus 0 percent). Compliance rates were high, as approximately 74 percent of patients completed one year of treatment.

●Standard-dose capecitabine – The addition of standard dose capecitabine to concurrent chemoradiation improved failure-free survival and was well tolerated in a randomized phase III trial. In this study, 180 patients with stage III to IVB disease with at least one high-risk feature were randomly assigned to concurrent cisplatin-based chemoradiation plus either eight cycles of adjuvant capecitabine (1000 mg/m² twice a day on days 1 through 14 of a 21 day cycle) or no adjuvant therapy [68]. High-risk features included T3-4 plus N2 disease or any T stage plus N3 disease; pretreatment plasma Epstein-Barr virus (EBV) DNA of >20,000 copy/mL; gross primary tumor volume of >30 cm²; maximum standard uptake value of >10 within the primary tumor on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)-computed tomography (CT); or multiple neck node metastases, any greater than 4 cm.

At median follow-up of 58 months, compared with observation, capecitabine improved five-year failure-free survival (79 versus 66 percent, HR 0.53, 95% CI 0.30-0.94) [68]. Three-year OS was similar between the two treatment arms (93 versus 88 percent, HR 0.62, 95% CI 0.29-1.32), and OS follow-up is ongoing. Compared with no adjuvant therapy, adjuvant capecitabine had higher grade ≥3 acute (60 versus 51 percent) and similar long-term (11 versus 9 percent) toxicity rates. Compliance rates were high, as approximately 80 percent of patients completed all eight cycles of capecitabine.

Can EBV DNA select patients for adjuvant therapy? — The use of Epstein-Barr virus (EBV) DNA to select patients for adjuvant therapy remains investigational. Developing a standardized assay is also a challenge. Further randomized trials are necessary prior to incorporating this approach into routine clinical practice. The role of posttreatment EBV DNA levels for surveillance is discussed below. (See 'Is there a role for EBV DNA in posttreatment surveillance?' below.)

Plasma EBV DNA is the most significant prognostic biomarker in NPC [69]. However, in a randomized trial, the addition of adjuvant chemotherapy to chemoradiation did not improve relapse-free survival in those with detectable postradiation EBV DNA levels [70]. In this study conducted by the HKNPCSG, 104 patients with residual detectable EBV DNA after completion of radiation or chemoradiation were randomly assigned to six cycles of GP or to routine follow-up after completion of chemoradiation [70]. There was no significant difference in relapse-free survival, the primary endpoint of the trial (HR 1.09, 95% CI 0.63-1.89) or in OS (HR 1.09, 95% CI 0.56-2.11).

INVESTIGATIONAL AGENTS — Various other agents have been investigated as a component of either concurrent chemoradiation or induction therapy regimens in patients with locoregionally advanced nasopharyngeal cancer. Further data are necessary before incorporating these agents into routine clinical practice.

Examples of agents that have been investigated as part of concurrent chemoradiation include cetuximab plus cisplatin [71], lobaplatin [72], nimotuzumab [73], bevacizumab [74], and tumor-infiltrating lymphocytes [75]. Examples of agents investigated as part of induction chemotherapy include lobaplatin plus fluorouracil, which was compared with cisplatin plus fluorouracil in a randomized phase III trial [72].

POSTTREATMENT FOLLOW-UP

Evaluation of treatment response — Documentation of a complete treatment response in the nasopharynx and neck through clinical and endoscopic examination and imaging studies is important. Our preference is to obtain a posttreatment baseline magnetic resonance imaging (MRI) scan of the skull base and neck and a full-body combined positron emission tomography (PET)/computed tomography (CT) scan approximately three months after treatment completion.

Distinguishing between viable residual tumor, slowly regressing tumor, and posttherapy changes may be difficult. MRI and PET/CT scans may achieve higher accuracy when combined, rather than individually, in detecting residual disease [76,77]. Obtaining imaging studies too early, in particular combined PET/CT scans prior to 12 weeks following treatment, can lead to false-positive results.

Surveillance for recurrence — Posttreatment surveillance is important for early detection of recurrent local or metastatic disease and for monitoring for toxicity. We follow patients every three months for years 1 to 2, every four to six months for years 3 to 5, and annually thereafter. Follow-up includes examination of the nasopharynx and neck, assessment of cranial nerve function, and evaluation of systemic complaints. Periodic upper endoscopy should be performed, similar to the approach used for other head and neck cancers. Most experts suggest reimaging only as indicated by signs and symptoms [78]. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

NPC has a greater propensity to recur later than head and neck cancers arising in other sites. Bone is the most frequent site for first distant metastases, followed by liver and then lung [79]. The treatment of recurrent and metastatic NPC is discussed separately. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma".)

Is there a role for EBV DNA in posttreatment surveillance? — While Epstein-Barr virus (EBV) DNA levels may also have a role in detecting disease recurrence, further prospective data confirming a survival benefit are needed before it is incorporated into routine posttreatment surveillance [80]. Observational data suggest that posttreatment cell-free EBV DNA is associated with higher rates of identifying disease recurrence, has a high sensitivity and specificity for detecting distant metastatic disease, and may detect disease recurrence earlier than imaging or clinical findings [81,82]; however, such studies are limited by patient selection bias and a nonuniform approach to blood tests and imaging [80]; long-term survival data are evolving [83]. As examples:

●In one retrospective study, 1984 patients with locoregionally advanced NPC treated with radiation therapy (RT) were periodically monitored with cell-free EBV DNA levels until disease recurred or for a median of five years [80]. Disease recurrence rates were higher among the approximately 39 percent with detectable EBV DNA (64 versus 9 percent). EBV DNA also identified recurrences approximately two months prior to radiographic or clinical evidence of disease. Sensitivity and specificity for detection of distant metastases were 91 and 80 percent, respectively. EBV DNA levels had a higher sensitivity for the detection of extrapulmonary versus pulmonary metastases (95 versus 78 percent) and were less sensitive and specific for the detection of local and regional recurrences. A majority of patients with detectable EBV DNA but without disease recurrence had levels that eventually normalized in long-term follow-up.

●Postradiation plasma EBV DNA clearance may serve as an early surrogate endpoint for long-term progression-free survival (PFS). In one prospective trial, 789 patients with locally advanced NPC treated with RT were randomly assigned to adjuvant chemotherapy versus observation. Among the patients with detectable postradiation plasma EBV DNA, five-year PFS was higher in those who experienced subsequent postradiation EBV DNA clearance compared with those without clearance (86 versus 23 percent) and was comparable to patients with initially undetectable plasma EBV DNA (77 percent) [83].

TREATMENT-RELATED COMPLICATIONS — A wide range of acute and late treatment-related complications can be seen after radiation therapy (RT) or concurrent chemoradiation [24,62,84-96]. The use of intensity-modulated RT (IMRT) may reduce the frequency or severity of such treatment-related complications.

●Common acute toxicities – For patients with NPC treated with RT alone, the predominant acute toxicity is mucositis. The addition of chemotherapy can also exacerbate mucositis and be associated with other acute toxicities such as neuropathy, emesis, neutropenia, nephrotoxicity, ototoxicity, and hematologic toxicity [49,97,98].

•(See "Management and prevention of complications during initial treatment of head and neck cancer".)

•(See "Overview of neurologic complications of platinum-based chemotherapy".)

•(See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

•(See "Nephrotoxicity of chemotherapy and other cytotoxic agents".)

•(See "Nephrotoxicity of molecularly targeted agents and immunotherapy".)

●Xerostomia – Xerostomia can be a long-lasting or permanent problem, although it often improves with time when patients receive IMRT, but not two-dimensional RT. Some trials have suggested that acupuncture may decrease symptoms and increase salivary flow rate [99,100]. Additional trials in larger numbers of patients are required to determine the role of acupuncture in this setting. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm".)

●Lhermitte sign – Lhermitte sign is a benign form of myelopathy with neck flexion that produces an unpleasant electric-shock sensation radiating down the extremities. It is self-limited and not associated with long-term sequelae. This sign is common after chemoradiation for NPC, and the treatment approach is discussed separately. (See "Management of late complications of head and neck cancer and its treatment", section on 'Myelitis'.)

●Trismus – Trismus can develop as a late side effect from fibrosis and requires careful evaluation to differentiate from local recurrence. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management of late complications of head and neck cancer and its treatment".)

●Hypothyroidism – Neck irradiation places patients at risk for developing hypothyroidism, and thus, monitoring of serum thyroid-stimulating hormone levels is routine [94]. (See "Delayed complications of cranial irradiation", section on 'Hypothyroidism'.)

●Cognitive function – RT has been associated with measurable deficits in cognitive function (short-term memory, language abilities); the extent of the deficit is related to the dose of radiation to the temporal lobe [101]. Temporal lobe necrosis, characterized by memory loss, complex partial seizures, and hypodense areas in one or both temporal lobes on neuroimaging may occur in up to 2 to 3 percent of patients and are significantly increased with higher doses of RT, some altered fractionation techniques, and shorter overall treatment times. IMRT and other conformal techniques minimize this risk, as compared with two-dimensional and three-dimensional techniques [24,84,92,95]. (See "Delayed complications of cranial irradiation", section on 'Neurocognitive effects'.)

●Osteoradionecrosis and carotid artery rupture – Skull base osteoradionecrosis with bleeding from the internal carotid artery is an uncommon, but potentially fatal, complication of irradiation for NPC [93,102]. (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis' and "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery rupture' and "Delayed complications of cranial irradiation", section on 'Endocrinopathies'.)

●Pituitary dysfunction – Pituitary dysfunction can occur, especially in settings of tumor involvement of the sphenoid sinus or middle cranial fossa. (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis' and "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery rupture' and "Delayed complications of cranial irradiation", section on 'Endocrinopathies'.)

●Bulbar palsy – Delayed bulbar palsy, developing 1 to 18 years post radiation, is reported in up to 20 percent of cases and can result in moderate to severe functional disability [89]. Deficits may include any combination of deafness, dysarthria, dysphagia, tongue and palatal weakness, and motor weakness of the sternocleidomastoid, trapezius, supraspinatus, infraspinatus, and rarely, the deltoid muscle.

●Subsequent primary cancers – Radiation-induced subsequent primary cancers are frequently Epstein-Barr Virus (EBV)-negative squamous cell carcinomas and occur in the tongue and temporal bone among other sites [86,87]. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

●Other late toxicities – A range of other late toxicities, such as carotid artery injury, can also be observed, which may be minimized with optimal RT technique. (See "Management of late complications of head and neck cancer and its treatment".)

PROGNOSIS — The five-year overall survival (OS) rates for patients with NPC are as follows (table 2). These data are based on an observational series of 3328 patients with NPC treated with intensity-modulated radiation therapy (IMRT), with or without chemotherapy. Their tumors were staged using the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) seventh edition staging system [28].

●Stage I disease – 93 percent

●Stage II disease – 87 percent

●Stage III disease – 81 percent

●Stage IVA disease (T4, N0-2 by AJCC/UICC seventh edition staging system) – 65 percent

●Stage IVB disease (any T stage, N3 by AJCC/UICC seventh edition staging system) – 63 percent

The combination of pre- and posttreatment Epstein-Barr Virus (EBV) DNA levels and staging also have prognostic significance, with higher levels conferring a worse prognosis, stage for stage [103-106].

●Pretreatment EBV DNA levels – Five-year survival rates according to Tumor, Node, Metastasis (TNM) stage grouping (by the AJCC/UICC seventh edition staging system) and pretreatment EBV DNA levels from a separate case series are as follows [106]:

•Stage I, II disease, low DNA (<4000 copies/mL) – 91 percent

•Stage I, II disease, high DNA (≥4000 copies/mL) – 64 percent

•Stage III, IVA/IVB disease, low DNA – 66 percent

•Stage III, IVA/IVB disease, high DNA – 54 percent

●Posttreatment EBV DNA levels – Posttreatment (ie, postradiation) plasma EBV DNA levels may have a role as a prognostic biomarker, although this approach requires further investigation [26,69,70,107,108]. As an example, in one analysis of 789 patients with NPC treated with chemoradiation, the addition of postradiation plasma EBV DNA to TNM stage improved the risk stratification of NPC patients to different adjuvant therapy or follow-up strategies [108]. Patients identified as low risk using this model had comparable five-year OS versus those with TNM stage II disease (89 percent each) and were twice as likely to be spared the toxicity of adjuvant therapy (65 versus 30 percent) [108].

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

●Radiation therapy for nasopharyngeal carcinoma (NPC) – Radiation therapy (RT), often as part of a multidisciplinary treatment approach, is the mainstay of initial treatment for patients with early and locoregionally advanced NPC. (See 'Principles of radiation therapy' above.)

●Early (stage I) disease – For patients with early (stage I) disease (table 1), we suggest RT alone rather than concurrent chemoradiation (Grade 2C), as this approach provides excellent locoregional control and avoids the potential toxicity of additional chemotherapy. (See 'Early (stage I) disease' above.)

●Intermediate (stage II) disease – The management of patients with stage II (T1 to T2, N1 or T2N0) disease (table 1) is based on the risk of disease recurrence. Patients with high-risk stage II disease have one or more of the following adverse features: cervical lymph nodes ≥3 cm, level IV or VB lymph nodes (figure 1), extranodal extension, or Epstein-Barr virus (EBV) DNA ≥4000 copies/mL. Patients with low-risk stage II disease have none of those features. (See 'Intermediate (stage II) disease' above and 'Risk classification' above.)

•Low-risk stage II disease – For patients with low-risk stage II disease, we suggest intensity-modulated radiation therapy (IMRT) alone rather than concurrent chemoradiation (Grade 2C). However, concurrent chemoradiation still remains a reasonable alternative, pending further follow-up confirming a long-term survival benefit for RT alone. (See 'Low-risk stage II disease' above.)

•High-risk stage II disease – For patients with high-risk stage II disease, we suggest concurrent chemoradiation rather than RT alone (Grade 2B). (See 'High-risk stage II disease' above.)

●Advanced (stage III and IVA) disease – For patients with advanced (stage III and IVA) disease (table 1), our treatment approach is as follows (see 'Advanced (stage III and IVA) disease' above):

•Stage III to IVA disease – For most patients with stage III to IVA (except for T3N0) disease and good performance status (table 3), we recommend induction chemotherapy followed by concurrent chemoradiation rather than concurrent chemoradiation alone (Grade 1B), as this approach improved overall survival (OS) in randomized trials. (See 'Selection of therapy' above and 'Induction chemotherapy' above.)

•T3N0 disease – For patients with T3N0 disease at low risk for recurrence (see 'Risk classification' above), we suggest RT alone rather than concurrent chemoradiation (Grade 2C). However, concurrent chemoradiation remains a reasonable alternative pending further follow-up confirming a long-term survival benefit for RT alone. (See 'Selection of therapy' above.)

For patients with T3N0 disease at high risk for recurrence, we suggest concurrent chemoradiation rather than radiation alone (Grade 2C), although trials evaluating chemoradiation have typically excluded these patients. The decision to add either induction chemotherapy or adjuvant chemotherapy is individualized and best made in a multidisciplinary treatment setting.

-Choice of induction chemotherapy – For patients who are candidates for induction chemotherapy, we suggest the use of the doublet regimen gemcitabine plus cisplatin (GP (Grade 2C)), as it improves OS, has a manageable toxicity profile, and is easier to administer than other regimens. Other alternative induction regimens include cisplatin plus docetaxel and fluorouracil (TPF), cisplatin plus paclitaxel and capecitabine (TPC), cisplatin plus either fluorouracil or oral capecitabine, or cisplatin plus docetaxel. (See 'Induction chemotherapy' above.)

-Cisplatin for concurrent chemoradiation – For patients receiving concurrent chemoradiation for NPC, we suggest the concurrent use of cisplatin with RT rather than other chemotherapy agents (Grade 2C). For patients who are ineligible for cisplatin, acceptable alternatives include carboplatin or oxaliplatin. (See 'Concurrent chemoradiation' above.)

•Ineligible for induction chemotherapy – For patients who are ineligible for or unable to tolerate cisplatin-based induction chemotherapy, we suggest concurrent chemoradiation followed by adjuvant chemotherapy rather than radiation alone (Grade 2C). However, concurrent chemoradiation alone is also a reasonable alternative for patients who chose to forego or cannot tolerate adjuvant chemotherapy (ie, due to decreased performance status (table 3) or comorbidities). (See 'Concurrent chemoradiation' above and 'Adjuvant chemotherapy' above.)

-Choice of adjuvant chemotherapy – For patients receiving concurrent chemoradiation followed by adjuvant chemotherapy, we suggest three cycles of adjuvant gemcitabine plus cisplatin rather than fluorouracil plus cisplatin (Grade 2C), which improved progression-free survival (PFS) in a randomized trial. For those who decline or are ineligible for adjuvant gemcitabine plus cisplatin (ie, due to concerns for hematologic toxicity), adjuvant therapy with three cycles of FU plus cisplatin is an appropriate alternative. (See 'Choice of adjuvant chemotherapy' above.)

For patients with a contraindication to cisplatin, we offer three cycles of adjuvant carboplatin plus fluorouracil.

●Management of the neck – For all patients with NPC, including those with a clinically negative neck, we perform bilateral neck radiation, given the propensity for early and bilateral involvement of regional lymph nodes. (See 'Radiation dosing and schedule' above.)

●Evaluation of treatment response – We obtain a posttreatment magnetic resonance imaging (MRI) scan of the skull base and neck, and a full body combined positron emission tomography (PET)/computed tomography (CT) scan approximately three months after treatment completion. (See 'Evaluation of treatment response' above.)