Approach

Discuss the treatment strategy with the multidisciplinary team for patients with advanced nasopharyngeal cancer (NPC).[2] 

For localized or locally advanced NPC, curative-intent radiation therapy, mainly intensity-modulated radiation therapy (IMRT) with daily image guidance, is the main treatment modality.[1]​​[2][19]​​​​ Concurrent chemotherapy is added for locally advanced disease.[19] Concurrent chemotherapy can be offered for selective patients with localized disease if there are adverse features such as bulky tumor volumes or high Epstein-Barr virus (EBV) DNA copy number.[1] 

For recurrent/metastatic NPC, potential curative-intent treatment, such as nasopharyngectomy, brachytherapy, radiosurgery, stereotactic radiation therapy, IMRT, or surgery followed by chemoradiation, should be considered first, if feasible.[2] Palliative chemotherapy can be considered for selected patients. For patients with newly diagnosed metastatic NPC, locoregional radiation therapy should be considered for locoregional control.[2]

When planning treatment, inquire about a history of prior cancer treatments and any residual toxicity, and any history of connective tissue diseases (these may increase complications from chemotherapy and radiation therapy). Ask the patient about any other drugs they are taking concurrently, including supplements.

Use a scale, such as the Eastern Cooperative Oncology Group (ECOG) performance status scale, to determine the patient’s current level of physical functioning and any support they might need. OncologyPRO: Performance scales - Karnofsky & ECOG scores Opens in new window​ Assessments that are useful to perform as baseline evaluations prior to starting treatment include:[2][19]

  • Audiogram (not required but highly recommended prior to platinum chemotherapy)

  • Speech and swallowing consultation and formal assessment by modified barium swallow/videofluoroscopy

  • Dental evaluation and counseling in preparation for radiation therapy

  • Nutrition evaluation

  • Screening for hepatitis B

  • Smoking cessation advice, where necessary

  • Screen for depression.

Early-stage disease (stage 1-2)

Radiation therapy is the mainstay of treatment for nonmetastatic NPC given that it is a radiosensitive tumor and typically in a location that limits complete surgical resection.[1][2]​​​[19]​ The goal of treatment is cure for patients with nonmetastatic NPC.[2]

Principles of radiation therapy

Conformal external beam radiation therapy (EBRT) techniques, including intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy, are considered the standard of care. Nodal metastases are common in NPC and subclinical radiation therapy targets generally encompass a large anatomical area that includes the retropharyngeal lymph nodes and bilateral II-V lymph node stations. Level IB is electively covered in select patients with a high burden of level II nodal disease or anterior nasal cavity involvement.[1][2]

Stage 1 (T1, N0, M0)

For patients with stage 1 disease, the recommended treatment is radiation therapy without concurrent chemotherapy.[2][19]​​​​ In patients with clinically and radiographically undetectable nodal metastases (N0), reducing the nodal elective radiation therapy target volume to exclude level IV (low neck) can be considered.[30]

Stage 2 (T2, N0, M0)

Similar to patients with stage 1 disease, for patients with low-risk stage 2 disease (N0 and pretreatment plasma EBV DNA <4000 copies/mL), the recommended treatment is radiation therapy without concurrent chemotherapy, but with concurrent chemotherapy if high-risk features are present (such as bulky tumor volumes or high EBV DNA copy number).[1][19]​​​​ In patients with clinically and radiographically undetectable nodal metastases (N0), reducing the nodal elective radiation therapy target volume to exclude level IV (low neck) can be considered.[1]

Stage 2 (T0 (EBV+)-T2, N1, M0)

Stage 2 disease with retropharyngeal or ipsilateral cervical nodal metastases (N1) is a heterogeneous category and additional high-risk features have been found to be prognostic for poorer outcomes (node ≥3 cm, level IV or VB lymph node [low neck], extranodal extension, pretreatment plasma EBV DNA ≥4000 copies/mL).[31][32][33] 

National Comprehensive Cancer Network (NCCN) guidelines recommend concurrent chemotherapy and radiation therapy for these patients.[19] Cisplatin should be considered as the standard concurrent chemotherapy agent.[1]​​[2]​​[19] For patients who cannot tolerate cisplatin (e.g., if there is preexisting chronic kidney disease or hearing impairment), carboplatin is a reasonable alternative.[1][19]

The addition of induction or adjuvant chemotherapy is generally not recommended but could be considered after multidisciplinary discussion in select patients with large tumor burden or very high pretreatment EBV DNA copy number.[1][19]

[Figure caption and citation for the preceding image starts]: Lymph node groups in the head and neck; the numbers refer to the anatomic levels of the lymph nodesCancer Research UK [Citation ends].com.bmj.content.model.Caption@24d83d9d

Advanced-stage disease (stage 3 and 4A)

Stage 3 (T3, N0, M0)

NPC with a more extensive primary tumor and without nodal metastases (T3, N0, M0) is a distinct category of advanced stage NPC that has traditionally been treated more akin to stage 1-2 NPC with either radiation therapy alone or concurrent chemoradiation.[19]

Current guidelines vary, though all generally recommend a risk-stratified approach with consideration for high-risk features, such as tumor volume and pretreatment EBV DNA levels.

Guidelines recommend radiation therapy plus concurrent chemotherapy for patients with stage 3 (T3, N0, M0) disease.[1][2][19]​​​​

The addition of induction or adjuvant chemotherapy is generally not recommended but could be considered after multidisciplinary discussion in select patients with large tumor burden or very high pretreatment EBV DNA levels.[19]

Stage 3-4A (T3, N1-3, M0; OR T4, N0-3, M0; OR T0 (EBV+)-T2, N2-3, M0)

For all other locally advanced NPC (3-4A, excluding T3, N0, M0), induction chemotherapy followed by concurrent chemoradiation is recommended for the majority of patients.[1][19]​​ Gemcitabine plus cisplatin, or docetaxel plus cisplatin plus fluorouracil are the preferred induction regimens.[1][19][34]​​​

For patients ineligible for induction chemotherapy, adjuvant chemotherapy with cisplatin plus fluorouracil is recommended after completion of concurrent chemoradiation.[19][35]​ 

Stage 3-4A (excluding T3, N0, M0) NPC is a particularly heterogeneous category. As such, participation in clinical trials is especially encouraged to better select subgroups of patients for more intensive treatments and other subgroups for less intensive treatments.[19]

Metastatic disease

The preferred first-line treatment for patients with metastatic NPC who have no surgery or radiation therapy options is toripalimab (a programmed cell death protein 1 [PD-1] inhibitor) plus cisplatin plus gemcitabine.[19] 

Other recommended first-line options include:[19]

  • cisplatin plus gemcitabine

  • cisplatin plus gemcitabine plus tislelizumab

  • cisplatin plus gemcitabine plus pembrolizumab or nivolumab

  • cisplatin plus fluorouracil

  • cisplatin or carboplatin plus docetaxel or paclitaxel

  • carboplatin plus cetuximab

  • gemcitabine plus carboplatin.

Locoregional nasopharyngeal and/or neck nodal recurrence

Salvage nasopharyngectomy and/or neck dissection should be considered for small locoregional recurrences amenable for surgical resection.[2] Radical, modified radical, or selective neck dissection can be used for nodal neck recurrence.[2] The NCCN classifies cervical lymphadenectomy as either comprehensive or selective.[19]

Adjuvant radiation or chemoradiation is frequently offered after salvage surgery. There are limited data supporting the practice, but reradiation therapy after salvage surgery is supported by consensus guidelines.[36] 

For unresectable locoregional recurrence, reradiation therapy should be considered before a chemotherapy-only approach. Reradiation therapy is challenging since many organs at risk have already been exposed to near maximal safe doses of radiation from the first course of radiation therapy and careful patient selection is needed.[2] International recommendations generally favor reradiation therapy after at least 12 months latency between courses of radiation therapy to allow normal tissues to recover from the initial course of radiation therapy.[36] Unlike the first course of radiation therapy that includes targeting subclinical disease, reradiation therapy targets gross recurrent tumor only. For bulky recurrences, induction with concurrent chemotherapy is favored among experts with reradiation therapy. 

IMRT/volumetric modulated arc therapy (VMAT) is viewed as an appropriate modality for reradiation therapy, although if particle therapy, such as proton therapy, is available it could be considered as well and may be preferred for select recurrences.[36] 

Locoregional recurrence not amenable for salvage surgery or reradiation therapy is treated with palliative chemotherapy.

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