Nasopharyngeal carcinoma develops from epithelial cells of nasopharynx and is clinically occult in early stages.
Nasopharyngeal carcinoma has a wide spectrum of clinical presentations, with hypoaesthesia, diplopia or facial numbness, due to cranial nerve damage, and neck masses.
An important hallmark of this type of cancer is the early metastasis, and the bones are the most affected(1).
Its incidence is related to geographical variations, with the highest prevalence described in Southeast Asia. Men are two or threefold more likely to develop the disease, with an incidence peak at 50-59 years of age(2).
Therapy of advanced and metastatic nasopharyngeal carcinoma
Even though radiotherapy techniques have been improved, providing up to 80% regional control rate of nasopharyngeal carcinoma, there is an increased risk of distant metastases. Consequently, an adequate systemic therapy is essential(3).
A randomized trial compared five different cisplatin-based regimens on 822 treatment-naive patients with advanced nasopharyngeal cancer. Cisplatin was administered with 5-FU, paclitaxel, gemcitabine, bleomycin plus 5-FU, or paclitaxel plus 5-FU, until disease progression or unacceptable drug toxicity.
This study supports the high platinum-based chemosensitivity of nasopharyngeal cancer, with similar overall survival rates among the five therapeutic groups (between 74% and 82%, at one year of follow-up)(4).
Platinum-based doublet regimens have been shown to improve the survival in a phase III Chinese clinical trial. This multicentre, phase III study randomly assigned 362 patients with recurrent or metastatic nasopharyngeal carcinoma, to receive up to six cycles of treatment with gemcitabine and cisplatin, or fluorouracil and cisplatin. The results showed that gemcitabine plus cisplatin enhances progression-free survival (7 months versus 5.6 months), supporting this doublet chemotherapy as the standard of care in the first-line metastatic disease(5-6).
When patients have metastatic disease at the initial diagnosis, there is a high risk of failure after systemic chemotherapy. Specialists consider that, despite the ability of chemotherapy to prolong the survival, consolidation radiotherapy improves the treatment outcome.
Therefore, the NCCN guideline recommends radiotherapy in patients with metastatic disease and complete response to systemic chemotherapy(5).
This concept is supported by a clinical trial that examined the role of radiation therapy in the treatment of 126 patients with de novo metastatic nasopharyngeal carcinoma and complete or partial imaging RECIST response, after three cycles of cisplatin plus fluorouracil. The patients were randomized to receive chemotherapy alone or associated with locoregional radiation therapy, up to six cycles, or until high toxicity, death or disease progression. The study met its primary end point of increased overall survival in favor of radiotherapy added to chemotherapy (76.4% versus 54.5%, p=0.004). Regarding adverse reactions, hematologic toxic effects were equaly reported in the two therapeutic arms, but higher specific radiotherapy adverse effects were reported in the combination arm (8.1% acute grade 3-4 dermatitis, and 33.9% grade 3-4 mucositis)(7).
Molecularly targeted therapy
Given the common overexpression of epidermal growth factor receptor (EGFR) in nasopharyngeal carcinoma, studies with several EGFR targeted molecules have been attempted. Cetuximab, a chimeric monoclonal antibody EGFR inhibitor, was tested associated with carboplatin in recurrent or metastatic nasopharyngeal carcinoma. This phase II study, which included 60 patients with EGFR expressing and progression after platinum-based regimens, demonstrated clinical activity with partial response in 11.7% of patients and stable disease responses in 48.3%(8).
Is plasma Epstein-Barr virus DNA a strong predictor for metastatic nasopharyngeal carcinoma?
According to World Health Organization, nasopharyngeal carcinoma is widespread in the southern China and Hong Kong, and is mostly nonkeratinizing and significantly associated with Epstein-Barr virus infection. Although Epstein-Barr virus infection is associated with almost all undifferentiated nasopharyngeal carcinomas and some salivary gland cancers, this virus is not identified in other head and neck tumors(9).
Several studies showed that PCR quantification of plasma Epstein-Barr virus can have a useful predictive and prognostic value in metastatic nasopharyngeal carcinoma treated by radiotherapy(10-12).
One trial including 127 patients with metastatic Epstein-Barr virus (EBV) associated with nasopharyngeal carcinoma, treated with palliative chemotherapy, demonstrated that both pretreatment and posttreatment plasma EBV DNA were strong predictors of survival. Plasma EBV DNA levels were assessed at baseline and after each chemotherapy courses. Higher progresion-free survival (PFS) and overall survival (OS) were described in subjects with lower baseline plasma EBV DNA (PFS of 8.2 versus 5.8 months, p<0.001, and OS of 18.9 versus 15.3 months, p<0.001), after 21 months of follow-up. Moreover, patients with undetectable plasmatic levels posttreatment showed important complete or partial response rates. For example, seven patients with complete responses had a posttreatment plasma EBV DNA decline to undetectable level, compared to nine patients with maintained high plasma concentrations and disease progression(13).
Epstein-Barr virus related nasopharyngeal carcinoma supplies rational targets for immunotherapy. Diverse types of immunotherapies are actively studied, including therapeutic Epstein-Barr virus vaccination, specific adoptive immunotherapy, or checkpoint inhibitor immunotherapy.
An important approach in treating Epstein-Barr virus related nasopharyngeal carcinoma is to stimulate specific cytotoxic T lymphocytes to target viral antigens expressed on cancer cells membrane.
Over 50% of nasopharyngeal carcinoma present high immunogenic viral antigens (LMPs, Epstein-Barr nuclear antigen 1 and 2 latent membrane proteins). These antigens determine an immune response via cytotoxic T lymphocyte (CTL) against tumor cells(14).
In 2001, Daniel Chua and his collegues published a pilot study regarding the treatment of nasopharyngeal carcinoma using adoptive cytotoxic T lymphocytes therapy(15).
Since then, several clinical trials have been tested the EBV cytotoxic T lymphocytes (EBV-CTL) immunotherapy. A phase 1/2 study on 21 patients with recurrent or metastatic EBV‐associated nasopharyngeal carcinoma evaluated the effect of autologous EBV immunotherapy. EBV-CTL were generated from the blood of eligible patients, while patients received palliative chemotherapy. Patients who progressed on standard chemotherapy received investigational immunotherapy intravenously, with EBV cytotoxic T lymphocytes, which multiplied and attacked EBV-infected cells.
Promising results have been described, with a median PFS of 2.2 months and median OS of 16.7 months. It is important to mention the fact that one complete response was reported after three cycles of immunotherapy, with over 100 months free of disease, and two other patients had stable disease for 18.7 months and 6.5 months, respectively(16).
Cancer vaccines attempt to initiate and promote a host immune response, by delivering selected tumor-associated antigens.
The first therapeutic vaccination study for nasopharyngeal carcinoma included injections in the inguinal lymph nodes with autologous dendritic cell, capable to activate naive CD4+ and CD8+ T lymphocytes, covered by Epstein-Barr LMP2 epitope peptides.
There were enrolled 16 patients with metastatic nasopharyngeal carcinoma treated with conventional chemotherapies. Vaccination improved specific T cell immune responses in nine patients, and partial tumor decrease was registered in two patients(17).
A trial of similar design, using autologous dendritic cell vaccination on 38 patients with advanced Epstein-Barr virus associated with nasopharyngeal carcinoma, after radiotherapy, demonstrated encouraging data, with a significant decrease of plasmatic EBV-DNA level in nine patients (p=0.0310)(18).
Checkpoint inhibitor immunotherapy
As mentioned before, virus-induced neoplasia make immunotherapy a promising treatment option, because proteins in the structure of the viruses are strong immunogens.
Nasopharyngeal carcinoma exhibits the expression of PD-1 in 89-95% of cases. This frequent expression provides a significant therapeutic outcome with PD-1 or PD-L1 inhibitors(19).
Findings from the multicohort, phase Ib KEYNOTE-028 trial demonstrated that pembrolizumab elicits durable responses in previously treated patients with recurrent or metastatic nasopharyngeal carcinoma, and over 1% PD-L1 expression. A total of 27 pretreated patients received pembrolizumab up to two years or until severe toxicity or disease progression. Pembrolizumab in monotherapy became a promising therapeutic option, with 6.5 months of progression-free survival, and fast and efficient response (1.9 months time to response, and 17.1 months the duration of response)(20).
An international, phase II trial of the Mayo Clinic Consortium (NCI-9742) aimed to prove the efficiency of nivolumab in 44 patients with previously platinum-based treated, recurrent or metastatic nasopharyngeal carcinoma. The subjects recieved nivolumab until disease progression. After 12.5 months of follow-up, the objective response rate with nivolumab was 20.5%. Regarding PD-L1 expression, the patients who tested positive for PD-L1 expression presented a higher response (33%) compared to negative PD-L1 patients (13%)(21).
CheckMate 358 was a phase I/II multicohort trial of nivolumab in five virus-associated tumors (cervical, vulvar and vaginal, anal, penian, nasopharyngeal). One cohort evaluated the subsequent therapy with nivolumab in patients with recurrent or metastatic PD-L1-unselected, Epstein-Barr associated nasopharyngeal carcinoma, treatment-naive, or previously treated with maximum two therapeutic lines. The therapy was administered every two weeks until disease progression or severe toxicity, and after a median of 26 weeks of follow-up, nivolumab had a 20.8% objective response rate. There must be noted that therapeutically naive patients had a superior outcome (40% objective response rate versus 15.8%)(22).
To date, the combination of cisplatin and gemcitabine has proven efficacy as first-line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma.
The optimal integration of the immune-based treatments has led to great progress in patient survival. Moreover, some researchers have speculated that plasma EBV DNA levels can be used as a biomarker for prognosis, monitoring or evaluation. However, second lines of therapy in this malignancy remain a challenge and the enrolment in clinical trials should be done whenever possible.