Managing the Complexities of Nasopharyngeal Cancer

Although the malignancy has an encouraging survival rate, it is necessary to be aware of the complexity of nasopharyngeal cancer. The intricacies surrounding radiation therapy, concurrent systemic treatment, and the potential for surgical intervention are essential to improving the chances of successful outcomes in this patient population, according to Nabil Saba, MD, FACP.

“If you see a patient [with nasopharyngeal cancer], usually they are better served when they're referred to high-volume centers,” Saba, director of the Head and Neck Medical Oncology Program, Winship Cancer Institute of Emory University, professor and vice chair for Quality and Safety, Department of Hematology and Medical Oncology, and adjunct professor in the Department of Otolaryngology, Emory University School of Medicine, told OncLive. “To begin with, head and neck cancer is not very common—it is not on the top list of the 3 or 4 most common cancers within this country. However, you add to the fact that nasopharyngeal cancer is considered a rare disease, which makes it even more complicated to manage.”

Nasopharyngeal cancer, which occurs in the upper part of the throat and behind the nose, commonly starts in the squamous cells that line the nasopharynx.¹ The malignancy, which falls under the umbrella of head and squamous cell carcinomas, is said to several risk factors, including Chinese or Asian ancestry, exposure to Epstein-Barr virus (EBV), and high alcohol consumption.

Saba explained that the disease is endemic in Southeast Asia, parts of Africa, and South America. The incidence of this disease is much lower in North America and the Western world, Saba added, although cases have been reported in these regions, as well.

“Its uniqueness is its association with the latent EBV infection, which, especially in EBV-endemic areas of the world, there are some environmental factors that have also been associated with the disease, such as smoking,” Saba said. “However, EBV continues to be the main predominant factor as far as risk [goes] for developing this disease.”

This, Saba added, leads to the question of how to best manage patients who have EBV-negative nasopharyngeal cancer, because “those patients also exist, and given the fact that they’re less common, there is a challenge in being able to decipher specific treatments for [them].”

Symptoms include a lump in the nose or neck, a sore throat, trouble with breathing or speech, nosebleeds, hearing issues, headaches, and/or ringing or pain in the ear. Diagnosis and staging are both straightforward, Saba said, through physical and neurological exams, tissue biopsy, magnetic resonance imaging, CT/PET scans, ultrasound, x-ray, blood assays, hearing tests, and assays for human papillomavirus (HPV) and EPV.

“As far as locoregional failure, nasal pharynx cancer is easier to treat than other sites of head and neck cancer,” Saba said. “When you look at the chance of the cancer recurring locally, in the large, randomized trials or the large phase 3 studies, the incidence of locoregional recurrence is close to 15%.”

However, the predominant failure in nasopharyngeal cancer is distant metastases, said Saba, who cited similarities between nasopharyngeal cancer and HPV-related oropharynx cancer. Additionally, both of these diseases are more sensitive to radiation and systemic therapy, and “more amenable to cure” in the locoregional setting, Saba added.

Chemoradiation has become a standard treatment approach over the past several years, based on the data from Study 0099,² which firmly established the value of adding chemotherapy to radiotherapy in the management of locally advanced disease.

“It proved the principle of concurrent therapy as a curative modality for this disease,” Saba noted.

Since data from Study 099 was published, research efforts have focused on determining whether additional cytotoxic chemotherapy in the pre- or post-radiation setting would add curative benefit to these patients, Saba added.

“It would be logical to add additional chemotherapy, given the fact that most of these failures appear to be distant metastases, and given that this disease is really chemotherapy sensitive,” Saba explained. “However, clinical trials have really not shown an impartial result in terms of showing benefit for additional adjuvant chemotherapy.”

Reasons for the negative data could be due to patients being unable to tolerate additional therapy. However, sequential chemotherapy was evaluated in an open-label, multicenter, randomized, controlled, phase 3 trial conducted at 10 Chinese institutions. Investigators enrolled previously untreated patients with stage III to IVB (except T3-4N0) nasopharyngeal carcinoma and they were randomized 1:1 to receive induction chemotherapy plus concurrent chemoradiation (n = 241) or concurrent chemoradiation alone (n = 239). Induction chemotherapy consisted of 3 cycles of docetaxel at 60 mg/m² on day 2, cisplatin at 60 mg/m² on day 1, and continuous fluorouracil at 600 mg/m² daily from day 1 to day 5 every 3 weeks prior to receiving concurrent chemoradiation, which comprised 3 cycles of cisplatin at 100 mg/m2 every 3 weeks concurrent with intensity-modulated radiotherapy.

Results showed that, at a median follow-up of 45 months, the 3-year failure-free survival rate was 80% in the induction therapy arm vs 72% in the concurrent chemoradiation–alone arm (HR, 0.68; 95% CI, 0.48-0.97; P = .034).³

“I believe there is still more interest in seeing whether additional chemotherapy post radiation is possibly beneficial,” Saba cautioned. “However, the more we study this, the more doubt exists now as far as the validity of this approach.”

Currently, the community is awaiting the results of the phase 2/3 NRG-HN001 (NCT02135042) trial that is being done in approximately 758 patients with stage II to IVB nasopharyngeal cancer based on EBV DNA.⁴ In the trial, which is currently enrolling, all patients will first undergo standard concurrent chemoradiation, and once this treatment is complete, investigators will test their detectable EBV DNA in their plasma. For patients whose EBV DNA is detectable in the plasma, treatment will consist of cisplatin/fluorouracil or gemcitabine/paclitaxel. The primary end point of the trial is progression-free survival (PFS) and noninferior overall survival (OS).

Immunotherapy: Hope in Nasopharyngeal Cancer?

While the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) have obtained indications in the wider realm of head and neck cancer, checkpoint blockade has not made headway in the specific scope of nasopharyngeal cancer.

In November 2016, nivolumab was FDA approved as a treatment for patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN) following progression on platinum-based therapy. More recently, in June 2019, the FDA gave the green light to pembrolizumab for the first-line treatment of patients with metastatic or unresectable SCCHN.

Saba predicted that immunotherapy has a place in nasopharyngeal cancer and will likely have more relevance in this field over time. However, there are challenges at the biologic level, Saba said, with antigen presentation and disease elimination, suggesting that the affinity to different HLA alleles affect the immune-editing process and further research is needed.

“More importantly, the clinical data of immunotherapy, at least in the early studies, when used in the recurrent, metastatic setting is encouraging,” said Saba. “The question is: Will these immune checkpoint inhibitors improve the efficacy of local therapy in the primary treatment setting? That remains to be seen.”

Also, given the fact that virally mediated cancers like HPV-related cancers tend to respond to immunotherapy, Saba suggested that checkpoint inhibition may, indeed, be effective in this patient subset.

Small, early studies showed response rates with PD-1 inhibitors in nasopharyngeal cancer. In 44 patients with pretreated recurrent or metastatic disease, nivolumab was given until disease progression. The objective response rate (ORR) was 20.5% with this approach; 1 patient had a complete response, and the rest achieved partial responses.⁵ The 1-year PFS rate was 19.3% (95% CI, 10.1%-37.2%) and the 1-year OS rate was 59% (95% CI, 44.3%-78.5%).

Additional data showed that responses correlated with PD-L1 positivity, and improved PFS correlated with loss of HLA class 1 protein expression (30.9%) vs those with expression (5.6%; log-rank P = .01). However, no line between survival and PD-L1 expression or plasma EBV DNA clearance was observed.

Furthermore, in the international, nonrandomized, multiarm, phase Ib KEYNOTE-028 trial (NCT02054806), pembrolizumab elicited an ORR of 25.9% and was found to be well tolerated in patients with PD-L1–positive recurrent or metastatic nasopharyngeal carcinoma.⁶ Patients on this cohort of the trial included those with unresectable or metastatic disease in whom prior standard therapy had failed and who have PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes.

“This is not very different from what we see in mucosal head and neck squamous cell carcinoma with single-agent immune checkpoint inhibitors,” Saba noted. “We appear to be having significant activity similar to what we're seeing with other agents in other diseases.”

Future Research Directions

The big question on Saba’s mind is how to sequence therapies for patients for nasopharyngeal cancer—specifically when to incorporate checkpoint inhibitors.

“A maintenance setting approach is attractive but given the fact that this is also a very chemotherapy-sensitive disease, incorporating immune checkpoint inhibitors early in the management, perhaps adding them to the induction phase of treatment, and following that with a maintenance phase of immunotherapy, may be an attractive design, as well,” Saba postulated.

Future trials, however, will ultimately shape the treatment of the nasopharyngeal cancer patient population. Ongoing studies are evaluating bispecific antibodies that are targeting transforming growth factor beta and PD-L1, as well as adjuvant approaches with adding cytotoxic therapy. Screening efforts are also of interest with EBV DNA, Saba added.

“It's important to remember that this is a very curable disease, and sometimes we lose this perspective because of the complexity of the treatment,” Saba concluded. “That may not be very clear to general practitioners. It's important to remember that we have very effective tools in treating [this disease], provided that we use these tools in a judicious way and provided that these tools are in the hands of experienced centers that have treated relatively larger volumes of these patients.”

References

1. Nasopharyngeal cancer treatment (adult) (PDQ)–patient version. National Cancer Institute. Updated July 26, 2019. Accessed April 12, 2021. https://bit.ly/2QuBkUr.
2. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998;16(4):1310-1317. doi:10.1200/JCO.1998.16.4.1310
3. Sun Y, Li W-F, Chen N-Y, et al. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016;17(11):1509-1520. doi:10.1016/S1470-2045(16)30410-7
4. Individualized treatment in treating patients with Stage II-IVB nasopharyngeal cancer based on EBV DNA. ClinicalTrials.gov. Updated March 2, 2021. Accessed April 15, 2021. https://clinicaltrials.gov/ct2/show/NCT02135042
5. MA BBY, Lim W-T, Goh B-C, 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(14):1412-1418. doi:10.1200/JCO.2017.77.0388
6. Hsu C, Lee S, 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(36):4050-4056. doi:10.1200/JCO.2017.73.3675