Head and neck cancer is a heterogeneous carcinoma, represented by a variety of cancerous tumors originating from and residing in the hypopharynx, oral or lip cavity, nasopharynx, oropharynx, or larynx. Many of these tumors differ in regard to etiology as well as the therapeutic strategy used for treatment. To date, head and neck cancer is the sixth most frequent malignancy occurring globally. Approximately 6 percent of cancers are head and neck carcinomas, contributing to roughly 1-2 percent of overall cancer mortality (Int J Cancer 2010;127(12):2893-2917).
Many patients presenting with head and neck cancer have locally advanced disease, necessitating the need for a multimodal and multidisciplinary approach to care. Currently, head and neck squamous cell carcinoma, particularly tumors that are in their advanced stages, is associated with poor prognosis. Despite improvements in medical technology and advancements in overall cancer care, head and neck cancers have experienced little survival improvement in the past few decades (Cancer Immunol Res 2015;3(1):12-17).
Role of Immunotherapy
When head and neck tumors are identified, the standard treatment approach has included radiotherapy, surgical intervention, chemotherapy, or a combination of all three strategies. Concerns over these treatment regimens are usually related to their high risk for toxicities. Some researchers speculate that immunotherapy may not only reduce treatment-related toxicities, but that these therapies may ultimately improve outcomes and short- and long-term prognosis.
Head and neck cancer, an immunosuppressive illness, is generally distinguished by impaired excretion of cytokines as well as dysregulation of immunocompetent cells (Expert Opin Biol Ther 2013;13(9):1241-1256). The majority of patients with this type of carcinoma experience impaired antitumor immune responses, and some researchers believe tumor progression or relapse in head and neck cancer is associated with deficits in immune function (Cancer Immunol Immunother 2004;53(10):865-878).
Typically, the immune system detects and destroys tumor cells that express tumor-associated antigens, a process known as “immunosurveillance.” Emerging research suggests that head and neck carcinogenesis involves significant immunity-related errors, partially driven by cancer cells' evasion of immunosurveillance caused by tumor heterogeneity as well as numerous genetic mutations (Ann Transl Med 2016;4(9):173).
During the evolutionary process of the tumor, interactions with antigen-presenting cells activate T cells. The main antigen-presenting cells involved in this process include macrophages, B cells, or dendritic cells, all of which are typically bound to major histocompatibility complex proteins. Cancer cells often manipulate co-inhibitory and co-stimulatory pathways essential for auto-immunity prevention as a means to evade immunosurveillance (Ann Transl Med 2016;4(9):173).
As research continues to support the idea that the immune system can represent a targetable focus for cancer therapy, identification of novel immunotherapy regimens has become more frequent in the clinical trials landscape.
Immuno-Oncology for Treatment
The still-evolving field of immuno-oncology demonstrates some promise for targeting head and neck cancer at its most basic and complex levels. Simply, immuno-oncology is the study and application of immunotherapies designed to utilize the cancer patient's immunity to fight the cancer directly. Immunotherapies harness the specificity, adaptability, and memory aspects of the immune system in order to cause an immune response in opposition of the progressing tumor. Ideally, this approach is directed to either eliminate the tumor or suppress tumor growth in addition to producing immunological memory to prevent recurrence.
According to a previously published panel interview with Kevin Harrington, MD, PhD, from The Royal Marsden NHS Foundation, combination immunotherapy may represent curative potential in head and neck cancers. Specifically, the combination of checkpoint inhibitors with radiation may be effective for some cases.
“Of course, the idea of bringing these therapies together and engendering an immunologically relevant and immunogenic cell death by radiation would allow us not to treat macroscopic metastatic disease,” Harrington noted, “but better still, at the time of first treatment, to get rid of micrometastatic disease that may subsequently lead to metastatic failure.”
One randomized trial published in 2008 potentially supports the idea that combination therapy may be helpful for head and neck cancer (N Engl J Med 2008;359(11):1116-1127). In the EXTREME trial, participants with recurrent or metastatic head and neck squamous cell carcinoma received either cisplatin or carboplatin in addition to fluorouracil only (chemotherapy only) or cisplatin or carboplatin plus fluorouracil in addition to cetuximab (cetuximab plus chemotherapy).
Those receiving cetuximab in addition to chemotherapy experienced a significantly greater median progression-free survival compared with the chemotherapy-only group (5.6 months vs. 3.3 months, respectively; HR for progression, 0.54; 95% CI, 0.43-0.67; p<0.001). Additionally, median overall survival was significantly longer in the cetuximab group (10.1 months; 95% CI, 8.6-11.2) than in the chemotherapy-only group (7.4 months; 95% CI, 6.4-8.3) (HR for death, 0.80; 95% CI, 0.64-0.99; p=0.04).
Promising research findings regarding immunotherapy have propelled new research initiatives to see whether immunotherapy protocols provide favorable survival outcomes in head and neck cancer. A fairly recent phase II clinical trial from the Dana-Farber Cancer Institute in Boston is comparing monotherapy with nivolumab—a relatively new immunotherapy medication that works as a checkpoint inhibitor—versus combination therapy with nivolumab plus ipilimumab in the setting of squamous cell head and neck carcinoma of the oral cavity (NCT02919683). Additionally, researchers are conducting a similar study (CheckMate 714, NCT02823574) comparing nivolumab and ipilimumab with nivolumab monotherapy. And another study is investigating ipilimumab and nivolumab versus standard of care in recurrent or metastatic head and neck squamous cell carcinoma (CheckMate 651, NCT02741570).
In a randomized, phase III trial by Ferris et al, (N Engl J Med 2016;375(19):1856-1867), investigators randomized patients with recurrent squamous-cell head and neck carcinoma (n=361) to either nivolumab every 2 weeks (n=240) or standard systemic therapy with cetuximab, docetaxel, or methotrexate (n=121). Response rates were higher in the nivolumab group versus those receiving standard systemic therapy (13.3% vs. 5.8%, respectively). Compared with standard therapy, patients receiving nivolumab immunotherapy had significantly better overall survival, increasing from 5.1 months to 7.5 months (HR = 0.70, CI: 0.51-0.96).
In addition, more patients in the nivolumab versus standard therapy group experienced greater overall survival at 1 year (36.0% vs. 16.6%, respectively). Robert Ferris, MD, PhD, lead investigator of the study, previously commented, “This is an upsetting disease where there are really no effective systemic agents, so creating a new standard of care is evasive and difficult for this population of patients with this very rapid progression.” In regard to the findings of this trial, Ferris added, “We have the first positive randomized phase III trial in head and neck cancer in over a decade.”
Future Outlook & Directions
Conventional medical treatment for head and neck cancer is associated with poor prognosis, particularly in advanced disease. Emerging science is providing evidence that the immune system can play a potent role in the fight against head and neck carcinoma via the utilization of new and innovative immunotherapy agents. More research is necessary to further understand the immune-related mechanisms associated with this form of cancer in order to develop immunotherapies that are targeted and associated with improved overall survival.
Brandon May is a contributing writer.