49.2.1 Biological Overview

Head and neck cancers have long been linked to exposure to tobacco carcinogens in association with accumulation of key genomic changes along the course of cancer development. ¹⁹ Within the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor in oropharyngeal squamous cell carcinoma (OPSCC). ²⁰ However, the presence of HPV is less common—approximately 25%—in oral cavity squamous cell carcinoma (OCSCC), and the role of HPV in the development of OCSCC still remains largely unclear. ^{21 , 22} There is no significant association between HPV status and prognosis in OCSCC, ²³ which could be a reflection of low transcriptional activity of viral oncoproteins E6 and E7 in OCSCC. ²⁴

Both HPV-positive and HPV-negative HNSCCs manifest dysregulated cell cycles from inactivation of the p53 and Rb pathways. ²⁵ Recent genomic landscape analysis of HNSCC confirmed frequent loss-of-function alterations in TP53 as well as loss of CDKN2A (leading to inactivation of p16^INK4A) in HPV-negative HNSCC; and helical domain mutations in PIK3CA as the most common genomic alteration in HPV-positive HNSCC. ²⁶ The scarcity of mutations in cell cycle regulating proteins among HPV-positive HNSCC is not suprising given that HPV-positive tumors already harbor disrupted p53 and Rb pathways through the actions of viral oncoproteins E6 and E7. ²⁷ Heightened proliferative activity due to dysregulated cell cycle has been the basis of traditional chemotherapeutic agents such as anti-metabolites, platinum-based drugs, and taxanes. Further insights from genomics research will continue to provide the grounds for development of novel therapies.

Early studies utilizing immunohistochemistry techniques have shown that overexpression of epidermal growth factor receptor (EGFR) is frequent in HNSCC in association with worse outcomes. ^{28 – 30} Subsequently confirmed by molecular techniques, EGFR amplification has been reported in up to 31% of OCSCCs ³¹ and 15% of all HPV negative HNSCCs. ²⁶ EGFR activation can trigger downstream oncogenic pathways such as PI3K-AKT-mTOR and RAS-MEK-ERK (▶ Fig. 48.3). The Cancer Genome Atlas (TCGA) analysis also demonstrated activating alterations of these downstream pathways, such as mutations in the PIK3CA and HRAS, reinforcing the critical role of these pathways in the oncogenesis of HNSCC. ²⁶ This has led to successful therapeutic strategies incorporating anti-EGFR agents and insight into resistance mechanisms to such therapies. ^{4 , 6 , 32 , 33}

Also in recent decades, landmark studies in cancer research renewed cognizance for the tumorigenic role of immune escape or immune editing by the tumor against immune surveillance mechanisms. ^{34 , 35} Key cellular components of an immune-suppressive?tumor microenvironment such as myeloid-derived suppressor cells, ³⁶ regulatory T cells, ³⁷ and tumor-associated macrophages ³⁸ have now been well-characterized. Dysregulation of inflammatory cytokines such as TGFß, ^{37 , 39} IL-6, ³⁸ IL-10, ^{37 , 38} and PGE2 ⁴⁰ has been shown to play a role in suppressing activation of dentritic cells, NK cells, and/or T cells. Furthermore, tumor cells are able to evade T cell-mediated immune recognition via mutations in HLA expression and antigen processing machinery. ⁴¹ In HNSCC, these concepts were not only recapitulated in large-scale genomic characterization of tumors revealing alterations in genes responsible for proper antigen presentation, ²⁶ but also in specific studies utilizing oral cavity cancer samples exploring specific ligand-receptor co-signaling interactions, e.g., PD-1/PD-L1, responsible for dampening T cell-mediated immune responses. ^{42 , 43} When comparing across many different cancer types, HNSCC is among those with the highest levels of overall immune cell infiltration, immunoregulatory presence as measured by regulatory T cell infiltration, and cytotoxic antitumor NK cells. ⁴⁴ These observations suggest that the HNSCC immune microenvironment may in fact be poised to respond to immune-modulating treatment approaches. Thus, much of the recent efforts on improving the treatment of HNSCCs have focused on establishing and expanding the role of immunotherapy in the overarching treatment paradigms.

49.2.2 Clinical Considerations

When treating patients with metastatic oral cavity cancers, major clinical factors to consider include the performance status and presence of other comorbidities. Performance status is useful for predicting how well the patient will tolerate intensive chemotherapy regimens. Developed by the Eastern Cooperative Oncology Group (ECOG) in 1982, ⁴⁵ the ECOG numeric scale is a common way to define a patient’s performance status, i.e., daily living abilities: Grade 0 represents patients who are fully active without restrictions; Grade 1 represents patients who are ambulatory and able to undergo limited exertion such as light house work or office work; Grade 2 is for patients who are capable of self-care but not work activities, with less than 50% of waking hours spent sitting down or lying down; Grade 3 defines patients who spend more than 50% of waking hours confined to bed or chair; Grade 4 represents complete disability without any self-care capabilities; and Grade 5 signifies death. Studies in the 1980s have shown that chemotherapy in patients with poor performance status does not lead to much benefit but rather high toxicities and short survival. ⁴⁶ Thus, both American Society of Clinical Oncology (ASCO) expert panel and National Comprehensive Cancer Network (NCCN) guidelines have generally advised against administering chemotherapy to patients with ECOG performance status of 3 or more. ^{47 , 48} For patients with ECOG performance status of 2, single-agent chemotherapy may be favored over multi-agent chemotherapy.

Patients’ comorbidities also play a critical role in determining the type of chemotherapy agent to be administered. Key platinum-based drugs used to treat metastatic oral cavity cancers include cisplatin and carboplatin. Cisplatin is notorious for nephrotoxicity and is thus avoided altogether in patients with compromised renal function or used cautiously with appropriate renal dosing and aggressive hydration protocols. Since this parameter serves as a critical limiting factor for the use of cisplatin, carboplatin is often used in place of cisplatin due to its lower toxicity profile. Both agents, however, are associated with development of peripheral neuropathy and should be used judiciously in patients who have history of diabetes or alcoholism. Along with platinum-based drugs, taxane-based chemotherapeutic agents, e.g., docetaxel and paclitaxel, are also used with caution in patients with increased risk of neurotoxicity.

49.2.3 Considerations for Oligometastatic Disease

In line with the “cascade” theory of metastatic spread as described by Viadana et al in the late 1970s, ⁴⁹ lung is thought to be a disseminating site for further metastatic spread of head and neck cancers. This has provided the rationale for studies involving surgical resection of pulmonary metastases of head and neck primary cancers. Collective evidence demonstrates that pulmonary metastasectomy in patients with oligometastatic relapse of head and neck squamous cell carcinomas without extrapulmonary metastasis may achieve 5-year survival in as much as 30% of patients. ^{50 – 52} Favorable features associated with survival advantage in prior studies include longer disease-free interval prior to metastatic relapse, ^{53 – 55} younger patients with age less than 50 or 60 years, ^{50 , 55 – 57} and complete resection. ^{50 , 51 , 53} Interestingly, however, several subset analyses have shown that, compared to other metastatic head and neck squamous cell carcinomas, oral cavity primary site is a predictor of poor outcome, i.e., no survival advantage was seen with pulmonary metastasectomy in patients with oral cavity primary. ^{53 , 57 – 59} Thus, while metastasectomy may be considered for select patients who exhibit positive prognostic characteristics as well as sufficient performance status and pulmonary function to undergo surgery, its utility remains unclear in patients with metastatic oral cavity cancers.

Development of stereotactic body radiation (SBRT) has enabled delivery of ablative doses of radiation to oligometastatic sites. SBRT has been adopted for palliative treatment and has been evaluated in many nonrandomized studies involving patients with various cancers; results from these studies suggest that SBRT is safe and effective, ⁶⁰ but data on the use of SBRT in oligometastatic HNSCC are limited. Likewise, there is no currently available data to support adjuvant chemotherapy after metastasis-directed local therapies (surgery or SBRT) for oligometastatic disease.