INTRODUCTION

Nowadays, head and neck malignancy is showing great progress in its management due to the advancement and refinement of the technology, instrumentation, and operation theatre set up. Head and neck squamous cell carcinoma (HNSCC) continues to be a challenge as the incidence is on the rise and its involvement with vital facial and head anatomic complexes that respons-

ible for breathing, speech, eating, hearing, and vision. Late presentation is a common feature of HNSCC patients, and this may be attributed to ignorance, poverty, poor access to health services, and patients consulting traditional healers and usage of traditional medicines [1]. Clinical presentation will depend on the regional anatomic involvement. Computed tomography is the mainstay for assessing and staging the head and neck malignancy whereas magnetic resonance imaging is the preferred tool for evaluating cartilage, bone, perineural, and perivascular invasion. Furthermore, in selected cases, a combination of fine-needle aspiration and neck ultrasonography increases the accuracy of cervical lymph node staging [2]. The prognosis of selected groups of HNSCC remains dismal despite extensive multimodality treatment incorporating surgery and chemoradiation.

With a median overall survival of less than 1 year, patients with chronic or metastatic HNSCC have a poor prognosis. This population includes patients whose disease has recurred locally or who, after initial treatment for localized disease, have developed distant metastases. A fair number of head and neck cancer patients present with loco-regional advanced disease or distant metastases at first presentation. The rate of second primary tumors after a diagnosis of HNC is about 3-7% per year [3]. A small number of patients with a limited recurrent disease can still be treated with curative intent, but the vast majority are treated with systemic therapy for palliative care [4]. Early-stage diseases are mainly treated with surgery and most patients experience a good quality of life with a regular follow-up scheme. A selected patient who presented with recurrent disease, locally or regionally, may be offered salvage surgery or chemoradiation.

For instance, conventionally, the normal treatment of NPC requires chemoradiation and surgery, in the majority of cases. Radiation therapy alone is known to be the main approach to NPC treatment, especially for early-stage disease. The concurrent chemoradiation has been a standard practice for stage III-IV diseases. Surgery mainly involves neck dissection in recurrent cases, in the patient who had exhausted chemoradiation and present with neck nodes that is not amenable to radiation. Surgery can also be performed in case of the patient had a small and limited recurrent tumor at the nasopharynx that can be addressed via transnasal nasopharyngectomy. Critically, deciding the best possible treatment method for a specific patient will depend on multiple factors such as tumor factors, patient’s comorbidity, expertise and equipment availability, and committed rehabilitation team.

At the time, as more treatment choices become available, it is rational to postulate that the results for HNSCC patients could be optimized with an acceptable succession of treatment regimens. This translates to better prognosis and survival for this subset of patients. One of the most effective instruments for providing full benefit to the patients is to increase the number of therapy lines and choices and refine the order in which these therapies should be delivered. Therefore, to produce a maximally efficient and tolerable multi-line continuum of care, it is important to incorporate as many potentially effective therapies as possible into the treatment model of head and neck malignancy [3]. In addition, only a minority of patients with HNSCC benefit from immunotherapy in clinical practice, and the need to discover novel biomarkers to improve treatment strategies is becoming increasingly important. Immunotherapy is based on host immune system functional restoration to counteract different strategies of tumor evasion. Immunotherapeutic approaches generally comprised of tumor-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents [5]. Immune checkpoint inhibitor and EGFR inhibitor is a strong example of immune-targeted therapy [6, 7]. EGFR inhibitor overexpression is seen in most head and neck cancer and is associated with poor prognosis [8, 9].

Presently, many ongoing trials focusing on discovering new biomarkers that can be used in managing head and neck malignancy are in progress. For instance, a study assessing the outcomes of using a combination of antiepileptic plus cisplatin and cetuximab that might escalate treatment outcomes with minimal complications [10]. There are other scientific studies that look at other combinations of therapy in order to escalate the treatment outcomes of head and neck malignancy [11]. This effort needs full support from the government and non-governmental bodies in terms of financial assistance and mutual collaborative work and programs. This will have a great impact on the discovery of potent new therapeutic markers or agents for HNSCC. These new agents can be made available locally at a fair cost and accessible to all disadvantaged HNSCC patients.

With regards to the management of HNSCC, primary tumor management is essential in order to reduce the progression of the tumor and later appearance of distant metastases. However, the side effects of radiotherapy cannot be overlooked, as it can cause second primaries and many significant related toxicities that can impair the patient’s quality of life. Multiple new techniques of radiation have been investigated in head and neck cancer patients in order to improve survival rates whilst minimizing the morbidities associated with radiation toxicity. Such regimes include hyperfractionated radiotherapy with the intention to reduce malignant cell repopulations by shortening the treatment interval time [10].

Critically, via modifying the tumor microenvironment, radiotherapy can also induce distant metastases. This may be partly attributed to the radioresistance that can be modulated via for instance microRNAs regulation [12]. MicroRNAs and their associated factors are responsible for controlling the intracellular pathways involved in DNA damage, repair, apoptosis, angiogenesis, and cell proliferation. For instance, in NPC, the microRNAs are upregulated and are reported to be responsible for the radiation resistance [13, 14]. Other inflammatory markers and gene aberrations have also been documented to involve in producing the radioresistance effects of radiation.

In addition, some studies have also shown that accelerated tumor cell growth and proliferation may occur about 3 to 4 weeks after radiation exposure, which can have significant clinical sequelae. If we can identify this critical stage of cell proliferation and inflammatory cascades that are involved in carcinogenesis, metastasis, and response to treatment, we might be able to identify and develop potential therapeutic targets that address this critical point of cell biology. These potential targets can modulate the important markers, proteins, cytokines, and peptides in the inflammation ecosystem and can be applied to produce the desired effects with minimal side effects. Thus, the molecular mechanisms of radiation resistance in head and neck cancer, for instance in NPC treatment, need to be thoroughly understood [15].

Chemotherapy also carries its own risk of complications and benefits. Multiple factors are involved in producing the desired chemotherapeutic effects and the unwanted side effects, and this largely involves the inflammatory markers and the immune-mediated mechanisms. Targeting the inflammatory-immune markers as a potential therapeutic target for NPC and other head and neck malignancy will allow the transformation of head and neck cancer management to another level. The finesse treatment approaches will produce highly efficacious therapeutic agents and avoid all unwanted complications that have significantly impaired head and neck cancer patient’s quality of life.

INFLAMMATION IN HEAD AND NECK MALIGNANCY

As in the previous chapter, several critical elements of inflammation concerning head and neck malignancy have been highlighted and discussed. This pertaining to the risk factors, assessment tools as well as treatment for head and neck cancer. In terms of the treatment paradigm of head and neck malignancy, currently, available therapy such as chemoradiation, targeted therapy, and immunotherapy are based on the critical elements of inflammation and their related mechanisms of actions within the inflammation ecosystem. Immunotherapy has been shown to be a highly effective therapeutic agent, especially for selected recurrent and metastatic HNSCC.

The most active immunotherapy field in HNSCC over the last decade has been the production of monoclonal antibodies (mAbs) targeting the tumor antigen (TA) on the cell surface. This targeted therapy focused on the unique tumor characteristic and aimed to improve the therapeutic response while minimizing the toxicity [16]. The bulk of research focused on the epidermal growth factor receptor (EGFR). EGFR is a transmembrane surface receptor that can be activated and modulated by multiple mechanisms. Overexpression of EGFR is linked with poor treatment response and impaired patient’s prognosis. Interestingly, tobacco can cause activation and upregulate the EGFR via specific mechanisms and is responsible for reduced treatment effectiveness [17].

Cetuximab is the most common EGFR monoclonal antibody (mAb) used in head and neck malignancy management. It is currently, the only FDA-approved EGFR targeting drugs for HNSCC. It is approved for three particular uses, firstly, in combination with radiation for locally aggressive disease, secondly, as a single agent for recurrent or metastatic disease following the failure of platinum-based chemotherapy, and thirdly, in combination with platinum-based chemotherapy plus 5-FU for first-line recurrent or metastatic HNSCC [16]. This existing treatment can be potentially enhanced with a combination of targeted inflammatory markers in the coming years in order to escalate the therapeutic ratio. This will be highly possible with the continuous effort from the scientific community at large. Another important anti-EGFR mAbs that were clinically tested in HNSCC is Panitumumab. This is a fully human IgG2 mAb which is potentially less immunogenic.

At this juncture, immunotherapy is a promising treatment strategy for effective management of head and neck malignancy. The immune landscape of the head and neck cancer microenvironment is heterogeneous. Multiple immune-targeted agents have been used in treating aggressive and locally advanced head and neck malignancies. As aforementioned, the monoclonal antibodies have been showing a good treatment response. Such example of mAbs that was used in malignant tumor management including, as mentioned earlier, cetuximab and trastuzumab. In comparison, Cetuximab is an EGFR receptor antibody, whereas trastuzumab is the anti-human epidermal growth factor receptor 2 (HER2). These two immune-targeted agents mainly act to counteract the proliferation and apoptosis mediated signaling pathways which are regulated by the growth factor transmembrane receptors.

In selected cases, for the same receptors involved, targeting mAbs yields superior clinical outcomes compared to targeting non-immunogenic small molecules of the same receptors. This can be explained by different immune mechanisms and signaling pathways that underlie the pathogenesis of mAB which give varied therapeutic efficacy. The EGFR overexpression in relation to intracellular phosphorylation cascades has a significant prognostication value in head and neck malignancy [18]. Cetuximab, the first molecularly targeted drug approved by the FDA for the treatment of HNSCC in combination with radiation for locally advanced disease [19]. It is a prototype of mAb with dual signaling and immunological mechanisms [20]. It has minimal side effects and its application has been extended to the new emerging HPV positive head and neck cancers [21]. For instance, the efficacy of cetuximab in combination with chemotherapy has been investigated in patients with low-risk oropharyngeal carcinoma [22, 23]. Multiple other factors especially the immune-related inflammatory markers that can be further explored for gaining maximal therapeutic outcomes for these HNSCC patients. The identification of specific immune-mediated inflammatory markers can be further investigated and incorporated into the immuno-targeted therapy armamentarium. Significant advances and refinement have been made in the assessment of the intrinsic and adaptive resistance mechanisms to immunotherapy [24]. Emerging evidence is looking at the Cetuximab resistance in the treatment paradigm of head and neck malignancy. Several mechanisms have been postulated to underlie the cetuximab radioresistance. These include activation of MET/MAPK signaling pathways, EGFR gene mutation that causes persistent activation of EGFR, and reactivation of selected signaling pathways such as tyrosine kinase, Her 2 and 3 [25].

At the other end of the spectrum, HPV-related head and neck malignancy has surged at certain geographic regions globally. Importantly, this subset of head and neck malignancy has a different biological profile in comparison with other HNSCC. However, the reason why HPV-positive head and neck carcinoma patients have a better prognosis than HPV negative patients remains controversial. The inflammatory constituents and their various mechanisms may play exquisite roles in these critical differences. In particular, the improved overall survival of positive HPV patients may rely on multiple immuno-inflammatory factors. The HPV-positive patients mainly involved the tonsillar carcinoma or oropharyngeal carcinoma and the oral cavity carcinoma [26]. The main modality of treatment of this subset of cancer is transoral surgery for early tumors (T1 and T2 tumor) and chemoradiation for late-stage tumor (T3 and T4 tumor). Importantly the HPV oncogenic proteins may influence the outcomes of the treatment approach. The positive factors that are related to patients with HPV positive tumors include younger age at diagnosis, higher performance status, lower smoking and alcohol-related morbidities, decreased risk of secondary primary tumors, and can tolerate a more aggressive treatment plan. Younger patients may have significant inflammatory responses that able to modify the effect of treatment. In addition, the beneficial outcome of HPV-positive HNSCC could be due to improved sensitivity to chemoradiation. Numerous proteins, peptides, and cytokines in the signaling pathways modulate the cell proliferation, the extent of DNA damage and repair, thus allowing the apoptotic response of cancer cells to chemoradiation [27]. The chemotherapy regime is continuously being investigated in terms of dosing, frequency, and interval of infusion in order to improve treatment outcomes and lessen the toxicity [28].

The ability to prevent immune destruction, in particular by T-lymphocytes and B-lymphocytes, macrophages and natural killer cells, is a proven hallmark of the multistep evolution of cancer. The complex process of initiation, activation, and progression leads to carcinogenesis with the resultant malignant tissue formation. Immunosuppression is frequently viewed as a failure of immunosurveillance, but this does not completely describe the dynamic interplay between cancer and immunity. Treatment of head and neck cancer with immune checkpoint blockade is potentially efficacious. The immune landscape of head and neck cancer serves as a promising frontier for research in immunotherapy [29]. This ultimately will enhance the therapeutic approach of head and neck malignancy.

Immunosurveillance is just part of a wider, complex mechanism known as cancer immunosurveillance. This cancer surveillance consists of three phases of tumor removal, balance, and escape from clinically overt disease. The immune system is thus capable of preventing and encouraging the development and growth of neoplastic tissue [9]. Immunomodulation and inflammation may act synergistically in producing numerous effects in carcinogenesis. This interaction also has significant value in therapeutic immunotherapy and can be exploited and enhanced to yield potent newer therapeutic markers.

Immunotherapy is based on the functional restoration of the immune system of the host. Its role is to help combat various techniques for tumor evasion. Interestingly certain malignant tumors are immunogenic than other tumors. This may be associated with tumor-associated antigens that drive immune activation activations, which may include the oncogenic HPV viral antigens [30]. Broadly speaking, immunotherapeutic methods may include tumor-specific antibodies, cancer vaccinations, cytokines, T-cell adoption, and immunomodulating agents [5]. Multiple immune cells, peptides, humoral factors, and cytokines influence and regulate the tumor microenvironment. The balance between these factors can either modulate the cells and tissue towards malignant changes or can be used as a target to treat cancer. Specifically, cancer immunotherapy is based on the functional restoration of certain signal cascades of the host immune system. It has been applied in clinical practice in the majority of solid human malignancy with the aim to effectively kills cancer cells and preserves viable normal cells. Cancer immunotherapy serves as an interesting research avenue to expand and facilitate the discovery of novel therapeutic agents.

The signal cascades help to counteract various strategies for tumor evasion. These include immunosuppressive microenvironment growth, cellular immune escape through regulatory T-cells or myeloid-derived suppressor cells a reduced antigen processing and presentation, and increased tumor-permissive cytokine profiles [29]. For instance, cancer-associated fibroblast (CAFs) play important roles in shaping the immunosuppressive microenvironment of the tumor in oral cavity cancers by inducing pro-tumoral TAM phenotypes [31]. CAFs also mediated autophagy reactions in oral cancers that are responsible for tumor progression. By controlling secreted factors involved in the autophagy, this CAF mediated autophagy can be controlled and allows blockage of the malignant cell proliferation [32, 33]. In the coming years, many of these modified therapeutic strategies to reverse this CAF-mediated immunosuppression should be considered.

These critical elements play dominant roles in the inflammation ecosystem and may be applied to the current understanding of radioresistance of head and neck cancers to chemoradiation as well as to the targeted therapy. Early immunosuppression identification in HNSCC patients resulted in clinical trials of available immunostimulatory strategies. The immunomodulation approach involves critical molecules, including interleukin (IL)-2 and interferon (IFN)-2a. The interleukin is an important protein that regulates many functions and signaling pathways in the process of carcinogenesis. This again will escalate possible effective treatment strategies for HNSCC. Tumor stromal cells, including immune system cells, modulate the development and progression of cancer. Regulatory T (Treg) cells that express transcription factors are often found at elevated levels of tumor lesions and are essential for the prevention of autoimmunity and maintenance of immune homeostasis [34]. Multiple cytokines and interleukins secreted in response to CAFs such as interleukin 6 play a significant role in head and neck cancer progression [35]. With numerous researches coming in the future, more molecules and markers can be identified.

TARGETTING INFLAMMATION AND REDUCE THE RISK FACTORS OF HEAD AND NECK MALIGNANCY

Roles of inflammation in carcinogenesis of head and neck malignancy has been extensively discussed in previous chapters. The risk factors serve as a target for screening and prevention programs for HNSCC, and this can be implemented at very early in the disease process. The chemoradiation as an integral treatment of the majority of recurrent and metastatic HNSCC carries several limitations inclusive of its significant related toxicities. The radiation-induced DNA damage not only occurs in the cancerous tissues but also within surrounding normal tissues. Of note, after radiation, cell death is proportionate to the dosage of radiation delivered. Critically, the percentage of apoptotic cells is also increased gradually in a dose-dependent manner. The adjacent tissues also exposed to radiation and are at risk of collateral damage. The evidence of damage induced by radiations which mainly involves the chromosomal double strands breakage can be visualized on immunofluorescence. They will appear as speckles of fluorescent foci [36]. The inflammatory markers can be identified and tagged in combination with immunofluorescence in order to further delineate the effects of radiation as well as chemotherapy on both the malignant and healthy tissues.

As described above, the function of the epidermal growth factor receptor in the development and progression of squamous cell carcinoma of the head and neck has been extensively studied. It is a promising biomarker that can be further assessed. It has multiple roles at various molecular levels including protein expression, polymorphism, genes activation, polymorphism, mutation, and EGFR ligand expression [37]. EGFR is a transmembrane glycoprotein member of the tyrosine kinase growth factor family that controls cell growth, apoptotic signaling, angiogenesis, cell proliferation, and metastases [18]. Several studies investigated the potential roles of EGFR as a prognostic indicator in head and neck cancer that was treated with surgery and radiation. The study by Lin et al. reported that overexpression of EGFR in laryngeal cancer is associated with the invasion and metastasis potential of the malignant laryngeal cells. Thus, by inhibiting the EGFR expression, the risk of malignant transformation and progression can be blocked.

Imperatively, this receptor is overexpressed in up to 90% of HNSCC and has been associated with reduced survival [38^–40]. Multiple studies reported on the potential roles of EGFR in monitoring response, predict survival, reducing the morbidity related effects, and improved prognosis. Accumulating evidence has contributed to the evaluation of EGFR pathways and their signaling cascades and the potential agents that can be combined with the current therapeutic approach in the armamentarium management of head and neck malignancy [11]. Cetuximab, Trastuzumab, Panitumumab, Olipamuzumab are examples of EGFR receptor antibodies that have been extensively studied. Cetuximab is a chimeric monoclonal IgG1 subclass antibody binds to the EGFR extracellular domain with a higher affinity [11]. Apart from the growth factor receptors, another interesting group biomarker in the immune-mediated inflammatory ecosystem that is of promising high values is the immune checkpoint inhibitors.

In reality, immunotherapy was revolutionized by the development of immune checkpoint inhibitors. The immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of head and neck malignancy and other human solid malignancies. Immune checkpoint proteins are physiologically responsible for regulating immune tolerance and preventing excessive immune injury. Tumor-induced immune evasion, partially mediated by T cell-suppressive immune checkpoints, is one of the major causes of HNSCC recurrence and metastasis [41]. In recent years, immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 (PD-1 / PD-L1) pathway have been widely administered and have shown promise in a range of malignancies [41].

In multiple tumor forms, anti-programmed cell death therapy is successful and can offer remarkable clinical advantages with minimal toxicity. Several studies are looking at the potential biomarkers that can predict the tumor response to the ICIs and also the possible adverse reactions [42^–44]. By modifying the identified adverse events that are highly linked to ICIs application, a novel effective marker can be developed that can escalate the therapeutic response with minimal or negligible side effects. Since HNSCC ‘s immune environment is very complex, new immune control point inhibitor applications need to be led by a more detailed understanding [44]. With future research, this brand-new targeted therapy in combination with the inflammatory marker can open up the availability of treatment choices for combatting HNSCC that will transform the whole landscapes of head and neck cancer management.

The head and neck cancer microenvironment is unique. It is characterized by the presence of inflammatory cells, immunosuppressive cytokines, secretory proteins, growth factors receptors, and many more. The cytokines group itself is a major constituent of the tumor microenvironment ecosystem. This family of proteins includes interferons, interleukins, chemokines, tumor necrosis factors, etc. Importantly these cytokines regulate cell growth and signaling and modulate cell migration and proliferation. The availability of systemic therapies that able to balance and reverse the immunosuppressive effects of these cytokines holds as a potentially viable therapeutic target. The inflammatory cytokines such as VEGF, IL6, and HGF are found in higher levels in head and neck cancer patients. Numerous studies highlight that these biomarkers are strongly related to disease progression and relapse [45].