Improving Radiotherapy Response in the Treatment of Head and Neck Cancer

Abstract

The application of radiotherapy to the treatment of cancer has existed for over 100 years. Although its use has cured many, much work remains to be done to minimize side effects, and in-field tumor recurrences. Resistance of the tumor to a radiation-mediated death remains a complex issue that results in local recurrence and significantly decreases patient survival. Here, we review mechanisms of radioresistance and selective treatment combinations that improve the efficacy of the radiation that is delivered. Further investigation into the underlying mechanisms of radiation resistance is warranted to develop not just novel treatments, but treatments with improved safety profiles relative to current radiosensitizers. This review is written in memory and honor of Dr. Peter Stambrook, an avid scientist and thought leader in the field of DNA damage and carcinogenesis, and a mentor and advocate for countless students and faculty.

I. RADIOTHERAPY FOR THE TREATMENT OF HEAD AND NECK CANCER

Prior to the advent of radiotherapy, surgery was the only curative treatment available to cancer patients. Patients whose tumors were inoperable had no other treatment options, leading to inevitable death. The first reports of the use of radiation for the treatment of cancer occurred in the late 1800s, predating the use of modern chemotherapy by nearly half a century.¹ Radiation was discovered only a few years prior to its use in cancer treatment and as such was still poorly understood.¹ The initial use of therapeutic radiation resulted in the death of many patients, researchers, and physicians. However, the evolving understanding of radiation biology and clinical applications of radiotherapy over the last century has resulted in radiotherapy becoming a successful treatment option for patients across a wide range of malignances, including head and neck cancer (HNC). Fractionated radiotherapy, or radiation delivered over multiple days to minimize radiation toxicity, is an integral aspect of the treatment of HNC and was first described by Coutard as early as 1934.² Modern radiotherapy is used to treat HNC either definitively or as an adjuvant treatment to surgical resection with or without chemotherapy to further improve treatment success. Additionally, radiotherapy is used palliatively, to reduce symptoms from incurable cancers.

Ionizing radiation induces cell death by direct and indirect actions; specifically, it can generate single-strand DNA breaks (SSBs) and double-strand DNA breaks (DSBs).³ However, most cellular damage is generated through induction of reactive oxygen species (ROS). ROS cause substantial damage to DNA, proteins, lipids, and RNA within the cell. This damage leads to cellular dysfunction and cell death. However, photon and electron-based radiotherapy have limited ability to generate the more lethal direct DSB.^4,5 As a consequence, heavier particles such as protons and alpha-particles are being increasingly studied because these particles can generate more direct DSB and may therefore have greater efficacy in killing tumor cells.^4,5

Chemotherapy alone does not improve survival in HNC patients, and many tumors are not surgically resectable. As a result, radiotherapy is used in the care of roughly 75% of HNC patients.⁶ However, radiotherapy fails to effectively treat tumors in a small subset of patients and many patients have tumor recurrence in previously irradiated fields.⁷ Both of these factors contribute to increased morbidity and mortality in patients with head and neck squamous cell carcinoma (HNSCC).

II. CURRENT LIMITATIONS OF HEAD- AND NECK-DIRECTED RADIOTHERAPY

Despite the success of radiotherapy in the treatment of cancer, radiation treatment will fail in some patients due to inherent and acquired radiation resistance in tumor cells. Though many of the mechanisms underlying radiation resistance remain to be discovered, several major contributors have been identified including hypoxia and altered intracellular signaling of key cell survival pathways.

A. Mechanisms of Radiotherapy Resistance

As radiotherapy is heavily reliant on the generation of ROS that leads to damage and subsequent tumor cellular toxicity, the presence of oxygen is critical to the success of radiation-mediated cell death. During tumor development, angiogenesis provides vital nutrients and oxygen to support tumor growth. However, this new vasculature is often abnormal and includes increased presence of anastomoses.⁸ The poorly constructed vasculature does not allow proper blood circulation and as tumors grow, their centers become increasingly hypoxic. The reduced presence of oxygen in these tumor tissues results in reduced substrate for the generation of ROS.⁹ By extension, the inhibition of ROS generation reduces tumor cell response to radiotherapy.

In addition to pre-existing genetic abnormalities that provide inherent tumor radioresistance, cancer treatment can also induce genetic and cell signaling alterations whereby the cells acquire resistance to radiotherapy. The latter is particularly problematic and up to half of patients with HNSCC develop tumor recurrence; the majority of which occur within previously irradiated fields.¹⁰ Radiation can also induce activation of the PI3K and MAPK signaling pathways, which contribute to the development of acquired radiation resistance.^11,12

B. Current Standards of Head and Neck Directed Radiation Therapy

The higher the radiation dose, the more DNA damage is achieved. However, a major limitation of escalating dose is the resultant damage to surrounding normal tissues, leading to short and long-term side effects that reduce quality of life. Numerous techniques have been employed to reduce exposure of normal tissues to the harmful effects of radiation. Image-guided delivery and intensity-modulated radiotherapy (Fig. 1A) and proton therapy (Fig. 1B) allow for greater accuracy in treatment delivery to the tumor while minimizing dose to normal tissues.¹³ Stereotactic radiation (Fig. 1C) delivers high doses of focal radiotherapy from multiple angles so that the tumor receives overlapping doses of radiation to ensure treatment efficacy while limiting exposure of normal tissues.¹⁴ Brachytherapy involves the strategic placement of radioactive seeds within tissue to deliver highly focal treatment to the tumor. Brachytherapy is commonly used in the treatment of prostate cancer, uveal melanoma, multiple gynecologic cancers, and select HNCs (Fig. 1D).^15,16

FIG. 1:

Modern radiation delivery techniques. (A) Standard intensity-modulated radiation delivery to a sinonasal cancer delivered with photons, spread over multiple beams to minimize toxicity. (B) Proton radiation plan for the same patient allows for more focal radiation delivery. (C) Stereotactic radiation therapy to the larynx allows for focal delivery of high doses of radiation therapy to just one vocal cord. (D) Brachytherapy, or radioactive seed placement (inset), allows for delivery of high doses of radiation within the operative bed with almost no dose to adjacent normal organs within the head and neck (image courtesy of Dr. Chad Zender, with permission).

Few Food and Drug Administration (FDA)–approved radiosensitizers exist to enhance the vulnerability of radioresistant tumors to radiotherapy. Cisplatin is the primary radiosensitizer used in the treatment of HNC and is hypothesized to enhance cell kill through multiple mechanisms. Although empiric evidence supports radiosensitization, cisplatin is highly toxic to kidneys, the nervous system and the auditory apparatus. This toxicity contributes to additional short and long-term side effects experienced by the patient^17,18 with rates of severe mucositis, dysphagia and dermatitis approaching 50% for the combination of cisplatin and radiation.¹⁹ Treatment related toxicity also results in treatment breaks with resultant adverse effects on tumor control and mortality. The current standard of care for HNC patients treated with cisplatin and external beam radiotherapy is administering 100 mg/m² cisplatin every 3 weeks for a total of 3 cycles.²⁰ Although multiple clinical trials have evaluated if a lower dose of cisplatin would provide equivalent tumor control with reduced side effects,²¹ a recent meta-analysis of 59 chemoradiotherapy trials determined that patients who received the standard dosing of cisplatin had greater overall survival than patients receiving lower doses.²² The ongoing trial NRG HN-009 seeks to conclusively establish whether low-dose weekly cisplatin and high-dose cisplatin given every 3 weeks can be used interchangeably.²³

III. RADIOSENSITIZERS IN THE TREATMENT OF HNC

A. Platinum-Based Compounds

Platinum-based compounds such as cisplatin and carboplatin have been used in the treatment of cancer since the 1970s²⁴ and are the most commonly used radiosensitizers in clinical practice; the combination of cisplatin and radiation is considered to be the historical standard treatment for HNC. Platinum-based compounds have multiple mechanisms of action to inhibit tumor growth; (1) interstrand and intrastrand crosslinking of DNA, (2) inducing cell cycle arrest, (3) interfering with repair of lethal and sublethal DNA damage, (4) inhibiting angiogenesis, and (5) increasing sensitivity of hypoxic tissues through the generation of ROS (Table 1).^24,25 Cisplatin alone does not prolong overall survival in the treatment of HNC.²⁴ However, concurrent use of cisplatin and radiotherapy following surgical resection is associated with improved tumor control in patients with high-risk HNC.²⁶

TABLE 1:

Classes and examples of radiosensitizers

Platinum-based compounds
Cisplatin24–26	Interstrand and intrastrand crosslinking of DNA, cell cycle arrest, inhibition of DNA damage repair, inhibition of angiogenesis, generation of oxidative stress
Carboplatin24,25
Taxanes
Docetaxel27	Antimicrotubular agents, cell cycle arrest
Paclitaxel28,29
Anti-metabolites
5-FU30,32	Pyrimidine analog, inhibits DNA replication and synthesis, cell cycle arrest
Gemcitabine30,33
Methotrexate30	Folic acid analog, inhibits de novo purine and thymidine synthesis, inhibition of DNA replication
EGFR inhibitors
Cetuximab37,38	EGFR inhibition
Afatinib37
Erlotinib41
Immunotherapy
Pembrolizumab74	PD-1 inhibition
Nivolumab74
Cemiplimab49
Enzyme inhibitors
Olaparib56,59	PARP inhibitor, inhibition of DNA damage repair, hypoxia sensitizer
Valproic Acid60,63	HDAC inhibitor
CUDC-10161,62	Inhibitor of EGFR, HER and HDAC
CB-83964	Glutaminase inhibitor
Hypoxia sensitizers
Nimorazole69,70	Oxygen mimetic, increases oxidative stress
Olaparib56,59	PARP inhibitor, inhibition of DNA damage repair, hypoxia sensitizer

B. Taxanes

Taxanes are antimicrotubular agents originally derived from the yew tree (Table 1). Microtubules are structural proteins that are critical for the formation of the mitotic spindle apparatus.²⁷ The mitotic spindle is essential for the correct segregation of chromosomes during mitosis. The disruption of the mitotic spindle by taxanes prevents tumor cells from successfully completing cell division. Taxanes also arrest cells in the G₂/M cell cycle phase, when the cell is more radiosensitive.²⁸ Paclitaxel has also been observed to improve oxygenation levels in breast cancer patients,²⁹ which may improve radiotherapy response by increasing substrate for the generation of DNA-damaging ROS. Docetaxel and paclitaxel are two taxanes that are approved for use in the treatment of HNC. Paclitaxel is used in combination with cisplatin or carboplatin to radiosensitize HNSCC.³⁰ The combination of paclitaxel and radiation in patients with locally advanced HNC is also currently being investigated in a clinical trial.³¹

C. Anti-Metabolites

Anti-metabolites are one of the oldest drug classes used in the treatment of cancer and are also used in the treatment of autoimmune diseases (Table 1). Anti-metabolites work to inhibit tumor cell growth by interfering with the cell’s ability to synthesize DNA and RNA. This prevents the DNA replication required to support tumor cell division and hinders production of proteins required for cell function. Some examples of anti-metabolites include 5-fluro-uracil (5-FU), gemcitabine, and methotrexate. 5-FU and gemcitabine are two commonly used pyrimidine analogs.³² 5-FU is an uracil analog that is eventually metabolized to 5-fluro-2ʹ-deoxyuridine-5ʹ-tri-phosphate (5-FdUTP). 5-FdUTP and dUTP are misincorporated into DNA, and are then hydrolyzed by uracil-DNA-glycosylase, leading to SSBs. 5-FdUTP additionally inhibits thymidylate synthase and therefore production of thymidine-5ʹ-tryphosphate (dTTP), which is required for DNA synthesis.³³ The depletion of dTTP inhibits repair of the SSBs.³² The deoxycytadine analog gemcitabine, 2’,2’-difluoro-2’-deoxycytidine (dFdCyd), is an anti-metabolite used to treat various solid tumors. Gemcitabine is metabolized into diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleotides, which disrupt DNA replication and synthesis during the S phase of the cell cycle, inducing G1/S cell cycle arrest and lead to cell death. Cells are unable to remove the incorporated dFdCTP, which prevents DNA polymerase from synthesizing DNA.³⁴ Additionally, gemcitabine disrupts production of deoxynucleotides through dFdCDP mediated inhibition of ribonucleotide reductase.³⁴ Methotrexate is a folic acid analog that is also used in the treatment of HNC. Methotrexate metabolites inhibit de novo purine synthesis (DNPS) and thymidine synthesis leading to impaired DNA replication by preventing folate reduction via dihydrofolate reductase (DHFR).³²

D. Targeted Therapy

There are few receptors specifically overexpressed in HNC cells to which therapy has been targeted (Table 1). Epidermal growth factor receptor (EGFR) is overexpressed in more than 90% of head and neck squamous cell carcinoma tumors.³⁵ Overexpression of EGFR leads to rapid tumor cell proliferation and is linked to significantly reduced patient survival.³⁶ In addition to the detrimental effects of EGFR overexpression in HNC, radiation activates EGFR signaling and further stimulates proliferation, cell survival, and DNA repair pathways.³⁷ This signaling occurs through the PI3K/AKT/mTOR signaling pathways and contributes to reduced patient survival. As such, several compounds have been developed to target EGFR overexpressing tumor cells. Cetuximab and afatinib bind to EGFR and prevent epidermal growth factor from binding to EGFR and stimulating EGFR-mediated cellular proliferation.³⁸ Although afatinib has only been used in the setting of metastatic HNC, cetuximab has been tested in combination with radiation to improve HNC cure rates. HNSCC patients receiving both cetuximab and radiotherapy were reported to have greater locoregional control and overall survival as compared to radiotherapy alone. Importantly, cetuximab was fairly well tolerated.³⁹ However, for patients with human papilloma virus (HPV)-mediated tumors, cetuximab with radiation was not superior to cisplatin with radiation. Patients treated with both cisplatin and radiation experienced greater local control and overall survival as compared to patients treated with cetuximab and radiation.⁴⁰ Cetuximab is most commonly used for patients with locally advanced HNSCC who are ineligible for cisplatin-based chemotherapy or in those with recurrent/metastatic disease. EGFR and protein-tyrosine kinase inhibitor, erlotinib, is currently being examined in combination with radiotherapy and cisplatin in patients with stage III or IV HNC (Table 2).⁴¹

TABLE 2:

Current and completed clinical trials examining radiosensitizers in HNC

NCT no.	Phase	Intervention	Disease	Study status
NCT00001442 31	I	Paclitaxel, radiotherapy	Head and neck squamous cell carcinoma	Completed
NCT00410826 41	III	Erlotinib hydrochloride, cisplatin, 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy	Stage III and IV squamous cell carcinoma of hypopharynx, larynx, lip and oral cavity, nasopharynx and oropharynx	Completed
NCT04722523 49	I	Cisplatin, carboplatin, docetaxel, cetuximab, cemiplimab, surgical resection, radiotherapy	Head and neck squamous cell carcinoma	Recruiting
NCT01384799 68	I	Cisplatin, CUDC-101, radiotherapy	Locally advanced head and neck squamous cell carcinoma	Completed
NCT01880359 72	III	Placebo, cisplatin, nimorazole	Locally advanced, HPV negative head and neck squamous cell carcinoma	Active, not recruiting
NCT02229656 66	I	Olaparib, radiotherapy	Stage II and III laryngeal cancer, head and neck squamous cell carcinoma	Active, not recruiting
NCT01507467 74	III	Nimorazole, accelerated fractionated radiotherapy	Head and neck squamous cell carcinoma	Terminated

E. Immunotherapy

The role of immune system modulating therapy in oncology is under avid investigation (Table 1). The immune system is critical in recognizing and killing cancerous cells. However, HNC cells have developed mechanisms to evade detection by the immune system. One such mechanism is through expression of programmed death-ligand 1 (PD-L1), which binds to PD-1 receptors on the surface of T cells.⁴² The binding of PD-L1 to PD-1 inactivates T cells rendering them incapable of killing tumor cells. PD-1/PD-L1 inhibitors act to block this inactivation, thereby allowing T cells to successfully kill tumor cells.⁴³ Cisplatin was discovered to increase PD-L1 expression in HNSCC cell lines as well as in tumor tissues of HNSCC patients, with almost 70% of patients who had PD-L1 negative tumors becoming PD-L1 positive.⁴⁴ Radiation treatment was also found to induce PD-L1 expression in colon cancer cells.^45,46 PD-L1 blockade resulted in significantly improved survival and tumor control when combined with radiation treatment in mice bearing colon cancer cell line CT26, triple negative cancer cell line 4T1 or melanoma xenografts.⁴⁶ Radiation adapted HNSCC cell line FaDu cells have significantly upregulated PD-L1 as compared to standard FaDu cells.⁴⁷

PD-1 inhibitors recently FDA approved for the treatment of recurrent/metastatic HNC include pembrolizumab and nivolumab. Given that radiotherapy can induce PD-L1 expression and that PD-L1 expression is associated with poor survival in several cancers, blockade of the PD-1 and PD-L1 checkpoint may increase survival in patients with HNSCC who receive radiotherapy. A recent phase II clinical trial demonstrated improved disease free survival in intermediate risk patients receiving pembrolizumab in combination with radiation in patients with resected HNSCC.⁴⁸ The NCT04722523 phase I trial is currently recruiting patients to examine the effects of the PD1 inhibitor cemiplimab in combination with chemotherapy, radiation, and surgery (Table 2).⁴⁹

F. Nanoparticles

Nanotechnology has revolutionized the field of cancer treatment with the development and exploration of the full potential of nanoparticles, 1- to 1000-nm-sized materials with unique physicochemical properties distinct from their bulk parent materials.⁵⁰ Although nanoparticles have been employed in imaging and diagnostic elements of cancer therapy, nanoparticle-based radiosensitization offers a mechanism by which a given radiation dose can result in a more intense, yet localized cell death, leading to a higher radiotherapeutic effect.⁵¹ Therefore, nanoparticle-based radiosensitizers sensitize tumor tissues by increasing oxidative stress through generation of ROS, which subsequently increase DSBs.³ Nanoparticles can serve as either therapeutic delivery agents by coupling with chemotherapeutic drugs such as cisplatin loaded polymeric nanoparticles, or they can serve as a direct therapeutic agent that augments the efficacy of radiotherapy as in the case of gold (Au), silver (Ag), and gadolinium (Gd)–based nanoparticles.^52,53 Drug loaded nanoparticles including cisplatin or paclitaxel loaded nanoparticles can kill tumor cells in the absence of radiation, but importantly also further augment the effect of irradiation (Fig. 2).^3,52

FIG. 2:

Schematic illustrating physical, chemical, and biological mechanisms by which metal nanoparticles (MNPs) enhance radiation mediated cellular damage. Inset depicts transmission electron microscopic micrograph of gold nanoparticles.

Among nanoparticle-based radiosensitization, high atomic number (Z) metals and metal oxide-based nanoparticles have been widely explored due to their ability to increase radiotherapeutic effectiveness by production of Auger secondary electrons. The short range (μm) of the Auger secondary electrons enhances radiation dose by increasing energy deposition in the tumor tissues upon absorption of ionizing radiation.^54–56 In the recent past, metal and metal oxide-based nanoparticles have been explored as radiosensitizers for HNC therapy.^56,57 Gold nanoparticles (AuNPs) have been widely explored as radiosensitizers in HNC therapy both in in vitro and in vivo systems. More than a decade ago, Hainfield and coworkers established the role of AuNPs in augmenting the efficacy of radiotherapy and established their effectiveness in the treatment of aggressive, radioresistant HNC in the SCCVII in vivo mouse model.⁵⁸ In another study, which led to a successful phase I clinical trial and now a phase II clinical trial, CYT-6091, tumor necrosis factor-α tagged to pegylated colloidal gold nanoparticles is being used in the treatment of solid tumors including melanoma.⁵⁹ To address radioresistance in HNC, a study was undertaken by Popovtzer and coworkers, using the monoclonal antibody Cetuximab, in combination with AuNPs. Their study demonstrated that targeted AuNPs improved radiotherapy response as indicated by reduced tumor growth.⁶⁰ Tyrosine kinase inhibitor coated AuNPs, AG1478, also improved radiotherapeutic effects in HNC.⁶¹ In addition to AuNPs, gadolinium^Z,64-based nanoparticles with trade name AGuIX (NHTheraguix; Crolles, France) also offer radiosensitization potential against solid tumors and have been explored in an orthotopic tongue tumor model in mice using human HNC cell line CAL33-Luc.⁶² The effectiveness of nanoparticle-based radiosensitizers depends on their physiochemical characteristics such as size, shape, composition, surface functionalization, stability in vivo, and immunological response. Though recent studies demonstrate potential efficacy of nanoparticle-based radiosensitizers in HNC in in vitro and in vivo systems, additional preclinical data is required to optimally transition this technology from the bench to the bedside.

G. Other Radiosensitizers

Numerous enzyme inhibitors have also been explored as potential radiosensitizers (Table 1). Poly-ADP-ribose polymerase (PARP) has a critical role in regulating cellular proliferation and repairing DNA damage.⁶³ In particular, PARP1 is critical in the repair of SSBs through base excision repair.⁶⁴ DSBs are more difficult to repair and are therefore more lethal as compared to SSBs. Ionizing radiation induces greater levels of SSBs relative to direct DSBs. However, left unrepaired these SSBs convert to secondary DSBs. The use of a PARP inhibitor to block repair of SSBs is likely to increase the presence of lethal DSB in cancer cells treated with radiation.⁶⁵ The PARP inhibitor, Olaparib, radiosensitizes HNSCC cells in vitro.⁶³ Olaparib in combination with radiotherapy is currently undergoing clinical investigation in patients with HNC.⁶⁶ Histone deacetylase (HDAC) inhibitors are also being examined as potential radiosensitizers. Histone hypomethylation, increased activity of HDAC and decreased activity of histone acetyl transferase (HAT) was associated with radioresistance in breast cancer cell lines.⁶⁷ Treatment of these radioresistant breast cancer cells with HDAC inhibitor, valproic acid, restored radiosensitivity.⁶⁷ A phase I clinical trial in HNC patients to examine the combined efficacy of cisplatin, radiotherapy and novel drug compound CUDC-101 was assessed for patient safety (Table 2).⁶⁸ CUDC-101 inhibits the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor type 2 (Her2) and HDAC.⁶⁹ A phase II trial combining HDAC inhibitor, valproic acid, with chemoradiotherapy also was recently completed. Although a higher response rate was observed when valproic acid was combined with chemoradiotherapy, increased toxicity was observed in patients and this pairing may not be a viable option.⁷⁰ Glutaminase enzyme inhibitor CB-839 (telaglenastat) is also of interest as a potential radiosensitizer. Increased glutaminase gene expression in the tumor tissues of patients with HNSCC was associated with significantly reduced patient survival.⁷¹ Glutaminase is a critical metabolic enzyme responsible for the conversion of glutamine to glutamate, which once converted to alpha-ketoglutarate, fuels the Krebs cycle. Preclinical studies of CB-839 in breast, renal and pancreatic cancers demonstrated CB-839’s ability to inhibit tumor cell growth. Importantly, CB-839 inhibits tumor cell growth and radiosensitizes tumor cells in HNSCC in vitro and in vivo mouse models.⁷¹

As mentioned above, hypoxia is associated with increased radioresistance. As such, hypoxia sensitizers were developed to examine if they can sensitize tumors to the effects of radiation. Several active clinical trials are testing drugs to sensitize hypoxic cells to radiation. The phase III clinical trial “AF CRT +/− Nimorazole in HNSCC”⁷² is examining the efficacy of combining nimorazole with cisplatin and radiotherapy (Table 2). Nimorazole is an oxygen mimetic that can assist in free radical production in radioresistant hypoxic tissues and by doing so, increases radiosensitivity.⁷³ The above mentioned PARP inhibitor, olaparib, also sensitizes hypoxic tumor tissues to radiation. The efficacy of olaparib and radiotherapy in HNC is being examined in a Phase I clinical trial (Table 2).⁶⁶ Additionally, nimorazole in combination with accelerated fractionated radiotherapy is being examined in a phase III clinical trial (Table 2).⁷⁴

IV. CONCLUSIONS AND FUTURE DIRECTIONS

Radiotherapy is pivotal to the successful treatment of many different cancers including HNC. Though largely effective, the success of radiotherapy is limited by substantial short and long-term side effects as well as inherent and acquired radioresistance. Side effects and radioresistance greatly contribute to reduced quality of life as well as reduced survival. Therefore, identifying novel radiosensitizers or treatment combinations is paramount to improving the lives of HNC patients. Currently, few FDA-approved radiosensitizers exist for the treatment of HNC. Significant opportunities exist to better understand not only how radiation mediated cell death can be enhanced, but also how radiation itself permits cellular changes that promote survival. However, promising pre-clinical and clinical research efforts continue to identify potential novel radiosensitizers that will surely alter the landscape of radiotherapy in HNC.