Oral Cavity and Oropharyngeal Cancer: Treatment

ABSTRACT

Background: The objective of this review is to outline the treatment of oral cavity and oropharyngeal cancers including surgery, radiation therapy and systemic therapy. Systemic therapy includes cytotoxic chemotherapy, immunotherapy and targeted therapy.

Types of studies reviewed: Textbooks, review articles and large institution databases and guidelines were used in this review as appropriate. Case studies and smaller retrospective studies applied in specific and more controversial areas. Current phase III clinical trials and their reports were used in reviewing the most recent developments.

Results: Surgery is the mainstay treatment for oral cavity cancer. Early-stage oropharyngeal cancer can be treated with either surgery and/or radiation therapy. Advanced-stage oropharyngeal cancers are best treated with radiation and possibly chemotherapy, and p16 positive tumors enjoy a much better prognosis. Recurrent disease and/or adverse pathologic features such as close or positive margins, perineural/ perivascular invasion and extracapsular lymph node spread may indicate the need for systemic therapy. Systemic therapy now includes the first-line use of the immunotherapy agent pembrolizumab (anti PD-1 mab) in addition to cytotoxic chemotherapy, typically cisplatin, and possibly targeted therapy, cetuximab, an epithelial growth factor receptor inhibitor.

Practical implications: Dental health care providers should realize that surgical excision is the main treatment for oral cavity cancer and that HPV p16 positive oropharyngeal cancers respond favorably to radiation therapy. Targeted therapy now includes several immunotherapeutic agents, pembrolizumab and nivolumab, and the (EGFR) epithelial growth factor inhibitor, cetuximab. Rapid advances in targeted therapy are likely to improve clinical outcomes (survival and morbidity) for patients with oral cavity and oropharyngeal carcinoma.

Key words: Oral cavity, oropharyngeal, carcinoma, surgery, immunotherapy, systemic therapy, radiation therapy, targeted therapy, cisplatin, pembrolizumab, nivolumab, cetuximab

AUTHORS

Robert S. Julian, DDS, MD, is the chairman and program director of the department of oral and maxillofacial surgery at Community Medical Centers/UCSF- Fresno.

Brian M. Woo, DDS, MD is the program director of the head and neck and microvascular surgery fellowship at Community Medical Centers/ UCSF-Fresno.

Eric C. Rabey, DDS, is a third-year resident in the department of oral and maxillofacial surgery at UCSF-Fresno.

Conflict of Interest Disclosure for all authors: None reported.

The overall survival rate for patients with oral cavity and oropharyngeal (OC/ OP) carcinoma has improved over the last 30 years from 50% to 65% overall. This is probably due to improved microvascular reconstructive techniques with less concern of leaving a surgical defect after tumor resection. Other factors that have improved survival include earlier-stage diagnosis, more liberal surgical treatment of the neck with elective contralateral neck dissections, improved radiation therapy techniques, adjuvant chemotherapy, immunotherapy and less delay time between surgery and radiation treatment [1,2] (TABLE).

Despite the specific treatment regimen, the stage at diagnosis is the single most important variable in predicting survival. Thus, prevention through screening, HPV vaccination and earlier diagnosis is the important public health priority. [7,8] Treatment delays are also a major factor in prognosis, and the dentist should always work diligently upon referring to a specialist to ensure timely evaluation and treatment for a suspected cancer patient. [9,10]

National Comprehensive Cancer Network (NCCN) guidelines state that surgery is “preferred” as the first-line treatment for early-stage oral cavity cancer and is recommended in advancedstaged disease, when feasible, along with adjuvant radiation therapy (RT) or chemoradiation therapy (CRT). [11] Despite this “preferred” status of surgery, outcomes are clearly better for patients who have surgical excision, and this is true for all stages. OC cancers are treated surgically with at least 1 cm margins, keeping in mind that margins tend to be around 20% to 25% smaller on pathologic specimens as compared to their in vivo dimensions. [12] Neck dissection typically is performed when lymph node disease is evident or when there is an elevated risk of occult regional metastasis as with depth of invasion of greater than 5 mm. [13] Stages III and IV OC cancer require combined therapy for best outcomes where surgery is the primary treatment modality when feasible followed by postoperative adjuvant RT. CRT therapy or, more recently and gaining standard-of-care implications, systemic/RT combined regimens that include immunotherapy with nivolumab/pembrolizumab (anti PD-1) and targeted therapy with cetuximab (EGFR inhibitor) are indicated for adverse findings such as positive surgical margins, perineural or lymphovascular invasion, N2 or N3 lymph node disease, lymph node disease in levels IV or V and/or extracapsular extension of tumor in lymph nodes. [14]

OP cancer treatment regimens are less standardized, and there is ongoing controversy especially about the advisability of deescalating RT regimens for p16+ tumors that are generally thought to be more radiosensitive. OP tumors, in general, are more radiosensitive, and generally outcomes are similar with and without surgery especially in p16+ tumors. Early-stage OP cancers can be treated with either radiation alone or surgery alone and this likely depends on potential surgical site morbidity and the patient’s functional health status. Surgery for early-stage OP cancer has recently been technically advanced using transoral robotic surgery (TORS), which generally greatly reduces surgical morbidity through reducing the “surgical access” that is required for excision. Advanced-stage OP cancers require combined therapy with either surgery followed by RT or primary CRT. Decision-making is difficult in advanced-stage cases given the functional and curative outcomes cannot always be predicted before treatment. Most advanced OP cancers are not in an anatomically favorable site for excision given their proximity to the skull base, carotid artery, cranial nerves, tongue base and/or vertebral column. Given the potential massive impairment of such surgery on speech, swallowing and airway, CRT has been the primary treatment. Such tumors have been thought of as unresectable and combined CRT has been used for decades with the recent realization that there is a p16+ subset of these patients that have a markedly more favorable prognosis. There are multiple ongoing trials that may well simplify and deescalate the treatment of this subset of patients. [15]

Given the majority of OC/OP cancer is diagnosed at advanced stages, radiation therapy, whether primary or adjuvant, is always a consideration. Definitive primary treatment of head and neck tumors that is organ (form and function) sparing has become the sole expertise of the radiation oncologist. They continue to improve organ sparing techniques especially with adaptive image-guided, intensity-modulated radiation therapy and have a proven evidence-based record of curing patients utilizing primary RT or CRT who have laryngeal, hypopharyngeal, nasopharyngeal and OP cancers. Hereto, p16+ OP cancer can, in most cases, be treated with definitive RT without surgery or systemic therapy. Importantly, modern definitive RT or CRT greatly improves quality of life through sparing salivary gland, thyroid gland, cranial nerve, pharyngeal constrictor and laryngeal function. [16] The quality of life improvements inherent in avoiding morbid surgical procedures and minimizing ionizing radiation damage to adjacent normal structures that are afforded by modern RT and CRT cannot be overstated. OC/OP cancer patients who have RT or CRT are benefiting greatly from the rapid technical and intellectual advances being made by the physicists, physicians, technicians and support staff who make up the radiation oncology team. Ionizing, meaning energetically removing an electron from an atom, radiation kills cancer cells through injury to DNA by direct energy transfer and indirectly through the creation of energetic free radicals, especially reactive oxygen species. Free radicals are created through the energy transfer to water molecules that produces a positive ion, H2O+, and a free electron. Studies show that cells are most sensitive to this electromagnetic damage during late mitotic phase (G2/M). [17] Cells that are not in active mitotic phase (G0) are injured, but the DNA repair and cellular repair mechanisms hold off apoptotic, autophagic and necrotic sequences in most cases. Short of actual cell death, quiescence, senescence or terminal differentiation are potential cell cycle consequences from the radiation damage. [18] The result is that radiation injures or kills cells that are rapidly dividing significantly more than non-neoplastic cells. Radiation has its main side effect profile related to the non-neoplastic tissues that have relatively high mitotic activity such as mucosal cells of the aerodigestive tract, skin epithelium and hematopoietic cell lines. Radiation dose is measured in gray (Gy), which is defined as the absorption of 1 joule of energy per kilogram of matter (water or human tissue). Per the previously common unit of measurement, one Gy is equal to 100 rad. The energy of the beam is expressed as megavoltage MV and the beam imparts energy to tissue as it penetrates requiring higher energy levels to reach deeper tissues. Head and neck tumors are generally superficial as compared to other visceral organs of the chest and abdomen, so the energy of the beam tends to be lower. [19]

Head and neck cancers generally require doses of 50–70 Gy and this is fractionated into 1.5–2.0 Gy per treatment over a period of five to seven weeks. [20] High-risk areas including the tumor, tumor bed and metastatic lymph nodes are treated with 66–70 Gy. Lymph node beds are treated at the lower end of this dosing scale unless there is gross disease in the neck or extracapsular extension found after removal. Despite normal tissue-sparing techniques with dosimetry mapping, doses of over 6,000 Gy are associated with higher risks of dysphagia, and depending on the location of the target tissues, xerostomia can be problematic at much lower doses. [21]

Systemic therapy for OC/OP squamous cell carcinoma antigen (SCCA) includes cytotoxic chemotherapy, immunotherapy and targeted therapy. The most important cytotoxic chemotherapeutic agent for treatment of head and neck cancer is cisplatin. Cisplatin and its analogs exert their cytotoxic effects by covalently binding to purine DNA bases forming inter- or intrastrand chain cross-linking, especially during cell division, disrupting the normal functions of cellular DNA. Tumor cells are essentially poisoned into an apoptotic state because they are rapidly dividing. The preferred chemotherapy regimen in the treatment of advanced head and neck cancer, according to NCCN guidelines, is cisplatin adjuvant concomitant CRT for early/moderate disease with adverse features and advanced disease or as part of a primary treatment regimen for very advanced recurrent and metastatic disease. A landmark randomized trial published in 1999 that addressed stages III and IV head and neck cancer demonstrated that CRT significantly improved the three-year survival rate (51% versus 31%) compared to RT alone. [22] The chemotherapeutic agent acts as a radiosensitizer (cisplatin), and there is category 1 evidence that such combined therapy is more effective than either modality alone. Given the possible synergy between immunotherapy and RT, CRT may well include immunotherapy in selected cases in the very near future. [23] The indication for primary systemic (chemotherapy and immunotherapy) is in very advanced locoregional and/ or metastatic disease, usually after failed surgery and/or radiation therapy and clinical scenarios where radiation and/ or surgery are not possible. There is some evidence that primary chemotherapy alone can help improve survival in advanced-stage OP/OC carcinoma when patients are not candidates for surgery or radiation therapy. [24] In 2008, the EXTREME regimen consisting of platinum-based (cisplatin or carboplatin) therapy combined with 5FU and cetuximab was found to be more effective than single-agent chemotherapy alone in patients with advanced-stage head and neck cancer. [25] The standard of care since 2008 in this setting was set by the EXTREME chemotherapeutic regimen, but currently the standard of care is evolving to include immunotherapy.

Immunotherapy has now become part of the standard treatment for advanced head and neck cancer, and immune checkpoint inhibitors such as nivolumab and pembrolizumab are modestly improving outcomes in advanced-stage disease. [26,27] Interestingly, in 2016, the immunotherapeutic drug nivolumab (anti PD-1) was approved as a second line of treatment for recurrent/ metastatic and persistent head and neck carcinoma but only in the setting of failed surgery, radiation and failed or failing chemotherapy. Further progress came in 2019 when pembrolizumab (anti PD-1) gained FDA approval for first-line combined adjuvant systemic/ RT for head and neck carcinomas that show significant PD-L1 activity based on a combined positive score (CPS) score of greater than 1. CPS is an immunohistochemistry assay that quantifies the percentage of the PD-L1 positive cells relative to all the cells in the tumor microenvironment. [28] Pembrolizumab can now be used in combination with platinum-based chemotherapy, and this combination has category 1 evidence for improving survival even in cases with disease progression on platinum-based chemotherapy if PD-L1 CPS ≥ 20. [29,30]

Ideally, our immune system, mainly T cells, can recognize various altered antigens on the surface of neoplastic cells and simply eliminate them. Tumor-specific CD4+, CD8+ and cytotoxic T cells together can destroy these antigen-bearing tumor cells. Tumor or neoplastic cells have multiple antigens that this cell-mediated response can recognize ( FIGURE 1).

However, these cytotoxic T cells are immune modulated and have receptors such as PDL or CTLA-4 for the corresponding ligands on normal cells. Such ligand binding acts as an immune checkpoint, and through this inhibition, normal non-neoplastic cells are not targeted for destruction. It turns out that cancer cells can express and upregulate these immune-checkpoint ligands on their surface and thus can down-modulate the T cell cytotoxic response. This behavior by tumor cells in known as tumor immune evasion ( FIGURE 2). Nivolumab (Opdivo, Bristol-Myers Squibb, New York) and pembrolizumab (Keytruda, Merck, Kenilworth, N.J.) are monoclonal antibodies that antagonistically bind the PD1 receptor on cytotoxic T cells thus not allowing the PD-L1 ligand on the tumor cells to downregulate their cytotoxic antineoplastic activity. T cells also have immune costimulatory receptors such at OX40 where agonistic binding of these sites could result in a more aggressive cytotoxic immune response. Host cells such as lymphocytes (TREGS), macrophages and others in the tumor microenvironment also express PD-L1 antigens on their surface as part of the natural check point immune homeostasis. Basically, it looks like tumor cells are imitating immune regulatory T cells in an effort to evade destruction by cytotoxic T cells.

Promising research and clinical trials (clinicaltrials.gov) are being completed to find combinations of blocking the inhibitory, and activating the stimulatory, signals for cytotoxic T cell activity against neoplastic cells. [31] To date, there are no FDA-approved T cell costimulatory agonists commercially available on the market for treating OC/ OP cancer, but through ongoing clinical trials, we may reach this goal very soon. [32] Multiple combinations of immune checkpoint inhibitors and immune co-stimulatory molecules are being studied in clinical trials and will most certainly improve treatment outcomes in the future. [33,34] Other investigational immune therapy includes patient-specific vaccines, T cell-directed therapy, various cytokines such as IRX-2, oncolytic viruses and other immune modulators along with immune-checkpoint inhibitors. [35]

Targeted Systemic Therapy

Cetuximab, an epithelial growth factor receptor inhibitor (EGFR), is the only FDA-approved targeted therapy for OC/OP cancer treatment and has only had a moderate effect on survival. Multiple cellular signaling pathways are currently being investigated in OC/OP cancer patients and examples include:

■ mTOR — everolimus.

■ Tyrosine kinase inhibitors (TKI) — adavosertib.

■ RAS — tipifarnib.

■ CDK4/6 — palbociclib.

■ STAT3 — fedratinib.

■ CHK1/2 — prexasertib.

Surgery

Surgery is the preferred treatment for early-stage oral cavity SCCA and is combined with adjuvant RT or adjuvant CRT for resectable late-stage disease. [36–38] Oral cavity SCCA must be resected with at least 1 cm margins, and frozen section margins are histopathologically evaluated at surgery to confirm complete removal. Frozen section evaluation of surgical margins is not particularly sensitive at 75% and is technique sensitive but is the best tool commonly used for margin evaluation. [39] Excision of OC and OP tumors requires proper access in order to control hemorrhage in a very vascular field and for oncologically sound radial excision of the primary tumor. Surgical excision in an early-stage tumor can be accomplished transorally, but more advanced tumors demand better access through a transfacial and/ or transcervical approach. (FIGURES 3) Given the aesthetic and functional considerations of the region, a thoughtful, graduated approach to surgical access is warranted. The least-morbid, surgical-access technique should be used that still allows for safe and complete oncologically sound excision. Most advanced-stage lesions can be excised transcervically by a combination of “degloving” and sectioning the mandible. The mandible can be excised segmentally if indicated and/or retracted laterally to gain access to a wide variety of anatomic sites. Carotid vascular control is feasible by working from inferior to superior during excision. Splitting the lower lip should be avoided but can improve access in specific situations such as when the posterior maxilla, infratemporal fossa and/or deep lateral pharyngeal wall are involved.

The inferior alveolar and/or lingual nerve is commonly sacrificed during the surgical oncologic extirpative process, and patients are left with profound anesthesia and/or dysesthesia of the lower lip or tongue, respectively. There is now bioengineered cadaveric nerve grafting (AxoGen Corporation, Alachua, Fla.) that is used successfully in peripheral, facial, inferior alveolar nerve and lingual grafting. Studies suggest that up to 90% of patients with such nerve graft reconstructions regain functional sensation. The effect of radiation of this promising success rate is currently being studied ( FIGURES 4 ). [40–43]

Radiosensitive early-stage p16+ oropharyngeal cancer can be treated with RT or CRT as primary treatment in cases where surgical morbidity or compromised medical condition precludes excision. Transoral robotic surgery (TORS) excision should be considered for any early or resectable advanced-stage OP cancer. This minimally invasive technique reduces morbidity through the use of transoral robotic arms that provide excellent surgical precision. However, in advanced-stage resectable OP tumors, this limited surgical access is not compatible with proper control of vasculature structures or threedimensional excision rationale and leads to suboptimal reconstructive options. Surgical excision of advanced-stage OP lesions, even if technically resectable, can result in significant morbidity with the loss of soft palate, base of tongue or superior pharyngeal wall resulting in dysphagia, speech difficulties and aspiration and/or airway compromise. Such radical surgical excision, however, must be considered for patients with p16– oropharyngeal SCCA, as survival outcomes are better for patients who are treated with multimodal therapy including surgery and chemoradiation. Many of the recent advancements in the treatment of OC/OP SCCA have been in the area of reconstruction. Over the past two decades, microvascular reconstruction after excision of stages T3 and T4 cancers has become the standard, improving oncologic, functional and qualityof-life outcomes. [44] The workhorse flaps for head and neck microvascular reconstruction include but are not limited to the radial forearm free flap, the fibula free flap and the anterolateral thigh free flap [45–49] ( FIGURES 56and 6).

Virtual surgical planning has not only revolutionized orthognathic surgery and dental implant surgery but has also revolutionized fibula microvascular reconstructive surgery of the maxillofacial skeleton. CT scans are typically used with fine 1-mm to 2-mm cuts to create a virtual 3D image, and through software manipulation, the virtual plan can help identify, analyze and/or manipulate osseous structures, blood vessels, dental structures and tumor involvement and dimensions. This has proven to shorten surgical excision and reconstruction times with surgical cutting/drill guides and templates that serve in both tumor excision and complex reconstructive procedures ( FIGURES 76and 8). Virtual plans allow for fabrication of milled and 3D printed titanium plates that have superior strength and rigidity and, because they are patient-specific implants, save time and effort at the time of surgery. ( FIGURE 9) Virtual planning for dental implants with the fabrication of surgical guides has become commonplace, and this logic can be translated to the fibula reconstruction construct. In vivo placement of implants in the fibula is possible now through virtual planning, and even same-day prosthetics “jaw in a day” at surgery are a possibility ( FIGURE 10 ). There are multiple publications on the subject of immediate dental rehabilitation during fibula microvascular reconstruction, and the reader is encouraged to look at the work of Hirsch, Qaisi, Patel, Cheng, Buchbinder and others for a more thorough and expert discussion. [50–55]

Advancements in microvascular reconstruction have also included anastomotic devices such as venous coupler devices ( FIGURE 11) and arterial vessel everters that have been used for both venous and arterial anastomosis. [56–59]

Additional advancements in microvascular reconstruction have been in the areas of intraoperative and postoperative monitoring using indocyanine green fluorescence, implantable dopplers, flowmeter, laser doppler, spectrophotometry and other emerging technologies [60–63] (FIGURES 12 and 13).

Recent advances in surgical treatment of the neck in patients with OC and OP cancer have led to improved outcomes. [64–67] Most of the improvements have evolved around treatment of node-negative patients. In stages T3 and T4 cases, if the neck is N0, elective neck dissection is recommended and observation or “wait and watch” for nodal metastasis is not recommended. Generally, it is accepted that a patient with N0 earlystage squamous cell carcinoma of the head and neck should be observed if the probability of occult cervical metastasis is less than 20%. Even in early-stage cancers with N0 neck, a neck dissection is recommended if the probability of occult metastasis is greater than 20%. In general, the treatment of the neck should ideally be the same modality as the treatment for the primary cancer. [68] Many studies have shown now that in the early-stage (T1, T2) oral cavity SCCA patient, elective neck dissections, typically levels 1,2,3 and sometimes 4, ( FIGURE 14 ) resulted in higher rates of overall and disease-free survival than did therapeutic neck dissection after a period of observation or wait and watch for nodal metastasis. [69–72] Elective/staging neck dissections are now recommended for small oral cavity tumors when they have a depth of invasion greater than 5 mm. This means with the new American Joint Committee on Cancer 8th edition Staging Manual, all patients with T2 lesions and above with N0 necks of all sites in the oral cavity should undergo a staging/ elective supraomohyoid (selective) neck dissection. There is also ample evidence recommending elective neck dissection for T1 and T2 cancers with a depth of invasion as little as 2 mm depending on the anatomic subsite, with tongue and floor of mouth being the high-risk sites for occult neck metastasis. [73,74]

The technique of sentinel lymph node biopsy for the treatment of melanoma and breast cancer is well established. It currently is not the standard of care for the treatment of head and neck squamous cell carcinoma and the treatment of the node-negative neck for oral cavity and oropharyngeal SCCA. Sentinel lymph node biopsy is showing promise for determining indications for N0 neck dissection in patients with T1-T2 oral cavity cancer that does not require a free flap or a wide-neck exposure for resection. [75,76] Two further advancements in the treatment of OP SCCA are the development of transoral robotic surgery (TORS) and transoral laser microsurgery. When compared to conventional surgery, TORS ( FIGURES 15 and 16) has been shown to have less complications and morbidity, but still requires multimodality treatment with RT or CRT especially for moderately advanced-stage disease. [77,78] When compared to primary RT for early-stage oropharyngeal cancers, TORS had similar survival outcomes with less adverse events and decreased need for chemotherapy and RT. In the TORS group, if patients had RT, they often received lower doses and also sometimes avoided the need for chemotherapy altogether .[79,80] However, the evidence is not conclusive and more trials are currently being conducted to evaluate deintensified RT/CRT versus TORS primary treatment regimen outcomes in patients with resectable HPV-related p16+ oropharyngeal carcinoma.

The complications related to surgery are myriad and beyond the scope of this article. However, there are several complications related to systemic and radiation treatment of head and neck cancer that are of significant interest to all dental health care professionals.

Prevention, if possible, of radiationinduced caries is best accomplished by frequent dental intervention and daily fluoride application that is initiated within one week of the completion of radiation treatment. Ideally, all patients requiring head and neck radiation should have optimal dental care completed before starting treatment and all dental extractions completed at least 14 days before. Once radiation treatment has been completed, oral hygiene, both by patient and hygienist, should be stressed and restorative dentistry should be aggressively pursued. Fluoride trays should be fabricated and 0.4% stannous fluoride gel or 1.1% sodium fluoride prescribed for use in trays at least once per day indefinitely. Dental extraction, especially in the irradiated mandible, should be avoided even if it would mean performing RCT on nonfunctional teeth. [81]

Osteoradionecrosis (ORN) is mainly (90%) a mandibular condition and can occur spontaneously or in response to trauma and most typically after dental extraction. [82] Pain, dysfunction, dysesthesia and secondary infection are all commonplace where radiation damages all tissues and results in hypocellularity, hypovascularity, hypoxia and fibrosis. Osseous tissues have slow cellular turnover and a relatively poor blood supply. As we age, the majority of blood flow to the mandible gradually shifts from central through the inferior alveolar artery to being dependent nearly completely on peripheral subperiosteal perfusion. [83,84] Treatment options for ORN include medical, surgical and hyperbaric oxygen. There is evidence that osteoradionecrosis in early stages can be treated with medical therapy alone before it becomes a painful, chronic and persistent condition. Medical treatment consists of antimicrobial rinses, pentoxifylline and tocopherol and may include bisphosphonates and/or systemic antibiotics. [81] The role of hyperbaric oxygen was originally thought to be an invaluable clinical treatment modality, but it’s effectiveness now remains controversial. [86,87] There is currently a controlled study being conducted in the U.K. and France to directly compare hyperbaric oxygen therapy to medical therapy (pentoxifylline, tocopherol and clodronate) in the treatment of ORN. The results of this study, due in 2021, may help us all approach the treatment of ORN in a more evidence-based manner. [88]

Oral mucositis is a common acute complication of chemotherapy and/or head and neck radiation. The mucositis is caused by a radiation-induced and/ or chemotherapeutic mitotic death of the basal cells in the oral mucosa. Clinical signs and symptoms include painful erythema and ulceration of the oral mucosa and difficulty with nearly all aspects of oral function. [89] This side effect generally takes hold around week four of RT, peaks at week five and then persists for several weeks with a gradual quelling of symptoms over time. [90]

Chemotherapy-related oral mucositis is part of a systemic effect that affects the entire aerodigestive tract and follows the timeline of the related symptoms of diarrhea and loss of appetite, which typically peak at one to two weeks post induction and resolve within several weeks afterward. Chemoradiotherapy (CRT) for head and neck cancer is known to increase the severity of mucositis over that of single modality therapy as the oral and oropharyngeal epithelial lining are profoundly affected. Management of RT/chemotherapy/ CRT-related mucositis includes prevention of infection and control of symptoms in a primary attempt to protect the airway and preserve oral intake capabilities. Pain control, nutritional support, oral decontamination, palliation of dry mouth, control of bleeding and therapeutic prevention are all valid interventions. Pain can be topically controlled with 2% viscous lidocaine that can be mixed with a variety of medications (Maalox, Benadryl, etc.) commonly known as “magic mouth rinse.” This can be tailored by the individual practitioner based on their experience and comfort level with such therapeutic mixtures. Some pharmacists have their own approach to this type of topical control of oral and oropharyngeal surface pain and their input can be invaluable. Xerostomia is nearly always part of the symptom complex of oral mucositis and longer term after head and neck radiation. Treatment with frequent sipping of water or other neutral fluids can be enough to palliate this symptom. Oral rinses with a solution of 1/2 teaspoon baking soda in 1 cup warm water several times a day may serve as a second-line and uncomplicated remedy. Salivary substitutes can be considered and sugarless chewing gum, for those who are capable, may help to physiologically improve the symptoms. Cholinergic agents such as pilocarpine 5 mg tabs four times a day can also be used in settings where there are no contraindications (acute angle-closure glaucoma, cardiovascular disease and pulmonary disease such as asthma, COPD and chronic bronchitis). The beneficial hypersalivatory state this agent affords may be outweighed by the potential deleterious side effects on heart rate and cardiac output, bronchial smooth muscle function and ocular anterior chamber function. Topical pilocarpine has also been used and can be combined with mucosal adhesive molecules for increased effectiveness. [91,92]

In summary, treatment of oral and oropharyngeal cancer is evolving with increasing surgical precision and improvements in reconstructive techniques. Importantly, targeted therapy and immunotherapy are already improving survival, and we can realistically expect their impact on both survival and reduced morbidity to be progressive and substantial. The combination of immunotherapy agents, targeted agents and more effective radiation therapy are highly likely to reduce the role of radical extirpative surgery in the treatment of head and neck cancer. Such improvements in treatment morbidity and outcomes are a near certainty over the next few decades and, depending on scientific discovery, could prove to be on an even more favorable timeline. [93–98]

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THE CORRESPONDING AUTHOR, Robert S. Julian, DDS, MD, can be reached at rjulianiii@gmail.com.