Management of symptoms and treatment-related toxicities of head and neck cancers

Characteristics

Airway obstruction is a leading cause of death for patients with locally-advanced head and neck cancer with approximately 70% of them requiring airway control at some point. Stenosis of the airway by extrinsic tumor compression or by tumor expanding within the airway results in stridor, dysphonia, dyspnea, and hypoxia.

Management

Managing upper airway compromise is essential when treating advanced head and neck cancers. Hypoxic patients should be given oxygen to maintain oxygenation status. Steroids (8 to 16 mg dexamethasone daily) may help reduce some tumor-related swelling, and opioids may help relieve dyspnea and anxiety. If possible, an evaluation with a CT scan can provide details on the degree and location of stenosis and give insight into the most appropriate management. Surgical management is often the preferred means of relieving the obstruction, because it is generally the quickest way to restore function. Deciding on the surgical approach depends on the location and degree of stenosis, patient functional/performance status, and disease extent. Tracheostomy is the classic means for safely and efficiently securing the airway. When expertise and equipment are available, intubation with CO ₂ debulking can also be considered to avoid tracheotomy and its associated risks and stigma. Laryngectomy should be reserved for advanced cases when other options are not feasible. The use of metal stents to open airways (particularly the trachea) for palliative purposes has been investigated for esophageal and thyroid tumors with good success and improved breathing. If surgery is contraindicated, RT can be used, but may initially cause edema, which could worsen respiratory status, and may take weeks to achieve its full therapeutic effect.

Characteristics

Advanced cancers can infiltrate the superficial structures of the skin and lymphatics thereby becoming draining, bleeding, and malodorous nonhealing wounds in up to 10% to 15% of patients. Due to impaired perfusion and lymphatic disruption, necrosis, and exudate are common after the skin erodes. The malodor secondary to infection and tissue necrosis can cause psychological and emotional distress, eventually leading to increased isolation and creating barriers between the patients and their caregivers.

Management

Keys elements that need to be addressed are encapsulated by the mnemonic HOPES (H-hemorrhage, O-odor, P-pain, E-exudate, and S-superficial infection). ^{, ,} In addition to systemic pain management, topical analgesics and even opioids can palliate pain, but with less systemic effects. A randomized double-blinded study of topical morphine (0.2% gel for mucosal lesions and 0.2% ointment for cutaneous lesions) versus placebo showed that the topical morphine was fast-acting, highly effective, and safe even without placing a limit on the number of applications per day. Wound care should include atraumatic cleaning with a saline solution, potential debridement to remove necrotic tissue, and the use of lesion-appropriate dressings to control exudate, infection, bleeding, pain, and odor management. The management of malodor includes routine wound care, topical or systemic antibiotics (topical metronidazole most studied), and silver impregnated dressing. Bleeding and oozing from friable granulation tissue can be addressed with a combination of absorbent pressure dressings and hemostatic agents (calcium alginates, collagen, oxidized cellulose, thrombin, silver nitrate, trichloroacetic acid, tranexamic acid, alum solution, or sucralfate). ^, Identifying and managing causes of decreased coagulation is also essential (vitamin K deficiency, anticoagulation use, abnormal platelet function). Initiating treatment with radiation and chemotherapy may alleviate symptoms and reduce suffering. Additionally, palliative surgery/surgical debridement may also benefit some patients.

Characteristics

Radiation dermatitis is an unfortunate, common toxicity associated with head and neck radiotherapy (RT). It is radiation dose and treatment volume dependent. The incidence of any grade of radiation dermatitis when patients receive greater than 60 Gy is nearly 100%. The pathophysiology of radiation dermatitis is thought to be related to the oxidative damage to the skin’s basal layer with subsequent disruption of the epidermal renewal process. Immune-mediated changes in the epidermal-dermal interface including an upregulation of pro-inflammatory chemokine and cytokine production with leukocyte recruitment.

Several grading scales for radiation dermatitis exist, including the Radiation Therapy Oncology Group (RTOG) criteria ( Table 30.1 ). The development and evolution of radiation dermatitis in a conventionally fractionated course of head and neck RT (1.8 to 2.0 Gy/fraction to a total dose of 60 to 70 Gy) is often reliably predictable. In weeks 1 to 2 of RT, most patients can be expected to develop RTOG G1-2 dermatitis. Without further intervention, radiation dermatitis can be expected to worsen with higher grade toxicity peaking toward the end of RT or in the first few weeks following the end of RT. Caution and increased awareness for worsening dermatitis should be paid when patients receive concurrent cytotoxic systemic therapy, in particular cetuximab, as data have shown higher incidences of dermatitis in these patients compared to those receiving RT alone.

Management

The management of radiation dermatitis can be divided into prophylactic versus therapeutic measures. Preferably, patients are instructed to begin prophylactic skin care with water or petroleum-based barrier creams/ointments at the start of RT as immune cascading and skin changes are known to occur hours after the first fraction of RT. The products utilized should be free from fragrances and irritants to avoid secondary contact dermatitis reactions and potential radiation sensitization. Patients should be instructed to apply barrier creams/ointments multiple times daily to keep the skin consistently moisturized throughout the day. The need to instruct patients to refrain from utilizing barrier creams prior to daily RT delivery is unnecessary if the thickness of the barrier is limited to less than 3 mm. Additionally, the immobilization mask can often confound the potential bolus effect of residual barrier cream during RT delivery. When utilizing intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), skin avoidance techniques can be used to mitigate excess radiation dosing to the skin. One common technique involves contouring the skin as an OAR with the inclusion of a 3 to 5 mm rind of tissue to encompass the epidermis, dermis, and subcutaneous fat and limiting planned target volumes (PTV) from expanding into this structure. This technique should be utilized with caution and only in cases where the disease is not infiltrating beyond the platysma into the subcutaneous fat and/or skin surface. Attempts should be made to keep the maximum dose to less than 55 Gy in the skin OAR. Special attention should also be paid to the supraclavicular region, as it is prone to developing radiation dermatitis, despite often receiving lower elective radiation doses. This is a consequence of the commonly delivered coplanar technique of IMRT and VMAT, whereby photons are often entering tangentially along the plane of the skin surface.

Management of symptomatic (RTOG G ≥1) dermatitis often requires additional therapy beyond barrier creams/ointments. One of the most effective therapies is the utilization of low to medium potency topical corticosteroids, such as mometasone furoate 0.1% once at night or twice daily. A meta-analysis for the use of topical corticosteroids during RT has been shown to reduce radiation dermatitis and its associated symptoms, including pruritis and burning. ^, Additionally, a small study noted that the utilization of silvadene may reduce the incidence of radiation dermatitis compared to usual skin care alone. Soaking the involved area with saline-soaked gauze for 15 to 20 minutes two to three times daily can relieve the burning sensation via evaporative cooling, moisturize the skin, and aid in the healing process.

Characteristics

Mucositis manifests as inflammation of the oral mucosa resulting in irritation, painful sloughing, and/or ulceration. This results in an erythematous and inflamed mucosa often encased with a whitish pseudomembrane. Factors that contribute to the development and severity of mucositis include concurrent chemotherapy, smoking, alcohol intake, oral infections such as candidiasis, consumption of hot or spicy foods, and poor dental hygiene. Nearly all patients (99%) report mucositis pain, with 85% rating it as severe to extreme. Many consider this the most debilitating side effect of head and neck cancer treatments. Mucositis seems to be the primary source of severe acute pain during treatment and the principal driver of morbidity during RT. Depending on the severity, mucositis results in pain, dysphagia, dehydration, copious oral secretions, increased risk of both local and systemic infections, and nutritional deficiencies which lead to weight loss and necessitate feeding tube placement. Additionally, mucositis can be the cause of costly treatment breaks and failure to complete treatment, which negatively affects tumor control. This underscores the necessity of mucositis management to help prevent these significant side effects. Links between xerostomia and radiation induced oral mucositis (OM) exist, so proper management of the former may minimize the severity of OM. Mucositis typically develops during the second to third week of treatment and gradually worsens, only to subside weeks after treatment finishes.

Management

The management of mucositis can be further categorized into dry mouth palliation, oral decontamination, pain control, nutritional support, and the management of oral bleeding and therapeutic interventions for OM. ^, Specific recommendations for oral hygiene are similar for mucositis and xerostomia and are addressed in the xerostomia section of this chapter.

Mucositis induces mouth and throat secretions, making it difficult for patients to maintain adequate hydration and nutrition. Regular salt and baking soda rinses help with symptoms of early phase secretions. However, the treatment management of later phase or larger volume mucus involves the use of combination narcotic and cholinergic agents such as guaifenesin. Scopolamine can be added for patients already taking narcotics for pain. Other interventions include 30-degree bed elevation, a cool mist vaporizer for lubrication, lorazepam to decrease repeat gagging or nausea, and a portable suction machine, especially in the postoperative setting.

Mucositis-related pain should be managed in a step-wise progression. Initial treatment begins with topical anesthetics such as 2% viscous lidocaine or “magic mouthwash” (formulation of lidocaine, Maalox, and Benadryl ± nystatin ± corticosteroid elixir), gabapentin, and finally opioid analgesics for more severe symptoms. ^, If symptoms persist or a patient cannot tolerate their pain level, a variety of opioid analgesics including short and long-acting narcotics can be used. However, the side effects of narcotics including nausea, vomiting, constipation, and drowsiness need to be addressed and managed simultaneously.

Doxepin may be helpful in managing OM pain. In a multi-institution, randomized, double-blind, placebo-controlled, phase 3 trial of 155 patients with a cross-over phase, doxepin (25 mg in 5 mL water) significantly reduced pain compared to placebo in both the initial and crossover phase. However, the side effects, including stinging/burning sensations, unpleasant taste, and increased drowsiness resulted in 64% of patients discontinuing usage during the optional continuation phase. If patients can tolerate the medication-related side effects, it is recommended for treatment-related mucositis.

Thrush (oral candidiasis) is a common condition experienced by almost 40% of head and neck cancer patients. It contributes to the development of OM and is one of the most common causes during the first half of RT. During cancer treatment, changes in the oral environment lead to the overgrowth of natural oral flora. Radiation, chemotherapy, and other drugs used as part of cancer management (steroids, antibiotics) contribute to the clinical manifestation of thrush by causing irritation and local damage to the mucosal lining, disrupting the normal oral flora, decreasing salivary flow, and causing immunosuppression, which lowers the body’s ability to keep fungal infections in check. ^, The most common manifestation of oral candidiasis is pseudomembranous candidiasis, which appears as a white curd-like pseudomembrane with surrounding erythema that can be easily scrapped off. Additional presentations of candidiasis include chronic hyperplastic (hyperkeratotic white patches that are firmly attached to the mucosa), erythematous (red inflamed areas of mucositis with burning pain), and angular cheilitis (erythema, fissuring, and crusting at the lip commissures). In addition to increasing the risk for mucositis, candidiasis can also cause burning pain, taste change, and foul-smelling breath, which impacts quality of life and reduces oral caloric intake. Management and treatment with antifungal therapy are warranted in any patient with suspected candidiasis. For mild disease, topical agents are effective, and have minimal interaction with other medications, but require contact with the oral mucosa and multiple daily uses. Topical options include clotrimazole troches, miconazole mucoadhesive buccal tablets, or nystatin suspension. ^, Therapy should not conclude early, because patients can relapse. For patients with xerostomia, nystatin suspension may be preferred as some level of saliva production is needed to dissolve the other options. For moderate to severe disease, oral fluconazole is effective and requires only a single daily dose, but does interact with multiple medications (fentanyl, warfarin, oral hypoglycemic agents, antiseizure medications, statins, and hypertension medications) and can affect liver function. ^, Fluconazole can also be used for prevention. For fluconazole-refractory disease, itraconazole solution, posaconazole suspension, voriconazole, or Amphotericin B deoxycholate oral suspension can be used. In addition to antifungal therapy administration, dentures, oral prosthesis, or obturators should be disinfected to prevent relapse.

Humidification during head and neck radiation treatment may also mitigate OM symptoms by limiting desiccation injury. The TROG 07.03 RadioHUM study, a phase 3 multi-center trial, evaluated the addition of domiciliary humidification to the institutional standard of care for mucositis management. Unfortunately, only 42% of patients met benchmarks for humidification compliance, which resulted in the overall trial showing no difference in the primary end point of decreasing clinical grade ≥2 mucositis. Despite this, several positive secondary endpoints suggested a reduction in mucositis symptoms with humidification and compliant patients, which resulted in a significant reduction in function mucositis, decreased mean total inpatient hospital days, and decreased proportion of patients requiring acute hospital admissions. ^, Additional work with a hand-held humidifier showed feasibility and promise for reducing treatment-related symptoms and increasing patient compliance.

As with other treatment-related symptoms, pre-treatment optimization of radiation fields with specific attention to the volume of surrounding organs receiving radiation dose may help prevent mucositis symptoms. Radiation dose to the oral cavity affects the rate, severity, and duration of mucositis. The volume of the oral cavity and swallowing structures that receive over 70 Gy correlates with an increased risk of severe mucositis. Additionally, the volume of the oral cavity receiving a weekly dose of at least 10.1 Gy, and the dose delivered to 21 cc of the oral cavity predicts for grade ≥3 mucositis. ^, Areas in the oral mucosa that receive at least 32 Gy are at risk for developing grade 2 mucositis. Efforts should be taken to reduce both the maximum and mean dose to the oral cavity.

Low-level laser therapy (LLLT) can also be considered for treating OM. Treatment with LLLT involves the mucosal application of a high-density monochromatic narrow band light source with wavelengths varying between 630 and 830 nm. This treatment may decrease pro-inflammatory cytokines and reactive oxygen species that contribute to the pathogenesis of mucositis. The decrease in inflammation may aid with wound healing effects. A meta-analysis of LLLT found a significant decrease in the relative risk for OM development.

Benzydamine hydrochloride, a nonsteroidal antiinflammatory drug, inhibits pro-inflammatory cytokines including TNF-α, and has been shown to reduce the severity of OM in head and neck patients in phase III trials. ^, Some groups recommend the use of benzydamine hydrochloride to prevent mucositis, but the product is not currently FDA approved and evidence is limited.

Growth factors may help increase the proliferation of oral epithelial cells to mitigate the incidence and severity of OM. Randomized trials of palifermin, an IV recombinant keratinocyte growth factor (KGF), as an agent for preventing OM in patients undergoing head and neck chemoradiotherapy showed that palifermin reduced the rate of OM, decreased the median duration of symptoms, and prolonged the time to develop severe mucositis, but failed to alter patient reported analgesic use, average mouth and throat soreness scores, or chemoradiation compliance, so the true clinical benefits remain unclear. ^, Additionally, some evidence suggests possible decreased effectiveness in controlling local tumors when growth factors (granulocyte colony stimulating factor) were given during chemoradiation.

Several compounds are under development for reducing OM. GC4419, a highly selective and potent small molecule dismutase mimetic that rapidly converts superoxide to hydrogen peroxide and oxygen resulted in promising severe OM reduction in open-label phase 1b/2a trials. A phase III randomized trial is underway. Alpha-tocopherol, the main constituent of vitamin E and a natural antioxidant present in human blood, functions to scavenge peroxyl free radicals in the cell membrane and has been evaluated in several different formulations and combinations. Several trials evaluating vitamin E as a radioprotective agent to decrease OM have shown encouraging results. However, there remain theoretical concerns that vitamin E could spare the tumor from the planned effects of RT.

Characteristics

Malnutrition in the setting of head and neck cancer is common and often multifactorial. Cancers in the head and neck region can directly impact smell, taste, appetite, nociception, and swallowing function. Treatment for head and neck cancer can also affect these same functions and may hasten malnutrition in patients with or without baseline nutritional deficiencies.

Management

It is important to narrow the specific cause of malnutrition if possible, as each may have potentially varying aims of treatment. Cancer cachexia, which is thought to result from a systemic pro-inflammatory, pro-catabolic state induced by the cancer is often associated with rapid recent involuntary weight loss (i.e., >5% in the past 6 months), low BMI (i.e., <20 kg/m ² ), decreased adiposity, and sarcopenia. ^, Patients with a mechanical blockage of the alimentary tract or dysphagia from a tumor may require temporary placement of a nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tube for supplemental feeding. Malnutrition from tumor-related pain may require optimization of pain management. Malnutrition from anorexia may be mitigated with the use of appetite stimulants such as megestrol acetate, dronabinol, or corticosteroids. Malnutrition from nausea and vomiting, often associated with cisplatin-based chemotherapy for patients undergoing definitive management of head and neck cancers, is best managed with a single or combination antiemetic regimen.

RT for head and neck cancer is associated with malnutrition and weight loss in a substantial proportion of patients undergoing therapy. Prophylactic feeding tube placement is an area of controversy but is often considered in patients that have low baseline BMI, recent weight loss, pre-therapy dysphagia, or in patients anticipated to suffer a high degree of acute toxicities, such as those scheduled to receive large volume and high dose RT to the mucosal axis and other OARs, particularly when given with concurrent radiosensitizing systemic therapy. Addressing other toxicities which manifest during RT will improve the nutritional intake capability of the patient. In addition to the role of symptom management, referral to a dietician or nutritionist if available will increase the odds that the patient will better understand his or her nutritional intake requirements and current options for supplements, which should translate into reduced weight loss over the course of their RT.

Characteristics

Xerostomia results from a decrease in salivary output, leading to hyposalivation and changes in salivary composition. This ultimately results in the sensation of dry mouth and sticky saliva. Additional complications include oral discomfort and pain, increased rates of dental caries and oral infection, difficulty speaking and swallowing, taste change, and decreased nutritional intake and weight loss.

Management

Pretreatment strategies focus on symptom prevention, with an emphasis on effective oral hygiene, nutritional intake, and early oral lesion detection. Medications that may exacerbate or result in dry mouth should be reviewed. A recent systematic review found 56 medications with strong evidence of interfering with salivary gland function. These medications include atypical antipsychotics, antipsychotics, antidepressants, appetite suppressants, antiperistaltic/spasmolytic agents, urologic agents, antinausea, antiglaucoma, antihypertensives, antiasthmatic, and hypnotic/sedatives. Pretreatment physician assessment for medications in these specific classes allows the clinician to discontinue or find an alternative that may help decrease any dry mouth symptoms during and after treatment.

Lifestyle modifications, including adequate hydration help decrease symptoms of dry mouth. Xerostomia also leads to difficulty chewing and symptoms of dysphagia, specifically with starting swallowing. Therefore, patients tend to avoid crunchy foods such as vegetables, sticky foods such as peanut butter, and dry foods such as bread. Instead they favor soft and moist foods, including sauces. Patients with xerostomia are more susceptible to dental caries, so they should avoid acidic or sugary foods and beverages.

Prior to starting radiation, all patients should be evaluated by a dentist. Patients should practice good oral hygiene including brushing with a soft toothbrush, flossing, and consistent use of nonmedicated saline or bicarbonate rinses (1 tsp baking soda + 1 tsp table salt dissolved in 1 quart warm water). Oral decontamination can help prevent systemic sepsis by decreasing the chance of infection in the oral cavity by opportunistic pathogens. Patients with radiation-induced xerostomia should also implement additional oral hygiene routines to remove plaque, increase remineralization, and prevent infection. High concentration topical 0.4% stannous fluoride gel helps maintain oral hygiene and can help with remineralization. Since these patients also have a higher predisposition to developing oral infections, antimicrobial rinses such as chlorhexidine, povidone-iodine, and tetracycline oral rinses help with the prevention of dental caries.

Radiation advances and modern techniques significantly influence post-treatment salivary gland function. IMRT can be used to reduce-dose the salivary glands which helps to preserve adequate salivary flow rates and prevent xerostomia. Randomized controlled trial data comparing conventional RT with parotid-sparing IMRT found a significantly lower grade 2 or worse xerostomia at 12 months and 24 months in the IMRT group compared to conventional RT group (38% vs. 74% at 12 months, 29% vs. 83% at 24 months). IMRT also achieved clinically significant improvements in patient-reported dry mouth and quality of life scores without a decrease in tumor control or overall survival. Multiple additional single institutional prospective and retrospective data further confirm the value of IMRT for the prevention of xerostomia without compromising oncologic outcome. ^, Keeping the cumulative mean dose of the submandibular gland to less than 39 Gy and parotid less than 26 Gy (unilateral) or 23 Gy (bilateral) produces clinically and statistically significant improved salivary flow rate. At 6-month post-treatment, it is estimated that the salivary gland flow rate decreases by approximately 50% and 75% for mean parotid doses of 16 Gy and 32 Gy, respectively. Additional radiation techniques such as proton therapy may help reduce patient toxicity outcomes and improve long term quality of life based on several planning comparative studies. Based on existing and validated normal tissue control probability (NTCP) models, proton therapy could reduce the risk of side effects in approximately 70% of the head and neck cases, specifically grade 2 or higher dysphagia and xerostomia. However, prospective randomized data and future trials should be conducted to confirm these results due to the significant costs.

Pharmacologic use of amifostine during treatment has been extensively studied due to its selective protection of normal tissue from radiation and chemotherapy-induced damage. Brizel et al. found a reduction in grade 2 or higher chronic xerostomia from 57% to 34% in patients receiving amifostine, without affecting survival or disease control differences. This led to FDA approval for xerostomia prevention. However, the drug can induce significant nausea and hypotension and must be administered daily by slow IV infusion before each radiation treatment which limits clinical applications.

Pharmacologic interventions with sialogogues, like pilocarpine, cevimeline, and bethanechol, can stimulate residual salivary glands and increase unstimulated salivary flow. Pilocarpine, a cholinergic agonist, has been the most clinically studied for post-radiation xerostomia. Although it increased salivary flow, it did not provide a protective or preventative benefit. Likewise, cevimeline increased unstimulated salivary flow compared to placebo in two double-blind randomized trials, but the effects on dry mouth symptoms were mixed. In contrast, phase 3 trials suggest that bethanechol administered during RT may provide a protective effect with the improved salivary flow, but benefits unfortunately cease once the drug is discontinued and long-term use of the drug is unstudied. ^, Common side effects of these sialogogues include nausea, rhinitis, diarrhea, and excessive sweating. Even though there is a low incidence of serious adverse events, the associated side effects may limit the clinical relevance for some patients.

Oral lubricants and salivary substitutes are frequently used to help with the sensation of a dry mouth. These include xantham gum, mucin, or carboxymethylcellulose containing saliva substitutes. Despite the multitude of options, patients seem to prefer xantham gum and mucin, which have superior wetting properties. ^, Chewing gums increase salivary production and decrease oral mucosal friction which help relieve symptoms. In addition, nighttime use of “gel-like” saliva substitutes, consisting of polyglycerylmethacrylate, statistically reduced severe xerostomia symptoms but not moderate or mild symptoms.

Data also exists for the use of more invasive procedures such as salivary gland transfer techniques. A phase II clinical trial from the University of Washington surgically transferred the submandibular salivary gland to the submental space in 43 patients before postoperative radiation and found protection of the transferred gland. With a median follow-up of 14 months, 81% of the patients had no or minimal xerostomia, whereas 19% developed moderate to severe symptoms.

Acupuncture may provide palliative relief by increasing salivary flow rates in patients with xerostomia for a duration of 6 months which can be extended to 3 years after additional treatments. RTOG 0537, a phase III trial found that twice-weekly 20-minute acupuncture-like transcutaneous stimulation (ALTENS) sessions decreased symptom burden at a similar rate compared to 5 mg pilocarpine administered 3 times daily for 12 weeks but with much less toxicity. More recently, a phase 3 randomized clinical trial from Fudan University Shanghai Cancer Center and MD Anderson Cancer Center compared a standard care control (SCC) with true acupuncture (TA) and sham acupuncture (SA) among patients with oropharyngeal or nasopharyngeal carcinoma being treated with RT. TA decreased the incidence of clinically significant xerostomia at 1 year after RT (34.6% vs. 47.8% and 55.1% in the SA and SCC group respectively). However, due to some inconsistencies between the SA and the standard control, further studies must confirm these results before they are broadly applied in the clinical setting.

Hyperbaric oxygen (HBO) seems to increase stimulated and unstimulated saliva flow rates indicating a potential treatment for radiation-induced salivary gland damage. Several small studies have shown a positive benefit of HBO on salivary flow rate in irradiated head and neck cancer patients with a significant decrease in xerostomia with a mild increase in both unstimulated and stimulated whole saliva flow, as well as an increased pH and decreased bacterial colony density after HBO. ^, However, a phase III randomized clinical trial comparing HBO to a standard control in head and neck cancer patients treated with radiation has yet to be performed.