Overview of approach to long-term survivors of head and neck cancer

INTRODUCTION — The term "cancer survivor" has been used variably in the literature; in general, a cancer survivor refers to any person who has been diagnosed with cancer until the end of life. There are more than half a million survivors who have been rendered cured of head and neck cancer in the United States [1]. The steady increase in the rate of head and neck cancer survivors is likely due to advances in treatment, decrease in smoking rates, and the improved prognosis associated with oropharyngeal carcinomas associated with human papillomavirus (HPV) infection [2]. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

This topic will review the long-term issues of survivors of head and neck squamous cell carcinoma (HNSCC), specifically discussing the group of survivors who are without evidence of disease for at least five years [3,4]. Other topics that discuss complications and quality of life in patients following a diagnosis of head and neck cancer are covered separately.

●(See "Health-related quality of life in head and neck cancer".)

●(See "Management and prevention of complications during initial treatment of head and neck cancer".)

●(See "Management of late complications of head and neck cancer and its treatment".)

OVERVIEW OF HEAD AND NECK CANCER

Primary tumor sites — Survivors of head and neck cancer may have been treated for disease arising from one of five anatomic regions of the head and neck. Further details on these specific primary tumor sites are discussed separately (see "Overview of the diagnosis and staging of head and neck cancer", section on 'Anatomic subsites'):

●The oral cavity (lips, buccal mucosa, anterior tongue, floor of the mouth, hard palate, and upper and lower gingiva)

●The pharynx (nasopharynx, oropharynx, and hypopharynx)

●The larynx (supraglottic, glottic, and subglottic regions)

●The nasal cavity and paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal)

●The salivary glands (parotid, submandibular, sublingual, and the minor glands)

Staging — The Tumor, Node, Metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) is used to classify cancers of the head and neck. TNM staging, which is based on primary tumor site, also impacts prognosis and follow-up in the long-term survivor of head and neck cancer. Further details on the staging of head and neck cancer are discussed separately. (See "Overview of treatment for head and neck cancer", section on 'TNM staging system'.)

Treatment — The management of head and neck squamous cell carcinoma (HNSCC) is based on whether the disease is early or advanced stage and the primary site of the tumor. Treatment modalities include surgery, radiation therapy (RT), and systemic therapies. Such treatment may impact prognosis, follow-up, and long-term complications in the survivor of head and neck cancer. Specific discussions for the management of early versus advanced disease by primary site are discussed separately. (See "Overview of treatment for head and neck cancer".)

Prognosis — The prognosis of HNSCC depends on stage at presentation and the site of involvement.

Five-year overall survival in patients with stage I or stage II disease is typically 70 to 90 percent. By contrast, the prognosis for patients who present with more advanced (stage III or IV) disease is poorer. As an example, patients with locoregionally advanced laryngeal carcinoma have an approximately 40 percent overall survival rate at five years. However, in patients with tobacco- and alcohol-related cancers, a 20 percent rate of second malignancy might be expected over five years.

For patients with human papillomavirus (HPV) associated locoregionally advanced disease, long-term survival rates are higher than those without HPV associated disease. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Prognosis'.)

GUIDELINES FOR FOLLOW-UP, SURVEILLANCE, AND SECONDARY PREVENTION IN THE LONG-TERM SURVIVOR — In general, the intensity of follow-up is greatest in the first two to four years following diagnosis, since approximately 80 to 90 percent of all recurrences occur within this timeframe. However, patients should continue to be followed beyond five years because of the risk of late complications, as well as the risk of late recurrence or second malignancies. This may be especially important for patients without human papillomavirus (HPV) associated oropharyngeal cancers. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

There are no data to guide the continued follow-up of the long-term head and neck squamous cell carcinoma (HNSCC) survivor. In general, these patients are seen for visits with an oncologist on an annual basis, highlighting the importance of coordinated care.

Components of follow-up — An overview of cancer survivorship for both primary care and oncology clinicians is covered separately. While not specific to HNSCC survivors, the issues discussed are relevant to this population as well. (See "Overview of cancer survivorship care for primary care and oncology providers".)

Head and neck cancer survivors should have a detailed cancer-specific follow-up every one to three months for the first year, every two to six months in the second year, every four to eight months during years 3 to 5, and annually beginning five years after the primary treatment. This should include [3-6]:

●History, including screening for any symptoms that might suggest a local recurrence (eg, new swelling, cough, dysphagia) or metastatic disease (eg, shortness of breath). Other than post-treatment baseline imaging of the primary and the neck if treated, there is no role of routine serial imaging in long-term survivors of head and neck cancer unless otherwise indicated by new signs or symptoms. However, patients with over 20 or more pack-years of smoking history would be candidates for annual low-dose helical computed tomography (CT) scan of the lung. Surveillance for recurrences is based on detailed clinical examination and fiberoptic visualization by the multidisciplinary treatment team. Utilization of imaging for follow-up should be done on a case-by-case basis for high-risk features or clinical indications. (See "Screening for lung cancer".)

●The history should also include any interval changes in the social environment (including partner status, life events, living arrangements, and occupational issues), lifestyle factors (eg, smoking and alcohol consumption), and an evaluation of sexual health and body image issues.

●Physical exam, including thorough inspection of the head and neck region, and periodic fiberoptic visualization and dental evaluation. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

●Patients with history of radiation therapy to the neck should have serum thyroid-stimulating hormone (TSH) levels every 6 to 12 months due to the risk of hypothyroidism.

●Encouragement of a healthy lifestyle, including assessment of diet and encouragement to remain (or become more) physically active. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

●Encouragement and education about cessation of smoking and the limiting of alcohol consumption for any survivor who continues to partake in either or both. (See 'Smoking and alcohol cessation' below and "Management of late complications of head and neck cancer and its treatment", section on 'Smoking cessation' and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Limitation in alcohol consumption'.)

●A speech, hearing, and swallowing evaluation and rehabilitation where clinically indicated should be performed.

●Age-appropriate screening for other malignancies.

Smoking and alcohol cessation — It is critical to encourage and educate head and neck cancer survivors about smoking cessation and limiting alcohol consumption [6,7]. Higher rates of secondary cancers are seen in survivors who continue to smoke or consume alcohol [8,9]. In addition, due to the synergistic effects of alcohol and smoking, survivors exposed to both together are at higher risk for recurrence and death. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

Even light alcohol consumption of less than one drink per day has been shown to be associated with oral cavity, oropharyngeal, and esophageal cancers in a meta-analysis [10]. A study of 165 survivors showed a persistent smoking and alcohol dependence in males, with young age and single status making a special case for referral to formal cessation programs for such patients [11]. Aggressive counseling for lifestyle modification including smoking and alcohol cessation should be provided at each follow-up visit. A combination of behavioral support and pharmacologic therapy may be needed. (See "Overview of smoking cessation management in adults" and "Alcohol use disorder: Psychosocial management".)

Diet and exercise — Lifestyle changes including diet and exercise have a significant impact on quality of life and secondary prevention in survivors. Pretreatment dietary counseling may help in improving long-term outcomes for survivors and could involve simple phone-based counseling for patients starting therapy [12]. In a meta-analysis of cancer survivors, the highest adherence score to a Mediterranean diet was significantly associated with a lower risk of all-cause cancer mortality (relative risk [RR] 0.87, 95% CI 0.81-0.93), also seen in head and neck cancer (RR 0.40, 95% CI 0.24-0.66) [13].

Exercise and physical activity in head and neck cancer survivors has been associated with improved quality of life and should be encouraged and incorporated in their counseling process [14,15]. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

LATE AND LONG-TERM COMPLICATIONS — Much of our understanding of the issues in head and neck squamous cell carcinoma (HNSCC) survivors comes from evaluations of patients followed for two to three years after treatment, although there are several landmark papers describing issues of long-term survivors [16-21]. As a result, there are little data to inform the issues experienced in long-term HNSCC survivors who are without evidence of disease for five years or more. However, they are at an increased mortality due to cancer and other causes, which persists for up to 10 years after diagnosis. As an example, one study evaluated almost 36,000 HNSCC survivors followed for a median of 7.7 years after initial diagnosis (range, 3 to 17.9 years) [22]. The rates of death at 5 and 10 years were 15.4 and 41 percent, respectively. Causes of death during follow-up consisted of:

●HNSCC (29 percent)

●Second primary malignancy (23 percent) with the most common malignancies being primaries of the lung (53 percent), esophagus (10 percent), and colorectal origin (5 percent)

●Cardiovascular disease (21 percent)

●Lung disease such as chronic obstructive pulmonary disease, pneumonia, and influenza (23 percent)

These data highlight the importance of follow-up, which should be coordinated between oncology and primary care. (See 'Coordination of care and specialist referral' below.)

Head and neck toxicity

Dental complications and oral health — Oro-dental care and follow-up are very important, especially after radiation therapy (RT) to the head and neck area. Poor oral health has been linked with inferior survival and worse outcomes [23,24]. Worsening of dental health after treatment is common and could lead to significant compromise in quality of life of long-term head and neck cancer survivors. Deterioration of dental and oral health is thought to be secondary to xerostomia, change in salivary pH to acidic, demineralization, and decreased vascularity associated with radiation [16,25]. Gradual dental decline, xerostomia and difficulties with ill-fitting dentures, coupled with the financial limitations including the lack of proper dental insurance coverage, can add to the burden of long-term survivors. In addition, inadequate dental rehabilitation results in a compromised ability to eat and has been directly linked to poor quality of life due to compromised eating and chronic pain [16].

Although data on the late effects of mucositis are limited, the patient’s dental status at one year post-treatment appears to be a strong predictor of quality of life of survivors five years from completion of therapy [17]. The incidence of dental caries increases 50-fold after RT and is seen at a rate of 2.5 per month [25,26]. They are often highly destructive and lead to extractions and osteoradionecrosis in up to 15 percent of irradiated head and neck cancer patients [27,28]. Dental status was found to have a direct impact on eating in public, chewing, swallowing, and normalcy of diet [16].

Patients undergoing RT for head and neck cancers may develop mucosal atrophy and telangiectasias, and may experience chronic mucosal pain and sensitivity [29]. Patients often describe the mucosal pain as a burning or a scalded sensation that may represent neuropathy. Hot and/or spicy and acidic foods and dry air reportedly exacerbate symptoms. Mucosal sensitivity may permanently alter food choices in this population.

Management emphasizes attention to the risk factors of hyposalivation, mucosal infection, and the neuropathic components of pain associated with mucositis [29]. Timely dental rehabilitation including dental restoration and dental prosthesis development and fitting may help improve quality of life of survivors. Our approach is consistent with the guidelines from the Department of Veterans Affairs and the National Comprehensive Cancer Network (NCCN) [3,30]. Further discussion on the oral complications and treatment guidelines for cancer survivors is covered separately. (See "Oral health in cancer survivors", section on 'Approach to the cancer patient'.)

Xerostomia — Xerostomia or dry mouth is common in most head and neck cancer survivors who have undergone radiation as a part of their treatment. It remains one of the main late complications of RT and a leading cause of compromise of quality of life of head and neck cancer survivors. There can be gradual recovery of some salivary secretion over time, with maximum recovery one to two years post-therapy [31-37], but this depends on the total radiation dose to the gland tissue. Xerostomia is a long-lasting and frequently permanent problem that adversely impacts quality of life, even years after diagnosis.

In long-term survivors (more than five years following treatment), symptoms of xerostomia can include dry mouth, sticky saliva, persistent need to drink water or fluids while eating, swallowing and speaking, difficulty eating and speaking, early dental decline, and poor oral health [18,19]. In one study, xerostomia was present in 64 percent of long-term survivors at a mean follow-up of 9.6 years following RT [20]. There is decreased rate of xerostomia with intensity-modulated radiation therapy (IMRT). In a study of long-term quality of life of head and neck survivors at five years after IMRT, nearly 84 percent of survivors reported saliva "of normal consistency" or "less saliva than normal but enough," and only 16 percent reported "too little saliva" [38]. (See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Radiation schedule and technique'.)

The management of xerostomia is discussed separately. (See "Management of late complications of head and neck cancer and its treatment", section on 'Salivary gland damage and xerostomia'.)

Osteoradionecrosis — Osteoradionecrosis can be seen in patients needing dental restorations or extractions in previously radiated areas [39,40]. The incidence of osteoradionecrosis with conventional RT or IMRT is in the range of 5 to 7 percent. (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis' and "Oral health in cancer survivors", section on 'Osteonecrosis'.)

Trismus — Trismus or lockjaw could occur in up to 35 percent of head and neck cancer patients following RT and in patients treated with surgery [41,42]. However, these estimates appear to be lower for patients treated with IMRT (5 to 15 percent) [41,43]. More commonly seen after oral cavity, oropharyngeal, and nasopharyngeal cancer therapy, trismus is caused by inflammation and fibrosis of the pterygoid and masseter muscles. It has an important repercussion on quality of life and could lead to poor dental hygiene, worsening xerostomia, and dental complications [41].

Active and passive exercise should be initiated as soon as post-treatment fibrosis becomes evident because if left untreated, it may impact the range of jaw movement. Unfortunately, once there is restriction clinically evident it is difficult to reverse. Pentoxifylline and botulinum toxin have been used to treat established trismus in long-term survivors with some evidence of a symptomatic benefit, although no objective improvement of trismus was seen [44,45]. (See "Oral health in cancer survivors", section on 'Trismus' and "Management of late complications of head and neck cancer and its treatment", section on 'Trismus' and "Physical rehabilitation for cancer survivors", section on 'Trismus'.)

Dysphagia — Patients treated for HNSCC can experience dysphagia during treatment and as both an acute and long-term complication. Speech and swallowing impairment are seen in over 50 percent of head and neck cancer patients even before the start of treatment [46]. In addition, impaired speech and swallow function are common after oral or oropharyngeal surgery and in over 50 percent of patients undergoing partial laryngectomy [47,48]. Subsequent malnutrition and unintended weight loss can also exacerbate dysphagia due to a reduction in the will to eat and a more global psychological toll on the patient.

Causes — A number of factors may result in or worsen dysphagia in long-term survivors of head and neck cancer, including:

●Loss of normal anatomic structures and/or altered relationships between normal structures (eg, loss of the hard palate or part of the larynx)

●Radiation-induced xerostomia and fibrosis

●Problems with dentition

●Trismus

Dysphagia may also result as a consequence of esophageal stenosis, which can occur as a late complication of progressive RT-related fibrosis. The rate of long-term grade 3 esophageal strictures appears to be higher for patients treated with IMRT and is thought to be due to a greater dose of radiation to pharyngeal constrictor muscles [49,50]. As an example, the rates of a pharyngoesophageal stricture with IMRT and conventional RT were 16.7 and 5.7 percent, respectively [50]. However, in another study of patients with nasopharyngeal carcinoma, late toxicity was significantly less severe with IMRT-based therapy rather than non-IMRT-based therapy, including neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis [51]. In preliminary results from one phase III trial (DARS), dysphagia-optimized IMRT improved patient-reported swallowing functions [52].

Clinical presentation — Patients who develop an esophageal stricture may present with subtle or significant complaints, including dysphagia (eg, feeling "something getting stuck in the throat/chest") or changing patterns of cough when swallowing food, indicating possible episodes of aspiration. New symptoms or other more subtle changes in a patient’s normal swallowing pattern should warrant a work-up to rule out esophageal stenosis, especially if these symptoms are persistent. (See "Approach to the evaluation of dysphagia in adults", section on 'Approach to diagnostic testing'.)

Treatment approach — Even for patients who present with longstanding dysphagia, we believe there is a role for cancer rehabilitation, including speech and language therapists. Therapy consisting of swallowing exercises and maneuvers, neuromuscular stimulation, and education regarding the importance of lifestyle modification (eg, changing the food consistency to prevent aspiration) can help prevent worsening (or more significant) morbidity. Speech and swallow rehabilitation is an inherent part of the multidisciplinary team involved in treatment. The rehabilitation services are freely available in the community as well. Dysphagia as a late complication of HNSCC treatment and the role of rehabilitation is covered separately. (See "Management of late complications of head and neck cancer and its treatment", section on 'Dysphagia' and "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

Feeding tube utilization — Despite preventive measures employed prior to and/or during treatment, 10 to 25 percent of HNSCC survivors become feeding tube-dependent for life [19,53]. This is seen in survivors with compromised oral cavity function due to treatment or those who have had multiple episodes of aspiration. The psychosocial burden of clinically significant dysphagia should be recognized and patients referred for counseling and support in order to prevent depression and distress in survivors (and in their caregivers).

Neuromuscular toxicity — Several neuromuscular complications may occur in long-term HNSCC survivors. These include: speech difficulties, chronic pain, ototoxicity, and/or peripheral or autonomic neuropathies. These are discussed below.

Speech intelligibility — Speech and articulation could be significantly impaired after treatment for oral cavity cancer, floor of the mouth or alveolar crest cancers, cancers requiring mandibular resection, and with total or partial glossectomy [54-56]. Voice and phonation issues affect patients with laryngeal cancer treated with chemoradiation and patients who have had a laryngectomy [57]. (See "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

Due to complications of total laryngectomy — Although long-term survivors are usually acclimated to the surgical outcomes, total laryngectomy continues to impart a high impact on quality of life of survivors even years after surgery [58]. Despite a multidisciplinary follow-up, long-term rehabilitation with these prostheses could be difficult and require guidance and support [59]. For patients who undergo voice rehabilitation with tracheoesophageal voice prosthesis, leakage from the site may add to long-term morbidity [60,61].

Lack of motivation, discouragement, depression, and continued need for lifestyle modification could have a cumulative impact on long-term survivors. Providers should be aware of the difficulty that can be experienced postlaryngectomy and provide continued support, counseling, and specialized care wherever needed. (See 'Psychosocial issues of the caregivers' below.)

Due to recurrent laryngeal nerve palsy — Recurrent laryngeal nerve palsy could occur as a rare late complication of head and neck radiation (mostly reported with conventional RT) leading to delayed mobility of vocal cord(s) and hoarseness [62,63]. It could lead to voice strain and speech unintelligibility in survivors several years from completion of therapy that could be frustrating. Speech rehabilitation and Botulinum injection in the vocal cords have limited benefit with temporary results, and lifestyle modification may be the only option in some cases [64].

Speech therapy is required to improve speech intelligibility. Advances in reconstructive surgical techniques with tissue transfer, mandibular plates, and palatal prosthesis have been helpful [65-67]. Voice therapy is indicated in patients with hoarseness and problems with phonation after chemoradiation for glottic cancer [68]. Speech rehabilitation after total laryngectomy could be challenging and requires motivation and perseverance. It could involve an artificial larynx, transesophageal puncture, or esophageal voice production [69,70].

Chronic pain — Chronic pain (including somatic, neuropathic, and neuralgic pain) involving the head or neck after treatment can be debilitating and is reported in some cancer survivors over five years post-treatment [71].

Chronic pain has been known to contribute to functional limitation and employment in survivors. In one study, nearly 40 percent of unemployed long-term survivors reported being in chronic pain [72,73]. In another observational study, chronic systemic symptoms, were noted in nearly 50 percent of head and neck cancer survivors at one year post-treatment completion, such as chronic widespread pain, fatigue, sleep disturbance, mood disorders, neuropsychiatric symptoms, and temperature dysregulation [74].

Although there are limited data beyond five years post-treatment, in one study, nearly 18 percent of head and neck survivors complained of chronic pain as a long-term effect of prior cancer-related treatment [17]. In this study, chronic pain, type of diet, and dental status at one year were strongly predictive of quality of life of these survivors at the five-year post-treatment time point. However, in a different study, the mean chronic pain scores (measured using the Head and Neck Cancer Inventory social disruption scores) showed there was no difference in pain scores among those who had received chemoradiation versus surgery followed by adjuvant radiation-based therapy [18].

Among the more recognized pain syndromes, shoulder and neck pain are two recognizable neuropathic conditions, particularly for those who underwent a neck dissection. Efforts to understand other specific pain predilections in long-term survivors are ongoing.

Interventions with drugs like gabapentin and carbamazepine, utilization of pain management services for treatment with narcotics and behavioral therapy, and incorporation of physical therapy may all be needed for appropriate pain control. Acupuncture has been shown to reduce pain and shoulder dysfunction after neck dissection [75]. Long-term opioid use and dependence is a well-described phenomenon and was noted in approximately 7 percent of long-term head and neck cancer survivors at one year post-treatment completion [76]. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain' and "Physical rehabilitation for cancer survivors" and "Overview of the clinical uses of acupuncture" and "Cancer pain management: General principles and risk management for patients receiving opioids".)

Ototoxicity — Both cisplatin and radiation could lead to compromise in hearing. Cisplatin-induced ototoxicity is well-recognized and is known occur as a result of cisplatin-induced damage of the outer hair cells of cochlea. Radiation to the cochlea has been known to induce sensory neural hearing loss. Cisplatin given concurrently with radiation lowers the dose of radiation that can cause hearing loss. The incidence ranges from 20 to 40 percent at one year post-treatment with IMRT to over 40 percent at 5 years with conventional RT [77,78]. The interindividual variation in the degree of cisplatin-induced toxicity endured is thought to be dependent on polymorphisms in the glutathione-S-transferases and other genetic variations [79]. For such cases, hearing augmentation may be required to improve quality of life and functioning. (See "Management of late complications of head and neck cancer and its treatment".)

Peripheral neuropathy — Long-term survivors may have to deal with residual peripheral neuropathy, both from cisplatin and taxanes. Peripheral neuropathy of some degree could be seen in over 80 percent of patients who have received 300 mg/m² of cumulative dose of cisplatin [80]. The neuropathy usually improves over time, but complete resolution is rarely seen [81]. No preventative strategy has been of benefit as per an analysis [82].

Autonomic dysfunction — Autonomic dysfunction usually presents as dizziness and near syncope, and it has been reported in long-term survivors, especially for those who received RT to the neck [83]. RT induces inflammation of the intimal layer, which is thought to result in fibrosis of the arterial walls of the neck. This is thought to contribute to the stiffening of the carotid sinus baroreceptors leading to decreased baroreceptor sensitivity, which causes blood pressure lability, including the onset of orthostasis-like phenomenon causing near syncope or syncope like events [84].

For patients with autonomic dysfunction, baroreceptor sensitivity may be improved with exercise, particularly in older patients with a sedentary lifestyle [84].

Musculoskeletal complications — Lymphedema involving the neck may present as a late complication, especially in patients who underwent a neck dissection or RT. In addition, neck stiffness is a common complaint that is encountered in clinic.

Lymphedema — Lymphedema of the neck is common, although poorly recognized and reported [85,86]. It could occur after surgery or RT to the head and neck area. Although lymphedema generally resolves with time, chronic lymphedema, if severe, could lead to permanent neck stiffness and disfigurement. Edema of the larynx and the pharynx could also be severe and cause airway obstruction and dysphagia [85,87].

Although late-onset neck lymphedema is not well-studied, it is not uncommon for long-term head and neck survivors to present with acute lymphedema. In one study evaluating patients with neck lymphedema, the median time to onset of symptoms measured from the time of treatment completion was 17 months. However, the authors did not solely evaluate long-term survivors; they included patients who presented with neck lymphedema between 3 and 156 months (13 years) of treatment completion [85].

Early institution of complete decongestive therapy is indicated. In our experience, it can provide quick relief of symptoms and prevent chronic complications [88]. (See "Clinical staging and conservative management of peripheral lymphedema", section on 'Complete decongestive therapy'.)

Neck stiffness — In our experience, neck stiffness is one of the more common chronic complaints of patients in long-term follow-up. Neck stiffness is usually caused by fibrosis of the neck muscles as a result of the longstanding effects of RT and/or neck surgery, and it is most common in patients who received both these treatment modalities [89-91].

Neck stiffness significantly impacts quality of life among head and neck cancer survivors [92]. Unfortunately, there are limited clinical studies addressing the treatment of neck stiffness. Physical therapy is the standard of care. Various regimens have been proposed, but all have demonstrated limited clinical benefit:

●Physical therapy – For patients with neck stiffness, physical therapy is useful, even for late symptoms. Physical therapy should be pursued with a therapist experienced in the treatment of radiation fibrosis [93].

●Botulinum toxin – As with trismus, botulinum toxin has been utilized to reduce symptoms from radiation-induced fibrosis in long-term survivors and may be applicable to neck stiffness, spasms, discomfort, and pain [44].

●Pravastatin – In a single-arm phase II clinical trial of pravastatin (40 mg daily for 12 months), an at least 30 percent reduction of chronic radiation-induced fibrosis was seen in 15 of 42 patients (36 percent) [94]. Patients reported improved quality of life and minimal toxicities (myalgias and esophagitis).

●Other treatment options include hyperbaric oxygen and vitamin E with pentoxifylline.

Additional information about radiation-induced fibrosis is presented separately. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis", section on 'Treatment'.)

Neurocognitive effects — RT and chemoradiotherapy as components of definitive therapy for head and neck cancer have been postulated to have effects on the central nervous system and result in neurocognitive deficits [95].

The risk of neurocognitive impairment was prospectively studied in a cohort of 80 patients undergoing definitive treatment for nonmetastatic squamous cell carcinoma of the head and neck and in 40 controls without cancer [96]. All patients received RT, 86 percent received systemic therapy (most with a platinum-based regimen), and 76 percent had a primary oropharyngeal carcinoma. Neurocognitive function was assessed at baseline, 6, 12, and 24 months using a cognitive battery assessing multiple domains. Progressive impairment in global cognitive function was observed in 22 of 58 patients (38 percent) at 24 months, but in 0 of 40 controls (0 percent).

Despite these studies, there are limited data confirming the degree of deficit and time to recovery. In clinical settings, it is important to take into consideration reversible causes for decline such as depression and to discriminate verbal decline due to lack of appropriate orodental rehabilitation from neurocognitive decline. Brain-sparing IMRT is now being used to help reduce the cognitive decline post-head and neck cancer therapy.

Damage to the carotid arteries — Following treatment of HNSCC, patients have an increased risk of stroke. However, there are no screening mechanisms in place for head and neck cancer survivors. Therefore, the prevention and management of stroke in long-term HNSCC survivors is similar to the approach to the general population and is discussed separately. (See "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery injury'.)

Nephrotoxicity — Some degree of nephrotoxicity is seen in up to 30 percent of patients treated with cisplatin [97]. Cisplatin has been known to damage the proximal and distal tubular epithelium and collecting ducts in animals and humans [98]. Elevated creatinine levels, hypomagnesemia, hypokalemia, hypocalcemia, occasionally sodium wasting, proteinuria, and albuminuria could all be seen in different combinations in long-term survivors [99,100]. Fortunately, long-term follow-up of patients exposed to cisplatin indicates that renal function remains stable or slightly improves over time. (See "Cisplatin nephrotoxicity".)

PSYCHOSOCIAL ISSUES

Sexual dysfunction — Long-term survivors may experience difficulty with sexual function. This may have an anatomic basis (eg, chemotherapy-induced peripheral neuropathy) or a more complex etiology related to intimacy issues and psychologic distress. (See "Overview of sexual dysfunction in female cancer survivors" and "Overview of sexual dysfunction in male cancer survivors".)

Short-term studies indicate that sexual dysfunction can be an important consequence of treatment for head and neck cancer. In a study of 262 patients with oral squamous cell carcinoma, 34 percent did not have sex at all in the six months following diagnosis, compared with 10 percent in the six months prior to diagnosis [101]. This change was present in all patients, regardless of whether they had human papillomavirus (HPV) associated disease. A persistence of dissatisfaction with sexual function was reported in another series at 12 months after treatment [102]. Unfortunately, there is a lack of data for longer-term survivors of head and neck squamous cell carcinoma (HNSCC).

Although sexuality is a key issue with head and neck cancer survivors, minimal attention has been given to it over time. Alterations in self-image, disfigurement, change in oral sensation and odor, anxiety, and depression have been thought to contribute. Chemotherapy could lead to altered sensation, arousal, and erectile dysfunction in men. Issues related to transmission of HPV to a spouse or partner may add a significant burden to a relationship. A clear understanding of the issues related to HPV and its transmission is crucial [103].

Body image issues — Facial disfigurement, loss or change of organ function, fear of recurrence, death, and revised self-image could all prove challenging to adjustment. Body image reintegration and adjustment are thought to happen over time and require compassion, patience, and encouragement from the family, friends, and the treating clinician.

In a report from a larger study of body image among 280 HNSCC patients who underwent surgery, and who were less than one month to more than five years from diagnosis, over 50 percent of patients reported concerns regarding body image at the time of assessment [104]. Major issues that can lead to social avoidance include limitations with speech and swallowing and concerns regarding appearance and disfigurement.

Poorer quality of life scores have been reported in the setting of body image dysfunction [105]. In another study that evaluated the aesthetics in long-term survivors, moderate to severe pain, minimal oral intake, and being edentulous at one year from treatment were associated with significantly low aesthetics scores at five years [17]. In a similar report by the same group, long-term survivors who had received chemoradiation-based therapy had better aesthetics scores than the surgically treated group at five years from treatment [18].

Depression, anxiety, and suicide risk — Anxiety and depression are common in head and neck cancer patients before and after completion of therapy and have been reported in nearly 30 percent of survivors at five years from completion of therapy [17,106]. Clinicians should regularly assess for such mental health conditions in long-term survivors to ensure that patients receive the support necessary [6]. (See "Patients with cancer: Clinical features, assessment, and diagnosis of unipolar depressive disorders".)

In one study of head and neck cancer survivors, factors that predicted depression included the presence of a tracheostomy tube or laryngeal stoma, gastrostomy tube dependence, and continued smoking at the time of follow-up [21]. Additional studies have identified comorbid psychiatric illness, long-term toxicity of treatment, as well as use of alcohol and/or drugs to cope with the diagnosis as risk factors for depression and suicide [107,108].

While several psychosocial parameters may improve with the passage of time from diagnosis, in one study, anxiety persisted and became more pronounced in survivors greater than five years from diagnosis [109].

Survivors of head and neck cancer have an increased rate of suicide [107,108,110,111]. One analysis using the Surveillance, Epidemiology, and End Results (SEER) database reported a suicide rate in this population of 63 suicides per 100,000 person-years [108]. When compared with survivors of other cancers as a whole, head and neck cancer survivors were approximately two times more likely to commit suicide; only pancreatic cancer survivors had a higher suicide rate than this population.

In a prospective study of 223 consecutive patients with newly diagnosed head and neck cancer followed for one year, 16 percent were suicidal, 0.9 percent attempted suicide, and 0.4 percent committed suicide [107].

These studies illustrate the severity of depression and suicide, which are two of the most concerning long-term sequelae of head and neck cancer treatment.

Employment — Over 50 percent of head and neck survivors were reported as being disabled from disease at the two-year post-treatment time point [72,112]. Unfortunately, data are limited in longer-term survivors.

Despite this, a number of reasons have been reported for the continued disability of HNSCC survivors, including:

●Long-term oral dysfunction, loss of appetite, deterioration in social functions, and high anxiety levels [113]

●More advanced stage at original presentation, alcohol use, and lower educational levels [112]

●Fatigue [72]

Survivors may also face challenges related to facial disfigurement, limitations in speech intelligibility, dietary limitation, and rarely even dependence on enteral tube feeding. These issues could lead to low self-esteem, lack of initiative in socializing and competing with peers, limitations in employment opportunities, and growth at work place. In a study of 208 head and neck cancer survivors, socioeconomic factors and comorbidities were found to be important predictors of quality of life [114].

Psychosocial issues of the caregivers — Psychosocial adjustments of survivors and their caregivers are intimately linked [115,116]. Active counseling of the patient and family members during and after treatment play an important role in minimizing the psychosocial burden and help in rehabilitation. Long-term help and support should be provided to caregivers and family in situations where survivors have multiple long-term complications of treatment. The care of a head and neck cancer survivor could still be very involved in cases with feeding tube, tracheotomy, and other disabilities like compromised speech intelligibility.

SUBSEQUENT PRIMARY CANCERS — Subsequent primary cancers have been reported in up to 20 percent of head and neck cancer survivors and are related to smoking and alcohol exposure. For those who develop a subsequent primary cancer, prognosis is generally poor, with a median overall survival typically around 12 months [117]. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

During the last 20 years, a clear decrease in the incidence of subsequent cancers in primary oropharyngeal tumors has been observed. This has been associated with an increasing incidence of human papillomavirus (HPV) associated oropharyngeal carcinomas [118]. With emerging data about difference in sexual practices of patients with HPV associated tumors, longitudinal follow-up is warranted [118,119].

Lifestyle modification, smoking, and alcohol cessation intervention programs are needed to help cancer survivors reduce their risks for a second primary [9]. Patients should be counseled for smoking and alcohol cessation routinely and aggressively. (See 'Smoking and alcohol cessation' above.)

COORDINATION OF CARE AND SPECIALIST REFERRAL — Care must be taken to communicate the plan of care and follow-up with the general medical provider or primary care clinician. A detailed communication of the plan of care with the primary dentist is also essential. In a study of oncologists and primary care physicians, the lack of clarity of who provides specific aspects of psychosocial care to cancer survivors brought to attention the need for better survivorship care coordination with the multidisciplinary head and neck oncology team [120].

Head and neck cancer survivors have to engage in intensive self-management protocols for oral care; skin care; complex drug schedules and delivery; complicated instrument care (eg, tracheostomy care and feeding tube care); and intense rehabilitation programs like oral-dental rehabilitation, speech and swallow rehabilitation, and occupational therapy with lymphedema management and physical therapy. Efforts have been made to better understand, categorize, and strategize the intensive self-management protocols to improve quality of life of head and neck cancer survivors [121].

Post-therapy survivor care plans should be formulated to organize adequate support and rehabilitation to the head and neck cancer survivors. A prospective, randomized, controlled trial of the H&N Cancer Survivor Self-management Care Plan (HNCP) involving pre- and post-intervention assessments showed improved quality of life of the survivors with unique needs by means of a tailored self-management care plan developed upon completion of treatment, delivered by trained oncology nurses [122].

Communications and coordination of care between the oncology team, the primary care clinician, the dentist, and any specialists involved in the management of the patient is recommended throughout the treatment and in the post-treatment period. Specific efforts should be made to include caregivers and spouses in the head and neck survivorship plans [123].

Several support groups and support sites are available to help guide head and neck cancer survivors and their treating clinicians in the management of late treatment-related complications [124].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Throat cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – There are more than half a million survivors who have been cured of head and neck cancer in the United States. The steady increase in the rate of head and neck cancer survivors is likely due to advances in treatment, decrease in smoking rates, and the improved prognosis of oropharyngeal carcinomas associated with human papillomavirus (HPV) infection. (See 'Introduction' above.)

●Prognosis – The prognosis of HNSCC depends on stage at presentation and the site of involvement. (See 'Prognosis' above.)

•Stage I or II disease – Five-year overall survival in patients with stage I or II disease is approximately 70 to 90 percent.

•Stage III or IV disease – The prognosis is poorer for patients who present with more advanced (stage III or IV) disease.

•HPV associated cancer – For patients with human papillomavirus (HPV) associated locoregionally advanced disease, long-term survival rates are higher than those without HPV associated disease. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Prognosis'.)

●Surveillance – In general, the intensity of follow-up is greatest in the first two to four years following diagnosis, since approximately 80 to 90 percent of all recurrences occur within this timeframe. However, patients should continue to be followed beyond five years because of the risk of late complications, as well as the risk of late recurrence or second malignancies. This may be especially important for patients without human papillomavirus (HPV) associated oropharyngeal cancers. (See 'Guidelines for follow-up, surveillance, and secondary prevention in the long-term survivor' above.)

●Prevention of subsequent primary cancers – Survivors should be routinely counseled for smoking and alcohol cessation, as subsequent primary cancers related to smoking and alcohol exposure have been reported in up to 20 percent of head and neck cancer survivors. (See 'Subsequent primary cancers' above.)

●Oral health and dental complications – Dental care and follow-up of oral health are very important, especially after radiation therapy to the head and neck area. Poor oral hygiene and dental health decline could lead to significant compromise in quality of life of the long-term head and neck cancer survivors. (See 'Dental complications and oral health' above.)

Worsening of dental health after treatment is common and is mostly as a result of dry mouth or "xerostomia" from head and neck radiation. (See 'Xerostomia' above.)

Other common complications include mucosal sensitivity, malocclusion of teeth or dental prosthesis (dentures), osteoradionecrosis, and trismus. (See 'Osteoradionecrosis' above and 'Trismus' above.)

●Dysphagia – Patients treated for HNSCC can experience dysphagia during treatment and as both an acute and long-term complication. Even for patients who present with longstanding dysphagia, we believe there is a role for cancer rehabilitation, including speech and language therapists. Despite preventive measures employed prior to and/or during treatment, 10 to 25 percent of HNSCC survivors become feeding tube-dependent for life. (See 'Dysphagia' above.)

●Neuromuscular toxicity – Several neuromuscular complications may occur in long-term HNSCC survivors. (See 'Neuromuscular toxicity' above.)

•Specific toxicities – These include speech difficulties, chronic pain, ototoxicity, and/or peripheral or autonomic neuropathies.

•Management – For many of these concerns, rehabilitation that involves speech and physical therapists is an important part of management.

●Musculoskeletal complications – Lymphedema involving the neck may present as a late complication, especially in patients who underwent a neck dissection or RT. (See 'Lymphedema' above.)

In addition, neck stiffness is a common complaint that is encountered in clinic. (See 'Neck stiffness' above.)

●Psychosocial issues – Survivors of HNSCC are at risk for psychosocial issues related to body image, speech unintelligibility, food-related lifestyle limitations, and sexual health. In addition, they are at high risk for mental health disorders, including depression, anxiety, and suicide. Fear of recurrence and fear regarding secondary cancers add to the burden of survivorship. Clinicians should be aware of these issues and regularly screen for them in follow-up to ensure that these patients get the support and counseling necessary. (See 'Psychosocial issues' above.)