Head and neck cancer (HNC) accounts for around 645 000 new cases each year, worldwide, 75% of them with stages III and IV disease, causing more than 350 000 deaths yearly . Patients diagnosed with head and neck squamous cell carcinoma (HNSCC), by far the most common histological type of HNC, must ideally be treated in accordance to multidisciplinary guidelines. Briefly, the adjuvant treatment of patients submitted to surgery with curative intent and presenting with risk features (e.g., positive margins and extracapsular spread of nodal disease) must include adjuvant cisplatin-based concurrent chemoradiation, and overall survival (OS) gains are seen in some subgroups [2–5]. For those patients with unresectable tumors, the recently updated results of the Meta Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC), including 93 studies and 17 346 patients, do confirm the absolute survival benefit for chemotherapy of 4.5% at 5 years in HNSCC (hazard ratio of death 0.88, P < 0.0001) and, for concurrent chemoradiation, the hazard ratio was 0.81 (P < 0.0001) and the absolute survival benefit 6.5% at 5 years. In those patients treated with concurrent platinum-based chemoradiation, the observed survival benefit was more pronounced (hazard ratio 0.75 versus 0.86, P < 0.01) [6••].
These survival gains were achieved with a substantial increase in toxicity. In the above-mentioned RTOG 95-01 adjuvant chemoradiation study , the frequency of acute grade 3 (or more severe) toxicities reached 77% in patients submitted to chemoradiation versus 34% in those patients submitted to radiation therapy alone (P < 0.0001). Mucositis, dermatitis and hematological toxicities are some of the most common acute toxicities observed in these HNSCC patients treated with chemoradiation and can negatively impact survival rates and quality of life, as well as diminishing treatment efficacy, due to unplanned radiation therapy breaks.
In this scenario, supportive care plays a crucial role. To be familiar with these toxicities, and their prompt diagnosis and treatment – the focus of this review – are essential aspects in the daily care of HNSCC patients.
Supportive care: essential aspects in head and neck squamous cell carcinoma patients
The most frequent acute adverse effects observed in HNSCC patients treated with chemoradiation include mucositis, dysphagia, dermatitis and anemia, which will be discussed below. In addition, xerostomia as a late toxicity will also be presented.
Mucositis and dysphagia
Oral mucositis is a major treatment-related complication of concurrent chemoradiation in HNSCC patients. It affects nutrition, pain control, quality of life and adequate treatment delivery, as it may lead to unplanned radiation therapy breaks, thus compromising treatment efficacy [7,8•].
Several measures have been studied to prevent or treat oral mucositis induced by chemotherapy or radiation therapy, but efficacy has not been consistently shown for any. A recent Cochrane systematic review  on the prevention of oral mucositis in cancer patients concluded that the strength of the evidence was variable among many interventions and that there is a need for well designed trials on this issue.
Low-level laser (LLL) is a promising preventive therapy. It has been used in the prevention and treatment of oral mucositis in several clinical settings, including radiation therapy in HNSCC patients and high-dose chemotherapy with hematopoietic stem cell transplantation [10–13]. These studies, in general, show that LLL treatment is well tolerated and there is some benefit for LLL-treated patients, but high-quality evidence is missing, mostly in the HNSCC patients under chemoradiation. In addition to this, the best LLL treatment schedule still needs to be defined. Our group has recently presented the results of a phase III, randomized, double-blind study to evaluate the efficacy of LLL to prevent or delay the appearance of severe oral mucositis induced by chemoradiation in HNSCC patients and its impact on unplanned radiation therapy interruptions in 75 patients treated with either daily He–Ne LLL 2.5 J/cm2 or placebo laser, before each fraction of radiation therapy. In both groups, it was allowed to receive basic oral care and analgesics. The number of patients diagnosed with grade 3 or 4 oral mucositis treated with LLL was significantly lower in week 4 (P = 0.04) and more patients treated with placebo had radiation therapy interruptions due to mucositis (6 versus 0, P = 0.02), which may translate in better chemoradiation efficacy and tolerability .
To reduce the extent of mucositis, special attention to radiation therapy planning techniques, allied to adequate oral care, are strongly recommended as preventive strategies. Systemic opioids to effectively treat mucositis-associated pain and close monitoring to nutrition and hydration must be offered. Hospitalization for intravenous analgesics, nutrition and hydration is sometimes necessary, as well as in those patients who developed secondary infection.
As a consequence of mucositis, dysphagia and odynophagia are commonly seen in HNSCC patients treated with radiation therapy. The use of prophylactic feeding tubes is controversial, but it may be necessary in some high-risk patients (e.g., large radiation therapy fields, previous severe weight loss) . A recently published randomized trial [16•] evaluating prophylactic gastrostomy in unresectable HNSCC treated with chemoradiation demonstrated higher posttreatment quality of life in those patients receiving systematic prophylactic gastrostomy, after adjusting for other potential predictive quality of life factors. Swallowing (at least liquids) and swallowing exercises must be always encouraged, even in those patients having a feeding tube.
Xerostomia is highly prevalent among HNC patients treated with radiation therapy, with a significant negative impact in terms of quality of life. Wijers et al.  reported that 64% of long-term HNC survivors after conventional radiation therapy experienced a moderate-to-severe degree of permanent xerostomia. It increases the risk for developing dental caries and compromises oral mucosal integrity, resulting in oral pain, loss of taste, difficulties with swallowing and chewing, sleep disorders and oral infections. Ultimately, this can lead to decreased nutritional intake and weight loss.
Xerostomia is the result of radiosensitivity of salivary glands, occurring during the first few days of radiation therapy, when the radiation damage on plasma membrane causes a signal transduction disturbance that affects the watery secretion mediated through muscarine receptor stimulation. A late damage seems to occur after death of progenitor cells caused by radiation therapy, thus preventing cell replacement. Extracellular microenvironment changes after radiation therapy may also play a role . The severity of salivary dysfunction depends on the dose received by salivary glands, the irradiated volume and time elapsed after radiation therapy. Braam et al.  reported an improvement of 32% in the salivary flow rate at 5 years after radiation therapy, in comparison with 12 months after radiation therapy, but other authors failed to demonstrate it .
A recently published guideline by the American Society of Clinical Oncology (ASCO) [21••] on the use of chemotherapy and radiation therapy protectants recommended that amifostine, as an acute and late xerostomia-preventive agent, may be considered in patients undergoing fractionated radiation therapy alone, but not in those treated with concurrent platinum-based chemoradiation. Three studies [22–24] showed significant reductions in grade 2 or greater acute or late xerostomia, but they were not placebo-controlled. On the contrary, in the setting of platinum-based chemoradiation, a placebo-controlled study  did not show significant reductions in grade 2 or greater acute or late xerostomia in 132 patients. No effect on tumor control has been suggested for amifostine .
As the incidence of xerostomia is directly related to the cumulative radiation dose in parotid glands, intensity-modulated radiation therapy (IMRT) as a strategy to sparing parotid glands is being studied to decrease both occurrence and severity of xerostomia. Delivered doses lower than 24–26 Gy seem to be crucial to preserve salivary flow rates after radiation therapy . The PASSPORT phase III study  included 94 patients with T1–4 N0–3 oropharynx or hypopharynx SCC that were randomly assigned to 65 Gy delivered in 30 fractions (over 6 weeks) either conventionally or using IMRT. The incidence of xerostomia at 12 months after radiation therapy was the primary endpoint, measured by late effects in normal tissues subjective, objective, management and analytic (LENT-SOMA) and Radiation Therapy Oncology Group (RTOG) scales. After a median follow-up of 31.9 months, the incidence of grade 2 xerostomia at 12 months was 74 versus 40% (P = 0.005, LENT-SOMA) and 64 versus 41% (P = 0.06, RTOG) for those patients treated with conventionally delivered or with IMRT, respectively, with no differences in terms of progression-free survival, OS or other late toxicities rates .
Pilocarpine is the only drug approved by U.S. Food and Drug Administration for the treatment of radiotherapy-induced xerostomia, and may be considered during conventional radiotherapy in order to preserve parotid function, but a phase III study  designed to assess quality of life in patients receiving pilocarpine as a hyposalivation-preventive agent failed to achieve any difference on patients’ assessment of salivary function, or quality of life, in those patients treated with pilocarpine, despite an objective preservation of salivary function. Many saliva substitutes may be useful to relieve xerostomia-related symptoms. A phase I/II clinical trial [30•], using a recombinant adenoviral vector to mediate gene transfer, employing the aquaporin-1 cDNA to treat patients with existing radiation-induced salivary hypofunction is currently underway.
Skin toxicity, radiation dermatitis and epidermal growth factor receptor-targeting agents
Radiation dermatitis occurs in the majority of patients undergoing radiation therapy, and approximately 20–25% develop severe skin toxicity . This toxicity is related to the total radiation therapy dose, the dose per fraction, the overall treatment time, the beam type and energy, the planned treatment area and concurrent therapies such as conventional cytotoxic (platinum derivatives) or molecular-targeted agents.
In addition to the well described acneiform rash associated with the epidermal growth factor receptor (EGFR) inhibitors, many reports have indicated that these agents may develop severe cutaneous reactions when administered concurrently to radiation therapy [32,33]. Irradiation of the skin leads to a complex pattern of direct tissue injury and inflammatory cell recruitment, after damage to epidermal basal cells and endothelial cells, with a reduction in Langerhans cell population . The increased expression of EGFR in keratinocytes then occurs, possibly as a mechanism for repopulating irradiated areas . At the same time, EGFR-targeting agents can inhibit basal keratinocytes and hair follicle cell proliferation, leading to growth arrest and subsequent inflammation . It could explain the possible interplay between radiation and EGFR-targeting agents in those patients presenting severe and sometimes life-threatening skin toxicities when treated with radiation therapy and concurrent EGFR-targeting agents such as cetuximab. Interestingly, there are some differences in terms of incidence of the acneiform rash among the different anti-EGFR antibodies. It seems to be less frequent and less severe in those patients treated with nimotuzumab, probably due to a different mechanism of EGFR inhibition, determined by the way in which the antibody binds to the receptor .
The first consensus guidelines [38••] on radiation dermatitis and coexisting acne-like rash in patients receiving radiation therapy and EGFR-targeting agents was published in 2008. All patients should be encouraged to maintain the irradiated area clean and dry, to minimize the risk of infection. Sunlight exposure and skin irritants, such as alcohol-based lotions, must be avoided. Topical treatment for palliation of symptoms and to induce skin healing may be helpful: drying paste for moist areas, gels in seborrhoeic areas and creams outside skin folds and seborrhoeic areas may be considered. The use of topical corticosteroids is not contraindicated but the overall treatment time should be as short as possible.
For mild reactions related to EGFR-targeting agents, topical treatment with antiacne or antirosacea can be used such as clindamycin or erythromycin gel. For moderated reactions, topical treatment can be used in association with an oral antihistamine (loratadine and hydroxyzine), when itching is present, and an oral tetracycline (doxycycline 10 mg/day, minocycline 100 mg/day or lymecycline 300 mg/day) .
When grades 2 and 3 radiation therapy dermatitis develops in these patients receiving the EGFR-targeting agents, antiseptic creams (chlorhexidine-based cream), hydrophilic dressing, anti-inflammatory emulsion (e.g., trolamine, and hyaluronic acid cream) and zinc oxide paste are useful. Medical judgment for management is important in case of infection. Systemic antibiotics may be necessary. Grade 4 radiation dermatitis, although extremely rare, should be treated under the supervision of wound care experts and sometimes need to stay in burn care unit.
Anemia occurs frequently in cancer patients and, as a consequence, fatigue and compromised performance and quality of life develop. Anemia has been demonstrated to be a negative prognostic factor in HNSCC patients treated with chemoradiation . Red blood cells transfusions are often prescribed to treat cancer-related anemia.
The use of erythropoiesis-stimulating agents (ESAs) in HNSCC patients under radiation therapy or chemotherapy is a matter of debate. Despite a clear improvement in hemoglobin levels in those patients treated with ESAs, worse survival outcomes, or neutral effects, were observed [41–43]. More recently, Hoskin et al. [44•] published a randomized trial on 301 HNSCC patients treated with radiation therapy along with epoietin alfa or radiation therapy alone. No difference was observed in terms of disease-free survival or OS, tumor control, cancer treatment-related anemia or fatigue.
In addition, a Cochrane systematic review  conducted on five randomized controlled trials (RCTs) and 1397 patients showed a significantly worse OS (Peto odds ratio 0.73, P = 0.005) and nonsignificantly worse local regional tumor control (relative risk 0.92, P = 0.15) in those patients treated with ESAs. However, the target hemoglobin concentration, which was higher than recommended in four RCTs, may have had a significant role. On the basis of these findings, ESAs should not be administered to HNSCC patients under radiation therapy or chemotherapy outside of the context of clinical trials.
The best outcomes in HNSCC patients treated in the multidisciplinary context can only be achieved with an adequate patient selection, an experienced and motivated team and if the best possible supportive care is offered. Suboptimal supportive care allied to poor nutritional status, comorbidities and adverse social aspects such as low income and low educational level, commonly observed in patients diagnosed with HNSCC, are among the most probable underlying causes of the low long-term survival rates presented by HNSCC patients who are candidates to aggressive therapies in the community setting. The search for new prognostic and predictive factors that will emerge from translational studies, and adequately powered randomized studies on many promising supportive therapies must be encouraged in HNC patients worldwide.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 291–292).
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