Reply to "Diet, Nutrition, and Cancer"

A descriptive review of the factors contributing to nutritional compromise in patients with head and neck cancer
Martin R. Chasen and Ravi Bhargava
from Supportive Care in Cancer, Volume 17, Number 11 / November, 2009

Introduction Malnutrition has been known to be associated with adverse outcomes in cancer patients. Patients who have been and/or are being treated for head and neck cancer have a compromised nutritional status. Nutritional deficits have a significant impact on mortality, morbidity, and quality of life.
Discussion The wasting in cancer cachexia involves loss of muscle and fat and reflects a catabolic metabolism induced by an abnormal host response to tumor presence and/or tumor factors. Disturbances of various physiological functions like taste, smell, dysphagia, xerostomia apart from cachexia can contribute to long-term nutritional complications and outcome.
Conclusion Improved management of patients in posttreatment for head and neck cancer may require a multimodal approach by a multidisciplinary team and is best commenced earlier in the trajectory of the disease.

Patients who have been and/or are being treated for head and neck cancer have a compromised nutritional status. Nutritional deficits have a significant impact on mortality, morbidity, and quality of life in patients with cancer. An overall 3-year survival of 55% and a disease-specific survival of 61% were found for patients with advanced head and neck cancer. Evidence shows that many persons in this population continue to experience sequelae of their treatment for months to years afterwards that are life altering. Most of these quality-of-life studies report clinically significant changes in perceived quality-of-life scores at 3, 6, and 12 months. Persons who have shorter survival times have lower quality of life and potentially more suffering than persons with longer survival. More than 50% of patients with advanced head and neck cancer have a markedly impaired nutrition and a significant involuntary weight loss at the time of diagnosis and before beginning treatment. Progressive depletion of lean body mass, muscle wasting, edema, and decline in motor and mental functions are also noted at the time of diagnosis. During the course of treatment, severe weight loss has been observed in up to 58% of patients in the absence of intensive nutrition support. Chronic dysphagia has been reported to occur in 12–69% of patients 6–9 months following treatment. In another study by Ward et al. 3 years after surgery, 42% of laryngectomy and 50% of pharyngolaryngectomy patients experienced long-term dysphagia leading to nutritional deficits and requiring a modification of their diet or tube feeding. Chronic xerostomia, which also impairs swallowing, can occur in patients up to 5 years after treatment.

Of the six important nutritional indicators, viz. percentage of weight loss, percentage of ideal body weight, nutrition index, serum albumin, total lymphocyte count, and body fat (20–67% range of abnormal scores), the one which has emerged as the most powerful predictor of major postoperative complications is a weight loss of >10% in the 6 months before surgery. An early prospective study of 114 patients showed that 38% with a nutritional deficit had a 2-year survival of only 7.5% compared with over 57% in the remainder of the cohort [13]. This manuscript will review both altered physiology in patients with head and neck cancers and the clinical consequences of those changes.

Physiological functions and changes that contribute to long-term nutritional complications

Taste and smell
The four modalities of taste (salt, sour, bitter, and sweet) are mediated via taste buds, which are present predominantly on the tongue. Studies have shown that the tip of the tongue is most sensitive to sweet or salty stimuli, whereas the lateral edges and posterior aspects of the tongue respond predominantly to sour and bitter substances, respectively. However, it is now known that all four taste qualities can be perceived in all areas of the tongue and palate where taste buds are located. The taste sensation in patients with head and neck cancer can be affected by antineoplastic drugs, e.g., cisplatin, carboplatin, 5-fluorouracil, and methotrexate. Since taste and olfactory receptors proliferate rapidly (every 10 and 30 days, respectively), they too may be sensitive to the cytotoxic effects of chemotherapy. This leads to not only altered smell but taste as well. Hypogeusia is a most common complaint in which patients describe a generalized loss of flavor. Dysguesia is an altered taste sensation that may be either heightened or suppressed.

Some patients will complain of a bitter taste during administration of the cytotoxic drug. Although such taste changes may last for a few hours to several days, there have been reports of these changes lasting for weeks or months. For example, 77% of patients treated with cisplatin experienced a metallic taste, which lasted for a few hours to 3 weeks. Many patients develop food aversions or loss of taste sensation due to radiation-induced damage to the taste buds. Radiation-induced salivary gland dysfunction also affects dentition and taste. It can be a factor in poor nutrition as a result of reduced tolerance to various food textures, temperatures, and acidities. The effect of radiation on taste in one of the study shows that taste loss was significantly associated with the proportion of tongue contained within the radiation treatment field. These data are in agreement with that of Conger and Wells, who suggested that taste loss is related more to area of tongue irradiated than of mouth dryness. Several investigators have observed complete recovery of taste function in patients 1–3 months after treatment while others like Schwartz et al. investigated the upper limit of taste detection thresholds from 6 months to 19 years (median, 2.4 years) after completing radiotherapy (RT; total radiation dose range, 36–72 Gy; median, 60 Gy) in 15 patients with head and neck cancer [4, 22–24]. They observed a return of nearly normal suprathreshold taste intensity perception. In contrast, others have not observed complete recovery of taste function in patients. Mossman et al. indicated that impairment of taste function may persist in some patients up to 7 years after RT and concluded that curative intent of RT for tumors of the head and neck may result in long-term changes in taste function. The complicated process of smelling begins when molecules released by the substances stimulate special nerve cells in the nose. These cells transmit messages to the brain, where specific smells are identified. Altered smell (dysosmia) during or after the administration of antineoplastic drugs is thought to occur as a result of the compound diffusing from the nasal capillaries to the olfactory receptors. Low doses of radiation have also been found to affect the olfactory system. Olfactory loss resulting from the direct toxic effects of radiation therapy may take over 6 months to resolve.

Oral mucosa and saliva
Saliva is important in preparing food for mastication, for swallowing, and for normal taste perception. Without saliva, mealtimes are difficult, uncomfortable, and embarrassing. The parotid salivary glands produce the majority (60–65%) of the oral salivary output. Radiation to the head and neck regions can cause xerostomia (dryness of mouth due to dysfunction of the salivary gland), stomatitis (inflammation of oral tissue, mucosa, dentition, and periodontium), anorexia, nausea/vomiting, and pain from mucosal ulcerations. Xerostomia may become progressively worse during and after treatment. Even a low dose of radiation can cause a change in the quantity and quality of saliva, and up to 100% of patients who undergo RT for head and neck cancer develop some degree of xerostomia. The symptoms of radiation-induced xerostomia are often permanent and lead to difficulty in mastication and swallowing. Other consequences include stomatitis, taste dysfunction, and increased susceptibility to dental caries. In addition, thick ropey secretions may interfere with food intake. These side effects can be severe. They occur in the majority of patients who undergo chemoradiation (CR) treatment for head and neck cancer during or after treatment and these problems limit a patient’s ability to eat in the long term and also affects the quality of life of patients. A recent study of oropharyngeal cancer patients revealed that reduction in saliva production continued for well over 1 year after chemoradiation therapy. Although the reduction of saliva production observed in this study did not correlate with inefficient swallowing, it did change patients’ perceptions of their ability to swallow. Xerostomia and/or altered taste perception may predispose the patient to decreased nutritional intake for many months after treatment. This further worsens the prognosis of the cachectic cancer patient .

The bolus of food or drink in the oropharynx sets off a chain reaction beginning with relaxation of the upper esophageal sphincter followed by waves of coordinated peristalsis that propels the bolus to the lower esophagus and then through a relaxed lower esophagogastric sphincter into the stomach. Extrinsic and intrinsic innervations, smooth muscle properties (response to distension), and humoral properties are all involved in the coordination of this event.

Dysphagia implies disruption in the swallowing process during bolus transport from the oral cavity to the stomach and is considered as the most common nutrition-related problem resulting from head and neck cancer and its therapy. Dysphagia may be caused by surgical ablation of muscular and nervous structures or may be attributable to the effects of antineoplastic agents including radiation and/or chemotherapy. The severity of the swallowing deficit is dependent on the size and location of the lesion, the degree and extent of surgical resection, and the nature of reconstruction and/or the side effects of medical treatments.

In a study by Ekberg and Nylander, five patients treated with radiotherapy were studied 1 year or more after completion of radiation therapy. These patients exhibited significant changes in pharyngeal peristalsis, presumably related to decreased flexibility in the pharyngeal constrictors because of increased fibrosis. As a result of the reduced peristalsis, patients exhibit residual food in the pharynx after the swallow and a tendency to inhale this residue into the airway after the swallow. Reduced pharyngeal peristalsis can become severe enough that it is difficult for the patients to move any food other than liquid through the pharynx and into the esophagus. The critical dose level of radiation, beyond which these permanent and long-term effects on the pharynx are created, has not been defined. The only patient in the Ekberg study who exhibited normal swallowing after radiation therapy had received less than 3,000 rads. It is reported that combined CR can increase the nutritional risk due to the combined toxicities of the two modalities and their effects on swallowing. In one report, 76% of patients with head and neck cancer treated with RT or CR therapy had significant mucositis, and 87% had significant dysphagia 1 month after beginning chemoradiation. In another report, over 40% of head and neck cancer patients continued to have dysphagia 3 years after surgery and radiation treatments. Esophageal strictures following chemoradiation occurs in 3.4–14% of head and neck cancer patients. The strictures can cause partial or complete obstruction of the esophagus. Compromised quality of life, anxiety, and depression are correlated with the severity of dysphagia as well as the patient perception of swallowing difficulties.

Cancer cachexia is defined by an aberrant energy and protein balance driven by a variable combination of reduced food intake and hypermetabolism. Over its course, cachexia is associated with functional impairment and fatigue. A key defining feature is ongoing loss of skeletal muscle mass which is not fully reversed by conventional nutritional support. Cachexia is classified depending on its cause as either primary or secondary. Primary cachexia is principally caused by a tumor-induced chronic inflammation involving aberrant cytokine and prostaglandin activation. Consequences include anorexia and poor food intake mediated through the effect of cytokines on the hypothalamus. Secondary cachexia stems from problems that may not be related to chronic inflammation; these problems impact on nourishment and must be identified.

The pathogenesis of cachexia is not simply an imbalance between energy intake and expenditure. Cachectic cancer patients have been shown to consume as many as 3,200 kJ (800 cal) less per day than patients without cachexia. However, the provision of energy alone in the cachectic patient does not result in weight gain, as demonstrated by the ineffectiveness of conventional nutrition support. People who are starved preserve muscle and weight is lost preferentially in the fat component of the body. Patients with cachexia, however, lose weight both in the muscle and fat component of the body. Weight loss in starvation, as encountered in some cancer patients with gastrointestinal obstructions is reversible by enteral and/or parenteral feeding, whereas no such techniques can currently reverse primary cancer cachexia.

Primary cachexia is the least understood cause of weight loss, and yet it is responsible for the greatest morbidity among patients with head and neck cancer. Secondary cachexia in patients with head and neck cancer is a multifactorial malnutrition. Firstly, the site of the primary tumor may mechanically obstruct the aerodigestive tract or cause odynophagia or dysphagia. Secondly, head and neck cancer patients may have underlying chronic malnutrition at presentation due to alcohol, tobacco abuse, and poor nutritional habits. Finally, treatment-related toxicities, such as radiation exposure to the aerodigestive tract and chemotherapeutic agents, may further impair the patient’s ability to obtain adequate nutrition due to mucositis or xerostomia. Contributors to secondary cachexia are discussed at length in other sections.

Psychological effects of nutritional compromise on quality of life[/b]
Patients with head and neck cancers who undergo surgery often report considerable psychological and emotional distress with impaired social functioning and experience malnutrition due to a decreased ability to ingest food. Difficulties with eating, chewing, and swallowing as well as changes in taste, smell, and drooling are all reported to play a major role in impairing the nutritional status of the patients after the treatment of head and neck cancer. This can lead to social isolation and reticence to eat with other people. When these alterations are severe, they do contribute to eating problems, weight loss and an altered perception of body image. In addition, cachexia can also lead to mental depression, lower quality of life, and a change in self-image.

Poor psychosocial status also affects the appetite and impacts long-term well-being of the patients. Such findings have been replicated in other studies, which demonstrate that anxiety and depression is also experienced by approximately 30% to 40% of patients following treatment for head and neck cancer. Malnutrition has also been linked to depression in several studies. One outcome of emotional distress is suicide, with Boulnd noting that patients with head and neck cancer form a relatively large proportion of suicide cases in cancer patients. This has also been acknowledged by Farberow et al., who concluded that two head and neck sites alone (tongue and pharynx) accounted for almost 20% of the total suicides among male patients with cancer. None of these studies have indicated that malnutrition alone was the cause of suicide but it certainly played a role among the constellation of symptoms that lead to this devastating outcome.

While psychosocial dysfunction is often the major concern for patients with head and neck cancer, relatively limited, systematic, and prospective investigation has been performed, and, therefore, little progress has been made to develop an effective rehabilitation program to enhance the quality of life for this group of patients.

Many patients with advanced head and neck cancer have percutaneous endoscopic gastrostomy (PEG) placed as a part of their therapeutic interventions [67] and it is appropriate therefore to discuss this topic.

PEG placement and long-term complications in patients with potentially curable disease
PEG tubes, first described by Gauderer et al. in 1980, are able to provide nutritional support in patients unable to feed orally. PEG placement is technically simple and can be performed in an outpatient setting. Compared with PEG tubes, radiologically placed gastrostomies often have inferior tube function and surgically placed tubes are associated with high morbidity and mortality. PEG tubes have been placed in head and neck cancer patients, with a success rate of 95% to 98%.

PEGs may be inserted because of the following reasons:

  • 1. Major causes of malnutrition during and after radiotherapy are painful mucosal inflammation of the oral cavity and pharynx, xerostomia, and taste alterations. In addition, severe mucositis normally occurs between 3 and 5 weeks after a dose of 30–50 Gy during a radiotherapy regimen with standard fractionation (single dose of 2 Gy, five fractions weekly). Chemotherapy can lead to severe mucositis up to 10 days after its application, depending on the substances used and their toxicity to the mucous membrane.
  • 2. Specific tumor-induced anorexia and metabolic dysfunction such as accelerated catabolism contribute to further deterioration of the nutritional state Piquet et al. suggest that the main objectives in providing nutritional support in this group of patients with head and neck cancer are to prevent or correct nutritional deficiencies and to achieve and maintain a desirable weight.

The complication rate of PEG placement is 4.9–10.8%. Infections at the PEG site occur in about 6% of patients. PEGs are suitable for long-term enteral nutritional support. If cared for properly, PEG tubes are durable, with an average longevity of approximately 1–2 years. Complications associated with long-term home enteral nutrition include diarrhea, constipation, leakage from the fistula tract, tube site infection, tube dislodgement, and tube clogging. In a study of 210 patients receiving PEG feeding (head and neck cancer accounting for 70% of the malignant diseases in the group), 21.9% had minor gastrointestinal problems (vomiting, diarrhea, constipation), which resolved after conservative management. In another study of patients receiving home PEG feedings (16% with head and neck cancer), 51% had no complications during the period of enteral support (mean 175 days). PEG site infections usually resolved with antibiotics. Patients with more severe PEG complications, e.g., embedded bumper, may require hospitalization. Variable hospitalization rates have been reported in the literature, ranging from 1% to 40%. Complication rates have fallen as expertise in gastrostomy insertion has improved. Patients who experience long-term difficulties with feeding require continued enteral feeding beyond the immediate treatment period. The duration of PEG dependence in this population varies according to the chronicity of dysphagia. In one of the reports, PEG tubes placed in head and neck cancer patients before RT were used for a median of 165 days. Another study, evaluating 36 patients treated with chemoradiation, reported a median duration of PEG use of 7 months. In a further study of 82 patients, 72% required enteral support for 1 year. It is noted however that, in up to 24% of patients receiving long-term enteral tube feedings, oral intake was resumed with a discontinuation of home enteral nutrition.

In some patients, dysphagia may persist long after eradication of the underlying cancer. Permanent enteral nutrition is then required to provide adequate nutrition and hydration. It is estimated that 10% of long-term head and neck cancer survivors require permanent enteral nutrition. Various studies demonstrate that the early use of enteral feedings during head and neck cancer treatment reduces weight loss, dehydration, malnutrition, and the associated need for hospitalization. An early prospective study of 114 patients showed that 38% with a nutritional deficit had a 2-year survival of only 7.5% compared with over 57% in the remainder of the cohort. Home enteral nutrition by PEG infusion has been well received by patients, with 80% reporting a positive experience. A prospective study of 212 head and neck cancer patients assigned to oral feeding vs. PEG feeding before RT demonstrated improvements in quality of life among those receiving enteral nutrition support. The quality-of-life scores in the oral nutrition group deteriorated during RT and showed only slow improvement after therapy, whereas the PEG-fed group maintained their quality of life. Another prospective study confirmed these findings that enteral nutrition improves the quality of life in patients with dysphagia.

Treatment of malnutrition in patients with head and neck cancer is supportive in nature and directed against a specific cause and prevention such as minimizing the volume and dose of radiation or adequate adjunctive measures such as analgesia for pain which could facilitate swallowing in patients with painful stomatitis. Different nutrition supplementations used and anticachectic agents may also play a role in alleviating some of the factors that contribute to nutritional compromise. Details fall outside the scope of this article. A very important component of treatment not discussed here is the value of the cancer rehabilitation team which includes physician, nurse, dietician, psychologist, and others health care professionals whose aim is to empower individuals who are experiencing loss of function, fatigue, malnutrition, psychological distress, and other symptoms as a result of cancer or its treatment to improve their own quality of life.

Nutritional compromise severely impacts on the short- and long-term outcome of patients with head and neck cancers. Many of the above-mentioned mechanisms which lead to the development of these long-term alterations of normal physiology are caused by the effects of the cancer and/or the different treatments on the normal physiology.

Disease control has improved over the past decades as we have started integrating multimodal therapies which are impacting the duration of survival of these patients. Increased acute toxicities have also translated into increased late toxicities which have impacted on the patient’s ability to maintain an adequate nutritional intake and acceptable social interaction. The goal for the future must surely be to maintain or improve the long-term mortality of these patients while decreasing their morbidity especially as it relates to nutrition.