ABSTRACT: Malnutrition plays a key role in the morbidity of head and neck cancer patients receiving surgery, chemotherapy, radiotherapy, or combined- modality therapy. In addition to weight lost prior to the diagnosis of head and neck cancer, the patient may lose an additional 10% of pretherapy body weight during radiotherapy or combined-modality treatment. A reduction of greater than 20% of total body weight results in an increase in toxicity and mortality. Severe toxicity can result in prolonged treatment time, which has been implicated in poor clinical outcome. Early intervention with nutritional supplementation can reduce the chance of inferior outcome in patients at high risk of weight loss. The preferred route of nutritional support for these patients is enteral nutrition. Two commonly used methods for enteral feedings are nasoenteric and percutaneous endoscopic gastrostomy. It is important to take into account the ethical considerations involved in providing long-term nutritional support, particularly for patients with terminal conditions. Nutritional directives are best evaluated through multidisciplinary efforts, including input from the patient as well as members of the nursing, nutritionist, and medical staff.
Commonly observed manifestations of cancer and its treatment include hypermetabolism, cachexia, and anorexia. Patients undergoing treatment for head and neck cancer are particularly prone to weight loss, both secondary to the disease process and due to treatment side effects. There is a direct correlation between more aggressive therapeutic modalities and progressive malnutrition, resulting in a diminished quality of life and poor outcome. Therefore, nutritional support can significantly benefit the malnourished patient who may then have a positive response to therapy. Appropriate nutritional support and early interven tion with temporary enteral access can result in improved nutritional status and therapy tolerance. This correlates with decreased hospitalizations, enhanced quality of life, and a reduction in morbidity and mortality.[5,6]
Etiology of Malnutrition
Patients with head and neck cancer have multiple etiologies for malnutrition as a consequence of the imbalance between nutrient intake and demand. Decreased nutrient intake may be associated with localized tumor effect[7,8] or the toxicities of treatment. Typically, the patient has lost weight prior to beginning therapy. Local tumor effect may obstruct the aerodigestive tract, impede mastication, or hinder deglutition. Patientrelated factors, such as poor dentition, unique anatomy, and nutritional history may also exacerbate the local tumor effect.
Lees reported on weight change in 100 consecutive patients with head and neck carcinoma prior to the start of radical or palliative radiotherapy. Approximately 57% had lost weight, whereas only 12% had gained weight prior to the start of radiotherapy. The mean weight loss was approximately 10% of total body weight and was considered unintentional in 95% of patients. Dry mouth and the inability to wear dentures secondary to mouth discomfort were the most common causative factors of weight loss.
Treatment modalities for head and neck cancer may include surgery, chemotherapy, radiotherapy, or combination therapy. Each of these treatment modalities may result in side effects that could affect nutritional status. Postsurgical changes may result in localized pain or difficulty with mastication and deglutition. Chemotherapy may induce mucositis, nausea, vomiting, stomatitis, fatigue, or neutropenia leading to infection that may contribute to a poor nutritional status. Radiotherapy can induce mucositis, dysgeusia, xerostomia, change in viscosity of saliva, fistula formation, infection, fatigue, stricture, gustatory dysfunction, or olfactory dysfunction that can also significantly impair nutritional status. The addition of concurrent chemotherapy to radiotherapy may significantly exacerbate these effects.
It has been well documented that standard radiotherapy fractionation schedules (2 Gy/d, 5 days per week to at least 60 Gy) result in an increased risk of weight loss both during and following treatment. Johnston et al reported on 31 patients receiving standard fractionated radiotherapy for localized head and neck cancer. This prospective study revealed that pretreatment dietary habits, serum albumin, or anthropometric measurements were not predictive for weight loss; however, weight loss could be predicted on the basis of field size and site irradiated. Tyldesley et al reported on 76 patients with head and neck cancer treated with radiotherapy alone who received gastrostomy tubes either electively (inserted during week 1), or only if a severe reaction occurred (inserted during week 3 on average) and compared them to a control group that did not receive a gastrostomy tube (G-tube). Initial weight loss and weight loss at followup was significantly less for patients who underwent elective or nonelective G-tube placement, which corresponded to fewer days hospitalized.
Peters et al reported on 240 patients with advanced stage head and neck cancer treated with surgical resection and randomized to receive escalating doses of postoperative radiotherapy. Three dose levels were analyzed, ranging from 52.2 to 68.4 Gy (field reduction at 57.6 Gy) in daily 1.8-Gy fractions. Overall, only 3.8% developed acute reactions that required a treatment interruption greater than 2 days (maximum interruption was 6 days). The average weight loss was 2.6 kg.
Novel radiotherapy technique and fractionation schedules continue to be investigated to improve local control and survival[13,14] with acceptable quality of life or organ preservation. However, most altered fractionation schedules and combinedmodality therapies have shown improved outcome at the cost of increased morbidity.[16,17]
Fu et al reported on the RTOG 9003 phase III trial that compared standard fractionation techniques with hyperfractionation and two variants of accelerated fractionation. This analysis involved 1,073 patients with locally advanced head and neck cancer. The study showed an improved locoregional control and a trend toward increased disease-free survival for patients who underwent the hyperfractionation technique (1.2 Gy per fraction twice daily for 5 days per week, to a total of 81.6 Gy) and accelerated fractionation with concomitant boost (1.8 Gy per fraction for 5 days per week with 1.5 Gy/d to a boost field for the last 12 treatments, to a total of 72 Gy) compared with standard fractionation (2 Gy per fraction for 5 days per week, to a total of 70 Gy) and accelerated fractionation with split (1.6 Gy per fraction twice daily for 5 days a week, to a total of 67.2 Gy with a 2-week break at 38.4 Gy).
Weight loss data were not reported for this study. The most common site of acute side effects included the mucous membranes and pharynx, whereas the most common site of late effects included the pharynx and salivary glands. The hyperfractionation technique and two variants of accelerated fractionation had significantly increased grade 3 or worse acute side effects compared to standard fractionation techniques. Only the accelerated fractionation with concomitant boost had a significant increase in grade 3 or worse late effects.
Concurrent Chemotherapy/ Radiotherapy
The addition of concurrent chemotherapy to radiotherapy for head and neck neoplasms has been shown to improve both local control and overall survival, but at the cost of increased severity and duration of acute side effects. Newman et al reported on 47 head and neck cancer patients who underwent concurrent radiotherapy (1.8-2.0 Gy daily fractions) with intra-arterial cisplatin(Drug information on cisplatin) and parenteral sodium thiosulfate(Drug information on sodium thiosulfate). Prior to the start of treatment, 53% of patients already had impaired swallowing and 9% were dependent on tube feedings. Investigators found a mean 10% reduction in total body weight during treatment and no significant changes in weight following treatment. No correlation between weight loss and tumor stage was seen. In a subgroup analysis, the 9% of patients who had a G-tube prior to treatment did not lose significant weight. During treatment, the cohort of patients with difficulty swallowing increased from 62% to 79%, which correlated with an increase of G-tubes from 9% to 26% by the end of treatment. However, swallowing difficulty was reported in only 28% of patients at 18 months after treatment.
Brizel et al reported on 116 patients with advanced head and neck cancer who were treated with a hyperfractionated radiotherapy technique and randomized to concurrent chemotherapy (cisplatin and fluorouracil(Drug information on fluorouracil) [5-FU]) or no chemotherapy. Locoregional control and overall sur vival was significantly improved with combined-modality therapy, and the investigators found no significant difference in the incidence of mucositis, although the mucositis took longer to resolve in the combined-modality group (6 weeks) than in the hyperfractionation radiotherapy-alone group (4 weeks). There was no significant difference in weight loss; however, 44% of patients in the combined-modality group had a temporary feeding tube placed (nasogastric or G-tubes), compared to 29% of the patients who received hyperfractionated radiotherapy only. In addition, the combined-modality therapy arm resulted in continued treatment sequelae a year after treatment, causing dietary restrictions, but this did not correlate with a significant change in quality of life.
Calais et al analyzed 226 patients in a phase III randomized trial that compared radiation therapy vs concurrent radiation therapy and chemotherapy (carboplatin and 5-FU) for advanced-stage oropharyngeal cancer. This revealed a significant improvement in local control and overall survival; however, there was also a significant increase in grade 3/4 mucositis in the combined-modality arm (71%) vs radiotherapy alone (39%). The nutritional status of the combined-modality arm was poor, based on a higher proportion of patients who lost more than 10% body mass. Moreover, the combinedmodality arm had an increased requirement for temporary G-tube or nasogastric feeding tubes.
Chan et al reported on a phase III randomized trial that compared radiotherapy vs concurrent chemotherapy and radiotherapy for the treatment of locoregionally advanced nasopharyngeal carcinoma. In this study, weight loss was significantly more pronounced in the combined-modality arm, which included 74% of patients losing more than 10% of body weight and 11% losing more than 20% of body weight, compared to 50% and 6% in the radiotherapy-alone arm. The combined-modality arm also showed a statistically significant increase in anemia, leukopenia, thrombocytopenia, nausea, vomiting, and stomatitis. This study demonstrated an improved progression-free survival for advanced tumor and nodal stages only in subgroup analysis.
In contrast, the results of the Intergroup study 0099 revealed improved overall and progression-free survival in the combined-modality arm. The Intergroup study concluded that combined modality is superior to radiotherapy alone for stage III/IV nasopharyngeal cancers. However, both studies agree that toxicity, including weight loss, is worse in the combinedmodality group.
Weight Loss and Other Metabolic Effects
Studies have revealed an association between weight loss and inferior outcome for the head and neck cancer patient. Bosaeus et al reviewed 297 cancer patients involved in an outpatient palliative care program and noted that a weight loss greater than 10% was present in 43% of the patients, while hypermetabolism was present in 48%. Hypermetabolism and weight loss were significant factors associated with decreased survival. Also, the sequelae of radiotherapyinduced toxicity including impaired nutrition may cause treatment delays and a prolonged treatment course that has been shown to affect local control and survival.[4,25]
Weight loss in the head and neck cancer patient is not caused exclusively by decreased nutritional intake. Surgery, radiotherapy, and chemotherapy also lead to acute metabolic stress and amplified nutrient demands. In addition, the increased nutrient demand may be associated with the systemic effect of the tumor,[26-29] which competes with the host for nutrients, resulting in metabolic disturbances leading to anorexia, increased basal metabolic rate, and abnormal metabolism of nutrients. Tumor necrosis factor-alpha, possibly with other cytokines such as interleukin-6 or interferon-gamma, have been implicated in cachexia in animal models and may be, in part, regulated by NF-kappaB.[30-33] A combination of cytokines from the host and tumor are released, causing abnormalities in carbohydrate, fat, and lipid metabolism. Muscle wasting is found in skeletal, cardiac, and smooth muscle types. Muscle loss can cause generalized weakness, reduced cardiac function, or decreased respiratory function.
Tube Placement and Technique
Providing adequate nutrition to this group of patients can be very challenging, despite the use of enteral supplementation, appetite stimulation, and dietary counseling. This has led to the role for enteral access and tube feeding to provide calories, fluids, and medications. Enteral nutrition is preferred over parenteral nutrition, because it preserves gut integrity, function, and immune mechanisms, and is also associated with lower risks and costs. Tube feeding should be considered for patients who have a functional gut but cannot or will not eat, and for whom a safe method of access is possible (Table 1).
Temporary enteral access can be obtained using nasogastric (NG) or nasojejunal (NJ) feeding tubes, and is particularly useful in patients who need short-term (< 30 days) nutritional support. These tubes have the benefit of easy placement and removal but are limited by becoming dislodged, easily clogged, or irritating to the upper aerodigestive tract in the head and neck cancer patient. Such problems have led to the development of more permanent endoscopically, radiologically, or surgically placed enteral access such as gastrostomy, gastrojejunostomy, or jejunostomy feeding tubes. These tubes are especially useful for patients who will need tube feeding for more than 30 days.
Over 216,000 percutaneous endoscopic gastrostomy (PEG) procedures are performed annually in the United States. Although the evidence base is limited, the available data support the use of PEG in patients with head and neck cancer. The absolute contraindications to PEG placement are the same as those of endoscopy, which include an inability to transilluminate the abdominal wall and appose the anterior gastric wall. Relative contraindications include ascites, coagulopathy, gastric varices, morbid obesity, and neoplastic, infiltrative, or inflammatory disease of the gastric or abdominal wall (Table 2).
Commercially available PEG tubes are sized 18F to 28F, made of polyurethane or silicone, and can last from 24 to 48 months. In most cases, preprocedure prophylactic antibiotics such as cefazolin(Drug information on cefazolin) are given to prevent infection. The procedure involves an initial endoscopy using conscious sedation to exclude gastric or duodenal obstruction, followed by the combined use of transillumination and finger indentation of the anterior abdominal wall to identify a suitable site. Once identified, the site is anesthetized with lidocaine(Drug information on lidocaine), and a sounding needle is advanced from the anterior abdominal wall into the stomach lumen with endoscopic guidance.
This is followed by a 1-cm incision at the site and the passage of a trocar through the incision into the stomach, so that a guidewire can be passed into the stomach. An endoscopic snare or forceps is then used to grasp the wire and pull it out of the mouth while the trocar is removed. Once the guidewire is released, a PEG tube is either fastened to the guidewire and pulled into position or pushed over the guidewire into position. An external bolster is then placed to keep the PEG tube in place. PEG tubes can be used for feeding within 3 to 4 hours of placement.
Variations of this technique include the push introducer (Russell), Versa (a combination of the push and introducer technique), and primary button methods. When there is esophageal obstruction, the PEG can also be placed radiologically under fluoroscopic guidance. Surgical placement is comparable to PEG but is more expensive (as general anesthesia is required) and requires more recovery time before use.
Other reported surgical techniques in the literature include laparoscopic gastrostomy, cervical esophagostomy used in patients with oropharyngeal cancer, and percutaneous needle pharyngostomy. Transnasal, straight laryngoscopic or intraoperative open (pharyngeal) endoscopy techniques have also been used to facilitate PEG tube placement in head and neck cancer patients, in whom partial or complete trismus and/or stenosis of the upper aerodigestive tract prevented oral insertion of the endoscope into the esophagus. Local expertise and accessibility should determine which approach to gastrostomy is performed; however, for gastric access using conscious sedation, the endoscopic approach is the most common.
Complications of gastrostomy tube placement in some series suggest a 17% morbidity rate, of which 3% were considered serious. The minor complications include pneumoperitoneum, temporary ileus, wound bleeding, wound infection, cutaneous or gastric ulceration, peristomal leakage, and tube clogging. Major complications include necrotizing fascitis, peritonitis, aspiration, septicemia, dislodgement, esophageal perforation, gastric perforation, bowel perforation, gastrocolocutaneous fistulae, inadvertent PEG removal and buried bumper syndrome. Buried bumper syndrome occurs when the external bolster of the PEG tube is placed too firmly against the abdominal wall, causing the internal bolster device to slowly erode into the gastric wall and resulting in pain and difficulty infusing tube feeds. Metastatic tumor deposits have also been reported at the PEG site. The mortality rate associated with the procedure is < 1%.
Jejunal access is primarily useful in patients with ileus, gastric feeding intolerance, tube feeding-related reflux esophagitis, gastroparesis, insufficient stomach from a prior resection, aspiration pneumonia, or chronic pancreatitis, and is occasionally useful in patients with an unresectable gastric or pancreatic malignancy. However, further evidence is required to confirm the long-term impact of jejunal feeding.
Jejunal enteral access can be achieved either by initially performing an 18-28F gastrostomy and then placing a 9-12F jejunal attachment endoscopically over a guidewire (PEG/J), or by endoscopic (DPEJ), radiologic, or surgical placement directly into the jejunum. PEG/J tubes are associated with a tube malfunction rate in 53% to 84% of cases, and aspiration in 17% to 60% of cases. The technique for DPEJ is an adaptation of a PEG, where an enteroscope or pediatric colonoscope is advanced to the jejunum, and then a similar method using a trocar and transillumination is performed.
Placement of a DPEJ is successful in 72% to 88% of patients and appears to provide superior jejunal access compared to the PEG/J but is technically considerably more difficult than a PEG. DPEJ placement is associated with major complications needing surgery in 2% of cases (including abdominal wall abscesses, bleeding, and colon perforations). Minor complications such as leakage, peristomal infections, and enteric ulcers occur in 8%, 7%, and 5% of patients, respectively. Aspiration of tube feeds with DPEJ is highly unlikely.
Overall, multiple safe and efficient endoscopic, radiologic, and surgical techniques are available to obtain enteral access and ensure adequate nutritional support in patients with head and neck cancer. However, although there is evidence suggesting advantages of enteral support, larger prospective studies are required to confirm this benefit.