Nutrition Support and Therapy in Patients with Head and Neck Squamous Cell Carcinomas
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- Gee, A.C., Kiraly, L., McCarthy, M.S. et al. Curr Gastroenterol Rep (2012) 14: 349. doi:10.1007/s11894-012-0273-5
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Head and neck squamous cell carcinomas (HNSCC) present a unique set of challenges in both the treatment of the disease and in support of the patient afflicted with the cancer. A major challenge is the nutritional support of these patients. Often, patients with HNSCC are malnourished at baseline due to an underlying dysphagia. Many others develop dysphagia as a result of their surgical resection and external beam radiation therapy. This dysphagia further exacerbates the chronic dehydration and malnutrition. This article will review strategies to provide nutritional support to HNSCC patients and also to review nutritional strategies that may decrease the morbidity and mortality associated with HNSCC treatment.
KeywordsHead and neck squamous cell carcinomasNutrition supportNutrition in head and neck cancer
Head and neck cancers comprise a diverse set of malignancies that can arise from a variety of organs and structures. The malignancies are commonly divided into endocrine (thyroid and parathyroid) cancers and nonendocrine, squamous cell cancers. The treatment of these two groups of malignancies is very different. Lesions of the thyroid and parathyroid glands are generally treated with glandular resection and on occasion, cervical lymph node dissection. Head and neck squamous cell carcinomas (HNSCC) are commonly treated with a combination of chemotherapy, radiation therapy and surgical resection. For the purposes of this review, we will be focusing the discussion on the role of nutritional therapy and support of patients with head and neck squamous cell carcinomas.
Over 40,000 new HNSCCs are expected to be diagnosed in 2012. The incidence rate in men is twice that in women . Known risk factors for this disease include tobacco use (both smoked and chewed), alcohol use, betel nut chewing, and human papillomavirus (HPV) infection of the oropharynx. Tobacco use damages DNA by the release of carcinogenic compounds as well as through free radical generation produced by the partial combustion of tobacco products. Alcohol is thought to lead to DNA damage primarily due to the production of acetaldehyde, a metabolite of ethanol. Tobacco and alcohol appear to act synergistically by enhancing the production of acetaldehyde from alcohol and the release of carcinogen compounds from tobacco . Ninety percent of the HNSCCs that are HPV-related are due to infection with the HPV subtype 16. Similar to anal and cervical cancers, HNSCCs develop as a result of DNA damage and HPV-mediated local immune dysfunction caused by chronic HPV infection [3–5].
Compounding this risk of alteration is the fact that it is common for patients with locally advanced disease to have dysphagia or odynophagia at baseline . Alcohol abuse may also be a contributing factor to malnutrition in this patient population. These preexisting issues combined with the tumor burden, anorexia, and cachexia results in many of these patients already being malnourished at the time of presentation. The cancer cachexia syndrome involves widely variable physiologic and metabolic derangements resulting in potentially life-threatening malnutrition. Furthermore, a cancer diagnosis may lead to depression, anxiety, anger, and fear, which can also affect appetite and the motivation for oral intake. All of these factors can result in severe weight loss, which potentially affects prognosis, ability to heal, length of recovery, and cost of care.
The first goal of this review is to discuss strategies for providing nutritional support of patients undergoing treatment for HNSCC, so that their protein-calorie malnutrition can be arrested and potentially reversed. A second goal is to review nutritional therapies that may decrease the morbidity and mortality associated with the treatment of HNSCC.
Materials and Methods
This article reviews publications relevant to nutritional therapy and support in head and neck squamous cell carcinomas. Articles were identified through a PUBMED search utilizing keywords (and combination of keywords) to include mucositis, nutrition, head neck cancer, arginine, omega-3 fatty acids, radiation injury, glutamine, PEG, and feeding tube.
Malnutrition is widely accepted as a risk factor for intolerance of chemotherapy or radiation therapy regardless of the malignancy. Numerous studies have demonstrated that patients with HNSCC who experience significant weight loss have a much higher incidence of treatment interruptions due to intolerance [7–9]. These interruptions, in turn, adversely affect the ability of chemoradiation therapy to impact local control and long-term survival [10–13]. Therefore, it is imperative that adequate nutrition support to HNSCC patients be considered a priority and an adjunct to complex oncologic therapies.
An estimated 90 % of patients undergoing chemoradiation for HNSCC develop xerostomia, fibrosis or mucositis in the oropharynx . Mucositis occurs with a wide spectrum of severity: from areas of mild erythema to full thickness, painful ulcerations. Those unfortunate enough to develop the more severe forms of mucositis have significantly decreased oral intake due to the severe pain that accompanies the lesions. Numerous treatments, utilizing both topical and systemic, have been evaluated in hopes of mollifying the mucositis, but results have been mixed at best . More recently, intravenous L-alanyl-L-glutamine supplementation has been trialed for prevention of radiation-induced mucositis (RIM). Glutamine is considered to be a conditionally-essential amino acid and plasma glutamine levels have been found to be diminished in patients with head and neck and gastrointestinal cancers. This has been postulated to be a result of the chronic malnutrition experienced by patients with malignancies in these locations . Studying HNSCC patients receiving chemoradiation, Cerchietti and coworkers were able to decrease the incidence of severe mucositis from 67 % to 15 % (p = 0.007) and also to demonstrate a significant decrease from 60 % to 14 % (p = 0.02) in the requirement for feeding tube placement in patients who received L-alanyl-L-glutamine, as compared to those who received a placebo .
When HNSCC patients present with locally advanced lesions, chemoradiation therapy alone is often not sufficient for treatment and thus a wide resection is indicated for these cases. The operations required can be fairly morbid, with over 40 % requiring mandibular resection and over 35 % requiring either a partial or total glossectomy [17•]. Many, but not all, patients undergoing these aggressive operations, done with curative intent, develop significant postoperative dysphagia that may become a lifelong complication. Thus far, factors including advanced age, advanced T classification, location of the primary tumor site and surgical treatment with a neck dissection have been associated with prolonged dysphagia [17•, 18•].
After a major resection for HNSCC, most patients receive an enteric feeding tube, either a nasoenteric tube or a percutaneous endoscopic gastrostomy (PEG) tube. Patients who do receive an enteric tube are able to more easily maintain their weight and meet nutritional goals during postoperative chemoradiation therapy and reportedly tolerate therapy with fewer interruptions .
PEG tubes are generally recommended for patients who are expected to have inadequate oral nutritional intake for at least 2 to 4 weeks [20–22]. Unfortunately, it remains difficult to accurately predict which patients will have dysphagia long enough to benefit from a PEG tube. Ideally, if a PEG tube is needed, it is preferable to place the tube prophylactically, such as one placed prior to the onset of chemoradiation or surgical therapy, so that it can be used early on for nutritional support. Delaying PEG tube placement until after the onset of therapy may increase the technical challenges of endoscopic placement and may mandate a surgical approach to tube placement. In fact, an endoscopic approach may be contraindicated due to the need to traverse areas that may be stenotic, fibrotic, friable or recently operated on. Placement of a PEG tube does have the potential for technical complications; there is a risk of tumor seeding the gastric wall and subcutaneous tissues (when a standard “pull-technique” is used for PEG tube placement), which will lead to greater physical, emotional, and financial cost to the patient . The exact risk of tumor seeding from the PEG tube is not known, but has been described and is a known risk.
However, in general, patients who have poor tumor characteristics or who have pretherapy dysphagia are the ones who will benefit the most from a prophylactic PEG tube placement given their propensity for chronic dysphagia . However, several recent studies, both retrospective and prospectively randomized, have suggested that patients who receive a prophylactic PEG tube develop a significantly longer duration of dysphagia as compared to patients who receive a nasoenteric tube or no tube at all [19, 22, 25, 26••]. Unfortunately, these studies cannot determine the etiology of the prolonged dysphagia in the patients who received a prophylactic PEG tube. Several authors have conjectured that it may be due to disuse of the swallowing mechanisms or that the nasoenteric tube stents the treatment area and thus minimizes the degree of stenosis. Therefore, the patients most likely to benefit from a PEG tube are those who are severely nutritionally depleted prior to onset of therapy or those who are unable to sustain themselves with oral intake alone.
Nutritional Assessment & Support
Assessment of a patient’s nutritional status ideally occurs relatively soon after diagnosis of an HNSCC, due to the fact that many patients are malnourished at baseline [11••, 27••, 28]. Early nutritional therapy have been shown to improve outcomes in the HNSCC patient population. Unfortunately, classic metrics for nutritional assessment (body mass index, lean body mass, and visceral protein levels) have not proven useful in assessing nutritional status in HNSCC patients. As with many other cancers, subjective global assessment (SGA) and the Karnofsky performance score are currently the two best predictors of therapy-related weight loss and ongoing malnutrition [29, 30]. Identification of at-risk patients enables earlier nutritional intervention by trained dieticians or earlier placement of an enteric feeding tube in patients who are not meeting nutritional goals.
As noted earlier, maintenance of adequate and appropriate nutrition during HNSCC treatment is important because malnutrition can cause an increase in treatment intolerance. Van Bokhorst-de van der Schueren and coworkers prospectively evaluated 64 patients beginning HNSCC treatment and found that a pretherapy weight loss of greater than 10 % is a predictor of postoperative complications . They were unable to identify other markers that were predictive of therapy intolerance or increased complications.
Under normal conditions, L-arginine is a considered a nonessential amino acid, but under stressed conditions, it becomes conditionally essential. While some de novo synthesis occurs in humans, the vast majority of the arginine is released through dietary intake and protein breakdown. Besides being a structural amino acid in proteins, L-arginine is utilized as a precursor for nitric oxide (NO) synthesis. Nitric oxide synthases, a family of enzymes, use L-arginine as a substrate for the generation of NO. NO is known to function as a neurotransmitter, a vasodilator and a mediator of host defense [32•]. Patients with malignancies, including those with head and neck cancers, are known to have decreased plasma concentrations of arginine at the time of presentation. This relatively decreased serum level of arginine is thought to be due to the metabolic changes that accompany cancer cachexia. These metabolic changes are caused by anorexia, altered muscle and visceral protein synthesis and breakdown, and increased gluconeogenesis .
Studies of arginine supplementation demonstrate its benefit in treating a variety of medical conditions . Research that specifically evaluated arginine supplementation in HNSCC patients consistently found that it was well tolerated by patients without any significant adverse effects [34–37]. The use of arginine improved overall survival and decreased local recurrence, particularly if the patients were severely malnourished at the time of presentation . De Luis and co-workers found that peri-operative arginine supplementation in HNSCC patients significantly decreased the incidence of postoperative fistula formation (17.6% to 5.2%, p = 0.026) and decreased the overall postoperative length of stay (36.1 ± 27 days to 24.3 ± 14 days, p = 0.036) [35••]. An equally important finding in this study was that no change occurred in the number of infectious complications between the treatment and control groups. Numerous other studies looking at immune-modulating tube feeding formulations also demonstrated that they resulted in fewer postoperative infections in a variety of enteric tract operations, including head and neck operations, but it is not clear from these studies whether the effects were due to the arginine, or another compound or combination of compounds contained in the formula .
The optimal timing of arginine administration is not yet known. Studies by Buijs and de Luis demonstrate benefit in both preoperative and postoperative arginine administration, but currently, no studies compare the outcomes to determine whether one method is more beneficial than the other. In theory, HNSCC patients would likely benefit from both administration strategies, since many of these patients are malnourished and therefore likely to be arginine deficient at presentation. In research utilizing animal models, surgical trauma lead to systemic arginine depletion [39••]. Therefore, supplementing arginine pre- and postoperatively would allow for the repletion of arginine, as well as the maintenance of serum levels.
The exact mechanism through which arginine supplementation improves clinical outcomes is not known. It is postulated that the arginine leads to an increased level of nitric oxide at the tissue level, thus allowing for local vasodilation leading to improved circulation at the surgical site, and thereby supporting the increased local metabolism demanded by wound healing. Additionally, immune cell function appears to be augmented. T cells and neutrophils utilize arginine as a substrate and have enhanced cancer cell killing potency [40, 41]. This enhanced immune function may be what causes the decreased locoregional occurrence that is observed with arginine supplementation.
Glutamine, in addition to being a structural amino acid in proteins, has long been recognized as a primary fuel source for lymphocytes and enterocytes, and as a precursor for glutathione. More recently, studies found that it induces heat shock protein production and also reduces inflammatory cytokine expression . Similar to arginine, glutamine is generally not an essential amino acid, but HNSCC patients who are chronically malnourished may have low stores of this amino acid.
Two studies have evaluated the use of glutamine supplementation to improve treatment tolerance in HNSCC treatment. Cercheitti and coworkers used an intravenous glutamine source and were able to demonstrate that it led to a decrease in the severity of mucositis experienced by patients undergoing external beam radiation therapy . There is not enough current evidence to recommend the routine use of glutamine to prevent mucositis since the available data are somewhat inconclusive; a meta-analysis by Stokman and co-workers did not find any significant benefit with glutamine supplementation . However, there is also no evidence that glutamine supplementation is associated with negative outcomes or is harmful.
Omega-3 Fatty Acids
Lipids are utilized by the body in a variety of functions, ranging from the structural basis of cellular membranes to intra- and intercellular signaling. The human diet has two main classes of essential polyunsaturated fatty acids: omega-3 and omega-6 fatty acids. Omega-6 fatty acids are primarily from plant sources, while omega-3 fatty acids are mostly commonly found in marine sources, such as fish and krill. Fish oils contain a relatively large amount of omega-3 polyunsaturated fatty acids. The two fatty acids with the highest abundance in fish oils are eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively). While omega-6 fatty acids (such as α-linoleic acid) can be converted into proinflammatory compounds, omega-3 fatty acids can be converted into anti-inflammatory mediators.
Supplementation of omega-3 fatty acids is considered beneficial in a wide range of disease processes. Unfortunately, few studies directly evaluate the benefit of omega-3 fatty acid supplementation in HNSCC patients. Benefits are therefore largely extrapolated from studies that evaluated the effects of omega-3 fatty acid supplementation on a variety of other oncologic and surgical conditions. There is a belief that many of these benefits are also afforded to patients undergoing HNSCC treatment [43–46]. Some of these identified benefits include decreased ICU and hospital length of stay, reduced mortality and attenuation of markers of inflammation. Omega-3 fatty acid supplementation was also found to protect lean body mass following esophageal surgery .
In HNSCC treatment specifically, omega-3 fatty acid supplementation is associated with decreased wound infections, inflammatory cytokine release and an increase in the lean body mass in postoperative patients . Thus far, no reports exist of negative outcomes or complications attributable to omega-3 fatty acid supplementation. Therefore, omega-3 fatty acid supplementation appears to be safe.
Lycopene is a potent, natural antioxidant belonging to the carotenoid family. Unlike many other carotenoids, lycopene cannot be converted into vitamin A by the body. A variety of fruits and vegetables contain lycopene, but the highest concentrations are found in tomatoes, guava and watermelon.
Utilizing a case-control methodology, De Stefani and coworkers demonstrated that a lycopene-rich diet was protective against the development of oropharyngeal cancers . Several other groups have studied lycopene supplementation as a way of decreasing the incidence of mucositis in those HNSCC patients who undergo external beam radiation therapy. Thus far, the most supportive data for lycopene protecting against radiation injury has been in animal studies, where lycopene supplementation decreased weight loss and overall oxidative stress in an animal model of external beam radiation therapy . Lycopene appears to function as an antioxidant and reduces the oxidative stress imparted by the radiation therapy, but fortunately does not appear to impart a protective effect to the cancer cells. However, more studies are required to demonstrate efficacy and safety in the setting of HNSCC treatment before supplementation can be recommended for HNSCC patients.
Based upon some of the studies highlighted above, several commercially available enteral formulas now incorporate immunomodulating compounds, such as arginine, glutamine, omega-3 fatty acids and antioxidants, in an attempt to affect clinical outcomes. Overall, the benefits of each additive appear to be retained when administered in a pre-made formula containing other immunomodulating compounds . Most biologic systems do not work in isolation and in fact, some of these compounds appear to work synergistically, thereby potentiating the beneficial effects of the immunomodulation .
The available literature supports the use of immunomodulating formulas, in both the preoperative and postoperative setting, in a variety of medical conditions. In cases of head and neck squamous cell carcinoma, immunomodulating enteral formulas have been shown to impact patient outcomes by decreasing hospital length of stay, infection rates, and overall burden of inflammatory cytokines [51, 52•, 53•].
Head and neck squamous cell carcinoma patients benefit from aggressive nutritional therapy beginning at the time of diagnosis. With this intensive support, patients can experience overall improved outcomes and tolerance to the therapies required to effectively treat and cure head and neck squamous cell carcinomas. Use of perioperative immunomodulating enteral feeds is highly encouraged in order to improve outcomes for patients undergoing treatment for head and neck squamous cell carcinoma.
No potential conflicts of interest relevant to this article were reported.