Print version ISSN 0212-1611
Nutr. Hosp. vol.27 no.3 Madrid May-June 2012
Immunoenhanced enteral nutrition formulas in head and neck cancer surgery; a systematic review
Fórmulas de inmunonutrición enteral en la cirugía del cáncer de cabeza y cuello; una revisión sistemática
P. Casas Rodera1, D. A. de Luis2, C. Gómez Candela3 and J. M. Culebras4
1Department of Otorhinolaryngology. Complejo Asistencial Universitario de León. León. Spain.
2Medicine School and Unit of Investigation. Institute of Endocrinology and Nutrition. Hospital Rio Hortega. University of Valladolid. Valladolid. Spain.
3Department of Clinical Nutrition. La Paz University Hospital. Madrid. Spain.
4Department of General Surgery. Complejo Asistencial Universitario de León and Institute of Biomedicine (IBIOMED). University of León. León. Spain.
Introduction: Significant malnutrition exists in a high percentage of patients with head and neck cancer. Malnutrition is associated with defects in immune function that may impair the host response to malignancy. Malnutrition and immunosupression make patients highly susceptible to postoperative infections and complications.
Objectives: Some studies of patients receiving immuno-nutrition in the perioperative period in head and neck cancer have shown beneficial effects on clinical outcome and inmune status. The authors carried out a systematic review of randomised control trials to determine whether perioperative immunonutrition has a role in the treatment of head and neck cancer.
Methods: 14 trials of polymeric nutritional supplementation with immunonutrition were identified. Two studies compared two types of immunonutrition.
Results: A reduction in the length of postoperative hospital stay was seen in some trials, but the reason for this reduction is not clear. Some studides showed statistical differences with less complications in arginine-enhanced group and also showed a significant decrease of fistula complications in patients treated with a high arginine dose enhanced formula, if compared with a medium dose of arginine.
Conclussion: Those planning future studies face challenges. A suitable powered clinical trial is required before firm recommendations can be made on the use of immunonutrition in head and neck cancer patients posto-peratively.
Key words: Immunonutrition. Arginine. Head and neck cancer. Enteral nutrition. Surgery.
Introducción: Un alto porcentaje de pacientes con cáncer de cabeza y cuello presentan un importante grado de malnutrición. Esta malnutrición está asociada defectos de la función inmune. Tanto la malnutrición como la inmunosupresión hacen a estos pacientes susceptibles de padecer complicaciones infecciosas en el postoperatorio.
Objetivos: Algunos trabajos de pacientes que han recibido inmunonutrición en el postoperatorio de cirugía por cáncer de cabeza y cuello han mostrado un efecto beneficioso en la evolución clínica y el estado inmune. Los autores han llevado a cabo una revisión sistemática de los ensayos clínicos realizados hasta la fecha, para determinar el papel que tiene la inmunonutrición enteral postoperatoria en el tratamiento del cáncer de cabeza y cuello.
Métodos: Se identificaron 14 trabajos en los que se habían utilizado fórmulas de inmunonutrición. Dos trabajos compararon dos tipos de inmunonutrición. Resultados: En algunos trabajos se observó una disminución en los días de estancia hospitalaria, aunque la razón para ello no está clara. Algunos estudios mostraron diferencias significativas con menos complicaciones en los grupos que recibieron nutriciones enriquecidas, presentando una disminución significativa en el número de fístulas en pacientes tratados con nutriciones con altas dosis de arginina, si se compara con una nutrición con una dosis media de arginina.
Conclusión: Los futuros trabajos presentan retos. Es necesario un ensayo clínico extenso, para poder realizar recomendaciones firmes sobre el uso de la inmunonutrición en el postoperatorio de pacientes intervenidos de cáncer de cabeza y cuello.
Palabras clave: Inmunonutrición. Arginina. Cáncer de cabeza y cuello. Nutrición enteral. Cirugía.
Significant malnutrition exists up to 35-50% of patients with cancer of the head and neck1. Many factors contribute to malnutrition in this patient population, including poor dietary practices, alcoholism, catabolic factors secreted by the tumor, such the cytokines tumor necrosis factor-α (TNF-α), interleukins (IL), and gamma-interferon, local tumor effects, anorexia, cancer-induced cachexia, and treatment effects2. Patients undergoing surgery because of a head and neck malignancy have a 20-50% incidence of postoperative complications3. These complications include major wound infections, fistula, anastomotic leakage, respiratory insufficiency, and septicaemia and may lead to not only a prolonged hospital stay but also a poorer prognosis. Several factors may contribute to this morbidity, one of which is malnutrition4.
Malnutrition is associated with defects in immune function that may impair the host response to malignancy5. The alterations in the host defence mechanism make patients highly susceptible to postoperative infections. Multiple components of the diet may affect immune function. There is evidence that giving patients perioperative nutritional supplements with immunonutritional additives can favourably modulate the immune and inflammatory response both in vitro and in patients with trauma, burns or those undergoing oncological surgery6. In particular, the important role of amino acids, dietary nucleotides, and lipids in modulating immune function has been recognized7. Arginine is a semiessential amino acid and the store can become depleted in times of stress. It plays an important role in T- and B-cell immunity as well as in the production of nitric oxide. Arginine is able to reduce the production of inflammatory mediators such as IL-1 beta, IL-6, and TNF-α at the site of injury in rat septic models8 and can accelerate tissue growth after trauma or infection9. Dietary supplementation with arginine has positive effects on immune function and reparative collagen synthesis10. Nucleotides are the building blocks of DNA and RNA and are derived from RNA in the diet. Nucleotide restriction is associated with a significant increase in mortality in a murine model of Candida sepsis11. RNA supplementation is essential for the proliferation of immune cells or cells involved in wound healing and greatly increases the survival rate of infected animals12. Dietary nucleotides, particularly the pyrimidine uracil, also appear to be essential to the normal lymphocytes maturation. Diets high in n-6 polyunsaturated fatty acids (PUFA) such as linoleic acid are associated with the production of arachidonic acid metabolites (prostaglandin E2 and leukotriene B4) with adverse effects on immune function13. Diets high in n-3 PUFA derived from fish oils, however, result in the substitution of prostaglandins of the dienoic series (PGE2) by prostaglandins of the trienoic series, with different biological activities and physiological effects14.
Omega-3 fatty acids are long-chain polyunsaturated acids that appear to have anti-inflammatory effects, possibly by interference with macrophage eicosanoid production15. They play a role on the structural and functional integrity of the cell membrane, intercellular signal transduction, and synthesis of eicosanoids. In particular, they influence the production of prostanoids from the dienoic to the trienoic variety, the later of which are much less immunosuppressive16. By replacing other fatty acids with omega 3 fatty acids, membrane flexibility is enhanced, which is essential for phagocytes17. Decrease of proinflamatory cytokines, such as Il-1β, IL-6, IL-8, and TNF-α has been found in patients with sepsis18.
It is reported that cancer patients receiving immuno-nutrition perioperatively tended to have fewer postoperative complications19.
Some studies of patients receiving immunonutrition in the perioperative period in head and neck cancer have shown beneficial effects on clinical outcome and inmune status. The authors carried out a systematic review of randomised control trials to determine whether perioperative immunonutrition has a role in the treatment of head and neck cancer.
Eligibility criteria and literature search
Clinical trials were eligible if patients undergoing head and neck surgery for cancer had been randomly allocated to be in a control group receiving either traditional care (i.v. fluids) or polymeric nutritional supplements and an interventional group receiving polymeric nutritional supplements with immunonutritional additives. The MeSH terms used were: head and neck neoplasms, enteral nutrition, immune, arginine, immu-nonutrition, surgery. Papers were identified by computerised searches of PubMed.
Data extraction and outcomes
Data were collected on age, sex, weight, body mass index, energy intake, duration of supplementation, the type of surgery, The outcomes recorded included biochemical changes, immunological changes, wound infections, fistula formation, mortality, and length of postoperative hospital stay.
Through data base searches, 2,017 references were identified. After applying limits of humans and clinical trial 232 were retrieved, after exclusion of duplicates and irrelevant references, 14 were retrieved. The remaining references described 14 trials that fulfilled the inclusion criteria and could provide data for review.
Characteristics of trials, patients and interventions
Fourteen randomised controlled trials published between 1999 and 2010 were identified with a total of 836 patients all undergoing surgery for head and neck cancer (tables I and 2)20-34. Twelve trials compared polymeric feeds with immunonutrition20-21,23-33 and two trials compared two types of immunonutrition started at hospital discharge22,34.
Table III illustrates baseline patient characteristics. All studies used isocaloric and isonitrogenous feed regimens.
Wound infection and fistula formation
The effects of immunonutrition on wound infections and fistula formation are detailed in table IV. Occurrence of wound infection was reported in five trials. The risk of wound infection ranged from 0% (0/45) to 4.8% (4/82) in immunonutrition fed groups and from 0% (0/45) to 12.5% (3/24) in control groups. The effects of immunonutrition in malnourished patients could only be ascertained from the study by RISO et al.27, where 13 patients were considered malnourished. These patients had reduced wound infections when given immunonutrition (p < 0.05). (tabla V)
Occurrence of fistula formation was reported in nine trials and ranged from 0% (0/23) to 5% (4/82) in immunonutrition fed groups and from 0% (0/38) to 18.9% (7/37) in control groups.
Mean postoperative hospital stays were long (table IV) with broad standard deviations. De Luis et al.23 reported a significant (p < 0.05) reduction in postoperative stay, 25.8 days versus 35 days in intervention and control groups, respectively. RISO et al.27 reported a reduced hospital stay in the intervention group (p < 0.05).
The trials examined reported on a broad range of biochemical and immunological parameters including interleukin-6, tumour necrosis factor-a, C-reactive protein, T-cell subsets and total lymphocyte counts. Riso et al.27 demonstrated an increase in total lymphocytes, CD4 and CD4/CD8 ratio on postoperative day 4 (p < 0.05).
Malnourished patients (n = 13) in the study by Riso et al.27 showed reduced preoperative immune status in some variables (CD4, CD4/CD8, IgA, IgG), with some parameters (CD4, CD4/CD8) increasing postoperativly compared with baseline but not between the two groups.
Casas-Rodera et al.31 showed no significant inter-group differences in the trend of the two plasma proteins, lymphocytes and weight. In the three groups that were compared there was a significant decrease of the transferrrin at the seventh postoperative day, in relation to preoperative levels, with a significant increase only in the enriched diet groups, at the fourteenth postoperative day. The control group showed the lower levels of lymphocytes at the seventh and fourteenth postoperative day. The control group showed the highest levels of TNFa at the fourteenth postoperative day.
Long-term survival and locoregional recurrence
Buijs et al.32 showed that the median overall long-term survival was 34.8 months in the arginine-supplemented group and 20.7 months in the control group (P = 0.019). Disease-specific survival was 94.4 months in the arginine-supplemented group and 20.8 months in the control group (P = 0.022). Locoregional recurrence occurred in 4 of the 17 patients in the arginine group and in 9 of the 15 patients in the control group.
The authors examined 14 trials that investigated the effects of immunonutrition in patients treated surgically for head and neck cancer. Where stated, all the studies looking at in-hospital postoperative nutrition used arginine as an immunonutrient, including a trial that studies the benefits of a high dose of arginine as a postoperative nutrition of head and neck cancer patients34.
A reduction in the length of postoperative hospital stay was seen in some trials, but the reason for this reduction is not clear. Lenght of hospital stay was reduced in six studies. Overall reduction in these studies conrresponded to about a 3.5 day, which is clinically and economically important. In two studies, fistula formation was more common in those patients receiving immunonutrition, yet length of hospital stay was reduced27-28.
Regarding the local complications, occurrence of fistula formation was reported in nine trials; in 5 trials20,23,25,33,34 decrease in fistula rate was detected and no effect was detected in 4 trials21,27,28,31. Luis et al. showed statistical differences with less complications in arginine-enhanced group20,23,25, and also showed a significant decrease of fistula complications in patients treated with the high arginine dose enhanced formula, if compared with a médium dose of arginine34. In this study, length of stay was similar in both groups, the presence of arginine in both groups could explain this fact. Perhaps, these differences in the literature could be explain by the diffent doses of arginine used.
Snyderman et al.28 demonstrated that a perioperative nutritional supplementation with an immune-enhancing formula was superior to standard formula in the prevention of postoperative infectious complications. There was no significant difference in wound healing problems or duration of hospitalization.
Riso et al.27 confirmed that an enteral diet supplemented with arginine in the early postoperative period improved postoperative immunological status and speed up recovery from the imunodepression following surgical trauma. On malnourished patients of this study, administration of an enriched formula reduced major postoperative complications and length of postoperative stay significantly.
Felekis et al.33, showed that the rate of complications was significantly reduced in the total number of patients receiving immunonutrition and in the particular subgroup of well-nourished patients receiving an immunoenhanced diet.
Buijs et al.32 showed that a nutritional intervention with arginine -enriched nutrition before and after surgery may improve survival.
Casas-Rodera et al.31 compare two immunoenhanced enteral nutritions with a control diet, and they found that the only general infection appeared in the control group. Wound infections tended to be also less frequent in the groups with enriched diets. Snyderman et al.28 said that it was interesting to note that the increased number of infectious complications that were observed in the control group (standard formulas) was mostly due to infections at distant sites (lungs, urinary tract, etc.) rather than operative wound infections. This finding implies that most operative wound infections and fistulas have different risk factors and may be attributable to surgical technique rather than depressed immune function. This result may explain why in our study, fistulas were more frequent in one of the groups with enriched diet (Group I). Fistulas, do not seem to relate exclusively to infectious processes, and thus to immunosuppression. Indeed, technical problems and nutritional status might play an equally important role, even independent of the immune status, and therefore we might have overestimated the positive effect of immunonutrition35.
Based on these results, those planning future studies face challenges. There is little evidence from the randomised controlled trials reviewed here to guide the choice of intervention, patient groups or the value of preoperative supplementation. Clinically important end-points such as fistula formation, wound infection and pneumonia should be addressed. Any reduction in length of hospital stay needs to be explained. A suitable powered clinical trial is required before firm recommendations can be made on the use of immunonutrition in head and neck cancer patients postoperatively.
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Pablo Casas Rodera.
Department of Otorhinolaryngology.
Complejo Asistencial Universitario de León.