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Journal Club Presentation Outline I. II. III. April 3rd, 2012 Introduction A. Perioperative arginine-supplemented nutrition in malnourished patients with head and neck cancer improves long-term survival Authors: Nikki Buijs, Marian AE van Bokhorst-de van der Schueren, Jacqueline AE Langius, C Rene Leemans, Dirk J Kuik, Mechteld AR Vermeulen, and Paul AM van Leeuwen B. Effect of preoperative immunonutrition and other nutrition models on cellular immune parameters Authors: Yusuf Gunerhan, Neset Koksal, Umit Yasar Sahin, Mehmet Ali Uzun, Emel Eksioglu-Demiralp C. Presented by Amrie Weiss Background A. Purpose: To study the “long-term overall survival, the long-term disease specific survival, locoregional recurrence, distant metastases, second primary tumors, and the (possible) cause of death of head and neck cancer patients.” i. Arginine-enriched nutrition is known to improve short-term outcomes such as local wound complications, fistula rates, length of hospital stay ii. the long-term effects of arginine supplementation have not yet been studied B. Rationale: It is possible to prevent malignant progression during the initiation and promotion phases of cancer. After surgical removal of malignant tumors, the proliferation of remnant cells may be comparable to the initiation and promotion phases of carcinogenesis. Low levels of arginine can contribute to immunosuppression, suggesting a possible benefit of supplementation. C. Significance: The long-term effects of arginine-enriched nutrition may augment specific and non specific antitumor mechanisms, such as retarding tumor growth and prolonging survival. The authors of this study state their study was the first to show a nutritional intervention with arginine-enriched nutrition before and after surgery may improve survival. Methodology A. Design of the experiment/trial: 1. Prospective, randomized, double-blind, controlled clinical trial B. Population/sample: 1. N= 32 (Arginine supplementation N=17; control N=15) 2. Subject Criteria: a. Inclusion: all subjects had a diagnosis of a histologically proven squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx. They each were undergoing head and neck surgery and were determined malnourished based on the definition of weight loss >10% over the past 6 months. b. Exclusion: Recipients of other investigational drugs or steroids; renal insufficiency; hepatic failure; any genetic immune disorder; confirmed AIDS diagnosis. C. Treatment allocation 1. The subjects were stratified for type of surgery (combined mandibular resection or total laryngectomy) and by previous radiation history. They were then randomly assigned to either the arginine supplement group or control group. 2. This sample is representative of a large portion of, yet not the entirety of the total population, as 35-50% of all head and neck cancer patients are malnourished. If referring to nutrition support in cancer as a whole, there may be different outcomes. 3. Enteral intake was based on 1.5 x BEE using actual body weight. They were allowed to take PO in addition preoperatively and 10 days postoperatively after a swallow evaluation. The arginine enhanced formula was discontinued after 10 days; it pt still needed tube feedings, the standard formula was given. 4. The control group was assigned randomly and did not statistically differ from the intervention group based on age, sex, tumor stage, tumor localization, co morbidity, weight loss, type of operation, and type of reconstructive surgery. 5. The final data was collected in 2007, 10 years after the conclusion of the study. There were not any drop-outs from this study. D. Data Collection 1. Survival or Death i. cause of death categorized with 1-3 as disease specific causes of death: ii. 0=alive iii. 1= in-hospital death iv. 2= death from recurrent cancer v. 3= death from second primary tumor vi. 4 = death other than cancer related 2. Occurrence of locoregional reoccurrence 3. Occurrence of distant metastases 4. Occurrence of second primary tumors E. Outcome Measurements 1. Events expressed as months after surgery date F. Statistical analysis (p<0.05) 1. Kaplan-Meier Method i. Estimates survival function from lifetime data ii. Figure 1: “Overall survival of severely malnourished patients with head and neck cancer after surgery” iii. Figure 2: “Locoregional recurrence-free survival…” 2. IV. Log-rank tests to compare the control group and arginine group i. Used to establish the efficacy of a new treatment compared to a control treatment when the measurement is the time to event (from surgery to time to death) 3. Cox Regression i. Estimates relative risk (in relation to time: chances of survival decrease with each month of age) ii. Confounding and effect modification: to exclude the influence of TNM stage, margins, lymph nodes, preoperative weight loss, sex and age on survival iii. N state was greatest confounder, followed by weight loss and T stage iv. Differences between groups remained significant (p=0.031) 4. Crude Hazard Ratios (HRs) computed with Cox Regression i. Higher number associated with higher risk or influence ii. Used to bring the effect of arginine supplementation into perspective iii. Tabulated for grouping variable, several well-known RFs (such as tumor size, metastases, weight loss, etc) Article Results A. Data collected 10 years post-study (2007) 1. Not all means and standard deviations reported. 2. All 15 of control patients had died 3. (14/17) arginine group patients had died 4. (16) deaths due to recurrent cancer (locoregional reoccurrence and/or distant metastases) i. locoregional-specific survival (p=0.010), even more pronounced with cofounders accounted for 5. (4) deaths due to secondary primary tumor 6. (3) in-hospital deaths within 30 days of surgery 7. (6) deaths due to causes other than cancer 8. Median overall long-term survival was significantly higher in the arginine group than in the control group (p=0.019) i. 34.8 mo (arginine) ii. 20.7 mo (control) 9. Disease specific survival significantly higher in arginine group (p=0.022) i. 94.4 mo (arginine) ii. 20.8 mo (control) V. Article Conclusion A. There is a plausible correlation between arginine and immunological defense which showed an increase in survival of malnourished head and neck surgical cancer patients B. Arginine-derived NO may help to activate intact p53 genes post-surgically, (imitating the initiation and promotion phases of carcinogenesis) and activate the immune system to clear the remaining “field” of residual cells VI. Secondary Article A. Similarities 1. perioperative immunonutrition supplementation 2. surgical cancer patients (although GI) 3. all subjects malnourished B. Differences: 1. shorter period of nutrition supplementation (7 days pre-op) 2. contained fatty acids and nucleotides in addition to arginine 3. Negative study (no significant difference in T cells, duration of hospital stay, postoperative complications) 4. Although they saw a significant difference in prealbumin levels in the immunonutrition group, another study in head and neck cancer patients did not produce the same results VII. Presenters’ Conclusion A. Strengths 1. Valid study design 2. Control methods for confounding variables in statistical analysis 3. Statistically significant results in survival rates of the arginine-enhanced group 4. Single nutrient supplementation 5. Homogenous patient groups 6. Long-term follow-up B. Limitations 1. small sample size 2. all subjects malnourished 3. minimal reporting of raw and/or tabulated data 4. not powered to rule out lifestyle factors C. Benefit of immunonutrition requires further investigation 1. Results must be reproducible 2. Questionable use in the ICU/trauma (questionable benefit; increased mortality with sepsis) 3. Concerns for promotion of tumor growth in some cases VIII. Questions/Discussion A. ASPEN Guidelines: 1. Specialized nutrition support may be beneficial: i. in moderately to severely malnourished patients when given 7-14 days preoperatively; must weigh the benefits and risks ii. in patients with inadequate ingestion or absorption of nutrients for a long period of time 2. Specialized nutrition support is not to be used: i. is not to be used routinely in patients undergoing major cancer operations ii. if it will cause a delay in the time of operation (due to recommendation of 7-14 days preoperatively) iii. in addition to chemotherapy or head and neck, abdominal, or pelvic irradiation. 3. The benefit of specific nutrient supplementation (e.g., fish oils) for cancer patients with weight loss and cachexia has not been sufficiently proven. 4. The use of immune-enhancing formulations, both oral and tube fed, is mentioned only in relation to GI surgical cancer patients and has been shown to decrease postoperative and infectious complications and length of stay in comparison to a standard formula. It has also been shown to be cost-effective. B. At what point would you consider arginine-enriched nutrition a standard for malnourished cancer patients? Would you base your decision on ASPEN guidelines or research studies? C. Which factor would be more significant in your decision: increase in long-term survival or increase in nutrition status parameters? D. What further research would you like to see? References Buijis N, van Bokhorst-de van der Schueren MAE, Langius JAE, Leemans CR, Kuik DJ, Vermeulen MAR, van Leeuwen PAM. Perioperative arginine-supplemented nutrition in malnourished patients with head and neck cancer improves long-term survival. Am J Clin Nutr. 2010;92:1151-6. Gottschlick, MM et. al. The A.S.P.E.N. nutrition support core curriculum: a case-based approach—the adult patient. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007. Gunerhan Y, Koksal N, Sahin UY, Uzun MA, Eksioglu-Demiralp E. Effect of preoperative immunonutrition and other nutrition models on cellular immune parameters. W J Gastroenterology. 2009;15(4):467-472.