Download A. Perioperative arginine-supplemented nutrition in malnourished

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.