ONC: Surgery (2006-2007)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

Patients with head and neck cancer undergoing surgery have a high incidence of postoperative complications which include anatomotic fistula, wound infection and septicemia.  The immune system is frequently affected in these patients.  Complications can lead to a long length of stay.  Hypothesis: Specific nutritional substrates such as arginine may improve immune function and reduce postoperative complications.  Purpose:

  • Investigate whether postoperative nutrition of head and neck cancer patients, using an immunonutrition diet, could improve nutritional variables as well as clinical outcomes, postoperative infections, wound complications and length of stay, when compared with an isonitrogenous, isocaloric control enteral diet.
Inclusion Criteria:
  • Men and  women diagnosed and staged with oral and laryngeal cancer undergoing surgery in 2 hospitals in Spain.
    • Baseline: complete history and physical exam.  General assessment of nutritional status with height, wt and BMI.
Exclusion Criteria:
  • severely impaired hepatic function ( total bilirubin concentration > 3.5 mg /dl)
  • severely impared renal function (serum creatinine concentration > 2.5 mg/dl)
  • ongoing infections
  • autoimmune disorders
  • steroid treatment
  • oral nutritional supplementation in the past six months
  • weight loss >10% of body weight
Description of Study Protocol:

Recruitment Not noted.  Appeared to be men and women who met inclusion/exclusion criteria treated at one of two Spanish hospitals

Design Randomized clinical trial carried out from March 1999 to July 2001

  • 47 patients enrolled with mean age 61.4=/-11.7 y (5 females/42 males)  n=23 in supplemented diet group (Gr I)  and n=24 in control group (Gr II). 
  • No significant differences in gender, mean age, body weight, BMI, location and stage of tumor between Gr I and Gr II
  • Similar % preoperative weight loss of 5.7% (Gr I) vs 4.8% (Gr II)
  • Same oral intake ( Gr I 1502=/-343 vs Gr II 1491 =/-323)  
  • Same distribution of surgery in Gr I and Gr 2   
  • Same treatment for Gr I and Gr II with exception of supplemented diet.  Looked at albumin, prealbumin, transferrin, lymphocytes, wt, postoperative infection complications, incidence of fistula, wound infection, GI problems related to enteral feeding, length of postoperative stay and mortality. 
  • post-operative complications assessed using "standard methods" and same investigator.

Blinding used (if applicable) Method of randomization at surgery not described.  Main investigator and patients remained blind to the treatment group.

 

Intervention (if applicable)

  • After baseline measurements were taken, Group I received immunonutrition enteral formula supplemented with arginine and dietary fiber. 
  • Group II received standard enteral formula 
  • Two enteral supplements almost exact except:
    • Gave 0.624 g Free L-arginine/100 ml and 0.9 g dietary fiber/100 ml (dietary fiber: oligofructose, inulin, soy polysaccharide, resistant starch, arabic gum and cellulose) enteral feeding to Group I.  
    • Standard enteral supplement did not contain added arginine or fiber. 
  • Feeding started within 24 hours of surgery for both groups at rate of 20/ml/h, via an intraoperatively placed nasogastric tube.  Infusion rate increased every 24 h until daily nutritional goal (32 total kcal/kg 1.7 g protein/kg) was reached on postoperative day 4.   Endpoint of nutritional support was minimum oral intake of 1500 kcal/day and 1g/kg/day of protein without supplementation with a minimum of 10 days of enteral support.  (Table 1 on p. 1127 of study shows composition of enteral feedings.)
  • Medicines provided: prophylactic antibiotic treatment given for 7 days postoperatively (deftazidime, 500 mg TID i.v. and clyndamicine 200mg  TID iv.)

Statistical Analysis:

  •  Sample size calculated to decrease fistula complication by 20% with 80% power and 5% significance.
  • Intention to treat with p<0.05 significance
  • Results shown as average +/- standard deviation
  • Distribution of variables analyzed with Kolmogorov-Smirnov test
  • used two-tailed paired or unpaired Student's t-test as needed on quantitative variables with normal distribution and ANOVA
  • Non-parametric variable analyzed with Friedman and Wilcoxon tests.

 

 

Data Collection Summary:

Timing of Measurements

  • Perioperatively, postop day 7 and 14:  weighed participants and drew fasting serum albumin (3.5-4.5g/dl), prealbumin(18-28 mg/dl), transferrin (250-350mg/dl), lymphocytes 1.2-3.5 10 3),  with an autoanalyzer
  • Not noted but calorie counts must have been done for kcals  and  protein to have been evaluated for minimum oral intake and end of nutriton support as well as ability to indicate that all patients reached 100% of calculated requirements.  
  • post-operative infection: measured immediately after surgery
  • As indicated by standard measures: respiratory tract infection, urinary tract infection, fistula and/or wound infection, GI problems related to enteral feeding (diarrhea ?5 liquid stools in 24 period or volume >200ml/day) 
  • mortality assessed 3 months after hospital discharge 

Dependent Variables

  • Variable 1: nutritional variables (Fasting serum albumin, prealbumin, transferrin, lymphocytes  and wt)
  • Variable 2: GI tolerance ( diarrhea)
  • Variable 3: mortality
  • Variable 4: postoperative infection
  • Variable 5: fistula
  • Variable 6: frequency of wound infection
  • Variable 7: length of postoperative stay 

Independent Variables:  arginine supplemented enteral feeding

Control Variables: standard enteral feeding

 

Description of Actual Data Sample:

Initial N: 47 ( 5 women/42 men)

Attrition (final N): 42: 5 died during 3 months after discharge (10.6% attrition) NS differences between Gr I and Gr II (13% vs 8.3%)

Age: mean: 61.4=/-11.7 y  Gr I 63.15 =/- 12.7  Gr II 59.3 =/- 10.5

Ethnicity:  not noted

Other relevant demographics:  more nutritionally repleted than previous studies ( < 10% wt loss vs > 10%)

Anthropometrics (e.g., were groups same or different on important measures)  No, no statistical differences.  See reviewers comments below.

Location:  Medicine School and Hospital Rio Horteg, Spain and Hospital Clinico, University of Valladolid, Valladolid, Spain

 

Summary of Results:

 

Variables

Treatment Group

Measures and confidence intervals

Control group

Measures and confidence intervals

Statistical Significance of Group Difference

Dep var 1:nutrition variables (albumin, prealbumin, transferrin, lymphocytes, wt) 

p<0.05

not noted

p<0.05

not noted

 NS

Dep var 2:GI tolerance to feeding

p< 0.05

17.4%

p< 0.05

8.3%

NS

Dep var 3: mortality

 

Dep var 4: Post op infection complication

 

 

Dep var 5: fistula

 

 

Dep var 6: wound inf

 

 

Dep var 7:  Hospital LOS

p< 0.05

13%

p< 0.05

21.7% 

 

 p< 0.05  

0%  

 

p< 0.05  

4.3%

 

p< 0.05  

22.8+/-11.8 days

 

p< 0.05

8.3%

p< 0.05

16.7%

 

p< 0.05

 20.8% 

 

p<0.05

12.5%

 

p< 0.05  

31.2+/-19.1  days 

NS

 

NS                

 

 

p<0.05

 

 

NS

 

 

NS

p=0.07

 

Other Findings: Note: average post operative  tube feeding was similar in both groups with average duration of 22+/-12 days ( No analysis given)

Author Conclusion:

With better nourished patients ( < 10% weight loss vs > 10% wt loss) than previous studies,:

  •  nutritional parameters improved with both standard and immune-enhancing formula (p<.050) so did not prove immunonutrition diet did it alone
  • wound complications were lower (fistulas p<0.05) in experimental group
  • NS difference in other parameters
  • Concluded that patients could benefit from an arginine and fiber enhanced enteral formula.  Enriched formula improves local wound complications (fistulas) in head and neck cancer patients.
Funding Source:
University/Hospital: Unversity of Valladolid (Spain), Institute of Endocrinology (Spain)
Reviewer Comments:
  • controlled for many factors well
  • study looked at less nutritionally compromised patients than previous studies and fed them longer postoperatively ( 22 days versus 9 in Van Bokhorst-de van der Schueren et al, 2001)
  • conerned about counfounding factor of use of supplemental enteral feeding with both fiber and arginine.  Difficult to separate impact fiber had versus no fiber. 
  • Diarrhea was higher in supplemental group even though NS.  Arginine is noted to have possible impact on increasing diarrhea.  Authors did not address. 
  • possibility that start of nutritional support within 24 hours as well as length of time patients were on nutrition support contributed to improvement in nutritional parameters.  ( However, last measurement of nutritional parameters were at postoperative day 14 versus mean of 22 days on supplemented feeding). 
  • question validity of serum albumin as a true indicator of nutritonal status due to half-life.  Measurements did not go out far enough in time to pick up (last measurement 14 days post operatively)
  •  Limited ability to generalize since only patients treated in Spain
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) ???
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? ???
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? ???
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? No
  7.6. Were other factors accounted for (measured) that could affect outcomes? ???
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? ???
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? N/A
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? ???
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? ???
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes