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Oncology

ONC: Nutrition Status and Outcomes in Adult Oncology Patients (2013)

Citation:

Odelli C, Burgess D, Bateman L, Hughes A, Ackland S, Gillies J, Collins CE. Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophagel cancer. Clinical Oncology. 2005;17:639-645.

PubMed ID: 16372491
 
Study Design:
Non-Randomized Controlled Trial
Class:
C - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
To evaluate a nutrition pathway that promoted early and aggressive dietetic intervention in patients receiving definitive chemoradiation for esophageal cancer.
Inclusion Criteria:
  • Synchronous chemoradiation
  • Most subjects were entered on the Trans Radiation Oncology Group (TROG) trials 89-04, 96-02 or 98-06 during 1990-2001
  • Previously untreated patients
Exclusion Criteria:
None listed
Description of Study Protocol:

Recruitment

Not described

 

Design

Retrospective chart review

  • Control group consisted of historical controls: any patient planned to receive definitive treatment for esophageal cancer from 1990-1996 prior to implementation of the nutrition pathway
  • Nutrition pathway (NP) group consisted of any patient presenting to the esophagel clinic from 1997-2001 who was planned to receive definitive treatment
Intervention

Nutrition Pathway group: Interviewed by RD at initial presentation to the esophageal clinic then weekly throughout chemoradiation courses
  • Initial consultation nutrition assessment
    • Nutrition risk (low, moderate or severe) determined by RD per NP criteria
      • Low risk subjects received information and support to help maintain nutritional status
      • Moderate risk subjects
        • Presence of anorexia/dysphagia and/or unintentional weight loss 5-9%
        • received consistency modified, high protein/high energy diet education
      • Severe risk subjects received PEG or nasogastric (NG) tube placement depending on the treatment week in which risk was identified
        • Severe dysphagia (puree/fluids only) and/or unintentional wt loss > 10% and/or BMI < 18 kg/m2
        • PEGs were placed for severe risk subjects before starting treatment in all cases and instruction for home use was provided.
        • Enteral feeding for both PEG or NG consisted of a 1.5 kcal/ml formula, nutritionally complete in 1690 calories.
        • Regular follow up occurred to assess nutritional status and nutrient prescriptions were adjusted as necessary.
  • Inpatients - Day 1 Chemoradiation Nutrition Assessment
    • Low risk: nutrition education addressing strategies for managing nausea/vomiting and fluid intake
    • Moderate risk: presence of anorexia/dysphagia and/or weight loss 5-9%
      • nutrition education including textured modified, high protein/energy diet and/or managing nausea/vomiting and fluid intake
    • Severe risk: severe dysphagia (puree only) and/or weight loss > 10%
      • PEG placement in the first 3 weeks of chemoradiation
  • Outpatients - Day 8 after chemotherapy
    • Low risk: weight loss < 4 kg in past week, adequate hydration
      • nutrition education reinforcing prior dietary advice
    • Moderate risk: weight loss > 4 kg in past week, dehydration
      • nutrition education addressing adequate fluid intake, strategies for managing nausea/anorexia, high protein/high energy diet (+/- texture modification)
  • Outpatients: weekly nutrition assessment
    • Low and moderate risk: weight stabilized
    • Severe risk: failure to stabilize weight, weight loss > 10%
      • NG tube placement if > 50% of chemoradiation therapy had been provideded
     
       
Control Group
  • Received nutrition support in a reactive manner
  • Referred to RD only as problems arose
  • Nutrition risk (low, moderate or severe) classified retrospectively per nutrition pathway criteria
Planned medical therapy
  • Chemoradiation treatment
    • Cisplatin 80 mg/m2 by IV infusion on day 1 and day 21 (or day 28) plus 5-fluorouracil 800 mg/m2 by continuous infusion on days 22-25 (or days 29-32)
    • Radiation dose of 60 Gy to the tumor-bearing volume and 30 Gy to the regional lymphatics using daily incremental fractions of 2 Gy over 6 weeks.
     
Statistics
  • Categorical variables were analyzed by chi-squared or Fisher's Exact test
  • Differences in continuous variables between groups were compared using Students t-test or Mann-Whitney test, depending on distribution
  • All statistical analyses were two-tailed and a value of P<0.05 was considered statistically significant
  • Statistics package SPSS 10.0 for Windows
Data Collection Summary:

Timing of Measurements

 

Dependent Variables

  • Weight status
  • Percentage of planned treatment delivered
  • Number of unplanned hospital admissions
  • Length of hosital stay during unplanned hospital admissions

Independent Variables

  • Nutrition pathway management

 

Control Variables

 

Description of Actual Data Sample:

Initial N:

Control: n=24

Nutrition pathway: n=24


Attrition (final N):

Control: n=24

Nutrition pathway: n=24


Age: See table below


Ethnicity: Not described


Other relevant demdographics: See table below


Anthropometrics See table below

Location:

Newcastle Mater Misericordiae Hospital, New South Wales, Australia


Comparison of demograpic, oncological and nutritional characteristics

    Nutrition Pathway P value
  (n=24) (n=24)  
% male 67 71 0.77
age (yrs)* 71.9±9.8 66.4±10.9 0.07
Tumor type %      
Squamous 71 71  
Adenocarcinoma 29 29 1.00
Tumor length (cm)* 6.1±2.2 6.3±3.2 0.34
Tumor position %      
Top 17 8 0.79
Middle 17 26  
Lower 58 58  
Esophago-gastric junction 8 8  
% patients w/ dysphagia 92 83 0.38
Usual BMI* 25.5±5.1 27.4±6.1 0.27
% usual wt loss at presentation* 7.3±5.6 7.4±6.3 0.92
Nutrition risk %      
At low risk 21 (n=5) 16 (n=4) 0.47
At moderate risk 25 (n=6) 42 (n=10)  
At severe risk 54 (n=13) 42 (n=10)  
*mean±standard deviation for normal variables

 

Summary of Results:

Timing and Reasons for Initial Dietetic Intervention

  Control Nutrition Pathway P value
  (n=24) (n=24)  
% patients w/ first intervention at:      
First presentation to the unit 38 (9)
96 23)
<0.05
Start of treatment 29 (7) 4 (1)  
During treatment* 33 (8) 0 (0)  
Reason for intervention %      
Dysphagia 100 (24) 83 (20) 0.04
Wt loss 83 (20) 79 (19) >0.05
Anorexia 46 (11) 46 (11) >0.05
Automatic referral per NP 0 (0) 96 (23) <0.05
Referred for other reasons§ 21 (5) 17 (4) >0.05
*Interventions occurred week 2 (n=6), week 3 (n=1), week 7 (n=1).

§Other reasons for referral in control group: enteral nutrition required pre-treatment (n=2), low albumin/diabetes/nausea (n=1 subject each). Other reasons for referral in NP group: enteral nutriiton review as enteral nutrition had been commenced elsewhere (n=1), reflux/social situation/diabetes (n=1 patient each).

  1. Automatic referral as a reason for intervention occurred in 23/24 subjects, highlighting excellent compliance (96%) with the nutrition pathway protocol.
  2. In the control group, 33% of the subjects not seen by a RD until at least the second week of treatment.
Comparison of Enteral Nutrition (EN) Delivered
  Control Nutrition Pathway Pvalue
  (n=8) (n=13)  
% Receiving EN 33 (8/24) 54 (13/24 >0.05
Week EN started 3.6±3.0 -0.31±2.8 0.001
Administration method %      
PEG 25 (2) 77 (10) 0.06
NG 63 (5) 15 (2)  
NG then PEG 12 (1) 8 (1)  
BMI at start of EN* 19.0±3.6 22.3±4.1 0.08
% usual wt loss at start of EN* 17.9±5.5 12.3±4.7 0.02
Problems during EN (%)      
Nausea 38 (3) 46 (6) >0.05
Diarrhea 13 (1) 0 (0) >0.05
Bloating 38 (3) 46 (6) >0.05
Tube blockage 13 (1) 23 (3) >0.05
Vomiting 25 (2) 15 (2) >0.05
Tube dislodgement 13 (1) 0 (0) >0.05
Reflux 13 (1) 15 (2) >0.05
PEG site infection 0 (0) 8 (1) >0.05
Subjects receiving EN by nutrition risk assessment (%)      
Severe 38 (5/13) 100 (10/10) 0.003
Moderate 33 (2/6) 30 (3/10) >0.05
Low 20 (1/5) 0 (0/10) >0.05
*mean±standard deviation for normal variables
  1. In the control group, 13 subjects were assessed retrospectively as "severe nutrition risk", but only 2 received a PEG pre-treatment. In contrast, all 10 subjects in the nutrition pathway group assessed as "severe nutrition risk received a PEG pre-treatment.
  2. There was a significant difference in the timing of EN between the groups; however, the total number of subjects receiving EN was not different.
Comparison of Weight Outcomes
  Control Nutrition Pathway P value
  (n=16) completed (n=22) completed  
% usual wt lost at end of treatment* 16.2±6.8 11.0±4.9 0.04
% wt change during treatment* -8.9±5.9 -4.2±6.4 0.03
% wt change over treatment course/nutrition risk*      
Severe -6.33±6.0 0.38±6.1 0.06
Moderate -11.8±7.6 -8.0±6.3 0.48
Low -9.5±4.4 -6.3±4.9 0.21
*mean±standard deviation for normal variables
  1. Subjects in the nutrition pathway group lost less weight over the treatment period.

Comparison of Chemotherapy Outcomes

  Control Nutrition Pathway P  value
  (n=24) (n=24)  
Treatment received      
2 cycles of cisplatin & 5-FU 92 (22) 83 (20)* 0.33
1 cycle of cisplatin & 5-FU 8 (2) 4 (1)  
1 cycle of cisplatin & 2 cycles of 5-Fu 0 (0) 8 (2)  
Half cycle of cisplatin & 5-FU 0 (0) 4 (1)  
% subjects experiencing chemotherapy delay 71 (17) 67 (16)  
Number of weeks delay§ median 1 (0-3) median 1 (0-3) 0.40
% subjects who had a dose reduction 42 (10) 29 (7) 0.34
% planned cisplatin dose received§ median 100 (50-100) median 100 (5-100) 0.40
% planned 5-FU dose received§ median 100 (50-100) median 100 (50-100) 0.29
* Three subjects had 4 cycles of cisplatin/5-FU, but only the first 2 cycles were included in the analysis
§ Median (range) for non-normal variables
  1. The nutrition pathway had no effect on chemotherapy delivery compared with controls.
  2. There was a trend towards fewer dose reductions in subjects in the nutrition pathway group.

Comparison of Radiotherapy Outcomes

  Control Nutrition Pathway P value
  (n=24) (n=24)  
% subjects completing radiotherapy 50 (12) 92 (22) 0.001
% subjects who had radiotherapy break (those completing treatment) 33 (4/12) 27 (6/22) 0.71
Number of days break (for those completing treatment)* 0 (0-18) 0 (0-13) 0.48
% planned radiotherapy dose delivered* median 95 (37-100) median 100 (60-100) 0.004
% radiotherapy dose delivered/nutrition risk*      
Severe 83 (37-100) 100 (60-100) 0.06
Moderate 100 (58-100) 100 (93-100) 0.20
Low 100 (50-100) 100 (100-100) 0.18
* Median (range) for non-normal variables.
  1. There was a significant difference in the percentage of subjects who completed the planned  radiotherapy course: 92% of the nutrition pathway group compared with 50% of the control group, p=0.003.
  2. the percentage of radiotherapy dose delivered to the nutrition pathway group was also more than the percentage delivered to the control group.
  3. In the control group, 9/12 subjects discontinued treatment because of side effects while only 2 subjects in the nutrition pathway group did not complete treatment (both because of coincidental myocardial infarctions).

Comparison of Hospital Admissions Outcomes

   Control Nutrition Pathway
P value
   (n=24) (n=24)
 
 % patients w/ UHA
75/(18)
46 (11)
0.04
Number of UHA/patient*
median 1 (0-2)
median 0 (0-4)
0.05
Total number UHA/group
24
16
 
Total LOS for all UHA (days)§
13.5±14.1
3.2±5.4
0.002
LOS admission 1 (days)*
median 6.5 (0-52)
median 0 (0-11)
0.002
LOS admission 2 (days)*
median 0 (0-31)
median 0 (0-17)
>0.05
Reason for admission 1: for EN (%)
33 (6/18)
9 (1/11)
>0.05
Reason for admission 2: for EN (%)
17 (1/6)
0 (0/3)
>0.05
Total LOS/nutrition risk (days)§
     
 Severe 16 (0-52)
2 (0-8)
0.006
Moderate
2.5 (0-11)
0 (0-20)
>0.05
Low
16 (0-34)
2 (0-16)
>0.05
* Median (range) for non-normal variables.
§ Mean±standard deviation for normal variables
UHA: unplanned hospital admission; LOS: length of stay; EN: enteral nutrition
  1. Subjects in the control group were more likely to have an unplanned hospital admission (UHA) during the treatment period with 75% of control subjects having a UHA compared with 46% of subjects in the nutrition pathway group (P=0.04).
  2. Although the total number of UHA was not not different betwen the groups (P=0.05), the total length of stay for all UHA was greatly reduced in the nutrition pathway group: 13.5 days (±14.1) for the control group compared with 3.2 days (±5.4) for the nutrition pathway group (P=0.002).
  3. Only one patient in the nutrition pathway group was admitted for enteral nutrition (1/11, a 1-day admisison for PEG placement for a patient crossing over from moderte to severe risk), whereas 6 of the 18 admissions in the control group were primarily for nutritional support.

 

Other Findings

 

Author Conclusion:
  1. Implementation of this nutrition pathway has been associated with improved clinical outcomes, including decreased weight loss, number of unplanned hospital admissions and length of stay during the treatment course, and a higher tolerance of planned treatment.
  2. Recommend that all patients with esophageal cancer who will receive definitive chemoradiation receive a proactive nutritional assessment by a RD specializing in oncology on initial presentation, and appropriate nutritional support and follow-up within the multidisciplinary team.
Funding Source:
Not-for-profit
0
Foundation associated with industry:
Reviewer Comments:
  • Primary weakness of the study was the use of historical controls; however, it would have been unethical to deny control subjects nutrition management via the nutrition pathway.
  • No data provided re: the amount of nutrition received vs goal
  • No survival data reported

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
  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
  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
  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
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. 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
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? 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
  2.1. 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
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? 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? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? ???
3. Were study groups comparable? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  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.) No
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) No
  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
  3.4. 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
  3.5. 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
  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. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? 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
  4.2. 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
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? 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
  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? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  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
  5.2. 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
  5.3. 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
  5.4. 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
  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. 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
  6.1. 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
  6.2. 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
  6.3. 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
  6.4. 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? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? ???
  6.6. Were extra or unplanned treatments described? ???
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  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
  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? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  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? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  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? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  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? ???
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? ???
  8.1. Were statistical analyses adequately described and the results reported appropriately? 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
  8.2. 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? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  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)? ???
  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)? ???
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  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? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
  9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  10. Is bias due to study's funding or sponsorship unlikely? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes