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Oncology

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

Citation:

Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Impact of nutrition on outcome: A prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy. Head and Neck. 2005 Aug; 659-668. 

PubMed ID: 15920748
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

The researchers' purpose was to determine if a cause-and-effect relationship exists between nutrition interventions, including dietary counseling or the use of oral nutritional supplements, and function and clinical outcomes in head and neck cancer patients receiving radiotherapy (RT).

Inclusion Criteria:
  • All consecutive, ambulatory patients receiving RT for head and neck cancer at the study center between July 2000 and March 2003 were considered eligible
  • No distinction was made between patients who received primary RT, RT adjuvant to surgery, RT combined with chemotherapy or RT received for palliation
  • Patient had to be receiving RT of 70 Gy in 35 fractions. 
Exclusion Criteria:
  • Renal disease
  • Diabetes mellitus.
Description of Study Protocol:

Recruitment

Not specifically mentioned; all consecutive study center patients who met the inclusion criteria during the study period were considered eligible.

Design

  • All patients were referred for pre-operative RT
    • All patients had previously received chemotherapy: 5-fluorouracil + cisplatin + folinic acid
  • Patients were randomized to one of three groups:
    • Group 1: Dietary counseling with regular foods
    • Group 2: Usual diet plus supplements
    • Group 3: Ad lib intake
  • Randomly assigned patients received identical scheduled visits and contact time with the research dietitian
    • The goal of nutrition therapy was to help each patient achieve his or her estimated energy and protein requirements
    • The dietitian prescribed a therapeutic diet using regular foods
      • Diet was modified to meet individual requirements based on:
        • Adequate intake
        • Alleviation of symptoms
        • Psychological factors
        • Functional capacity of the GI tract
      • Diet was designed to be as close to each patient's usual eating pattern as possible
      • The diet prescription identified the type, amount and frequency of feedings
        • Goal calorie and protein level was specified
        • Restrictions, limitations or increases in dietary intake were specified
    • Patients randomly assigned to the nutrition supplement group received oral nutrition supplements as an adjunct to the patients' regular diet
      • Ready to use, high-protein, energy-dense commercial supplements were used
      • All supplements were the same brand (brand not mentioned)
      • Patients could select their preferred flavors
      • Patients received two cans of supplement per day
      • Each 200ml can of supplement contained 200kcal per 20g protein
      • Supplement consumption records were kept daily by patients and verified by a caretaker
    • Patients assigned to the ad lib intake group were instructed to maintain their regular diet
  • Study measures were assessed and results were calculated.

Blinding Used

  • Patients were stratified by cancer stage prior to randomization:
    • Patients were randomized in permutation blocks of three
    • Sequential, numbered, opaque sealed envelopes contained computer-generated random assignments
  • Study personnel were blinded to the randomization sequence; a copy was kept separate from study personnel
  • Randomization envelopes were opened prior to each patient's first appointment by a person blinded to the study procedures. 

Intervention

  • Individualized nutrition counseling by the study dietitian
  • Provision of two oral supplements per day in addition to regular diet; supplements provided a total of 400kcals per 40g protein per day
  • Ad lib intake.

Statistical Analysis

  • Power calculations were completed for the study:
    • Minimum sample size of 40 patients was required to detect, with a significance level of 0.01 and power of 0.85:
      • Difference in body weight of 1.9kg
      • Difference in nutritional intake of 25%
      • Difference in QOL score of 20%
    • Power calculations were based on changes observed in a previous pilot study of 36 patients
  • Statistical analysis completed with SPSS 11.5 (SPSS Inc., Chicago, IL), and EPI-Info 2000 (Centers for Disease Control, Atlanta, Georgia)
  • All analysis were conducted on an intent-to-treat basis; any missing data was replaced with the average of the study group, which would have no effect on the estimators 
  • Continuous variables were analyzed using one-way analysis of variance (ANOVA) or Wilcoxen rank sum tests
  • Categorical variables, incidence, prevalence and frequency were analyzed with the chi-square test
  • Univariate or multiple correlations were analyzed with two-tail non-parametric Spearman tests
  • Two-tailed multiple correlation analysis was performed to determine the relationship of dietary intake and RT-induced symptoms on worsening nutritional status
  • Statistical significance level was P<0.05.
Data Collection Summary:

Timing of Measurements

Data Collection by Days
    Baseline RT Treatment Period End RT Three Months Following End RT
  Day   7 14 21 28 35 42 49 139
Measure                  
Demography                  
Medical history                  
Informed consent                  
Randomizations                   
Medications*   
PG-SGA nutritional status   
Weight   
Diet history                 
24-hour recall     
RT-induced morbidity     
QOL s/EORTC QLQ-C30               
Nutritional intervention (Gp 1, Gp 2)     
Acceptability and compliance     

*Note: Use of dietary supplements was also monitored.

Dependent Variables

  • Variable 1:
    • Nutrition outcomes:
      • Nutritional intake (energy and protein intake)
        • Basal energy requirements estimated using the World Health Organization formula for patients 60 years or less, or the Owen et al formula for patients older than 60 years
        • To estimate daily energy requirements (EER), basal requirements were multiplied by a 1.5 activity factor
        • Protein requirements were estimated from age and sex standardized reference values, and ranged from 0.8g per kg per day to 1.0g per kg per day
        • Burke's diet history, along with multiple and sequential 24-hour recall evaluations (two weekdays and one weekend day), were performed at each
      • Nutritional status [measured using Ottery's Patient Generated Subjective Global Assessment (PG-SGA)]
        • Validated tool designed for patients with cancer
        • Measures three areas:
          • Weight changes, symptoms, alterations in food intake and functional capacity
          • Components of metabolic stress
          • Physical examination
        • Patients were classified as normal, moderately malnourished or severely malnourished
  • Variable 2: Symtom-induced morbidity
    • Measured using the PG-SGA
      • Addresses symptoms: Anorexia, nausea, constipation, mucositis, vomiting, diarrhea, xerostomia, pain
  • Variable 3: Quality of life (QOL)
    •  Assessed with the EORTC Quality of Life questionnaire version 3.0
      • Includes six function scales (physical, emotional, cognitive, social, role and global health/QOL
      • Includes three symptom scales (fatigue, pain, nausea/vomiting)
      • Includes six single items (symptoms, financial impact)

Independent Variables

  • Dietary counseling
  • Oral nutrition supplements.

Control Variables

  • Presence of head and neck cancer
  • Receiving radiation therapy.
Description of Actual Data Sample:
  • Initial N: N=75 (60 males, 15 females)
    • Group 1 (individualized dietary counseling based on regular foods): N=25
    • Group 2 (supplement group): N=25
    • Group 3 (control group; ad lib intake): N=25
  • Attrition (final N): 
    • All data was analyzed on an intent-to-treat basis; all enrolled patients accounted for; no patients lost to follow-up
    • All patients completed the study
    • No patients took any other dietary supplements during the study period
  • Age: 60±11 (36 to 79) years
  • Other relevant demographics:
    • Patients had cancers of the base of the tongue, nasopharynx, oropharynx or larynx
    • 30 patients with Stage I/II disease; 45 patients with Stage III/IV disease
      • 16 patients in Group 1 were malnourished; 14 patients in Group 2 were malnourished; and 15 patients in Group 3 were malnourished
      • 56% of the malnourished patients had Stage III/IV disease; 4% of the malnourished patients had Stage I/II disease 
    • All patients had received prior chemotherapy with an identical regimen (5-flourouracil + cisplatin + folinic acid)
    • All patients were receiving radiotherapy in preparation for surgery
  • Anthropometrics: At baseline, there were no significant differences between groups for energy and protein intake, prevalence of malnutrition or presence of symptom-induced morbidity
  • Location: Radiotherapy Department, University Hospital of Santa Maria, Lisbon, Portugal. 

 

Summary of Results:

Nutritional Outcomes

  • Energy intake:
    • Energy intake at end of RT compared with initiation of RT:
      • Group 1: Net increase, +521kcal per day (358 to 732), P=0.002
      • Group 2: Net increase, +322kcal per day (286 to 412), P=0.005
      • Group 3: Net decrease, -400kcal per day (201 to 502), P<0.01
    • Energy intake at three-month follow-up:
      • Group 1: Maintained increase in energy intake
      • Group 2: Energy intake decreased to either baseline or below baseline, P=0.005
      • Group 3: Energy intake decreased to either baseline or below baseline, P=0.005
  • Protein intake:
    • Protein intake at end of RT compared with initiation of RT:
      • Group 1: Net increase, +26g per day (20 to 34), P=0.006
      • Group 2: Net increase, +35g per day (20 to 44), P=0.001
        • Group 2 protein intake was higher than Group 1 protein intake, P=0.06
      • Group 3: Net decrease, -15g per day (9 to 21), P<0.01
    • Protein intake at three-month follow-up:
      • Group 1: Maintained increased protein intake
      • Group 2: Protein intake decreased to either baseline or below baseline, P<0.05
      • Group 3: Protein intake decreased to either baseline or below baseline, P<0.05
  • Nutritional status:
    • Group 1: Eight of 16 malnourished patients at initiation of RT improved their nutrition status [net average recovery at three-months follow-up: 4kg (two to six)]
    • Group 2: No patient showed improved nutrition status
    • Group 3: No patient showed improved nutrition status.

Changes in Nutritional Status during RT and at Three Months 

  Group 1 Group 2 Group 3    
  Decline Maintaind/Improved Decline Maintained/Improved Decline Maintained/Improvedd    
Method End RT Three Months End RT Three Months End RT Three Months End RT Three Months  End RT Three Months End RT Three Months P1* P2*
PG-SGA 5 3 20 22 19 24 6 1 24 25 1 0 <0.002 <0.001

*P1 describes the significance of the statistical difference between the intervention groups regarding nutritional decline, at the end of RT and at three months follow-up.

*P2 describes the significance of the statistical difference between the intervention groups regarding maintenance or improvement of nutritional status, at the end of RT and at three months' follow-up.

Symptom-induced Morbidity Outcomes

  • By end of RT, 90% of the study participants experienced radiation-induced toxicity
    • The incidence did not differ significantly between groups (P<0.08)
    • A trend for reduced symptoms was found in Group 1 vs. Groups 2 and 3 (P<0.07)
  • At three-month follow-up, a significant difference in Grade 1 and 2 anorexia, nausea/vomiting, xerostomia and dysgeusia was found between Group 1 patients (90% showed improvement), Group 2 patients (67% showed improvement) and Group 3 patients (51% showed improvement); P<0.0001. Reduction of Grade 1 + 2 dysphagia/odynophagia was not significant between groups.
  • During RT, medications (oral antifungal solutions, local anesthetics and anti-inflammatories) were prescribed as appropriate for symptom control in 57% of Group 1 patients, 61% of Group 2 patients and 68% of Group 3 patients; however, the difference was not significant
  • Dietary intake was correlated significantly with nutritional status in all groups (R≤-0.59, P≤0.002).

RT-induced Morbidity According to Severity Grade

  Group 1  Group 2 Group 3      
  Grade 1 Grade 2 Grade 1 Grade 2 Grade 1 Grade 2       
Symptoms End RT Three Months End RT Three Months End RT Three Months End RT Three Months End RT Three Months End RT Three Months P1* P2* P3*
Anorexia  10  <0.05  <0.12  <0.001 
Nausea/Vomiting  <0.001  <0.10  <0.05 

Xerostomia 

12  10 10  <0.04  <0.05  <0.0003 

Dysgueusia

10  10  11  11  12  <0.04  <0.008  <0.0004 

Odynophagia/dysphagia

14  12  10  12  12  <0.0001  <0.05  <0.0002 

*P1 describes the significance of the statistical difference between the intervention groups regarding the reduction of Grade 1 symptoms, at the end of RT and at three months' follow-up.

*P2 describes the significance of the statistical difference between the intervention groups regarding the reduction of Grade 2 symptoms, at the end of RT and at three months' follow-up.

*P3 describes the significance of the statistical difference between the intervention groups regarding the reduction of Grade 1 + 2 symptoms, at the end of RT and at three months' follow-up.

Quality of Life Outcomes

  • At end of RT:
    • For Group 1, all QOL scores significantly improved (P<0.003)

      • QOL scores were correlated with increases in energy and protein intake (R<0.83; P<0.001)
      • QOL scores were related to improvement in nutritional status (P<0.05)
    • For Group 2, all function scores improved (P<0.009); function scores were correlated with improvement in protein intake (R<0.58; P<0.05)
    • For Group 3, all QOL scores worsened as nutritional intake and nutritional status worsened (P<0.0001, P<0.002, respectively)
  •   At three-month follow-up: 
    • For Group 1, all patients maintained or improved overall QOL
      • QOL was positively correlated with maintenance or improvement of nutritional status (P<0.008) and adequate energy and protein intake (P<0.01)
      • Function scores were improved or maintained
      • Symptom scales were significantly improved over baseline (P<0.002)
    • For Group 2, patients either maintained or experienced a decline in QOL (P<0.03). Decline in QOL was associated with poor dietary intake (P<0.003) and worsened nutritional status (P<0.002)
    • For Group 3, function scores deteriorated further when compared with baseline and end of RT
      • Decline in function scores was associated with inadequate energy and protein intake (P<0.001) and worsened nutritional status (P<0.002)
      • Symptom scores were worse than at baseline (P<0.003). The worst symptom scores were associated with poor energy and protein intake (P<0.005).
Author Conclusion:
  • Nutrition is a key determinant of quality of life in patients with cancer
  • Both at end of RT and at three months' follow-up, dietary counseling resulted in significantly improved QOL function scores, in conjunction with sufficient intake and adequate nutritional status
  • Patients in Group 2 showed an improvement in QOL function scores as long as supplementation continued, but when supplementation was discontinued, QOL scores declined
  • Patients in Group 3, who received no nutrition counseling or supplementation, showed a significant decrease in QOL function scores throughout the entire study period
  • The benefits of dietary counseling for QOL scores included improved physiological and clinical outcomes
  • Nutrition intervention, including nutrition assessment, dietary counseling, diet education, monitoring compliance and symptom management, was central to the improvement of patients' outcomes, both nutritional and non-nutritional
  • Both dietary counseling and oral supplementation improved patient outcomes in the short term, with dietary counseling showing an equal or greater benefit than supplementation; however, at the three-month follow-up, only dietary counseling resulted in improved patient outcomes
  • The authors urge early nutrition intervention in this patient population.
Funding Source:
University/Hospital: Instituto de Medicina Molecular Faculdade de Medicina da Universidadede Lisboa (Portugal), Santa Maria University Hospital (Portuagal)
Reviewer Comments:
  • Well-designed RTC; included power calculation, randomization with blinding of investigator assigning patients to groups; used validated instruments to measure outcomes; used concurrent controls
  • Patients receiving RT combined with chemotherapy and RT combined with surgery were included in the study
  • Records of supplement consumption were kept by patients and patient caregivers 
  • Basal energy requirements, EER and protein requirements were calculated from formulas and reference values; 1.5 activity factor was used for all patients
  • Many more men than women in study; no information provided for number of males and females in each study group. 
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) 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.) 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? 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? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  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? Yes
  6.6. Were extra or unplanned treatments described? 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
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
  7.2. 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
  7.4. 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
  7.6. 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? 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)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? 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? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? No
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes