ONC: Chemotherapy (2007)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To evaluate (1) the effectiveness of TPN in reducing frequency, grade, and length of myelotoxicity, and frequency and grade of GI tract toxicity; (2) the extent and grade of chemotherapy induced alterations of the nutritional status; and (3) whether alterations in nutritional status can be prevented and/or corrected by TPN.
Inclusion Criteria:
  • Histologically documented malignancy
  • No previous chemotherapy
  • Karnofsky performance status >50
  • Life expectancy >3 months
  • Scheduled to receive at least two identical courses of chemotherapy
  • Normally nourished or >10% loss of usual body weight in the last 6 months
Exclusion Criteria:
  • Diabetes mellitus
  • Heart, pulmonary, liver or kidney failure
  • Sepsis
  • Bone marrow involvment
  • 6%-10% loss of usual body weight
Description of Study Protocol:

Recruitment Not described

 

Design Randomized, crossover study

 

Blinding used Not described

 

Intervention

  • Chemotherapy regimen
    • Small cell lung cancer subjects
      • Cisplatin: 20 mg/m2 IV on days 1 to 5
      • Etoposide: 75 mg/m2 IV on days 1 to 5
    • Non-Hodgkin lymphoma
      • Adriamycin: 25 mg/m2 on day 1
      • Cyclophosphamide: 650 mg/m2 on day 1
      • Etoposide: 120 mg/m2 IV on day 1
      • Mechlorethamine: 6 mg/m2 on day 8
      • vincristine: 1.4 mg/m2 IV on day 8
      • Procarbazine: 100 mg/m2 by mouth on days 8 to 15
      • Methotrexate: 500 mg/m2 on day 15
      • Prednison: 60 mg/m2 by mouth on days 1 to 15
    • Bladder cancer
      • 5-fluorouracil: 500 mg/m2 IV on day 1 and 8
      • Epirubicin: 60 mg/m2 IV on day 1
      • Cisplatin: 50 mg/m2 IV on day 1
  • Randomization
    • Randomized in blocks of four divided into two groups:
      • Group A:
        • Course 1: chemotherapy + TPN
        • Course 2: chemotherapy
      • Group B
        • Course 1: chemotherapy
        • Course 2: chemotherapy + TPN
      • Time between the first and second course was 21 or 28 days according to the chemotherapy schedule or was prolonged until recovery from myelosuppression.
      • TPN was administered concomitantly with chemotherapy
  • Study procedures
    • Determination of basal energy expenditure (BEE)
    • Recording of food intake (oral)
    • Evaluation of hematologic and GI toxicities
    • Evaluation of nutritional status
    • Monitoring of septic and metabolic complications

Statistical Analysis

  • Sample size calculation:
    • Because hematologic and GI toxicities observed in patients undergoing the chemotherapy regimens used in the present study were  generally higher than 40%, the authors hypothesized that TPN could reduce toxicity by half (from 40% to 20%).
    • It was estimated that, accepting a type I error of 5% with a power of 90% to test the null hypothesis in toxicity rates between the chemotherapy group and the chemotherapy plus TPN group, at least 50 subjects should be enrolled in a crossover trial.
  • Statistics
    • Descriptive statistics, inlcuding means and standard deviations, median, and ranges were used.
    • To evaluate whether the chronologic order in the administration of the two treatments had any influence on both chemotherapy toxicity and nutritional indices, data weere analyzed separately for the 2 groups according to the treatment that was given first.
    • To compare two means, the Student's t test for paired observations was used.
    • The significance of statistical differences between proportions was tested by means of the X2 (Fisher's exact test when appropriate) or the X2 test for trends for ordered variables with three or more levels.

 

Data Collection Summary:

Timing of Measurements

  •  Nutritional status: days 0, 7, 14, 21 of each chemotherapy course
  • Others not described

Dependent Variables

  • Food intake
    • No restriction of oral intake during the study periods
    • Quantitative food intake was reported on a preprinted form by specifically trained nurses.
    • Caloric and protein intake was estimated by RD
  • Hematologic toxicities
    • White blood cell count, platelets, hemoglobin nadirs
    • Evaluated using WHO criteria
    • White blood cell count on day 21 was used to evaluate recovery from bone marrow suppression
  • GI toxicitiy
    • Nausea, vomiting, diarrhea
    • Evaluated using WHO criteria
  • Nutritional status
    • Anthropometric measurements: body weight; arm, arm muscle, and thigh circumferences; triceps, biceps, subscapular, abdominal, and suprailiac skinfold thickness; creatinine/height ratio
    • Immunologic: total lymphocytes and subsets, C3 and C4 complement fractions, immunoglobulin G, immunoglobulin A, and immunuglobulin M
    • Biochemical: prealbumin, transferrin, retinol-binding protein, ceruloplasmin, albumin, and urinary nitrogen for determination of nitrogen balance
  • Septic and metabolic complications
    • Septic: monitored during both courses
      • Divided into two types: microbiologically documented and clinically documented
      • Septicemia: positive blood culture in whom no other sites of infection were detected
      • Pneumonia: positive chest x-ray with positive cultures from sputum or blood
      • Catheter-related septicemia: clinical episode of sepsis for which no other cause was detectable, which subsided upon catheter removal and was confirmed by finding the same organism (species, biotype, and antibiotype) in peripheral blood and intravascular CVC segment cultures.
      • Clinically documented infections: pneumonia, cellulitis or other soft tissue infects for which an organism was not isolated
    • Metabolic complications: moniotring during both courses of chemotherapy

 

Independent Variables

  • TPN
    • BEE determined by Harris-Benedict formula
      • Additional factors added to provide adequate calories
        • 30% of the BEE values corresponded to energy expenditure for sedentary activity
        • 10% for the specific dynamic action of food
        • 20% for mean caloric expenditure caused by neoplasia-related metabolic requirements LBM destroyed in the catabolic period
        • Malnourished only subjects: 20% to improved the synthesis of the LBM destroyed in the catabolic period
    • Formulation
      • Caloric intake was 35±5 kcal/kg per day.
      • Nonprotein calories were divided between dextrose (60%) and lipids (40%, Intralipid).
      • Crystalline amino acids (Freamine III) were provided at a calorie:nitrogen ratio of 160 kcal:1 gm nitrogen (1.4±0.2 gm of amino acids/kg/day.
      • Mineral salts as clinically indicated (sodium, potassium, chlorine, magnesium, phosphorus, calcium)
      • Trace elements (5 ml trace element mix) were added
      • Prepared in ethylvinylacetate bags
      • Insulin was not added to the bags nor injected into the subjects
      • Hydro- and liposoluble vitamins and iron were administered orally or parenterally but never added to the TPN bags
    • Volume prescribed
      • Supplementary TPN was determined by taking into account the subject's oral intake in the 2 days preceding chemotherapy.
      • Conversely, at the start of chemotherapy and regardless of oral intake, the entire amount of calculated required calories and protein was provided by TPN for at least 7 days.
      • From day 8 onward, parenteral nutrition was provided taking into account the oral intake.
      • TPN was discontinued as soon as food intake reached 80% of the calculated requirement.
    • Administration
      • Infused daily through a subclavian polyurethane catheter over 24 hr via an infusion pump
      • Bags and infusion sets were changed daily by specifically trained nurses from the clinical nutrition unit
    • Care of line
      • Catheter inserted in the operating room after a strict aseptic procedures
      • Catheter dressing was replaced three times a week

Control Variables

 

Description of Actual Data Sample:

 

Initial N: N=50

  • Group A: N=24
  • Group B: N=26

Attrition (final N): N=43 (26 men/17 women)

  • Group A: N=20
    • Small cell lung cancer (SCLC): N=1
    • Non-Hodgkin lymphoma (NHL): N=1
    • Bladder cancer: N=2
  • Group B: N=23
    • SCLC: N=2
    • NHL: N=1
  • Reasons for withdrawal across both groups
    • Could not be evaluated because of changes in the chemotherapy regimen after the first course of chemotherapy because of disease progression (N=4).
    • Refusal of venous catheterization (N=2)
    • Death from pulmonary embolism related to leg vein thrombosis (N=1)

Age: Based on N=43

  • Median age: 58 years (range 23-75 years)

Ethnicity: Not described

Other relevant demographics:

Anthropometrics

Subjects at randomization

  Group A   Group B  
  N=24   N=26  
  Normally nourished Malnourished Normally nourished Malnourished
Small-cell lung cancer 2 (1)* 4 4 (1)* 5 (1)*
Non-Hodgkin lymphoma 1 (1)* 3 2 (1)* 4
Bladder cancer 6 (1)* 4 (1)* 4 4

* Subjects which could not be evaluated.

  • Median weight loss prior to chemotherapy (unsure whether the N=50 or 43)
    • Normally nourished: 2% (range 0%-5%)
    • Malnourished: 13% (range 11%-22%)

Location: Centro di Riferimento Oncologico, Istituto Nazionale di Ricovero e Cura a Carattere Scientifico, Aviano, Italy

 

Summary of Results:
  • Because no differences in chemotherapy-related toxicity and nutritional parameters were found when the analysis was performed according to the treatment that was first given, the results are presented for each treatment (chemotherapy or chemotherapy + TPN) for the 43 subjects who concluded the study.  
  • The results of statistical analysis did not show differences even when the seven subjects excluded were taken into consideration.

Hematologic/GI Toxicity

  Chemotherapy Chemotherapy + TPN
Leukopenia 75% 79%
Thrombocytopenia 7% 11%
Anemia 70% 72%
Nausea/vomiting 96% 93%
Diarrhea 33% 28%

  1. Parenteral nutrition did not affect chemotherapy toxicity in pooled analysis.
  2. By analyzing normally nourished subjects or malnourished subjects alone, TPN did not affect chemotherapy toxicity.
  3. Differential analysis of chemotherapy toxic effects among normally nourished and malnourished subjects during chemotherapy alone or chemotherapy + TPN did not show any differences.
  4. Recovery from bone marrow suppression was equal for both treatments.
    • On day 21, a total of 5 subjects who had received chemotherapy alone and another 5 who had undergone chemotherapy + TPN displayed bone marrow toxicity over grade one (three grade 2 and two grade 3 for each course).

Nutritional Status

Fast-Turnover Visceral Protein and Nitrogen Balance in Malnourished Subjects

    Chemotherapy + TPN     Chemotherapy  
Day Prealbumin Retinol Binding Protein Nitrogen Balance Prealbumin Retinol Binding Protein

Nitrogen Balance 

0 19.99±8.24 3.84±1.69 0.98±3.39 23.2±7.27 4.59±1.45 —1.34±3.89
7 25.09±8.17* 5.08±1.61* 3.14±3.92*§ 20.61±6.61* 4.41±1.60 —4.05±5.21*§
14 26.74±10.37* 5.15±1.36* 4.90±4.65*§ 22.62±8.01 3.98±1.67 —3.35±3.80*§
21 26.69±7.93* 5.04±1.41* 1.95±2.95 22.34±8.79 4.72±2.09 —1.58±3.50

* Intracycle analysis: days 0 vs days 7, 14, and 21 (P<0.03).

§ Intercycle analysis: days 0, 7, 14, and 21 (P<0.001).

  1. All nutritional indices (anthropometric, immunologic and biochemical) did not change in all subjects at the intracycle or intercycle analysis.
  2. Normally nourished subjects did not show any difference at the intracycle or intercycle analysis.
  3. In malnourished subjects, prealbumin, retinol binding protein and nitrogen balance increased (P<0.02) at the intracycle analysis in the chemotherapy + TPN course.
  4. The same subjects during chemotherapy alone showed a decrease in prealbumin and nitrogen balance (P<0.03).
  5. The intercycle analysis in malnourished subjects showed significant changes in nitrogen balance at days 7 and 14 only (P<0.001).

Septic and Metabolic Complications

  • Chemotherapy alone course
    • 1 case of septicemia
    • 2 cases of pneumonia
    • 1 case of subcutaneous abscesses
  • Chemotherapy + TPN
    • 2 episodes of septicemia (1 CVC related)
    • 1 case of pneumonia
    • 1 case of urinary tract infection
  • In both courses, 2 clinically but not microbiologically documented infections were observed: pneumonia and urinary tract infection.
  • No major metabolic complications were detected in either the chemotherapy alone or the chemotherapy + TPN group.

Other Findings

  1. Median duration of TPN treatment was 13 days (range 10-21 days).
  2. Line placement complications did not occur.
Author Conclusion:
  • TPN as provided in this study may not be able to modify hematologic and GI toxicities related to the administration of cytotoxic chemotherapy.
  • Normally nourished subjects may not require standard TPN support to prevent hypothetical chemotherapy-associated modifications of the nutrtional status, inasmuch as such alterations were never detected in our subjects after administration of the chemotherapy regimens adlopted in the study.
  • Severely undernourished patients may benefit from TPN because such a procedure is able to correct, at least temporarily, pre-existent nutritional alterations and to prevent the occurrence of a chemotherapy related worsening of the nutritional status.
  • TPN, when applied after an appropriate procedure, is not associated with major metabolic complications.
Funding Source:
Not-for-profit
0
Foundation associated with industry:
Reviewer Comments:

Heterogeneous sample in terms of type of cancers included in the study.

Baseline measurements not provided for skinfold measurements, laboratory indices, tumor stage, metastatic disease.

Number of subjects completing the trial less than the calculated sample size.

Determination of the number of calories to administer via TPN confusing in the methods section.

Skinfold measurements are highly dependent on the skill of individual performing the measurements; no information was provided about individual performing these measurements. Length of time between measurements probably not long enough to see changes.

No information provided about weight status, nutrient intake (calories and protein) or skinfold measurements during the course of the study.

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? ???
  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? ???
  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? Yes
  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.) No
  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? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  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? No
  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? ???
  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? ???
  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)? 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
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes