ONC: Radiation Therapy (2006)
Gothard L, Cornes P, Earl J, Hall E, MacLaren J, Mortimer P, Peacock J, Peckitt C, Woods M, Yarnold J. Double-blind placebo-controlled randomized trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer. Radiotherapy and Oncology 2004, 73: 133-139.
PubMed ID: 15542159
Eligible patients: · Ipsilateral arm lymphoedema following treatment for breast cancer causing >20% increase in arm volume · Previous radiotherapy treatment to the breast/chest wall plus axilla and /or supraclavicular fossa · Freedom from cancer recurrence · Availability for follow-up · Written informed consent |
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Recruitment
Twenty consecutive symptomatic outpatients with endoscopically documented radiation proctitis seen in a single gastroenterology clinic.
Design
· 68 patients recruited and randomly assigned to a treatment or placebo arm
· Patients receive either combination vitamin E and pentoxifylline or placebo for 6 months
· Change in ipsilateral arm volume, breast induration, appearance, and quality of life was assessed at various end points (12 months being the primary end point).
Blinding used (if applicable)
· Neither the patients nor the investigators were informed of treatment allocation made by member of the hospital pharmacy department
Intervention (if applicable)
· Dl-alpha tocopheryl acetate (500 mg twice a day orally) plus pentoxifylline (400 mg twice a day orally) or corresponding placeboes, for 6 months
Statistical Analysis
· Sample of 68 patients would allow power of 85% with a significance level of 10% assuming a mean and standard deviation of percentage reduction in volume of approximately 10 and 15%, respectively
· Change in ipsilateral arm volume at baseline and 12 months was examined using a t-test
· Health status scales were derived from the QoL questionnaires using standard methods
· Change in breast induration and appearance were recorded for each individual patient
· Percentage of patients with a change in induration score of 2 or more were calculated and comparison between treatment groups was made by chi-squared test
Timing of Measurements
· Baseline
· 6 months and 12 months after start of treatment
· QoL measures also taken at 3 and 9 months after start of treatment
Dependent Variables
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Volume of the ipsilateral limb measured opto-electronically using a perometer
o Volume of the ipsilateral limb expressed as a percentage of the contralateral (control) limb volume at 12 months post-randomization
· Clinical assessment by oncologist of subcutaneous induration within the radiotherapy volume. Induration scored by palpatation using graded scale
o 0=none
o 1=a little
o 2=quite a lot
o 3=very much
o Response was defined as an improvement of at least 2 grades at 12 months post-randomization
· Clinical photographs of breast/chest wall, pectoral fold and/or supraclavicular fossa – change in photographic appearance of irradiated skin or arm at 12 months was not predefined
· Patient self-assessments of arm swelling, tissue induration and physical functioning. Assessments made using the EORTC core quality of life questionnaires:
o QLQ-C30 incorporated five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea and vomiting), a global health status/QoL scale and a number of single items assessing dyspnea, loss of appetite, insomnia, constipation and diarrhea and perceived financial impact of the disease
o Breast module BR23 assesses disease symptoms, side effects of treatment, body image, sexual functioning and future perspective
Independent Variables
· Dl-alpha tocopheryl acetate (500 mg twice a day orally) plus pentoxifylline (400 mg twice a day orally) or corresponding placeboes, for 6 months
Control Variables
· Volume of the contralateral limb
Initial N: N=68 (35 treatment group, 33 placebo group)
Attrition (final N):
· N=63/68 (94%) (3/35 treatment arm and 1/33 placebo arm; 1 patient missed the 6 mon assessment, but made the 12 mon assessment)
· Reasons for attrition defined
o 1 diagnosed with met static breast cancer, 1 new primary cancer
Age: Median age 63 years (range 37-87)
Ethnicity: Not reported
Other relevant demographics:
Anthropometrics (e.g., were groups same or different on important measures)
· 67 female, 1 male
· Median time from radiotherapy treatment to trial was 15.5 years (range 2-41)
· 2 of 68 had no primary surgery
Location: Sutton, Surrey, UK
Compliance:
· Plasma samples of a-tocopherol indicated good compliance to the protocol
Difference in ipsilateral and contralateral arm volume at baseline and 12 months post-randomization
Symptoms |
Difference in ipsilateral and contralateral arm volume at baseline (%) |
Difference in ipsilateral and contralateral arm volume at 12 months (%) |
Change in arm volume difference at 12 months from baseline (%) |
All, mean (SD)* |
40.8 (19.1) |
42.6 (21.6) |
1.8 (9.5) |
Placebo, mean (SD) |
40.5 (21.7) |
41.7 (24.2) |
1.2 (10.9) |
Treatment, mean (SD) |
41.1 (16.4) |
43.6 (18.9) |
2.4 (8.0) |
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*SD = Standard Deviation
· Mean change in arm volume in the treatment group was 2.5% (95% CI –0.4 to 5.3)
· Mean change in the placebo group was 1.2% (95% CI –2.8 to 5.1)
· Mean change for all 64 evaluable patients was 1.8% (95%CI –0.6 to 4.2)
Clinical assessments including tissue induration and clinical photographs
· Number of indurated sites recording a response was 6/31 (19%) in the treatment group, and 8/34 (24%) in the placebo group
· Clinical photographs were taken at baseline and 12 months post-randomization, but did not provide and additional information
Quality of Life
No significant changes in self-assessed function and Quality of Life were seen in either of the randomization groups over the study period
Not-for-profit |
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· Small sample size
· Ethnicity of patients was not mentioned
· Method of randomization not described, only the position of the person who did it
Quality Criteria Checklist: Primary Research
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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? | Yes | |
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? | ??? | |
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? | 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? | N/A | |
6.6. | Were extra or unplanned treatments described? | N/A | |
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? | N/A | |
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? | 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? | 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)? | N/A | |
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? | 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 | |