EAL

ONC: Radiation Therapy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

Validate with a double-blind placebo controlled randomized trial clinical findings that alpha-tocopherol (vitamin E) and pentoxifylline used as an antifibrotic treatment in breast cancer patients results in clinical regression of superficial radiation-induced fibrosis.

Inclusion Criteria:

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

Exclusion Criteria:

None stated

Description of Study Protocol:

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

Data Collection Summary:

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

   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

Description of Actual Data Sample:

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

Summary of Results:

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)

*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

Author Conclusion:

The study fails to demonstrate efficacy of dl-alpha tocopheryl acetate plus pentoxifylline in patients with arm lymphoedema following axillary surgery and lymphatic radiotherapy, nor does it suggest any benefits of these drugs in radiation-induced fibrosis in the breast, chest wall, pectoral fold, axilla or supraclavicular fossa.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

· 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
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