ONC: Radiation Therapy (2006)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To assess the maximal efficacy and the time it takes to achieve maximal efficacy after combined pentoxifylline-vitamin E (PTX-vitE)(pentoxifylline 800 mg/day) and (vitamin E 1,000 IU/day) is used as an antifibrotic treatment in breast cancer patients with measurable and symptomatic areas of superficial breast chronic radiation-induced fibrosis.
Inclusion Criteria:

·          Patients who had adjuvant postoperative radiation therapy (RT) for a malignant breast tumor

·          No evidence of recurring disease

·          Measurable radiation-induced fibrosis

Patients treated with combination pentoxifylline and a-tocopherol between April 1995 and April 2000
Exclusion Criteria:

·          Second cancer

·          Head/neck RIF

·          Breast hardness within 6 months of radiation therapy completion

·          Patients not interested in the study

·          Drug intolerance

Description of Study Protocol:


·       Among 500 patients treated with pentoxifylline and vitamin E over a 5 year period, 62 homogeneous patients with measurable superficial radiation-induced fibrosis were selected

·          62 patients had 74 distinct measurable zones of superficial chronic RT damage

·          18 patients (19 superficial RIF) were excluded for defined reasons



 ·          Measurable superficial RIF was assessed in patients treated by RT for breast cancer in a long-treatment (24 to 48 months) PTX-vitE (LPE) group of 37 patients (47 RIFs) and in a short-treatment (6 to 12 months) PTX-vitE (SPE) group of seven patents (8 RIFs)

·          Patients treated with daily combination of pentoxifylline and vitamin E

·          Clinical investigators assessed participants before, during and after treatment including

o        Palpitation of the edges of the fibrotic bock, with measurements of width and length of the projected cutaneous surface

o        Completion of Subjective Objective Medical Management and Analytic Evaluation of Injury (SOMA) score

·          Patients were used as their own controls (paired data)


Blinding used (if applicable)

 Not applicable 

Intervention (if applicable)

 Combination of twice-daily pentoxifylline 400 mg (800 mg/day) and vitamin E 500 IU (1,000 IU/day)  

Statistical Analysis

 ·          All tests were two sided, and P<0.05 was considered significant

·          Data are presented as numbers and percentages for qualitative variables and as means ± standard deviations for quantitative variables

·          Comparisons of variables across groups were performed using Fisher’s exact test initially and then the Wilcoxon rank sum test

·          Change in RIF surface area with treatment was analyzed relative to baseline using nonlinear mixed models

·          Specific hypotheses regarding fixed effects were tested using the Wald or likelihood ratio tests.  CIs for predicted values were obtained using the parametric bootstrap of estimated models based on 100,000 numerical simulations.

·          Changes in RIF surface area after the end of treatment were analyzed using linear mixed models





Data Collection Summary:

Timing of Measurements

·        Results of treatment were evaluated at 6, 12, 18, 24, 36, and 48 months

·          Duration of treatment based on clinical observation of timing of fibrosis regression

o        7 patients (8 RIF sites) included before 1997 had short PTX-vitE (SPE) treatment (mean, 9 months; range 6 to 12 months)

o        37 patients (47 RIF sites) received long PTX-vitE (LPE) and were treated until fibrosis regression peaked at a mean of 36 months (range, 24 to 48 months)

·          All RIF sites were assessed at 6 and 12 months after stopping the PTX-vitE treatment (off drug variation)


Dependent Variables

 Variable 1: percent change of the surface area of the fibrosis surface every 6 months (during a mean period of 5 years), which was defines as follows:  (measurement at x months - measurement at inclusion)/measurement at inclusion

    • Variable 2: Subjective Objective Medical Management and Analytic Evaluation of Injury (SOMA) score, which was assessed every 6 months according to the SOMA system devised in 1995 and modified recently, Cancer Terminology Criteria for Adverse Events, http://ctep.cancer.gov/reporting/ctc.html)
      • Items assessed included scaliness, pruritus or pain, local edema, pigmentation changes, ulcer or necrosis, telangiectasia, fibrotic scarring, atrophy or tissue contraction and medical management of local pain or compressive edema.
  • ~Independent Variables

 Combination of twice-daily pentoxifylline 400 mg (800 mg/day) and vitamin E 500 IU (1,000 IU/day) 

Control Variables

 ·          Age

·          Years since RT

·          RIF location


Description of Actual Data Sample:


Initial N:

44 eligible women with 55 gradually worsening measurable superficial breast RIF included

Attrition (final N):

All included in analysis, but of differing treatment duration

  • 7 patients (8 RIF) received short duration treatment
  • 37 patients (47 RIF) received long duration treatment



Short PTX-vitE (n=7) Mean, SD, range

Long PTX-vitE (n=37) Mean, SD, range


Age, years

59 (8.4) 45-69

59 (8.6) 37-82


No. of Areas




Years since RT

4 (3) 2.5-12

7 (4) 1-18


RIF surface area, cm2

19.2 (12.3) 5-42

48.3 (55) 6-330


SOMA score

9.4 (3.6) 3-14

10.7 (3.2) 10-20


RIF surface area was significantly greater among the long PTX-vitE group

Location: Paris, France




Summary of Results:

RIF Surface Area Regression Assessed During and After Stopping PTX-vitE Treatment

RIF Reg,%*

3 mon    % (SD)

6 mon      % (SD)

12 mon      % (SD)

18 mon      % (SD)

24 mon      % (SD)

36 mon      % (SD)

SPE (n=8)


-69(15) 8





LPE (n=47)


-46(19) 47












*RIF Surface Area Regression, % Mean and Standard Deviation

·          Combined PTX-vitE was continuously effective over several months and years and resulted in exponential RIF surface area regression.  The table below reports significant mean RIF regressions

·          Statistical modeling of the relative RIF regression under treatment in the LPE group revealed the best representative model of the time-course regression

o        Model showed significant RIF regression (P<0.0001), with the maximal effect of treatment corresponding to a mean of 68%(95% CI, 64% to 73%) RIF surface area regression

o        The mean time to maximum RIF regression was significantly shorter with recent RIF (<6 years since RT) than older RIF (> 6 years since RT)(P=0.0003) RIF (16 months; 95% CI, 12 to 19 months verses 28 months; 95% CI, 23 to 33 months, respectively

o        After stopping PTX-vitE treatment, a significant initial increase (P = .037) in RIF surface area was observed

o        Fibrotic increase was significantly lower and asymptomatic in the LPE group with (8%/yr; 95% CI, 1% to 16%/yr) compared with the SPE group with (40%yr; 95% CI, 24% to 56%/yr; P = .0012)


SOMA Score Regression Assessed During and After Stopping of PTX-vitE Treatment

SOMA Score Reg., %*

3 mon      % (SD)

6 mon      % (SD)

12 mon      % (SD)

18 mon      % (SD)

24 mon      % (SD)

36 mon      % (SD)

SPE (n=8)







LPE (n=47)














·          All RIF areas responded well to treatment, and symptom severity diminished exponentially by half as assessed by the SOMA score

·          Mean SOMA scores improved significantly and was similar to the improvement to the RIF surface area regression, with an average slope of 0.6 (P<.0001)

·          All RIF areas exhibited various but evident softening of the tissues involved with a regression of fibrosis adhesion to underlying tissues.

Other Findings

·          In the LPE group, after achievement of two-thirds maximal RIF surface area regression in 24 months, residual RIF (mean, 3.6+/- 1.8 cm at 24 and 36 months) was often stable and approximately one third of the initial RIF surface area (mean, 6.7 +/- 3.4 cm at baseline)


Author Conclusion:
Under combined pentoxifylline –vitamin E treatment, radiation-induced fibrosis regression was exponential, with a two-thirds maximum response after a mean of 2 years. There was a risk of a rebound effect if treatment was too short.  Long treatment (> 3 years) is recommended in patients with severe radiation-induced fibrosis.
Funding Source:
University/Hospital: Hôpital Saint-Louis (Paris), Fontenay aux Roses (France)
Reviewer Comments:
Ethnicity of subjects not 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
  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? No
  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? No
3. Were study groups comparable? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) 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
  3.6. 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? 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.) 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? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? 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? ???
  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? 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? ???
  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? ???
  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? 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)? 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