Trial Information

Phase III Randomized Pair Comparison of a Barrier Film vs. Standard Skin Care in Preventing Radiation Dermatitis in Women With Breast Cancer Receiving Adjuvant Radiation Therapy

Rationale

Radiation dermatitis is a common problem in a significant proportion of breast cancer
patients. In addition, radiation dermatitis is a quantifiable complication which is
relatively easily observed and graded according to modified Radiation Therapy Oncology Group
(RTOG) criteria for toxicity. Radiation dermatitis is thought to be related to abrasion that
degrades the keratinized skin surface. This results in decreased ability of skin stem cells
to regenerate which leads to moist desquamation. A barrier film could potentially form a
protective scaffold for new skin growth and repair. Cavilon No Sting Barrier Film (BF) has
been shown in randomized trials involving post-mastectomy radiation patients to reduce the
duration and frequency of radiation-induced moist desquamation. However, this treatment has
not been studied in the statistically more prevalent situation of an intact breast.
Therefore, we propose to investigate Cavilon to reduce side-effects of radiation treatment
in intact breast cancer patients treated with conservative surgery and adjuvant radiation
therapy.

2.0 STUDY OBJECTIVES 2.1 Primary Objectives To evaluate effectiveness of preventing Grade II
or greater radiation dermatitis induced by adjuvant radiation therapy in women with breast
cancer. The grading of dermatitis will be obtained according to modified RTOG scale for
visual assessment of radiation-induced skin erythema. This is attached as Appendix A. In
addition, Skin Toxicity Assessment Tool (STAT) will also be used by the patient and
physician validated against the quality of life tools and toxicity tools. This is attached
as Appendix B.

2.2 Secondary Objectives Quality of Life The European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) will be used to measure
overall quality of life. Quality of life has been considered an important contributor to
overall performance status and outcome. Quality of life consists of multiple components
(e.g. physical, social, and psychological aspects, etc.). Improved quality of life
translates into better outcomes, especially in the context of palliation. Global quality of
life was found to be significantly associated with survival in a general population of
cancer patients in Canada . In fact, many clinical trials in palliative care include
improved quality of life for cancer patients as a primary outcome. The EORTC Quality of Life
Questionnaire (QLQ-C30) was developed in Europe and is frequently used to measure quality of
life and its related components . The EORTC QLQ C-30 is attached in appendix C.

Time to develop radiation dermatitis On each follow up visit, all patients will be assessed
for development of any grade of radiation dermatitis. The time to develop grade I, II and or
grade III radiation dermatitis will be calculated from the date of first dose of radiation
therapy delivered to the date of visit at which the grade of dermatitis is observed. Time to
additional treatment, i.e. over-the-counter or prescription interventions, will also be
measured.

Image An observer, blind to the regions treated by Cavilon, will also grade each paired
photographic image.

Qualitative Questions Qualitative questions are meant to ask personal opinion and
perspectives. The answers provide further insight into the related issue or question. We
have designed a very simple approach with 2-3 open-ended questions for both patient and
practitioner. See Appendix D.

3.0 OVERALL STUDY DESIGN AND PLAN 3.1 Study Design Randomized paired comparison design,
conducted at a single centre, the London Regional Cancer Program (LRCP), Ontario, Canada. A
total of 47 patients will be accrued for this study. Eligible patients will be contacted
and study details will be reviewed with them. The schedule for BF will be two times per week
throughout the duration of radiation therapy. Each BF treatment will be applied immediately
before radiation treatment by the radiation therapist using a film template. The template
is a cellophane sheet with two quadrants physically removed. The quadrants removed will be
randomly selected to receive the film spray treatment. The template is used only at the time
of BF application. Other quadrants may receive standard treatment. No placebos will be used.
To ensure the template is placed at the correct location for each treatment, localization
will use the permanent tattoos used for radiation treatment localization. This is an
intention-to-treat trial.

3.1.1 Baseline/Accrual (Visit 1)

Patients with a histopathologically or cytologically confirmed diagnosis of breast cancer
scheduled to receive adjuvant radiation therapy may be screened. The following
procedures/assessments will take place during this visit for the patient:

- Obtaining written informed consent

- Reviewing inclusion/exclusion criteria

- Obtaining disease history, including date of first diagnosis, and the history of the
course of the patient's histopathologically or cytologically confirmed diagnosis of
breast cancer, and information about prior radiation or chemotherapy

- Obtaining medical history (past or concurrent clinically significant disease(s))

- Obtaining demographic data including history of radiation sensitivity or radiation
sensitizers

- Obtaining information about any planned treatment

- Perform a general physical examination

- A patient who meets all eligibility criteria will be enrolled in the study and the
following additional procedures will be performed:

- Completion of questionnaire for STAT, modified RTOG visual assessment of erythema,
qualitative questionnaire and QLQ-C30

- Assign two of four regions by random number list

3.1.2 Treatment Phase (Weekly assessment)

After the Baseline visit, patients will return to the study site for scheduled follow-up
visits, also called Patient Review (PR). The following procedures/assessments will be
performed during these visits:

- Evaluation and documentation of any grade radiation dermatitis using STAT and the
modified RTOG erythema scale

- Documentation of any new medication use including use of skin creams

3.1.3 Follow-up Visit (One week post treatment completion)

The following procedures/assessments will be performed during the follow-up visit:

- Evaluation and documentation of any grade radiation dermatitis

- Completion of questionnaire for QLQ-C30

- Completion of qualitative questions

- Completion of global questionnaire

4.0 SELECTION OF STUDY POPULATION

The study will be conducted in patients with histopathologically or cytologically confirmed
diagnosis of breast cancer, scheduled to receive adjuvant radiation therapy as outpatients
at the London Health Sciences Centre, London, Ontario.

5.0 STATISTICAL EVALUATION 5.1 Determination of Sample Size The primary endpoint will be a
comparison of region 1 (region treated with standard care) and region 2 (region treated with
BF). Based on the same endpoint measure, we estimate the baseline/standard care risk of
grade 2 toxicity and higher to be approximately 60% at any point during the assessment
period. Studies with the same and similar products demonstrate an expected reduction of
grade 2 or higher toxicity to approximately 30%. This is also a clinically important
significant difference . The sample size required is 42 (paired analysis). This assumes a
Type I error of 0.05 and a power of 80% to reject the null hypothesis. With an expected 5%
excess added due to loss to follow up or non-evaluable data, we would require a sample size
of 47 patients. This is consistent with landmark Uppsala randomized study demonstrating the
value of corticosteroid cream with 42 patients.

5.2 Statistical Analysis SAS (SAS Institute, Cary, NC) was used to generate a random
allocation list with two stratification blocks (i. chemo no chemo; ii. breast
separation).The physician will be unaware of the treatment allocation, but the patient and
radiation therapist administering the film will not be blinded. For qualitative measures,
McNemar's (McNemar) chi-square test for paired proportions will be used. For quantitative
measures, a paired t-test or a signed rank test will be used. For the 'time to event'
variables that will be paired, Kaplan Meier estimates to graphically demonstrate the 'time
to event' will be used. The statistical comparisons will be performed using proportional
hazards models with a sandwich estimator to account for the pairing with a sandwich
estimator. A repeated measures ANOVA will be used to assess the four quadrants. If the data
is poorly distributed then we will take a median of the two treated areas and two control
areas and apply a singed rank test. Note that this is not the principle endpoint of the
trial. The principle endpoint of the trial is a 1-to-1 comparison of the BF treated area and
the area treated using standard options. A multivariable analysis will be performed to
determine factors impacting on skin toxicity. The multivariable analysis will not be used
for between patient comparisons as differences will be accounted for by the pairing. All
significant tests will be two-sided and performed at the 5% level.