BRCA1 Mutation, BRCA2 Mutation, Breast Cancer, Breast Diseases, Neoplasms, Pain, Postoperative
Conditions
Keywords
Mastectomy, Mammaplasty, Breast reconstruction, Tissue expansion, Botulinum toxins, Type A, Quality of Life, Acellular dermal matrix
Brief summary
Each year, the number of breast cancer survivors who choose post-mastectomy breast reconstruction keeps rising. Among women who elect to pursue breast reconstruction, approximately 75% will choose prosthetic breast reconstruction. Implant-based breast reconstruction is frequently achieved in two-stages. The first stage consists of the placement of a tissue expander after mastectomy. This is followed by a period of biweekly tissue expansions that can last several months. In the second stage, the tissue expander is removed in a surgical procedure and replaced with a permanent breast implant. Tissue expansion is a well-established breast reconstruction technique characterized by high success rates and high patient satisfaction. Despite the well-recognized advantages of this successful breast reconstruction technique, the subpectoral placement of a tissue expander is associated with significant pain and discomfort in the immediate post-operative period and during the phase of tissue expansion. Pectoralis major muscle spasm is a frequently reported problem during tissue expansion. Legeby et al. recently showed that women who underwent prosthetic breast reconstruction had higher pain scores and took more analgesics that those who did not choose post-mastectomy reconstruction. In the past 10 years, publications on the use of botulinum toxin A (BTX-A) for pain relief in a wide array of clinical conditions have increased tremendously. BTX-A is one of the neurotoxins produced by Clostridium botulinum bacteria. By reversibly inhibiting neurotransmitter release, BTX-A has both analgesic and paralytic properties. The analgesic action of BTX-A was initially thought to be related to its effects on muscular contraction. However, a recent in vitro study of embryonic rat dorsal neurons did confirm that BTX-A inhibits release of substance P, a neurotransmitter associated with pain and inflammatory reactions. The presence of analgesic properties of BTX-A is increasingly supported by several clinical observations: pain relief with BTX-A injections has been reported for migraine headaches, chronic pelvic, chronic tennis elbow, and post-operative pain control for lower limb lengthening correction, among others. This aspect has never been studied in breast cancer survivors who elect to pursue breast reconstruction with tissue expanders. Furthermore, physical function outcomes are important to consider with BTX-A use because the link between temporary muscle paralysis and improvements in participation in daily activities is not a given. The investigators propose to complete a double-blinded prospective randomized controlled trial of women undergoing unilateral and bilateral mastectomies with immediate placement of tissue expanders, to establish the efficacy and safety of BTX-A in alleviating pain and in improving physical well-being during the expansion period.
Detailed description
Consecutively enrolled eligible women will be randomized into one of two different treatment groups: 1) Group receiving BTX-A, and 2) Group receiving a placebo. All consenting subjects will be randomized to receive either a single injection of 100 units of BTX-A, or a placebo (saline water), during surgery in the pectoralis major muscle on the operated side once the mastectomy and the breast reconstruction have been completed. Expected duration of subject participation is 4 months.
Interventions
DRUGBotulinum Toxin Type A
DRUGPlacebo
5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A
Sponsors
Allergan
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Women at least 18 years of age, who will undergo immediate unilateral or bilateral tissue expander breast reconstruction following therapeutic skin-sparing or nipple-sparing mastectomy * Women at least 18 years of age, who will undergo immediate bilateral tissue expanders breast reconstruction following risk-reduction (prophylactic) skin-sparing or nipple-sparing mastectomy
Exclusion criteria
* Subjects who are unable to read or speak English * Breast reconstruction using the latissimus dorsi flap combined with a tissue expander * Documented diagnosis of chronic pain, upper limb spasticity, cervical dystonia, axillary hyperhidrosis, strabismus or blepharospasm * Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation * Infection at the proposed site of injection * Pre-existing neuromuscular disorders (including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis) * Aminoglycosides intake at the time of surgery (these antibiotics can potentiate the effect of BTX-A) * Women who are pregnant or breast feeding * Presence of breast implants from previous breast surgery * Reported use of Botox within 4 months prior to planned surgical date
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Average Pain Scores Using a Numeric Pain Intensity Scale | preoperative visit, first postoperative visit (1-2 weeks post surgery) | The numeric pain intensity scale (NPIS) will be completed at the preoperative visit and again at the first postoperative visit. The NPIS is a visual analog scale (VAS) commonly used to assess clinical pain. Subjects are asked to rate their pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable. |
| Physical Well-Being Using the BREAST-Q, Reconstruction Module | first post-operative visit (1-2 weeks post surgery) | The Physical Well-Being scale of the BREAST-Q, Reconstruction module, will be used for this purpose. The BREAST-Q is a validated patient-reported outcome measure to accurately assess quality of life and patient satisfaction. The Reconstruction module Physical Well-Being scale has questions on the function and participation in activities before and after breast reconstruction. For this study, subjects were asked to answer 16 questions on how often they experienced each symptom, using score of 1 to 5, where 1 was none of the time and 5 was very often. Answers from these questions were combined to provide a total physical well-being score (for a total possible range of 16-80) for each patient at each visit. Lower scores reflected fewer symptoms and higher satisfaction where higher scores reflected more symptoms and less satisfaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Initial Intraoperative Fill Volume in Milliliters (mL) | Single intra-operative measurement at first surgery | The amount of initial intraoperative fill volume in milliliters (mL) in the tissue expander at the time of surgery divided by the manufacturers recommended total tissue expander volume will be measured. Each breast will be measured separately. |
| Number of Tissue Expansion Visits | up to 24 weeks post-operatively | The total number of tissue expansion visits completed post-operatively. |
| Total Volume of Tissue Expansion | Up to 24 weeks post-operatively | Measurement of total expansion volume in milliliters (mL). |
| Rate of Reconstruction Failure | 6 months after first surgery | The rate of reconstruction failure will be measured by the number of subjects who have tissue expander removal. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A - Botulinum Toxin Type A 100 Units of Botulinum toxin A diluted in 5 mL 0.9% Sodium Chloride (NaCl) in the pectoralis major muscle in each operated breast
Botulinum Toxin Type A | 68 |
| Group B - Placebo 5 mL 0.9% NaCl injection to the pectoralis major muscle in each operated breast
Placebo: 5 mL 0.9% NaCl solution to mimic Botulinum Toxin Type A | 63 |
| Total | 131 |
Baseline characteristics
| Characteristic | Group A - Botulinum Toxin Type A | Group B - Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49.9 years STANDARD_DEVIATION 11.1 | 48.4 years STANDARD_DEVIATION 11.5 | 49.1 years STANDARD_DEVIATION 11.3 |
| Body Mass Index (BMI) | 27.6 kg/m^2 STANDARD_DEVIATION 5.9 | 26.6 kg/m^2 STANDARD_DEVIATION 8.1 | 27.1 kg/m^2 STANDARD_DEVIATION 7 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 68 participants | 63 participants | 131 participants |
| Sex: Female, Male Female | 68 Participants | 63 Participants | 131 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 63 |
| other Total, other adverse events | 15 / 68 | 14 / 63 |
| serious Total, serious adverse events | 0 / 68 | 0 / 63 |
Outcome results
Primary
Change From Baseline in Average Pain Scores Using a Numeric Pain Intensity Scale
The numeric pain intensity scale (NPIS) will be completed at the preoperative visit and again at the first postoperative visit. The NPIS is a visual analog scale (VAS) commonly used to assess clinical pain. Subjects are asked to rate their pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable.
Time frame: preoperative visit, first postoperative visit (1-2 weeks post surgery)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - Botulinum Toxin Type A | Change From Baseline in Average Pain Scores Using a Numeric Pain Intensity Scale | 2 score on a scale |
| Group B - Placebo | Change From Baseline in Average Pain Scores Using a Numeric Pain Intensity Scale | 3 score on a scale |
p-value: 0.43Wilcoxon (Mann-Whitney)
Primary
Physical Well-Being Using the BREAST-Q, Reconstruction Module
The Physical Well-Being scale of the BREAST-Q, Reconstruction module, will be used for this purpose. The BREAST-Q is a validated patient-reported outcome measure to accurately assess quality of life and patient satisfaction. The Reconstruction module Physical Well-Being scale has questions on the function and participation in activities before and after breast reconstruction. For this study, subjects were asked to answer 16 questions on how often they experienced each symptom, using score of 1 to 5, where 1 was none of the time and 5 was very often. Answers from these questions were combined to provide a total physical well-being score (for a total possible range of 16-80) for each patient at each visit. Lower scores reflected fewer symptoms and higher satisfaction where higher scores reflected more symptoms and less satisfaction.
Time frame: first post-operative visit (1-2 weeks post surgery)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - Botulinum Toxin Type A | Physical Well-Being Using the BREAST-Q, Reconstruction Module | 63 score on a scale |
| Group B - Placebo | Physical Well-Being Using the BREAST-Q, Reconstruction Module | 60 score on a scale |
p-value: 0.56Wilcoxon (Mann-Whitney)
Secondary
Initial Intraoperative Fill Volume in Milliliters (mL)
The amount of initial intraoperative fill volume in milliliters (mL) in the tissue expander at the time of surgery divided by the manufacturers recommended total tissue expander volume will be measured. Each breast will be measured separately.
Time frame: Single intra-operative measurement at first surgery
Population: Volume measurements were not captured for all subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A - Botulinum Toxin Type A | Initial Intraoperative Fill Volume in Milliliters (mL) | Right breast | 63.5 mL | Standard Deviation 23 |
| Group A - Botulinum Toxin Type A | Initial Intraoperative Fill Volume in Milliliters (mL) | Left breast | 60.1 mL | Standard Deviation 23.1 |
| Group B - Placebo | Initial Intraoperative Fill Volume in Milliliters (mL) | Right breast | 60.4 mL | Standard Deviation 20 |
| Group B - Placebo | Initial Intraoperative Fill Volume in Milliliters (mL) | Left breast | 60.0 mL | Standard Deviation 21.1 |
Comparison: Right breast initial percent volume expansionp-value: 0.45Wilcoxon (Mann-Whitney)
Comparison: Left breast initial percent volume expansionp-value: 0.98Wilcoxon (Mann-Whitney)
Secondary
Number of Tissue Expansion Visits
The total number of tissue expansion visits completed post-operatively.
Time frame: up to 24 weeks post-operatively
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - Botulinum Toxin Type A | Number of Tissue Expansion Visits | 3 visits |
| Group B - Placebo | Number of Tissue Expansion Visits | 3 visits |
p-value: 0.43Wilcoxon (Mann-Whitney)
Secondary
Rate of Reconstruction Failure
The rate of reconstruction failure will be measured by the number of subjects who have tissue expander removal.
Time frame: 6 months after first surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A - Botulinum Toxin Type A | Rate of Reconstruction Failure | 1 Participants |
| Group B - Placebo | Rate of Reconstruction Failure | 0 Participants |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Total Volume of Tissue Expansion
Measurement of total expansion volume in milliliters (mL).
Time frame: Up to 24 weeks post-operatively
Population: Volume measurement were not captured on all subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - Botulinum Toxin Type A | Total Volume of Tissue Expansion | 80 mL |
| Group B - Placebo | Total Volume of Tissue Expansion | 75 mL |
p-value: 0.37Wilcoxon (Mann-Whitney)